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Regulation of pediatric cancer drug development: an industry perspective

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REGULATION Of PEDIATRIC CANCER DRUG DEVELOPMENT:
AN INDUSTRY PERSPECTIVE
by
Penny Wai Ping Ng

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

December 2019

Copyright 2019 Penny Wai Ping Ng

ii
TABLE OF CONTENTS
TABLE OF CONTENTS .................................................................................................... II
LIST OF TABLES ............................................................................................................. V
LIST OF FIGURES ......................................................................................................... VII
DEDICATION .................................................................................................................. IX
ACKNOWLEDGMENTS ................................................................................................. X
ABSTRACT ...................................................................................................................... XI
CHAPTER 1. OVERVIEW ...................................................................................... 12
1.1 Introduction .................................................................................................. 12
1.2 Statement of the Problem ............................................................................. 15
1.3 Purpose of the Study .................................................................................... 17
1.4 Importance of the Study ............................................................................... 18
1.5 Limitation, Delimitations, Assumptions ...................................................... 19
1.6 Organization of Thesis ................................................................................. 20
CHAPTER 2. LITERATURE REVIEW .................................................................. 21
2.1 Pediatric Cancer as a Drug Development Challenge ................................... 21
2.1.1 How Are We Doing? Current Pediatric Cancer Development
Programs ......................................................................................... 23
2.1.2 Basic Research: Non-Clinical Models ............................................ 24
2.1.3 Clinical Research ............................................................................ 27
2.1.3.1 Timing of Pediatric Research Relative to Adult
Programs ........................................................................... 29
2.1.3.2 Current Clinical Study Landscape..................................... 35
2.1.3.3 Role of Precision Medicine ................................................ 37
2.1.3.4 Master Protocol Approach ................................................ 38
2.2 Pediatric Cancer as a Regulatory Challenge ................................................ 39
2.2.1 Pediatric Regulatory Framework in the United States (US) ........... 40
2.2.1.1 Early Pediatric Regulations .............................................. 40
2.2.1.2 Evolution through Legislative Actions ............................... 41
2.2.1.3 Effectiveness of PREA, BPCA, and RPDPRV in
Pediatric Cancer Drug Development ................................ 49
2.2.2 Paediatric (Pediatric) Regulatory Framework in the European
Union (EU) ..................................................................................... 62

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2.2.3 Key Differences Between the US and EU Pediatric Regulations ... 63
2.2.3.1 Difference in US and EU Pediatric Oncology Study
Requirement: Recent Example ........................................... 67
2.3 Framing the Study of Pediatric Oncology Drug Development .................... 69
CHAPTER 3. METHODOLOGY ............................................................................ 74
3.1 Introduction .................................................................................................. 74
3.2 Survey Development and Focus Group Feedback ....................................... 74
3.3 Survey Dissemination and Analysis ............................................................ 76
CHAPTER 4. RESULTS .......................................................................................... 78
4.1 Profiles and Background of Participants ...................................................... 78
4.2 Experience in Pediatric Oncology Development for Drugs/Biologics ........ 80
4.3 Organizational Structure for Pediatric Oncology Development .................. 91
4.4 Experience with FDA and EMA Interactions ............................................ 101
4.5 Exploratory: Cross Tabulations by Size of Organizations ......................... 121
CHAPTER 5. DISCUSSION .................................................................................. 123
5.1 Methodological Considerations ................................................................. 123
5.1.1 Delimitations ................................................................................ 123
5.1.2 Limitations .................................................................................... 125
5.1.2.1 Availability of Representative Participants ..................... 125
5.1.2.2 Survey Methodology ........................................................ 127
5.2 Consideration of Results ............................................................................ 128
5.2.1 From Exploration to Installation ................................................... 128
5.2.1.1 Obtaining Information about Regulatory Requirements . 128
5.2.2 From Installation to Implementation ............................................ 132
5.2.3 Full Implementation ..................................................................... 136
5.2.3.1 Challenges in Clinical Programs .................................... 136
5.2.3.2 Interactions with Health Authorities ............................... 138
5.2.3.3 Current Incentive Structures............................................ 139
5.2.3.4 Global Collaboration and Knowledge Sharing ............... 141
5.3 Conclusions and Future Directions ............................................................ 143
REFERENCES ............................................................................................................... 144
APPENDIX A. ................................................................................................................ 153
APPENDIX B. ................................................................................................................ 154
APPENDIX C. ................................................................................................................ 161

iv
APPENDIX D. ................................................................................................................ 171
APPENDIX E. ................................................................................................................ 186

v
LIST OF TABLES
Table 1: Differences between Blastoma Versus Carcinoma .........................................22
Table 2: PREA Versus BPCA (Under FDAAA) ..........................................................47
Table 3: Approved Adult Oncology Products with PREA Exemption (January
2016 to September 2017) ...........................................................................50
Table 4: FDA Approved Oncology Drugs Qualified for Disease-Specific
Waivers (January 2016 to October 2017) ..................................................52
Table 5: Recent Adult Oncology Drugs Approvals Granted with Orphan Drug
Designation (January 2016 to October 2017) ............................................53
Table 6: Listing of Rare Pediatric Disease Priority Review Vouchers Awarded
(as of October 2017) ..................................................................................57
Table 7: EU Paediatric Regulation: Obligations Versus Incentives .............................63
Table 8: Differences in Pediatric Regulations: EU Versus US.....................................64
Table 9: Grounds for Waiver Request for Pediatric Studies .........................................65
Table 10: US and EU Pediatric Status of Approved Anti-PD1/L1 Agents (as of
October 2017) ............................................................................................68
Table 11: Outline of Implementation Stages: Industry’s Feedback of the
Practice-Policy Loop ..................................................................................72
Table 12: List of Focus Group Participants ....................................................................75
Table 13: Personal Experience in Pediatric Oncology Drug/Biologic
Development in the US and in the EU .......................................................81
Table 14: Roles in Pediatric Oncology Drug/Biologic Development Within the
Organization ...............................................................................................83
Table 15: Timing of Pediatric Planning Initiation ..........................................................92
Table 16: Participation in Meetings and Workshops ......................................................93
Table 17: Ranking of Challenges Within the Company/Organization in
Pediatric Oncology Development Planning (n =26) ..................................97
Table 18: Ranking of Frequency of Approaches Taken by Organizations for
Development Programs ............................................................................101
Table 19: Experience in Inclusion of New Study Design Elements in Proposals
to Health Authorities ................................................................................102
Table 20: Satisfaction with Current Mechanisms for Development Plan
Feedback from the US FDA and/or EU PDCO .......................................106

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Table 21: Experience Regarding FDA Discussions on Selected Topics Related
to Pediatric Development Plans ...............................................................109
Table 22: Experience Regarding EMA Discussions on Selected Topics Related
to Pediatric Development Plans ...............................................................111
Table 23: Reasons for Not Receiving 6-Months Pediatric Exclusivity from the
US FDA ...................................................................................................115
Table 24: Reasons for Not Receiving 6-Months Pediatric Extension from EU
CHMP ......................................................................................................115
Table 25: Industry’s Perspective on Adequacy of Current Incentives for
Pediatric Oncology Drug Development ...................................................117
Table 26: Respondents’ Opinion on Key Drivers to Advance Early Pediatric
Oncology Drug Development ..................................................................119
Table 27: Respondents’ Opinion on Key Drivers to Increase Pediatric Stand-
Alone Programs Specific for Pediatric Cancers .......................................120
Table 28: Other Experience with Pediatric Oncology Development Programs ...........121

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LIST OF FIGURES
Figure 1: Timing of Pediatric Drug Development Program in Relation to Adult
Program ......................................................................................................30
Figure 2: Pediatric Drug Development Program with Waiver or Exemption ................31
Figure 3: Earlier Pediatric Clinical Program Initiation ..................................................33
Figure 4: Pediatric Focused Clinical Program Initiation ................................................35
Figure 5: Timeline of US Laws and Regulations for Pediatric Drug
Development ..............................................................................................41
Figure 6: Timeline of Dinutuximab Development (Clinical to US BLA
Approval) ...................................................................................................61
Figure 7: Four Stages of Implementation Framework ...................................................71
Figure 8: Feedback Loop: Practice-Policy Communication Cycle ................................72
Figure 9: Current Job Title of Respondents ...................................................................78
Figure 10: Functional Areas of Respondents Within the Company .................................79
Figure 11: Size of Company by Number of Employees ..................................................80
Figure 12: Utilization of FDA Guidance Documents ......................................................85
Figure 13: Utilization of Other FDA Information and Mechanisms ................................86
Figure 14: Clarity of FDA Guidance Documents and Information on Pediatric
Study Plan Development............................................................................87
Figure 15: Utilization of EMA Guideline and Information on Pediatric
Investigational Plan Development .............................................................88
Figure 16: Clarity of EU Guidance Documents and Information ....................................89
Figure 17: Helpfulness of Publicly Available Information ..............................................90
Figure 18: Resources Within Organizations for Pediatric Oncology
Development ..............................................................................................94
Figure 19: Challenges in Pediatric Oncology Development Plan ....................................96
Figure 20: Challenges/Disagreements in Key Elements of Pediatric Oncology
Development Plan ......................................................................................98
Figure 21: External Factors Contributing to Challenges in the Implementation of
the Pediatric Oncology Development Plan ..............................................100
Figure 22: Receptivity of the US FDA to Novel Study Design Elements .....................103
Figure 23: Receptivity of the EU CHMP to Novel Study Design Elements..................104

