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Regulatory harmonization in a resource-limited setting: the World Health Organization Collaborative Procedure for Accelerated Registration

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Regulatory harmonization in a resource-limited setting: the World Health Organization Collaborative Procedure for Accelerated Registration

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Content REGULATORY HARMONIZATION IN A RESOURCE-LIMITED SETTING: THE WORLD HEALTH ORGANIZATION COLLABORATIVE PROCEDURE FOR ACCELERATED REGISTRATION by Lori Alquier A Dissertation Presented to the FACULTY OF THE USC SCHOOL OF PHARMACY UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF REGULATORY SCIENCE August 2021 Copyright 2021 Lori Alquier ii Dedication To Laurent, who makes everything possible iii Acknowledgments It may take a village to raise a child, but it took the kindness of people spread across five continents to create this thesis. The survey supporting this research took place during a pandemic. Although NMRA and industry professionals had unprecedented amounts of work responding to this crisis, somehow over 120 people took time to carefully complete this survey, providing their experiences, thoughts, and suggestions. Without their generosity and support, this dissertation would not have been possible. Onyenoha Chukwumerije and Philip Papadopoulos, in particular, were sources of encouragement and help at a point when the survey enrollment looked particularly bleak. Through this process, I am so grateful to have met Dr. Luther Gwaza, who generously shared his knowledge about the WHO-CRP and his insights and his vision for the WHO-CRP in the future. Conversations with Dr. Mercè Caturla and Dr. Lawrence Liberti were very helpful at the start of the process to help me crystalize my topic and with Dr. Murray Lumpkin, whose experience, insight and advice kept me on track. Rob Bovey altruistically developed and provided software that saved me hours of work. Every time I created a graph, I silently thanked him for his talent and generosity. My friends and colleagues at Janssen have always been there to support me when I needed it most, particularly in this endeavor. My thanks to Dr. Nyasha Bakare, Dr. Tine DeMarez, Dr. Annelies Goeminne, Dr. CC Lee, Lisa Perrella, Chhaya Patel, Teresa Scheuble, and Dr. Carmen Vieira. I am very fortunate to be part of the DrSC 2018 cohort. The experience in the program has been truly life changing. I am exceptionally thankful to have been a part of an extraordinary group of talented and creative industry professionals. Their selfless support and generous iv encouragement through this entire process has been truly inspirational. Despite our physical distance, I feel close to each of them. I know that none of us will feel truly finished with our degree until everyone in the cohort is done. I would like to express my deepest appreciation to my committee, Dr. Frances Richmond, Dr. Eunjoo Pacifici, Dr. Susan Bain and Dr. C. Benson Kuo, who have supported my academic journey from beginning to end. Their interest, encouragement and suggestions provided a rich and supportive environment in which I could grow. I am also grateful to Dr. Terry Church for his careful review. I owe a special debt of gratitude to my advisor, Dr. Frances Richmond, who eagerly embraced the challenge of a topic that was not mainstream. Through the process, she guided with questions that were especially astute and thought-provoking. I could not have asked for a more dedicated and exceptional mentor. She is what every graduate student wishes for in an advisor and very few are lucky enough to have. My children, Steve and Jeff, and their partners, Dahlia and Addison, have been a wonderful source of sustenance during this process. I can only hope that they feel that I supported their education as much as I feel they have supported mine. I am also grateful to my brother, Steve, who continues to be a role model. And finally, I am so grateful to my husband, Laurent. He has unwaveringly supported me in this expedition and has steadfastly believed in me, even when I did not believe in myself. He has patiently listened to endless hours of dialogue about everything I have read and written and managed to still ask the interested question. Like so many things in my life, I do not know how I would have done this without him. v TABLE OF CONTENTS Dedication ....................................................................................................................................... ii Acknowledgments.......................................................................................................................... iii List of Tables ............................................................................................................................... viii List of Figures ................................................................................................................................ ix Abstract ......................................................................................................................................... xii Chapter 1. Overview ........................................................................................................................1 1.1 Introduction ................................................................................................................. 1 1.2 Statement of the Problem ............................................................................................ 4 1.3 Purpose of the Study ................................................................................................... 5 1.4 Importance of the Study .............................................................................................. 6 1.5 Limitation, Delimitations, Assumptions ..................................................................... 7 1.6 Definitions ................................................................................................................... 9 1.7 Organization of the Thesis ........................................................................................ 10 Chapter 2. Literature Review .........................................................................................................11 2.1 Introduction ............................................................................................................... 11 2.2 Background to the Literature Review ....................................................................... 11 2.3 The Development of Harmonized Practices ............................................................. 13 2.3.1 European Pharmaceutical Regulatory Harmonization ................................. 15 2.3.1.1 Political Harmonization in the European Union ............................. 15 2.3.1.2 Pharmaceutical Regulatory Harmonization in the European Union .............................................................................................. 17 2.3.2 Harmonization in Great Britain ................................................................... 21 2.3.3 ICH and the Common Technical Document................................................ 23 2.4 Pharmaceutical and Regulatory Development in Africa ........................................... 27 2.4.1 Early Pharmaceutical Manufacturing in Africa ........................................... 27 2.4.2 Political Pressures for Rapid Registration of Drugs in Africa ..................... 28 2.4.3 African Union Model Law........................................................................... 31 2.5 Regional Regulatory Harmonization Initiatives in Africa ........................................ 32 2.5.1 African Medicines Regulatory Harmonisation Initiative ............................. 35 2.5.2 Regulatory Harmonization in the Arab Maghreb Union ............................. 37 2.5.3 Regulatory Harmonization in the Intergovernmental Authority on Development (IGAD) Regional Community .............................................. 39 2.5.4 Regulatory Harmonization in the Community of Sahel-Saharan States (CEN-SAD) ................................................................................................. 40 2.5.5 Regulatory Harmonization in the Economic Community of West African States (ECOWAS) .......................................................................... 40 vi 2.5.6 Regulatory Harmonization in the Economic Community of Central African States (ECCAS) .............................................................................. 41 2.5.7 Regulatory Harmonization in the COMESA ............................................... 41 2.5.8 Southern African Development Community (SADC) Medicines Regulatory Harmonization Project .............................................................. 42 2.5.9 ZAZIBONA Regulatory Harmonization Project ......................................... 44 2.5.10 Regulatory Harmonization in the East African Community (EAC) ............ 45 2.6 The WHO Collaborative Registration Procedure ..................................................... 51 2.6.1 History of the WHO .................................................................................... 51 2.6.2 Prequalification of Medicines Program ....................................................... 52 2.6.3 Collaborative Procedures for Accelerated Registration ............................... 55 2.6.3.1 Component 1: CRP-PQP ................................................................ 56 2.6.3.2 Component 2: CRP-SRA ................................................................ 58 2.7 Research Approach and Evaluative Frameworks...................................................... 61 Chapter 3. Methodology ................................................................................................................69 3.1 Introduction ............................................................................................................... 69 3.2 Creation of Survey .................................................................................................... 69 3.2.1 Development of the Survey Tool ................................................................. 69 3.2.2 Survey Population ........................................................................................ 69 3.2.3 Survey Development and Validation ........................................................... 71 3.2.4 Survey Deployment ..................................................................................... 71 3.2.5 Survey Analysis ........................................................................................... 72 Chapter 4. Results ..........................................................................................................................73 4.1 Survey Participation .................................................................................................. 73 4.2 Demographic Profiles of Respondents ...................................................................... 74 4.2.1 NMRA Respondent Profiles ........................................................................ 78 4.2.2 Industry Respondent Profiles ....................................................................... 80 4.3 Context ...................................................................................................................... 82 4.3.1 Need for Harmonization .............................................................................. 82 4.3.2 Barriers to Harmonization ........................................................................... 87 4.3.3 Harmonization Readiness ............................................................................ 90 4.4 Input .......................................................................................................................... 94 4.4.1 Development of Harmonized Pathways ...................................................... 95 4.4.2 Use of WHO-CRP in Africa ...................................................................... 101 4.5 Process .................................................................................................................... 104 4.5.1 WHO-CRP Process .................................................................................... 104 4.5.1.1 Dossier Submission ...................................................................... 104 4.5.1.2 Dossier Review ............................................................................. 106 4.5.1.3 Dossier Decision ........................................................................... 108 4.5.1.4 Electronic Dossier Handling ......................................................... 110 vii 4.5.2 WHO-CRP Process Resource Requirements ............................................. 112 4.5.3 WHO-CRP Process Improvements............................................................ 113 4.5.4 Post WHO-CRP Process National Requirements ...................................... 115 4.5.5 National Requirements for GMP Inspections ............................................ 117 4.6 Product .................................................................................................................... 123 4.6.1 Reach ......................................................................................................... 123 4.6.2 Impact ........................................................................................................ 133 4.6.3 Effectiveness: Duration ............................................................................. 134 4.6.4 Sustainability: Future Availability ............................................................. 140 4.6.5 Sustainability: Challenges ......................................................................... 141 4.6.6 Did the WHO-CRP Program Meet the Needs? ......................................... 145 4.7 Final Comments ...................................................................................................... 147 Chapter 5. Discussion ..................................................................................................................149 5.1 Overview ................................................................................................................. 149 5.2 Considerations of Study Methodology.................................................................... 149 5.2.1 Delimitations ............................................................................................. 149 5.2.2 Limitations ................................................................................................. 151 5.3 Consideration of Results ......................................................................................... 155 5.3.1 Context....................................................................................................... 156 5.3.1.1 Legislative and Political Harmonization Readiness ..................... 156 5.3.1.2 Regulatory Capacity ..................................................................... 158 5.3.2 Input ........................................................................................................... 159 5.3.2.1 Engagement of NMRAs ............................................................... 159 5.3.2.2 Role of Industry ............................................................................ 161 5.3.3 Process ....................................................................................................... 161 5.3.3.1 Impact of Resource Restrictions ................................................... 163 5.3.3.2 Country-Specific Requirements .................................................... 164 5.3.3.3 Availability of Instructions and Process Status ............................ 166 5.3.4 Product ....................................................................................................... 167 5.3.4.1 Achievement of Program Objectives ............................................ 167 5.3.4.2 User Satisfaction ........................................................................... 168 5.3.4.3 Sustainability ................................................................................ 169 5.4 Conclusions and Recommendations ....................................................................... 171 References ....................................................................................................................................174 Appendices ...................................................................................................................................194 Appendix A. List of Terms and Acronyms ..................................................................... 194 Appendix B. Survey Questions ....................................................................................... 196 Appendix C. Participant Comments ............................................................................... 247 viii List of Tables Table 1: Membership of Regional Economic Communities .........................................36 Table 2: Goals Achieved by PQ Program .....................................................................55 Table 3: CIPP Framework ............................................................................................67 Table 4: Participant WHO-CRP Experience by Location ............................................76 Table 5: Barriers to Regulatory Harmonization: Selected NMRA Opinions ...............88 Table 6: Barriers to Regulatory Harmonization: Selected Industry Opinion ...............89 Table 7: Pace of Harmonization Pathway Development and Implementation: Selected NMRA Opinions ........................................................................................91 Table 8: Pace of Harmonization Pathway Development and Implementation: Selected Industry Opinions.......................................................................................94 Table 9: NMRA Role in the Development of Harmonized Pathways: Selected NMRA Opinions .....................................................................................................96 Table 10: Level of Industry Influence in the Development of Harmonized Procedures: Selected NMRA Opinions .........................................................................97 Table 11: Level of Industry Influence in the Development of Harmonized Procedures: Selected Industry Opinions ........................................................................98 Table 12: Level of Industry Influence in the Design of National Regulatory Pathways: Selected Industry Opinions ........................................................................99 Table 13: Level of NMRA Influence in the Design of Regional Regulatory Pathways: Selected NMRA Opinions .......................................................................101 Table 14: WHO-CRP Process: Dossier Submission .....................................................105 Table 15: WHO-CRP Process: Dossier Review ...........................................................107 Table 16: WHO-CRP Process: Dossier Decision .........................................................109 Table 17: WHO-CRP Process: Electronic Dossier Handling .......................................111 Table 18: Value of GMP Inspections: Selected NMRA Opinions ...............................122 Table 19: Value of GMP Inspections: Selected Industry Opinions ..............................123 Table 20: Selected Reasons Why Participants Did Not Use the Procedure .................124 Table 21: Selected Comments About Future Use of WHO-CRP .................................125 Table 22: Overall impression of the WHO-CRP: Selected Non-User Opinions ..........127 Table 23: Overall impression of the WHO-CRP: Selected NMRA Opinions ..............128 Table 24: Overall Impression of the WHO-CRP: Selected Industry Opinions ............129 Table 25: Key Factors Influencing Use of WHO-CRP: Selected Industry Opinions ...131 Table 26: Duration of WHO-CRP Process Steps Compared to Other Pathways .........137 Table 27: Influential factors on Future Use: Selected NMRA Opinions ......................144 Table 28: Influential factors on Future Use: Selected Industry Opinions ....................145 Table 29: Satisfaction with the Process: Selected NMRA Opinions ............................146 Table 30: Satisfaction with the Process: Selected Industry Opinions...........................147 Table 31: Additional Comments ...................................................................................148 ix List of Figures Figure 1: Literature Search .............................................................................................13 Figure 2: Key Milestones in the History of Drug Regulation in Europe and in the United Kingdom ...................................................................................23 Figure 3: Regional Economic Communities in Africa ...................................................33 Figure 4: Regional Economic Community Membership ...............................................34 Figure 5: The WHO Prequalification Process ................................................................54 Figure 6: The WHO Collaboration Registration Procedure Process ..............................57 Figure 7: Four Components of the CIPP Framework ....................................................65 Figure 8: Survey Responses ...........................................................................................73 Figure 9: Scope of Responsibility ..................................................................................74 Figure 10: Primary Location of Employer .......................................................................75 Figure 11: Participant Organization Size .........................................................................76 Figure 12: Geographical Scope of Employer ...................................................................77 Figure 13: Primary Sector of Participant's Organization .................................................77 Figure 14: Exposure to the WHO-CRP ............................................................................78 Figure 15: Geographical Distribution of NMRAs ............................................................79 Figure 16: WHO-CRP Experience by Product Type: NMRA Responses .......................79 Figure 17: WHO-CRP Experience by Number of Reviews: NMRA Responses .............80 Figure 18: WHO-CRP Experience by Type of Product: Industry Responses ..................81 Figure 19: WHO-CRP Experience by Number of Submissions: Industry Responses ...................................................................................................81 Figure 20: Time Since Last WHO-CRP Submission: Industry Responses ......................82 Figure 21: Harmonized Pathway versus National Pathway: NMRA and Industry Responses ...................................................................................................83 Figure 22: Advantages of a Harmonized Pathway Versus National Pathways: NMRA and Industry Responses.................................................................84 Figure 23: Advantages of a Harmonized Pathway Versus National Pathways: Generic versus Brand Manufacturer Responses ........................................85 Figure 24: Advantages of National Pathways Versus Harmonized Pathways: Industry Responses ....................................................................................86 Figure 25: Advantages of National Pathways Versus Harmonized Pathways: Generic versus Brand Manufacturer Responses ........................................87 Figure 26: Legal Framework Support of WHO-CRP: NMRA Responses ......................90 Figure 27: Regulatory Harmonization Speed: NMRA Responses ...................................90 Figure 28: Regulatory Harmonization Speed: Industry Responses .................................92 Figure 29: Regulatory Harmonization Speed: Generic versus Brand Manufacturer Responses ............................................................................93 x Figure 30: NMRA Role in the Development of Harmonized Pathways: NMRA Responses ...................................................................................................95 Figure 31: Level of Industry Influence in the Development of Harmonized Procedures: NMRA and Industry Responses .............................................97 Figure 32: Industry Role in the Development of National Procedures: Industry Responses ...................................................................................................99 Figure 33: NMRA Role in the Development of Harmonization Pathways: NMRA Responses ....................................................................................100 Figure 34: African Countries Where the WHO-CRP Was Used ...................................102 Figure 35: African Countries Where Respondents Would Like to Use the WHO- CRP ..........................................................................................................103 Figure 36: Ex-African Countries Where Respondents Would Like to Use the WHO-CRP ...............................................................................................104 Figure 37: WHO-CRP Process: Dossier Submission .....................................................106 Figure 38: WHO-CRP Process: Dossier Review ...........................................................108 Figure 39: WHO-CRP Process: Dossier Decision .........................................................109 Figure 40: WHO-CRP Process: Electronic Dossier Handling .......................................111 Figure 41: WHO-CRP Process Resource Requirements: NMRA Responses ................112 Figure 42: WHO-CRP Process Resource Requirements: Industry Responses ..............113 Figure 43: WHO-CRP Process Improvements: NMRA Responses ...............................114 Figure 44: WHO-CRP Process Improvements: Industry Responses .............................115 Figure 45: National Requirements Reported by NMRAs ..............................................116 Figure 46: National Requirements: Industry Responses ................................................117 Figure 47: GMP Inspection Requirements Reported by NMRAs ..................................117 Figure 48: GMP Inspection Requirements: Industry Responses ...................................118 Figure 49: GMP Inspections: Generic versus Brand Manufacturer Responses .............118 Figure 50: GMP Inspection Lead Time: NMRAs and Industry Responses ...................119 Figure 51: Type of GMP Inspections Conducted: NMRA and Industry Responses .................................................................................................120 Figure 52: Value of GMP Inspections: NMRA and Industry Responses ......................121 Figure 53: Reasons Why Participants Did Not Use the Procedure ................................124 Figure 54: Future Use of WHO-CRP .............................................................................125 Figure 55: Overall impression of the WHO-CRP: Non-User Responses ......................126 Figure 56: Overall impression of the WHO-CRP: NMRA and Industry Responses .................................................................................................128 Figure 57: Key Factors Influencing Use of WHO-CRP: Industry Responses ...............132 Figure 58: Publicity about the WHO-CRP: Is it sufficient? ...........................................133 Figure 59: Publicity about the WHO-CRP: Industry Responses ...................................134 Figure 60: Duration of WHO-CRP Process Steps Compared to Other Pathways .........138 Figure 61: Duration of WHO-CRP: NMRA and Industry Responses ...........................139 xi Figure 62: Duration of WHO-CRP versus a National Registration Procedure ..............140 Figure 63: Process Sustainability - Future Availability: NMRA and Industry Responses .................................................................................................141 Figure 64: Process Sustainability - Future Use: NMRA and Industry Responses .........142 Figure 65: Influential factors on Future Use: NMRA Responses .................................142 Figure 66: Influential factors on Future Use: Industry Responses .................................143 Figure 67: Influential factors to Recommend Future Use: NMRA Responses ..............143 Figure 68: Influential factors to Recommend Future Use: Industry Responses ............145 Figure 69: NMRA and Industry Opinions on Whether the WHO-CRP Meets Their Needs ..............................................................................................146 xii Abstract The large numbers of diseases that can only be treated with expensive drugs create economic and societal problems in resource-limited regions. The problem can be exaggerated by burdensome regulatory processes that limit patient access to necessary medicines. Regulatory harmonization of drug approval pathways can potentially reduce the time and costs of registration and thus help to improve patient access to these important medicines. This survey-based research examines the views of National Medicines Regulatory Agencies (NMRAs) and industry professionals on the benefits and barriers associated with a specific regulatory harmonization program, the World Health Organization (WHO) Collaborative Registration Procedure (WHO-CRP) as it is used in Africa. The WHO-CRP is a unique regulatory pathway whose evaluation is particularly useful because the work-sharing and reliance activities of the WHO-CRP program are used across much of Africa. Results reflect the views and experience of 124 participants working in NMRAs and industry. The broadly positive feedback suggests that the primary stakeholders welcome the WHO-CRP program, which not only to creates a more efficient pathway for product registration but also achieves its goal of improving the capabilities of less mature NMRAs. The biggest challenges appear to exist outside the specific scope of the regulatory pathway itself. The absence of consistent legislation to facilitate regulatory harmonization, limitations on resources, and continuing challenges of improving regulatory capacity now appear to be the biggest problems to solve. Changes in these elements might have a positive impact on the timeliness and quality of the review and approval processes, not only for the WHO-CRP pathway but for other pathways that depend on harmonization and reliance. The lack of consistent legislation identified in this xiii study reinforces the conclusions drawn previously about the need for common or consistent legislation. Responses from both NMRA and industry underscore the need for more AU Member States to implement the Model Law if the speed of harmonization is to improve. Once that is achieved, it will facilitate the creation of a self-sustaining infrastructure of interactive NMRAs across the entire continent of Africa that employs work-sharing, which is expected to improve the regulatory capacity of the NMRAs. Improving the visibility and awareness of the program may also be beneficial, particularly if this is coupled with the exploration of a reasonable sliding scale of registration funding. Moving to a self-supporting financial model that supports small, local, and regional production of medicines but would also provide incentives to larger companies outside the region, perhaps by guaranteed timelines and increased transparency, may provide a sustainable future for the program. 1 Chapter 1. Overview 1.1 Introduction Healthcare is a basic human right. The Constitution of the World Health Organization (WHO) states that “The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition” (International Health Conference, 2002). About a quarter of the world’s lower- and middle-income countries have explicitly guaranteed specific rights to public health and medical care in their national constitutions (Heymann et al., 2013). Nonetheless, over 2 billion people worldwide do not have sufficient access to essential medicines. Increasing access to high-quality medicines could save 10 million lives each year, including the 4 million people who live in Africa and South-East Asia (Zarocostas, 2018). Equitable access to medicines is an essential component of good health (Aldis, 2008). Pharmaceutical products are an indispensable component of healthcare systems to prevent, diagnose and treat disease. Still, resource-limited countries are challenged to provide essential medicines of high-quality in a timely manner. Virtually every country provides pharmaceutical regulation and oversight through its own regulatory authority. Those authorities are responsible for regulating the drug development and approval process; however, the effectiveness of this oversight varies. Regulatory authorities differ significantly in their capabilities and, as a result, in their ability to protect their citizens by providing them with safe and effective pharmaceutical products. Not surprisingly, pharmaceutical regulation has been recognized as a key function to ensure that the drugs to which the public has access will function appropriately, safely 2 and effectively when needed (Hill and Johnson, 2004). Nonetheless, approximately 75% of National Medicines Regulatory Agencies (NMRAs) globally are limited in their capacity to perform core regulatory functions (Nayyar et al., 2015). According to the WHO regulatory-systems strengthening database, less than 4% of the NMRAs in Africa have a moderate functional capacity (Broojerdi et al., 2020), and the WHO estimates that 90% of NMRAs in Africa have insufficient capacity to undertake basic regulatory functions (Nayyar et al., 2015). Further, the speed at which countries approve pharmaceutical products varies significantly from country to country. A typical delay of 4 to 7 years can be identified from the time in which the first filing submission is made in a high-income country to its approval in Sub-Saharan Africa (Ahonkhai et al., 2016). Disparate and repetitive regulatory actions in different countries are well-known to cause delays in drug access and have been targeted by regulatory harmonization initiatives around the world (Azatyan, 2020). How best to develop and implement those harmonized approaches is a difficult question to answer. Some have suggested that harmonization initiatives should be coordinated with the work of Stringent Regulatory Authorities (SRAs), a designation used for national drug regulatory authorities, including the United States (US) Food and Drug Administration (FDA), European Medicines Agency (EMA), or Pharmaceuticals and Medical Devices Agency (PMDA) that are members, observers, or associates of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (Brennan et al., 2007; Doua and Geertruyden, 2014). Others have suggested that harmonization efforts should be pursued in conjunction with large organizations such as the ICH (Molzon et al., 2011). However, initiatives largely designed using the rules and 3 experience of highly industrialized economies may require under-resourced countries to implement standards beyond the economic means of their manufacturers or regulators. For that reason, recent harmonization efforts in Africa have favored more locally-driven programs (African Press Organization, 2012; Luthuli and Robles, 2017; Ndomondo- Sigonda and Ambali, 2011). While all countries in Africa, with the exception of the Sahrawi Arab Democratic Republic, have some type of NMRA (Ndomondo-Sigonda et al., 2017), these agencies vary significantly in their funding, functionality, and capacity (Moran et al., 2011; Wirtz et al., 2017), making a “one size fits all” solution elusive so far. Nevertheless, approximately 85% of countries in Sub-Saharan Africa are involved in one or more initiatives to increase regulatory harmonization (Luthuli and Robles, 2017; Ndomondo- Sigonda et al., 2018). Specifically, partnering countries have been experimenting over the last decade with ways in which they can share the reviews of new pharmaceutical entities and at the same time maintain their rights to decide individually upon the merits of a drug application (Arthur, 2019; Bollyky, Cockburn, and Berndt, 2010). These efforts have resulted in alternatives to standard pathways, often called Facilitated Regulatory Processes (FRPs), to accelerate product development, simplify market authorization application (MAA) submissions, or shorten regulatory reviews. Each program takes a different approach, but all share the goal of reducing the resources needed by both industry and health authorities. Programs such as the Economic Community of West African States (ECOWAS), East African Community (EAC), Southern African Development Community (SADC), and ZAZIBONA initiatives have been set up regionally during that time to capitalize on regional economic organizations and build 4 upon the framework of regional pharmaceutical regulatory organizations and existing legal tools. Nevertheless, their goals can be more aspirational than realistic. The World Health Organization Collaborative Procedure for Accelerated Registration (WHO-CRP) is a more recent regulatory harmonization initiative to advocate and plan resource sharing. The program was initially conceived in 2012 to address the increasing backlog of pending applications for drug registration in many low- and middle-income countries. Its goal is to facilitate and accelerate national regulatory approvals by supplying a member NMRA with confidential access to the evidence that a relevant SRA had used to approve and register a pharmaceutical product in its own jurisdiction (with the permission of the Sponsor) (Azatyan, 2019). A pilot program was initially implemented and then followed by a more disseminated final program at the end of 2018. The supra-regional approach used by the WHO to create the newly finalized WHO-CRP program differs from some of its predecessors in that the program is built using flexible tools that allow the underlying infrastructure of national regulatory approval within a country to be used within a structured framework of harmonization. As regulators on the African continent makes continued efforts to pursue additional harmonization efforts, examination of the strengths and pitfalls of the WHO- CRP program from the perspective of regulators, industry and other key stakeholders can provide valuable learnings to incorporate into future regulatory harmonization efforts. 1.2 Statement of the Problem Because the limited resources of African regulatory agencies are being expended to support harmonization programs, it is critical to assess whether harmonization initiatives are value-added or resource-draining. Liberti has recently provided an 5 overview of the FRPs and described significant diversity in the FRPs from the regulatory agencies of resource-limited countries by region (Liberti et al., 2016). Some researchers have analyzed specific harmonization systems, such as the East Africa Community Harmonization Program (EAC) (Dansie, Odoch, and Årdal, 2019), harmonization efforts in West Africa (Kamwanja et al., 2011) and the SADC (Calder, 2016), but these evaluations have not yet extended to the WHO-CRP as an FRP, since the WHO-CRP final program is relatively new compared to some of the other more established regional programs. Caturla Goñi (2016) presented some case studies of experiences that corporations have reported with respect to the WHO-CRP Pilot Program, a precursor to the WHO-CRP final program. These reports suggested that the overall experiences that corporations have had with the pilot program were positive and had the potential to improve the efficiency of participating regulators. To date, no systematic study has evaluated the WHO-CRP in Africa to determine factors specific to these Africa FRPs that might present significant opportunities or barriers to a fully efficient FRP. 1.3 Purpose of the Study This study evaluated the state of implementation and functionality of the new WHO-CRP program. The goal of this research was to examine the views of stakeholders who are using the finalized WHO-CRP in Africa to determine if the process is useful and represents an overall improvement from the programs that were previously available. It also aimed to identify the perceived barriers pertaining to the use of this pathway and best practices for overcoming these challenges that might inform facilitated regulatory pathways being set up in Africa and other resource-limited settings around the world. Specifically, this research addressed the following research questions: 6 1. Does the WHO-CRP program meet the needs of the industry professionals and regulators who use the process for product registration in Africa? 2. Does the WHO-CRP program represent an overall improvement over the programs that were previously available for product registration? 3. What are the perceived barriers pertaining to the use of this pathway and positive attributes of the process that might inform facilitated regulatory pathways being set up in Africa and other resource-limited settings around the world? The research was carried out using the CIPP Framework, a well-established framework developed by Stufflebeam and Coryn (Stufflebeam and Coryn, 2014) that has been in use for over 60 years. The CIPP Framework was used to guide the development of questions that were disseminated to a diverse group of NMRA professionals and key stakeholders using an electronic survey tool. By using an electronic survey tool directed at NMRA professionals and key stakeholders, questions about the best practices and hurdles of the use of the WHO-CRP in Africa were evaluated to assess its perceived effectiveness from the perspective of these key stakeholders. 1.4 Importance of the Study Significant resources, time, and effort are needed to set up a harmonized regulatory process in a region in which resources for even basic regulatory functions are scarce. By understanding the benefits and challenges of the procedure, regulators can make informed choices about their participation in the program. A better knowledge of the process might help to identify specific areas of concern and dissonance related to the implementation of the WHO-CRP program. Moreover, these results could inform future 7 harmonization efforts and best practices based on real world experience to ensure that more robust and efficient processes can be put into place in the future. Companies and consumers may also benefit from this study if it increases regulatory efficiency. By reducing the perceived barriers that exist in planned harmonization programs, the typical delay of 4 to 7 years between the first filing submission in a high-income country and approval in Sub-Saharan Africa may be reduced, resulting in faster deployment of needed medicines to waiting patients in that region. Companies that are contemplating entrance into an African market may be able to develop a better strategy by knowing what barriers might be anticipated and, to some extent, addressed. Further, by reducing the barriers to regulatory approval across Africa, small and mid-sized companies with limited resources may be incentivized to market their products in the region, providing additional treatment options to underserved populations. 1.5 Limitation, Delimitations, Assumptions This study was delimited to evaluating the WHO-CRP facilitated regulatory pathway that is currently in place on the continent of Africa. It was specific to pharmaceutical products only; diagnostic products, medical devices, and over the counter products were out of the scope of this research. The participants were restricted to individuals who have direct experience with this program within its lifetime in one of two ways, either by using or planning to use the program to register or review products, or by developing or administering the procedures that form the basis of the pathway. The survey was launched in the latter part of 2020, so it provides a snapshot in time that may 8 not be typical as time passes but can serve as a benchmark against which future programs may be measured. Several limitations were potential challenges in a survey like this. Surveys are known to be limited by response numbers and rate. In addition to querying other stakeholders, such as health authorities, the intention was to obtain a cross section of pharmaceutical companies based on size and location. This resulted in relatively small numbers in each group, as many companies do not register their products in Africa. Thus, caution is needed when trying to use the small sample as a fair representation of that industry segment. Further, the numbers of individuals with appropriate experience restricted the size of the pool from which participants were drawn, particularly because the WHO-CRP final program has been in place for a relatively short period of time. Many respondents resided in Africa, which made the identification of suitable participants more difficult. In addition, the survey was only provided in English and in French, which created a language limitation, since not all countries in Africa rely on English or French as their primary language. These factors created challenges to secure the cooperation of enough study participants to effectively represent the overall populations. Because potential participants are often influenced by the length of the survey when choosing to participate, another limitation was the number of questions that I felt could be presented to the survey participants. This placed a limitation on the depth and breadth of the topics that could be covered and the degree to which dropouts occurred. By limiting the number of questions, certain topics may not have been fully explored, and this may constrain the analysis. Each question had to be framed carefully. Using a focus 9 group to critique the survey helped to ensure better validity, but limitations still exist related to the capabilities and biases of the researcher and the maturity of the program. The research was based upon my ability to exercise fair balance and objectivity during the conduct of the study and the analysis of the results. To some extent, this bias was identified and controlled by working with faculty who have more experience with survey research and by employing an external focus group of experts to critique the survey for bias and clarity. While the countries in Africa are geographically and culturally diverse, for this study, I assumed that the views of study participants were determined predominantly by their experience with the process and the political framework under which the process operates, but not cultural or social aspects of their countries. Nevertheless, the cultural and social norms specific to these regions may have influenced the recommendations made as a result of this research. As a result, recommendations from this research may not be entirely applicable to the creation of a facilitated pathway in another region. Inherent in this research was also the assumption that all respondents were truthful in their evaluations and expressed their own opinions and experience. Therefore, the survey was conducted to ensure anonymity of responses and participants, and this limited the ability to relate specific data to identifiers of the respondent and his/her organization and location. 1.6 Definitions A list of terms and acronyms used throughout this thesis may be found in Appendix A. 10 1.7 Organization of the Thesis The thesis is organized in five chapters. Chapter 1 provides an introduction the study including the problem statement, the purpose, the delimitations, limitations, and importance of the study. It also provides a brief rationale for the approach that will be taken. Chapter 2 provides a more detailed overview of the background and history of the facilitated regulatory pathway programs by presenting some background on the evolution of the facilitated regulatory pathway programs and a literature review representing the current state of knowledge on this topic. Chapter 3 describes the research methodology used for this study. Appendices to this thesis include Appendix A, which includes a list of terms and acronyms used throughout this thesis, and Appendix B, the survey that was distributed. 11 Chapter 2. Literature Review 2.1 Introduction Regulatory harmonization is a strategic imperative to increase the access of patients to pharmaceutical products by streamlining regulatory review by NMRAs (Liberti et al., 2018). Harmonization can decrease the amount and costs of research needed to commercialize drug products and can preserve scarce NMRA resources that review and register these drug products. It is not surprising, then, that multiple harmonization initiatives have taken place over the last few decades in different geographical regions and across different epochs of time. This chapter will trace the evolution of regulatory harmonization over the past 30 years to show the genesis and evolution of harmonization efforts that have influenced the development of such efforts in Africa. The chapter will then describe more specifically the historical development of the WHO-CRP program on which this dissertation will focus. 2.2 Background to the Literature Review The literature review has three main parts. A brief history of regulatory harmonization related to drug evaluation around the world is followed by a deeper review of existing literature concerning regulatory harmonization amongst African regulatory systems. Finally, literature specifically relating to the WHO-CRP will be examined in detail. As the literature review will show, academic literature becomes sparse as attention is focused on African initiatives. The database PubMed was used as a starting point with the goal of obtaining scientific publications, books, white papers, and conference presentations on regulatory 12 harmonization. The initial search was limited to begin in the year 2000 to capture contemporary perspectives, but it was subsequently expanded to earlier years to capture the historical perspective of the topic. Relevant references from the selected papers were also assessed and included as appropriate. BIOSYS Previews (1993 to 09 July 2020), Derwent Drug File (1964 to 2020 Week 27), Embase (1974 to 09 July 2020), and MEDLINE® (1946 to 08 July 2020) were used to expand the search results. The initial search terms used were regulatory harmonization, and regulatory reliance, and regulatory convergence. The search criteria were intentionally kept broad to capture as many publications related to the topic as possible. The WHO website was a rich source of additional content and guidance documents on the projects that they are undertaking to develop harmonization initiatives in Africa. The collected literature was then reduced to focus on articles relevant to the topic of present research. Publications that were not in English or French were omitted from review. Publications written about harmonization programs outside the scope of this thesis, such as those occurring in Latin America (Bruce, 2019), were also excluded. I also excluded conference agendas, educational catalogs, and abstracts without specific information on the topic of regulatory harmonization. In order to identify writings with most impact, the results were narrowed to those with a minimum of 25 citations. Next, to ensure that important results from more recent publications were not excluded and to highlight the more current dialogue, I revised the search results to include the 2015-present timeframe, and incorporated all results, regardless of the number of citations. This step allowed me to focus on most of the 13 harmonization efforts relevant to this topic. Subsequently, the initial results were expanded by examining the relevant references from key papers to produce the grouping of 1282 reviewed publications that informed the work presented here (Figure 1). Figure 1: Literature Search 2.3 The Development of Harmonized Practices Pharmaceutical products have been important for disease management for thousands of years; however, practitioners have recognized the dangers of substandard quality for as long as those products have been used. Today, societies understand that effective pharmaceutical practice rests on a regulatory system to ensure that drugs are safe and effective. Thus, most countries have implemented review programs to assure that drugs can only enter the market after their quality and performance have been scrutinized. Historically, such assessments come after a drug has completed a long developmental process that culminates in a submission to the national regulatory 14 authority. That regulatory authority studies the submission, asks questions, does its own research, and after several months, may give the product an approval if it is felt to be adequately safe and effective. Such a system is resource intensive both for the manufacturer that must carry out product development and sustain the quality systems and for the regulators who typically take many months to review in detail the dossiers describing those development activities. At the end of the process, the product is approved only for the country or countries in which the regulatory authority has jurisdiction. Approval in a different jurisdiction requires the oversight of a different NMRA associated with that new national system. Consequently, the market approval process is reiterated many times in every country or economy in which the drug is to be sold. It is therefore not surprising that both companies and regulators have attempted to find ways to shorten and streamline that submission and review process. One way of doing this is by developing programs to fast- track new drugs for serious or life-threatening conditions. Such prioritization can often shorten the timeline of drug approval but relies on an even more intensive application of human resources to accomplish the accelerated review in the target timeframe. Therefore, other approaches that reduce time and effort are needed. Some NMRAs have taken a regulatory harmonization approach while others have pursued a path of regulatory convergence. Regulatory harmonization is defined as the process whereby regulatory and scientific guidelines are developed to be identical (Matsuda, 2019) whereas regulatory convergence describes a process by which the regulatory and scientific guidelines are adopted to become more similar or “aligned” over time (Chong, Lim, and Tominaga, 2018). Convergence does not require harmonization of 15 laws and regulations. Two examples of different types of regulatory harmonization initiatives that had influence on the formation of the WHO-CRP system are those implemented in Europe and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). 