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Figure 24: Respondents’ Experience on Timing of PSP and PIP Coordination ............108
Figure 25: Experience in Reaching Agreement on PPSR with the FDA within
the Estimated Timeframe (N=27) ............................................................112
Figure 26: Experience on Timing and Delay in Reaching Agreement with the
US FDA or the EU PDCO .......................................................................113
Figure 27: Experience in Receiving Pediatric Rewards/Incentives ...............................114

ix
DEDICATION
This dissertation is dedicated to my father, Charles Chak Nang Ng, who taught me that learning is
a gift and a blessing.
May there be more people working together to free the world from fear, disease, and heartache.

x
ACKNOWLEDGMENTS
I want to express my deepest appreciation to my advisor, Dr. Frances J. Richmond, for her
guidance, supports, and patience over the past 5 years. Dr. Richmond is an excellent researcher,
mentor, instructor, and role model. This dissertation would not be possible without her persistent
guidance.
I also thank my thesis committee, especially Drs. Nancy Pire-Smerkanich and Neal Storm, my
fellow DRSc students, and members of my focus group for all their reviews and invaluable inputs
on my research project. And to all who generously shared their time and insights by participating
in the survey, making this survey possible, thank you.
I want to acknowledge with gratitude, the support, and love of my family, my parents Charles Ng,
Maria Ho-Ng (deceased), and Jennifer Au-Ng; my siblings (Kathleen Ng, Susanna Siu-Ng, Edith
Ng, and David Ng); my husband, Tommy Cheng; and my daughter, Cadence Cheng. They have
been very patient with me, keeping me healthy physically, helping me stay focused and sane as I
pursued my continuing studies.
I thank God, my heavenly Father, for His provisions and the countless blessings.

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ABSTRACT
Drugs for cancer represent perhaps the largest and fastest source of new drug submissions in the
last decade, accounting for 21% of new molecular entities (NMEs). Most of these drugs are for
adults, for whom cancers are the second leading disease-related cause of death. However, drugs
are often unavailable for children, for whom cancers are the leading cause of such deaths. This
challenge has led both the Food and Drug Administration (FDA) in the United States (US) and
the European Medicines Agency (EMA) to institute new pediatric regulations that include
additional incentives and removal of pediatric study-requirement exemptions for companies that
develop applicable targeted therapies. Both the US FDA and EMA are also attempting to
encourage the earlier conduct of trials focused specifically on pediatric disease. The purpose of
this research was to explore current industry views on the challenges and opportunities in
pediatric cancer drug development under the existing regulations. Using a survey method,
regulatory professionals and consultants with experience in pediatric drug development and/or
design were provided with an electronic survey tool through a web-based interface. Data analysis
was conducted on responses 46 participants from large and small companies undertaking
pediatric oncology drug/biologic development. Results showed that most companies have
allocated internal resources for pediatric oncology development and viewed the current pediatric
incentives as at least “somewhat adequate”, yet they continued to face challenges with the
implementation of pediatric planning and execution of innovative study designs. Factors that
appear to inhibit uptake of early or dedicated pediatric oncology programs were difficulties in
developing a globally harmonized regulatory plan and knowledge gaps in optimizing pediatric
study designs.

12
CHAPTER 1. OVERVIEW
Introduction
Children are not little adults.
Although children suffer from many of the same diseases as adults and have been treated with the
same medications, drug effects and disease pathology can be different because children are still
maturing physically and mentally. This is particularly reflected in oncology – the biology of
pediatric tumors is different from that of adult malignancy. Hence, therapeutic paradigms are
usually not the same (e.g. differ in sensitivity to chemotherapy regimen or choice of targeted
therapies to a specific molecular pathway).
Cancer is the leading disease-related cause of death for children aged 1-19. The American
Cancer Society estimated in 2016 that 10,380 new cancer cases were diagnosed and 1,250 cancer
deaths occurred in American children aged 0 – 14; 4,280 new cancer cases were diagnosed and
600 cancer deaths occurred among children aged 15 - 19 (ACC, 2016). Similar statistics were
also reported in Europe, where 15,000 children are diagnosed with cancer each year, accounting
for 1% of all cancers in humans (Vassal, 2009).
The goal of childhood cancer therapy is not only to prolong survival or management as a chronic
disease, as is typical for many adult cancer treatment programs but to cure the patients (Raeman,
2015). However, among pediatric survivors, two-thirds are projected to develop long-term and
late-term treatment-related complications including a high risk of long term cardiovascular
sequelae from chemotherapies, and further risk of developing another cancer from radiotherapies.
Thus, a clear need exists to develop drugs for childhood cancers that currently have no effective

13
treatment and to provide new drugs with reduced and manageable adverse, including potential
late and long-term safety effects.
At the same time, pediatric cancers must compete with adult cancers for attention and resources.
Cancer in American adults is the second most common cause of mortality and the primary health
threat for years-of-life lost. The huge health burden caused by adult cancer has driven a dramatic
increase in research and development (R&D) over the last decade. This effort resulted in a
proliferation of new drugs, as evidenced by the fact that oncologic drugs represent 21% of the
total new molecular entities (NMEs) for all diseases over the last 10 years (Milne, 2017).
However, this encouraging record is not also observed in the pediatric sector. Pediatric cancers
are typically viewed as relatively rare diseases where commercial returns can be difficult to
achieve. As noted by Milne (Milne, 2017), the eight approvals per year for adult cancers from
2013 to 2015 greatly outpaces the introduction of only eight new drugs with a pediatric cancer
primary indication in the whole of the last 25 years.
Finding treatments for childhood cancers is complicated not only by the relatively small size of
the target markets but also by the heterogeneity of their cancers with respect to those in adults.
Some cancers are seen in both children and adults, but cancers that affect both populations in a
similar way are not common. For example, the four most common adult cancers that have been
the focus of oncology drug development (lung, breast, prostate, and colorectal) are essentially
absent in children. More commonly, the causes of pediatric cancer are specific to children.
When developing targeted agents, it is difficult to repurpose adult drugs for childhood cancers
because many of the target signaling pathways that are active in some adult cancers may be
essential for normal development in children. Therefore, the R&D programs currently directed at
adult cancer are often not applicable to the needs of pediatric indications. Further, childhood

14
cancer is a collection of “multiple diseases” with varying tumor development/genomic
abnormalities. For example, children can have four distinct types of medulloblastoma based on
genomic phenotype, each with its own prognosis and therapeutic strategy. A traditional
randomized study design with one defined study population is not feasible when populations are
substratified until they contain disease groupings with only a small number of patients.
Improving the therapeutic options for pediatric patients has been an important goal for the leading
regulatory authorities in the developed world. To this end, the European Medicines Agency
(EMA) developed specific mandatory pediatric regulations and the United States Food and Drug
Administration (US FDA) implemented both the mandatory and voluntary incentive programs to
address all indications for drugs that may be used in children. In both constituencies, drugs
developed to treat adult indications (US FDA) or adult conditions (EMA) must be tested in
children “when appropriate”. Because the biology of cancer is different in adults and children,
and hence might be considered “inappropriate”, most drugs targeting adult cancers had, however,
been waived or exempted from pediatric testing. To encourage new pediatric drugs for these
situations, in 2002, the US FDA put in place a voluntary incentive program linked to the Best
Pharmaceuticals for Children Act (BPCA) that extended patent and statutory market protections
by 6 months for pediatric drugs. This incentive proved insufficient to overcome the development
and commercial challenges faced by industry when attempting to develop pediatric oncologic
drugs. Thus, to encourage drug development for pediatric rare disease, Congress added an
additional incentive as part of the Creating Hope Act in 2012. The Act grants the marketing
applicant a transferable priority review voucher if the first approved indication of a new
molecular entity (NME) or biologic is for a pediatric rare disease. In the EU, the EMA has
periodically updated the class waivers list and requesting mechanism of action-driven based
pediatric investigational plan instead of based on the adult’s condition. The goal of these

15
regulations is to require sponsors to discuss their strategies for future pediatric development with
the respective health authorities early in the overall development program or provide justification
for not doing such trials. However, the effectiveness of these regulatory mechanisms to improve
drug development for pediatric rare disease is yet to be determined because by the time that the
Creating Hope Act became effective (GAO, 2016), all the products (including the 2 products
approved with a pediatric oncology indication) that received the rare pediatric disease priority
vouchers to date were already near commercialization.
Statement of the Problem
Pediatric regulations implemented by the US FDA and the EMA have become increasingly
complex with the expanding scope of pediatric regulations and more frequent and demanding
interactions with regulatory agencies to determine a pediatric investigational plan. The US and
the EU pediatric regulatory frameworks and scientific elements of the U.S. Pediatric Study Plan
(PSP) under the Pediatric Research Equity Act (PREA) and EMA Paediatric Investigational Plan
(PIP) are similar, usually referred to as the “stick”. They include assessments of the sponsor’s
plan for waiver or deferral, the need for juvenile animal toxicity studies, and the development of a
pediatric formulation, for example. Both US PSP and EMA PIP are tied to the adult conditions
and indication, respectively. In the US, there is also an incentive mechanism for drugs exempted
from PREA, under the Best Pharmaceutical Children Act (BPCA), a sponsor is granted a 6-month
pediatric exclusivity award upon completion of pediatric studies in accordance with the FDA’s
issued Written Request. Although both US and EU apply a “stick/carrot” program, significant
differences exist in other important areas of policy. Different policies can have unintended
consequences, limiting the progress of pediatric drug development in some therapeutic areas. A
previous survey conducted in 2012 by Premier Research on 55 biotech and pharmaceutical firms