2.3.1 European Pharmaceutical Regulatory Harmonization 2.3.1.1 Political Harmonization in the European Union To understand how Europe has approached the regulatory harmonization of pharmaceutical products, it is important to first understand how the European Union (EU) was formed. The framework of that political and economic harmonization provided the foundation for the subordinate structure of the European drug regulatory system. As early as 1464, the Bohemian King George of Podebrady envisioned Europe as a single political entity (Ash, 1998). Napoleon Bonaparte referred to the “United States of Europe”, a term echoed by others, including Victor Hugo, William Penn Kant (Metzidakis, 1994), and Leon Trotsky (Trotsky, 1929) throughout the 19th and 20th century. That idea became a reality only after Winston Churchill (1946) called for a “United States of Europe” after World War II to create a supranational sovereign entity that would be a deterrent against future wars. Still, it took over 50 years for the EU to move from concept to reality. Although the Treaty of Rome (European Parliament, 1958) established the European Economic Community (EEC) in 1957, it was not until the Maastricht Treaty (European Union, 1992) was signed in 1992 and came into force in 1993 that the EU officially came into being. The Maastricht Treaty was an important milestone that facilitated the kind of cooperation important for international harmonization efforts, including those for drug 16 regulation and management. Soon thereafter, the major industrialized regions that dominated the pharmaceutical industry at that time were motivated to form the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) (Kidd, 1996). Prior to this point, such an effort was not feasible because the number of countries that would have had to be involved to encompass Europe would have been too large to gain any meaningful consensus on initiatives in a practical timeframe. In the 1990s, the movement of goods, services, people, and money were reorganized to strengthen the unification of the European market. The Maastricht Treaty and the Treaty of Amsterdam (European Union, 1997) consolidated political harmonization efforts related to the environment, security and defense. The Schengen Agreement (Eur-Lex, 1985) allowed people within the EU to travel freely without having their passports checked at the borders. This free movement of human resources also provided the platform for the free movement of pharmaceuticals and other goods. At the same time, the size of the EU was growing. The collapse of communism across central and eastern Europe foreshadowed the expansion of the Single Market in 1993. Austria, Finland, and Sweden joined the EU in 1995, and in 1994, the European Economic Area was established. This organization allowed European Free Trade Association states to enter the Single European Market and encouraged the development of economic measures to integrate its trade. Early in 1999, the Euro was introduced as the common currency of the EU and the European Central Bank was instituted and the currencies of the Member States were replaced with Euros in early 2002. The single economic system reinforced the EU’s objective to achieving harmonization within the 17 legislative system and it also defined the EU as a single economic entity. The Treaty of Nice came into force on 1 February 2003 (Eur-Lex, 2001). Among other important aspects, this treaty amended the Maastricht Treaty and the Treaty of Rome to create subsidiary courts to streamline the decision-making process used by the EU and to deal with special areas of law, such as patents. Patent law harmonization was important to extend pharmaceutical product exclusivity across all Member States. Ten additional Member States joined the EU after the ratification of the Nice Treaty, which brought the total number of Member States in 2004 to 25. Europe was now poised to support a single regulatory system, with free borders, a common currency, patent protection, and a fundamental regulatory framework. 2.3.1.2 Pharmaceutical Regulatory Harmonization in the European Union Regulatory harmonization was discussed in the EU as early as 1963 (Eakin, 1998; Orzack, Kaitin, and Lasagna, 1992), and in 1965, the EU issued its first pharmaceutical directive, Directive 65/65 EEC (Eur-Lex, 1965). This directive required Member States to establish common premarket approval requirements as the foundation for a collaborative drug-review system (Kingham, Bogaert, and Eddy, 1994). That collaborative system was controversial when enacted (Orzack, Kaitin, and Lasagna, 1992) and was only ratified by seven of the twelve-Member States that then composed the European Community (Vogel, 1998), but it set into motion the harmonization of the European drug regulatory system then poised to evolve over the next 30 years. The subsequent evolution of the harmonized regulatory system rested on two directives developed by the European Commission (EC), the executive branch of the European Union. Directive 75/318/ EEC (The Council of the European Communities, 18 1975) addressed the harmonization of analytical, pharmaco-toxicological, and clinical standards to provide a unified set of requirements across all Member States. Directive 75/319/ EEC (Eur-Lex, 1975) created a Committee on Proprietary Medicinal Products (CPMP) that functioned as an advisory committee to the EC. The mission of the CPMP was to exchange the drug regulatory systems of the EC Member States by a single agency that could review applications and then disapprove, approve, or conditionally approve them. Favorable opinions were then transmitted to the EC, the Member States, and the applicant. Over time the system developed different procedures for the review and approval of different types of products: 1. Mutual Recognition procedure: The CPMP shaped an initial multistate procedure now known as the Mutual Recognition System. Under this optional system, a drug manufacturer could submit a dossier for drug registration to one Member State and, once approval was granted, would receive approval in a maximum of six other Member States as well. Alternatively, manufacturers could receive approvals from one state at a time (Orzack, Kaitin, and Lasagna, 1992). 2. Centralized procedure: The Centralized Procedure was created in 1995 under Directive 87/22/ EEC (Eur-Lex, 1986). The Centralized System allowed the approval of a single dossier across all Member States, reinforcing the structure of the EU as a single entity. Approval gave a singular marketing authorization that allowed the holder to sell the medicine throughout the EU, Norway, Iceland and Liechtenstein. These directives were later supplemented by Directive 2001/83/ EC (European Parliament and the Council of the European 19 Union, 2003) and Regulation (EC) No 726/2004 (European Parliament and of the Council of the European Union, 2004) that set down requirements and procedures for marketing authorization. The directives also include harmonized provisions for the manufacture, wholesale, and advertising of medicinal products for human use. This restructuring was intended to make the regulatory process more robust by enforcing strict review timelines and pooling scientific expertise across Europe rather than relying on a group of country-based experts. A secondary goal was to eliminate the nationalist tendencies of independent countries unwilling to approve new drugs that might compete with those already produced by domestic drug manufacturers (Kaufer, 1989). Building on these directives, the Council Regulation EEC/2309/93 (The Council of the European Communities, 1993) implemented the European Medicines Evaluation Agency (EMEA). The CPMP was repositioned within the EMEA as the decision-making body to evaluate drug registration applications and grant marketing authorizations under the Centralized Procedure. EMEA, which changed its name to the EMA in 2009, was designed to be an advisory board in which advice was to be given to national regulatory authorities (Kidd, 1996), but today is the official body that grants marketing authorizations. The creation of EMEA in the 1990s was driven in part by the escalating costs to the applicant that were associated with the submission of separate marketing applications to different EU countries. An estimated €300 million per year was spent in the early 1990s by pharmaceutical companies to obtain those separate approvals (Burstall and 20 Reuben, 1988; Melloan, 1994; Vogel, 1998). Without fixing its fragmented system, the EU was faced with the challenge of maintaining a healthy innovation climate. This loss of competitiveness was evident from data showing that 65% of all biotechnology patents were from the US versus 15% from Europe and that the share of biotechnology medicines was in decline. By forming a centralized agency, Europe sought to harmonize the work of the national regulatory bodies in order to improve the long-term business climate (Green, 1997). A timeline of key milestones is shown in Figure 2. The harmonizing directives formed the scaffolding upon which the common market for medicines in Europe became possible. The centralized application procedure achieved the goal of putting regulatory approval at the level of the EU rather than at the member state level. This was key for EMA to show the benefit of the harmonization efforts. In this new harmonized procedure, manufacturers could now submit a single application to the EMA, which would then be reviewed by an integrated group of reviewers. Strict timelines were put into place so that manufacturers could anticipate when a product could be launched, based upon a reliable review duration. The new process cut the length of the review cycles to up to half of what companies had previously experienced (Kingham, Bogaert and Eddy, 1994). Once approved, the product automatically became valid throughout the EU. This new process resulted in regulatory decisions that were predictable, less expensive, and provided approvals in multiple counties simultaneously. It did not take long for the advantages of the harmonized system to be recognized. Pharmaceutical companies could submit one application rather than 15, with an industry cost savings of approximately $350 million annually (European Medicines Agency, 21 2021; Green, 1997). Although the cost of the centralized application was initially approximately 200,000 ECUs (approximately €200,000 at the time ECUs were converted to Euros), it was approximately half the cost of filing in all fifteen countries individually (European Medicines Agency, 2021; Vogel, 1998). Further, common packaging allowed free distribution of product throughout the EU, significantly reducing supply chain costs. Therefore, the European model is heralded as an example of a successful harmonized system and provides a promising framework for independent countries to pool their resources without sacrificing their individual decision-making independence. Not surprisingly many of its tenets were copied by other regulatory agencies around the world and those tenets form the foundation of the WHO-CRP that is the subject of this dissertation. 2.3.2 Harmonization in Great Britain The large-scale harmonization taking place across the EU also influenced harmonization activities more regionally, particularly in Great Britain. The control of medicines was evident in England as early as the sixteenth century, during the reign of King Henry VIII of England (1491–1547). At that time, the Royal College of Physicians of London was given the task of inspecting inventories at apothecaries in London and was granted the power to destroy defective stock. Approximately 200 years later, the Medical Act of 1858 created an entity known as the General Council of Medical Education and Registration of the United Kingdom that had responsibility and oversight of medical practitioners. The Pharmaceutical Society of Great Britain was established by the 1925 Therapeutic Substances Act to control the retail sale of vaccines, devices, and drugs. The organization was the regulatory body for pharmacists and pharmacy 22 technicians in the three constituencies of England, Wales, and Scotland from 1841 to 2010 (Pharmaceutical Society of Great Britain, 2020). The organization of the regulatory system underwent change in response to the shock of a major public health tragedy, related to the marketing of an anti-emetic for morning sickness called thalidomide between 1957 to 1961 (Fintel, Samaras, and Carias, 2009). The dramatic teratogenic effects of the drug on over 100 infants brought into sharp relief the insufficiencies of drug regulations that many felt would allow the drug manufacturer to market any product without adequate proof of efficacy and safety. The Committee on Safety of Drugs (CSD) was established in 1963 as a temporary regulatory measure prior to establishing a formal legal system to license new medicines in the United Kingdom (Mann, 1989). The CSD did not have any legal powers, but instead worked with industry to impose voluntary controls on manufacturers and drug providers. By the late 1960s, it became apparent that voluntary controls could not achieve full cooperation, so the 1968 Medicines Act (Great Britain Parliament, 1968) was enacted to strengthen the statutory framework for the control of medicines in the United Kingdom. Since the EEC already had established the Council Directive 65/65, the Medicines Act was written to be consistent with that directive. Its licensing requirements came into force in late 1971 and implementation of its various elements continued over the subsequent decade. The Medicines Act also required the creation of the Medicines Commission. The Medicines Commission was responsible for overseeing the development, manufacture, packaging, labeling, distribution, and advertising of medicinal products. The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom was later created in April 2003 through the union of the 23 Medicines Control Agency and the Medical Devices Agency (Griffin, 2013). This central authority now controls the approval and oversight of medicinal products and medical devices for England, Scotland, Ireland, and Wales. A timeline of key milestones is shown in Figure 2. Figure 2: Key Milestones in the History of Drug Regulation in Europe and in the United Kingdom 2.3.3 ICH and the Common Technical Document It is not always possible to develop the kinds of deeply integrated systems that have been created by the EU or the United Kingdom, particularly when harmonization is sought between countries such as the US or Japan that already have mature legal frameworks and regulations that would be difficult to mesh retroactively. Another way that some degree of harmonization can be achieved is to dissect out specific elements that can be harmonized between countries with dissonant laws without changing the associated regulatory frameworks of each country. This has been the approach taken by 24 an increasingly influential non-profit organization called the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The ICH was established in 1990 by an association of drug regulatory authorities and research-based pharmaceutical industries from the EU, Japan, and the US. Its mission is to converge certain scientific and technical aspects of pharmaceutical product registration (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, n.d.) to minimize the duplicative requirements of product registration, testing, and document preparation to speed regulatory approvals and market registrations across regions. Perhaps the most influential deliverable published by the ICH was the Common Technical Document (CTD), which has become the template for drug submissions worldwide. The CTD lays out a harmonized heading structure for clinical trial or marketing applications to regional regulatory authorities in participating countries. The CTD has been characterized as “offering potential benefits to industry far greater than any other single ICH topic” (Molzon et al., 2011) by facilitating concurrent submission, approval, and launch of new drugs in multiple countries. Rules for submitting these dossiers using electronic methods were then elaborated by different agencies such as the US FDA (United States Food and Drug Administration, 2020) and EMA (European Medicines Agency, 2016) so that participating health authorities could access the submissions on their computers almost immediately upon receipt. The ability to disseminate a common dossier of organized information to health authorities has significant advantages. For the pharmaceutical industry, resources and time are saved because the data does not have to be reformatted for each constituency of 25 interest. Accuracy is improved because the information does not need to be transcribed repeatedly. For health authorities, the predictable format makes the dossier easier to navigate and more efficient to review. By having a consistent format, it is also easier for reviewers to compare the information in submissions for similar products; this can facilitate the development of consistent messaging across companies with related products. Collaboration and discussion between internal reviewers or even different health authorities is also facilitated because different groups of reviewers can base their discussions on the same CTD. The ICH does not concern itself only with submissions. It also develops harmonized ICH Guidelines on Safety, Quality and Efficacy topics. It also has a group of guidelines on multidisciplinary topics, such at the CTD template described above and an important Medical Dictionary for Regulatory Activities (MedDRA). Its achievements have been broadly regarded as beneficial and influential. However, they can also be challenging and controversial to apply outside of the richer countries that have historically participated in the development of the guidelines. Smaller, resource-limited countries have asserted that developing countries have limited opportunities to provide input in the development of the ICH guidelines. To participate in ICH, countries must accept the ICH guidelines intact, without the ability to customize them for the country’s use. Those guidelines often set a benchmark for quality expectations that are higher than those required by national regulatory authorities. Implementing these higher guidelines can require levels of resource allocation unattainable for countries still developing their systems. In those evolving systems, the regulatory authority often must 26 increase its pharmaceutical expectations incrementally, to remedy the largest risks first. In the interim, however, these countries would be considered as non-adherent to ICH guidelines and cannot fully participate in the ICH framework. Thus, they cannot influence the guidelines according to their views, priorities, and needs (Dagron, 2012). The cost of adhering to certain types of guidelines can also make the ICH approaches unaffordable for pharmaceutical companies in emerging economies. For example, the WHO Prequalification inspections have been estimated to cost as much as US$100,000 (Mackintosh et al., 2016). This can be an enormous and typically unsubsidized burden for fledgling companies. Nonetheless, these local small companies are important to the economies of emerging countries. Often, vital drugs required for the prevention and treatment of locally endemic diseases are supplied by local industry or by generic manufacturers. These suppliers provide jobs and local, cost-effective medicines without the tariffs and transportation that would be associated with imported drugs. If local suppliers are unable to meet the rigorous ICH guidelines, however, withdrawal of these drugs could risk more seriously the health of the population than would be experience by failing to satisfy all of the many elements in the ICH guideline, especially if those deficiencies had minimal effect on drug quality. The WHO fears that the failure to develop local drug suppliers could “lead to diverting limited national resources to unnecessary expenses entailed by the adoption of more costly regulatory requirements” (World Health Organization, 2002). As a result, supranational harmonization remains a controversial topic, particularly in areas such as Africa, where the disease burden is high, and the infrastructure is still developing. 27 2.4 Pharmaceutical and Regulatory Development in Africa 2.4.1 Early Pharmaceutical Manufacturing in Africa Pharmaceutical manufacturing in many African countries remains under- developed despite a history that began at the same time as in the Western world. Manufacturing operations in some of those economies were then driven by multinational European companies that set up subsidiaries in “colonies” as early as the 1930s. Between 1930 and 1935, for example, Glaxo set up a subsidiary in Kenya, Abbott in South Africa and May and Baker in Nigeria. Such manufacturing operations continued in those countries until the 1960s, when the decolonization that occurred in and after that period caused many foreign owned pharmaceutical companies to close their sites in Africa (Banda, Wangwe, and Mackintosh, 2016). Africa was then faced with the need to transition quickly from decolonization to globalization. As countries attempted to establish their individual identities free from colonial rule, many resisted harmonization initiatives that could be seen to challenge their highly valued sovereignty. As a result, the countries showed little appetite for harmonization. At the same time, however, economic imperatives affected the capacities of the countries to carry out stand-alone regulatory activities. The early years of independence saw an explosion in local financing and creation of new companies (Mkandawire, 2001) but the boom was temporary. The oil crisis in the late 1970s sharply reduced foreign trade and hobbled industrial activity. This economic downturn was exacerbated by a severe drought in the region. A period of deindustrialization then occurred across most of Africa. Significant investment into pharmaceutical manufacturing did not resume until the mid-1990s, when a second wave of pharmaceutical manufacturing spread across the African continent, funded mostly by 28 local investors. Since demand for pharmaceutical products was still rather low, it could mostly be satisfied by local manufacturers. Thus, the locally manufactured products were not distributed in any large volume outside of their region of origin (Banda, Wangwe, and Mackintosh, 2016). 2.4.2 Political Pressures for Rapid Registration of Drugs in Africa The human immunodeficiency virus (HIV)/ acquired immunodeficiency syndrome (AIDS) epidemic changed the African healthcare landscape dramatically (Brandt, 2013). First appearing in Africa in 1985 (Serwadda et al., 1985), the rapid escalation of AIDS into a global pandemic had major human and economic ramifications both in Africa and in the rest of the world. Within ten years, the number of affected patients swelled to 1.9 million (Mann and Tarantola, 1996). By 1999, HIV/AIDS had become the primary cause of death in Africa, where approximately 70% of the worldwide HIV/AIDS cases were reported (Dixon, McDonald, and Roberts, 2002). The human cost of HIV/AIDS was devastating. For example, in southern Africa, the average life expectancy increased from 44 years to 59 years between the early 1950s and late 1990s, only to revert to the original levels seen in the early 1950s as HIV/AIDS ravaged the population. One in five deaths was caused by that disease at the conclusion of the 20 th Century (Piot et al., 2001). The cumulative number of children orphaned by HIV/AIDS worldwide was in excess of 13.2 million; 95% of those children resided in Africa (UNAIDS, 2000). The economic impact of the disease was shocking as well. The annual cost associated with the reduction in productivity from HIV/AIDS was estimated to be as high as $300 per employee. This had serious ramifications on the competitiveness and profits 29 of African industries (Bollinger and Stover, 1999). Lower domestic productivity reduced exports and led to growing trade imbalance. Governments were faced with financial challenges from two fronts with a dramatic increase in healthcare costs and a marked decrease in governmental tax revenues resulting from the declining economy. One way that countries could respond to the new need for expensive medicines is to make their own. However, patent restrictions for the new HIV medicines stood in the way. Of special concern were the challenges imposed on international trade by a patent- protecting agreement, the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), that had been instituted in 1995 by World Trade Organization (WTO) (‘t Hoen, 2009). The TRIPS agreement, managed by the WHO, specified minimum requirements for the protection of intellectual property, including a 20-year period of patent protection for pharmaceutical products. Members of WTO had to enforce the patent protection provisions or rescind their membership in the WTO. Although less than 5% of the drugs included in the Essential Medicines List (EML) of the WHO were limited by these provisions, many of the new drugs to treat HIV/AIDS, including the costly antiviral regimens, were still under patent protection at that time. Many people therefore held TRIPS responsible for the high cost of medicines during the HIV/AIDS crisis, which kept antivirals out of the reach of patients, especially in resource-limited settings. By 2000, in response to that growing public outcry, five of the patent-holding pharmaceutical companies began to offer pricing discounts on HIV/AIDS-related medicines and diagnostics in developing countries. 30 Price reductions for drugs produced abroad helped the immediate crisis in Africa but did not fix an underlying problem of wide-ranging deindustrialization. Between 1997- 2008, hyper-inflation damaged the industrial base; skilled people emigrated, and the physical infrastructure fell apart. Attempts to stimulate local production were blocked by an ensuing economic crisis that caused most local drug manufacturers to close. The public health system then lost its capacity to obtain drugs and forced it to rely on outside funding and externally-sourced drugs (Banda, 2013). Similar cycles, from growth of internal domestic production development to catastrophic economic failure and subsequent reliance on external aid, was repeated all over Africa during this period. Between 2002 to 2012, HIV/AIDS therapies improved worldwide, and this improvement was seen to some extent in Africa. However, the distribution of HIV/AIDS medicines in Africa remained nonuniform. It was accomplished by a patchwork of parallel programs sponsored by national governments and non-government organizations (NGOs), including many that relied on donated medicines approved for commerce elsewhere, or, in some cases, medicines that had received no regulatory approval at all. Concerns about the quality of these inexpensive drugs drove the US FDA to require bioequivalence studies to speed approvals of generic products that could be secured through US purchasing programs, such as the President's Emergency Plan for AIDS Relief (PEPFAR). Still, the regulatory bodies in developing countries in Africa were slow to approve those medicines, due in part to limited drug regulatory capacity. The WHO and other organizations recognized the difficulties of obtaining inexpensive and effective drugs and encouraged local health authorities to build the capacity to regulate incoming drug products (World Health Organization, 2010). In 31 response, the number of harmonization efforts initiated in Africa increased significantly after 2010. 2.4.3 African Union Model Law In a situational analysis performed in 2010, regulatory harmonization in the African Union (AU) Member States was found to be limited by dissonant laws on the continent (Kamwanja et al., 2010). The Model Law on Medical Products Regulation (NEPAD, 2016b) was developed by New Partnership for Africa’s Development (NEPAD) Agency, the African Union Commission (AUC) and Pan African Parliament and was adopted by the AU Summit in January 2016 (Glover et al., 2018; Ndomondo- Sigonda et al., 2017). This law is a template to be used by Member States to update their current laws to facilitate regulatory harmonization in the region. A main component of the law is the harmonization of regulatory standards and procedures by outlining mechanisms for regional and sub-regional cross-registration and facilities inspections. The Model Law provides nonprescriptive guidance to be used by Member States and RECs to update their current laws to facilitate regulatory harmonization and is consistent with WHO and international quality and safety standards (The Access and Delivery Partnership, 2017). A main component of the law is the harmonization of regulatory standards and procedures by outlining mechanisms for regional and sub- regional cross-registration and facilities inspections. Once endorsed, the Model Law is used to update and enact regional legal frameworks and national laws on the regulation of medicines to make them consistent with the country’s constitution and legal system and amend or repeal any inconsistent laws in place, while retaining each country’s sovereignty (Luthuli and Robles, 2017). 32 The Model Law is currently being used by Member States to review their existing legislation or establish new laws to better accommodate future regulatory harmonization initiatives; however, the Model Law is only a template to provide policy and technical guidance for AU Member States as they review existing national laws to be in alignment with international standards to ensure more effective regulation of medical products. While it will facilitate the overall harmonization process in the region, the implementation of a single pharmaceutical regulatory pathway in the region will likely require more extensive harmonization of pharmaceutical regulations in each country (The Access and Delivery Partnership, 2017). Presently, 17 countries have adopted the AU Model Law (Sithole et al., 2020), which is below the implementation target of domestication by at least 25 countries and adoption by 3 RECs by 2020 (NEPAD, 2020b). 2.5 Regional Regulatory Harmonization Initiatives in Africa Given the challenges discussed above, it is not surprising that heightened regulatory demands on the under-resourced governments of most African countries might cause them to reevaluate their approaches with respect to regulatory harmonization. The countries in Africa have organized into eight Africa's Regional Economic Communities (RECs) to provide the overarching framework for continental economic integration, as shown in Figure 3 (Africa Trade Development Center, 2019). 33 Figure 3: Regional Economic Communities in Africa Map of Africa showing the regional economic community membership of each country (Africa Trade Development Center, 2019) On average, each country in Africa belongs to 2.5 RECs (Mengistu, 2015), and this created difficulties for harmonization efforts (Figure 4). Thus, initial attempts at harmonization proved difficult. Obstructions such as inadequate pharmaceutical legislation, poor infrastructure and limited resources proved too formidable for early regional initiatives to overcome (Ravinetto et al., 2016; World Health Organization, 2010). 34 Figure 4: Regional Economic Community Membership More recently, two types of harmonization approaches have been tried. One approach has been that of leveraging international organizations and resources to facilitate harmonization efforts. The WHO, described in more detail below, has played a pivotal role in these activities. A second type of harmonization is a more regionally constructed effort, an approach predominantly favored in Africa. These initiatives are described below in Sections 2.5.1-2.5.10. Approximately 85% of Sub-Saharan Africa is involved with one or more Medicine Regulatory Harmonisation (MRH) projects (Luthuli and Robles, 2017; Ndomondo-Sigonda et al., 2018). Some of the more modest initiatives are described first below. An expanded description of the EAC and the SADC regulatory harmonization initiatives are then presented because these are more advanced and are operating in parallel with the initiatives that have been promoted by the WHO. 35 2.5.1 African Medicines Regulatory Harmonisation Initiative The WHO, which is described further in Section 2.6.1, has been at the forefront of drug regulatory harmonization for over two decades. The WHO sponsors an annual forum, called the International Conference of Drug Regulatory Authorities (ICDRA), for the regulatory authorities of the WHO Member States to meet and discuss collaboration topics of mutual interest. At the 13th ICDRA meeting in 2008, concerns were raised about the need for regulatory harmonization in many regions of the world, particularly in Africa (Stuckler, King, and McKee, 2008). The outcome of the meeting was a “NEPAD Planning and Coordinating Agency”, a program designed to encourage Africa’s development by addressing the socioeconomic, political, and environmental factors discouraging the advancement of public health. In 2009, the NEPAD Agency coordinated the formation of a more specific African Medicines Regulatory Harmonisation (AMRH) initiative (Ndomondo-Sigonda et al., 2018) to transition drug regulation from a nationally-focused approach to a more collaborative regional approach. Its ambitious vision was to ensure that all people across Africa would have access to essential medical products and technologies of high-quality by building effective medicines regulation and registration systems through regional harmonization and capacity building (Ndomondo- Sigonda and Ambali, 2011). The AMRH works with the eight RECs shown in Table 1 to ensure that the initiatives being undertaken by these communities are aligned with the AU’s harmonization plan for Africa. 36 Table 1: Membership of Regional Economic Communities REC Community Members Arab Maghreb Union (UMA) Algeria, Libya, Mauritania, Morocco, and Tunisia Common Market for Eastern and Southern Africa (COMESA) Burundi, Comoros, Democratic Republic of Congo, Djibouti, Eritrea, Egypt, Eswatini, Ethiopia, Kenya, Libya, Madagascar, Malawi, Mauritius, Namibia, Rwanda, Seychelles, Uganda, Zambia and Zimbabwe Community of Sahel- Saharan States (CEN- SAD) Benin, Burkina Faso, Cape Verde, Central African Republic, Chad, Comoros, Djibouti, Egypt, Eritrea, Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Kenya, Liberia, Libya, Mali, Mauritania, Morocco, Niger, Nigeria, São Tomé and Principe, Senegal, Sierra Leone, Somalia, Sudan, Togo and Tunisia EAC Burundi, Kenya, Rwanda, South Sudan, Uganda and United Republic of Tanzania Economic Community of Central African States (ECCAS) Angola, Burundi, Cameroon, Central African Republic, Chad, Republic of the Congo, Democratic Republic of the Congo, Equatorial Guinea, Gabon, Rwanda and São Tomé and Principe Economic Community of West African States (ECOWAS) Benin, Burkina Faso, Cape Verde, Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone and Togo Intergovernmental Authority on Development (IGAD) Djibouti, Ethiopia, Eritrea, Kenya, Somalia, Sudan, South Sudan and Uganda Southern African Development Community (SADC) Angola, Botswana, Comoros, Democratic Republic of Congo, Eswatini (Swaziland), Lesotho, Madagascar, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Tanzania, Zambia and Zimbabwe AMRH approached its mandate by attempting to harmonize and streamline the technical requirements for product registration. It provided a framework to address capacity issues and institute efficiencies in the regulatory processes of African regulators (Buch and Hogerzeil, 2009). The group then solicited proposals from its regional partners to identify programs that it could help to support in order to achieve its objectives. The first region of focus was an initiative focused in East Africa, designated as the EAC Medicines Regulatory Harmonization initiative. This regional community was 37 selected because it had already developed a drug-related legal framework appropriate to support regulatory harmonization, so the region was primed for harmonization efforts (Mwangi, 2016). A summary of this EAC Medicines Regulatory Harmonization initiative is provided in Section 2.5.10. Following the successful rollout of the AMRH, the AU is in the process of deploying a single African Medicines Agency (AMA), which was established by African Union Heads of State and Government during their 32nd Ordinary Session of the Assembly on 11 February 2019 in Addis Ababa, Ethiopia (Office of the Legal Counsel (AUC), 2019). The goal of the AMA is to create a more fertile environment for cooperation and harmonization amongst players in the pharmaceutical industry (Luthuli and Robles, 2017; Ndomondo-Sigonda et al., 2017). Article 38 of the treaty makes its formation contingent on ratification by fifteen AU Member States (Zarocostas, 2018). As of February 2021, the Treaty has been signed by 19 countries and ratified by 8 (IFPMA, 2021). 2.5.2 Regulatory Harmonization in the Arab Maghreb Union The Arab Maghreb Union (UMA) was created under the Marrakech Treaty of 1989 (Governments of Morocco, 1989) to strengthen bonds between the five Member States, Algeria, Morocco, Mauritania, Libya, and Tunisia, that gained their independence in the middle of the 20 th Century. The UMA represents approximately 19% of the African land mass and a population burdened by financial disparity and volatile and unbalanced economic and political dissonance. The Maghreb countries have one of the lowest rates of trade between themselves in the world (Hufbauer and Brunel, 2008) despite having ties with one another dating back to at least 3000 years before Christ. While Algeria, 38 Morocco, and Tunisia have a high potential for pharmaceutical development, historically, this development has been limited by barriers in the pharmaceutical regulatory system that mirror those in the economic sector (Finaish and Bell, 1994). Countries in the region recognize the benefits of removing barriers that hinder rapid medical product access, but until recently, these efforts were largely directed at streamlining national regulatory processes rather than promoting regional harmonization (Merimi, 2018). In Morocco, Decree No. 2-14-841 on Marketing Authorization of Medicinal Products for Human Use was implemented in early 2016. A key benefit of this procedure was the introduction of the “recevabilité” step, which is much like the dossier validation done in Europe prior to the acceptance of a dossier. Unfortunately, this procedure was not adopted across the region. The Agency also implemented goals around review times. Tunisia put process improvements in place to verify dossier completion prior to review with the implementation of its Guidelines Related to Registrations and Variations in 2016. Algeria launched an independent agency for pharmaceuticals, the Agence Nationale des Produits Pharmaceutiques in early 2017 with a promise that this new agency would streamline registration processes; however, it may be too early to see whether this aspiration is being realized. In the last few years, however, explorations of regional harmonization have begun. Key stakeholders came together at the First Regional Conference for Regulatory Harmonisation in Maghreb in early 2018 to discuss how barriers to drug development could be addressed. Harmonization was a major theme because regulatory cooperation was recognized to encourage work-sharing. Further, the regulatory guidelines of Algeria, Morocco, and Tunisia are aligned with the WHO, ICH, and EMA guidelines. This could 39 simplify their ability to rely additionally on the reviews and approvals from countries with SRAs without changing the existing legal framework of the Member States. All three regulatory authorities recognized the value of using input from the regulatory reviews of SRAs, but concerns lingered regarding the need to preserve national sovereignty. As Yacine Sellam of the Pasteur Institute in Algeria stated, “Automatic recognition of approvals is not possible but abridged evaluation could be an option in the future for Algeria.” (Merimi, 2018). At this time, no additional conferences for drug regulatory harmonization in the UMA have been announced. 2.5.3 Regulatory Harmonization in the Intergovernmental Authority on Development (IGAD) Regional Community The Intergovernmental Authority on Development (IGAD) was created in 1996 to represent the interests of member countries in the region of Eastern Africa (IGAD, 1996). IGAD built on the success of the Intergovernmental Authority on Drought and Development, which was instituted in the mid-1980s to address the multiple natural disasters that had plagued the region. In 2016, the IGAD Member States initiated the IGAD Medicine Regulatory Harmonization program with a mandate to strengthen NMRAs and fortify partnerships between IGAD Member States (Owusu-Danso, 2019). Under the IGAD-MRH Project, IGAD developed common requirements that would increase standardization and improve the quality of submitted data used to base registrations, in order to use resources in a more efficient and collaborative way (IGAD, 2020). The current focus of the IGAD-MRH program is to enhance training and procedures related to Good Manufacturing Practices (GMP) and Quality Management 40 Systems (QMS). The program also attempts to create a system for joint inspections of drug manufacturing sites and a roadmap to implement QMS based on nationally or internationally recognized standards. While IGAD aims to assure the timely dossier review and approval of essential medicines, most NMRAs in the region still struggle with a chronic shortage of human and technical resources, mainly due to budgetary constraints (IGAD, 2018). 2.5.4 Regulatory Harmonization in the Community of Sahel-Saharan States (CEN- SAD) The Community of Sahel-Saharan States (CEN-SAD) is one the of largest geographic blocs to be formed in Africa. In 1998, six countries, Burkina Faso, Chad, Libya, Mali, Niger, and Sudan, founded the trade bloc, but since that time it has grown to 29 Member States. The primary goal of the community is to promote the economic, cultural, political, and social integration of its members. However, many of the CEN- SAD Member States belong to other overlapping customs unions whose activities and degrees of integration are more advanced. Thus, it is likely that the regulatory harmonization efforts of the CEN-SAD bloc will not go forward intact because its members are making more progress under competing blocs (Reuters, 2007). 2.5.5 Regulatory Harmonization in the Economic Community of West African States (ECOWAS) Even before any MRH initiatives were conducted in West Africa, the WHO performed an assessment of regulatory capacity. The assessment showed a system characterized by heterogeneous laws and regulations, variability of NMRA capacity, and an absence of a mutually recognized legal framework (Kamwanja et al., 2011). 41 In 2018, the ECOWAS launched its Medicines Regulatory Harmonization program, which was endorsed by all fifteen participating countries (Burkina Faso, Mali, Niger, Nigeria, Ghana, Côte d’Ivoire, Senegal, Togo, Benin, Cape Verde, Guinea, Guinea-Bissau, Sierra Leone, Liberia, and Gambia). This new program draws on experiences from the EAC-MRH program, with similar aims, to develop and implement harmonized product registration requirements, guidelines, and standards first, and then eventually to encompass all regulatory functions. 2.5.6 Regulatory Harmonization in the Economic Community of Central African States (ECCAS) Harmonization efforts in the Economic Community of Central African States (ECCAS) started in 2013 with the adoption of common pharmaceutical policy by Member States of Angola, Burundi, Cameroon, Central African Republic, Chad, Congo, Democratic Republic of the Congo, Equatorial Guinea, Gabon, Rwanda, São Tomé, and Principe. Three years later, the group completed a gap analysis to establish the status of regulatory systems in these countries and provided this information to the AMRH project development process. This activity culminated in the formation of a Steering Committee for the implementation of the MRH Project in November 2016 with a goal to provide oversight in the implementation of joint activities. The ECCAS has joined the AMRH initiative, although it is still premature to report any progress (Ndomondo-Sigonda et al., 2020). 2.5.7 Regulatory Harmonization in the COMESA Comprised of Burundi, the Comoros, the Democratic Republic of Congo, Djibouti, Egypt, Eritrea, Ethiopia, Kenya, Libya, Madagascar, Malawi, Mauritius, Rwanda, Sudan, Swaziland, Seychelles, Uganda, Zambia, and Zimbabwe, the COMESA 42 was established in 1993 by the COMESA Treaty (Southern African States, 1993) to create a free trade region. In 2008, the Member States of COMESA, the EAC, and the SADC agreed to merge to become a single free trade area; however, this merger is not yet complete due to unresolved trade-related issues. Thus, they are still operating somewhat independently from a drug regulatory standpoint. 2.5.8 Southern African Development Community (SADC) Medicines Regulatory Harmonization Project The SADC region currently consists of fifteen countries, including Angola, Botswana, Democratic Republic of Congo, Lesotho, Madagascar, Malawi, Mauritius, Mozambique, Namibia, Seychelles, South Africa, Swaziland, Tanzania, Zambia, and Zimbabwe. Originally called the Southern African Development Coordination Conference (SADCC), the SADC is thought by many to have come from the “political alliance” of countries in southern Africa that fought against white oppression in the 1970s. Economic instability has led to a disproportionate reliance on donor funding in most of the region (Hwang, 2007). Further, this group has been identified to have organizational challenges related to poor communication and lack of cohesion among members, so the SADC Pharmaceutical Programme was created in 1999 to facilitate disease management with a focus on HIV/AIDS, tuberculosis, and malaria (Kamwanja et al., 2010; SADC Secretariat, 1993). Subsequently, the SADC established the Medicine Registration Harmonisation project in 2011. A 2012 study (Narsai, Williams, and Mantel-Teeuwisse, 2012) evaluated barriers to regulatory harmonization within the SADC region through the eyes of 33 representatives of pharmaceutical companies in South Africa with a presence in other SADC countries. The results suggested that resource limitations hampered access to high- 43 quality medicines. Pharmaceutical companies were also reluctant to export their products to certain countries because of their dissonant requirements and costs to secure registration, retention, and inspection. Approximately 82% of pharmaceutical company respondents were proponents of harmonizing legislative frameworks for drug regulation and led the authors to recommend that the SADC region harmonize legislative and regulatory requirements as soon as possible. Within the SADC Medicine Registration Harmonisation project framework, the SADC Ministers for Health and Ministers for HIV and AIDs streamlined the SADC Regional Registration Guidelines to conform to international standards (ICH, WHO and FDA) in 2015 (Mushayi, 2019). In 2015, the SADC-MRH program was launched under the name ZAZIBONA, which is discussed more fully in the next section. In the last five years, this initiative has completed some key harmonization deliverables, such as the development of the SADC Medicines Regulatory Strategic Framework 2015-2020, regional guidelines for drug registration, adoption of the CTD format, and the establishment of a robust collaborative procedure for medicines registrations between four SADC countries (Zambia, Zimbabwe, Botswana, and Namibia). The ZAZIBONA initiative has evaluated 154 product applications as of October 2019 (Owusu-Danso, 2019). Since the adoption of the ZAZIBONA initiative, multiple aspects of regulatory harmonization have been implemented, such as work-sharing in the form of joint dossier assessments and manufacturing facility inspections. Challenges still remain in the harmonization of labeling requirements, which has adversely affected the accessibility of essential medicines for patients. Changes to regulations to remediate this issue were estimated to be achievable in less than four years (Mushayi, 2019). 44 2.5.9 ZAZIBONA Regulatory Harmonization Project With technical support from the WHO Prequalification team, the ZAZIBONA process is a collaborative registration procedure among fourteen SADC countries whose national regulatory authorities jointly evaluate medicines for registration purposes. The word “zazibona” means “look to the future” in the Nyanja language of Zambia. It is also the word formed from the first two letters of each of the founding participating countries. Established in 2013, the goal of the ZAZIBONA process is to improve the availability of appropriate and quality medicines using a work-sharing model for dossier review and inspection of testing and manufacturing facilities (Luthuli and Robles, 2017). Currently nine participating countries, Zambia, Zimbabwe, Botswana, Namibia, South Africa, Democratic Republic of Congo, Mozambique, Malawi, and Tanzania have active member status. The other seven Member States are not active participants in dossier assessment but are involved in training programs and information sharing on products approved through the collaborative procedure. Ultimately, the goal is for all SADC countries to participate actively in the program. Like the Centralized Procedure in Europe, a product that has been approved by the ZAZIBONA process gains marketing authorization in all participating countries. The ZAZIBONA process was endorsed by the SADC Ministers of Health & Ministers Responsible for HIV & AIDS in November 2013 (Lahlou, 2016). The SADC guidelines for the registration of medicines and the use of a CTD format are based on the EAC Model. Additional work was being done to adapt the GMP and QMS standards as well. 45 In 2017, the ZAZIBONA initiative evaluated 179 product applications with a final decision reached for more than 90 products and a mean time to recommendation for registration estimated to be nine months (Ndomondo-Sigonda et al., 2018). 2.5.10 Regulatory Harmonization in the East African Community (EAC) The EAC is one of the oldest regional blocs in Africa, formed by the countries of Burundi, Kenya, Rwanda, South Sudan, Tanzania, and Uganda. It is the only REC that aspires to become a political federation (Tharani, 2017). Its population of 172 million people (East African Community, 2020) represents approximately 14% of the African populace (Sillo, Kisoma, and Zweygarth, 2016). For most, life expectancies are well below the global average. Of its members, only Kenya is not considered to be a low- income country because its economic base is diversified, and most political and economic systems are stable. However, the economy of EAC is expanding despite the challenges of high poverty rates, unemployment, and low levels of infrastructure and industrialization. The EAC is an important REC to understand more fully both because it has prioritized regulatory harmonization and it has an influential reach in this regard throughout Africa. Therefore, its history gives insight into the unique challenges that the region has faced. Cooperation between countries occurred as early as in 1905 when Kenya and Uganda established a common currency. In 1917, a Customs Union was formed to allow free trade between Kenya and Uganda, and a decade later with an additional member, Tanganyika. Kenya and Uganda were united by postal and telegraph services in 1924 and railways in 1926. Tanganyika linked into these services in 1933 and 1948, respectively. 