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across therapeutic areas (but not limited to rare disease or oncology companies) in both the North
American and European markets noted key problems faced by industry when attempting to
comply with pediatric regulations. These include the challenges of recruiting sufficient children
that meet the study criteria to participate in clinical trials. They also identify that biopharma
companies have a limited understanding of the pediatric regulations, especially with the different
recommendations from the FDA Pediatric Review Committee (PeRC) versus the EMA Paediatric
Committee (PDCO) on study designs. The European Federation of Pharmaceutical Industries and
Associations (EFPIA) recently noted that companies are not clear on circumstances under which
health authorities may or may not accept extrapolating data rather than new randomized studies,
especially in cases of rare disease and oncology, when conducting randomized studies is not often
feasible (Sharma, 2018).
At the same time, the Premier Research survey noted the substantial demand that these trials
place on the company’s financial resources. About 50% of the survey respondents across both
regions indicated that they had to increase their R&D budgets because of PREA requirements,
and 9% of EU respondents scaled back new drug development to pay for PIP studies. With
regard to their perspective on the use of the 6-month period of pediatric exclusivity as a reward,
60% of both European and US respondents strongly or fairly strongly believed that a longer
patent exclusivity extension should be put into place (Premier Research, 2012).
The fact that most information that we have about industry views has been extracted by a single
general survey several years ago underlines how sparse is the information available from industry
across the spectrum of company sizes in the pediatric cancer subsector. Over the years,
occasional workshops have been conducted between industry, health authorities, patient groups,
and academia addressing specific aspects of the FDA and EMA pediatric regulations. The

17
selected few companies chosen to participate in those workshops in order to represent the
industry’s perspective were mainly from major pharmaceutical companies. In 2016, the Tufts
Center for the Study of Drug Development held a round table discussion including senior leaders
from major drug companies on strategy to maximize efficacy while complying with FDA and
EMA regulations in pediatric oncology drug development. A recent workshop held by the
Friends of Cancer Research included three representatives from the industry to discuss the 2017
change in PREA requirements of new pediatric study requirements for certain cancer drugs.
Aside from these few and limited materials, we know little about the nature and impact of current
pediatric regulations when companies attempt to adapt, plan, and implement pediatric oncology
drug programs. There is currently no systematic approach to collect the experience from industry
across the spectrum of company sizes, and especially from smaller companies, from which many
oncolytic drugs emerge.
Purpose of the Study
The research proposed here explored the challenges and opportunities that the current regulations
present for companies that are pursuing the development of pediatric oncology drugs. To focus
the study, particular attention was directed at the different areas of clinical development that must
satisfy both the US and EU pediatric regulations. The study first reviewed literature related to
pediatric oncology drug development, so that the reader has a high-level appreciation of the
challenges from a scientific and practical perspective. It then reviewed the pediatric regulations
in the US and EU to identify what has changed over the last two decades and what some of the
challenges with these regulations have been. A survey instrument was used to probe the
experience, concerns, and insights of the biopharmaceutical industry regarding the evolving
regulatory landscape and its impact on the development and implementation of pediatric cancer

18
drug programs relative to the overall cancer drug programs for that same product. Of specific
interest was the way in which they have implemented changes in their drug development
programs based on the relatively new regulations and incentives. Respondents to the survey
included regulatory and clinical professionals at middle to senior levels in regulatory and clinical
roles, as well as consultants to companies involved in planning and development activities for one
or more pediatric oncology drugs.
Importance of the Study
International pediatric drug development has been driven by pediatric legislation in the US and
the EU. Although there are many similarities, differences exist between the rules in the two
countries. The literature review of this study is an effort to enhance understanding of the
pediatric legislation in both regions, to gain insight into the impact and effectiveness of legal and
regulatory changes. For companies focusing in oncology drug development, it is important to
understand the legislative requirements that must be met along with incentives that exist in the
US and the EU, and also to understand if their experiences when attempting to align those
requirements with their drug development program are shared across the industry.
Understanding the experience from the industry’s perspective is helpful to assess if the current
process is effective in supporting the goal of facilitating the pediatric cancer drug development in
a global setting. By examining differences in survey responses for companies of different types
and sizes, it may also be possible to fuel broader discussions among stakeholders to address the
gaps and develop actionable strategies to improve the regulatory interactions. In particular, the
information may help regulators and legislators to understand where policy or even legislative
change might be needed to improve the development, submission, and approval processes
essential to bringing new cancer drugs to market.

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Limitation, Delimitations, Assumptions
This research delimits its exploration to the experience and activities of industry participants who
are involved specifically in pediatric oncology clinical development and not that of companies
that developing drugs for other types of indications. Further, it did not specifically explore other
stages interposed along the drug development path, such as preclinical activities or
reimbursement programs. It is not designed to examine specific logistical issues, such as those
related to clinical trial management, local health authorities’ feedback in reviewing protocol for
study initiation, or informed consent. Because current pediatric regulation is substantially driven
by policies set forth by the EMA and the US FDA, the survey delimited its scope to the
knowledge, views, and experience of respondents with respect to the impact of regulations
developed by the EMA and the US FDA.
The survey results may be limited by the availability of the respondents and their experience with
the global pediatric development process as well as their openness in sharing their experiences in
addressing the regulatory requirements. Because a new initiative has been signed into US law
requiring that companies design their drug development programs around the specific biology of
the cancer and the mechanism of action of the drug/biologic rather than target organ (FDA,
2017b), it is possible that many companies with ongoing programs are not aware of these changes
and might have found some questions difficult to answer. Because the respondents are assumed
to be busy professionals with limited time to allocate to survey participation, the length of the
survey must be constrained and this may limit the ability to delve deeper into certain areas of
exploration. It is assumed that the participants answered truthfully, but concerns about
maintaining the confidentiality of proprietary information may reduce the enthusiasm of

20
respondents to answer some questions, even if assurances of anonymity and confidentiality are
given.
Organization of Thesis
This research study has five main chapters. Chapter 1 presents an overview of the problem and
an introduction to the research. Chapter 2 is divided into three main sections. The first section
provides a backdrop to provide the reader with foundational information about the current state of
pediatric cancer research from a clinical and drug development perspective. The second
examines the current regulatory landscape of pediatric cancer drug development, including
summaries and analyses from relevant academic and regulatory literature, and a discussion of
challenges that can be discerned from the numbers of approvals and feedback from stakeholders
so far available in the literature. As part of a description of the current regulatory landscape,
Chapter 2 includes a retrospective analysis of pediatric information made publicly available on
the US FDA and EMA websites. The intent of this analysis is to provide information about the
current timing of pediatric oncology trials with respect to adult programs. The third part outlines
the nature of the research questions and the framework under which this investigation operated.
Chapter 3 describes the methodology used to investigate and analyze the problem, including a
description of the survey development, plans for its implementation, and a data analysis plan.
Chapter 4 includes an analysis of the resulting survey data (descriptive statistical analysis), and
Chapter 5 concludes the study with a high-level discussion of these data.

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CHAPTER 2. LITERATURE REVIEW
Pediatric Cancer as a Drug Development Challenge
Cancer is one of the most difficult problems facing medicine. Since the 1970s when President
Nixon declared “war on cancer” and signed the National Cancer Act of 1971, much intensive
research has been directed at developing cancer cures. Funding for cancer research has averaged
nearly five billion dollars each year. Still, as reflected in the launch of the 2016 Cancer
Moonshot national initiative to end cancer, cancer remains one of the top three killers of adults in
the US. Thus, it is not surprising that most work has focused on adult cancers.
Treatments for childhood cancer have received less attention compared to those for adults.
Cancers in children account for less than 1% of all diagnosed cancers, and they often differ in
etiology from those causing adult malignancy. Adult epithelial malignancies, for example,
typically originate from mature tissues that undergo step-wise carcinogenesis. In contrast,
pediatric tumors commonly develop as blastomas from stem cells with mutations that never
differentiated into mature cells. Thus, many pediatric cancers are not seen in adults (ACC, 2016).
The fact that cancers from blastoma formation are composed of less differentiated cells suggests
that they will be more susceptible to therapy than those of adults. Further, the number of genetic
mutations in childhood tumors is on average about a hundred-fold lower than is typical for adult
tumors. This may present an opportunity to develop targeted treatment for pediatric cancers
because their incidence is less likely linked to the multiple possible instigators of carcinogenesis
such as long-term exposures to environmental toxins or lifestyle habits, including smoking or
dietary preferences. Thus, one might anticipate a better opportunity to correct the mutation with a
therapy directed against this mechanism of action (Pearson et al., 2016).

22
Unlike adult cancers that are typically classified according to the anatomical site of the primary
tumor, pediatric cancers are classified by the International Classification of Childhood Cancers
schema (ICCC) into 12 major groups related to the histology of a specific tissue type (ACC,
2016). Other biological differences between adult and pediatric tumors are listed in Table 1
below (Toretsky, 2009):
Table 1: Differences between Blastoma Versus Carcinoma
Biological Differences Blastoma Carcinoma
Mutation Two-hit hypothesis (e.g. loss of
tumor suppressor genes)
Multiple hits, step-wise
carcinogenesis
Link to Etiology Not clear. Does not seem linked
to environment
Can be related to behavior and
environment
Response to Chemotherapy Responsive Resistant
Cell Differentiation Poorly differentiated Often well differentiated
p53 Mutation Not usually involved Often observed

Although some cancers, such as acute myeloid leukemia (AML), Hodgkin and non-Hodgkin
lymphoma (HL, NHL), melanoma, and glioblastoma, are seen in both children and adults, those
of children often can be differentiated into distinct biological subtypes with different genetic
fingerprints; thus, they may exhibit different clinical phenotypes and require a different treatment
strategy (ACC, 2016). Health authorities recognize these biological differences when they advise
biopharmaceutical companies on specific pediatric programs. For example, in the case of AML,
a blood/bone marrow cancer that occurs mostly in elderly patients, the Paediatric Committee of
the EMA noted in the standard AML Paediatric Investigational Plan (PIP) that

23
…not all biologic characteristics are similar (e.g., NPMI mutations)…the
therapeutic settings and uses of medicines often cannot be compared across
all ages (curative intention pursued with intensive front-line and first relapse
treatment in young patients, in contrast to choices for palliation with low-
toxicity treatment in the elderly. (EMA, 14 February 2013)
Therapeutic development is complicated further by differences in the same cancer between
children of different ages and this makes clinical trial design and implementation more complex.
Differences in prognosis may relate to the presence of different molecular abnormalities and gene
mutations as the children grow. In the case of AML, for example, 5-year event-free survival
declines as children age, from 54% in young children to 28% in young adults; a similar pattern is
also typical for adult lymphoblastic leukaemia (ALL) (EMA, 2013a; ACC, 2016).
How Are We Doing? Current Pediatric Cancer Development Programs
Survival from childhood cancers has improved steadily from 1960 to 2000 (ACC, 2016).
However, such encouraging statistics may be misleading if they are used to suggest that drug
treatments for pediatric cancer have improved overall. The increased survival statistics can be
attributed primarily to the improved cures of children with ALL, the most common childhood
cancer. However, much of this improvement cannot be attributed to the discovery of new drugs
even for ALL; about 50% of the drugs used to treat childhood ALL have been on the market since
the 1960s. Additionally, the current treatment regimen/approach even for childhood ALL cannot
be considered as adequate by most standards. A combination of up to 13 anticancer treatments
over 2 to 4 years may be needed to sustain remission, leaving in its wake an array of chronic and
disabling morbidities (Vassal et al., 2015; Norris & Adamson, 2012). Children with cancers that
do not respond or reoccur quickly after conventional treatment have an overall survival rate
below 25%. Other common pediatric cancers, such as neuroblastomas, medulloblastomas, high-
grade gliomas, and metastatic sarcomas, have a much bleaker prognosis.

24
All drugs intended for children will face certain types of challenges. Drug dosage will obviously
have to be studied and modified accordingly. Additional pharmacokinetic considerations can
come into play if children differ in their rates of absorption, metabolism or excretion. In some
cases, a new formulation may be needed specific for pediatric patients, especially those in
younger age groups.
However, as noted in Section 2.1above, drugs for oncological applications become more complex
to develop because childhood cancers often differ in ways that go beyond their pharmacokinetic
differences. Thus, the path for pediatric drug discovery may diverge from the adult model
starting even at the preclinical stage. To some extent, the lack of progress in developing new
drugs to treat childhood cancer can be attributed to building pediatric programs simply as
extensions to adult programs, rather than constructing a more targeted program that builds on a
translational and clinical foundation specific to the pediatric disease. Such an approach has had
several problems that show themselves at different stages of the drug development path.
Basic Research: Non-Clinical Models
Even at the preclinical stage, the differences between pediatric and adult cancers will affect drug
development. In the past, new drugs for children relied on adult tumor models (Adamson,
Houghton, Perlong & Pritchard-Jones, 2014) because well-characterized cell lines and animal
models did not exist for all pediatric cancers. However, such approaches may misguide pediatric
drug development. The same identified gene or target may have different effects on adult versus
childhood tumor development, so that agents that inhibit specific pathways in adult cancers may
provide little or no benefit for children. Thus, an understanding of the molecular pathways,
disease biology and key permissive factors that contribute to childhood cancer can help
researchers create more appropriate drugs. Meaningful preclinical data is particularly important

25
as a foundation for subsequent drug development because pediatric cancer patients are rare.
Thus, eventual clinical trials can only be justified if there are persuasive non-clinical safety data
from developing animals and evaluations of efficacy that can be linked to underlying
physiological mechanisms. For drugs intended for a specific pediatric population, little adult
experience may exist, so animal studies that identify potential developmental concerns for target
organs should be followed by toxicological and developmental studies in juvenile animals before
multiple-dose pediatric studies are initiated (FDA, 2010).
A strong preclinical base of knowledge is also fundamental to guide treatment choices based on a
tumor’s molecular characteristics (Pearson et al., 2016; ACC, 2016). For example, a research
study in which the IKZF1 gene was sequenced from more than 5,000 children with ALL found
that most gene variants were linked to the development of leukemia. When the gene variants
were introduced into cultured cells, several of these significantly reduced the sensitivity of
leukemic cells to the chemotherapeutic agent, dasatinib (ASCO, 2016). It is important to have
appropriate biomarkers to evaluate how well-matched and effective the drug will be to different
cancers, but few such biomarkers are currently available or identified for pediatric indications.
The choice of an inappropriate biomarker can inadvertently provide misleading signals that might
cause the pediatric development team to terminate the program or to point it in the wrong
direction.
The National Cancer Institute (NCI) in the US acknowledged the need to expand the mechanistic
understanding of pediatric cancers by investing in early-stage research. It has funded a large
Preclinical Pediatric Testing Programme (PPTP) since the mid-2000s to study pediatric cancer
pathology and to prioritize cancer drugs provided by more than 50 pharmaceutical companies for
early phase clinical studies in children (Vassal, 2009). One of the most important findings from

26
the PPTP was that many agents efficacious to treat adult cancers have limited activity in pediatric
preclinical models. Such information is valuable because it reduces the risk to apply unhelpful
drugs in the pediatric clinical setting. Where investigational drugs did show substantial activity
in models relevant to pediatric cancers, the risks of pursuing drug development were reduced and
companies appeared more willing to advance those development programs. For example,
pediatric clinical trials are now underway for two such drugs, the MEK (mitogen-activated
protein kinase) inhibitor, selumetinib, for gliomas with mutations in the BRAF (proto-oncogene
protein B-raf) gene, and the PARP (poly-ADP ribose polymerase) inhibitor, talazoparib, given in
combination with low-dose temozolomide for Ewing sarcoma (NIH, 2015). The outcome of this
program is further discussed in Section 2.1.3.3, including a recent successful example described
in Section 2.2.1.3.
Using advanced technologies to develop genomically-based biomarkers has advantages beyond
the capability to increase the quality of clinical studies in children. By understanding the nature
of inherited genetic mutations, it may even be possible to screen family members and to tailor
therapies to the particular pathophysiology elicited by that mutation. To advance this cause, the
NCI TARGET initiative to examine childhood cancer genomics was launched in collaboration
with St. Jude Children Research Hospital and Washington University Pediatric Cancer Genome
Project. Findings from this work, in which about 4,000 tumor samples were sequenced,
confirmed that childhood cancers have fewer gene mutations than adult cancers, many of which
are rare or absent in adult cancers.
It is also important to understand the mechanisms of action for pediatric cancers because
regulators rely increasingly on knowledge related to the mechanism of action and disease biology
when drugs are approved for market. In May 2017, for example, FDA approved KEYTRUDA

27
(pembrolizumab) for the treatment of adult and pediatric patients with unresectable or metastatic,
microsatellite instability-high (MSI-H) or mismatch-repair- deficient (dMMR) solid tumors that
have progressed following prior treatment. The approval of this particular drug relied on the use
of a pan-tumor predictive biomarker in both adults and children. As part of its evidence for
pediatric approval, the company rationalized that it could predict the potentially positive results in
children from the good results in adults with the same biomarker profile as children. It could then
rely instead on information about safety and pharmacokinetics gained from the use of the same
drug in other pediatric cancer types. Because pediatric oncology clinical trials are so difficult to
do, preclinical verification has become particularly important in the drug approval process.
Clinical Research
Preclinical evidence for the safety and efficacy of a drug can never substitute for the additional
insight that a well-constructed clinical trial can provide. Such trials of new cancer drugs must
demonstrate convincingly that the new drug will have better clinical benefit and/or reduced
adverse effects compared to available therapies. However, special hurdles can complicate the
design and conduct of pediatric clinical studies. For example, few acceptable/qualified clinical
endpoints and validated assessment tools are available for pediatric cancers. Frequent
consultations are needed with the clinical experts, health authorities and pediatric oncology
cooperative groups/organizations that focus on childhood cancers to select appropriate study-
design elements.
Clinical studies in pediatric patients, especially in early phases, differ from conventional drug
development in several ways. First, most pediatric studies have significant risks beyond those
that would normally be acceptable in a phase 1 adult study to determine the maximum tolerated
dose of an agent, where subjects are carefully managed to avoid more than minimal risk. These