46 Throughout the 1920s, the concept of further unification of the East African countries was deliberated (Great Britain, 1930; Malinowski, 1929; Secretary of State for the Colonies, 1925; Wilson, 1929), but little progress was made. It was not until World War II that the British Governors of Uganda, Tanganyika, and Kenya coordinated efforts to make the region as self-sufficient as possible to cope with the unreliable supply of food and other imports caused by the war (Banfield, 1963). Once hostilities ceased in 1945, Africans attending the Fifth Pan African Congress demanded decolonization across the continent, and the conference reflected the new militant leadership in Africa that vowed to make colonial liberation a reality (Padmore, 1963). As European powers struggled with the crippling costs of rebuilding Europe, they could no longer afford the costs associated with maintaining control of their colonies. As a result, numerous territories saw a forward path to independence. Between 1 January 1948 and 9 December 1961, the British Governors of Uganda, Kenya, and Tanganyika created the East Africa High Commission to coordinate the postal network, telecommunications, railways, and ports. The East African Common Services Organization (1961-1967) was subsequently led by the member countries as they demanded autonomy from Britain. The EAC was first instituted in 1967 but dissolved a decade later. Three of its members, Kenya, Uganda, and Tanzania, came back to the table to develop a Mediation Agreement in 1984 (East African Community, 1987) that encouraged the exploration of future integration. Over the following decade multiple agreements were developed. An “Agreement for the Establishment of the Permanent Tripartite Commission for East African Cooperation” was established in 1993. It presaged a subsequent agreement in 1999 establishing the Permanent Tripartite Commission for the East African Cooperation 47 Treaty (East African Community, 2007) and the subsequent reorganization of the EAC by Kenya, Tanzania, and Uganda. The EAC added the Republics of Rwanda, Burundi and South Sudan over the next decade and a half. While the roots of regulatory harmonization in the EAC arise from the strong influences and precedent example set by Europe, differences in the legal, political, and socioeconomic context of the EAC required that harmonization activities had to be modified. The powers of the EAC were not differentiated explicitly from those of its participating members as they are in the EU. Because many countries did not have the resources to conduct some activities at the national level, the partner countries permitted the EAC to make policies, enact legislation, make regulations, issue directives, and make recommendations to advance the objectives of the collective group (Binda, 2017). Drug harmonization could not wait for political reorganization, so the WHO stepped in to accelerate the pace of harmonization by developing an assessment methodology that could evaluate the member countries according to criteria considered to be critical for effective regulation. This assessment procedure has since been used in other regions as well. Initially, only the National Authorization Procedure was available for product approval in this region. The WHO recognized that this would challenge harmonization because each participating country had its own national laws that had to be satisfied in addition to requirements imposed by the harmonized procedure. Further, each NMRA differed in its institutional capacity, infrastructure, and drug registration requirements (Kamwanja et al., 2010). The assessment concluded that the EAC partner states had sufficient coverage of all required activities, although the capacity and experience varied 48 significantly between countries (Sillo, Kisoma and Zweygarth, 2016; World Health Organization, 2014). In 2011, the World Bank set up the Global Medicines Regulatory Harmonization Multi-Donor Trust Fund with funding from the Bill & Melinda Gates Foundation to initiate and scale up regulatory harmonization activities. The EAC was the first REC to receive support through the Global Trust Fund. The EAC Medicines Registration Harmonization (EAC-MRH) project mirrored the Mutual Recognition pathway used in Europe. Established in 2012, the EAC-MRH project includes harmonized guidelines, requirements, and standards for GMP, MER, and QMS that were put in place as early as 2014. Member state NMRAs in conjunction with the WHO and other stakeholders began joint dossier assessment as early as 2015 (Owusu-Danso, 2019). The EAC initiative incorporated a common document package, risk-based approaches to resource utilization, joint dossier assessments, and manufacturing inspections, and the creation and use of information sharing systems (East African Community, 2014; NEPAD, 2016). It established a framework to mutually recognize regulatory decisions based on Chapter 21, Article 118 of the East African Community Treaty (NEPAD, 2016) that aimed to harmonize technical requirements, information management systems, and QMS in each country to build the regulatory capacity needed for regional harmonization (African Press Organization, 2012). Further, its longer-term goals were to construct a platform for information sharing and expand a framework for mutual recognition of regulatory decisions. These efforts required that the countries expand their regulatory capabilities to carry out the harmonization initiatives. To 49 accomplish these goals, additional funding was provided through national governments to offset the incremental staffing required for institutional strengthening. The EAC-MRH program has two parts. The first component addresses regional organization and regulatory capacity building by developing standardized procedures and an agreement on best practices for capacity building. In September 2014, the EAC-MRH approved harmonized guidelines for product registration, the implementation of the CTD, the requirement for GMPs, and a Quality Management System best practice. The guidelines for these topics were launched in January 2015. The second component was directed at hiring and training staff for the newly established NMRAs in the areas of project management, quality assessments, safety assessments, and GMP inspections. Funding was also available for in-country workshops and consultations, consultant support, and supply of Information and Communication Technology equipment and software. The EAC-MRH procedure allows each member country to use its own procedure for the approval of medicines under its National Authorization Procedure, although EAC harmonized guidelines are used for product registration. This is because the EAC does not have a regional regulatory agency that can legally issue marketing authorization of drug products; the national procedures only permit approvals in the country where the submission had been submitted. The National Authorization Procedure builds on the approval procedures from the individual country. The EAC Joint Assessment may be used when registration is desired in two or more participating countries. Because the participating countries have different 50 capabilities and capacities, the procedure pairs a well-developed NMRA with a less developed one to build evaluator capacity to ensure consistent reviews. Prior to the deployment of the EAC-MRH process, the EAC participating countries also jointly reviewed product dossiers that had been submitted to the individual countries as well as dossiers that had been submitted for the WHO Prequalification. The purpose of this activity was to not only use actual dossiers to harmonize on review practices, but also to accelerate approval of medicines by performing assessments on dossiers that were awaiting regulatory review. For the initial pilot, some reviews showed a two-month improvement from the typical 18-month review period, and products in some participating countries were approved in only 7 months (Dansie, Odoch, and Årdal, 2019). To build capacity efficiently, the EAC initiative leveraged the WHO-developed data collection tool as an objective means to evaluate their regulatory systems and monitor their progress. As a result of the capacity building exercises, draft regulatory tools and guidelines have been developed, joint manufacturing inspections are being carried out, and a knowledge database has been set up in conjunction with the WHO that contains information on regulatory guidance and standards (Sillo, 2016). The WHO has also assisted in linking the EAC with the ICH Global Cooperation Group to enable the EAC to participate in ICH meetings. As of 2016, the EAC Joint Assessment Procedure had received 32 applications. Of these, the NMRAs had assessed 27, resulting in four product registrations (Sillo, 2016). The EAC-MRH committee estimates that the evaluation procedure was completed 51 30 - 40% faster than the national procedures would have taken, resulting in significant cost and time savings (Sillo, 2016). In addition, the EAC-MRH completed joint GMP inspections of nine manufacturing facilities between 2015 and 2016 (Sillo, Kisoma and Zweygarth, 2016). As discussed in an earlier section, in 2016, the EAC also instituted the African Union Model Law on Medical Products Regulation. This law is based on the WHO recommendations and international safety and quality standards and is expected to increase the speed of medicinal product registration by providing a guide to the member countries for regulatory harmonization. Each member country can adopt this law and repeal any local legislation that that creates inconsistencies with the harmonized guidelines. This is an important landmark of the implementation phase of the AMRH initiative across Africa (Arthur, 2019). 2.6 The WHO Collaborative Registration Procedure One of the newest of the specific initiatives to develop harmonization models in Africa has been that initiated by the WHO. This initiative, called the “Collaborative Registration Procedure”, is the approach that will be specifically studied in this research; therefore, it has been described below in some detail. 2.6.1 History of the WHO The WHO was created in 1948 to coordinate health initiatives amongst countries of the United Nations. Initially, it worked with member countries to study and manage important public health threats, including not only such generalized health issues as nutrition and sanitation, but also the treatment of prevalent diseases such as malaria and tuberculosis. Its initiatives emphasize resource sharing amongst resource-limited 52 countries to improve access to pharmaceutical products, according to its Medicines Strategy (World Health Organization, 2013a). The WHO can receive requests to initiate a new project or develop a new standard from many sources. As a project manager, it then manages the progression of these projects by consulting with the WHO Member States, national and regional authorities, international agencies and specialists from industry, national institutions, and nongovernmental organizations (Lezotre, 2014b). The WHO also participates in capacity building by acting as an information broker and technical support provider to align resource-limited countries incrementally with the international “gold-standards”. 2.6.2 Prequalification of Medicines Program One of the most notable of the WHO’s accomplishments in the medicines sector is the WHO Prequalification Procedure, which has been responsible for bringing important medicines to multiple resource-limited countries. Its formation was driven by the AIDS/HIV epidemic in Africa that illuminated the shortcomings of the healthcare systems. The prevalence of locally purchased medicines of poor quality led outside entities that were funding the drug acquisitions to demand a process to stretch their investments as far as possible without compromising medicine quality (Smid and Zweygarth, 2014). In 2001, the WHO formed a partnership with UNICEF, UNAIDS, and the United Nations Population Fund and obtained support from the World Bank to establish the Prequalification (PQ) of Medicines Program (PQP) (World Health Organization, 2013c). Originally designed for UN procurement, the PQP was initially set up to assure that high- 53 quality medicines would be available for HIV/AIDS, but quickly expanded to meet similar drug needs for other diseases, such as tuberculosis and malaria. It also enlarged its scope to encompass vaccines and in-vitro diagnostic products. The PQP helps to assure product safety and efficacy by providing a transparent, scientifically robust quality assessment of the low-cost generic drugs, vaccines, and In- vitro Diagnostics (IVDs) that were becoming increasingly available in resource-limited countries. It was created as an alternative to costly registration by SRAs, although the output of the process is not drug registration. The PQP operates as a centralized process using multinational teams composed of in-house and external assessors (mostly from SRAs) to spare individual countries from having to perform individual assessments (Figure 5). However, it then leaves the drug registration itself to its individual partners. The assessment starts when the WHO solicits an Expression of Interest for certain selected medicines. Only products listed as essential medicines or that are recommended by the WHO treatment guidelines can be prequalified (World Health Organization, 2021c; World Health Organization, 2011). Sponsors of individual brands then provide either product dossiers developed specifically for this purpose or marketing application dossiers that have been submitted to SRAs that are accompanied by the SRA Assessment Report. A multinational team performs a dossier review, a performance assessment and if appropriate, site inspections, using the WHO, ICH, and specific PQP guidelines as well as the standards in the International Pharmacopoeia and other pharmacopoeias to ensure consistency. 54 By making the assessments transparent and augmenting the assessment program with extensive training programs, the PQP allows individual countries to focus their valuable resources on more specialized issues important to promoting healthcare in their jurisdictions. The program is voluntary and minimal fees have been assessed to sponsors for the use of the service since 2013. Figure 5: The WHO Prequalification Process In 2001, the WHO PQP process was endorsed by the Interagency Pharmaceutical Coordination group, an organization of senior pharmaceutical advisors of all UN Agencies. In 2002, the WHO published its first list of 41 approved HIV/AIDS antiretroviral therapy (ARV) medications. Program goals achieved as stated by the WHO are provided in Table 2 (World Health Organization, 2019a). The PQP program has been remarkably effective in supporting access to medicines of high-quality in developing countries ('t Hoen et al., 2014). As of 2019, the WHO PQP has prequalified over 1600 55 products (World Health Organization, 2019b) and, in 2012, over 80% of the 8 million people receiving treatment for HIV/AIDS received the WHO-prequalified ARVs (UNAIDS, 2012). Table 2: Goals Achieved by PQ Program Improved public health outcomes and value for money through quality assurance of generic medicines, which has stimulated price competition and as a result enabled more medicines to be procured with the funds available so that millions more patients suffering from HIV/AIDS, tuberculosis or malaria can be treated. About 70% of the WHO-prequalified medicines are generic. Increased uptake of medicines designed specifically to meet low-income country needs including pediatric formulations for HIV/AIDS, tuberculosis (TB) and malaria, combination therapies to prevent HIV transmission from mothers to their newborns, affordable antimalarials, and second-line medicines for drug- resistant HIV and TB. Strengthened regulatory capacity in low-income countries (LIC) by providing professional development and training for their national medicine regulators, and opportunities to participate in innovative regulatory initiatives. Developed an effective mechanism that significantly reduces registration time for prequalified finished pharmaceutical products (FPPs) that helps minimize the time it takes to get medicines to those who need them. (A similar procedure is now being piloted for medicines with Stringent Regulatory Authority approval). Improved capacity to manufacture FPPs and active pharmaceutical ingredients to international standards by providing effective feedback and guidance during Prequalification evaluation and organizing training and technical assistance. The improved capacity is applicable not only to the FPP or Active Pharmaceutical Ingredient (API) that has been submitted for evaluation but to any FPP or API that the manufacturer produces. Increased the availability of medicines testing services through Prequalification of Quality Control Laboratories (QCLs). Prequalified QCLs now exist in every WHO geographic region and are able to work together with their national medicines regulatory authority to monitor the quality of medicines on the national market, be these manufactured locally or imported. 2.6.3 Collaborative Procedures for Accelerated Registration Although the WHO Prequalification Procedure facilitates the procurement of pharmaceutical products, it does not directly improve the lengthy methods used by 56 NMRAs to register pharmaceutical products. Thus, the WHO has developed a two- component program called the “Collaborative Procedures for Accelerated Registration” (CRP). 2.6.3.1 Component 1: CRP-PQP The first component, the Accelerated Registration of Prequalified FPPs (CRP- PQP), facilitates the national registration reviews of WHO-prequalified pharmaceutical products. The process was created after a WHO assessment of regulatory systems in 26 sub-Saharan African countries concluded that few NMRAs effectively used the WHO PQP to improve their registration processes. The CRP-PQP process starts when the applicant supplies the dossier of the prequalified medicine that is listed on the WHO Prequalification website. In parallel, the applicant gives the participating NMRAs permission to access the WHO’s assessments. The NMRA then has 90 days to decide whether the WHO assessments are applicable for this program. Finally, the NMRAs decide whether the product will be approved for sale in their respective countries (Figure 6). The program can support applications for national registration of any FPP that has been successfully assessed for WHO Prequalification and has WHO-prequalified status. It is a voluntary program that accelerates registration timelines and conserves regulatory resources by improving information sharing between NMRAs and the WHO Prequalification of Medicines Program (PQP) (Ndomondo-Sigonda and Ambali, 2011). Over 40 countries around the world, including over 12 countries in Africa, participate in this program (World Health Organization, 2021d). 57 Figure 6: The WHO Collaboration Registration Procedure Process NMRAs may decide how to use any information provided by the PQ Process in their own registration assessment or even if the procedure should apply to a dossier that they receive. Rarely, an NMRA may decline to apply the procedure because the FPP does not conform with specific national treatment recommendations, or the FPP evaluation by the NMRA is already well advanced, so that the NMRA prefers to complete registration conventionally through its national route. The WHO recommends that the NMRA verifies essential data to ensure that the FPP under review is the same as the prequalified product. If an NMRA chooses, the NMRA’s own independent conclusions after its review can be compared with the WHO Prequalification outcomes (as described in the assessment and inspection reports) for training or other purposes. The NMRA may also provide their own assessment with special attention to specific aspects of the product that may be especially relevant to the 58 local population or to the national context. If the assessment of the NMRA differs from the PQ assessment, it should provide the reason to the WHO. Differences in product name, name of the applicant/registration holder, data format, language, level of detail related to product information, or details of package labeling can be acceptable deviations if they do not affect product quality. However, no deviations would be expected in other aspects: the manufacturing chain; processes and controls of materials and final product; specifications of active pharmaceutical ingredient and finished product; or the elements in the drug profile including its indications, contraindications, dosing, special warnings and precautions for use, adverse drug reactions, storage conditions and shelf-life limitations (World Health Organization, 2013b). 2.6.3.2 Component 2: CRP-SRA The second component of the WHO Collaborative Registration Procedure is the Accelerated Registration of FPPs Approved by SRA process (CRP-SRA). The program was piloted in 2013, and then converted into a final program in 2018. The program was created for sponsors who wish to register in countries that participate in the program by leveraging the regulatory review and/or inspection for an FPP already accepted by a globally recognized NMRA, such as the US FDA or EMA. The program follows a similar process as that defined in the CRP-PQP process for collaborative registration, but instead relies on assessments conducted by SRAs that are accessed confidentially by the NMRAs. The process is designed to augment the CRP-PQP process by providing a voluntary, alternative pathway to facilitate product registration. Voluntary participants of the program include Botswana, Burkina Faso, Burundi, Cameroon, Caribbean 59 Community, Côte d'Ivoire, Democratic Republic of the Congo, Ethiopia, Georgia, Ghana, Kenya, Malawi, Mali, Mozambique, Namibia, Nigeria, Senegal, Sierra Leone, Tanzania, Uganda, Zambia, and Zimbabwe. (World Health Organization, 2021e). Through the SRA-CRP, the drug manufacturer provides the assessment and inspection outcomes from a consenting SRA. The participating health authorities in Africa use that documentation to support their decisions regarding registration as shown in Figure 6, but the evaluation process itself is unchanged. The WHO acts as an intermediary between the applicant, participating health authorities, and the SRAs. The WHO can also participate in a procedure if the WHO considers that the product under review will affect public health. By enabling NMRAs to use the previously performed evaluations and inspections, some work is not duplicated, and approvals can be faster. Its goal is to help NMRAs to decide on registration within 90 days after completing the validation process. The procedure does not include any risk management plans or pharmacovigilance follow-up. No fee is paid to participate in the procedure. However, the usual registration fees associated with registration at the national level will be levied by the NMRAs unless they are waived. Ten MRAs participated in the pilot phase which started in the latter half of 2012 and this was expanded to fifteen African countries by early 2014 (Smid and Zweygarth, 2014). As of October 2018, six products were approved in 42 countries under the CRP- SRA pilots. During the pilot, participating NMRAs appeared to communicate more, especially regarding the practices that they used during document review. It also became clear that SRA reports often lacked certain types of information appropriate for some resource-limited settings, such as Zone 3 and 4 stability data, or special studies done after 60 the SRA approval to evaluate the clinical aspects of the drug in specific demographic populations (Caturla Goñi, 2016). Further, the assessment and approval time was reduced from several years to an average of 78 days (World Health Organization, 2016). Overall, the reaction to the program were positive. William Wekwete, the Head of Evaluations and Registrations Division of the Medicines Control Authority stated: “The PQP Collaborative Procedure was a relief for us in Zimbabwe. … From the pilot phase we established that approval within 90 days is doable. … The procedure allows us to save our meagre resources and focus them on risky products which have not been subjected to rigorous PQP quality assurance.” (World Health Organization, 2013c). Participants in the pilot phase program were queried about their experience and provided some suggestions for improvement, such as highlighting the need for additional regulatory training for sponsors from low- and middle-income countries, using abridged dossiers to reduce the workload, and reminding applicants of the need to keep the regulatory status and documentation synchronized between the WHO-CRP countries and the SRAs quality (Smid and Zweygarth, 2014). As of January 2020, 43 NMRAs are using the process, including 29 NMRAs in Africa (World Health Organization, 2020b). The program has also been expanded to new programs that encompass diagnostics and vaccines (Azatyan, 2019). In recognition of the program’s impact, UNITAID recently expressed its support of the program (UNITAID, 2020): Today, the programme is widely recognized for having made an enormous contribution in terms of accelerating and increasing access to critical quality-assured products that are affordable and adapted for markets in low- and middle-income countries. This program illustrates well the WHO philosophy on harmonization and its beneficial outcomes for stakeholders. Manufacturers benefit because they can create and 61 use a single dossier for registration in multiple countries and that these dossiers may then move more quickly and predictably through the registration process. This also can simplify their post-registration maintenance. NMRAs from resource-limited countries can learn from assessors and inspectors of stringent NMRAs and thereby build in-country capabilities. National decisions are respected, but collaboration is encouraged. Most importantly, patients receive accelerated access to important and high-quality medications. 2.7 Research Approach and Evaluative Frameworks Regulators create regulatory systems to assure that patients can obtain the safe and effective drugs that they need. Despite good intentions, though, regulatory processes may not meet all the needs of the stakeholders that they serve. Thus, regulatory programs should be evaluated to assure that they are achieving their objectives. However, any such evaluation must be systematic and unbiased. Further, as stated by Brown: “The mere fact that there is widespread dissatisfaction with the performance of these new regulatory systems does not mean that there is also a consensus as to what the problems are” (Brown et al., 2006). Early approaches to the implementation and evaluation of regulatory harmonization programs relied upon experience, good science, and common sense (Eccles et al., 2005). More recently, multiple reviews of implementation research have consistently shown the value of formal program design (Carden et al., 2019; Roberts et al., 2016), evidence based implementation (Grol and Grimshaw, 1999; Riley et al., 2017) and program assessment frameworks (Deeming et al., 2017; Kahan, 2008) Therefore, a formal evaluation framework can provide a more balanced structure to evaluate 62 established programs and additionally can improve the credibility and use of the research findings (Eccles et al., 2005). Brownson suggests that an effective evaluation can answer questions about program needs, the implementation process, and outcome tracking to improve future programs (Brownson et al., 2010). Rossi notes that efforts to implement a program can fail because the intervention is insufficient, the intervention is inappropriate, or the intervention is not standardized or controlled when it is put into place (Rossi, 1987). Fixsen, a leader in the field of implementation science, also cautions that the program must be evaluated carefully for its effects on its intended recipients (Fixsen et al., 2005). Otherwise, the program may not achieve its intended outcomes. The WHO-CRP program described above has now been in place for several years, so it seems timely to gather the views of stakeholders regarding successes and limitations, so that future program implementations can profit from the lessons learned. As identified above, an evaluation of this type has been conducted to date by only one study, and that was directed early at the pilot WHO program rather than its later and larger subsequent approach. Many types of evaluation frameworks exist that could be used to examine programs such as that developed by the WHO. Each type has a different objective and/or approach, and some are better than others at assessing programs at different stages of maturity. Formative evaluations are typically done at early stages of program implementation to predict whether a program is likely to be feasible, effective, and meaningful for its intended use. In contrast, process evaluations examine how the program is being delivered, to understand whether and how a similar program might be 63 implemented in other situations (Thompson, Kegler, and Holtgrave, 2006). Other categories of evaluation frameworks include impact evaluations, which focus on whether the program objectives are being met and outcome evaluations, which are primarily used in the context of health and quality of life assessments. For this research, a program evaluation approach was selected because program evaluation frameworks focus both on the implementation of a program (Brownson et al., 2010) and also on the benefit the program provides. This approach may allow the results to inform the construction and implementation of future regulatory harmonization programs. From Kahan’s overview of the major program evaluation frameworks (Kahan, 2008), the CIPP Framework (Stufflebeam and Coryn, 2014) appeared particularly well- suited for assessing the implementation success of the WHO-CRP process because the framework takes into consideration the environment and context surrounding the program being evaluated. This is a particularly important feature because the stress imposed in the resource-limited setting is an important consideration in how the WHO-CRP program was developed and how it is carried out. Further, the use of a comprehensive evaluation framework, such as CIPP may produce a more credible, valid, and useful evaluation than more limited frameworks (Stufflebeam and Shinkfield, 2007). This framework has been used for over 60 years (Kahan, 2008), has been cited in almost 1000 publications and is versatile, having been used to evaluate a wide swath of programs from policies (Mashingia and Patel, 2017) to public health programs (Walden and Baxter, 2001) to educational instruction programs (Nicholson, 1989). By using this framework as a basis for questions to probe the perceptions and experience with those participating in the WHO-CRP process, the research is expected to evaluate the activities 64 and challenges of the WHO-CRP process implementation in an efficient and comprehensive manner. CIPP stands for context (of the program), input (into the program), process (within the program), and product (of the program). The framework was developed by Stufflebeam in the 1960s and is designed to guide evaluations at different stages of maturity from design to post-implementation. It supports the evaluator’s efforts to understand the program by looking at only four areas of focus as shown in Figure 7 (Mazur, 2013). In this research project, the evaluation will be achieved by using a survey of people who have had exposure to the WHO-CRP process, although interviews can also be used (Al-Khathami, 2012; Nicholson, 1989) (Table 3). 65 Figure 7: Four Components of the CIPP Framework “Context Evaluation” strives to understand the needs of stakeholders through a needs assessment so that goals and priorities can be set appropriately. It takes into account the constraints imposed by the external environment and can include limitations in human resources, funding and time, as well as cultural and historical considerations. Typically, this step can use interviews, conference workshops, or literature to understand what changes are needed that the program will address. Because this is a needs analysis, this step is typically done prior to the development of the program (Abbas, Nurbaya and Dkawa, 2018). Nevertheless, it continues to affect the success of a program going forward, and part of the assessment can evaluate whether the needs the program addresses are appropriate. 66 “Input Evaluation” is focused on the planning and development of the system that has been put into place to accomplish the goals defined in the Context Evaluation step to assess what changes are possible. It addresses the appropriateness of the program design. This step can use literature searches, familiarity with other programs, or ideas from experts to determine whether the design is practical. Further, it can provide guidance about what changes are possible and feasible (Nicholson, 1989). “Process Evaluation” is directed at understanding whether the process is working as planned. This step can be considered a process monitoring step and encompasses not only how closely the program adheres to the defined process, but also the functionality of the program from the perspective of the manufacturers who use the program to submit registration dossiers, the NMRAs who review the registration dossiers and the WHO overseers who designed and implemented the program. Since this step is carried out to ensure that the changes are being performed as intended and to identify issues with implementation, it relies on querying users of the process to understand the expected and unexpected results. “Product Evaluation” examines the perspectives of stakeholders to assess if the program has actually worked and has made a positive impact. Decisions can be made about whether the program should be continued, modified, or dropped by comparing the actual program outcomes with the expected outcomes. 67 Table 3: CIPP Framework Formative Summative Context Input Process Product Aim To assess needs, assets, and barriers to implementation To identify and assess program strengths and weaknesses, critically examine potential approaches and recommend effective strategies To ensure that the suggested changes are being carried out as intended and to identify problems in implementation by monitoring, documenting, and evaluating program activities To find out when the program had an impact by measuring, interpreting, and assessing process results, benefits, and validity Purpose Identify beneficiaries, group needs, obstacles for meeting needs, potential resources to address needs, and baseline goals Test potential solutions to choose the most appropriate process Determine whether the implementation is following the process plan and that the participants are correctly carrying out their roles Identify and document the desired and unwanted results of the program, including long-term outcomes Method Interviews, surveys, workshops, and analysis of the literature Conduct literature searches, prepare cost projections, assess pilot programs, and carry out evaluations of existing programs Interviews, surveys, workshops, and analysis of the literature Interviews, surveys Decision- Making To provide a basis for deciding what changes are needed To find where there is support for change and determine which solutions are feasible To help in fine tuning the program, provide data to interpret the impact of the change, and inform the development of new programs To decide whether the changes should be continued, terminated, or modified Key Questions Is the program missing important needs? Is the program addressing needs that don’t exist? Is the design too complex? Is the design practical? Are there steps that are not needed? Is the program responsive to the needs? What are the merits and issues? Is the program feasible? viable? How does the program strategy compare with others? Does the program meet the goals? Does the program design need modification? What identified issues can be overcome and how? Adapted from (Abbas, Nurbaya and Dkawa, 2018; Al-Khathami, 2012; Nicholson, 1989) The elegance of the CIPP Framework is that it is very flexible (Kozica et al., 2015) and can be used at different stages of a program’s lifecycle. The CIPP Framework can be thought of as being divided into a formative component, which encompasses the Context and Input Evaluation components and a summative component, which includes 68 the Product and Process Evaluation steps. The formative component can be done at the program development stages, whereas the summative component is generally more applicable after the program is implemented; however, the formative component can also be used to assess whether the program was designed appropriately. In this study, I used survey methods to gather evidence. The survey framework followed the CIPP approach. The research attempted to relate program activities to the aims of the program, such as the program’s ability to deliver a decision in a suitable amount of time, the participation level of program users, the level of satisfaction with the program by the users of the program and the efficiency of the program to provide a frame of reference for the development of the survey. The scope of this research project focused primarily on the Process Evaluation and Product Evaluation components of the framework to examine the functionality of the program and whether the program meets the needs of the key stakeholders but some information on all phases was sought. 69 Chapter 3. Methodology 3.1 Introduction The goal of this research was to examine stakeholder assessments of benefits and barriers pertaining to the use of a new WHO-CRP facilitated regulatory pathway in Africa. The study began with a literature review and was followed by an exploratory research survey. The literature review in Chapter 2 focused on developing a broad understanding of pharmaceutical harmonization and facilitated regulatory pathways, particularly in Africa. The survey development, deployment, and data collection methodologies are detailed below. 3.2 Creation of Survey 3.2.1 Development of the Survey Tool The survey tool was developed based on a previously described survey conducted in the SADC region by Calder (2016), whose approaches were extended and modified with information obtained from the literature review, and discussions with the research thesis committee from the USC International Center for Regulatory Science. As stated above, the CIPP Framework was selected to guide the selection of survey questions. The survey primarily focused on all four components of the CIPP, Context, Input, Process Evaluation and Product Evaluation. 3.2.2 Survey Population The survey engaged two distinct populations: NMRA and Industry. Two other groups were also captured: those who wanted to use the procedure but didn’t and those who did not use the procedure. 70 One panel of respondents was composed of NMRA reviewers, selected primarily from African countries that participate in the WHO facilitated pathway program. Throughout this document, this group is represented in purple. This panel of NMRA participants was selected to provide a view of the process from the perspective of those who must engage in reviews and approvals. A second panel consisted of product sponsors from small and large pharmaceutical manufacturers who had or planned to submit dossiers to support a product registration using the WHO-CRP. Throughout this document, this group is represented in blue. This panel provided the “user experience” perspective of the process. Respondents to the survey included regulatory professionals at various levels and positions, as well as consultants to companies who have participated in submission related activities. Additional experts and stakeholders from the WHO and other groups involved in structuring and facilitating the WHO-CRP harmonization efforts used in Africa were included to provide insight on obstacles and best practices from an oversight perspective. Appropriate individuals with familiarity with the WHO-CRP either known by me and expanded using snowball methods or identified through their LinkedIn ® profiles were approached to determine their willingness to participate in the study. In addition, some individuals known to write or speak about African harmonization efforts sought from relevant literature, professional meetings, and internet searches were asked to participate. Extensive searching was done to identify the rare individuals with sufficient experience with this procedure. Almost all survey candidates were individually contacted to explain the purpose of the research, describe the survey, and answer any questions. 71 3.2.3 Survey Development and Validation A focus group was used to provide greater insight into the topic and to refine and test the questions being considered for the survey. This group included participants selected based upon their knowledge of regulatory harmonization pathways and/or survey development. The survey was composed of approximately 30 questions for each group (NMRA and industry) and presented in various formats, such as multiple choice, matrix, scaled, rank order, yes/no, and open text-entry formats. The survey was designed to complete within 20 minutes. Open text boxes were included to capture any additional comments or related text from study participants. After the preliminary survey questions were defined, the focus group was provided a copy of the draft survey so that they could familiarize themselves with the content. The goal of the focus group was to assess each question and provide input on the applicability, wording, and suitability of the question. This assessment by the focus group helped validate the survey method. Focus group participants participated remotely via the internet because of travel restrictions imposed by the coronavirus epidemic. The focus group meeting commenced with a brief introduction to the study and survey, followed by a review of each question and a discussion to optimize the relevance, clarity, and information value of each question. All input from the focus group was recorded and considered as the survey was finalized. 3.2.4 Survey Deployment Once input of the focus group had been captured and the survey questions were finalized, the survey was reviewed to ensure survey functionality by three reviewers who were not involved in the study. A finalized version of the survey was provided to survey 72 participants in their choice of English or French through an open-access anonymous link distributed by email using the development and distribution platform, Qualtrics (http://www.qualtrics.com). The email from the Qualtrics Mailer included a brief message that briefly described the purpose and general approach to the study. Each participant was also provided with the option to decline to participate in the survey. The survey remained open to participants for approximately 6 weeks. Survey participation was anonymous. Respondents received a single reminder by email from the Qualtrics system to remind them to complete the survey. Results of the survey were stored electronically in the Qualtrics system. Survey questions are provided in Appendix B. 3.2.5 Survey Analysis Once the survey was closed to additional responses, the results were analyzed to identify trends. Data from binary questions (“yes/no”), multiple choice questions (single and multiple responses), and rank order scaling questions were graphed and analyzed with simple descriptive statistics and tables, as appropriate. Open-ended questions and text responses were evaluated for content and analyzed for patterns that might yield insights from study participants that may have not been fully captured from the more structured questions. Translation of comments from French to English was done by the author, as needed. 73 Chapter 4. Results 4.1 Survey Participation The survey was activated on 30 November 2020. Between 30 November 2020 and 11 January 2021, 800 subject matter experts were contacted from my personal network or based upon their LinkedIn ® profile and invited to participate in the survey (Figure 8). Based upon their responses, the survey was distributed to 459 individuals. In addition, the survey invitation was shared with the RAPS Regulatory Exchange and LinkedIn discussion group sites, resulting in 30 additional participants via an anonymous link. From all sources, 124 participants completed at least one question for a response rate of 27% (124/459). Of the 124 participants who completed at least one question, 93 participants completed the survey for a completion rate of 75% (93/124). Of those who did not complete the survey, 39% (12/31) dropped out after completing the last question of the demographic section. 1 Figure 8: Survey Responses 1 For ease of reviewing the survey responses in this chapter, NMRA responses are presented in purple and industry responses are presented in blue. 74 4.2 Demographic Profiles of Respondents The first set of questions collected demographic information, including the respondent’s span of responsibility (Figure 9), the primary location of the respondent’s employer (Figure 10), the size of their employer’s organization (Figure 11), the geographical scope of the organization with which they were affiliated (Figure 12), and the sector of their employer (Figure 13). Participants were asked whether they worked as either a single contributor, supervisor, or manager (Figure 9). Most were single contributors (42%, 49/116) or supervisors (43%, 50/116). A minority supervised one or more groups (15%, 17/116). Figure 9: Scope of Responsibility Most respondents reported that their employer (Figure 10) was located in Africa (62%, 72/117). Fewer employers were in North America (12%, 14/117), the United Kingdom and Europe (18%, 21/117), Asia Pacific (including India) (3%, 4/117), Middle East (4%, 5/117), or South America (1%, 1/117). 42% (49/116) 43% (50/116) 15% (17/116) 0% 20% 40% 60% I have no people reporting to me I supervise one or more individuals I supervise one or more groups of individuals Percent How would you classify your present role in your organization? 75 Figure 10: Primary Location of Employer Over 40% of the participants from Africa were employed by NMRAs (42%, 30/72) (Table 4). Industry participants were from North America (17%, 5/29), Europe and United Kingdom (24%, 7/29), Africa (52%, 15/29), and Asia (7%, 2/29). Most NMRAs were from Africa (81%, 30/37), but a few were from Europe and United Kingdom (8%, 3/37), or North America (11%, 4/37). Of those who considered using the WHO-CRP but did not, most were from Africa (67%, 10/15). Two participants were from Europe and United Kingdom (13%, 2/15) and one from North America, South America, and Asia Pacific (7%, 1/15). Most who did not consider using the WHO-CRP were from Africa (47%, 17/36) and fewer were from Europe and United Kingdom (25%, 9/36), North America (11%, 4/36), Asia Pacific (11%, 4/36), or the Middle East (6%, 2/36). 4% (5/117) 3% (4/117) 62% (72/117) 18% (21/117) 1% (1/117) 12% (14/117) 0% 20% 40% 60% 80% Other Middle East Asia Pacific Africa Russia United Kingdom and Europe South or Central America North America Percent What geographical area best describes your most recent employer's primary location? 76 Table 4: Participant WHO-CRP Experience by Location What geographical area best describes your most recent employer's primary location? Total North America South or Central America United Kingdom and Europe Africa Asia Pacific Middle East Have you either used or considered using the WHO-CRP in conjunction with a product registration in one or more African countries? Considered using the WHO-CRP, but did not 15 1 1 2 10 1 0 Manufacturer or consultant familiar with the WHO-CRP 29 5 0 7 15 2 0 Health Authority familiar with the WHO-CRP 37 4 0 3 30 0 0 Did not use or consider using the WHO-CRP 36 4 0 9 17 4 2 Total Count 117 14 1 21 72 7 2 Respondents were employed by companies across a full range of sizes (Figure 11), described in four categories: less than 100 employees (25%, 29/116); 101- 1000 employees (34%, 39/116); 1001-20,000 employees (13%, 15/116); and more than 20,000 employees (27%, 31/116). Two respondents did not know (2%, 2/116). Figure 11: Participant Organization Size 2% (2/116) 27% (31/116) 13% (15/116) 34% (39/116) 25% (29/116) 0% 10% 20% 30% 40% Don't know More than 20,000 employees 1001 - 20,000 employees 101 - 1000 employees Less than 100 employees Percent What statement best describes the size of your overall organization? 77 Participants were queried about the geographical reach of their employers (Figure 12). Half classified their organization as global (51%, 59/115); fewer classified their organization as either local (28%, 32/115), or regional (21%, 24/115). Figure 12: Geographical Scope of Employer Most survey respondents (Figure 13) were affiliated with NMRAs (27%, 32/117), or with manufacturers of generic or branded products (15%, 18/117; 32%, 38/117, respectively). A few were employed by CMOs (2%, 2/117) or non-government agencies (6%, 7/117), or were professional (7%, 8/117) or academic consultants (10%, 12/117). Figure 13: Primary Sector of Participant's Organization Participants were then asked whether they had used the WHO-CRP in one or more African countries and were given four options (Figure 14). Respondents in an 51% (59/115) 28% (32/115) 21% (24/115) 0% 20% 40% 60% Primary focus is global or international Primary focus is local or within country Primary focus is multinational or regional Percent How would you classify your company or organization? 10% (12/117) 7% (8/117) 6% (7/117) 27% (32/117) 2% (2/117) 15% (18/117) 32% (38/117) 0% 10% 20% 30% 40% Academia Contractor/Consultant/Agent Non-Government Agency Government Agency Contract Manufacturing Organization Manufacturer of Generic Products Manufacturer of Branded Products Percent What sector describes your current or most recent employer? 78 NMRA who became familiar with the WHO-CRP process by reviewing regulatory submissions (31%, 36/115) were directed to additional questions (Section 4.2.1). Respondents who worked with a manufacturer or as a consultant and became familiar with the WHO-CRP process by making a product submission (25%; 29/115) were also led to a similar series of questions regarding the use of the WHO-CRP process (Section 4.2.2). Participants who selected either “Considered using procedure but did not” or “Did not consider/consider process” were directed to a series of exit questions (12%, 14/115 and 31%, 36/115, respectively). Their responses are discussed in Section 4.6.1. Figure 14: Exposure to the WHO-CRP 4.2.1 NMRA Respondent Profiles Participants working at NMRAs were asked about the RECs in which they worked (Figure 15). Most of the participants were from the SADC (47%, 16/34) and EAC (35%, 12/34). Other RECs included AMU/UMA (9%, 3/34), COMESA (12%, 4/34), ECOWAS (9%, 3/34), and IGAD (12%, 4/34). This group represented all NMRAs of countries who use the WHO-CRP process actively. Six percent (2/34) of participants 31% (36/115) 31% (36/115) 25% (29/115) 12% (14/115) 0% 10% 20% 30% 40% Did not use/consider process Familiar with review process Familiar with submission process Considered using procedure, but did not Percent Have you used or considered using the WHO-CRP in Africa? 79 picked “other”. The number of responses exceeded the number of respondents because some respondents participate in more than one REC (Ndomondo-Sigonda et al., 2018). Figure 15: Geographical Distribution of NMRAs Approximately two-thirds of NMRA participants used the WHO-CRP most commonly to review prequalified generic products (68%, 21/31). The remainder (29%, 9/31) most commonly reviewed brand/proprietary products previously approved by a Stringent Regulatory Authority (Figure 16). One participant selected “other” (3%, 1/31), explained as an emergency use product. Figure 16: WHO-CRP Experience by Product Type: NMRA Responses 6% (2/34) 47% (16/34) 12% (4/34) 9% (3/34) 35% (12/34) 12% (4/34) 9% (3/34) 0% 10% 20% 30% 40% 50% Other SADC IGAD ECOWAS ECCAS EAC CENSAD COMESA AMU/UMA Percent In which Regional Economic Community are you working? 3% (1/31) 29% (9/31) 68% (21/31) 0% 20% 40% 60% 80% Other Brand name product Generic Product Percent What type of product(s) do you use the WHO-CRP to assess most frequently? 80 NMRA participants were asked about their breadth of experience with the WHO- CRP (Figure 17). About 70% had used the procedure to review more than three products (71%, 22/31), and about 20% (19%, 6/31) had reviewed 2 or 3 products. Only three respondents (10%, 3/31) used this procedure to review a single product. Figure 17: WHO-CRP Experience by Number of Reviews: NMRA Responses 4.2.2 Industry Respondent Profiles Industry participants were asked about their experiences with the WHO-CRP (Figure 18). More participants used it for proprietary product submissions (50%, 13/26) than generic submissions (42%, 11/26). Two participants selected “other” (8%, 2/26) and one of those users specified that the procedure was used for “vaccine”. 10% (3/31) 19% (6/31) 71% (22/31) 0% 10% 20% 30% 40% 50% 60% 70% 80% One 2 or 3 More than 3 Percent How many products have you reviewed using the WHO-CRP? 81 Figure 18: WHO-CRP Experience by Type of Product: Industry Responses Industry participants were also asked about experience with the WHO-CRP (Figure 19). More than a third participated in 2 or 3 submissions (42%; 10/24) or more than three submissions (25%, 6/24). Fewer participated in a single submission (33%, 8/24). Figure 19: WHO-CRP Experience by Number of Submissions: Industry Responses Over half of the participants had filed product submissions in the last 6 months (52%, 13/25) (Figure 20). Most of the others filed the submission between 12-18 months ago (16%, 4/25), 18-24 months ago (16%, 4/25), or 24-36 months ago (4%, 1/25). Three participants (12%, 3/25) participated in submissions more than 3 years ago. 8% (2/26) 50% (13/26) 42% (11/26) 0% 10% 20% 30% 40% 50% 60% Other Proprietary/brand product Generic product Percent What product category does your organization most frequently register using the WHO-CRP? 33% (8/24) 42% (10/24) 25% (6/24) 0% 10% 20% 30% 40% 50% 1 2 or 3 More than 3 Percent In how many submissions have you been involved using the WHO-CRP? 82 Figure 20: Time Since Last WHO-CRP Submission: Industry Responses 4.3 Context A “Context Evaluation” considers the constraints imposed by the external environment and includes the limitations in human resources, funding, and time, as well as cultural and historical considerations. 4.3.1 Need for Harmonization Participants were asked whether they felt that regional or joint regulatory harmonized procedures offered more advantages than national regulatory pathways. Both NMRA and industry groups agreed overwhelmingly (NMRA: 94%, 29/31; Industry: 96%, 22/23) that regional harmonized procedures offered an advantage over national pathways (Figure 21). Only one industry (4%, 1/23) and one NMRA (3%, 1/31) respondent answered “no” and one NMRA participant answered, “don’t know” (3%, 1/31). 12% (3/25) 4% (1/25) 16% (4/25) 16% (4/25) 52% (13/25) 0% 10% 20% 30% 40% 50% 60% More than 3 y 2 to 3 y 18 m to <2 y 1 y to < 18 m 6 m to < 1 year < 6 months Percent How long ago was your most recent experience using the WHO-CRP procedure? 83 Figure 21: Harmonized Pathway versus National Pathway: NMRA and Industry Responses Respondents from industry were then asked to choose up to three advantages of a regional/joint procedure versus a national pathway from a list of offered choices. Most selected the advantages of shorter time (NMRA: 76%, 22/29; Industry 68%, 15/22), better efficiency (NMRA: 93%, 27/29; Industry: 59%, 13/22), and transparency to the review process (NMRA: 72%, 21/29; Industry: 64%, 14/22) (Figure 22). Less commonly selected were fewer requirements (NMRA: 17%, 5/29; Industry 14%, 3/22) and the ability to leverage the dossier for other purposes (NMRA: 14%, 4/29; Industry 23%, 5/22). A few industry participants identified lower cost as an advantage (11%, 6/22). 3% (1/31) 3% (1/31) 94% (29/31) 4% (1/23) 96% (22/23) 0% 20% 40% 60% 80% 100% 120% Don't know No Yes Industry NMRA In general, do you think that regional/joint harmonized procedures offer more advantages than your national regulatory pathway? 84 Figure 22: Advantages of a Harmonized Pathway Versus National Pathways: NMRA and Industry Responses The responses to this question were stratified to capture differences between the views of generic versus brand manufacturers (Figure 23). Participants who classified themselves as “other” were not included in the stratified count. About the same percentage of generic and brand manufacturers selected shorter time (generic: 27%, 6/19; brand: 35%, 8/23) and lower cost (generic: 11%, 2/19; brand: 9%, 2/23). Generic manufacturers selected transparent process (generic: 42%, 8/19; brand: 17%, 4/23), better efficiency (generic: 37%, 7/19; brand: 17%, 4/23), and fewer requirements (generic: 11%, 2/19; brand: 4%, 1/23), more frequently than brand manufacturers. Brand manufacturers selected the ability to leverage the dossier for other purposes more frequently than generic manufacturers (generic: 5%, 4/19; brand: 17%, 4/23). 23% (5/22) 14% (3/22) 64% (14/22) 59% (13/22) 68% (15/22) 27% (6/22) 14% (4/29) 14% (4/29) 17% (5/29) 72% (21/29) 93% (27/29) 76% (22/29) 0% 20% 40% 60% 80% 100% Other Don't know Ability to leverage dossier for other purposes (reimbursement, etc.) Fewer requirements Transparency to the review process Better efficiency Shorter time Lower cost Percent NMRA Industry What advantages do you think that a regional or joint regulatory harmonized procedure will offer compared to a national regulatory pathway? 85 Figure 23: Advantages of a Harmonized Pathway Versus National Pathways: Generic versus Brand Manufacturer Responses Industry participants also provided their views on the advantages of a national pathway (Figure 24), compared to a regional or joint harmonized pathway. Advantages associated with the national pathway include its lower cost (27%, 7/26), shorter time (19%, 5/26), better efficiency (15%, 4/26), and fewer requirements (12%, 3/26). The ability to leverage the document for other purposes (8%, 2/26), the number of requirements (12%, 3/26) and transparency (4%, 1/26), were selected less frequently. Some advocates for the national procedure as an advantage did not know (15%, 4/26). 17% (4/23) 4% (1/23) 17% (4/23) 17% (4/23) 35% (8/23) 9% (2/23) 5% (4/19) 11% (2/19) 42% (8/19) 37% (7/19) 27% (6/19) 11% (2/19) 0% 10% 20% 30% 40% 50% Ability to leverage dossier Fewer requirements Transparent process Better efficiency Shorter time Lower cost Percent Generic Manuf Brand Manuf What advantages do you think that a regional/joint procedure will offer compared to a national pathway? 86 Figure 24: Advantages of National Pathways Versus Harmonized Pathways: Industry Responses The responses to this question were stratified to capture differences between the views of generic versus brand manufacturers (Figure 25). Brand manufacturers selected the shorter time (brand: 14%, 1/7; generic: 25%, 4/16), ability to leverage the document for other purposes (brand: 14%, 1/7; generic: 0%, 0/16), and transparent process (brand: 14%, 1/7; generic: 0%, 0/16) as advantages of a national process. Generic manufacturers more frequently selected lower cost (brand: 0%, 0/7; generic: 31%, 5/16), better efficiency (brand: 0%, 0/7; generic: 25%, 4/16), and the number of requirements (brand: 0%, 0/7; generic: 19%, 3/16). Some advocates for the national procedure as an advantage were not aware of the advantages of this procedure relative to the regional procedures (regional: 0%, 0/56, national: 17%, 4/24). 15% (4/26) 8% (2/26) 12% (3/26) 4% (1/26) 15% (4/26) 19% (5/26) 27% (7/26) 0% 5% 10% 15% 20% 25% 30% Other Don't know Ability to leverage dossier Fewer requirements Transparent process Better efficiency Shorter time Lower Cost What advantages do you think that a national pathway offers compared to a regional/joint harmonized procedure? 87 Figure 25: Advantages of National Pathways Versus Harmonized Pathways: Generic versus Brand Manufacturer Responses 4.3.2 Barriers to Harmonization NMRA participants were asked to identify the most significant barrier to regulatory harmonization in their region (Table 5). Comments were then classified according to CIPP class and category. Most comments noted political barriers to harmonization. Procedural challenges, such as training, were also mentioned frequently. 57% (4/7) 14% (1/7) 14% (1/7) 14% (1/7) 25% (4/16) 25% (4/16) 19% (3/16) 31% (5/16) 0% 20% 40% 60% Don't know Other Better efficiency Transparent process Shorter time Ability to leverage dossier Fewer requirements Lower cost Percent Generic product Proprietary or brand name product What advantages do you think that a national (single country) regulatory pathway will offer compared to a regional or joint regulatory harmonized procedure? 88 Table 5: Barriers to Regulatory Harmonization: Selected NMRA Opinions What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? CIPP Category Comment Context Political All countries to have legislations and capacitated regulatory authorities Context Political Elimination of national regulations which still need to be met Context Political Language barrier Context Political Political will Context Readiness Capacity differences in Member States in regulatory issues. Input Roles and Responsibilities Inclusion of all regulatory agencies as active members Process Procedure Awareness and training Process Procedure Information sharing on regulatory harmonization process/ documents Process Resources Funding and training Process Resources Human resources issues Industry respondents were asked the same question (Table 6). Most of their comments were split between readiness and procedural concerns, but political concerns were also seen as barriers. 89 Table 6: Barriers to Regulatory Harmonization: Selected Industry Opinion What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? CIPP Category Comment Context Political Corruption Context Political Disparity of national requirements and conflicting national interests Context Political Lack of a central body with legislative authority, a good example is EMA in Europe that works with the European Commission which has legislative powers Input Collaboration Countries should be more open to use reliance pathways, not only from the SRA but also between African countries. Especially for GMP related matters. Input Collaboration Different countries at different levels of regulatory proficiency, it makes it difficult to harmonize because there is no trust and respect among participating Member States Input Collaboration There should be more efforts from SRA countries to share their technical knowledge with Africa nras, especially when it comes to assessing critical products that have been reviewed in their (SRA) countries. Input Readiness Gaps in in scientific knowledge Process Procedure Communication to applicants and status of review processes should be improved. Process Procedure Electronic submission should be compulsory Process Procedure Process and procedure clarification on product dossier registration Process Procedure Technical support provided by the SRAs for Africa NRA is lacking and can be improved. Process Procedure Viable online platform where stakeholders have easy access to all information pertaining to registration and other things Process Resources Member States also fear losing revenue from application fees Participants, from NMRAs only, were asked how their country’s legal framework supports the WHO-CRP (Figure 26). Most (86%, 24/28) reported that it supported international cooperation between NMRAs, and somewhat fewer that it supported regulatory harmonization (79%, 22/28) or information sharing (57%, 16/28). 90 Figure 26: Legal Framework Support of WHO-CRP: NMRA Responses 4.3.3 Harmonization Readiness Respondents from NMRAs (Figure 27) and industry (Figure 28) were asked about the pace of the development and implementation of harmonization pathways in Africa. About half from NMRAs indicated that the pace was progressing too slowly (56%, 14/25). About a third indicated that it was progressing at an appropriate speed (36%, 9/25). Only two respondents (8%, 2/25) felt that it was progressing too quickly. Figure 27: Regulatory Harmonization Speed: NMRA Responses 79% (22/28) 86% (24/28) 57% (16/28) 0% 20% 40% 60% 80% 100% Harmonization of regulations International cooperation between health authorities Information sharing between health authorities Percent Does your country's legal framework allow for: 36% (9/25) 56% (14/25) 8% (2/25) 0% 20% 40% 60% Progressing at an appropriate speed Progressing too slowly Progressing too quickly Percent What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? 91 When asked to explain why harmonization was progressing too slowly (Table 7), reasons given by NMRAs could be classified as political, readiness (capacity), and procedural issues. Many felt that more political will was needed to push the agenda. Lack of budget, skilled professionals, and regulatory structure in some countries were other reasons for the slower progress. Two respondents mentioned that not all countries are receiving regular updates on harmonization. Table 7: Pace of Harmonization Pathway Development and Implementation: Selected NMRA Opinions What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? Progressing too slowly. Please explain your answer: CIPP Category Comment Context Political ZAZIBONA was long initiated but still no recognition between those countries Context Political In ECOWAS, Language barrier has been a huge challenge. The Anglo/Franco/Lusophone divide had slowed things down. We need to get over this to speed up the process!!! Context Political It has stalled somewhat. There is need for political will to push the agenda Context Readiness Different capacities of regulatory authorities are derailing progress Context Readiness LACK OF: budget, skilled professional, political commitment, regulatory structure in some of the country Process Procedure There are still lots of bottlenecks. Process Procedure Impact of the developments have not been felt in-country Progressing at an appropriate speed. Please explain your answer: CIPP Category Comment Context Political The legal frameworks of countries should allow these processes. In addition, the advantages and disadvantages should be analysed critically Context Political Since some countries did not have Medicines Agencies, it was difficult to sit everyone together sometimes where other countries do not even have functional regulatory agencies. They won’t be able to make strategic decisions. Now it has progressed at the appropriate speed because regulatory agencies are being set. Context Political I think it is progressing at an appropriate speed judged by the fact that each economic region currently has its own harmonization process going on. The African Medicines Agency ratification process is somehow a bit slow. Context Readiness They are doing the best they can. Process Procedure Approval and review take optimum time 92 The opinions of industry participants on the pace of harmonization were also captured (Figure 28). Only 10% (2/20) felt that regulatory harmonization was progressing too quickly, whereas 60% (12/20) felt that it was progressing too slowly and 30% (6/20) that it was progressing at an appropriate speed. Figure 28: Regulatory Harmonization Speed: Industry Responses The responses of generic versus brand respondents were stratified (Figure 29). The majority of both brand and generic manufacturers felt that the pace of regulatory harmonization in Africa was progressing too slowly (brand: 60%, 6/10; generic: 57%,4/7). Fewer felt that it was progressing at an appropriate speed (brand: 40%, 4/10; generic: 29%, 2/7; other: 50%, 2/4). A minority of generic manufacturers felt that the pace was progressing too quickly (generic: 14%, 1/7; other: 50%, 2/4). 30% (6/20) 60% (12/20) 10% (2/20) 0% 10% 20% 30% 40% 50% 60% 70% Progressing at an appropriate speed Progressing too slowly Progressing too quickly Percent What do you think about the pace of the developemnt and implementation of regulatory harmonization pathways in Africa? 93 Figure 29: Regulatory Harmonization Speed: Generic versus Brand Manufacturer Responses Industry respondents were also asked for additional comments about the pace of harmonization (Table 8). Political and procedural issues were mentioned most frequently. Procedural issues were mentioned more frequently by those who responded that the pace of harmonization was moving too slowly. 29% (2/7) 57% (4/7) 14% (1/7) 40% (4/10) 60% (6/10) 50% (2/4) 50% (2/4) 0% 10% 20% 30% 40% 50% 60% 70% Progressing at an appropriate speed Progressing too slowly Progressing too quickly Percent Other Proprietary or brand name product Generic product What do you think about the pace of the development and implementation of regulatory 94 Table 8: Pace of Harmonization Pathway Development and Implementation: Selected Industry Opinions What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? Progressing too quickly. Please explain your answer: CIPP Category Comment Process Procedure It's progressing quickly but the processes are too slow. We have opted to drop all regional harmonisation programs such as zazibona, waho, eac, Igad and only use WHO harmonisation process for PQ products. These regional harmonisation programs either don’t have enough resources or not well coordinated. We would rather go in-country than harmonised programs Progressing at an appropriate speed. Please explain your answer: CIPP Category Comment Context Political I recognise international coordination is not easy. Context Readiness Many Health Authorities are still struggling with the WHO benchmarking. In the coming years I believe more countries will have better scores Context Readiness Infrastructure still lacking. Process Procedure Should adopt electronic submission Progressing too slowly. Please explain your answer: CIPP Category Comment Context Political African countries would benefit from a fully harmonized procedure throughout the continent. However, national interest may prevent this even in the long term Context Political The progress has been slow due to the mindset of the Regulators who are too "nationalistic" and are failing to adjust to globalization and appreciate the advantages of. The other major problem is that the regional harmonisation authority groupings can only recommend their decisions to Member States who at times take long to implement without any consequences, they do not have legislative authority Process Procedure Regional Regulatory Authority need more training on the review and requirements. Process Procedure Most African Countries still need to implement eCTD format. Process Procedure I think there are a number of systems in place with the regional initiatives - they just need to be used and experience gained Process Procedure There is a rise of Regulatory Harmonization pathways, but the review processes take long and less time is given to the dossiers and other supplementary documentation. 4.4 Input An “Input Evaluation” assesses whether program strategy and design are appropriate for the purposes of a program. Questions posed next explored the appropriateness and sufficiency of inputs to the WHO-CRP program design. 95 4.4.1 Development of Harmonized Pathways NMRA participants were asked whether health authorities had an important role in the development of regulatory harmonization pathways in Africa. All but three answered in the affirmative (yes: 91%,32/35; don’t know: 9%,3/35) (Figure 30). Comments on the nature of those roles, shown in Table 9, focused on the need for active participation and leadership to minimize duplication of work and resources. Figure 30: NMRA Role in the Development of Harmonized Pathways: NMRA Responses 9% (3/35) 91% (32/35) 0% 20% 40% 60% 80% 100% Don't Know No Yes Percent Do you feel that an NMRA has an important role in the development of regulatory harmonization pathways in Africa? 96 Table 9: NMRA Role in the Development of Harmonized Pathways: Selected NMRA Opinions Do you feel that a health authority has an important role in the development of regulatory harmonization pathways in Africa? Yes. Please explain what this influence could look like: CIPP Category Comment Context Political There are a number of country-specific requirements that must be addressed before harmonization can be agreed upon due to difference laws in different countries. Context Readiness Embracing harmonized evaluation as a process that will increase medicines, diagnostics availability to needy patients at affordable costs. Combined Strengthened systems will also better enforcement that will ensure only quality efficacious products are allowed in the market therefore managing Illicit and counterfeits that find opportunities where there are gaps of affordable health care to take care to the needy. Context Readiness Since HA's in Africa have a great variety of maturity/resources, all HA's need to be involved and guide the process to enable a harmonized pathway to work for all countries/regions involved. This may also need better communication between HA's, making a agreements on reliance etc. Context Readiness Thought and collaboration leadership Process Procedure The Health Authority is in a good position to balance country-specific requirements with regional requirements Process Resources Availing resources e.g. human, financial to run the harmonisation processes, Other Comments CIPP Category Comment Context Readiness Knowledge sharing and capacity building of regulators during such meetings. Context Readiness Opportunity to learn from experienced Regulators if you are a startup NMRAs were asked if product manufacturers should have more influence in the development of regional or joint harmonized procedures (Figure 31). Almost two-thirds (62%, 18/29) agreed, mostly by providing input to the processes and procedures (Table 10). A quarter answered “No” (24%, 7/29) and a few answered, “Don’t know” (14%, 4/29). NMRA participants were not asked whether product manufacturers should have more influence in the development of national pathways because their views might be restricted to experiences with their own national procedure, but they were also invited to provide comments. One respondent agreed: It’s all about stakeholders’ engagement and local manufacturers can own the regulatory pathway. 97 Figure 31: Level of Industry Influence in the Development of Harmonized Procedures: NMRA and Industry Responses Table 10: Level of Industry Influence in the Development of Harmonized Procedures: Selected NMRA Opinions Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? Yes. Please explain what this influence could look like: CIPP Category Comment Context Readiness Advocacy and Lobbying that it would enable better access of quality and affordable medicines across those who need them reducing complexities seen in national Systems. Input Design Taking active part in committees and defining best practices Process Procedure They are key stakeholders whose view must be taken into consideration Process Procedure They should collaborate and comment as well as make suggestions for an improved procedure Respondents from industry also agreed that product manufacturers should have more influence in the development of regional regulatory pathways (Figure 31): 73% ((16/22) responded “Yes”, 9% (2/22) responded “No”, and 18% (4/22) responded “Don’t know”. Industry respondents frequently favored a role in providing input to the design or execution of its processes and procedures (Table 11). 18% (4/22) 9% (2/22) 73% (16/22) 14% (4/29) 24% (7/29) 62% (18/29) 0% 20% 40% 60% 80% Don't know No Yes Percent NMRA Industry Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? 98 Table 11: Level of Industry Influence in the Development of Harmonized Procedures: Selected Industry Opinions Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? Yes. Please explain what this influence could look like: CIPP Category Comment Context Readiness explain the challenge of supply, distribution and production. Influence of having harmonized/global label to be used in all the countries to make sure to shift product easily as needed in different countries. Process Procedure As stakeholders they need to assist the regulator to come up with procedures that will help them register and reach other countries apart from their country of origin faster. Process Procedure For innovator products that are already assessed by a reliable authority, manufacturers could impress the need for even more simple dossier packages ie to ask for the assessment reports to be shared directly between strict and destination health authorities (for new submission & lifecycle management), without the manufacturer's involvement. A suitable confidential data sharing platform however needs to be set up for this. Process Procedure I believe Industry can help NRAs streamline their processes by sharing their experience and expertise from a different perspective to that of the NRAs. For example NRAs can reduce the amount of information they request during dossier evaluation by better information management eg creation of an API database Product Effectiveness Important to get stakeholder feedback on the efficiency and effectiveness of the pathway from stakeholders who have experience as part of good review practices. Product Sustainability In our experience the Company was a full partner in the CRP-SR procedure. This shows that companies have their say. Given the advantages for all partners, including the patients, it would seem a win-win situation if the manufacturers would help promoting these procedures Product Sustainability When more manufacturers are willing to share the dossier submitted to WHO with other Country Health Authorities, it shows their commitment to transparency and improving the health sector of those countries Most industry professionals (81%, 13/16) also favored more influence in the development of national regulatory pathways (Figure 32). Only one (6%, 1/16) disagreed and two replied “Don’t know” (13%, 2/16). 99 Figure 32: Industry Role in the Development of National Procedures: Industry Responses Industry participants were also invited to provide their views on their role in the design of national regulatory pathways in Africa (Table 12). Table 12: Level of Industry Influence in the Design of National Regulatory Pathways: Selected Industry Opinions Do you feel that product manufacturers should have more influence in the development of national regulatory pathways? Yes. Please explain what this influence could look like: CIPP Category Comment Context Political Not all products are WHO-prequalified. So these products need to follow the single country pathway but dossier review in any SRA can be leveraged upon for faster processing. The collaboration from manufacturers in this regard will strengthen trust Input Design Feedback on proposals as well as guidance to ensure that the pathway is practical and usable Process Procedure Yes, they need to be consulted as they are the biggest stakeholders in the development of regulatory guidelines used for these national pathways Product Sustainability It will enable a more robust pathway When asked whether the health authority with which the respondent was affiliated had previously played an important role in developing the existing harmonization pathways (Figure 33), the response was overwhelmingly affirmative (83%, 29/35), ); only two said no (6%, 2/35), and four did not know (11%, 4/35). 13% (2/16) 6% (1/16) 81% (13/16) 0% 20% 40% 60% 80% 100% Don't know No Yes Percent Do you feel that product manufacturers should have more influence in the development of national regulatory pathways? 100 Figure 33: NMRA Role in the Development of Harmonization Pathways: NMRA Responses NMRA respondents were then invited to explain the role played by their NMRA during that development (Table 13). 11% (4/35) 6% (2/35) 83% (29/35) 0% 20% 40% 60% 80% 100% Don't know No Yes Percent Do you feel that the health authority with which you are affiliated has had an important role in the development of regulatory harmonization pathways in Africa? 101 Table 13: Level of NMRA Influence in the Design of Regional Regulatory Pathways: Selected NMRA Opinions Do you feel that the health authority with which you are affiliated has had an important role in the development of regulatory harmonization pathways in Africa? (If you answer "yes", please also explain what this role was). Yes. Please explain what this role was: CIPP Category Comment Context Readiness We are the leading Authority in the SADC region and we help build capacity for other members, develop the system for harmonisation Input Design IGAD try to contribute it role on harmonization of regulation in Africa. It comprise eight countries. Starts Joint assessment and it is on good progress. Input Design Namibia, was among one of the countries that formed the first Southern Africa harmonization that is called Zazibona(Zambia, Zimbabwe, Botswana & Namibia)... Currently Zazibina initiative have currently 14 members state(SADC. Input Design NDA has participated in both EAC and IGAD harmonisation guidelines for registration, GMP and pharmacovigilance Input Design The authority is very active in SADC initiative processes. Input Design They are actively involved in the harmonization via West African Health Organization (WAHO) which is trying to come up with common regulations and registration for the region. Input Design We are active in ZAZIBONA programme which allow for reliance. Input Design Yes. It was the initiating and founding member of the SADC Medicines Regulatory Harmonisation project commonly known as Zazibona. Process Improvement Actively supporting harmonization. Offered key well trained staff to train regional peers for adoption of better processes and procedures. Sharing of best practices in Regional meetings supportee by the likes of NEPAD. Pioneer in online submissions, evaluation and approvals. Process Procedure Harmonization of Regulatory Frameworks, Guidelines, Procedures for Medical Products and Devices Process Procedure Provision of in-house expertise to support development of relevant guidelines and regulations. Process Procedure Testing of samples Product Effectiveness Cross-border joint surveillance; opening harmonized market registration system; and the like Product Effectiveness Yes. We are the end users of the WHO-CRP and therefore provide valuable feedback 4.4.2 Use of WHO-CRP in Africa Industry participants reported a total of 123 submissions, lodged in most countries participating in WHO-CRP (Figure 34), including 24 of the 28 countries listed by the WHO as eligible for the WHO-CRP. One selected “Other” but did not elaborate. 102 Figure 34: African Countries Where the WHO-CRP Was Used Industry participants were asked about other countries in which they wanted to register their product using the WHO-CRP (Figure 35). Nineteen countries, including Benin, Republic of Congo, Egypt, Madagascar, Mauritania, and Mauritius, were all identified. 1 8 1 8 9 10 1 2 1 8 9 9 2 3 1 11 7 6 4 3 6 5 2 7 0 2 4 6 8 10 12 Other Zimbabwe Zanzibar Zambia Uganda Tanzania Sudan South Africa Sierra Leone Senegal Rwanda Nigeria Namibia Mozambique Mali Malawi Madagascar Kenya Ghana Ethiopia Eritrea DR Congo Côte d'Ivoire Comores Cameroon Burundi Burkina Faso Botswana Count, N=124 For which countries in Africa did you use the WHO-CRP? 103 Figure 35: African Countries Where Respondents Would Like to Use the WHO- CRP Industry participants were also asked about countries outside of Africa in which they used or wanted to use the WHO-CRP (Figure 36). Almost three-quarters (70%, 14/20) replied “No”. Only 3 (15%, 3/20) responded “Yes” and identified those 1 1 1 2 2 3 2 2 2 1 1 1 1 1 3 1 1 4 1 0 1 2 3 4 5 Other Western Sahara Tunisia Togo Sudan South Sudan Somalia Seychelles Sao Tome & Principe Niger Morocco Mauritius Mauritania Madagascar Libya Liberia Lesotho Guinea-Bissau Guinea Gambia Gabon Eswatini Eritrea Equatorial Guinea Egypt Djibouti Congo Chad Central African Republic Cabo Verde Benin Angola Algeria Count, N=31 Were there countries in Africa where you wanted to register your product that do not use the WHO-CRP? 104 constituencies as “Bangladesh”, “Regulated Markets”, and “mainly MENA-GCC” 2 . Three participants (15%, 3/20) did not know. Figure 36: Ex-African Countries Where Respondents Would Like to Use the WHO-CRP 4.5 Process A “Process Evaluation” considers whether the process design is well executed and includes the examination of the barriers and facilitators of the process as well as resource utilization. 4.5.1 WHO-CRP Process Both NMRA and industry participants were asked to evaluate statements about each component of the WHO-CRP, using a 5-point Likert Scale, ranging from 1=Strongly Disagree to 5=Strongly Agree (Figure 37, Figure 38, Table 14, and Table 15). 4.5.1.1 Dossier Submission NMRA and industry respondents were asked about two elements, application instructions and application requirements, related to dossier submission (Table 14, Figure 37). Approximately one-half (53%, 16/30) of the NMRA respondents strongly 2 MENA-GCC is an acronym referring to the Middle East and North Africa. There is no formal agreement on which countries are included, but the most frequently included countries are: Algeria, Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Syria, Tunisia, United Arab Emirates and Yemen. 15% (3/20) 70% (14/20) 15% (3/20) 0% 20% 40% 60% 80% Don't know No Yes Percent Were there countries outside of Africa where you used or wanted to use the WHO-CRP? 105 agreed that the registration instructions were clear and easy to understand. An additional 40% (12/30) agreed, and the remainder neither agreed nor disagreed (7%, 2/30). Somewhat less than half (43%, 9/21) of the industry participants strongly agreed, 38% (8/21) somewhat agreed, 14% (3/21) neither agreed nor disagreed, and 5% (1/21) somewhat disagreed. Asked if the requirements for a successful application were clear, all but one of the NMRA respondents strongly (59%, 17/29), or somewhat agreed (38%, 11/29); one neither agreed nor disagreed (3%, 1/29). Industry participants were less positive about whether the process requirements were clear (38%, 8/21 strongly agreed, 43%, 9/21 somewhat agreed, 14%, 3/21 neither agreed nor disagreed, 5%, 1/21 somewhat disagreed). Table 14: WHO-CRP Process: Dossier Submission Process Step Question Respondent Strongly Agree Somewhat Agree Neither Agree nor Disagree Somewhat Disagree Strongly Disagree Step 1 Product registration instructions are clear and easy to understand Industry, N=21 9 (43%) 8 (38%) 3 (14%) 1 (5%) 0 (0%) NMRA, N=30 16 (53%) 12 (40%) 2 (7%) 0 (0%) 0 (0%) Step 2 Application requirements are clear and well-defined Industry, N=21 8 (38%) 9 (43%) 3 (14%) 1 (5%) 0 (0%) NMRA, N=29 17 (59%) 11 (38%) 1 (3%) 0 (0%) 0 (0%) 106 Figure 37: WHO-CRP Process: Dossier Submission 4.5.1.2 Dossier Review NMRA and industry respondents were asked about three aspects of dossier review, including scientific soundness, reviewer accessibility, and question management (Table 15, Figure 38). Both groups were broadly positive that the application reviews are scientifically sound (NMRA: 57%, 16/28 strongly agreed; 36%, 10/28 somewhat agreed; 7%, 2/28 neither agreed nor disagreed. Industry: 38%, 8/21 strongly agreed; 33%, 7/21 somewhat agreed; 29%, 6/21 neither agreed nor disagreed). They also had similar views on the process to discuss questions with the reviewer (NMRA: 39%, 11/28 strongly agreed; 29%, 8/28 somewhat agreed; 21%, 6/28 neither agreed nor disagreed; 7%, 2/28 somewhat disagreed; and 4%, 1/28 strongly disagreed; 8 (38%) 17 (59%) 9 (43%) 16 (53%) 9 (43%) 11 (38%) 8 (38%) 12 (40%) 3 (14%) 1 (3%) 3 (14%) 2 (7%) 1 (5%) 1 (5%) 0% 20% 40% 60% 80% Industry, N=21 NMRA, N=29 Industry, N=21 NMRA, N=30 Requirements for a successful product application are clear and well-defined Product registration instructions are clear and easy to understand Percent Please indicate whether you agree or disagree about the following statements regarding the WHO-CRP: Strongly Disagree Somewhat Disagree Neither Agree nor Disagree Somewhat Agree Strongly Agree 107 Industry: 36%, 8/22 strongly agreed, 27%, 6/22 somewhat agreed, 18%, 4/22 neither agreed nor disagreed and 18%, 4/22 somewhat disagreed). Only the industry respondents were asked whether the lead reviewer was accessible after dossier submission. About half agreed, but the largest subgroup neither agreed or disagreed and two disagreed (36%, 8/22 strongly agreed, 14%, 3/22 somewhat agreed, 41%, 9/22 neither agreed nor disagreed, 5%, 1/22 somewhat disagreed, and 5%, 1/22 strongly disagreed). Table 15: WHO-CRP Process: Dossier Review Question Strongly Agree Somewhat Agree Neither Agree nor Disagree Somewhat Disagree Strongly Disagree Dossier reviews are scientifically sound Industry, N=21 8 (38%) 7 (33%) 6 (29%) 0 (0%) 0 (0%) NMRA, N=28 16 (57%) 10 (36%) 2 (7%) 0 (0%) 0 (0%) The lead reviewer was accessible after submission Industry, N=22 8 (36%) 3 (14%) 9 (41%) 1 (5%) 1 (5%) Process to discuss questions with the reviewer are clear Industry, N=22 8 (36%) 6 (27%) 4 (18%) 4 (18%) 0 (0%) NMRA, N=28 11 (39%) 8 (29%) 6 (21%) 2 (7%) 1 (4%) 108 Figure 38: WHO-CRP Process: Dossier Review 4.5.1.3 Dossier Decision NMRA and industry respondents were asked about two elements associated with the communication and discussion of dossier decisions (Figure 39). Opinions diverged when asked if an official report of the decision is provided. Almost all NMRA participants agreed (57%, 16/28 strongly agreed, 39%, 11/28 somewhat agreed, 4%, 1/28 strongly disagreed), whereas the experience of industry was mixed (32%, 7/22 strongly agreed, 27%, 6/22 somewhat agreed, 32%, 7/22 neither agreed nor disagreed and 9%, 2/22 somewhat disagreed). About half of the respondents in each group agreed that an appeal process is available when applications are rejected, but many neither agreed nor 8 (38%) 16 (57%) 8 (36%) 8 (36%) 11 (39%) 7 (33%) 10 (36%) 3 (14%) 6 (27%) 8 (29%) 6 (29%) 2 (7%) 9 (41%) 4 (18%) 6 (21%) 1 (5%) 4 (18%) 2 (7%) 1 (5%) 1 (4%) 0% 10% 20% 30% 40% 50% 60% Industry, N=21 NMRA, N=28 Industry, N=22 Industry, N=22 NMRA, N=28 Dossier reviews are scientifically sound The lead reviewer was accessible after submission Process to discuss questions with the reviewer are clear Percent Strongly Disagree Somewhat Disagree Neither Agree nor Disagree Somewhat Agree Strongly Agree 109 disagreed or disagreed (NMRA: 25%, 7/28 strongly agreed, 29%, 8/28 somewhat agreed, 36%, 10/28 neither agreed nor disagreed, 7%, 2/28 somewhat disagreed and 4%, 1/28 strongly disagreed; Industry:14%, 3/21 strongly agreed, 33%, 7/21 somewhat agreed, 38%, 8/21 neither agreed nor disagreed and 14%, 3/21 somewhat disagreed). Table 16: WHO-CRP Process: Dossier Decision Question Strongly Agree Somewhat Agree Neither Agree/ Disagree Somewhat Disagree Strongly Disagree Applicants who have their drug applications rejected have an appeal process Industry, N=21 3 (14%) 7 (33%) 8 (38%) 3 (14%) 0 (0%) NMRA, N=28 7 (25%) 8 (29%) 10 (36%) 2 (7%) 1 (4%) Applicants receive an official written report with the application decision Industry, N=22 7 (32%) 6 (27%) 7 (32%) 2 (9%) 0 (0%) NMRA, N=28 16 (57%) 11 (39%) 0 (0%) 0 (0%) 1 (4%) Figure 39: WHO-CRP Process: Dossier Decision 3 (14%) 7 (25%) 7 (32%) 16 (57%) 7 (33%) 8 (29%) 6 (27%) 11 (39%) 8 (38%) 10 (36%) 7 (32%) 3 (14%) 2 (7%) 2 (9%) 1 (4%) 1 (4%) 0% 10% 20% 30% 40% 50% 60% Industry, N=21 NMRA, N=28 Industry, N=22 NMRA, N=28 Applicants who have their drug applications rejected have an appeal process Applicants receive an official written report with the application decision Percent Strongly Disagree Somewhat Disagree Neither Agree nor Disagree Somewhat Agree Strongly Agree 110 4.5.1.4 Electronic Dossier Handling Respondents were asked if it is easy to review and submit dossiers using the WHO-CRP (Table 17, Figure 40). Most NMRAs either strongly or somewhat agreed that product registration applications are easy to receive and review electronically (40%, 12/30 strongly agreed, 43%, 13/30 somewhat agreed, 13%, 4/30 neither agreed nor disagreed, and 3%, 1/30 somewhat disagreed). Fewer industry participants considered that the product registration applications were easy to submit electronically (36%, 8/22 strongly agreed, 27%, 6/22 somewhat agreed, 23%, 5/22 neither agreed nor disagreed, and 14%, 3/22 somewhat disagreed). NMRA respondents were asked if it was easy to share product registration applications with other NMRA reviewers; 50%, 14/28 strongly agreed, 39%, 11/28 somewhat agreed, 4%, 1/28 neither agreed nor disagreed, and 4%, 1/28 somewhat disagreed. 111 Table 17: WHO-CRP Process: Electronic Dossier Handling Question Strongly Agree Somewhat Agree Neither Agree/ Disagree Somewhat Disagree Strongly Disagree Product registration applications are easy to receive and review electronically NMRA, N=30 12 (40%) 13 (43%) 4 (13%) 1 (3%) 0 (0%) Product registration applications are easy to share electronically with other reviewers NMRA, N=28 14 (50%) 11 (39%) 1 (4%) 1 (4%) 1 (4%) Product registration applications are easy to submit electronically Industry, N=21 8 (36%) 6 (27%) 5 (23%) 3 (14%) 0 (0%) Figure 40: WHO-CRP Process: Electronic Dossier Handling 12 (40%) 14 (50%) 8 (36%) 13 (43%) 11 (39%) 6 (27%) 4 (13%) 1 (4%) 5 (23%) 1 (3%) 1 (4%) 3 (14%) 1 (4%) 0% 10% 20% 30% 40% 50% 60% NMRA, N=30 NMRA, N=28 Industry, N=22 Product registration applications are easy to receive and review electronically Product registration applications are easy to share electronically with other reviewers Product registration applications are easy to submit electronically Percent Strongly disagree Somewhat disagree Neither agree nor disagree Somewhat agree Strongly agree 112 4.5.2 WHO-CRP Process Resource Requirements NMRA participants were also asked to agree or disagree with certain statements specific to the resource requirements of the WHO-CRP (Figure 41). Almost three- quarters of NMRA respondents (72%, 21/29) agreed that the procedure was a cost- effective way to review dossiers. However, only 41% (12/29) agreed that they had sufficient time to assess dossiers and 34% (10/29) agreed that they had sufficient time to address applicant questions. Although 79% (23/29) agreed that the procedure supports regional harmonization efforts, only 10% (3/29) indicated that the procedure was aligned with their country’s reimbursement strategy. Figure 41: WHO-CRP Process Resource Requirements: NMRA Responses Industry participants were also asked about resource requirements needed to support activities related to the WHO-CRP (Figure 42). When asked whether they agreed with the statement, “The resources planned for filing a WHO-CRP submission were sufficient”, 70% (14/20) agreed, 15% (3/20) disagreed and 15% (3/20) did not know. 79% (23/29) 10% (3/29) 72% (21/29) 41% (12/29) 34% (10/29) 0% 20% 40% 60% 80% 100% The procedure supports regional harmonization efforts in Africa The procedure is aligned with my country's reimbursement strategy The procedure is a cost-effective way to review dossiers I have sufficient resources to assess WHO-CRP procedure dossiers I have sufficient time to address applicant questions Percent With which of the following statements about the WHO-CRP do you agree? 113 When asked whether “The WHO-CRP was a cost-effective way to register my product”, over half agreed (53%, 10/19), 16% disagreed (3/19) and 32% (6/19) did not know. Figure 42: WHO-CRP Process Resource Requirements: Industry Responses 4.5.3 WHO-CRP Process Improvements Participants from NMRAs were asked whether changes to the WHO-CRP would have made the procedure easier to use by providing 12 possible options from which the participants could select 5 (Figure 43). The four top choices, chosen by about half or more of the respondents were: “easier accessibility to other reviewers” (56%, 15/27); “improved ability to access previous reviews” (52%, 14/27); “improved documentation about how to assess variations” (48%, 13/23); and “elimination of post-WHO-CRP national requirements” (48%, 13/27). Other responses selected less frequently were having “improved documentation on how to assess dossiers” (41%, 11/27), “improved documentation on how to use the process” (30%, 8/27), “simpler process” (33%. 9/27) and “other” (19%, 5/27). Fewer chose having “easier access to the WHO” (22%, 6/27), 15% (3/14) 32% (6/19) 15% (3/14) 16% (3/19) 70% (14/20) 53% (10/19) 0% 20% 40% 60% 80% The resources planned for filing a WHO-CRP submission were sufficient (N=20) The WHO-CRP procedure was a cost-effective way to register my product (N=19) Percent I am concerned that the WHO-CRP procedure will not be available after the next three years Agree Disagree Don't know 114 “easier access to the documentation” (22%, 6/27), “easier access to the applicant” (26%, 7/27) or “a more efficient process” (26%, 7/27). Figure 43: WHO-CRP Process Improvements: NMRA Responses Similarly, industry participants were asked whether changes to the WHO-CRP process would have made the procedure easier to use by providing 10 possible options, from which the participants could select 5 (Figure 44). “Elimination of redundant national requirements” was the most common selection (89%, 16/18). Four other factors were selected by at least half of the participants: “improved documentation on how to prepare variations” (80%, 12/15); “improved documentation on how to prepare the 19% (5/27) 33% (9/27) 26% (7/27) 48% (13/27) 52% (14/27) 22% (6/27) 30% (8/27) 41% (11/27) 48% (13/27) 22% (6/27) 26% (7/27) 56% (15/27) 0% 20% 40% 60% Other Simpler process More efficient process Elimination of redundant national requirements Improved ability to access SRA or WHO reviews More accessible documentation about the process Improved documentation on how to use the process Improved documentation on how to assess dossiers Improved documentation on how to assess variations Easier accessibility to the WHO Easier accessibility to the applicant(s) Easier accessibility to other reviewers Percent Would any of the following changes have made the WHO-CRP easier to use? 115 dossier” (73%, 11/15); “improved process by which they are notified about the progress of the review” (61%, 11/18); and “improved process on how to use the process” (53%, 8/15). Fewer chose “easier access to the reviewer” (47%, 7/15), “more accessible documentation”, (40%, 6/15), “more efficient process” (28%, 5/18), and “simpler process” (22%, 4/18). Two of the participants (13%, 2/15) answered “other”, and one expanded this selection by suggesting “ease of communicating feedback from the reviewers to the manufacturers”. Figure 44: WHO-CRP Process Improvements: Industry Responses 4.5.4 Post WHO-CRP Process National Requirements The WHO-CRP is designed to be a fully comprehensive and self-contained process to register products in a country; however, only a fifth (19%, 5/26) of NMRA respondents reported that their country had no additional national requirements beyond the WHO-CRP process (Figure 45). Product samples (81%, 21/26), country-specific labeling (73%, 19/26), and requirements for additional certifications including a Certificate of Pharmaceutical Product (62%, 16/26), GMP Certificate (58%, 15/26), or 13% (2/15) 53% (8/15) 73% (11/15) 80% (12/15) 40% (6/15) 47% (7/15) 22% (4/18) 28% (5/18) 61% (11/18) 89% (16/18) 0% 50% 100% Other Improved documentation on process use Improved documentation on dossier preparation Improved documentation on variations preparation More accessible process documentation Easier access to the NMRA reviewer(s) Simpler process More efficient process Improved notification during review Elimination of redundant national requirements Percent Would any of the following changes have made the WHO-CRP easier to use? 116 manufacturing license (54%, 14/26) were national requirements identified by more than half of the NMRA participants. GMP inspections were identified to be necessary by only 38% (10/26) of the respondents. No respondents selected “Don’t know” or “Other”. Figure 45: National Requirements Reported by NMRAs As might be expected, industry respondents also reported that national requirements were added to WHO-CRP requirements in order to obtain product registration (Figure 46). All reported having to satisfy national requirements, which most frequently included: providing product samples (74%, 14/19), providing a Certificate of Pharmaceutical Product (58%, 11/19), and country-specific labeling (58%, 11/19). Providing a manufacturing license (58% ,11/19), a GMP Certificate (47%, 9/19), or completing a GMP inspection (42%, 8/19) were requirements also identified commonly. Three respondents selected “Other”. One of those participants stated that s/he had to provide a price certificate, and the other stated that a local Risk Management Plan (RMP) document was required. The third respondent did not describe the “Other” requirement needed. 73% (19/26) 38% (10/26) 58% (15/26) 54% (14/26) 62% (16/26) 81% (21/26) 19% (5/26) 0% 20% 40% 60% 80% 100% Other Don't know Country specific labeling Undergo a GMP Inspection GMP Certificate Manufacturing License Certificate of Pharmaceutical Product Product samples No specific national requirements Percent What national requirements are required to obtain registration post WHO-CRP? 117 Figure 46: National Requirements: Industry Responses 4.5.5 National Requirements for GMP Inspections Survey participants were asked whether GMP inspections were carried out under the WHO-CRP, given that the procedure relies already on WHO Prequalification or Stringent Regulatory Authority approval (Figure 47). Approximately two-thirds of NMRA respondents (67%, 18/27) indicated that their NMRA required GMP inspections less than 25% of the time and about 20% that they were required at least half the time (50%-75%, 7%; 2/27, >75%; 11%, 3/27).). Four participants (15%, 4/27) did not know. Figure 47: GMP Inspection Requirements Reported by NMRAs 16% (3/19) 5% (1/19) 58% (11/19) 42% (8/19) 47% (9/19) 47% (9/19) 58% (11/19) 74% (14/19) 0% 20% 40% 60% 80% Other Don't know Country specific labeling GMP Inspection GMP Certificate Manufacturing License Certificate of Pharm Product Product samples No national requirements Percent What national requirements did you have to satisfy after completing the WHO-CRP to obtain registration? 15% (4/27) 11% (3/27) 7% (2/27) 67% (18/27) 0% 10% 20% 30% 40% 50% 60% 70% Don't know 75% or greater 50% to < 75% 25% to < 50% 0 to < 25% Percent What percentage of products using the WHO-CRP required a GMP inspection of a manufacturing facility? 118 Industry participants were also asked whether GMP inspections were required as part of the WHO-CRP process (Figure 48). Over half of the respondents agreed (57%, 12/21) one-third disagreed (33%, 7/21), and two respondents did not know (10%, 2/21). Figure 48: GMP Inspection Requirements: Industry Responses Generic manufacturers reported GMP inspections (Figure 49) more often than brand manufacturers (Yes: brand: 40%, 4/10, generic: 75%, 6/8; No: brand: 50%, 5/10, generic: 25%, 2/8; Don’t know: brand: 10%, 1/10). Figure 49: GMP Inspections: Generic versus Brand Manufacturer Responses 10% (2/21) 33% (7/21) 57% (12/21) 0% 10% 20% 30% 40% 50% 60% Don't know No Yes Percent In the process of using WHO-CRP, did you have a GMP inspection of your manufacturing facility? 25% (2/8) 75% (6/8) 10% (1/10) 50% (5/10) 40% (4/10) 0% 20% 40% 60% 80% Don't know No Yes Proprietary or brand name product Generic product In the process of using WHO CPAR procedure for product registration, did you have a GMP inspection of your manufacturing facility? 119 Both NMRA and industry were asked to estimate the length of time needed to schedule a required GMP inspection (Figure 50). About a third of NMRA respondents (33%, 9/27) reported that inspections were scheduled within three months and about half (55%, (9+6)/27), within six months of submission. Fewer reported scheduling delays beyond 6 months (6 to <9 months: 15%, 4/27; 9+ months: 11%, 3/27). The remaining respondents (19%, 5/27) did not know. Amongst the industry subgroup, approximately 40% (42%, 5/12) reported that GMP inspections were scheduled in under 6 months, and a quarter (25%, 3/12) between 6 and 9 months. Only 8% (1/27) reported that the GMP inspection was scheduled after 9 months and 25% (3/12) did not know. Figure 50: GMP Inspection Lead Time: NMRAs and Industry Responses NMRA respondents reported that only 19% (5/26) of the GMP inspections involved an in-person site visit (Figure 51). About two-thirds instead relied on remote inspections (62%, 16/26). For 35% (9/26), these remote inspections were motivated by concerns related to COVID-19, whereas 27% (7/26) reported that it was unrelated to COVID-19. Nineteen percent (5/26) did not know. 25% (3/12) 8% (1/12) 25% (3/12) 42% (5/12) 19% (5/27) 11% (3/27) 15% (4/27) 22% (6/27) 33% (9/27) 0% 10% 20% 30% 40% 50% Don't know 9 months or longer 6 to < 9 months 3 to < 6 months 0 to < 3 months Percent How long did it take to schedule the manufacturing site visit? NMRA Industry 120 Industry respondents reported that GMP inspections occurred as an on-site visit more frequently (42%, 5/12). One-third reported that their remote inspection was due to COVID-19 concerns (33%, 4/12), and 17% (2/12), unrelated to COVID-19 concerns. One industry respondent (8%, 1/12) did not know. Figure 51: Type of GMP Inspections Conducted: NMRA and Industry Responses NMRA and industry respondents were asked whether they felt that the GMP inspection added value to the WHO-CRP process (Figure 52). Over half of NMRA respondents (56%, 15/27) felt that a GMP inspection added value; the others were equally split between thinking that they did not (22%, 6/27), or not knowing (22%, 6/27). 