28
risks can be associated not only with the therapeutic agent itself but also from the invasive study
procedures often required to assess the effects of the drug. Collection of fluids such as bone
marrow, cerebral spinal fluid, or bronchial fluids are often seen as essential to evaluate clinical
effects of drugs in children with cancer (e.g. leukemia and lymphoma). These painful and
sometimes risky procedures can be particularly hard to carry out in children where the volumes of
such fluids are small. Thus, the frequency and volumes must be reduced as much as possible by
considering whether the value of the data outweighs the associated risk to the patient.
Second, conventional study design may have to be modified even in the first study. Unlike adult
studies, most pediatric oncology studies are “phase 2” studies, carried out in a population with the
disease because the drug typically has adverse effects that make the participation of a healthy
child problematic from an ethical perspective. Initial studies are usually not randomized against
another treatment because the primary goal of the study is to determine response rate and adverse
reactions associated with the new agent.
Most phase 2 oncology pediatric studies take a step-wise approach in which the activity of the
drug is assessed in a series of cohorts of increasing size and decreasing age. Typically, the drug
is given first to a small cohort of subjects older than 12 years of age with about three subjects per
dosing group. The design would then extend the testing to more or younger subjects if the
observed activity of the drug exceeds a predetermined endpoint and if adverse reactions are
manageable. However, it is the difficulty in extrapolating the results of three patients in one age
group to a younger group whose responses may differ. This is particularly important for the
classes of drugs with potential developmental toxicities that would not have been identified in
adults but could be seen in children given the specific molecular targets or signaling pathways
affected by the drug (Gore et al., 2017). When genomic differences can be recognized between

29
children of different ages, pediatric cancer populations may have to be subdivided not only by age
but also by stage or additional characteristics that further diminish the size of the already rare
disease. The stratification can turn each subgroup into an “ultra-rare/orphan pediatric” indication.
Thus, statistically robust study design may not be available given the small numbers of pediatric
patients with certain cancers. The observations from such a small sample size may not support
meaningful correlations or conclusions regarding efficacy. They may only provide enough safety
information to base future studies if such studies are feasible.
2.1.3.1 Timing of Pediatric Research Relative to Adult Programs
Clinical research exposes its participants to a certain level of risk; the earlier the phase of that
research, the greater the risk. According to the International Conference of Harmonization (ICH)
Directive 2001/20/EC, timing of pediatric studies in an overall product development program
may vary depending upon whether the target disease is exclusive to the pediatric population.
Figure 1 below shows the typical timings of a typical pediatric development program relative to
the regulatory requirements in the EU and the US for a Pediatric Study Plan. When a similar
cancer is present in both adults and children, industry usually begins its planning for pediatric
development after completing phase 1 or phase 2 adult trials, as required by EMA and FDA
respectively. This “follow on” step-wise approach is to take advantage of the lessons provided by
adult data on clinical pharmacology, preliminary efficacy and safety data. It may even be the
case that pediatric trials will lag the approval of an adult oncology product even further if health
authorities agreed to defer requirements for a pediatric trial until after the adult drug has been
marketed (Figure 1).

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Figure 1: Timing of Pediatric Drug Development Program in Relation to Adult
Program

(Adapted from ACC, 2016; Certara, 2016)
Deferring pediatric studies until after the drugs have been approved in adults has been viewed to
have a negative impact on a pediatric development program. It can be more difficult to accrue
pediatric patients into clinical trials if the adult drug is available off-label for pediatric use. When
the drug is used off-label, it is not possible to collect research data systematically.
Off-label use eliminates the opportunity to collect data on safe and effective use of drug
products in other children who might potentially benefit or be spared from the toxicity of
an ineffective drug. (Gore et al., 2017)
EU PIP=European Paediatric Study Plan; US
PSP=United States Pediatric Study Plan;
Ph=Phase; Ped.=pediatric;
PK/PD=pharmacokinetic/pharmacodynamic

31
A recent annual report from FDA on the status of postmarketing requirements (PMRs) and
postmarking commitments (PMCs) published in the 08 December 2017 Federal Register noted
that that 49% (517 of 1,051) of the open (i.e. ongoing) NDA PMRs and 45% (123 of 272) of the
open BLA PMRs were pending as of 30 September 2016. The largest category of pending PMRs
were the deferred pediatric studies required under the Pediatric Research Equity Act. Notably,
drugs do not have to be studied in children at all if they have orphan designations (in the US) or
have received pediatric study waivers from the EMA or FDA (Figure 2) unless sponsors conduct
them voluntarily, as discussed in more detail below.
Figure 2: Pediatric Drug Development Program with Waiver or Exemption

It is easy to understand why pediatric studies are often delayed with respect to those in adults.
Targeting a pediatric population early in development may pose a significantly greater risk of trial
failure for reasons that seem obvious from the challenges described above. Further, the
experience gained about the safety and efficacy of a drug from preliminary studies in an adult
population can benefit the design of the more vulnerable pediatric clinical program. However, for
childhood cancers with poor existing treatment options, clinicians, regulatory authorities, and

32
parents/patients may want to see earlier trials. Patient advocacy and clinician groups have
expressed concerns that much needed drugs for children have not been made available in a timely
manner, or worse, have not been studied in children at all because of orphan drug exemptions or
waivers. For example, the advocacy group, KIDS vs Cancer (Kids vs Cancer, 2017), advocates
that children should be included in all cancer trials unless a scientific or ethical rationale would
justify their exclusion. In relapsed or refractory cancers, when the prognosis is dismal and no
other options exist, early phase pediatric trials may give hope to families and provide insight into
the ways in which promising experimental treatments can be combined with other approved
agents in treating advanced disease.
The health authorities, FDA and CHMP, encourage a seamless clinical development approach in
which adult and pediatric trials are integrated. As stated in a 2016 interview with Richard Pazdur,
Director of the Oncology Center of Excellence and Office of Hematology and Oncology Products
at the FDA’s Center for Drug Evaluation and Research (Ratain, 2016):
…if a trial is evaluating a drug associated with a biomarker, then an
expansion cohort might enroll patients with that particular biomarker. A
pediatric population could be included in an expansion cohort to more
rapidly develop drugs for children. The US FDA would like to see earlier
initiation of pediatric studies once an active dose is defined in adults.
As one step in this direction, FDA is currently suggesting that adolescents aged 12-18 years be
included in adult clinical trials if their “actionable targets”- their cancers and pharmacological
profiles- are similar. This may be the case, for example, in Hodgkin lymphoma. Such an
approach would eliminate the delays between development phases and accelerate the addition of
pediatric expansion cohorts as described above (Beaver, Ison, & Pazdur, 2017) (Figure 3).

33
Figure 3: Earlier Pediatric Clinical Program Initiation

However, enrolling younger patients under 12 years of age when data from toxicity studies are
still incomplete remains unacceptable to the Agency because younger children may respond
differently than older children (Jenks, 2017).
Industry is often characterized as more cautious than patient groups or governments. This caution
is probably justified. Exposing a vulnerable population to drugs with limited understanding of
safety profile is a concern. In addition, the negative results in early pediatric clinical trials cannot
help but affect the whole strategy for the development of that drug including the adult program.
For example, an early-stage clinical trial in children might uncover adverse events that are unique
to children because of their less mature and more vulnerable physiologies. Even if those same
safety issues in children are absent or are less frequent or severe in adults, their presence might
cause a company to terminate a drug development program in totality, and risk depriving adults
EU PIP=European Paediatric Study Plan; US
PSP=United States Pediatric Study Plan;
Ph=Phase; Ped.=pediatric; MoA= mechanism of
action;
PK/PD=pharmacokinetic/pharmacodynamic

34
of a useful treatment. Further, if the drug fails to show efficacy, this also may be a reason to
prematurely stop the drug development program altogether in the adult indication(s) for an
otherwise potential effective and safe drug in adults. It may be rare that a product would fail in
adults but still be sufficiently covering the development costs from the pediatric market; making
justifying the risk and expense of a pediatric program alone a challenge from the business
perspective. In such a situation, the company may be concerned that early additional pediatric
trials would be an investment without financial reward.
From a clinical design perspective, questions remain about the best approach to assess the risk
and benefit of new pediatric clinical studies, especially with drugs still in the proof-of-concept
stage. In a recent analysis conducted by the US FDA (Green, 2017), 6 of the 7 pediatric oncology
studies conducted under FDAAA 2007 failed to demonstrate efficacy. FDA noted that,
…it is not clear whether these failures mean the drugs do not work in
children or whether investigators did not select the right drug, identify the
right patient population, choose the right dose, use the right trial design, or
identify the right endpoints for their trials. Many sponsors also said they were
unable to complete their studies because they couldn’t recruit subjects for the
trials. (McCune, 2017)
The EMA and FDA have recently published a Strategic Collaborative Approach document on
drug development in rare diseases using Gaucher disease as a guide and noted that this example
may provide insights to other rare pediatric diseases, including cancers. It highlights some
considerations when a step-wise age-cohort approach is used for pediatric clinical studies. For
example, it questions whether specific pediatric expertise is needed related to assessing growth
and puberty in the adolescent cohort when that cohort is part of the adult study and if there should
be different long-term follow-up requirements for different cohorts (EMA, 2017b). A multi-
stakeholder working group including patient advocates, industry, investigators, and regulators