8% (1/12) 42% (5/12) 17% (2/12) 33% (4/12) 19% (5/26) 19% (5/26) 27% (7/26) 35% (9/26) 0% 10% 20% 30% 40% 50% Don't know Manufacturing site visit Remote inspection unrelated to Covid- 19 concerns Remote inspection due to Covid-19 concerns Percent) Was the GMP inspection of your manufacturing facility done remotely ("desk inspection")? NMRA Industry 121 Figure 52: Value of GMP Inspections: NMRA and Industry Responses When asked to provide more detail about their answers, one NMRA respondent, who felt that the GMP inspection added value, mentioned the benefit of an external opinion to improve compliance (Table 18). Others offered more measured opinions, suggesting a that risk-based approach might be a more beneficial use of resources. Those who did not feel that the GMP inspection added value focused on the redundancy and waste of resources, given that other inspections would have taken place either by the WHO or by a stringent regulatory authority. . 8% (1/12) 33% (4/12) 58% (7/12) 22% (6/27) 22% (6/27) 56% (15/27) 0% 10% 20% 30% 40% 50% 60% 70% Don't know No Yes Percent Do you feel that the GMP inspection added value to the process? NMRA Industry 122 Table 18: Value of GMP Inspections: Selected NMRA Opinions Please state why the GMP inspection of manufacturing facilities do or do not add value to the WHO-CRP process: Do add value: CIPP Category Comment Process Improvement An outside review of the process always provides fresh insight to use to improve compliance. Process Improvement There have been certain instances of confirming sameness of product and site. Where there are VERY STRONG suspicion a GMP inspection may add value to the WHO-CRP, else it does not Process Procedure Companies may have multiple blocks for different markets at the same site with varying standards Process Procedure They add value because you verify with evidence compliance of the manufacturing facility to GMP, assuring the quality of the products from the facility Process Resources Sharing experience from the skilled inspectors report may be the advantage. But - it is wasting the manufacturer and authority time to inspect the already inspected company. -increases the cost of the manufacturer -duplication of efforts Don't add value: CIPP Category Comment Process Resources The GMP inspection by WHO would already have addressed most if not all issues that would be raised by our own inspectors Process Resources These sites are already inspected by the WHO inspectorate. The country inspection would not add any value except to deplete resources as this would be duplication of effort. Most industry participants (58%, 7/12) also felt that a GMP inspection added value to the WHO-CRP (Figure 52). A third (33%, 4/12) thought that it did not add value, and a single respondent did not know (8%, 1/12). Those who felt that the GMP inspections added value (Table 19) clarified that it highlighted areas needing improvements or provided confidence that the product was manufactured in a compliant manner. Those who did not feel that it provided value mostly echoed the opinion of the NMRAs that it was redundant and wasted resources. 123 Table 19: Value of GMP Inspections: Selected Industry Opinions Please state why the GMP inspection of manufacturing facilities do or do not add value to the WHO-CRP process: Do add value: CIPP Category Comment Process Improvement It provides confidence that product is manufactured by compliant facilities Process Improvement It highlighted areas that needed to be improved Do not add value: Input Scope Inspection is mainly focused on the 21CFR and cGMP whereas WHO- CRP is about the process of getting product dossier registration. Process Resources The facilities are regularly GMP inspected by highly-regulated authorities Process Resources No need for multiple GMP inspections of already globally approved and marketed product 4.6 Product A “Product Evaluation” considers whether the program succeeded and includes the examination of the impact, sustainability, and user satisfaction of the process. 4.6.1 Reach The survey asked participants (a) who had not used the procedure and (b) who considered using the procedure, but did not, in order to understand the reasons why they did not use the WHO-CRP (Figure 53). Some were “not aware of the process” (25%, 14/56), “the countries where registration was desired were not in scope of the procedure” (11%, 6/56) or that “more appealing pathways were available” (5%. 3/56). A cluster of responses was related to a lack of clarity about the process, such as the need for “training to understand and use the procedure” (11%, 6/56), “insufficient instructions about the procedure were available” (7%, 4/56) or “the process appeared complex” (4%, 2/56) or “lengthy” (2%, 1/56). No participants thought that the “review progress was not transparent”. 124 Figure 53: Reasons Why Participants Did Not Use the Procedure Participants were encouraged to explain other reasons (Table 20). Two respondents replied that the political framework did not allow them to participate in the process, and two others responded that the program was not offered to them. Table 20: Selected Reasons Why Participants Did Not Use the Procedure Why did you not use the WHO-CRP? CIPP Category Comment Context Political Not ruled by law Context Political Working in the Regulatory Unit within the Ministry of Health, the legislation in my country previously had no provisions for product registration. Provisions have since been included thus there is an ongoing discussion on using the WHO-CRP as one of the product registration pathways. Product Reach Not invited or no chance of engaging in it Product Reach The procedure is used for essential medicines for now These respondents were also asked if they would consider using the WHO-CRP process in the future (Figure 54) The majority agreed (61%, 35/57), but 7% (4/57) would not, and the remainder thought that they might (32%, 18/57). 2% (1/56) 4% (2/56) 5% (3/56) 7% (4/56) 11% (6/56) 11% (6/56) 25% (14/56) 36% (20/56) 0% 10% 20% 30% 40% Review progress was not transparent Procedure appeared too long Complex Procedure More appealing pathways available Insufficient procedure instructions Additional training is required Desired countries out of WHOCRP scope Unaware of the process Other Percent Why did you not use the WHO_CRP procedure? 125 Figure 54: Future Use of WHO-CRP When asked to elaborate on their answers (Table 21), the most common reason was the potential for shortening timelines. Many who had not yet decided about using the procedure in future expressed interest in understanding it more fully before deciding. Table 21: Selected Comments About Future Use of WHO-CRP Would you consider using the WHO-CRP in the Future? Yes CIPP Category Comment Context Barriers When I get the chance to work in it, I will take it happily as an assessor Process Duration If by using this process, the timelines of approvals will reduce and the cost and will include multiple countries approvals, will surely be a robust pathway to follow Process Duration If it will offer abridged reviews and shorten registration timelines Maybe CIPP Category Comment Context Readiness Depends on product and access priorities Context Readiness If I get any chance definitely, I would like to explore Context Readiness Must first see how the current effort turns out. Input Design We are interested in a limited number of Countries and the dossiers for registration, still need to be submitted in each country Process Resources Depends on economic conditions and further clarification of local variations Process Resources If we consider WHO as main body along with national authorities then, there are chances of early approval and product can be launch with short timelines. There would be benefit in terms of time, resources & money. A significant majority (61%, 37/61) of participants had a favorable view of the WHO-CRP (Figure 55); only a single survey respondent had an unfavorable view (2%, 32% (18/57) 7% (4/57) 61% (35/57) 0% 10% 20% 30% 40% 50% 60% 70% Maybe No Yes Percent Would you consider using the WHO-CRP in the future? 126 1/61). The remainder were either undecided (15%, 9/61) or did not know (23%, 14/61). Text responses suggested that time savings were an appealing factor. Some suggested that they would be influenced by positive experiences of others (Table 22). Figure 55: Overall impression of the WHO-CRP: Non-User Responses 23% (14/61) 15% (9/61) 2% (1/61) 61% (37/61) 0% 10% 20% 30% 40% 50% 60% 70% Don't know Undecided Unfavorable Favorable Percent What is your overall impression of the WHO-CRP? 127 Table 22: Overall impression of the WHO-CRP: Selected Non-User Opinions What is your overall impression of the WHO-CRP? Favorable CIPP Category Comment Context Readiness Seems credible, challenge is getting markets to almost same level of regulatory requirements and processes Input Design The objective of the procedure is clear, and the procedure should be very helpful to manufacturers for the registration of drug products in Africa. Process Duration Allows shorter time to registration of essential medicines in African countries. Ensures broad access of quality medicines. Process Procedure It is favorable, because it required less requirement that the national procedure, just one thing that we prefer to include also some reduction on the number of samples as some countries does required over than 50 samples for one registration or for lifecycle management so I think if there is any negotiation on it, a lot of companies will use this procedure than the national one. Process Resources Even though have currently not used the procedure but I believe it would one way of enabling our regulatory agency to use our limited resource sensibly Process Resources Our regulatory authority has less than ten (10) assessors and we receive more than three hundred (300) applications per year therefore we do not have the capacity to do full assessments for all the products. Using the WHO-CRP route means the availability of medicines is accelerated. Product Effectiveness I have seen how maturing agencies benefit from its use Unfavorable - Text CIPP Category Comment Context Political Pharmaceuticals has a highly regulatory environment while CRP is out of any regulation; reliance mechanism can only be implemented between institution with same regulatory framework which is not the case between NRA and WHO Respondents from industry and health authorities who used the procedure were asked about their impression of the WHO-CRP (Figure 56). Both groups of respondents had a high level of satisfaction (90%, 28/31 and 91%, 20/22 for NMRA and industry respondents, respectively). Two industry respondents had an unfavorable impression (9%, 2/22), and one NMRA respondent was undecided (10%, 1/31). 128 Figure 56: Overall impression of the WHO-CRP: NMRA and Industry Responses NMRA participants most commonly mentioned time savings as influencing their overall impression of the WHO-CRP (Table 23). Respondents also generally recognized the value of the program’s objectives and goals. Table 23: Overall impression of the WHO-CRP: Selected NMRA Opinions What is your overall impression of the WHO-CRP? (Please explain your answer if favorable or unfavorable) Favorable CIPP Category Comment Input Collaboration It has a lot of potential. The African regulators can leverage from the review done by SRAs and learn from it also Input Design Forward looking, gradually many regulatory authorities in Africa will make amendments to adopt in phases. Input Design The procedure is detailed and unambiguous Input Design The procedure works but is too bureaucratic. Process Duration It reduces workload and also shorten time for product to be available on the market Process Duration The process takes shorter timelines and if product is pre-qualified. The outcomes are mostly positive Process Procedure Facilitate the registration of the product and we would like to have the same procedure for renewals (lifecycle management of the product) Process Resources It simplifies the workload we have as regulators while not negatively affecting the quality of work Process Resources The potential benefits of collaborative procedure by the reference SRA are significant and it can really help to reduce time and costs of regulatory approvals. I strongly hope that companies can utilize this regulatory process to combine resources and share workload to ensure timely access to the medicine to patients. Product Effectiveness These would facilitate access of medicines to the public which are of adequate quality, safety and efficacy 9% (2/22) 91% (20/22) 10% (3/31) 90% (28/31) 0% 20% 40% 60% 80% 100% Don't know Undecided Unfavorable Favorable Percent NMRA Industry What is your overall impression of the WHO-CRP procedure? 129 Industry respondents appreciated the time savings associated with the WHO-CRP (Table 24). Some also generally recognized the value of the program’s objectives and goals. Table 24: Overall Impression of the WHO-CRP: Selected Industry Opinions What is your overall impression of the WHO-CRP? Favorable CIPP Category Comment Context Political Favorable but still a lot to improve. It is not fully harmonized, National requirements/commitments still to be fulfilled. Input Design The process is a brilliant way of getting quick registrations in Africa as your application goes through an abridged evaluation process; however, i found the process too bureaucratic, with WHO prequaliification team taking long to respond at times. Process Duration Review timelines for certain countries may be more predictable. Further, regulatory burden may be lessened for some (not all the participating countries) Process Duration Simplified dossier requirements are currently the main advantage, at least at the submissions start. In some case also faster review timelines are seen. Process Duration Timelines were drastically reduced in CRP-participating countries. Work was more effective due to the reuse of the EMA dossier and worksharing among the CRP countries. Feedback from participating countries was positive. Process Resources It has helped a lot of companies in Africa and foreign companies looking to register and invest in Pharma. Registration is faster, less complicated, cost-effective and time efficient. Unfavorable CIPP Category Comment Process Duration Review times take years Industry participants were asked to what extent each of nine factors influenced them to use the procedure (Table 25, Figure 57). Most influential were: “shorter review timelines” (80%, 16/20 strongly influenced; 10%, 2/20 moderately influenced; 10%, 2/20 did not influence); “inclusion of countries intended for registration” (68%, 15/22 strongly influenced; 23%, 5/22 moderately influenced; 5%, 1/22 did not influence; 5%, 1/22 did not know); “more predictable timelines” (68%, 15/22 strongly influenced; 27%, 6/22 moderately influenced; 5%, 1/22 did not influence); and “the desire to support regional 130 harmonization in Africa” (57%, 12/21 strongly influenced; 14%, 3/21 moderately influenced; 19%, 4/21 did not influence; 10%, 2/21 did not know). Approximately half of the respondents were strongly influenced by “simpler requirements” compared to other pathways (50%, 11/22 strongly influenced; 32%, 7/22 moderately influenced; 14%, 3/22 did not influence; 5%, 1/22 did not know) and “simpler post-registration maintenance of dossiers and variation documents” (48%, 10/21 strongly influenced; 29%, 6/21 moderately influenced; 19%, 4/21 did not influence; 5%, 1/22 did not know). Less influential factors were the “ability to receive marketing authorization in multiple countries based on a single dossier” (43%, 9/21 strongly influenced; 43%, 9/21 moderately influenced; 14%, 3/21 did not influence); potential to have “closer interactions with NMRAs during the review” (36%, 8/22 strongly influenced; 27%, 6/22 moderately influenced; 27%, 6/22 did not influence; 9%, 2/22 did not know); or the potential of reusing submission components for other purposes, such as reimbursement (9%, 2/22 strongly influenced; 27%, 6/22 moderately influenced; 41%, 9/22 did not influence; 23%, 5/22 did not know). 131 Table 25: Key Factors Influencing Use of WHO-CRP: Selected Industry Opinions Strongly influenced Moderately influenced Did not influence Don't know Submission components can be reused for other purposes, N=22 9% (2/22) 27% (6/22) 41% (9/22) 23% (5/22) The procedure could offer closer interactions with Health Authorities during review, N=22 36% (8/22) 27% (6/22) 27% (6/22) 9% (2/22) Applicants can submit a single dossier and receive marketing authorization in multiple countries, N=21 43% (9/21) 43% (9/21) 14% (3/21) 0% Post-registration maintenance of dossiers and variation submissions might be easier, N=21 48% (10/21) 29% (6/21) 19% (4/21) 5% (1/21) Requirements and process appeared simpler than other pathways, N=22 50% (11/22) 32% (7/22) 14% (3/22) 5% (1/22) My organization wanted to support regional harmonization efforts in Africa, N=21 57% (12/21) 14% (3/21) 19% (4/21) 10% (2/21) The procedure may have more predictable timelines than other pathways, N=22 68% (15/22) 27% (6/22) 5% (1/22) 0% The procedure is used by the countries where I wanted to register my product, N=22 68% (15/22) 23% (5/22) 5% (1/22) 5% (1/22) Review timelines may be faster than with other pathways, N=20 80% (16/20) 10% (2/20) 10% (2/20) 0% 132 Figure 57: Key Factors Influencing Use of WHO-CRP: Industry Responses 2 (9%) 8 (36%) 9 (43%) 10 (48%) 11 (50%) 12 (57%) 15 (68%) 15 (68%) 16 (80%) 6 (27%) 6 (27%) 9 (43%) 6 (29%) 7 (32%) 3 (14%) 6 (27%) 5 (23%) 2 (10%) 9 (41%) 6 (27%) 3 (14%) 4 (19%) 3 (14%) 4 (19%) 1 (5%) 1 (5%) 2 (10%) 5 (23%) 2 (9%) 1 (5%) 1 (5%) 2 (10%) 1 (5%) 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% Submission components can be reused for other purposes, N=22 The procedure could offer closer interactions with Health Authorities during review, N=22 Applicants can submit a single dossier and receive marketing authorization in multiple countries, N=21 Post-registration maintenance of dossiers and variation submissions might be easier, N=21 Requirements and process appeared simpler than other pathways, N=22 My organization wanted to support regional harmonization efforts in Africa, N=21 The procedure may have more predictable timelines than other pathways, N=22 The procedure is used by the countries where I wanted to register my product, N=22 Review timelines may be faster than with other pathways, N=20 Which of the following factors influenced your decision to use the WHO-CRP? Don't know Did not influence Moderately influenced Strongly influenced 133 4.6.2 Impact An impact evaluation assesses a program’s reach to its target audience. NMRA and industry respondents were asked whether the WHO-CRP is sufficiently publicized (Figure 58). Over two-thirds of NMRA respondents (67%, 18/27), and almost three-quarters of industry participants (71%, 15/21) thought that it was not. Less than a quarter of participants thought that it was (NMRA: 22%, 6/27; Industry: 24%, 5/21) with fewer respondents saying they did not know (NMRA: 11%, 3/27; Industry: 5%, 1/21). Figure 58: Publicity about the WHO-CRP: Is it sufficient? Over half (55%, 16/29) of the industry respondents stated that they heard about the procedure directly from the WHO or NMRA website (Figure 59) or became aware through a colleague or coworker (24%; 7/29). Less than 15% heard about it from a news source (10%; 3/29) or conference 10%; 3/29). Neither “other” nor “participated in the process design” were selected. . 5% (1/21) 71% (15/21) 24% (5/21) 11% (3/27) 67% (18/27) 22% (6/27) 0% 20% 40% 60% 80% Don't know No Yes Percent NMRA Industry Do you feel the WHO-CRP is sufficiently publicized? 134 Figure 59: Publicity about the WHO-CRP: Industry Responses 4.6.3 Effectiveness: Duration One goal of the WHO-CRP program is to reduce the time that it takes to register a product. Participants were asked about the duration of different steps in the process to identify bottlenecks. Participants were asked to rate each step as “longer than expected”, “shorter than expected”, “about what was expected”, or “timelines were not monitored” (Table 26, Figure 60). The first step, authorizing the WHO to share the assessment and inspection outcomes for the product, showed varying experiences by NMRA (42%, 11/26 “shorter than expected”, 27%, 7/26 “about what was expected”, 19%, 5/26 “longer than expected” and 12%, 2/26 “timelines not monitored”), and by industry (22%, 4/18 “shorter”, 39%, 7/18 “about what was expected”, 17%, 3/18 “longer” and 22%, 4/18 “timelines not monitored”). NMRA and industry respondents differed with regards to the dossier sharing step. Most NMRA respondents thought that it went faster than they expected (42%, 10/24 “shorter”, 33%, 7/24 “about what was expected”, 17%, 4/24 “longer” and 8%, 2/24 “timelines not monitored”), whereas most industry participants felt that it went slower 10% (3/29) 55% (16/29) 24% (7/29) 10% (3/29) 0% 20% 40% 60% Other Participated in the process design Conference or meeting Health Authority or WHO website Colleague or coworker Article, press release, or other news source Percent How did you become aware of the WHO-CRP? 135 than expected (14%, 2/14 “shorter”, 21%, 3/14 “about what was expected”, 57%, 8/14 “longer” and 7%, 1/14 “timelines not monitored”). Half of the NMRA respondents thought that the dossier review went faster than expected (50%, 13/26 “shorter”, 23%, 6/26 “about what was expected”, 23%, 6/26 “longer” and 4%, 1/26 “timelines not monitored”), whereas half of the industry participants felt that it was about what they expected (24%, 4/17 “shorter”, 47%, 4/17 “about what was expected”, 18%, 3/17 “longer” and 12%, 2/17 “timelines not monitored”). When asked about the duration of the request for supplemental information step, the responses of NMRA participants were divided between having a shorter duration than expected and longer than expected (43%, 10/25 “shorter”, 39%, 9/25 “about what was expected”, 17%, 4/25 “longer” and 0%, 0/25 “timelines not monitored”), whereas that of industry participants skewed toward a duration that was longer than expected (22%, 4/18 “shorter”, 22%, 4/18 “about what was expected”, 50%, 9/18 “longer” and 6%, 1/18 “timelines not monitored”). Similarly, the response of the applicant to the request for information was either shorter or about what was expected for most of the NMRA participants (NMRA: 36%, 10/25 “shorter”, 40%, 10/25 “about what was expected”, 20%, 5/25 “longer” and 4%, 1/25 “timelines not monitored”), but longer than what industry participants expected (12%, 2/17 “shorter”, 24%, 4/17 “about what was expected”, 53%, 9/17 “longer” and 12%, 2/17 “timelines not monitored”). The duration of the GMP inspection step for the NMRA respondents was mostly shorter than or similar to expectations (23%, 5/22 “shorter”, 45%, 10/22 “about what was 136 expected”, 18%, 4/22 “longer” and 14%, 3/22 “timelines not monitored”), but skewed toward being a little longer for the industry subgroup (17%, 2/12 “shorter”, 25%, 3/12 “about what was expected”, 33%, 4/12 “longer” and 25%, 3/12 “timelines not monitored”). The time needed to communicate a registration decision to the applicant was skewed for the NMRA respondents toward shorter than expected (50%, 13/26 “shorter”, 35%, 9/26 “about what was expected”, 15%, 4/26 “longer” and 8%, 2/26 “timelines not monitored”) but for industry participants skewed toward longer (24%, 4/17 “shorter”, 18%, 3/17 “about what was expected”, 47%, 8/17 “longer” and 12%, 2/17 “timelines not monitored”). Similarly, NMRA tended to view the time needed to issue a registration license as faster than expected (48%, 12/25 “shorter”, 20%, 5/25 “about what was expected”, 24%, 6/25 “longer” and 0%, 0/25 “timelines not monitored”), whereas industry participants tended to see it as longer (31%, 5/16 “shorter”, 13%, 2/16 “about what was expected”, 44%, 7/16 “longer” and 13%, 2/16 “timelines not monitored”). 137 Table 26: Duration of WHO-CRP Process Steps Compared to Other Pathways Question Shorter than expected About what was expected Longer than expected Timelines were not monitored Applicants authorize WHO to share its assessment and inspection outcomes for the specific product NMRA (N=26) 11 (42%) 7 (27%) 5 (19%) 2 (12%) Industry (N=18) 4 (22%) 7 (39%) 3(17%) 4 (22%) Dossier is shared using a secure internet-based platform NMRA (N=24) 10 (42%) 7 (33%) 4 (17%) 2 (8%) Industry (N=14) 2 (14%) 3 (21%) 8 (57%) 1 (7%) The reviewer reviews the dossier NMRA (N=26) 13 (50%) 6 (23%) 6 (23%) 1 (4%) Industry (N=17) 4 (24%) 4 (47%) 3 (18%) 2 (12%) The reviewer sends requests to the applicant for supplemental information NMRA (N=25) 10 (43%) 9 (39%) 4 (17%) 0 (0%) Industry (N=18) 4 (22%) 4 (22%) 9 (50%) 1 (6%) Applicant responds to the request for supplemental information NMRA (N=25) 9 (36%) 10 (40%) 5 (20%) 1 (4%) Industry (N=17) 2 (12%) 4 (24%) 9 (53%) 2 (12%) GMP inspection is performed NMRA (N=22) 5 (23%) 10 (45%) 4 (18%) 3 (14%) Industry (N=12) 2 (17%) 3 (25%) 4 (33%) 3 (25%) Reviewer communicates decision to applicant NMRA (N=26) 13 (50%) 9 (35%) 4 (15%) 2 (8%) Industry (N=17) 4 (24%) 3 (18%) 8 (47%) 2 (12%) Registration license is issued to the applicant NMRA (N=25) 12 (48%) 5 (20%) 6 (24%) 0 (0%) Industry (N=16) 5 (31%) 2 (13%) 7 (44%) 2 (13%) 138 Figure 60: Duration of WHO-CRP Process Steps Compared to Other Pathways 11 (42%) 4 (22%) 10 (43%) 2 (14%) 13 (50%) 4 (24%) 10 (43%) 4 (22%) 9 (36%) 2 (12%) 5 (23%) 2 (17%) 13 (46%) 4 (24%) 12 (52%) 5 (31%) 7 (27%) 7 (39%) 7 (30%) 3 (21%) 6 (23%) 8 (47%) 9 (39%) 4 (22%) 10 (40%) 4 (24%) 10 (45%) 3 (25%) 9 (32%) 3 (18%) 5 (22%) 2 (13%) 5 (19%) 3 (17%) 4 (17%) 8 (57%) 6 (23%) 3 (18%) 4 (17%) 9 (50%) 5 (20%) 9 (53%) 4 (18%) 4 (33%) 4 (14%) 8 (47%) 6 (26%) 7 (44%) 3 (12%) 4 (22%) 2 (9%) 1 (7%) 1 (4%) 2 (12%) 1 (6%) 1 (4%) 2 (12%) 3 (14%) 3 (25%) 2 (7%) 2 (12%) 2 (13%) 0 2 4 6 8 10 12 14 NMRA (N=26) Industry (N=18) NMRA (N=24) Industry (N=14) NMRA (N=26) Industry (N=17) NMRA (N=25) Industry (N=18) NMRA (N=25) Industry (N=17) NMRA (N=22) Industry (N=12) NMRA (N=26) Industry (N=17) NMRA (N=25) Industry (N=16) Assessment & inspection shared by WHO Dossier is shared using a secure platform Reviewer reviews the dossier Reviewer requests supplemental information Applicant provides supplemental information GMP inspection is performed Reviewer communicates decision Registration license is issued COUNT The WHO-CRP has several steps. Please indicate how the duration of each step compares to other registration procedures you have used. Timelines were not monitored Longer than expected About what was expected Shorter than expected 139 Although most timelines met or exceeded expectations, only half of NMRA participants identified that the entire process for a most recent or typical product took less than 6 months (< 6 months: 48%, 12/25; 6-12 months: 28%, 7/25; 12-18 months: 8%, 2/25; 18-24 months:16%, 4/25) (Figure 61). Industry participants reported that only 17% (3/18) of reviews took less than 6 months to complete, and less than half (45%, 8/18) were complete within the year; 6-12 months: 28%, 5/18; 12-18 months: 33%, 6/18; 18-24 months:11%, 2/18; 2-3 years: 6%, 1/18; > 3 years: 6%, 1/18). Figure 61: Duration of WHO-CRP: NMRA and Industry Responses NMRA: Please think about either the most recent product or a typical product that you reviewed using the WHO-CRP process. How long did it take from the time you received the dossier to the time you issued a regulatory decision? Industry: Please think about either the most recent product or a typical product that you registered using the WHO-CRP process, how long did it take from the time you submitted the dossier to the country to the time you received a regulatory decision? 6% (1/18) 6% (1/18) 11% (2/18) 33% (6/18) 28% (5/18) 17% (3/18) 16% (4/25) 8% (2/25) 28% (7/25) 48% (12/25) 0% 10% 20% 30% 40% 50% 60% More than 3 years 2 to 3 years 18 months to less than 2 years 1 year to less than 18 months 6 months to less than 1 year Less than 6 months Percent NMRA Industry 140 Despite these varying experiences, both groups felt that the WHO-CRP took less time than national procedures [National procedure longer: (NMRA 88%, 21/24: Industry: 58%, 11/19); WHO-CRP procedure longer (NMRA 8%, 2/24: Industry: 11%, 2/19); both about the same: (NMRA: 4%, 1/24, Industry:16%, 3/19); or did not know (NMRA: 0%, 0/23, Industry: 16%, 3/19)]. (Figure 62). Figure 62: Duration of WHO-CRP versus a National Registration Procedure 4.6.4 Sustainability: Future Availability About a quarter (23%, 6/26) of NMRA and industry respondents (25%, 5/20) were concerned that the WHO-CRP process would not be available after 2023, whereas almost a third of NMRA respondents (31% 8/26), and 10% (2/20) of industry respondents were not (Figure 63). The remainder (NMRA: 46% 12/26; Industry: 65%, 13/20) did not know whether the program would persist. 16% (3/19) 16% (3/19) 58% (11/19) 11% (2/19) 4% (1/24) 88% (21/24) 8% (2/24) 0% 20% 40% 60% 80% 100% Timelines were not monitored Don't know Both procedures have about the same duration National procedure takes longer WHO-CPAR procedure takes longer Percent NMRA Industry How does the timing of the WHO-CRP procedure compare to those of your national registration procedure? 141 Figure 63: Process Sustainability - Future Availability: NMRA and Industry Responses 4.6.5 Sustainability: Challenges When asked which factors would influence their decision about whether to recommend (NMRA) or use (Industry) the WHO-CRP process (Figure 64) in the future, almost three times as many NMRA respondents felt that the process was too complex compared to industry respondents (NMRA: 16%, 4/25, Industry: 6%, 2/34). Nearly half of NMRA participants suggested that additional training is required to understand and use the procedure (47%, 16/34) compared to about a quarter of industry participants (24%, 6/25). About the same percentage of NMRA respondents as industry respondents felt that the process was too long compared to other procedures (NMRA: 12%, 4/34, Industry: 12%, 3/25) and that the process was too lengthy (NMRA: 9%, 3/34, Industry: 12%, 3/25). Both groups agreed that the estimated timelines were not accurate or reliable (NMRA: 15%, 5/34, Industry: 24%, 6/25). Both groups also agreed that the benefits of the procedure are less appealing than for other pathways (NMRA: 12%, 4/34, Industry: 12%, 3/25). 65% (13/20) 10% (2/20) 25% (5/20) 46% (12/26) 31% (8/26) 23% (6/26) 0% 10% 20% 30% 40% 50% 60% 70% Don't know Agree Disagree Percent NMRA Industry I am concerned that the WHO-CRP procedure will not be available 142 Figure 64: Process Sustainability - Future Use: NMRA and Industry Responses Many NMRA participants stated that instructions were unclear for the reviewers (29%, 5/17) and applicants (41%, 7/17). Five (29%, 5/17) said that other factors would influence their decision about whether they would use the procedure in future (Figure 65). “Other” comments included “None of the above” and “Process is optimum as it is”. Figure 65: Influential factors on Future Use: NMRA Responses 12% (3/25) 12% (3/25) 24% (6/25) 12% (3/25) 24% (6/25) 16% (4/25) 12% (4/34) 9% (3/34) 15% (5/34) 12% (4/34) 47% (16/34) 6% (2/34) 0% 10% 20% 30% 40% 50% Benefits are less appealing than other pathways Process duration was too lengthy Estimated timelines were not accurate/reliable Procedure was too long compared to other procedures Additional training is required Process was too complex Percent NRMA Industry Which of the following factors will influence your decision about whether you will use (Industry) or recommend the use (NMRA) of the WHO-CRP in the 29% (5/17) 29% (5/17) 41% (7/17) 0% 10% 20% 30% 40% 50% Other Procedure instructions were insufficient for reviewers Procedure instructions were insufficient for Applicant Percent What factors will influence your decision about whether to use the WHO-CRP in the future? 143 Almost half (48%, 10/21) of the industry participants do not plan to register product in the countries within the scope of the procedure (Figure 66). Some felt that the review progress was not transparent (24%, 5/21), important information, such as timelines, was not communicated (19%, 4/21), and instructions about how to use the procedure were insufficient (10%, 2/21). Figure 66: Influential factors on Future Use: Industry Responses NMRA participants were asked if they would recommend the WHO-CRP in the future (Figure 67). Overwhelmingly, these participants agreed that they would (88%, 23/26). One respondent would not (4%, 1/26) and two others did not know (8%, 2/26). Figure 67: Influential factors to Recommend Future Use: NMRA Responses 10% (2/21) 19% (4/21) 24% (5/21) 48% (10/21) 0% 20% 40% 60% Instructions about how to use the procedure were insufficient Important information such as deviations from expected timelines were not communicated Review progress was not transparent to me Future plans do not include countries within the scope of the procedure Count Which of the following factors will influence your decision about whether you will use the WHO-CRP in the future? 8% (2/26) 4% (1/26) 88% (23/26) 0% 20% 40% 60% 80% 100% Don't know No Yes Percent Based upon your experience with the WHO-CRP procedure, will you use the WHO-CRP procedure again in the future? 144 When asked to comment further about their impressions of the WHO-CRP (Table 27), favorable NMRA respondents pointed out its value in reducing backlogs, simplifying work, and providing additional time to address other important work. One participant stated that further training was needed. Table 27: Influential factors on Future Use: Selected NMRA Opinions Based upon your experience with the WHO-CRP procedure, will you recommend the use of the WHO-CRP procedure in your organization in the future? Positive CIPP Category Comment Input Collaboration Offers better audit trails and collaboration Input Design Impetus to effective standardisation of activities Process Resource Efficient procedure Process Resource Gives time to assessors to work on other applications which are not prequalified Process Resource Reduces our backlog Process Resource The benefits of capacity building, quicker turnaround time therefore freeing up resources for products with higher risk No CIPP Category Comment Process Procedure Further training needed Industry participants were asked whether they would use the procedure in the future (Figure 68). Almost all (90% 19/21) agreed, but one respondent was undecided (5%, 1/19) and one did not know (5%, 1/19). Overall, the industry respondents echoed NMRA counterparts citing the advantages of speed and efficiency (Table 28). One expressed the hope that the program would be expanded to cover additional countries. 145 Figure 68: Influential factors to Recommend Future Use: Industry Responses Table 28: Influential factors on Future Use: Selected Industry Opinions Based upon your experience with the WHO-CRP, will you use the WHO-CRP again in the future? Yes CIPP Category Comment Input Design Would really love to cover more countries in one application under the harmonization program. Process Duration I will use it again since a number of African NMRAs prefer it to the standard pathways because of the short time spent on reviews Product Effectiveness The procedure is maturing, and I believe that in the future the advantages of the procedure will become clearer and easier to apply, once all stakeholders become more familiar. Product Reach Presently involved in product prequalification exercise. Hope to use the produce in registering the dossier on other countries. 4.6.6 Did the WHO-CRP Program Meet the Needs? Survey respondents were asked whether the WHO-CRP met the needs of their organization (Figure 69). The responses of NMRA respondents were mostly affirmative (Yes: 81%, 21/26; No: 8%, 2/26; Don’t know: 12%, 3/26). Some participants expanded their answers (Table 29) by noting that the faster process helped to reduce the backlog and providing quicker assessments when needed for public safety. Another noted that the process can be delayed because the applicant does not respond quickly. 5% (1/21) 5% (1/21) 90% (19/21) 0% 20% 40% 60% 80% 100% Don't know Undecided No Yes Percent Based upon your experience with the WHO-CRP procedure, will you use the WHO-CRP procedure again in the future? 146 Figure 69: NMRA and Industry Opinions on Whether the WHO-CRP Meets Their Needs Most industry participants also agreed (Yes: 85%, 17/20; No: 10%, 2/20; Don’t know: 5%, 1/20). Comments from industry participants echoed the benefit of speed to get products registered. One participant mentioned that it cut costs by 40%. Others who stated that the process did not meet the needs of industry cited the lengthy duration of the procedure and the need to simplify the requirements (Table 30). Table 29: Satisfaction with the Process: Selected NMRA Opinions Did the WHO-CRP meet the needs of your organization? (Please explain your answer if you answer "yes" or "no") Yes CIPP Category Comment Context Readiness Capacity Building Input Design Yes, it’s easier than the requirements of the national procedure Process Duration Faster registration of products which equates to timely access of the much-required medicines to patients. Process Duration Most of the CRP applications are completed within the time frame. NB. Sometimes it will be delayed by the applicant not responding the additional information. Process Procedure Flexible process Product Need Alignment of life cycle of registered product with WHO PQ Product Need It meets the need but due to regulations, although you have a CRP approval and can start marketing, you still have to go through the national registration process Product Need For access to quality drugs and vaccine not produced locally...Yes Product Effectiveness Our procedure is still in progress and is not complete Product Effectiveness The quality of the reports is satisfactory 5% (1/20) 10% (2/20) 85% (17/20) 12% (3/26) 8% (2/26) 81% (21/26) 0% 20% 40% 60% 80% 100% Don't know No Yes Percent NMRA Industry Did the WHO-CRP procedure meet the needs of your organization? 147 Table 30: Satisfaction with the Process: Selected Industry Opinions Did the WHO-CRP meet the needs of your organization? (Please explain your answer if you answer "yes" or "no") Yes CIPP Category Comment Process Duration We received some approvals within 90 days during the pilot SRA CRP Process Resources It did cut costs by 40% Product Effectiveness We were able to register products in several countries. Product Need It did meet the requirements. We did get approval in the stated timelines and helped ease the launch of our product No CIPP Category Comment Process Duration Years have passed and we are still waiting for decision Product Need One of the needs is faster registration in African countries, WHO-CRP does not fully meet this need. Also the need to simplify/remove country-specific requirements or GMP requirements is not fully met at this moment. 4.7 Final Comments At the end of the survey, participants had the opportunity to comment further (Table 31). One NMRA participant stated, “Respect for sovereignty and non outsourcing of national decision” was an important consideration. Comments from industry varied. One respondent observed that filings made using African harmonized pathways may not be allocated the same amount of review time as those submitted using national procedures. A few focused on the cost of the process, and two were concerned about the long-term sustainability of the program. Finally, another participant from industry noted, “It seems to me that there's no strong regulations and commitment on which harmonisation is premised”. 148 Table 31: Additional Comments Do you have any comments that were not captured above that you would like to include? NMRA Respect for sovereignty and non outsourcing of national decision Industry African Regulatory Harmonization pathways are not given much time by the regulators as compared to when submissions are made to the independent NMRAs. fees can comfortably sustain these project It seems to me that there's no strong regulations and commitment on which harmonisation is premised. Manufacturers can pay necessary fees above country fees if there's commitment on timelines. The funding mechanism is based on donations from NGOs. This is not sustainable. The product registration fees for this procedure should be cheaper 149 Chapter 5. Discussion 5.1 Overview Regulatory harmonization is widely recognized as an essential step to facilitate the delivery of needed medicines to waiting patients; however, comprehensive evaluations are still needed to assess the effectiveness of pathways designed to increase harmonization and reliance. This research expands the existing body of knowledge on regulatory harmonization in Africa by exploring systematically the use of the WHO-CRP across the continent. The results present and compare the perspectives of industries that use this process to register their products with those of the NMRAs that use the process to review their submissions; however, the delimitations and limitations associated with this exploratory research should be first acknowledged to assist the interpretation of these results. 5.2 Considerations of Study Methodology 5.2.1 Delimitations A study such as this can become unfocused if suitable boundaries are not placed on its scope. Many harmonized regulatory pathways exist in Africa; however, this study was delimited to evaluating the WHO-CRP facilitated regulatory pathway that is currently in place to facilitate pharmaceutical registrations in Africa. Although the pathway also operates in other constituencies, such as the Caribbean Community, the survey was directed specifically on its use in Africa. Results from other continents, while interesting, might blur the findings that already include two different stakeholder groups, regulators and industry participants, whose views are somewhat different. By focusing 150 specifically on the many African countries that use the WHO-CRP pathway, specific challenges for the African participants are less likely to be lost than they would be in a more general study of the WHO-CRP use across multiple, diverse regions. A more focused analysis could also be important if it is to be used to inform African development planning. However, only about half of the countries in Africa use the WHO-CRP process for dossier review, and not all companies use the WHO-CRP for product registration. Therefore, it is important to acknowledge that the results may not generalize easily to other regulatory pathways or other regions outside of Africa without further study in those regions. The extent to which results can be generalized will depends upon assuring an appropriate sample of respondents to represent its key stakeholders (Kelley et al., 2003). Those key stakeholders included both those who work for regulated entities using the pathway for product registration and regulators who use the pathway to review dossiers, so both subpopulations were included in the study. This drove a diligent search to enroll enough respondents with sufficient exposure to the WHO-CRP to obtain a balanced view, as discussed below. A further issue of research design that can delimit the kinds of questions that are asked is the choice of framework to structure the study. The CIPP Framework, described in Chapter 2, is a well-recognized evaluation framework that provides a comprehensive architecture upon which to evaluate a program such as the WHO-CRP (Eccles et al., 2005). It has been used extensively over 60 years (Kahan, 2008) and has been cited in almost 1000 publications of diverse scope, including public health programs (Walden and Baxter, 2001), so it is well-suited and validated to frame this research. However, because 151 this framework focusses on program evaluation and assessment, it does not provide insights into other aspects of the WHO-CRP program, such as its perceived strategic advantages at the governmental or societal level or its financial or healthcare benefits downstream. These may be topics worthy of further study in future. 5.2.2 Limitations Perhaps the single limitation of greatest concern at the beginning of this study was its delimitation to experienced professionals directly involved in the WHO-CRP process. This posed challenges to assure that enough participants could be recruited to participate in the survey because only a small overall pool of individuals have such direct experience. A recent presentation by the WHO reported that over 600 registration applications had been made using the WHO-CRP process by 24 companies, but over 250 of these applications were submitted by a single company, and almost 500 were submitted by three companies. Ten companies submitted less than five applications each using this procedure (Azatyan, 2020). Therefore, the population of regulatory professionals familiar with this process was anticipated to be small. Finding suitable participants was also complicated because specific lists of WHO- CRP users do not exist, and scientific literature about its use is scanty. Thus, as identified in Methodology (Section 3.2.2), extensive searching was needed to identify active employees of pharmaceutical companies and NMRAs who were familiar with the WHO- CRP. This kind of targeted sampling approach was particularly suited to identify candidates for this research; targeted sampling is considered to be more powerful than convenience sampling and more efficient than random sampling (Huang et al., 2016). 152 One important tool for participant search was LinkedIn ® , a professional social networking site reported to have almost 740 million members in over 200 countries worldwide (Osman, 2021). However, few individuals specifically identified the WHO- CRP by name in their profile, so less precise search terms, such as “regulatory harmonization”, “regulatory Africa” and “regulatory prequalification” were used to identify potential participants. These search terms are clearly imprecise, so the results yielded many respondents who did not work in Africa or were not acquainted with the procedure and thus failed to qualify for participation. Nevertheless, it was encouraging, to find that a strong contingent of qualified regulators and industry professionals were willing to complete the survey. Engagement in a study is often measured by participation rate, which in this study was 27%. This rate of response appeared to be in line with other evaluations of response rate for academic studies, which can range as low as 20% (Nulty, 2008). Further, response rate is perhaps not the most important performance metric for a specialized study such as this. Baruch and Holtom suggest that representativeness rather than participation rate should be the main concern. They advance the view that a survey population can be representative despite a low response rate (Baruch and Holtom, 2008). Since the participants were comprised of fourteen participating NMRAs in Africa that represented all of the RECs and 11 of the top 14 NMRAs actively using the WHO-CRP, as well as industry participants from a diverse sample of both large and small generic and brand-name companies that were most familiar with the WHO-CRP, the participant pool was considered to be representative. 153 It was not always possible to filter the potential participants completely, especially in those instances where an anonymous survey link was provided to allow respondents to reach out to others who might have useful input. Dropouts after starting the survey were anticipated because many companies do not register their products using the WHO-CRP in Africa. Of those that do, other pathways may be favored, as suggested by the fact that nearly a third of those starting the survey did not even consider using the WHO-CRP pathway. At the same time, about two-thirds of respondents here at least considered its use, suggesting that the right audience had been reached. In addition, industry respondents reported that they had registered 124 products using the WHO-CRP (Figure 34). Azatyan reported that 612 registrations using the WHO-CRP has been made as of 30 November 2020, a timeframe that matches this study. Industry participants in this study had therefore been involved with at least 20% (124/612) of the total registrations using the CRP process (Azatyan, 2020). Their informed opinions, particularly in text responses, provided detailed and specific comments related to the procedure. All of these considerations led me to believe that my recruitment strategy had been successful in finding a highly qualified sampling of industry candidates alongside the appropriate NMRA respondents. In this study, a survey method was selected as the research vehicle over other options, such as interviews or focus groups. Surveys can reach a broad range of individuals within a reasonable time and cost (Queirós, Faria and Almeida, 2017; Draugalis, Coons and Plaza, 2008). The advantage of this broader electronic reach was important here because most participants were geographically dispersed in Africa, Europe, or India. The asynchronous nature of an electronic survey enabled the 154 participants to complete the survey at their convenience, regardless of time zone or work schedule, potentially improving the completion rate (Callegaro, Manfreda, and Vehovar, 2015). However, electronic surveys also have disadvantages that can decrease participation rate. Participation rates in web-based surveys having declined steadily over the years (Adams and Umbach, 2012; Avery et al., 2006), a trend that was potentially magnified during the COVID-19 pandemic. The pandemic resulted in higher workloads for the pharmaceutical industry and NMRAs, as both sectors responded to the unprecedented disruptions that it caused. For health authorities, a much higher level of guidance development and rapid product approvals were needed to support the introduction of new medicines and other therapeutic products to address COVID-19 needs (Escalante, 2020). For industry, disruptions as diverse as supply chain and distribution challenges, clinical trial disruptions and acceleration of product development for emergency use products placed stress on regulatory professionals. The fact that the response rate was as robust as it was may reflect the success of the efforts used to improve participation rate, such as personal emails to each potential participant, an approach suggested to be beneficial by others (Dusek, Yurova, and Ruppel, 2015). In addition to engaging respondents so that they would open the survey, it was also important to ensure that they would complete it. Methodological literature has emphasized the effects that survey length and question suitability can have in assuring the engagement of participants (Herzog and Bachman, 1981). Therefore, the survey was designed to be comprehensive enough to be informative, but not so long as to be onerous. A focus group was employed to ensure the questions could be easily understood (Ouimet 155 et al., 2004). Also, the participants were told in the introductory survey invitation how long the survey would be. This has also been reported to improve survey engagement rates (Galesic and Bosnjak, 2009). These efforts probably helped to assure that the completion rate was high, 75%. Most who dropped out did so after they had finished describing their roles and experience, suggesting that they recognized deficits in their background or experience related to the specialized subject matter. The survey was offered in both French and English so that respondents could complete the survey in a language that was more familiar to them, allowing for richer critical expression (Rao, 2009). In addition, the Qualtrics platform allowed participants to complete the survey anonymously. An assurance of confidentiality is known to increase survey response rate (Singer, 1993). While none of the questions in the survey asked the respondents to disclose confidential or proprietary information, the anonymous platform afforded participants the assurance that they were sharing opinions in a confidential manner. 5.3 Consideration of Results The WHO-CRP is a unique regulatory pathway whose evaluation is particularly useful because the work-sharing and reliance activities of the WHO-CRP program are used across much of Africa. Using the CIPP Framework as a guide, this section discusses whether the finalized WHO-CRP program in Africa is useful. . It also evaluates the perceived barriers related to the use of this pathway and best practices for overcoming these challenges. These insights may inform the development of the facilitated regulatory pathways being set up in Africa and other resource-limited settings around the world. 156 5.3.1 Context In the CIPP Framework, “Context” is a term that refers to the effect that the external environment has on the new program. These externalities affect the appropriateness of the goals and processes set for the program. Some factors that can affect success include limitations in human resources, funding and time, as well as cultural and historical considerations. Defining the context of the WHO-CRP procedure in Africa is critical because these constraints are already known to affect the conduct of other harmonized processes in this region (Ahonkhai et al., 2016; Calder, 2016; Dansie, Odoch, and Årdal, 2019; Kamwanja et al., 2011; Ndomondo-Sigonda, 2018; Ndomondo- Sigonda et al., 2020; Sithole et al., 2020). Several areas of significance can be identified in the results presented here. Two in particular were identified by both NMRAs and industry participants as key impediments to optimum performance: the absence of consistent legislation to support regulatory harmonization throughout the RECs and the challenges of developing regulatory capacity throughout the continent. 5.3.1.1 Legislative and Political Harmonization Readiness When organizations partner, it is helpful if they operate under a consistent set of rules. Differences in national laws can impede effective harmonization (Lim, 2018). This challenge has been recognized by the WHO, which considers political and governmental support to be a key enabler of good regulatory practice (World Health Organization, 2021b) The lack of consistent legislation identified in this study reinforces the conclusions drawn previously about the need for common or consistent legislation 157 (Ndomondo-Sigonda et al., 2017; Rago et al., 2014; World Health Organization, 2016). As one respondent summarized the problem: “It seems to me that there's no strong regulations and commitment on which harmonisation is premised”. Legislative frameworks in Africa, like most other parts of the world, are based on laws that were developed at the national level at a time when the need to demonstrate sovereignty was more important than a desire for harmonization. This heterogeneous legislative environment has been recognized to impede harmonization for more than a decade (World Health Organization, 2010), yet adjacent countries within RECs continue to have different legislative, and therefore different regulatory, systems for approving medicines. The African Union Model Law attempted to remediate this problem by providing a framework to be used by Member States to update their current laws in ways that would facilitate regulatory harmonization in the region. However, this Model Law has been “domesticated” (i.e., adopted in principle, but not set into law) by only slightly more than a quarter of the AU Member States (Ndomondo-Sigonda et al., 2020). The actual number of countries whose laws fully support harmonization is as yet unclear (Ncube, Dube, and Ward, 2021). Insufficient ratification of the legislation continues to have a long-term effect on the speed of harmonization. Responses from both NMRA and industry underscore the need for more AU Member States to implement the Model Law if the speed of harmonization speed is to improve. As one participant states: “regional harmonisation authority groupings can only recommend their decisions to member states who at times take long to implement without any consequences, they do not have legislative authority”. 158 5.3.1.2 Regulatory Capacity Another significant barrier that was identified by respondents in both government and industry is the difference in regulatory proficiency amongst NMRAs that participate in the program. Weaknesses in the capabilities of some regulatory staff in Africa have been recognized for over a decade (World Health Organization, 2010), although recent reports show an overall improvement in capability and capacity (World Health Organization, 2018, 2020a). NMRA respondents gave examples to illustrate how things have changed over the years: Since some countries did not have Medicines Agencies, it was difficult to sit everyone together sometimes where other countries do not even have functional regulatory agencies. They won’t be able to make strategic decisions. Now it has progressed at the appropriate speed because regulatory agencies are being set. Working in the Regulatory Unit within the Ministry of Health, the legislation in my country previously had no provisions for product registration. Provisions have since been included thus there is an ongoing discussion on using the WHO-CRP as one of the product registration pathways. Thus, the WHO-CRP program seems not only to create a pathway for product registration, but also achieves its goal of providing a pathway for improving the capabilities of less mature NMRAs. Nonetheless, both industry and NMRA participants were aligned in theirs views that gaps in knowledge and training were a key barrier to regulatory harmonization in their region. A respondent acknowledged the benefit of the WHO-CRP, but felt that it needed to go further: 159 Technical support provided by the SRAs for Africa NRA is lacking and can be improved. There should be more efforts from SRA countries to share their technical knowledge with Africa NRAs, especially when it comes to assessing critical products that have been reviewed in their (SRA) countries. 5.3.2 Input In the CIPP Framework, “Input” evaluates whether the program strategy and design are sufficiently suitable and practical to support the success of a program. Typical factors include the adequacy of resources and staff needed to deliver the program. If the WHO-CRP had been designed ab initio, this component of the analysis would assess how well the planned resources would be able to meet the needs for program conduct. Evaluating these plans for the WHO-CRP may be less important as part of the input analysis here because the program has had to build on existing systems of personnel and financing. However, multiple approaches can be used to assess the match between program goals and process design (Dorst and Cross, 2001; MacNeil, et al., 2021; Nixon, 1999). Looking at the engagement from the feedback of a community of users can be one straightforward way of assessing views on usefulness and practicality (Wellman et al., 2001). 5.3.2.1 Engagement of NMRAs The success of the WHO-CRP and other harmonization activities will depend on the goodwill and trust of the harmonizing partners. While much has been said about what is lacking in the region, what may not be recognized are the interest, motivation, and cooperation of those using the harmonized regulatory processes in Africa. NMRA participants typically agreed that their agencies supported harmonization initiatives despite the significant workloads needed to implement them. This suggested considerable 160 interest and engagement in these initiatives, including ZAZIBONA, SADC, EAC, WAHO and IGAD initiatives as well as pharmacovigilance and cross-border surveillance initiatives. Further, participants often considered that their role in harmonization included a broader responsibility to build the capacity of other less developed agencies. As stated by two respondents: “We are the leading Authority in the SADC region and we help build capacity for other members, develop the system for harmonization” and “Offered key well trained staff to train regional peers for adoption of better processes and procedures”. However, that is not to say that all respondents shared the same opinions. A few respondents identified lack of trust as a barrier: “it makes it difficult to harmonize because there is no trust and respect among participating member states”. Some suggested that harmonized processes such as the WHO-CRP could help to improve the trust between regions as the regions continue to work together, providing: …opportunities to share experience, work sharing, learning to trust and then rely upon each other. Not all products are WHO prequalified. So these products need to follow the single country pathway but dossier review in any SRA can be leveraged upon for faster processing. The collaboration from manufacturers in this regard will strengthen trust. These views are consistent with previous suggestions of Giaquinto, that regulatory harmonization initiatives can have the additional benefit of building trust between regulators if they work together in a transparent way (Giaquinto et al., 2020). Dansie reported that this is what occurred in the EAC harmonization initiative: “…the countries did not necessarily trust the capabilities of others, so that this gradual start allowed the trust to grow” (Dansie, Odoch, and Årdal, 2019). 161 5.3.2.2 Role of Industry Both NMRA and industry participants appeared to recognize the value of collaborations not only between NMRAs, but also with industry. Some NMRAs saw the role of industry as that of advocacy, a responsibility embedded in some harmonization initiatives across the continent (Mashingia et al., 2020; Sithole et al., 2020). Others reinforced the benefit of leveraging industry’s technical knowledge and submission experience to improve not only the process, but also the backgrounds of regulators (Ndomondo-Sigonda et al., 2018; Sithole et al., 2020). The responses of industry were similar. Some industry respondents saw their role as conferring a more practical view of requirements and guidelines with an intent to improve both. Some industry participants also felt that process could benefit if industry could share its technical experience as part of capability building. As stated by one respondent: It is important that both on implementation or production of guidelines agencies should provide opportunity to get feedback to ensure they are aware of possible areas that may build in disincentives due to increased burden. 5.3.3 Process In the CIPP Framework, the “Process” element looks beyond environment and resource availability to evaluate whether the program’s operational activities were executed well. Because harmonized programs aim to accelerate the availability of safe and effective medicines, it was important to capture the views of regulators and industry on the ability of the WHO-CRP process to facilitate reviews and approvals. Reducing the time between dossier submission and regulatory decision has been identified as a key measure of the effectiveness of the WHO-CRP program (Caturla Goñi, 2016). The 162 importance of this acceleration to patient health seems clear from the modeling research of PATH, an international nonprofit global health organization based in Seattle. According to their models, accelerating access by 2 years for only two products, a heat- stable synthetic form of oxytocin for postpartum hemorrhage and a dispersible tablet of amoxicillin for the treatment of pneumonia in young children, could save more than 23,000 lives in eastern and southern Africa alone (PATH, 2018). Many respondents appeared to agree that WHO-CRP was shortening the approval path. For example, one participant identified that: Timelines were drastically reduced in CRP-participating countries. Work was more effective due to the reuse of the EMA dossier and worksharing among the CRP countries. Feedback from participating countries was positive. Nonetheless, some experiences were not so positive. This was clear from the succinct comment of an industry participant, who stated that “Review times take years”. An NMRA participant offered a possible explanation: Most of the CRP applications are completed within the time frame. NB. Sometimes it will be delayed by the applicant not responding the additional information. However, it is unlikely that this explanation is sufficient for all lengthy dossier reviews and approvals. Other factors that might contribute include the challenges of working within the restrictions of staffing and funding that have already been described above. Three elements appeared to be particularly significant as potential areas of process improvement and evaluation. Changes in these elements might have a positive impact on the timeliness and quality of the review and approval processes. They include: the availability of NMRA resources; the reduction of country-specific requirements; and the improved clarity of instructions and review actions. 163 5.3.3.1 Impact of Resource Restrictions Less than half of the NMRA participants agreed that they had sufficient time to assess dossiers, and even fewer that they had sufficient time to address applicant questions. The often-low staffing levels of the different NMRAs were identified as far back as 2013 (Weisfeld and Lustig, 2013). More recently, Calder studied this issue in one regional group of NMRAs belonging to the SADC (Calder, 2016). Calder found substantial differences in NMRA staffing, from 20 to 200 evaluators who were charged with reviewing and registering 143 to 552 medicines annually. When ratios were computed, workloads in different companies varied from 2.8 to 18.7 registrations per reviewer annually. Sillo also reported recently that Kenya and Uganda have only 11 qualified staff evaluators and Rwanda and Zanzibar have 2 (Sillo et al., 2020). However, even these low numbers may underestimate the workloads of some participants. One NMRA participant noted that annual review rates were between 2- and 10-fold higher than the rates noted by Calder, suggesting the situation may be becoming worse: Our regulatory authority has less than ten (10) assessors and we receive more than three hundred (300) applications per year therefore we do not have the capacity to do full assessments for all the products. Using the WHO-CRP route means the availability of medicines is accelerated. This observation was not surprising. Previous studies have pointed to the need to strengthen the numbers and capabilities of personnel in order to improve operational efficiency and quality in Africa (Lezotre, 2014a; Ndomondo-Sigonda et al., 2020; Sillo et al., 2020). Some have suggested that the registration process has been further taxed by the increasing number of generic medicines placed on the WHO’s Essential Medicines List; numbers have grown by about 75% over a 10 year period (Keyter et al., 2020). This has 164 significant implications in Africa, where many medicines are supplied by international agencies. These agencies require that the medicine is registered or prequalified as a prerequisite to being on the Essential Medicines List. The requirement puts further demands on the regulators. It suggests that metrics to judge the effectiveness of the harmonized procedures over time may be confounded by rising workloads related to increased submission numbers (Leng, Sanders, and Pollock, 2015), which would mask increases in efficiency per unit dossier. Since the low staffing levels at NMRAs limit throughput regardless of the pathways that they use for reviews, any intervention that can reduce the burden on reviewers cannot help but be useful. The high demands on reviewers may contribute to the rapid turnover of personnel seen in African NMRAs (Mashingia et al., 2020; Ncube et al., 2021; World Health Organization, 2018). When these reviewers leave their jobs, others must be found and trained. The loss of experienced reviewers and the burden of training new reviewers will exert continued operational drag on timelines and have long-term effects on the sustainability of the process (Gesinde and Adejumo, 2011). As legislators consider not only the health of their country’s population, but also the sustainability of their NMRAs, many suggest that elimination of redundant country- specific requirements through programs such as the WHO-CRP will be important to reduce the burden on these under-resourced agencies. (Ahonkhai et al., 2016; Mwangi, 2016). 5.3.3.2 Country-Specific Requirements Another major barrier to drug registration is that created by the country-specific requirements called out in the laws of individual countries (Calder, 2016; Narsai, 165 Williams, and Mantel-Teeuwisse, 2012). Of particular concern to respondents were requirements that the submitting manufacturer undergo a GMP inspection conducted by the local NMRA. This requirement makes sense in an environment where a GMP inspection by the NMRA is the only check on manufacturing quality. The resources expended for inspections become the cost of doing business that, nevertheless, can be difficult to afford in resource-limited companies. The need for local inspections could be reduced if NMRAs were permitted to rely on GMP inspections that have already been carried out on the submitting manufacturer by another respected regulatory authority. This would reduce the resource burden on the NMRA (Weisfeld and Lustig, 2013). Questions were therefore included in the survey to identify whether survey participants viewed GMP inspections by a local NMRA as beneficial, given the fact that the WHO- CRP procedure is predicated on WHO Prequalification or Stringent Regulatory Authority approval. Not surprisingly, most NMRA and industry respondents agreed that the GMP inspection did add value, but only if it is not redundant with another inspection done recently for the same purpose. Those who disagreed focused on the redundancy and waste of resources that duplicative inspections would entail. Relying on the GMP inspections of a stringent regulatory authority can have its downside. One concern is the sensitivity in some countries to its risk of abrogating national sovereignty. Still, inspections can also play a role in capacity building. Participation in joint reviews, for example, can strengthen the inspectional capabilities of the local regulators; reliance alone does not provide a good training opportunity. One NMRA respondent who felt that the GMP inspection added value mentioned the benefits of external opinions to improve assessment quality. Their views are consonant with 166 previous views that joint or reliant reviews can strengthen trust between NMRAs and build the capacity of reviewing teams (Mashingia et al., 2020). Having a cadre of capable inspectors is still important because not all drug submissions can use a harmonized procedure such as the WHO-CRP and therefore will still need to be inspected. New companies in particular will need inspections to learn where their activities are non-compliant or insufficient (Sillo et al., 2020). An intermediate approach might then be to use a risk-based approach to inspections, in which inspections are directed at only those companies that pose greatest concerns, either because of the nature of the product or their history of inspections. Some respondents regarded such an approach as a more efficient use of resources. Nonetheless, legislation may need to be amended in some countries to permit such an approach. Obtaining such legislative change could be difficult in some countries because the requirement for NMRA inspections may be seen by some politicians as a nontariff trade barrier that can protect local industry (Lezotre, 2014b). However, the requirement would then discourage cross-border trading and dampen African drug production and distribution, since local markets are small and neighboring countries might put in nontariff barriers of their own. 5.3.3.3 Availability of Instructions and Process Status No specific bottlenecks with the process steps were noted by NMRA or industry participants with respect to the process steps of submission, review, and approval. This finding seems to suggest that the program has been well-designed from a logistical perspective. Nonetheless, results were valuable in pointing to areas that could be improved further. Some felt that more detailed directions on how to submit the dossier 167 would streamline the process. Others identified that more transparency regarding decisions regarding the dossiers could also improve the processes. These two issues are relatively minor areas of improvement that have not been discussed in previous literature to my knowledge but could be “quick wins” for the NMRAs. 5.3.4 Product In the CIPP Framework, the term, “Product”, defines activities to determine whether the WHO-CRP program is seen to be successful. Success can be defined in multiple ways (Mazur, 2013), but others have relied on three types of outcomes: achievement of program objectives, user satisfaction, and long-term sustainability (Al- Khathami, 2012; Frye and Hemmer, 2012). These outcomes were adopted here as well because they all reflect different aspects of success. 5.3.4.1 Achievement of Program Objectives The program objectives of WHO-CRP are more ambitious than many other programs because they are designed to improve capability of NMRAs across the continent in addition to achieving the goal of faster registration. Further, the goals of the WHO-CRP have a broader vision of developing the pharmaceutical industry in Africa to assure that quality medicines reach waiting patients. If the program does not impact these broader goals, the value of the WHO-CRP would diminish. Both NMRA and industry users felt strongly that the WHO-CRP met the needs of their organization. Further, most NMRA and industry participants and even non-users were aligned that the program delivered on its goal to reduce the review time of product registrations. Median time to registration from 2013 to 2019 show registration times 168 between 75 and 114 days (Azatyan, 2020), a significant improvement over the 4 to 7 years using national procedures (Ahonkhai et al., 2016). NMRA and industry participants recognized improvements in the regulatory capability in the context of the WHO-CRP, such as reduced review times and high- quality reviews. While no assessment of regulatory capability improvements specifically due to the WHO-CRP is currently available, multiple indicators of advancement in the regulatory capability of participating NMRAs have been achieved, such as an increase of countries participating in the WHO-CRP, and an upsurge in dossier reviews per country per year (Azatyan, 2020). In addition, two countries have achieved Regulatory Systems Maturity Level 3. Their accomplishment suggests that their regulatory systems are well functioning and have all the required elements to ensure stable performance, and further suggests that the WHO-CRP is achieving its goal of fostering an improvement in regulatory capability in participating NMRAs. 5.3.4.2 User Satisfaction User satisfaction was seen to be critical because industry can choose between multiple pathways to achieve registration. If the WHO-CRP program is not efficient or valuable, it will not satisfy the stakeholders and will cease to be used. Despite the isolated concerns noted by the participants, such as the lack of legislative support for the program in some countries and the length of review time noted above, results here suggest that satisfaction is high amongst both NMRA and industry participants. Most appreciated its explicit goal to shorten timelines and some hoped to see its use expanded to currently countries not yet participating in the program. One NMRA participant commented: 169 It has helped a lot of companies in Africa and foreign companies looking to register and invest in Pharma. Registration is faster, less complicated, cost-effective and time efficient. These results may not be surprising, considering the high utilization of the WHO- CRP recently reported by Azatyan (Azatyan, 2020). Even some non-users expressed positive impressions of the procedure and appeared to appreciate the goals of shortening timelines and strengthening regulatory capacity: The potential benefits of collaborative procedure by the reference SRA are significant and it can really help to reduce time and costs of regulatory approvals. I strongly hope that companies can utilize this regulatory process to combine resources and share workload to ensure timely access to the medicine to patients 5.3.4.3 Sustainability Even though the enthusiasm for the WHO-CRP program was high, few respondents were confident that the WHO-CRP would still be viable after 2024. Multiple registration pathways, such as ZAZIBONA and the EAC Joint Assessment Process, currently exist in Africa. These may pose a competitive risk to the WHO-CRP, even though they are region-specific (Dansie, Odoch, and Årdal, 2019; Kamwanja et al., 2011 Therefore, it will be important to address the user concerns identified above to ensure that the WHO-CRP remains competitive with the other regional processes, which are used in regions where the legislative environment is more favorable. In addition, the funding of the WHO-CRP is entirely supported by donor contributions. Others have pointed to the need for increased financing and personnel development to improve access to medicines in Africa (Sillo et al., 2020; Ndomondo- Sigonda et al., 2020). These were not surprisingly also seen to be elements of concern in the present studies. 170 This vulnerability has already been faced by the WHO with respect to its Prequalification program (World Health Organization, 2019a). In the first 10 years of the WHO PQP, no fees were charged, and the PQP depended on donations from UNITAID and the Bill and Melinda Gates Foundation. In 2013, application fees were introduced to the PQP, in order to provide a more stable foundation for the program (Dellepiane and Wood, 2015). This strategy has been successful, as the number of prequalified products has risen steadily since that time (World Health Organization, 2019a). For the WHO-CRP, additional research is still needed to investigate how funding models can be modified to stabilize its financial viability in the future. Now would be a good time to undertake such work, while funding remains available for the existing program. Otherwise, the WHO-CRP program may collapse once that donor funding is eventually withdrawn. As one study participant stated: “The funding mechanism is based on donations from NGOs. This is not sustainable.” This opinion is echoed by PATH (PATH, 2018): Though the EAC has a strong interest in regulatory harmonization, governments have not committed significant financial resources to harmonization efforts. Instead, the EAC-MRH initiative is largely funded by donors, such as WHO, World Bank, and the Gates Foundation. These donors have been instrumental in initiating harmonization efforts, but a lack of partner state investment poses long-term challenges for sustainability. One participant suggested that “manufacturers can pay necessary fees above country fees if there's commitment on timelines”. Such fees are under consideration by WHO and reflect the approaches that have been used elsewhere to support additional reviewing capabilities (World Health Organization, 2011). Because the program fees would be added on top of the NMRA registration fee and the fees associated with either 171 prequalification under the PQP or product registration by an SRA, fee structures would have to be reasonable to stay within the financial reach of the users. One model might become that currently being considered by the EAC-MRH for the EAC consortium (Giaquinto et al., 2020), which proposes a scheme that follows the same user fee model adopted by FDA, EMA and PMDA. It was surprising that a large majority of NMRA and industry participants felt that the WHO-CRP was not sufficiently publicized. This challenge was reinforced by the large number of respondents who stated that they did not use the process because they did not know about it. Dansie and colleagues also noted in 2019 that promotional activities could be improved (Dansie et al., 2019), but this need seems still to be resolved. It is an initiative that should be easy to correct, and should be prioritized, given the uncertainty expressed by the participants over the long-term viability of the program, despite the overall satisfaction with the program. 5.4 Conclusions and Recommendations The COVID-19 pandemic has illustrated on a global level the importance of a strong and agile regulatory framework to provide needed medicines to a waiting population. This may be especially important in Africa, where many under-resourced countries have been repeatedly assaulted by public health crises, from HIV to Ebola to the current COVID- pandemic. Further, these countries have many other less dramatic health challenges that have yet to be managed with effective pharmaceutical treatment. Programs that can make it easier to place needed drugs in the hands of patients are 172 important to foster. The WHO-CRP program seems well designed and well-implemented but still may be vulnerable in the long term. Three areas seem to be particularly important to address. The first is procedural improvements of the program. While minor, the availability of more detailed directions on how to submit the dossier, and more transparency regarding decisions regarding the dossiers could be easily implementable improvements to the processes that may further improve user satisfaction. The positive feedback of both NMRA and industry participants suggest that the primary stakeholders welcome the WHO-CRP initiatives. The biggest challenges now exist outside the specific scope of the regulatory pathway itself. The absence of consistent legislation to facilitate regulatory harmonization and the continuing challenges of improving regulatory capacity now appear to be the biggest problems to solve. Creating a self-sustaining infrastructure of interactive NMRAs that employs work-sharing is one step along that path. Efforts to domesticate and then adopt legislation like that suggested by the AU Model Law are thus important to facilitate harmonization or regulatory requirements and elimination of redundant documentation and activities. It would alleviate some of the burden currently placed on NMRAs that must satisfy redundant national requirements. The third area to consider is the overall sustainability of the program. Improving the visibility and awareness of the program may also be beneficial, particularly if this is coupled with the exploration of a reasonable sliding scale of registration funding that would be supportive of small, local and regional production of medicines, but would also 173 provide incentives, perhaps by guaranteed timelines and increased transparency, to larger companies who are outside the region. 174 References ‘t Hoen, E. (2009). The global politics of pharmaceutical monopoly power: Drug patents, access, innovation and the application of the WTO Doha Declaration on TRIPS and public health. Netherlands: AMB Publishers Available at: https://msfaccess.org/sites/default/files/MSF_assets/Access/Docs/ACCESS_book_Global Politics_tHoen_ENG_2009.pdf. (Accessed: 11 April 2019) ‘t Hoen, E., Hogerzeil, H.V., Quick, J.D., and Sillo, H.B. (2014). A quiet revolution in global public health: The World Health Organization’s prequalification of medicines programme, Journal of Public Health Policy, 35(2), pp. 137-161. Abbas, S., Nurbaya. and Dkawa. Y. (2018). Practical framework for evaluating community service programs based on service learning with CIPP Model, International Conference on University - Community Engagement, Ministry of Religious Affairs, in Cooperation with Universitas Islam Negeri Maulana Malik Ibrahim, 08-10 October, Malang: UIN Maliki Press, pp. 910-920. Available at: https://www.researchgate.net/profile/Samsul_Arifin8/publication/334950164_LOCAL_ WISDOM_DEVELOPMENT_OF_PESANTREN_BASED_COUNSELING_DESIGN_ WITH_APPROACH_SERVICE- LEARNING/links/5d4644a3a6fdcc370a79d9a4/LOCAL-WISDOM-DEVELOPMENT- OF-PESANTREN-BASED-COUNSELING-DESIGN-WITH-APPROACH-SERVICE- LEARNING.pdf#page=124 (Accessed: 17 July 2020). Adams, M.J., and Umbach, P.D. (2012). Nonresponse and online student evaluations of teaching: Understanding the influence of salience, fatigue, and academic environments, Research in Higher Education, 53(5), pp. 576-591. Africa Trade Development Center (2019). Regional economic communities. Available at: https://africatdc.com/rec/ (Accessed: 18 July 2020). African Press Organization. (2012). EAC to launch project on harmonization of medicines registration 30 March 2012 / Harmonization of registration systems will ensure access to medicines of assured quality, says EAC Secretary General, [Press release], 15 March. Available at: https://appablog.wordpress.com/2012/03/15/eac-to- launch-project-on-harmonization-of-medicines-registration-30-march-2012- harmonization-of-registration-systems-will-ensure-access-to-medicines-of-assured- quality-says-eac-secretary-general/ (Accessed: 30 July 2020). Ahonkhai, V., Martins, S.F., Portet, A., Lumpkin, M., et al. (2016). Speeding access to vaccines and medicines in low- and middle-income countries: A case for change and a framework for optimized product market authorization, PLoS One, 11(11): e0166515. Aldis, W. (2008). Health security as a public health concept: A critical analysis, Health Policy and Planning, 23(6), pp. 369-375. 175 Al-Khathami, A.D. (2012). Evaluation of Saudi family medicine training program: The application of CIPP evaluation format, Medical Teacher, 34(sup1), pp. S81-S89. Arthur, H. (2019). Harmonisation in Africa, Quality Assurance and Safety of Crops & Foods, 11(7), pp. 613-622. Ash, T.G. (1998). Europe's endangered liberal order, Foreign Affairs, 77(2), pp. 51-65. Avery, R.J., Bryant, W.K., Mathios, A., Kang, H., et al. (2006). Electronic course evaluations: Does an online delivery system influence student evaluations? The Journal of Economic Education, 37(1), 21-37. Available at: https://wiki.albany.edu/download/attachments/20415113/_...Does+an+online+system+aff ect+student+evals_Avery_2006.pdf (Accessed: 15 April 2021). Azatyan, S. (2019). Collaborative registration procedures: A brief introduction, [Power Point presentation], Improving the Response of Global Public Health in a Fast-changing World: Joint UNICEF, UNFPA and WHO meeting with manufacturers and suppliers of in-vitro diagnostic products, vaccines & immunization devices, finished pharmaceutical products, active pharmaceutical ingredients, contraceptive devices and vector control products, UN City, 2-5 December, Copenhagen, Denmark. Available at: https://extranet.who.int/prequal/sites/default/files/documents/14.00%20Azatyan.pdf (Accessed: 01 July 2020). Azatyan, S. (2020). Collaborative registration procedure - overview of main principles. [Power Point presentation], Virtual Joint Meeting 30 November – 3 December 2020. Available at: https://extranet.who.int/pqweb/sites/default/files/documents/CRP_Overview.pdf (Accessed: 24 April 2021). Banda, G. (2013). Finance as a ‘forgotten technological capability’ for promoting African local pharmaceutical manufacture, International Journal of Technology Management & Sustainable Development, 12(2), pp. 117-135. Banda, G., Wangwe, S. and Mackintosh, M. (2016). Making medicines in Africa: An historical political economy overview, in Mackintosh, M., Banda, G., Tibandebage, P. & Wamae, W. (eds.), Making medicines in Africa: the political economy of industrializing for local health, (International political economy series). Hampshire: Palgrave Macmillan, pp. 7-24. Banfield, J. (1963). Federation in east Africa, International Journal, 18(2), pp. 181-193. Baruch, Y., and Holtom, B.C. (2008). Survey response rate levels and trends in organizational research, Human Relations, 61(8), pp. 1139-1160. Binda, E.M. (2017). The legal framework of the EAC, in E. Ugirashebuja, J. E. Ruhangisa, T. Ottervanger, and A. Cuyvers (eds.), East African Community Law. Boston: Brill, pp. 103-118. 176 Bollinger, L. and Stover, J. (1999). The economic impact of AIDS in South Africa, The Policy Project. Available at: http://www.policyproject.com/pubs/SEImpact/southafr.pdf (Accessed: 07 April 2019). Bollyky, T.J., Cockburn, I.M. and Berndt, E. (2010). Bridging the gap: Improving clinical development and the regulatory pathways for health products for neglected diseases, Clinical Trials, 7(6), pp. 719-734. Brandt, A.M. (2013). How AIDS invented global health, New England Journal of Medicine, 368(23), pp. 2149-2152. Brennan, M.J., Fruth, U., Milstien, J., Tiernan, R., et al. (2007). Development of new tuberculosis vaccines: A global perspective on regulatory issues, PLoS Medicine, 4(8), p. e252. Broojerdi, A.K., Sillo, H.B., Dehaghi, R.O.A., Ward, M., et al. (2020). The World Health Organization global benchmarking tool an instrument to strengthen medical products regulation and promote universal health coverage, Frontiers in Medicine, 7, p. 457. Brown, A.C., Stern, J., Tenenbaum, B., and Gencer, D. (2006). Handbook for evaluating infrastructure regulatory systems. Washington, DC: The World Bank. Available at https://openknowledge.worldbank.org/handle/10986/7030 (Accessed: 07 April 2019). Brownson, R.C., Baker, E.A., Leet, T.L., Gillespie, K.N., et al. (2010). Evaluating the program or policy, in Brownson, R.C., Baker, E.A., Deshpande, A.D. and Gillespie, K.N. (eds.). Evidence-based public health. New York: Oxford University Press, pp. 232-258. Bruce, F. (2019). Latin America inches towards greater regulatory harmonization, Pink Sheet – Informa Pharma Intelligence, 21 February. Available at: https://pink.pharmaintelligence.informa.com/PS124793/Latin-America-Inches-Towards- Greater-Regulatory-Harmonization (Accessed: 18 March 2020). Buch, E. and Hogerzeil, H. (2009). African medicines registration harmonisation (AMRH) Initiative: Summary, status and future plans. Hard copy in possession of Lori Alquier and available upon request. (Accessed: 20 April 2019). Bulletin of the World Health Organization. (2020). Accelerating regulation in response to COVID-19. Bulletin of the World Health Organization, 98, pp. 514-515. Burstall, M.L., and Reuben, M.G. (1988). The 'cost of non-Europe' in the pharmaceutical industry. Luxembourg: Office for Official Publications of the European Community. London: Economist Advisory Group LTD. Available at: http://aei.pitt.edu/47988/1/A9324.pdf. (Accessed: 19 March 2019). 177 Calder, A. (2016). Assessment of potential barriers to medicines regulatory harmonization in the Southern African Development Community (SADC) region. Johannesburg: University of the Witwatersrand. Available at: http://wiredspace.wits.ac.za/bitstream/handle/10539/21166/875651-Amanda%20Calder- Research%20Report.pdf?sequence=1&isAllowed=y (Accessed: 03 April 2019). Callegaro, M., Manfreda, K.L., and Vehovar, V. (2015). Web survey methodology: Sage, pp. 344. Available at: https://research.google/pubs/pub43811/ (Accessed: 19 March 2021). Carden, T., Goode, N., Read, G.J. and Salmon, P.M. (2019). Sociotechnical systems as a framework for regulatory system design and evaluation: Using work domain analysis to examine a new regulatory system, Applied Ergonomics, 80, pp. 272-280. Caturla Goñi, M. (2016). Accelerating regulatory approvals through the World Health Organization collaborative registration procedures, Pharmaceuticals Policy and Law, 18(1-4), pp. 109-120. Chong, S.S.F., Lim, J.C. and Tominaga, T. (2018). Developing key performance indicators to measure the progress of regional regulatory convergence and cooperation in Asia-Pacific Economic Cooperation (APEC), AAPS Open, 4(4), pp. 1-8. Churchill, W. (1946). Speech to the academic youth at the University of Zurich, 19 September 1946. Available at: https://www.churchill-in-zurich.ch/en/churchill/en- churchills-zurcher-rede/ (Accessed: 07 August 2019). Dagron, S. (2012). Global harmonization through public-private partnership: The case of pharmaceuticals (1556-5068), IRPA GAL Working Paper 2012/2. Available at: https://images.irpa.eu/wp-content/uploads/2019/03/IRPA.WP.2012.2.Dagron.pdf (Accessed: 03 April 2019). Dansie, L.S., Odoch, W.D. and Årdal, C. (2019). Industrial perceptions of medicines regulatory harmonization in the east African community, PLoS ONE, 14(6), pp. 1-15. Deeming, S., Searles, A., Reeves, P. and Nilsson, M. (2017). Measuring research impact in Australia’s medical research institutes: A scoping literature review of the objectives for and an assessment of the capabilities of research impact assessment frameworks, Health Research Policy and Systems, 15(1), p. 22. Dellepiane, N., and Wood, D. (2015). Twenty-five years of the WHO vaccines prequalification programme (1987–2012): Lessons learned and future perspectives, Vaccine, 33(1), pp. 52-61. Dixon, S., McDonald, S. and Roberts, J. (2002). The impact of HIV and AIDS on Africa's economic development, BMJ, 324, pp. 232-234. Dorst, K., and Cross, N. (2001). Creativity in the design process: co-evolution of problem–solution, Design Studies, 22(5), pp. 425-437. 178 Doua, J.Y. and Van Geertruyden, J.P. (2014). Registering medicines for low-income countries: how suitable are the stringent review procedures of the World Health Organisation, the US Food and Drug Administration and the European Medicines Agency? Tropical Medicine & International Health, 19(1), pp. 23-36. Draugalis, J.R., Coons, S.J., and Plaza, C.M. (2008). Best practices for survey research reports: A synopsis for authors and reviewers. American Journal of Pharmaceutical Education, 72(1), p. 11. Dusek, G.A., Yurova, Y.V., and Ruppel, C.P. (2015). Using social media and targeted snowball sampling to survey a hard-to-reach population: A case study. International Journal of Doctoral Studies, 10(1), pp. 279-299. Eakin, D.V. (1998). The International Conference on Harmonization of Pharmaceutical Regulations: Progress or stagnation, Tulsa Journal of Comparative & International Law, 6(2), pp. 221-245. Available at: https://digitalcommons.law.utulsa.edu/tjcil/vol6/iss2/5/ (Accessed: 06 April 2019). East African Community (1987). East African Community Mediation Agreement Act, 1987. Governments of the United Republic of Tanzania, the Republic of Uganda and the Republic of Kenya (Arusha, Tanzania). Available at: https://www.uaipit.com/uploads/legislacion/files/1394799670_3._The_east_African_com munity_Mediation_agreement_act__N._7_of_1987_(1987)_EN.pdf. (Accessed: 01 June 2020) East African Community (2007). Agreement for the establishment of the permanent tripartite commission for East African co-operation. Available at: https://www.eacj.org/wp-content/uploads/2012/08/EACJ-Treaty.pdf (Accessed: 01 June 2020). East African Community. (2014). Ministerial communiqué - advocacy and support for the harmonization and strengthening of medicines regulation in the East African community partner states and the African continent, All Africa (Africa). Available at: https://allafrica.com/stories/201410201750.html (Accessed: 19 March 2019). East African Community. (2020). Quick facts about EAC. Available at: https://www.eac.int/eac-quick-facts (Accessed: 01 June 2020). Eccles, M., Grimshaw, J., Walker, A., Johnston, M., et al. (2005). Changing the behavior of healthcare professionals: The use of theory in promoting the uptake of research findings, Journal of Clinical Epidemiology, 58(2), pp.107-112. Eur-Lex. (1965). Council Directive 65/65/EEC. Available at: https://eur- lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31965L0065:EN:HTML. (Accessed: 07 August 2020). 179 Eur-Lex. (1975). Second Council Directive of 20 May 1975 on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal products, Official Journal of European Communities. Available at: https://eur- lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:31975L0319&from=en (Accessed: 05 March 2020). Eur-Lex. (1985). Schengen Agreement. Available at: https://eur-lex.europa.eu/legal- content/EN/TXT/HTML/?uri=CELEX:42000A0922(02)&from=EN (Accessed: 13 March 2020). Eur-Lex. (1986). Council Directive 87/22/EEC. Official Journal of the European Communities, 15(17.1), pp. 38-41. Available at: https://eur- lex.europa.eu/eli/dir/1987/22/oj. (Accessed: 07 August 2020). Eur-Lex. (2001). Treaty of Nice. Official Journal of the European Union, 80(10.3), pp. 1-87. Available at: https://eur-lex.europa.eu/legal- content/EN/TXT/?uri=CELEX:12001C/TXT. (Accessed: 08 August 2019). European Medicines Agency. (2016). Harmonised technical guidance for eCTD submissions in the EU. Available at: http://esubmission.ema.europa.eu/tiges/docs/eCTD%20Guidance%20v4%200-20160422- final.pdf (Accessed: 31 March 2020). European Medicines Agency. (2021). European Medicines Agency’s Facebook page. Available at: https://www.facebook.com/pages/European-Medicines- Agency/135627683135752 (Accessed: 18 March 2021). European Parliament and of the Council of the European Union. (2004). Regulation (EC) No. 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. European Parliament and of the Council (Strasbourg). Available at: https://eur-lex.europa.eu/legal- content/EN/TXT/HTML/?uri=CELEX:32004R0726&from=EN (Accessed: 13 March 2020). European Parliament and the Council of the European Union. (2003). Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC. European Parliament and of the Council (Strasbourg). Available at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol- 1/dir_2002_98/dir_2002_98_en.pdf (Accessed: 20 July 2020). European Parliament. (1958) Treaty of Rome (EEC), About Parliament (European Parliament). Available at: http://www.europarl.europa.eu/about-parliament/en/in-the- past/the-parliament-and-the-treaties/treaty-of-rome (Accessed: 13 March 2020). 180 European Union. (1992). Treaty on European Union. Available at: https://europa.eu/european- union/sites/europaeu/files/docs/body/treaty_on_european_union_en.pdf (Accessed: 29 March 2020). European Union. (1997). Treaty of Amsterdam. Available at: https://europa.eu/european- union/sites/europaeu/files/docs/body/treaty_of_amsterdam_en.pdf (Accessed: 29 March 2020). Finaish, M., and Bell, E. (1994). The Arab Maghreb Union 1/. IMF eLibrary, Working Paper of the International Monetary Fund, Available at: https://www.elibrary.imf.org/view/IMF001/06791-9781451969122/06791- 9781451969122/06791-9781451969122_A001.xml?redirect=true (Accessed: 03 June 2020). Fintel, B., Samaras, A.T., and Carias, E. (2009). The thalidomide tragedy: Lessons for drug safety and regulation. Helix. Available at: https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and- regulation (Accessed: 03 April 2019). Fixsen, D.L., Naoom, S., Blase, K., Friedman, R., et al. (2005). Implementation research: A synthesis of the literature. Tampa, Florida: Louis de la Parte Florida Mental Health Institute. Available at: https://nirn.fpg.unc.edu/resources/implementation-research- synthesis-literature. (Accessed: 24 May 2020). Frye, A. W., & Hemmer, P. A. (2012). Program evaluation models and related theories: AMEE guide no. 67, Medical Teacher, 34(5), e288-e299. Galesic, M. and Bosnjak, M. (2009). Effects of questionnaire length on participation and indicators of response quality in a web survey, Public Opinion Quarterly, 73(2), 349-360. Gesinde, A. and Adejumo, G. (2011). Effect of burnout on work performance of helping professionals: Implication for development goals in Africa, IRCAB Journal of Social and Management Science, 1(1), pp. 71-78. Available at: http://eprints.covenantuniversity.edu.ng/3913/#.YGkCCJ1KguV (Accessed: 03 April 2021). Giaquinto, A.R., Grignolo, A., Liberti, L., Lim, J.C., et al. (2020). Improving access to quality medicines in East Africa: An independent perspective on the East African community medicines regulatory harmonization initiative, PLoS Medicine, 17(8), e1003092. Glover, B., Akinbo, O., Savadogo, M., Timpo, S., et al. (2018). Strengthening regulatory capacity for gene drives in Africa: Leveraging NEPAD’s experience in establishing regulatory systems for medicines and GM crops in Africa, BMC proceedings, 12(8), p. 11. Available at: https://bmcproc.biomedcentral.com/articles/10.1186/s12919-018-0108-y (Accessed: 10 July 2020). 181 Governments of Morocco, T., Algeria, Libya, and Mauritania. (1989). Treaty instituting the Arab Maghreb Union. Available at: https://www.wipo.int/edocs/lexdocs/treaties/en/amu/trt_amu.pdf (Accessed: 01 June 2020). Great Britain Parliament. (1968). Medicines Act 1968, Chapter 67. Available at: https://www.legislation.gov.uk/ukpga/1968/67/pdfs/ukpga_19680067_en.pdf (Accessed: 13 March 2020). Great Britain. (1930). Statement of the conclusions of his majesty's government in the United Kingdom as regards closer union in East Africa. London: H.M. Stationery Office. Green, D. (1997). Fast track to approval: New regulator has become ‘part of the scenery’ within two years of operation, [Editorial], Financial Times, (European Medicines Evaluation Agency: 6 Pharmaceuticals), 24 April. Available at: http://tinyurl.galegroup.com/tinyurl/97WrM4 (Accessed: 03 April 2019). Griffin, J.P. (2013). A history of drug regulation in the UK, in Griffin, J.P., Posner, J. and Barker, G.R. (eds.). The Textbook of Pharmaceutical Medicine. Oxford: John Wiley & Sons, Ltd., pp. 317-346. Grol, R. and Grimshaw, J. (1999). Evidence-based implementation of evidence-based medicine, The Joint Commission Journal on Quality Improvement, 25(10), pp. 503-513. Herzog, A.R. and Bachman, J.G. (1981). Effects of questionnaire length on response quality, Public Opinion Quarterly, 45(4), pp. 549-559. Heymann, J., Cassola, A., Raub, A., and Mishra, L. (2013). Constitutional rights to health, public health and medical care: The status of health protections in 191 countries, Global Public Health, 8(6), pp. 639-653. Hill, S. and Johnson, K. (2004). Emerging challenges and opportunities in drug registration and regulation in developing countries. DFID Health Systems Resource Centre, Fretwells, Ltd. (London). Available at: http://heart-resources.org/wp- content/uploads/2012/10/Emerging-challenges-and-opportunities-in-Drug-registration- and-regulation.pdf (Accessed: 03 April 2019). Huang, F.H., Wang, Q.L., Ridings, J., Watts, S., et al. (2016). Global regulatory requirement and development strategy for pediatric drugs [Chinese]. Chinese Journal of New Drugs, 25(19), 2174-2182. Available at: http://www.newdrug.cn/ (Accessed: 10 July 2020). Hufbauer, G.C and Brunel, C. (eds.) (2008). Maghreb regional and global integration: A dream to be fulfilled. Washington, DC: Peterson Institute for International Economics. Available at: https://www.piie.com/bookstore/maghreb-regional-and-global-integration- dream-be-fulfilled. (Accessed: 20 June 2020). 182 Hwang, K.D. (2007). The historical evolution of SADC (C) and regionalism in Southern Africa, International Area Studies Review, 10(1), pp. 55-72. IFPMA. (2021). Call to heads of state of the African Union to ratify the African Medicines Agency Treaty. Available at: https://www.ifpma.org/resource-centre/call-to- heads-of-state-of-the-african-union-to-ratify-the-african-medicines-agency-treaty/ (Accessed: 21 April 2021). IGAD. (1996). Agreement establishing the Inter-Governmental Authority on Development (IGAD). Available at: https://www.uneca.org/sites/default/files/uploaded- documents/ORIA/igad_agreement.pdf (Accessed: 01 January 2020). IGAD. (2018). IGAD and WHO train for harmonisation of medicines registration. Available at: https://igad.int/divisions/health-and-social-development/1920-igad-and- who-train-for-harmonisation-of-medicines-registration (Accessed: 01 June 2020). IGAD. (2020). IGAD MRH Program. Available at: https://mrh.igad.int/Reference.html (Accessed: 01 June 2020). International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (n.d.). Perspectives on ICH: Our mission. ICH (Switzerland). Available at: http://www.ich.org/about/vision.html (Accessed: 03 April 2019). International Health Conference. (2002). Constitution of the World Health Organization, 1946, Bulletin of the World Health Organization, 80, p. 983. Kahan, B. (2008). Excerpts from review of evaluation frameworks. Available at: https://docplayer.net/11232456-Review-of-evaluation-frameworks.html (Accessed: 03 July 2020). Kamwanja, L.A., Saka, J., Awotedu, A., Fute, I., et al. (2011). Situation analysis study on medicines registration harmonisation in Africa: Final report for the economic community of West African States (ECOWAS). Available at: https://www.nepad.org/publication/situation-analysis-study-medicines-registration- harmonisation-africa-final-report-2 (Accessed: 03 April 2019). Kamwanja, L.A., Saka, J., Awotedu, A., Fute, I., et al. (2010). Situation analysis study on medicines registration harmonisation in Africa. Available at: https://www.nepad.org/publication/situation-analysis-study-medicines-registration- harmonisation-africa-final-report-1 (Accessed: 01 April 2019). Kaufer, E. (1989). The regulation of drug development: In search of a common European approach. Florence: European University Institute. Available at: http://hdl.handle.net/1814/23024 (Accessed: 09 March 2019). Kelley, K., Clark, B., Brown, V., and Sitzia, J. (2003). Good practice in the conduct and reporting of survey research, International Journal for Quality in Health Care, 15(3), pp. 261-266. 