35
recently issued an article to provide specific recommendations for children might be included in
early-phase investigational cancer drug trials but
...discussing reasons for why a pharmaceutical sponsor may choose to
include or exclude children in early-phase trials using the recommendations
we propose is beyond the scope of this article. (Gore et al., 2017)
It is important to understand the industry’s perspective and experience regarding the challenges
and potential opportunities of including pediatric patients earlier in the clinical drug development
(Figure 3 above). To date, most pediatric drug-development programs are tied to the adult
development programs. Thus, it is also important to understand if the current incentives from the
health authorities may attract companies to undertake a pediatric registration program, especially
for childhood cancers that do not occur in adults (Figure 4).
Figure 4: Pediatric Focused Clinical Program Initiation

2.1.3.2 Current Clinical Study Landscape
Few pediatric cancer therapies have yet to be approved, so pediatric patients commonly gain
access to treatment by either enrolling in clinical trials or receiving off-label therapy with

36
approved adult products. As discussed above, cancer studies unique for children are seldom
carried out by industry, but rather are part of a program that also has ongoing or completed
clinical studies in adults. In the US, most stand-alone pediatric trials are managed by specialized
pediatric cancer centers belonging to national cooperative study groups (COGs) and funded by
the National Cancer Institute (NCI). However, pharmaceutical companies may provide new
drugs to NCI’s Cancer Therapy Evaluation Program (CTEP) for evaluation in children to
facilitate early-phase pediatric cancer studies. COG clinical sites are estimated to treat about 90-
95% of children diagnosed in the US under the age of 15 (ACC, 2016). About 4,000 children
enter NCI-sponsored clinical trials every year (NIH, 2013). Pediatric cancer trials, like other
types of clinical trials, are typically listed on ClinicalTrials.gov, the US online registry of publicly
and privately supported clinical studies. As of April 2013, 1,673 clinical trials relevant to
pediatric cancer were listed as open for enrollment on this database. Of these, 46% were either
being conducted at an NCI-designated cancer center or at a university with an NCI-designated
cancer center (NIH, 2013).
A network for clinical research in pediatric oncology also exists in the EU. The European
Society for Paediatric Oncology (SIOP Europe) represents around 250 clinical centers in the EU
that participate in major European phase 3 clinical trials for front-line therapies and late phase 2
trials for patients who have relapsed. The SIOP regards this collaborative approach as central to
the development of new treatments:
Clinical research is necessary to combat the burden of cancer: over the past
40 years paediatric oncology in Europe made considerable progress in
increasing patient survival rates of up to 80% from previously 10%. This was
only achievable through close collaboration in multinational clinical trials
(SIOP, 2017).

37
Pediatric cancer centers nationally and worldwide are a key resource for enrolling sufficient
numbers of participants because of the rarity of the patients. In addition, only these specialty
centers have the experts with direct experience and access to experimental therapies. These
centers are also equipped with better expertise and technology to conduct genetic profiling, a key
to identify the molecular characteristics of specific tumors.
2.1.3.3 Role of Precision Medicine
In the past, tumors were often defined by their site of origin in a specific part or tissue of the
body. However, as discussed above in 2.2.1, the genomic characteristics of these patients may be
at least as important in defining the nature and appropriate treatment for a tumor as its body
location. This has begun to change the way that drug development is approached by scientists
and regulators. Experience with adult cancers at the National Cancer Institute (NCI)-Molecular
Analysis for Therapy (MATCH) has shown that a “precision medicine” approach guided by
molecular markers can be very powerful. Pediatric patients with advanced solid tumors including
non-Hodgkin lymphomas, brain tumors, and histiocytoses that are not responding to treatment are
assigned to an experimental treatment based on the genetic markers associated with their tumors
rather than on their type of cancer or cancer site.
The primary study goal of pediatric MATCH is to determine the objective response rate of
identified genomic mutations to specific pathway-targeted agents, selected and prioritized by the
Pediatric MATCH Target and Agent Prioritization (TAP) Committee. The identification of
treatment arms relied on multi-stakeholder discussions with the US FDA and pharmaceutical
companies to select agents of interest with good potential to treat a specific cancer. As of
August 2017, 7 treatment arms (paired with their respective molecular targets) have been opened
(NIH, 2017b).

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It is encouraging that the lessons learned from the adult MATCH program are being used to
improve pediatric cancer clinical research early in the drug development process. From that
experience, a supportive research infrastructure and early consultations with regulators and
industry appear critical to translate important opportunities into clinical trials. The TAP
Committee continues to evaluate whether target-agent pairs should be included/removed when
additional evidence becomes available about the clinical activity of additional drugs and when
knowledge of genomic makeup of cancers provides relevant further insights into appropriate
choices (Allen et al., 2017).
2.1.3.4 Master Protocol Approach
Because pediatric cancer patients are often rare, traditional randomized studies requiring analysis
with frequentist statistics can require unrealistically prolonged enrollment periods. One example
of such a challenge is detailed below, in which a 7-year enrollment period was needed to test
dinutuximab. The FDA has been encouraging pediatric master protocols with Bayesian models
that allow data extrapolation from the results of previous studies, to facilitate pediatric trials as
described in the MATCH study above (Cipriano, 2016). Having a Master Protocol is one
overarching study design to evaluate one or more interventions in multiple diseases or a single
disease. The goal of this innovative approach is to integrate predictive biomarkers to enable
simultaneous study of multiple targeted agents across different tumor types in small populations
of patients.
Because many new drugs are being evaluated in the early phase and because detection of a
treatment effect can be diluted by heterogeneous groups, traditionally designed early phase
studies that test treatments one at a time in heterogeneous groups of patients have not been
optimal for evaluating treatment effect. Further, they may pose higher risks to patients who may

39
not receive the most promising therapy. Thus, the MATCH infrastructure can be used to add new
agents into the same study as a different cohort, without having to initiate a separate study.
Some researchers also noted that such study designs bring multiple stakeholders (including
different companies evaluating their respective drugs in the same study) together to improve
efficiency and streamline regulatory review (Former, 2017) and study logistics. As noted in the
published report by the American Cancer Society, “Translating Discovery Into Cures for Children
With Cancer”, the rarity of childhood cancer can make sufficient accrual into traditionally
designed studies difficult. Competitions among research projects are fierce, with multiple studies
targeting the same population. The small size of the population may offset an advantage
promised by any financial incentives that might be in place. In particular, the incentive of a
6-month exclusivity extension may not be sufficient to justify investment for a pediatric
development program. Adaptive multigroup trials such as those using a master protocol approach
have the potential to answer several questions simultaneously and more efficiently than
traditionally designed trials; i.e. which of several promising therapies appear best suited for
larger, confirmatory trials? Which patients should be asked to participate in those trials? Is the
chance of success in subsequent larger trials sufficient to justify the expense and time needed?
(Harrington & Parmigiani, 2016). How the data from Master Protocol design can be used for
regulatory activities such as registration for pediatric indications, labeling for BPCA, or satisfying
the PIP EU paediatric regulation (described below) is yet to be resolved.
Pediatric Cancer as a Regulatory Challenge
One of the most significant challenges facing the regulatory sector today is that of encouraging
early pediatric cancer drug development, yet at the same time assuring that safety measures are in
place for such a vulnerable population by designing the right study. It is also important that the

40
implementation of the pediatric plan does not jeopardize the development and approval of
potentially lifesaving products for the general population. Thus, health authorities have made
considerable efforts to understand and facilitate best practices for testing pediatric oncolytics.
The most influential approaches are those in the largest markets for medical products, the US and
the EU. Over the last two decades, legislation implemented by the US Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) has changed the landscape of
pediatric drug development.
Pediatric Regulatory Framework in the United States (US)
2.2.1.1 Early Pediatric Regulations
Efforts to facilitate the development of pediatric products can be recognized as early as the 1970s
when the FDA focused its attention on communicating information about the use of drugs for
children on the labels of approved products. The 1979 Labeling Requirement mandated
manufacturers to specify on the labels of pharmaceutical products whether safety and efficacy
information for children had been established. However, this requirement did not assure
sufficient prescribing information for pediatricians because sponsors were not required to perform
specific pediatric research if information related to appropriate pediatric dosing did not exist.
Fifteen years later, the 1994 Pediatric Labeling Requirements (21 CFR 201.57) were enacted to
ensure that drug sponsors included information from new clinical studies or publications relevant
to pediatric use on the labeling when they submitted a supplement (sNDA) for FDA approval.
However, sponsors were still not required to conduct pediatric studies if such pediatric
information was unavailable. Instead, the label could bear the statement, “Safety and
effectiveness in pediatric patients have not been established”. An FDA analysis concluded that
the 1994 Rule did not substantially increase the availability of safety and effectiveness