183 Keyter, A., Salek, S., Banoo, S., and Walker, S. (2020). A proposed regulatory review model to support the south African health products regulatory authority to become a more efficient and effective agency, International Journal of Health Policy and Management, p. 115. Kidd, D. (1996). The International Conference on Harmonization of pharmaceutical regulations, the European Medicines Evaluation Agency, and the FDA: Who's zooming who? Indiana Journal of Global Legal Studies, 4(1), pp. 183-206. Available at: https://www.repository.law.indiana.edu/ijgls/vol4/iss1/10/ (Accessed: 03 April 2019). Kingham, R.F., Bogaert, P.W. L., and Eddy, P.S. (1994). The new European Medicines Agency, Food and Drug Law Journal, 49(2), pp. 301-322. Available at: https://heinonline.org/HOL/LandingPage?handle=hein.journals/foodlj49&div=28&id=& page= (Accessed: 17 February 2019). Kozica, S., Lombard, C.B., Hider, K., Harrison, C.L., et al. (2015). Developing comprehensive health promotion evaluations: A methodological review, MOJ Public Health, 2(1), 00007. Lahlou, O. (2016). Accelerating patient access to medicines in the Economic Community of West African States, the Southern African Development Community and the organization for the coordination of the fight against endemic diseases, Pharmaceuticals Policy and Law, 18(1-4), pp. 99-108. Leng, H., Sanders, D., and Pollock, A.M. (2015). Pro-generics policies and the backlog in medicines registration in South Africa: Implications for access to essential and affordable medicines, GaBI, 16(21). Available at: https://qmro.qmul.ac.uk/xmlui/bitstream/handle/123456789/12619/Lancaster%20Pro- generics%20policies%20and%20the%20backlog%202015%20Published.pdf?sequence=1 (Accessed: 03 April 2021) Lezotre, P-L. (2014a). International cooperation, convergence, and harmonization of pharmaceutical regulations:A global perspective. Oxford: Academic Press. Lezotre, P.-L. (2014b). Part III - Recommendations to support the next phase of international cooperation, convergence, and harmonization in the pharmaceutical domain, in Lezotre, P-L. (ed.). International cooperation, convergence, and harmonization of pharmaceutical regulations: A global perspective. Oxford: Academic Press, pp. 221-294. Liberti, L., Breckenridge, A., Hoekman, J., Leufkens, H., et al. (2016). Accelerating access to new medicines: Current status of facilitated regulatory pathways used by emerging regulatory authorities, Journal of Public Health Policy, 37(3), pp. 315-333. Liberti, L., McAuslane, N., Stolk, P., Breckenridge, A., et al. (2018). A proposed framework for a globally applicable pragmatic approach to using facilitated regulatory pathways, Therapeutic Innovation & Regulatory Science. doi:10.1177/2168479018813977. 184 Lim, J.C. (2018). Strengthening health products regulatory systems to enhance access to quality health products in the Asia-Pacific, Therapeutic Innovation and Regulatory Science, 52(6), pp. 751-754. Luthuli, M.N., and Robles Sr, M.W. (2017). Africa medicines regulatory harmonization initiatives. Available at: https://www.wcgcares.org/wp-content/uploads/2018/01/White- Paper-on-Africa-Harmonization-Initiatives-FINAL-041817-1.pdf (Accessed: 02 February 2019). Mackintosh, M., Banda, G., Tibandebage, P., and Wamae, W. (2016). Making medicines in Africa: The political economy of industrializing for local health. Hampshire: Palgrave Macmillan. Available at: https://link.springer.com/content/pdf/10.1007%2F978-1-137- 54647-0.pdf (Accessed: 31 March 2020). MacNeil, S., Ding, Z., Boone, A., Grubbs, A.B., and Dow, S.P. (2021). Finding place in a design space: Challenges for supporting community design efforts at scale. 15 April. ACM Conference on Computer Supported Cooperative Work and Social Computing. doi:10.1145/3449246. Malinowski, B. (1929). Report of the commission on closer union of the dependencies in eastern and central Africa, Africa, 2(3), pp. 317-320. Mann, J.M., and Tarantola, D. (1996). AIDS in the world II: Global dimensions, social roots, and responses. Oxford: Oxford University Press on Demand. Available at: https://books.google.com/books?hl=en&lr=&id=_UdYAgAAQBAJ&oi=fnd&pg=PR1&o ts=zzPifiY7tU&sig=8QoSnA9tzLFSa12crlLm28jQCLc#v=onepage&q&f=false (Accessed: 05 April 2019). Mann, R.D. (1989). The historical development of medicines regulations, in Walker, S.R. and Griffin, J.P. (eds.). International medicines regulations, CMR Workshop Series, Dordrecht: Springer, pp. 3-18. Available at: https://link.springer.com/chapter/10.1007%2F978-94-009-0857-4_1 (Accessed: 11 June 2020). Mashingia, J.H., Ahonkhai, V., Aineplan, N., Ambali, A., et al. (2020). Eight years of the East African Community Medicines Regulatory Harmonization Initiative: Implementation, progress, and lessons learned, Plos Medicine, 17(8), p. e1003134. Mashingia, J., and Patel, A. (2017). Pharmaceutical policy in the east African community: Burundi, Kenya, Uganda, Rwanda, Tanzania, in Babar, Z.-U.-D. (ed.). Pharmaceutical Policy in Countries with Developing Healthcare Systems, Cham: Springer, pp. 13-24. Matsuda, Y. (2019). Global regulatory landscape. AAPS PharmSciTech, 20(1), p. 2. 185 Mazur, A. (2013) The CIPP evaluation model: A summary, A journey through the evolution of educational technologies, 13 June. Available at: https://amberhartwell.wordpress.com/2013/06/10/the-cipp-evaluation-model-a-summary/ (Accessed: 20 June 2020). Melloan, G. (1994, 18 April). Why Europeans are being shorted on miracle drugs, Wall Street Journal. Hard copy in possession of Lori Alquier and available upon request (Accessed: 17 February 2019). Mengistu, M.M. (2015). Multiplicity of African regional economic communities and overlapping memberships: A challenge for African integration, International Journal of Economics, Finance and Management Sciences, 3(5), pp. 417-425. Available at: http://article.sciencepublishinggroup.com/html/10.11648.j.ijefm.20150305.12.html (Accessed: 15 June 2020). Merimi, Z. (2018). Maghreb: Ongoing regulatory reforms and efforts for regional convergence. 29 June. Available at:https://www.linkedin.com/pulse/maghreb-ongoing- regulatory-reforms-efforts-regional-association/ (Accessed: 31 May 2020). Metzidakis, A. (1994). Victor Hugo and the idea of the United States of Europe, Nineteenth-Century French Studies, 23(1/2), pp. 72-84. Available at: http://www.ncfs- journal.org/?q=node/996 (Accessed: 07 August 2020). Mkandawire, T. (2001) Thinking about developmental states in Africa, Cambridge Journal of Economics, 25(3), pp. 289-314. Available at: http://ww.w.rrojasdatabank.info/Mkandawire.pdf (Accessed: 07 April 2019). Molzon, J.A., Giaquinto, A., Lindstrom, L., Tominaga, T., et al. (2011). The value and benefits of the international conference on harmonisation to drug regulatory authorities: Advancing harmonization for better public health, Clinical Pharmacology & Therapeutics, 89(4), pp. 503-512. Moran, M., Strub-Wourgaft, N., Guzman, J., Boulet, P., et al. (2011). Registering new drugs for low-income countries: The African challenge, PLoS Medicine, 8(2-e1000411), pp. 1-6. Mushayi, G. (2019) Developing a regionally recognised framework to support regulatory harmonisation of labelling requirements in the Southern Africa Development Community (SADC). Johannesburg: University of the Witwatersrand. Available at: http://wiredspace.wits.ac.za/bitstream/handle/10539/29109/892170%20GM%20Mushayi %20-Research%20Report-06112019.pdf?sequence=1&isAllowed=y (Accessed: 05 July 2020). Mwangi, J.M. (2016). Towards African medicines regulatory harmonization: The case of the east African community, Pharmaceuticals Policy and Law, 18(1-4), pp. 91-98. 186 Narsai, K., Williams, A., and Mantel-Teeuwisse, A.K. (2012). Impact of regulatory requirements on medicine registration in African countries–perceptions and experiences of pharmaceutical companies in South Africa, Southern Medical Journal, 5(1), pp. 31-37. Nayyar, G.M.L., Attaran, A., Clark, J.P., Culzoni, M.J., et al. (2015). Responding to the pandemic of falsified medicines, American Journal of Tropical Medicine and Hygiene, 92(Suppl. 6), pp. 113-118. Ncube, B.M., Dube, A., and Ward, K. (2021). Establishment of the African Medicines Agency: Progress, challenges and regulatory readiness, Journal of Pharmaceutical Policy and Practice, 14(1), pp. 1-12. Ndomondo-Sigonda, M., and Ambali, A. (2011). The African medicines regulatory harmonization initiative: Rationale and benefits, Clinical Pharmacology & Therapeutics, 89(2), pp. 176-178. Ndomondo-Sigonda, M., Miot, J., Naidoo, S., Ambali, A., et al. (2018). The African medicines regulatory harmonization initiative: Progress to date, Medical Research Archives, 6(2), pp. 1-15. Ndomondo-Sigonda, M., Miot, J., Naidoo, S., Dodoo, A., et al. (2017). Medicines regulation in Africa: Current state and opportunities, Pharmaceutical Medicine, 31(6), pp. 383-397. Ndomondo-Sigonda, M., Miot, J., Naidoo, S., Masota, N., et al. (2020). Harmonization of medical products regulation: A key factor for improving regulatory capacity in the east African community, Research Square, pp. 1-34. NEPAD. (2016). African medicines regulatory harmonisation programme plan for implementation of PMPA - strategic plan 2016 – 2020, South Africa: New Partnership for Africa's Development. Hard copy in possession of Lori Alquier and available upon request (Accessed: 12 August 2019). NEPAD. (2020a). Gabon Republic signs Treaty for the Establishment of the African Medicine Agency (AMA). Available at: https://www.nepad.org/news/gabon-republic- signs-treaty-establishment-african-medicine-agency-ama (Accessed: 10 July 2020). NEPAD. (2020b) AMRH Strategic Framework 2016-2020. Available at: https://www.nepad.org/publication/amrh-summarized-strategic-framework-2016-2020 (Accessed: 11 March 2020). Nicholson, T. (1989). Using the CIPP model to evaluate reading instruction, Journal of Reading, 32(4), pp. 312-318. Available at: http://www.jstor.com/stable/40029929 (Accessed: 17 July 2020). Nixon, B. (1999). Evaluating design performance, International Journal of Technology Management, 17(7-8), pp. 814-829. 187 Nulty, D.D. (2008). The adequacy of response rates to online and paper surveys: What can be done? Assessment and Evaluation in Higher Education, 33(3), pp. 301-314. Office of the Legal Counsel (AUC). (2019). Treaty for the Establishment of the African Medicines Agency. Available at: https://archives.au.int/handle/123456789/7186 (Accessed: 20 July 2020). Orzack, L.H., Kaitin, K.I. and Lasagna, L. (1992). Pharmaceutical regulation in the European community: Barriers to single market integration, Journal of Health Politics, Policy and Law, 17(4), pp. 847-868. Osman, M. (2021). Mind-blowing LinkedIn statistics and facts (2021). Kinsta Blog, March 18, 2021. Available at: https://kinsta.com/blog/linkedin-statistics/ (Accessed: 18 March 2021). Ouimet, J.A., Bunnage, J.C., Carini, R.M., Kuh, G.D., et al. (2004). Using focus groups, expert advice, and cognitive interviews to establish the validity of a college student survey, Research in Higher Education, 45(3), pp. 233-250. Owusu-Danso, P. (2019). African Medicines Regulatory Harmonization -AMRH: Current Trends. Paper presented at the WCBP 2019 Scientific Conference, Ghana. https://cdn.ymaws.com/www.casss.org/resource/resmgr/wcbp/wcbp_2019/2019_owusu- danso_patrick_sli.pdf. Padmore, G. (ed.) (1963). History of the Pan-African congress. London: Hammersmith Bookshop. Available at: https://www.marxists.org/archive/padmore/1947/pan-african- congress/ch09.htm (Accessed: 24 August 2019). PATH. (2018). Making the case: How regulatory harmonisation can save lives in Africa. Washington, DC: PATH. Available at: https://path.azureedge.net/media/documents/Regulatory_harmonisation_report.pdf. (Accessed: 22 January 2021). Pharmaceutical Society of Great Britain. (2020). Who we are. Available at: https://www.rpharms.com/about-us/who-we-are (Accessed: 11 June 2020). Piot, P., Bartos, M., Ghys, P.D., Walker, N., et al. (2001). The global impact of HIV/AIDS, Nature, 410(6831), pp. 968-973. Queirós, A., Faria, D., and Almeida, F. (2017). Strengths and limitations of qualitative and quantitative research methods, European Journal of Education Studies, 3(9). Rago, L., Sillo, H., ‘t Hoen, E., and Zweygarth, M. (2014). Regulatory framework for access to safe, effective and quality medicines, Antiviral Therapy, 19(Suppl. 3), pp. 69- 77. 188 Rao, P. (2009). International survey research: Understanding national cultures to increase survey response rate, Cross Cultural Management: An International Journal, 16 (2), p. 165. Ravinetto, R., Vandenbergh, D., Macé, C., Pouget, C., et al. (2016). Fighting poor-quality medicines in low-and middle-income countries: The importance of advocacy and pedagogy, Journal of Pharmaceutical Policy and Practice, 9(1), p. 36. doi:10.1186/s40545-016-0088-0. Reuters. (2007, 1 July). FACTBOX-Africa's Trading Blocs. [Press Release]. Available at: https://www.reuters.com/article/africa-blocs/factbox-africas-trading-blocs- idUSL2965989620070701 (Accessed: 20 July 2020). Riley, B., Willis, C., Holmes, B., Finegood, D., et al. (2017). Systems thinking and dissemination and implementation research, in Brownson, R.C., Colditz, G.A. and Proctor, E.K. (eds.), Dissemination and implementation research in health: Translating science to practice. San Francisco: Oxford University Press, pp. 1-24. Roberts, J.P., Fisher, T.R., Trowbridge, M.J., and Bent, C. (2016). A design thinking framework for healthcare management and innovation healthcare, Healthc (Amst), 4(1), pp.11-14. Rossi, P.H. (1987). The iron law of evaluation and other metallic rules, in J. L. Miller and M. Lewis (eds.), Research in Social Problems and Public Policy, 4, pp. 3-20. SADC Secretariat. (1993). Declaration and Treaty of the Southern African Development Community. Windhoek, Namibia. Available at: https://www.sadc.int/files/8613/5292/8378/Declaration__Treaty_of_SADC.pdf (Accessed: 10 July 2020). Secretary of State for the Colonies. (1925). Report of the East African Commission (Vol. 2387), His Majesty's Stationery Office (London). Available at: http://www.waado.org/colonial_rule/east_africa/east_africa_commission_1925.pdf (Accessed: 24 August 2019). Serwadda, D., Sewankambo, N., Carswell, J., Bayley, A., et al. (1985). Slim disease: A new disease in Uganda and its association with HTLV-III infection, The Lancet, 326(8460), pp. 849-852. Sillo, H. (2016). East African Community Medicines Regulatory - Harmonization (EAC MRH) Programme: Progress and lessons learnt, 17th International Conference of Drug Regulatory Authorities. Cape Town, 27 November to 02 December 2016. Hard copy in possession of Lori Alquier and available upon request. Sillo, H.B., Kisoma, S. and Zweygarth, M. (2016). Medicines regulation: Comparison of medicines legislation in the east African community, WHO Drug Information, 30(4), pp. 567-576. Available at: https://apps.who.int/iris/handle/10665/331006 (Accessed: 17 February 2019). 189 Sillo, H., Ambali, A., Azatyan, S., Chamdimba, C., et al. (2020). Coming together to improve access to medicines: The genesis of the East African Community’s Medicines Regulatory Harmonization initiative, PLoS Med, 17(8), e1003133. Singer, E. (1993). Informed consent and survey response: A summary of the empirical literature, Journal of Official Statistics, 9(2), p. 361. Available at: https://search.proquest.com/openview/970596f2406469cc58b69527fca91fc6/1?pq- origsite=gscholar&cbl=105444 (Accessed: March 20, 2021) Sithole, T., Mahlangu, G., Salek, S., and Walker, S. (2020). Evaluating the success of ZaZiBoNa, the Southern African Development Community Collaborative Medicines Registration Initiative. Therapeutic Innovation & Regulatory Science, pp. 1-11. Smid, M. and Zweygarth, M. (2014). A promising start for WHO collaborative registration procedure for medicines in developing countries. Scrip Regulatory Affairs. Available at: https://pink.pharmaintelligence.informa.com/PS117761/A-promising-start- for-WHO-collaborative-registration-procedure-for-medicines-in-developing-countries (Accessed: 12 July 2020). Southern African States. (1993). Treaty establishing the common market for eastern and southern Africa adopted in Kampala, Uganda on 5 November 1993. Centre for Southern African Studies (University of the Western Cape). Available at: https://www.dipublico.org/100564/treaty-establishing-the-common-market-for-eastern- and-southern-africa-comesa/ (Accessed: 01 June 2020). Stuckler, D., King, L. and McKee, M. (2008). African Medicines Regulatory Harmonization Initiative (AMRHI): A WHO concept paper, WHO Drug Information, 22(3), pp. 182-190. Available at: https://apps.who.int/iris/bitstream/handle/10665/74289/22_3_2008.pdf?sequence=1&isAl lowed=y (Accessed: 03 April 2019). Stufflebeam, D.L. and Coryn, C.L. (2014). Evaluation theory, models, and applications (Vol. 50). San Francisco: John Wiley & Sons. Available at: https://www.wiley.com/en- us/Evaluation+Theory,+Models,+and+Applications,+2nd+Edition-p-9781118074053 (Accessed: 08 July 2020). Stufflebeam, D. and Shinkfield, A. (2007). The nature of program evaluation theory. Evaluation theory, models and applications. San Francisco: Jossey-Bass, pp. 57-79. Available at: https://books.google.com/books?id=xx6UgC6UdFMC&pg=PA57&source=gbs_toc_r&ca d=4#v=onepage&q&f=false (Accessed: 18 July 2020). Tharani, A. (2017). Harmonization in the EAC, in Ugirashebuja, E. , Eudes Ruhangisa, J.E., Ottervanger T., and Cuyvers A. (eds). East African Community Law. Boston: Brill Nijhoff, pp. 486-499. 190 The Access and Delivery Partnership. (2017). African union model law for medical products regulation: Increasing access to and delivery of new health technologies for patients in need. New York. Available at: https://adphealth.org/upload/resource/AU%20Model%20Law.pdf (Accessed: 20 July 2020). The Council of the European Communities. (1975). Council Directive of 20 May 1975 on the approximation of the laws of member states relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of proprietary medicinal products. Available at: https://eur-lex.europa.eu/legal- content/en/ALL/?uri=CELEX%3A31975L0318. (Accessed: 27 April 2021). The Council of the European Communities. (1993). Council Regulation (EEC) 2309/93,7. European Agency for the Evaluation of Medicinal Products: Brussels. Available at: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol- 1/reg_1993_2309/reg_1993_2309_en.pdf (Accessed: 13 March 2020). Thompson, N., Kegler, M.C. and Holtgrave, D.R. (2006). Program evaluation. Available at: https://psycnet.apa.org/record/2006-10070-008 (Accessed: 27 June 2020). Trotsky, L. (1929). Disarmament and the United States of Europe. New York: Bulletin of the Russian Opposition, 6, pp. 154-158. Available at: https://www.marxists.org/archive/trotsky/1929/10/disarm.htm (Accessed: 09 August 2019). UNAIDS. (2000). Report on the global HIV/AIDS epidemic. Geneva, Switzerland: UNAIDS. Available at: http://www.unaids.org/sites/default/files/media_asset/2000_gr_en_0.pdf (Accessed: 07 April 2019). UNAIDS. (2012). World AIDS Day Report. Geneva: UNAIDS. Available at: https://www.unaids.org/en/World_AIDS_Day (Accessed: 18 January 20219). UNITAID. (2020). Support for WHO prequalification of diagnostics and medicines. Available at: https://unitaid.org/project/support-prequalification-diagnostics- medicines/#en (Accessed: 19 July 2020). United States Food and Drug Administration. (2020). Providing regulatory submissions in electronic format. Food and Drug Administration (United States). Available at: https://www.fda.gov/media/135373/download (Accessed: 31 March 2020). Vogel, D. (1998). The globalization of pharmaceutical regulation, Governance, 11(1), pp. 1-22. 191 Walden, V.M. and Baxter, D. (2001). The comprehensive approach: An evaluation model to assess HIV/AIDS-related behaviour change in developing countries, Evaluation, 7(4), pp. 439-452. Available at: https://www.researchgate.net/publication/238433153_The_Comprehensive_Approach_A n_Evaluation_Model_to_Assess_HIVAIDS- related_Behaviour_Change_in_Developing_Countries (Accessed: 04 July 2020). Weisfeld, V. and Lustig, T.A. (2013). International regulatory harmonization amid globalization of drug development: Workshop summary. Washington, DC: National Academies Press. Available at: https://www.ncbi.nlm.nih.gov/books/NBK153504/ (Accessed: 26 March 2019). Wellman, B., Haase, A. Q., Witte, J., and Hampton, K. (2001). Does the internet increase, decrease, or supplement social capital? Social networks, participation, and community commitment, American Behavioral Scientist,45(3), pp. 436-455. Wilson, S. (1929). Report on Sir Samuel Wilson his visit to east Africa, 1929. London: His Majesty’s Stationery Office. Available at: https://dspace.gipe.ac.in/xmlui/bitstream/handle/10973/36079/GIPE- 032323.pdf?sequence=3 (Accessed: 24 August 2019). Wirtz, V.J., Hogerzeil, H.V., Gray, A.L., Bigdeli, M., et al. (2017). Essential medicines for universal health coverage, The Lancet, 389(10067), pp. 403-476. World Health Organization. (2002). The impact of implementation of ICH guidelines in non-ICH countries - Regulatory Support Series No. 009. Available at: http://digicollection.org/hss/en/d/Jh2993e/10.html (Accessed: 07 July 2020). World Health Organization. (2010). Assessment of medicines regulatory systems in sub- Saharan African countries: An overview of findings from 26 assessment reports, in Essentials Medicines and Health Products. Available at: https://www.who.int/medicines/publications/assesment_africa/en/ (Accessed: 20 July 2020). World Health Organization. (2011). 45 th report of the WHO expert committee on specifications for pharmaceutical preparations: Annex 10: Procedure for prequalification of pharmaceutical products. World Health Organization: Geneva, Switzerland. Available at: https://www.who.int/publications/i/item/forty-fifth-report-of- the-who-expert-committee-on-specifications-for-pharmaceutical-preparations (Accessed: 27 April 2021). World Health Organization. (2013a). WHO Medicines Strategy - Countries at the core 2004 – 2007. (Geneva). Available at: https://www.who.int/management/background_4a.pdf (Accessed: 09 February 2019). 192 World Health Organization. (2013b). WHO expert committee on specifications for pharmaceutical preparations, in Essentials Medicines and Health Products. Available at: https://www.who.int/medicines/services/expertcommittees/pharmprep/en/ (Accessed: 18 January 2019). World Health Organization. (2013c). WHO prequalification of medicines programme, WHO Drug Information, 27(4), pp. 325-331. Available at: https://www.who.int/medicines/publications/druginformation/27-4_collaborative- procedure.pdf?ua=1 (Accessed: 18 January 2019). World Health Organization. (2014). WHO support for medicines regulatory harmonization in Africa: Focus on east African community, WHO Drug Information, 28(1), pp. 11-15. Available at: https://www.who.int/medicines/publications/druginformation/DI_28-1_Africa.pdf?ua=1 (Accessed: 12 February 2019). World Health Organization. (2016). Improving the quality of medical products for universal access, in Essentials Medicines and Health Products. Available at: https://www.who.int/medicines/regulation/fact-figures-qual-med/en/ (Accessed: 17 February 2019). World Health Organization. (2010). Assessment of medicines regulatory systems in sub- Saharan African countries. Available at: https://www.who.int/medicines/publications/assesment_africa/en/ (Accessed: 27 April 2021). World Health Organization. (2019a). Benefits of WHO Prequalification. Available at: https://extranet.who.int/pqweb/medicines/benefits-who-prequalification (Accessed: 10 April 2019). World Health Organization. (2019b). Impact assessment of WHO prequalification and systems supporting activities. Available at: https://www.who.int/medicines/news/2019/report_Impact-assessment_WHO-PQ-Reg- systems.pdf (Accessed: 16 April 2019). World Health Organization. (2020a). List of National Regulatory Authorities (NRAs) operating at maturity level 3 (ML3) and maturity level 4 (ML4) (as benchmarked against WHO Global Benchmarking Tool (GBT), in Essentials Medicines and Health Products. Available at: http://www.who.int/medicines/areas/regulation/nras_ml3_ml4/en/ (Accessed: 31 March 2021). World Health Organization. (2020b). NMRAS participating in the WHO collaborative procedure. Available at: https://extranet.who.int/prequal/sites/default/files/documents/Country_List- 28January2020.pdf (Accessed: 19 July 2020). World Health Organization. (2021a). Model list of essential medicines. Available at: https://list.essentialmeds.org/ (Accessed: 11 April 2021). 193 World Health Organization. (2021b). TRS 1033 - 55th report of the WHO expert committee on specifications for pharmaceutical preparations, in Expert Committee on Specifications for Pharmaceutical Preparations. Geneva. Available at: https://www.who.int/teams/health-product-and-policy-standards/standards-and- specifications/norms-and-standards-for-pharmaceuticals/expert-committee-on- specifications-for-pharmaceutical-preparations (Accessed: 11 April 2021). World Health Organization. (2021c). FPPs and APIs eligible for prequalification ("EOIs"). Available at: https://extranet.who.int/pqweb/medicines/products-eligible- prequalification (Accessed: 22 January 2021). World Health Organization. (2021d). Accelerated Registration of Prequalified FPPs. Available at: https://extranet.who.int/pqweb/medicines/collaborative-registration-faster- registration (Accessed: 28 May 2021). World Health Organization. (2021e). Accelerated Registration of FPPs Approved by SRAs. Available at: https://extranet.who.int/pqweb/medicines/faster-registration-fpps- approved-sras (Accessed: 28 May 2021). Zarocostas, J. (2018). Health ministers adopt African medicines agency treaty, The Lancet, 391(10137), p. 2310. 194 Appendices Appendix A. List of Terms and Acronyms AIDS Acquired immunodeficiency syndrome AMA African Medicines Agency AMRH African Medicines Regulatory Harmonization API Active Pharmaceutical Ingredient ARV Antiretroviral therapy AU African Union AUC African Union Commission CEN-SAD Community of Sahel-Saharan States CIPP Context, Input, Process and Product Evaluation Model COMESA Common Market for Eastern and Southern Africa CRP Collaborative Procedure for Accelerated Registration CRP-PQP Collaborative Procedure between the World Health Organization Prequalification of Medicines Programme and National Medicines Regulatory Authorities in the Assessment and Accelerated National Registration of WHO-prequalified Pharmaceutical Products CRP-SRA Collaborative Procedure for Accelerated Registration of Finished Pharmaceutical Product Approved by Stringent Regulatory Authorities CPMP Committee for Proprietary Medicinal Products CRP Collaborative Registration Procedure CSD Committee on Safety of Drugs CTD Common Technical Document EAC East Africa Community EAC-MRH East African Community Medicines Registration Harmonization project EC European Commission ECCAS Economic Community of Central African States ECOWAS Economic Community of West African States EEC European Economic Community EMA European Medicines Agency EMEA European Medicines Evaluation Agency EML Essential Medicines List EOI Expression of Interest EU European Union FDA United States Food and Drug Agency FPP Finished Pharmaceutical Product FRP Facilitated Regulatory Processes GMP Good Manufacturing Practices HA Health Authority 195 HIV Human immunodeficiency virus HIV/AIDS Human immunodeficiency virus/ acquired immunodeficiency syndrome ICDRA International Conference of Drug Regulatory Authorities ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IGAD Intergovernmental Authority on Development IVD In-vitro Diagnostics LIC Low-Income Country MAA Market Authorization Application MHRA United Kingdom Medicines and Healthcare Products Regulatory Agency MRH Medicine Regulatory Harmonisation NEPAD United States Agency for International Development NGO Nongovernmental organizations NMRAs National medicines regulatory authorities PEPFAR U.S. President's Emergency Plan for AIDS Relief PMDA Pharmaceuticals and Medical Devices Agency PQ Prequalification PQP Prequalification Program QCL Quality Control Laboratory QIS Quality Information Summary QMS Quality Management System RAPS Regulatory Affairs Professional Society REC Regional Economic Community RMP Risk Management Plan SADC Southern African Development Community SADCC Southern African Development Coordination Conference SRA Stringent Regulatory Authorities SSA Sub-Saharan Africa TB Tuberculosis TRIPS Trade-Related Aspects of Intellectual Property Rights UMA Union du Maghreb Arabe (Arab Maghreb Union) UNAIDS United Nations Programme on HIV and AIDS UNFPA United Nations Population Fund UNICEF United Nations International Children’s’ Emergency Fund US United States WAHO West African Health Organization WHO World Health Organization WTO World Trade Organization ZAZIBONA Regulatory collaboration process involving Botswana, Namibia, Zambia, and Zimbabwe 196 Appendix B. Survey Questions CPAR Survey - with French Start of Block: Welcome Block Q1 This survey is designed to examine user experiences when using the WHO Collaborative Registration Procedures for Accelerated Registration (WHO-CPAR) to register pharmaceutical products in Africa. The goal of this study is to identify best practices so that future harmonized registration processes are more efficient and cost- effective. Your answers are central to the success of this study and its implications for collaborative registration programs for medicines. If you have used this process for multiple products, please consider either the most recent product or the most typical product as you answer these questions. The survey should not take longer than 10 minutes to complete. Survey responses are completely anonymous, but if you would like your participation to be acknowledged in my dissertation, please email me at the email address at the end of the survey. Thank you for your participation. 197 Q2 What geographical area best describes your most recent employer's primary location? If you are a consultant, please consider the main organization for which you provide service related to the WHO-CPAR process and provide its location. o North America o South or Central America o United Kingdom and Europe o Russia o Africa o Asia Pacific o Middle East o Other (please specify) ________________________________________________ 198 Q3 What sector describes your current or most recent employer? If you are a consultant, please consider the main organization for which you provide service related to the WHO- CPAR process and provide its main type of business. o Manufacturer of Innovator/Branded Pharmaceutical or Biological Products o Manufacturer of Generic Pharmaceutical or Biological Products o Contract Research or Manufacturing Organization o Government Agency (Regulator, Ministry of Health, Health Authority, etc.) o Non-Government Agency (WHO, MSF, etc.) o Contractor/Consultant/Agent o Other (please specify) ________________________________________________ Q4 What statement best describes the size of your overall organization based on the number of employees? If you are a consultant, please consider the main organization for which you provide service related to the WHO-CPAR process and estimate its size. o Less than 100 employees o 101 - 1000 employees o 1001 - 20,000 employees o More than 20,000 employees o Don't know 199 Q5 How would you classify your present role in your organization? o I have no people reporting to me o I supervise one or more individuals o I supervise one or more groups of individuals Q6 How would you classify your company or organization? o Primary focus is local or within country o Primary focus is multinational or regional o Primary focus is global or international End of Block: Welcome Block Start of Block: Direction Block D1 Have you either used or considered using the WHO-CPAR procedure in conjunction with a product registration in one or more African countries? o Considered using the procedure, but did not o Manufacturer or consultant (including Academic or NGO) involved or familiar with the WHO-CPAR process in conjunction with SUBMITTING a product registration o Health Authority involved or familiar with the WHO-CPAR process in conjunction with EVALUATING regulatory submissions o Did not use or consider using this process End of Block: Direction Block Start of Block: MA Questions 200 M1 What product category does your organization most frequently register using the WHO-CPAR procedure? o Generic product o Proprietary or brand name product o Other (Please specify) ________________________________________________ M2 In how many submissions have you been involved using the WHO-CPAR procedure? o 1 o 2 or 3 o More than 3 M3 How long ago was your most recent experience using the WHO-CPAR procedure? Less than 6 months ago 6 months to less than 1 year ago 1 year to less than 18 months ago 18 months to less than 2 years ago 2 to 3 years ago More than 3 years ago Most recent experience o o o o o o 201 M4 For which countries in Africa did you use the WHO-CPAR procedure? (Please select all answers that apply) ▢ Botswana ▢ Burkina Faso ▢ Burundi ▢ Cameroon ▢ Comores ▢ Côte d'Ivoire ▢ The Democratic Republic of the Congo ▢ Eritrea ▢ Ethiopia ▢ Ghana ▢ Kenya ▢ Madagascar ▢ Malawi ▢ Mali ▢ Mozambique ▢ Namibia 202 ▢ Nigeria ▢ Rwanda ▢ Senegal ▢ Sierra Leone ▢ South Africa ▢ Sudan ▢ Tanzania ▢ Uganda ▢ Zambia ▢ Zanzibar ▢ Zimbabwe ▢ Other ________________________________________________ 203 M5 Are there countries in Africa where you wanted to register your product that do not use the WHO-CPAR procedure? (Select all answers that apply) ▢ Algeria ▢ Angola ▢ Benin ▢ Cabo Verde ▢ Central African Republic ▢ Chad ▢ Comoros ▢ Congo ▢ Djibouti ▢ Egypt ▢ Equatorial Guinea ▢ Eritrea ▢ Eswatini ▢ Gabon ▢ Gambia ▢ Guinea 204 ▢ Guinea-Bissau ▢ Lesotho ▢ Liberia ▢ Libya ▢ Madagascar ▢ Mauritania ▢ Mauritius ▢ Morocco ▢ Niger ▢ Sao Tome & Principe ▢ Seychelles ▢ Somalia ▢ South Sudan ▢ Sudan ▢ Togo ▢ Tunisia ▢ Western Sahara 205 ▢ Other ________________________________________________ ▢ Not applicable ▢ Don't know M6 Were there countries outside of Africa where you used or wanted to use the WHO- CPAR procedure? o Yes (Please indicate which countries) ________________________________________________ o No o Don't know 206 M7 Please indicate the extent to which each of the following factors affected your decision to use the WHO-CPAR procedure: 207 Strongly influenced Moderately influenced Did not influence Don't know The procedure is used by the countries where I wanted to register my product o o o o Applicants can submit a single dossier and receive marketing authorization in multiple countries o o o o The procedure could offer closer interactions with Health Authorities during review o o o o Review timelines may be faster than with other pathways o o o o The procedure may have more predictable timelines than other pathways o o o o Requirements and process appeared simpler than other pathways o o o o 208 Submission components can be reused for other purposes (reimbursement, etc.) o o o o My organization wanted to support regional harmonization efforts in Africa o o o o Post-registration maintenance of dossiers and variation submissions might be easier o o o o M8 What is your overall impression of the WHO-CPAR procedure? (Please explain your answer if favorable or unfavorable) o Favorable ________________________________________________ o Unfavorable ________________________________________________ o Undecided o Don't know 209 M9 Based upon your experience with the WHO-CPAR procedure, will you use the WHO-CPAR procedure again in the future? (Please explain your answer if favorable or unfavorable) ▢ Yes ________________________________________________ ▢ No ________________________________________________ ▢ Undecided ▢ Don't know M10 In general, do you think that regional or joint regulatory harmonized procedures offer more advantages than national (single country) regulatory pathways? o Yes o No o Don't know 210 M11 What advantages do you think that a regional or joint regulatory harmonized procedure will offer compared to a national regulatory pathway? (Please select up to three most beneficial advantages) ▢ Lower cost ▢ Shorter time ▢ Better efficiency ▢ Transparency to the review process ▢ Fewer requirements ▢ Ability to leverage dossier for other purposes (reimbursement, etc.) ▢ Don't know ▢ Other ________________________________________________ M12 Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? o Yes. Please explain what this influence could look like: ________________________________________________ o No o Don't know 211 M13 What advantages do you think that a national (single country) regulatory pathway will offer compared to a regional or joint regulatory harmonized procedure? (Please select up to three most beneficial advantages) ▢ Lower Cost ▢ Shorter time ▢ Better efficiency ▢ Transparency to the review process ▢ Fewer requirements ▢ Ability to leverage dossier for other purposes (reimbursement, etc) ▢ Don't know ▢ Other ________________________________________________ M14 Do you feel that product manufacturers should have more influence in the development of national regulatory pathways? o Yes. Please explain what this influence could look like: ________________________________________________ o No. o Don't know 212 M15 Please indicate whether you agree or disagree about the following statements regarding the WHO-CPAR procedure: Strongly agree Somewhat agree Neither agree nor disagree Somewhat disagree Strongly disagree Product registration instructions are clear and easy to understand o o o o o Requirements for a successful product application are clear and well-defined o o o o o Process to discuss questions with the reviewer are clear o o o o o Applicants who have their drug applications rejected have an appeal process o o o o o 213 M16 Please indicate whether you agree or disagree about the following statements regarding the WHO-CPAR procedure: Strongly agree Somewhat agree Neither agree nor disagree Somewhat disagree Strongly disagree Product registration applications are easy to submit electronically o o o o o The lead reviewer was accessible after dossier submission o o o o o The review was scientifically sound o o o o o Applicants receive an official written report with the application decision o o o o o 214 M17 Would any of the following changes have made the WHO-CPAR procedure easier for you to use? (Please select up to three factors) ▢ Improved documentation on how to use the process ▢ Improved documentation on how to prepare the dossier ▢ Improved documentation on how to prepare variations ▢ More accessible documentation about the process ▢ Easier access to the health authority reviewer(s) ▢ Other ________________________________________________ M18 Would any of the following changes have made the WHO-CPAR procedure easier for you to use? (Please select up to two factors) ▢ Simpler process ▢ More efficient process ▢ Improved process to be notified about the progress of the dossier during review ▢ Elimination of redundant national requirements that must be added to the WHO-CPAR procedure ▢ Other ________________________________________________ 215 M19 The WHO-CPAR procedure has several steps. Please indicate how the duration of each step compares to other registration procedures you have used. 216 Longer than expected Shorter than expected About what was expected Not applicable Timelines were not monitored Applicants authorize WHO to share materials with health authorities of the countries in which registration is sought o o o o o Applicants submit the dossier for assessment using a secure internet- based platform o o o o o The health authority reviews the dossier o o o o o Applicants receive requests for supplemental information o o o o o Applicants respond to the requests for supplemental information o o o o o GMP inspection is performed o o o o o 217 Reviewer communicates decision to applicant o o o o o Registration license is issued to the applicant o o o o o M20 Please think about either the most recent product or a typical product that you registered using the WHO-CPAR process, how long did it take from the time you submitted the dossier to the country to the time you received a regulatory decision? Less than 6 months 6 months to less than 1 year 1 year to less than 18 months 18 months to less than 2 years 2 to 3 years More than 3 years Duration o o o o o o M21 Based upon your experience with the WHO-CPAR procedure, which of the following best describes the timing of the WHO-CPAR procedure compared to the timelines of a national registration procedure? o WHO-CPAR procedure takes longer o National procedure takes longer o Both procedures have about the same duration o Don't know o Timelines were not monitored 218 M22 What national (specific country) requirements did you have to satisfy after completion of the WHO-CPAR procedure to obtain registration? (Select all answers that apply) ▢ I did not have to complete any specific national requirements ▢ Provided product samples ▢ Provided a Certificate of Pharmaceutical Product ▢ Provided a Manufacturing License ▢ Provided a Good Manufacturing Practice (GMP) Certificate ▢ Completed a GMP Inspection ▢ Required to have country specific labeling ▢ Don't know ▢ Other ________________________________________________ 219 M23 Please provide your opinions about the WHO-CPAR procedure: Agree Don't know Disagree The resources planned for filing a WHO-CPAR submission were sufficient o o o The WHO-CPAR procedure was a cost-effective way to register my product o o o I am concerned that the WHO-CPAR procedure will not be available after the next three years o o o 220 M24 Which of the following factors will influence your decision about whether you will use the WHO-CPAR procedure in the future? (Please select up to four factors) ▢ Future plans do not include countries within the scope of the procedure ▢ Process was too complex ▢ Instructions about how to use the procedure were insufficient ▢ Additional training is required to understand and use the procedure ▢ Procedure was too long compared to other procedures ▢ Review progress was not transparent to me ▢ Important information such as deviations from expected timelines were not communicated to me ▢ Estimated process timelines were not accurate/reliable ▢ Process duration from submission to decision was too lengthy ▢ Benefits of the process are less appealing than other registration pathways 221 M25 What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? o Progressing too quickly. Please explain your answer: ________________________________________________ o Progressing too slowly. Please explain your answer: ________________________________________________ o Progressing at an appropriate speed. Please explain your answer: ________________________________________________ M26 What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ M27 Do you have any comments that were not captured above that you would like to include? ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ 222 M28 In the process of using WHO CPAR procedure for product registration, did you have a GMP inspection of your manufacturing facility? o Yes o No o Don't know M29 Was the GMP inspection of your manufacturing facility done remotely ("desk inspection") or was it conducted by a visit to your manufacturing site? o Remote inspection due to Covid-19 concerns o Remote inspection unrelated to Covid-19 concerns o Manufacturing site visit o Don't know M30 How long did it take to schedule the manufacturing site visit? o 0 to < 3 months o 3 to < 6 months o 6 to < 9 months o 9 months or longer o Don't know 223 M31 Do you feel that the GMP inspection of your manufacturing facility added value to the process? o Yes o No o Don't know M32 Please state why the GMP inspection of manufacturing facilities did or did not add value to the WHO-CPAR process: ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ 224 M33 How did you become aware of the WHO-CPAR procedure? (Select all answers that apply) ▢ Article, press release, or other news source ▢ Colleague or coworker ▢ Health Authority or WHO website ▢ Conference or meeting ▢ Participated in the process design ▢ Other (please specify the other way you became aware of the WHO-CPAR procedure other than the previous choices) ________________________________________________ M34 Did the WHO-CPAR procedure meet the needs of your organization? (Please explain your answer if you answer yes or no) o Yes ________________________________________________ o No ________________________________________________ o Don't know 225 M33 Do you feel that the WHO-CPAR procedure is sufficiently publicized? o Yes o No o Don't know End of Block: MA Questions Start of Block: HA H1 In which Regional Economic Community are you working? (Select all answers that apply) ▢ Arab Maghreb Union (AMU/UMA) ▢ Common Market for Eastern and Southern Africa (COMESA) ▢ Community of Sahel-Saharan States (CENSAD) ▢ East African Community (EAC) ▢ Economic Community of Central African States (ECCAS) and Central African Economic and Monetary Community (CEMAC) ▢ Economic Community of West African States (ECOWAS) ▢ Intergovernmental Authority on Development (IGAD) ▢ Southern African Development Community (SADC) ▢ Other ________________________________________________ 226 H2 Do you feel that a health authority has an important role in the development of regulatory harmonization pathways in Africa? (If you answer "yes", please also explain what this role could look like). o Yes. Please explain what this influence could look like: ________________________________________________ o No o Don't know H3 Do you feel that the health authority with which you are affiliated has had an important role in the development of regulatory harmonization pathways in Africa? (If you answer "yes", please also explain what this role was). o Yes. Please explain what this role was: ________________________________________________ o No o Don't know H4 What type of product(s) do you use the WHO-CPAR procedure to assess most frequently? o Generic product o Proprietary or brand name product o Other ________________________________________________ 227 H5 How many products have you reviewed using the WHO-CPAR procedure? o 1 o 2 or 3 o More than 3 H6 Does your country’s legal framework allow for: (Please select all answers that apply) ▢ Harmonization of regulations ▢ International cooperation between health authorities ▢ Information sharing between health authorities H7 In general, do you think that regional or joint regulatory harmonized procedures offer more advantages than your national (single country) regulatory pathway? o Yes o No o Don't know 228 H8 What advantages do you think that a regional or joint regulatory harmonized procedure will offer compared to your national regulatory pathway? (Please select up to three most beneficial advantages) ▢ Shorter time ▢ Better efficiency ▢ Transparency of review ▢ Fewer requirements ▢ Ability to leverage dossier for other purposes (reimbursement, etc.) ▢ Don't know ▢ Other ________________________________________________ H9 Do you feel that product manufacturers should have more influence in the development of regional or joint regulatory harmonized procedures? o Yes. Please explain what this influence could look like: ________________________________________________ o No o Don't know 229 H10 What advantages do you think that a national (single country) regulatory pathway will offer compared to your regional or joint regulatory harmonized procedure? ▢ Shorter time ▢ Better efficiency ▢ Transparency to the review process ▢ Fewer requirements ▢ Ability to leverage dossier for other purposes (reimbursement, etc) ▢ Don't know ▢ Other ________________________________________________ H11 Do you feel that product manufacturers should have more influence in the development of national regulatory pathways? o Yes. Please explain what this influence could look like: ________________________________________________ o No o Don't know 230 H12 Please indicate whether you agree or disagree about the following statements regarding the WHO-CPAR procedure: Strongly agree Somewhat agree Neither agree nor disagree Somewhat disagree Strongly disagree Product registration instructions are clear and easy to understand o o o o o Requirements for a successful product application are clear and well-defined o o o o o Process for applicants to discuss questions with the reviewer are clear o o o o o Applicants who used the WHO-CPAR procedure who have their drug applications rejected have an appeal process o o o o o 231 H13 Please indicate whether you agree or disagree about the following statements regarding the WHO-CPAR procedure: Strongly agree Somewhat agree Neither agree nor disagree Somewhat disagree Strongly disagree Product registration applications are easy to receive and review electronically o o o o o Product registration applications are easy to share electronically with other reviewers o o o o o Dossier reviews are scientifically sound o o o o o The Health Authority provides an official written report to communicate the application decision o o o o o 232 H14 What is your overall impression of the WHO-CPAR procedure? (Please explain your answer if favorable or unfavorable) o Favorable ________________________________________________ o Unfavorable ________________________________________________ o Undecided o Don't know H15 With which of the following statements about the WHO-CPAR procedure do you agree: (Select all answers that apply) ▢ I have sufficient time to address applicant questions ▢ I have sufficient resources to assess WHO-CPAR procedure dossiers ▢ The procedure is a cost-effective way to review dossiers ▢ The procedure is aligned with my country’s reimbursement strategy ▢ The procedure supports regional harmonization efforts in Africa 233 H16 Would any of the following changes have made the WHO-CPAR procedure easier for you to use?(Please select up to three factors) ▢ Improved documentation on how to use the process ▢ Improved documentation on how to assess dossiers ▢ Improved documentation on how to assess variations ▢ More accessible documentation about the process ▢ Easier accessibility to the applicant(s) ▢ Easier accessibility to other reviewers ▢ Easier accessibility to the WHO ▢ Other ________________________________________________ 234 H17 Would any of the following changes have made the WHO-CPAR procedure easier for you to use? (Please select up to two factors) ▢ Simpler process ▢ More efficient process ▢ Improved ability to access previous reviews about similar products reviewed by the Stringent Regulatory Authority or WHO ▢ Elimination of redundant national requirements to be satisfied in addition to the WHO-CPAR procedure ▢ Other ________________________________________________ 235 H18 The WHO-CPAR procedure has several steps. Please indicate how the duration of each step compares with other registration procedures you have used. 236 Longer than expected Shorter than expected About what was expected Not applicable Timelines were not monitored Health authorities agree to review the applicant's dossier using the WHO- CPAR procedure o o o o o Applicants authorize WHO to share its assessment and inspection outcomes for the specific product(s) with the health authority (authorities) of the country in which accelerated registration is sought o o o o o The dossier assessment report is shared using a secure internet- based platform o o o o o The reviewer reviews the dossier o o o o o 237 The reviewer sends requests to the applicant for supplemental information o o o o o Applicants respond to the requests for supplemental information o o o o o GMP inspection is performed o o o o o Reviewer communicates decision to applicant o o o o o Registration license is issued to the applicant o o o o o H19 Please think about either the most recent product or a typical product that you reviewed using the WHO-CPAR process. How long did it take from the time you received the dossier to the time you issued a regulatory decision? Less than 6 months 6 months to less than 1 year 1 year to less than 18 months 18 months to less than 2 years 2 to 3 years More than 3 years Duration o o o o o o 238 H20 Based upon your experience with the WHO-CPAR procedure, how does the timing of the WHO-CPAR procedure compare to those of your national registration procedure? o WHO-CPAR procedure takes longer o National procedure takes longer o Both procedures have about the same duration o Don't know o Timelines were not monitored 239 H21 What national (specific country) requirements are required to obtain registration in your country after completion of the WHO-CPAR procedure? (Select all answers that apply) ▢ Applicants do not have to complete any specific national requirements ▢ Applicants must provide product samples ▢ Applicants must provide a Certificate of Pharmaceutical Product ▢ Applicants must provide a Manufacturing License ▢ Applicants must provide a Good Manufacturing Practice (GMP) Certificate ▢ Applicant must undergo a GMP Inspection ▢ Applicant's product is required to have country specific labeling ▢ Don't know ▢ Other ________________________________________________ 240 H22 Please provide your opinions about the WHO-CPAR procedure: Agree Don't know Disagree The resources planned for reviewing a dossier were sufficient o o o I am concerned that the WHO-CPAR procedure will not be available after the next three years o o o 241 H23 Which of the following factors will influence your decision about whether to recommend the use of the WHO-CPAR procedure in the future? (Please select up to four factors) ▢ Process was too complex ▢ Instructions about how to use the procedure were insufficient for the Applicant ▢ Instructions about how to use the procedure were insufficient for reviewers ▢ Additional training is required to understand and use the procedure ▢ Procedure was too long compared to other procedures ▢ Process duration from submission to decision was too lengthy ▢ Estimated process timelines were not accurate/reliable ▢ Benefits of the process are less appealing than other registration pathways ▢ Other ________________________________________________ H24 Did the WHO-CPAR procedure meet the needs of your organization? (Please explain your answer if you answer "yes" or "no") o Yes ________________________________________________ o No ________________________________________________ o Don't know 242 H25 Based upon your experience with the WHO-CPAR procedure, will you recommend the use of the WHO-CPAR procedure in your organization in the future?(Please explain your answer if you answer "yes" or "no") o Yes ________________________________________________ o No ________________________________________________ o Don't know H26 What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? o Progressing too quickly. Please explain your answer: ________________________________________________ o Progressing too slowly. Please explain your answer: ________________________________________________ o Progressing at an appropriate speed. Please explain your answer: ________________________________________________ H27 In your organization, what percentage of products using the WHO CPAR procedure for product registration required a GMP inspection of a manufacturing facility? o 0 to < 25% o 25% to < 50% o 50% to < 75% o 75% or greater o Don't know 243 H28 If a GMP inspection is required, on average, how long does it generally take to schedule the manufacturing site visit? o 0 to < 3 months o 3 to < 6 months o 6 to < 9 months o 9 months or longer o Don't know H29 If a GMP inspection of a manufacturing facility was conducted, do you feel that the GMP inspection added value to the process? o Yes o No o Don't know H30 Please state why the GMP inspection of manufacturing facilities do or do not add value to the WHO-CPAR process: ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ 244 H31 Were the majority of the GMP inspections related to your dossier reviews conducted remotely ("desk inspection") or were they done by a visit to the manufacturing site? o Remote inspection due to Covid-19 concerns o Remote inspection unrelated to Covid-19 concerns o Manufacturing site visit o Don't know H32 Do you feel that the WHO-CPAR procedure is sufficiently publicized? o Yes o No o Don't know H33 What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ 245 H34 Do you have any comments that were not captured above that you would like to include? ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ ________________________________________________________________ End of Block: HA Start of Block: No block Q80 Why did you not use the WHO_CPAR procedure? o The countries where I wanted to register my product are not included in the scope of the procedure (please indicate countries below): ________________________________________________ o Procedure appeared too complex o Instructions about how to use the procedure were insufficient o Additional training is required to understand and use the procedure o Procedure appeared too long compared to other procedures o Review progress was not transparent to me o Benefits of the process are less appealing than other registration pathways o I was not aware of the process o Other ________________________________________________ 246 Q81 Would you consider using the WHO-CPAR procedure in the future? (Please explain your answer): o Yes ________________________________________________ o Maybe ________________________________________________ o No ________________________________________________ Q82 What is your overall impression of the WHO-CPAR procedure? (Please explain your answer if favorable or unfavorable) o Favorable ________________________________________________ o Unfavorable ________________________________________________ o Undecided o Don't know End of Block: No block 247 Appendix C. Participant Comments Table 5: Barriers to Regulatory Harmonization: Selected NMRA Opinions What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? CIPP Category Comment Context Political All countries to have legislations and capacitated regulatory authorities Context Political Elimination of national regulations which still need to be met Context Political Language barrier Context Political Legislation Context Political Political commitment Context Political Political differences Context Political Political will Context Political The FDA is the boss, if they no want, then it does not happen. Context Readiness Capacity development for mutual recognition of competencies Context Readiness Capacity differences in Member states in regulatory issues. Context Readiness Regulatory capacity building amongst regulators in Africa who are able to assess all product applications and dosage forms. Context Readiness Strengthening the regulatory systems within the member countries Input Roles and Responsibilities Inclusion of all regulatory agencies as active members Process Procedure Awareness and training Process Procedure Information sharing on regulatory harmonization process/ documents Process Procedure Online training and encourage the companies to use it Process Procedure refresher training to Reviewers Process Procedure Report/Data sharing Process Procedure skilled professionals/training Process Resources Technical support from academicians Process Resources Funding and training Process Resources Funding and trainings for personnel Process Resources Human resources issues Process Resources Human resources More regional training Process Resources Budget 248 Table 6: Barriers to Regulatory Harmonization: Selected Industry Opinions What is the most significant barrier which must be overcome to improve regulatory harmonization in your region? CIPP Category Comment Context Political Corruption Context Political Disparity of national requirements and conflicting national interests Context Political La volonte politique* [political will] Context Political Lack of a central body with legislative authority, a good example is EMA in Europe that works with the European Commission which has legislative powers Context Political Mindset of regulators Context Political National legislation does not always support harmonization Context Political The lack of flexibility in the local requirements for the products that are already approved in a strict country. Input Collaboration Communication between the health authority and stakeholders Input Collaboration Countries should be more open to use reliance pathways, not only from the SRA but also between African countries. Especially for GMP related matters. Input Collaboration Different countries at different levels of regulatory proficiency, it makes it difficult to harmonize because there is no trust and respect among participating member states Input Collaboration Mutual recognition of documents approved by individual countries Input Collaboration Poor coordination Input Collaboration There should be more efforts from SRA countries to share their technical knowledge with Africa nras, especially when it comes to assessing critical products that have been reviewed in their (SRA) countries. Input Collaboration Trust Input Readiness Gaps in in scientific knowledge Process Procedure Clear procedure available Process Procedure Communication to applicants and status of review processes should be improved. Process Procedure Electronic submission should be compulsory Process Procedure Electronic submissions. Process Procedure Ensuring that the dossier provided by the manufacturer was exactly what was approved by WHO Process Procedure No clear timelines Process Procedure Process and procedure clarification on product dossier registration Process Procedure Technical support provided by the SRAs for Africa NRA is lacking and can be improved. Process Procedure Viable online platform where stakeholders have easy access to all information pertaining to registration and other things Process Resources Member states also fear losing revenue from application fees Regulatory harmonization in my region works well 249 Table 7: Pace of Harmonization Pathway Development and Implementation: Selected NMRA Opinions What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? Progressing too slowly. Please explain your answer: CIPP Category Comment Context Political ZAZIBONA was long initiated but still no recognition between those countries Context Political Skepticisms, economic factors, political differences, disparities in disease areas of priorities. Context Political In ECOWAS, Language barrier has been a huge challenge. The Anglo/Franco/Lusophone divide had slowed things down. We need to get over this to speed up the process!!! Context Political Process is fast in SADC but not in other RECs. Political will to support harmonisation; impact on fees revenue Context Political It has stalled somewhat. There is need for political will to push the agenda Context Readiness Different capacities of regulatory authorities are derailing progress Context Readiness LACK OF: budget, skilled professional, political commitment, regulatory structure in some of the country Process Procedure It’s slow and hinders access to Therapies for the overall population Process Procedure There are still lots of bottlenecks. Process Procedure I think not all countries are given regular updates Process Procedure Impact of the developments have not been felt in-country Process Procedure I haven't seen major milestones in the harmonisation program Process Resources There is little time dedicated by the member states Progressing at an appropriate speed. Please explain your answer: CIPP Category Comment Context Political The legal frameworks of countries should allow these processes. In addition, the advantages and disadvantages should be analysed critically Context Political Since some countries did not have Medicines Agencies, it was difficult to sit everyone together sometimes where other countries do not even have functional regulatory agencies. They won’t be able to make strategic decisions. Now it has progressed at the appropriate speed because regulatory agencies are being set. Context Political I think it is progressing at an appropriate speed judged by the fact that each economic region currently has its own harmonization process going on. The African Medicines Agency ratification process is somehow a bit slow. Context Readiness It’s progressing in a medium speed. Health authorities began to familiarize with this procedure Context Readiness They are doing the best they can. Process Procedure Approval and review take optimum time 250 Table 8: Pace of Harmonization Pathway Development and Implementation: Selected Industry Opinions What do you think about the pace of the development and implementation of regulatory harmonization pathways in Africa? Progressing too quickly. Please explain your answer: CIPP Category Comment Process Procedure It's progressing quickly but the processes are too slow. We have opted to drop all regional harmonisation programs such as zazibona, waho, eac, Igad and only use WHO harmonisation process for PQ products. These regional harmonisation programs either don’t have enough resources or not well coordinated. We would rather go in-country than harmonised programs Progressing at an appropriate speed. Please explain your answer: CIPP Category Comment Context Political Evolution progressive en fonction de la collaboration avec le politique [Progressive evolution as a function of collaborating with politics]* Context Political The faster the better but understanding the complexity of the landscape we cannot expect it to go much faster. Context Political I recognise international coordination is not easy. Context Readiness Many Health Authorities are still struggling with the WHO benchmarking. In the coming years I believe more countries will have better scores Context Readiness Infrastructure still lacking. Process Procedure Should adopt electronic submission Progressing too slowly. Please explain your answer: CIPP Category Comment Context Political Aub regional bodies are not keen on having an harmonised process Context Political African countries would benefit from a fully harmonized procedure throughout the continent. However, national interest may prevent this even in the long term Context Political The progress has been slow due to the mindset of the Regulators who are too "nationalistic" and are failing to adjust to globalization and appreciate the advantages of. The other major problem is that the regional harmonisation authority groupings can only recommend their decisions to member states who at times take long to implement without any consequences, they do not have legislative authority Process Procedure Regional Regulatory Authority need more training on the review and requirements. Process Procedure Some traction is seen across Africa but there's still room for improvement. Process Procedure Most African Countries still need to implement eCTD format. Process Procedure I think there are a number of systems in place with the regional initiatives - they just need to be used and experience gained Process Procedure There is a rise of Regulatory Harmonization pathways, but the review processes take long and less time is given to the dossiers and other supplementary documentation. Process Procedure Principle are there but in practice there is still a lot to improve. Process Procedure It's taken over four years to get here and yet there are several bottlenecks yet to be resolved like mutual recognition of GMP Certification 251 Table 9: NMRA Role in the Development of Harmonized Pathways: Selected NMRA Opinions Do you feel that a health authority has an important role in the development of regulatory harmonization pathways in Africa? Yes. Please explain what this influence could look like: CIPP Category Comment Context Political Cross-border joint surveillance; opening harmonized market registration system; and the like Context Political There are a number of country-specific requirements that must be addressed before harmonization can be agreed upon due to difference laws in different countries. Context Readiness A health authority…has an important role in the development of regulatory harmonisation pathways in Africa through removing any non - critical country-specific requirements which are not part of the CTD in module 1. For example having and adopting a single guideline for both quality, efficacy and product information related materials. This not only facilitates the ease of registration of products seamlessly across the region but also afford timely access of medicines to patients. Context Readiness Active participation in the harmonisation of processes Context Readiness An HA has the ultimate authority for approval of a marking application. Their role and buy-in is critical to success. Context Readiness Contribute to development of harmonized guidelines, Availing resources e.g. human, financial to run the harmonisation processes, Context Readiness Developing guidelines considering the challenges different countries experience during medicines registration Context Readiness Embracing harmonized evaluation as a process that will increase medicines, diagnostics availability to needy patients at affordable costs. Combined Strengthened systems will also better enforcement that will ensure only quality efficacious products are allowed in the market therefore managing Illicit and counterfeits that find opportunities where there are gaps of affordable health care to take care to the needy. Context Readiness HAs develop the guidances for implementation and facilitate information exchange Context Readiness Opportunities to share experience, work sharing, learning to trust and then rely upon each other. Context Readiness Promotion regulatory convergence, capacity building, resource optimization Context Readiness Providing leadership and guidance to regulatory harmonisation Context Readiness Since HA's in Africa have a great variety of maturity/resources, all HA's need to be involved and guide the process to enable a harmonized pathway to work for all countries/regions involved. This may also need better communication between HA's, making a agreements on reliance etc. Context Readiness Thought and collaboration leadership Context Readiness Ultimate execution of the decisions made, policies and guidelines developed lies with the health authority/national regulatory authority Context Readiness Without the authority being receptive of the outcomes of harmonization i.e reliance and recognition all the efforts of harmonization will be in vain Process Procedure Ensuring that the medicines used are safe and efficacious Process Procedure Establishing harmonised guidelines together with other neighbouring countries e.g. in the EAC Process Procedure Having a central medicine registration procedure where one application submitted to the collaborative procedure results in the registration of the drug in several countries at the same time. 252 Process Procedure Important role in helping the access of the essential medicines and facilitate the registration Process Procedure In work sharing, it helps the agency with backlog and fast track the registration of essential medicine. Process Procedure Maintenance of dossiers in ectd format Process Procedure Minimize duplication of work and resource Process Procedure Monitoring medicines post-registration will allow other Authorities to make informed decision. Process Procedure Save the authorities and manufacturer time. Process Procedure Scientific assessment of medical product dossiers, inspections, surveillance, Pharmacovigilance and Quality Control Process Procedure The harmonization mutual requirements and would ensure no duplication of requests Process Procedure The Health Authority is in a good position to balance country-specific requirements with regional requirements Process Procedure The role of Regulatory Authority could be registration of products, inspections of manufacturing sites, post approval changes approval and Post marketing surveillance of approved products. Process Procedure There is need to safeguard public health by only allowing access to safe, effective and quality products Process Procedure These would be beneficial to all stakeholders including manufacturers, regulators and general public. Also, to decrease the amounts of substandard and counterfeit medicines within the continent Process Resources Availing resources e.g. human, financial to run the harmonisation processes, Other Comments CIPP Category Comment Context Readiness Capacity Building Context Readiness Knowledge sharing and capacity building of regulators during such meetings. Context Readiness Opportunity to learn from experienced Regulators if you are a startup 253 Table 10: Level of Industry Influence in the Development of Harmonized Procedures: Selected NMRA Opinions Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? Yes. Please explain what this influence could look like: CIPP Category Comment Context Readiness Advocacy and Lobbying that it would enable better access of quality and affordable medicines across those who need them reducing complexities seen in national Systems. Context Readiness Involved in review and validation of harmonized regulatory frameworks Input Design Taking active part in committees and defining best practices Process Procedure By advocating and being at the forefront of having harmonised product information requirements in the region. Process Procedure Efficiency, fast tracking and local data collections including Real World Data (RWD) Process Procedure joint regulatory harmonized procedures Process Procedure Manufacturers often have more detailed information on product development compared to HAs, especially for newer technologies. Process Procedure Past experience and knowledge from other regulators available with manufacturer can be shared Process Procedure Since they are the clients...their voice should be heard. Could help to develop more suitable systems Process Procedure Submitting their applications in the community will strengthen the harmonization. Process Procedure The industry should be to contribute to the technical content of the guidelines through consultative processes Process Procedure They are key stakeholders whose view must be taken into consideration Process Procedure They are the main beneficiaries and should contribute to processes that best suit them Process Procedure They should collaborate and comment as well as make suggestions for an improved procedure Process Procedure They should provide critical feedback to the proposed procedures and guidances Process Procedure Yes. They need to understand the requirements and advantages. General contribution to help both ends Product Duration Faster approval timelines 254 Table 11: Level of Industry Influence in the Development of Harmonized Procedures: Selected Industry Opinions Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? Yes. Please explain what this influence could look like: CIPP Category Comment Context Readiness explain the challenge of supply, distribution and production. Influence of having harmonized/global label to be used in all the countries to make sure to shift product easily as needed in different countries. Input Design A balanced process has input from all users Input Design If the product manufacturers are involved, then the procedures will be more realistic and factor in the specific challenges currently encountered with a view to profer solution Input Design Taking active part in committees and defining best practices Input Design The manufacturers are a big stakeholder to the development of Joint Harmonized Procedures, they offer there expertise in formulating of these procedures and hence deserve the influence Process Procedure As stakeholders they need to assist the regulator to come up with procedures that will help them register and reach other countries apart from their country of origin faster. Process Procedure faster approval timelines Process Procedure For innovator products that are already assessed by a reliable authority, manufacturers could impress the need for even more simple dossier packages ie to ask for the assessment reports to be shared directly between strict and destination health authorities (for new submission & lifecycle management), without the manufacturer's involvement. A suitable confidential data sharing platform however needs to be set up for this. Process Procedure I believe Industry can help NRAs streamline their processes by sharing their experience and expertise from a different perspective to that of the NRAs. For example NRAs can reduce the amount of information they request during dossier evaluation by better information management eg creation of an API database Process Procedure SE SONT LES UTILISATEURS DONC APTE A APPRECIER [Are the users and therefore able to appreciate <the process>]* Process Procedure Yes development pathways should be cleared like USFDA guidances for product development. Product Effectiveness Important to get stakeholder feedback on the efficiency and effectiveness of the pathway from stakeholders who have experience as part of good review practices. Product Effectiveness It is important that both on implementation or production of guidelines agencies should provide opportunity to get feedback to ensure they are aware of possible areas that may build in disincentives due to increased burden. Product Sustainability In our experience the Company was a full partner in the CPSR procedure. This shows that companies have their say. Given the advantages for all partners, including the patients, it would seem a win-win situation if the manufacturers would help promoting these procedures Product Sustainability When more manufacturers are willing to share the dossier submitted to WHO with other Country Health Authorities, it shows their commitment to transparency and improving the health sector of those countries 255 Table 12: Level of Industry Influence in the Design of National Regulatory Pathways: Selected Industry Opinions Do you feel that product manufacturers should have more influence in the development of national regulatory pathways? Yes. Please explain what this influence could look like: CIPP Category Comment Context Political Not all products are WHO prequalified. So these products need to follow the single country pathway but dossier review in any SRA can be leveraged upon for faster processing. The collaboration from manufacturers in this regard will strengthen trust Input Design Feedback on proposals as well as guidance to ensure that the pathway is practical and usable Input Design Influence on making the dossier requirements for national regulatory pathways more fit for purpose. Specifically, some African health authorities have adopted the use of the Quality Information Summary (QIS) document for new registrations and license maintenance. The WHO publishes the QIS template for use in the prequalification of generic products however, recognising the needs of the SRA-approved products are different, the WHO also published a QIS-SRA template for prequalification. Hence, for the countries that has adopted the QIS in national regulatory pathways, the HAs should allow manufacturers to use either the QIS & QIS-SRA templates as appropriate for their products. Input Design the regulatory framework in new procedures are always helpful Process Procedure PARCE QUE SE SONT LES UTILISATEURS [Because they are the users]* Process Procedure So that the regulator can come up with procedures/guidelines on registration of product dossiers and to shorten the evaluation period. Process Procedure Yes, they need to be consulted as they are the biggest stakeholders in the development of regulatory guidelines used for these national pathways Product Sustainability It will enable a more robust pathway Do you feel that product manufacturers should have more influence in the development of regional/joint regulatory harmonized procedures? Yes. Please explain what this influence could look like: It’s all about stakeholders’ engagement and local manufacturers can own the regulatory pathway 256 Table 13: Level of NMRA Influence in the Design of Regional Regulatory Pathways: Selected NMRA Opinions Do you feel that the health authority with which you are affiliated has had an important role in the development of regulatory harmonization pathways in Africa? (If you answer "yes", please also explain what this role was). Yes. Please explain what this role was: CIPP Category Comment Context Readiness We are the leading Authority in the SADC region and we help build capacity for other members, develop the system for harmonisation Context Readiness We do participate in regional meetings to develop guidelines Input Design Being one of the first countries in the SADC region to initiate harmonized registration processes (…ZAZIBONA) Input Design By contributing to the discussions towards harmonisation both during the heads of agencies meetings and technical meetings Input Design Contributing in development of harmonized labeling guidelines, variation guidelines, quality and safety guidelines Input Design Ensuring that the medicines used are safe and efficacious Input Design Founding country of harmonization initiative. Coordinating agency for a harmonization in Africa Input Design IGAD try to contribute it role on harmonization of regulation in Africa. It comprise 8 countries. Starts Joint assessment and it is on good progress. Input Design In developing guidelines and conduct training on assessments of product dossier and carry out assessment. Input Design Namibia, was among one of the countries that formed the first Southern Africa harmonization that is called Zazibona(Zambia, Zimbabwe, Botswana & Namibia)... Currently Zazibina initiative have currently 14 members state(SADC. Input Design NDA has participated in both EAC and IGAD harmonisation guidelines for registration, GMP and pharmacovigilance Input Design The authority is very active in SADC initiative processes. Input Design There is full participation in the development of policies and regulations as well as joint assessments and joint inspections. The Organization has adopted some of the approved regional regulatory guidance documents Input Design They are actively involved in the harmonization via West African Health Organization (WAHO) which is trying to come up with common regulations and registration for the region. Input Design We are active in ZAZIBONA programme which allow for reliance. Input Design Yes. It was the initiating and founding member of the SADC Medicines Regulatory Harmonisation project commonly known as Zazibona. Input Design ZAZIBONA Process Improvement Actively supporting harmonization. Offered key well trained staff to train regional peers for adoption of better processes and procedures. Sharing of best practices in Regional meetings supportee by the likes of NEPAD. Pioneer in online submissions, evaluation and approvals. Process Procedure Harmonization of Regulatory Frameworks, Guidelines, Procedures for Medical Products and Devices Process Procedure It’s one of the leading regulatory authorities in Africa Process Procedure Provision of in-house expertise to support development of relevant guidelines and regulations. Process Procedure Testing of samples Process Procedure The agency responsible for all operational activities 257 Do you feel that the health authority with which you are affiliated has had an important role in the development of regulatory harmonization pathways in Africa? (If you answer "yes", please also explain what this role was). Yes. Please explain what this role was: CIPP Category Comment Process Procedure yes. it has been recently involved in ZaZiBoNA, A SADC collaborative procedure, where 14 countries joint assess a drug submission made to atleast 2 SADC countries. Product Effectiveness Cross-border joint surveillance; opening harmonized market registration system; and the like Product Effectiveness Yes. We are the end users of the WHO-CRP and therefore provide valuable feedback 258 Table 18: Value of GMP Inspections: Selected NMRA Opinions Please state why the GMP inspection of manufacturing facilities do or do not add value to the WHO-CRP process: Do add value: CIPP Category Comment Process Improvement An outside review of the process always provides fresh insight to use to improve compliance. Process Improvement I also feel it is a learning process and an opportunity to get documentation Process Improvement There have been certain instances of confirming sameness of product and site. Where there are VERY STRONG suspicion a GMP inspection may add value to the WHO-CPAR, else it does not Process Procedure Assure quality, compliance of set guidelines to regulatory authorities. Process Procedure Companies may have multiple blocks for different markets at the same site with varying standards Process Procedure Confidence in the registered product and facility where the product is manufactured Process Procedure It just is part of the process and something that needs to get done! Process Procedure It’s for the regulatory authority to confirm the compliance of the manufacturing site with GMP standards. In the same way the dossier is also reviewed by the assessors. Process Procedure Local report is required Process Procedure They add value because you verify with evidence compliance of the manufacturing facility to GMP, assuring the quality of the products from the facility Process Resources Sharing experience from the skilled inspectors report may be the advantage. But - it is wasting the manufacturer and authority time to inspect the already inspected company. -increases the cost of the manufacturer -duplication of efforts Don't add value: CIPP Category Comment Process Resources Because the sites would have been inspected by WHO Process Resources For our country this is not a requirement. the GMP inspection done by WHO is adopted Process Resources GMP are important but we usually recognize GMPs from stringent regulatory authorities and not conduct them ourself Process Resources Since the CRP procedure rely on the medicines that are already approved by the reference SRA and inspection outcomes from the reference SRA are shared with the WHO-CRP-participating country (in the registration dossier), I don't believe there is a need to perform GMP inspections by the HAs. Process Resources The GMP inspection by WHO would already have addressed most if not all issues that would be raised by our own inspectors Process Resources The GMP inspection is not required for the national procedure, normally … the GMP certificate is enough so I think it preferable to use just the GMP certificate than the GMP inspection that usually takes time to have it specially. Most of African countries required an original hard copy. Process Resources These sites are already inspected by the WHO inspectorate. The country inspection would not add any value except to deplete resources as this would be duplication of effort. 259 Table 19: Value of GMP Inspections: Selected Industry Opinions Please state why the GMP inspection of manufacturing facilities do or do not add value to the WHO-CRP process: Do add value: CIPP Category Comment Process Improvement ELLE A APPORTE UNE VALEUR AJOUTEE DANS L OPTIMISATION DE LA PRODUCTION DES PRODUITS DE QUALITE [It provided added value in the optimization of the production of quality products]* Process Improvement It provides confidence that product is manufactured by compliant facilities Process Improvement It highlighted areas that needed to be improved Do not add value: Input Scope Inspection is mainly focused on the 21CFR and cGMP whereas WHO- CRP is about the process of getting product dossier registration. Process Resources The facilities are regularly GMP inspected by highly-regulated authorities Process Resources Facility is inspected often by multiple health authorities. Would be value- added if a country could use a GMP inspection from a Stringent Regulatory Authority Process Resources No need for multiple GMP inspections of already globally approved and marketed product Table 20: Selected Reasons Why Participants Did Not Use the Procedure Why did you not use the WHO-CRP? CIPP Category Comment Context Political Not ruled by law Context Political Working in the Regulatory Unit within the Ministry of Health, the legislation in my country previously had no provisions for product registration. Provisions have since been included thus there is an ongoing discussion on using the WHO-CRP as one of the product registration pathways. Product Reach Not invited or no chance of engaging in it Product Reach The procedure is used for essential medicines for now 260 Table 21: Selected Comments About Future Use of WHO-CRP Would you consider using the WHO-CRP in the Future? Yes CIPP Category Comment Context Barriers When I get the chance to work in it, I will take it happily as an assessor Context Readiness if it is a mandatory Input Design There are more guidelines for harmonization within African region, so the Authorities are really open to the idea Process Improvement The procedure accelerates registration through improved information sharing between WHO PQP and National MRAs Process Duration As it has the potential of providing an expedited product registration pathways. Thus, may enable the registration of WHO PQ products faster Process Duration Because it can accelerate the registration of the drug product in African countries and then can allow to equity in the access to medicines in Africa. Process Duration Efficient and less timelines Process Duration If by using this process, the timelines of approvals will reduce and the cost and will include multiple countries approvals, will surely be a robust pathway to follow Process Duration If it will offer abridged reviews and shorten registration timelines Process Duration Normal review/registration procedures can take very long (sometimes years). Most African Authorities recognize approvals from Stringent Regulatory Authorities, as well as the WHO prequalification program. These approvals are crucial to obtain quicker registrations, without the need for full review of the dossiers. Process Duration the experiences from countries that have used it, have reported success and gains to the country Process Duration The timelines are shorter Process Duration Yes. It gives shorter approval /registration time so you can market product early Process Procedure Certain SSA countries are adapting it and hence we may use if for those who prefer it in lieu of ICH CTD Process Resources As a regulator it supports resource optimization Process Resources help save authority's resources Process Resources Helps in marketing the product widely Process Resources I understand is value globally Maybe CIPP Category Comment Context Readiness After further training Context Readiness Depends on product and access priorities Context Readiness If I get any chance definitely, I would like to explore Context Readiness Must first see how the current effort turns out. Context Readiness Need to know specifics of the process first Context Readiness Need to understand it more Input Design We are interested in a limited number of Countries and the dossiers for registration, still need to be submitted in each country Process Resources Depends on economic conditions and further clarification of local variations Process Resources If we consider WHO as main body along with national authorities then, there are chances of early approval and product can be launch with short timelines. There would be benefit in terms of time, resources & money. 261 Would you consider using the WHO-CRP in the Future? Yes CIPP Category Comment Product Effectiveness Need to consider the benefits of the procedure and then will decide. Product Reach Je ne connais pas cette procedure. Tous les enregistrements pour les pays French West Africa suivent la procedure UEMOA [I do not know this procedure. All the registrations for the French West African countries follow the UEMOA procedure]* Product Reach si c'est pour un vaccin ou un innovateur c'est plus interessant [If it is for a vaccine or innovative product, it is more interesting]* 262 Table 22: Overall impression of the WHO-CRP: Selected Non-User Opinions What is your overall impression of the WHO-CRP? Favorable CIPP Category Comment Context Readiness Seems credible, challenge is getting markets to almost same level of regulatory requirements and processes Input Design However, the process has to be improved to attract more NMRA Input Design J'y suis favorable si c'est pour un produit innovateur, produit orphelin ou vaccin pour les générique les autres voies semblent meilleures [I am in favor of it if it is for an innovative product. For an orphan product or a generic vaccine, the other routes seem better]* Input Design The objective of the procedure is clear, and the procedure should be very helpful to manufacturers for the registration of drug products in Africa. Process Duration Allows shorter time to registration of essential medicines in African countries. Ensures broad access of quality medicines. Process Duration Eliminating duplication of work, speeding up the delivery of quality-assured products and making these more widely available Process Duration Offers better timelines, audit and collaboration Process Duration Reduces backlog Process Duration Shorter time to product registration Process Duration Shorter time to registration. Process Duration The timelines are shorter Process Duration This will assist to fast-track registration that are needed in Africa. Process Procedure Interaction with WHO PQ Process Procedure It is favorable, because it required less requirement that the national procedure, just one thing that we prefer to include also some reduction on the number of samples as some countries does required over than 50 samples for one registration or for lifecycle management so I think if there is any negotiation on it, a lot of companies will use this procedure than the national one. Process Procedure Yes, it will align the documentation. Process Resources Even though have currently not used the procedure but I believe it would one way of enabling our regulatory agency to use our limited resource sensibly Process Resources Our regulatory authority has less than ten (10) assessors and we receive more than three hundred (300) applications per year therefore we do not have the capacity to do full assessments for all the products. Using the WHO- CRP route means the availability of medicines is accelerated. Product Effectiveness I have seen how maturing agencies benefit from its use Product Effectiveness It will help Product Effectiveness Its favorable, but I am not a decision maker, so it all depends on higher management. Unfavorable - Text CIPP Category Comment Context Political Pharmaceuticals has a highly regulatory environment while CRP is out of any regulation; reliance mechanism can only be implemented between institution with same regulatory framework which is not the case between NRA and WHO 263 Table 23: Overall impression of the WHO-CRP: Selected NMRA Opinions What is your overall impression of the WHO-CRP? (Please explain your answer if favorable or unfavorable) Favorable CIPP Category Comment Context Political But extreme care needs to be taken to ensure that national decisions are not outsourced on the platter of Input Collaboration Enable collaboration Input Collaboration It has a lot of potential. The African regulators can leverage from the review done by SRAs and learn from it also Input Collaboration Transparency in the review and communication pathway between authorities and WHO PQ Input Design Forward looking, gradually many regulatory authorities in Africa will make amendments to adopt in phases. Input Design It provides a standardised approach which makes it easy in the harmonisation initiatives Input Design The procedure is detailed and unambiguous Input Design The procedure works but is too bureaucratic. Process Duration the products that would have been prequalified take at least 3 months to registration which is the shortest time possible when compared to other products. Process Duration It is very important to save time, share skill and experience from the very experienced assessors. Process Duration It reduces the time to register and avoids duplication of effort and wastage of resources as evaluation would already be done by WHO PQTm. Process Duration It reduces workload and also shorten time for product to be available on the market Process Duration The process takes shorter timelines and if product is pre-qualified. The outcomes are mostly positive Process Procedure Facilitate the registration of the product and we would like to have the same procedure for renewals (lifecycle management of the product) Process Procedures Very transparent Process Resources As we share assessment reports already done by stringent regulatory Authorities Process Resources It simplifies the workload we have as regulators while not negatively affecting the quality of work Process Resources Prevents duplication of work already done by experts Process Resources The potential benefits of collaborative procedure by the reference SRA are significant and it can really help to reduce time and costs of regulatory approvals. I strongly hope that companies can utilize this regulatory process to combine resources and share workload to ensure timely access to the medicine to patients. Product Effectiveness These would facilitate access of medicines to the public which are of adequate quality, safety and efficacy 264 Table 24: Overall Impression of the WHO-CRP: Selected Industry Opinions What is your overall impression of the WHO-CRP? Favorable CIPP Category Comment Context Political Favorable but still a lot to improve. It is not fully harmonized, National requirements/commitments still to be fulfilled. Process Duration The dossier review timeline was shorter Input Design Enables a reliance route to be used which for low-income countries will be of value especially with treatments for covid etc Input Design FACILITE LES ENREGISTREMENTS DANS PAYS AFRICAIN [Facilitates registrations in African countries]* Input Design The process is a brilliant way of getting quick registrations in Africa as your application goes through an abridged evaluation process; however, i found the process too bureaucratic, with WHO prequaliification team taking long to respond at times. Process Duration It is favourable and provides expedited reviews for regulatory submissions Process Duration Mostly improved predictability of timelines Process Duration Registration time is speeded up. Process Duration Review timelines for certain countries may be more predictable. Further, regulatory burden may be lessened for some (not all the participating countries) Process Duration Simplified dossier requirements are currently the main advantage, at least at the submissions start. In some case also faster review timelines are seen. Process Duration Timelines were drastically reduced in CRP-participating countries. Work was more effective due to the reuse of the EMA dossier and worksharing among the CRP countries. Feedback from participating countries was positive. Process Resources It has helped a lot of companies in Africa and foreign companies looking to register and invest in Pharma. Registration is faster, less complicated, cost- effective and time efficient. Process Resources single dossier gives you multiple MA in different countries Product Effectiveness It's easier to explain the regional Regulatory Authority on the registration process. Unfavorable CIPP Category Comment Process Duration Review times take years 265 Table 27: Influential factors on Future Use: Selected NMRA Opinions Based upon your experience with the WHO-CPAR procedure, will you recommend the use of the WHO-CPAR procedure in your organization in the future? Positive CIPP Category Comment Input Collaboration Offers better audit trails and collaboration Input Design Impetus to effective standardisation of activities Process Duration Lesser timelines Process Duration Timelines to registration for WHO - CRP procedure are far much shorter than our normal conventional registration pathway. Process Procedure Yes, it simplifies things and it is a learning tool Process Resource Efficient procedure Process Resource Gives time to assessors to work on other applications which are not prequalified Process Resource It eases our work as assessors Process Resource -It saves assessment time -share experience from the report -minimize assessment cost Process Resource Reduces our backlog Process Resource The benefits of capacity building, quicker turnaround time therefore freeing up resources for products with higher risk Process Resource Yes, its efficace that the national procedure (sic) No CIPP Category Comment Process Procedure Further training needed Table 28: Influential factors on Future Use: Selected Industry Opinions Based upon your experience with the WHO-CRP, will you use the WHO-CRP again in the future? Yes CIPP Category Comment Input Design Would really love to cover more countries in one application under the harmonization program. Process Duration Definitely it's easier and faster than the other route of registration Process Duration Eventual decision to use the WHO-CRP procedure will be dependent on availability of product registration reports from the SRA concerned and the speed at which these reports are provided. Process Duration I will use it again since a number of African NMRAs prefer it to the standard pathways because of the short time spent on reviews Process Duration RAPIDITE ET MOINS COMPLEXE [Rapid and less complex]* Product Effectiveness It depends on strategy Product Effectiveness The procedure is maturing, and I believe that in the future the advantages of the procedure will become clearer and easier to apply, once all stakeholders become more familiar. Product Reach Presently involved in product prequalification exercise. Hope to use the produce in registering the dossier on other countries. 266 Table 29: Satisfaction with the Process: Selected NMRA Opinions Did the WHO-CRP meet the needs of your organization? (Please explain your answer if you answer "yes" or "no") Yes CIPP Category Comment Input Design Due to shared assessment reports Context Political Not fully embraced Context Readiness Capacity Building Input Design Yes, it’s easier than the requirements of the national procedure Process Duration Faster registration of products which equates to timely access of the much-required medicines to patients. Process Duration In cases where quicker assessments were required for public safety Process Duration Most of the CRP applications are completed within the time frame. NB. Sometimes it will be delayed by the applicant not responding the additional information. Process Duration Product registration is shortened hence reducing the backlog Process Duration Quicker Turn Around Time Process Duration Shorter registration timeline Process Procedure Flexible process Product Need Alignment of life cycle of registered product with WHO PQ Product Need It meets the need but due to regulations, although you have a CRP approval and can start marketing, you still have to go through the national registration process Product Need For access to quality drugs and vaccine not produced locally...Yes Product Effectiveness Our procedure is still in progress and is not complete Product Effectiveness The quality of the reports is satisfactory Table 30: Satisfaction with the Process: Selected Industry Opinions Did the WHO-CRP meet the needs of your organization? (Please explain your answer if you answer "yes" or "no") Yes CIPP Category Comment Process Duration EFFICACITE Process Duration Gained experience. Some timeline improvement Process Duration It's faster and easier Process Duration There was a wish to have shorten timelines in African countries Process Duration We received some approvals within 90 days during the pilot SRA CRP Process Resources It did cut costs by 40% Product Effectiveness The product was registered in SRA countries. Product Effectiveness We were able to register products in several countries. Product Need It did meet the requirements. We did get approval in the stated timelines and helped ease the launch of our product No CIPP Category Comment Process Duration Years have passed and we are still waiting for decision Product Need One of the needs is faster registration in African countries, WHO-CRP does not fully meet this need. Also the need to simplify/remove country-specific requirements or GMP requirements is not fully met at this moment. 267 Table 31: Additional Comments Do you have any comments that were not captured above that you would like to include? NMRA Respect for sovereignty and non outsourcing of national decision Industry African Regulatory Harmonization pathways are not given much time by the regulators as compared to when submissions are made to the independent NMRAs. fees can comfortably sustain these project It seems to me that there's no strong regulations and commitment on which harmonisation is premised. Manufacturers can pay necessary fees above country fees if there's commitment on timelines. The funding mechanism is based on donations from NGOs. This is not sustainable. The product registration fees for this procedure should be cheaper *All translations were done by the author

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Asset Metadata

Creator Alquier, Lori (author)

Core Title Regulatory harmonization in a resource-limited setting: the World Health Organization Collaborative Procedure for Accelerated Registration

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Degree Conferral Date 2021-08

Publication Date 07/16/2021

Defense Date 05/26/2021

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Africa,OAI-PMH Harvest,regulatory harmonization,World Health Organization Collaborative Procedure for Accelerated Registration

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Kuo, Chiaoyun (committee member), Pacifici, Eunjoo (committee member)

Creator Email alquier@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC15600912

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