41
information for drug and biologic products in pediatric use (FDA, 1998). As stated by the FDA,
“Of the supplements submitted, approximately 75 percent did not significantly improve pediatric
use information”. However, FDA did not have the authority to require that manufacturers carry
out studies when existing information was insufficient to support the addition of pediatric-use
information on the label.
2.2.1.2 Evolution through Legislative Actions
Figure 5: Timeline of US Laws and Regulations for Pediatric Drug Development

Modified from (Turner, 2014)
The FDA could only go so far on its own to incentivize pediatric initiatives without stronger
legislative authority. That authority soon was provided by a series of new laws as shown in
Figure 6. A first step took place in 1997 when the Food and Drug Administration Modernization
Act (FDAMA) of 1997 established marketing incentives for drug sponsors conducting studies of
drugs in children. Specifically, section 505A of the FD&C Act provided six months of additional
marketing exclusivity and patent protection for companies of on-patent drugs if they conducted
trials in children in accordance with pertinent laws and regulations. A year later, the FDA
published the Pediatric Rule, an important piece of legislation that required manufacturers to
FDAMA=The Food and Drug Administration Modernization Act; BPCA=Best Pharmaceuticals for
Children Act; PREA=Pediatric Research Equity Act; FDAAA=Food and Drug Administration Amendments
Act; FDASIA=Food and Drug Administration Safety and Innovation Act; FDARA=Food and Drug
Administration Reauthorization Act

42
conduct pediatric studies in certain drugs. The 1998 Pediatric Rule further required companies to
include pediatric assessments in their supplemental NDA/supplemental BLA for new indications,
dosage forms, dosing regimens, or routes of administration for indications in adults that were
submitted on or after April 1, 1999. Companies could obtain a waiver or study deferral if the
prevalence of the adult indication was low in the pediatric population. Without such a waiver or
deferral, however, the product could be denied market authorization.
The Pediatric Rule has been controversial. The obvious goal of the Rule was to ensure that drugs
commonly used in children were appropriately tested for safety and efficacy so that pediatricians
would not have to estimate or extrapolate proper dosing. Not surprisingly, the FDA and
American Academy of Pediatrics (AAP) supported the rule (Arshagouni, 2002). However, the
Rule also had opponents in the medical community, such as the Association of American
Physicians and Surgeons (AAPS). The AAPS advanced the view that “the Pediatric Rule does
harm” because it denies potentially life-saving drugs to adult patients by delaying drug approval
until the drug has been tested in children. This was seen to be a particular problem in those cases
in which the drug had little or no likely benefit in pediatrics (AAPS, 2002).
The Best Pharmaceuticals for Children Act (BPCA; Public Law 107-109) was then passed in
January 2002. It expanded on the approaches that regulators could take to encourage pediatric
trials and to secure pediatric exclusivity. One goal of the BPCA remained the same as that of the
Pediatric Rule, to encourage industry-sponsored pediatric studies to improve the labeling of drug
products used in children by granting an additional 6 months of patent exclusivity. Under BPCA,
FDA could issue a Written Request to the drug sponsor requesting it to conduct pediatric drug
studies if the FDA determined that the drug could provide health benefits to children. FDA
developed a program for pediatric oncology Written Requests (WRs) specifically to encourage

43
development of treatments for pediatric cancer. FDA was expected to issue WRs to sponsors of
new drugs that could benefit the pediatric patients with cancers and provide them with guidance
(FDA, 2000). FDA would also be flexible in its regulatory approaches to refractory pediatric
cancers with no available therapies. For example, approval could be based on meeting surrogate
endpoint(s) likely to predict clinical benefits as described in Subpart H and Subpart E of 21 CFR
Part 314 and Part 601(Accelerated Approval). Unlike non-oncology programs, FDA could
approve pediatric oncology drugs based on their Phase 2 study results (21 CFR 312.82(b)); in
addition, Phase 3 studies usually would not be requested in a WR and would not be a prerequisite
to a grant of Pediatric Exclusivity. Last, the FDA was directed to encourage applicants to discuss
protocol designs and enrollment plans with a pediatric research cooperative group, such as
NCI-COG.
FDA now expects WRs for an overall pediatric development program of the drug whose plans
will encompass a strategy from the early phase 1 studies for pharmacokinetics and dose-setting to
Phase 2 studies for evaluation of responsive tumors/cancer types. The general requirements for
phase 1 and phase 2 study designs are outlined in Appendix A.
Exclusivities play an important role in defining a strategy for pediatric programs. FDA will add a
6-month period of pediatric extension to the existing exclusivity in the Orange Book based on the
quality and ability of the submitted report to meet the terms outlined by the FDA issued Written
Request. However, the grant of PE does not imply that the results of the pediatric clinical
program have demonstrated the medicine provides clinical benefits in the pediatric population.
Further, pediatric exclusivity does not apply to off-patent drugs, and without this incentive,
companies might decline the request to conduct a pediatric trial. In such a case, the NIH has been
authorized to conduct relevant studies instead. BPCA provides a mechanism for NIH to prioritize

44
therapeutic areas and sponsor clinical research on drug products that are seen to need further
study in children (NIH, 2017a).
In 2002, the FDA created an Office of Pediatric Therapeutics (OPT) as mandated by Congress
under BPCA. The OPT now is responsible to coordinate pediatric activities, including a
mandated pediatric review on the safety of drug and biologic products, to take place 18 months
after labeling changes driven by results from pediatric studies.
The FDA’s actions under the 1998 Pediatric Rule were soon to be challenged. In October 2002,
the U.S. District Court for the District of Columbia held that FDA had overstepped its authority
by demanding that testing be conducted for drug indications not claimed by the
manufacturer/sponsor of the application. To address this problem, the Pediatric Research Equity
Act of 2003 (PREA) was signed into law on December 3, 2003. PREA amended the FD&C Act
by adding section 505B, which explicitly authorized the FDA to require the conduct of pediatric
studies for certain drugs and biologic products. In so doing, the Act codified the 1998 Pediatric
Rule. Like the Pediatric Rule, it required sponsors to conduct a pediatric assessment for all new
NDAs, BLAs, or supplements for new ingredients, indications, dosage forms, dosing regimens, or
routes of administration filed on or after September 2007, unless they had a waiver or deferral for
such assessment. Under PREA, the pediatric assessment had to contain data gathered using
appropriate formulations for different age groups. Further supporting data had to show that the
drug was sufficiently safe and effective for the claimed indications in all relevant pediatric
subpopulations. The assessment also had to contain dosing and methods of administration
appropriate for each pediatric subpopulation (FDA, 2005). However, PREA had exceptions for
drugs/biologics granted with orphan drug designations. Congress felt that the need for an
additional pediatric clinical trial might diminish the likelihood that a company would embark on

45
drug development for adult orphan diseases. This exception has recently changed for some
products in the latest version of the FDA Reauthorization Act (FDARA) (H.R.2430) as of August
2017 (further described below).
In 2007, both BPCA and PREA were reauthorized under the Food and Drug Administration
Amendments Act (FDAAA). FDAAA broadened the definition of “pediatric studies” to include
preclinical studies such as juvenile animal toxicity studies before initiating the pediatric clinical
studies. It also narrowed the timeframe for sponsors to qualify for pediatric exclusivity; the
sponsor must complete the studies in response to a Written Request, submit the data package to
the Agency for review, and allow time for FDA’s determination of pediatric exclusivity, no later
than 9 months prior to the expiration of existing patent/exclusivity. FDAAA also imposed new
requirements directed at the FDA to increase transparency by tracking and making publicly
available certain information from the pediatric clinical trials. Congress instructed FDA to
establish a new committee, called the Pediatric Review Committee (PeRC), that would serve as a
consultative body, and would review materials such as Pediatric Study Plans (under PREA) and
Proposed Pediatric Study Requests (under BPCA) submitted to the FDA by drug/biologics
sponsors. By having a designated group of pediatric experts to review plans centrally, it was
hoped that quality and consistency could be assured across the FDA review divisions (Woodcock,
2007).
Nonetheless, pediatric initiatives across therapeutic areas were still seen to be managed in a less
controlled way than might be desired. In the decade to follow the 1998 Pediatric Rule, only one
draft guidance, “Guidance for Industry: How to Comply with the Pediatric Research Equity Act”,
has been issued to provide instruction on how to develop a pediatric plan. The lack of guidance
appeared often to cause poorly developed or delayed submissions. For example, the FDA had

46
stated its expectation that “applicants are encouraged to submit and discuss the pediatric plan no
later than the end-of-phase 2 meeting”. In 2008, however, the Pediatric Review Committee
(PeRC) commented that 57% of the PeRC Pediatric Plan submissions were last-minute rushes,
with 74% and 57% submitted during the NDA/BLA review, just 4 weeks and 2 weeks before the
completion of the NDA/BLA review, respectively. Thus, further measures to strengthen rather
than weaken the incentives were seen to be important. In 2012, Congress took additional
measures to address some deficiencies that were seen to cause problems and noncompliance,
when it permanently authorized BPCA and PREA under the Food and Drug Administration
Safety and Innovation Act (FDASIA). Under FDASIA, PREA included a provision that required
sponsors planning to submit an NDA application for a drug/biologics subject to PREA to provide
their initial Pediatric Study Plan (iPSP) within 60 days of the End-of-Phase 2 FDA Meeting
(FDA, 2016b).
The BPCA and the PREA have often been characterized respectively as “a carrot”, that provides a
financial incentive to sponsors, and “a stick”, that introduces mandatory testing requirements,
enforced by threat of penalties (Table 2).

47

Table 2: PREA Versus BPCA (Under FDAAA)
List of Comparison PREA BPCA
Scope

● Drugs and biologics
● Studies may only be required for
approved adult indication(s)

● Drugs and biologics
● Studies relate to entire moiety
and may expand indications
beyond the approved adult
indication(s)
Required/Voluntary ● Required studies ● Voluntary studies
Orphan Drug Context

● Products with orphan
designation are exempted from
requirements
● Under 2017 FDARA, PREA
applies to for certain
molecularly targeted cancer
drugs/biologics
● Studies may be requested for
products with orphan designation
Outcome of Pediatric
Studies

● Pediatric studies, results positive
or negative, must be included in
the product label
● Pediatric studies, results positive
or negative, must be included in
the product label
Reward

● No reward as PREA
requirement. If not meeting
requirement as Post-Marketing
Required study, risk of non-
compliance actions from the
FDA
● 6-months extension to existing
pattern and exclusivity if studies
meet terms within FDA issued
Written Request
(FDA, 2017b)
The complex system of requirements for pediatric studies seemed still to miss its goal of
encouraging pediatric clinical trials, due in part to the waivers and exclusions for orphan drugs.
The carrot of BPCA was seen to need some form of sweetening, to encourage pediatric clinical
evaluation earlier in the drug development process, particularly for rare pediatric diseases with no
adult counterparts (FDA, 2016c). Thus, a new program of incentives, the Rare Pediatric
Disease Priority Review Voucher (RPDPRV) Program, under Section 529 of the FD&C Act, was
developed as a collaborative effort that was championed by the non-profit patient advocacy
group, Kids vs. Cancer.

48
The RPDPRV program was authorized under the Creating Hope Act in 2012 as part of FDASIA.
It was intended to encourage the development of new drugs and biologics for certain rare
pediatric diseases by awarding a voucher for priority review from the FDA to the developer of
that pediatric program upon approval of the pediatric indication. By applying the RPDPRV to a
subsequent submission, the FDA committed to complete the review of the submission in
6 months (compared to the standard 10 months) even if the product did not meet any of the
normal priority review requirements. Shortening the review clock was seen to give an important
business advantage by allowing the approval of a submission ahead of that for a similar
competing product. The value of the voucher was further increased by allowing the holder to
apply the voucher not only to their own future product but alternatively to transfer or sell the
voucher to another company. Further, the ownership of a voucher did not disqualify a sponsor
from participating in other incentive programs, such as the 6-month pediatric exclusivity
incentive under BPCA and/or the marketing exclusivity awarded under the Orphan Drug Act.
The rules to be eligible for a voucher have been clearly defined. The definition of a “rare
pediatric disease” is consistent with that of the Orphan Drug Act, in that prevalence in the
U.S. had to lie below 200,000, but with the added requirement that more than 50% of patients
with the disease would also have to be under through 18 years of age (FDA, 2014). Eligible
applications had to satisfy the following criteria:
● Were for a human drug or biologic to prevent or treat rare pediatric disease containing no
active ingredient that has been previously approved in any other application
● Were regulated under 505(b)(1) or 351(a)
● Were eligible for priority review
● Did not seek approval for an adult indication in the original rare pediatric disease product
application
● Relied on clinical data derived from studies examining a pediatric population and dosages
of the drug intended for that population

49
As stated in the fourth bullet, an applicant cannot receive a voucher if the applicant seeks
approval for an adult indication as part of the original product application for a rare pediatric
disease. However, if the applicant seeks approval for use by pediatric and adult populations
with the SAME rare pediatric disease, the applicant would still be eligible for a voucher if the
approved use includes both adult and pediatric use. An example is the award of a voucher to
the first chimeric antigen receptor T cell (CAR-T) therapy, KYMRIAH, approved not only
for the children below 18 years of age with B-cell precursor ALL that is refractory or in
second or later relapse but also including young adults (up to 25 years old) in the same
approved indication.
The Act was enacted as a pilot program which was set to sunset one year after the issuance of
three vouchers. The award of the third pediatric voucher for a neuroblastoma drug
(dinutuximab), triggered this sunset clause and drove the Creating Hope Act to expire on March
17, 2016. However, on September 30, 2016, the voucher incentive was re-authorized under the
Advancing Hope Act of 2016 (Public Law No: 114-229) which amended Section 529 of the
FD&C Act. The Act removed restrictions on the number of vouchers that could be issued and
modified the definition of “rare pediatric disease” to include “any pediatric cancers” and “any
form of sickle cell disease” regardless of numbers of patients. Pursuant to the 21st Century
Cures signed into law on December 13, 2016, the Creating Hope Act pediatric RPDPRV was
reauthorized until September 20, 2020.
2.2.1.3 Effectiveness of PREA, BPCA, and RPDPRV in Pediatric Cancer Drug Development
The Stick: Pediatric Research Equity Act (PREA): The spate of legislative and regulatory
activities to foster the study of pediatric oncology drugs is sufficiently mature that its effects can

50
be examined. The results are not encouraging. From January 2016 to September 2017, for
example, 57 oncology and hematology drug and biologic products have received initial or
supplemental drug/biologic approvals. Of these products, 35 were granted Orphan Drug
designation (and so were PREA exempted) and 21 were given a pediatric waiver. Only 6 of the
57 approvals included pediatric indications as part of the approval.
Table 3: Approved Adult Oncology Products with PREA Exemption (January 2016
to September 2017)
Approval Date Sponsor Drug/Biologic Approved Indications
01 September
2017
Pfizer Inc. MYLOTARG
(gemtuzumab
ozogamicin)
Treatment of newly-diagnosed CD33-positive
AML in adults and for treatment of relapsed or
refractory CD33-positive AML in adults and
in pediatric patients 2 years and older
30 August 2017 Novartis
Pharmaceuticals
Corp.
KYMRIAH
(tisagenlecleucel)
Treatment of patients up to age 25 years with
B-cell precursor acute lymphoblastic leukemia
(ALL) that is refractory or in second or later
relapse
01 August 2017 Bristol-Myers
Squibb
Company
OPDIVO
(nivolumab)
Treatment of patients 12 years and older with
mismatch repair deficient (dMMR) and
microsatellite instability high (MSI-H)
metastatic colorectal cancer that has
progressed following treatment with a
fluoropyrimidine, oxaliplatin, and irinotecan
23 May 2017 KEYTRUDA
(pembrolizumab)
Accelerated Approval: Treatment of adult and
pediatric patients with unresectable or
metastatic, microsatellite instability-high
(MSI-H) or mismatch repair deficient
(dMMR) solid tumors that have progressed
following prior treatment and who have no
satisfactory alternative treatment options or
with MSI-H or dMMR colorectal cancer that
has progressed following treatment with a
fluoropyrimidine, oxaliplatin, and irinotecan
23 March 2017 EMD Serono,
Inc.
BAVENCIO
(avelumab)
Accelerated Approval: treatment of patients 12
years and older with metastatic Merkel cell
carcinoma (MCC)
15 March 2017 Merck and Co.,
Inc.
KEYTRUDA
(pembrolizumab)
Accelerated Approval: treatment of adult and
pediatric patients with refractory classical
Hodgkin lymphoma (cHL), or those who have
relapsed after three or more prior lines of
therapy

51
This may not be surprising. PREA has been viewed as irrelevant in the pediatric cancer drug
development setting as the requirement for pediatric studies is based on the adult indications and
it is exempted for drugs with an orphan drug designation. Further, the FDA guidance, “Guidance
for Industry: How to Comply with the Pediatric Research Equity Act”, provided a list of “adult-
related conditions that may qualify the drug product for disease-specific waivers” (FDA, 2005);
drugs for these indications could be waived from the pediatric-studies requirement. A review of
recently approved oncology drugs shows that significant numbers of these products have
approved adult indications eligible for pediatric waivers (FDA, 2018).

52
Table 4: FDA Approved Oncology Drugs Qualified for Disease-Specific Waivers
(January 2016 to October 2017)
Adult-Related Conditions
(Cancer) May Qualify for
Disease-Specific Waivers
under PREA (FDA, 2005)
Approvals from January 2016 to October 2017
Basal cell and squamous
cell cancer

• Nivolumab (OPDIVO) approved on 10 November 2016
• Pembrolizumab (KEYTRUDA) approved on 5 August 2016
Breast cancer

• Abemaciclib (VERZENIO approved on 28 September 2017
• Neratinib (NERLYNX) approved on 17 July 2017
• Palbociclib (IBRANCE) approved on 31 March 2017 and 19
February 2016
• Ribociclib (KISQALI) approved on 13 March 2017
Colorectal cancer
• Mvasi (bevacizumab-awwb) approved on 14 September 2017
• Nivolumab (OPDIVO) approved on 01 August 2017
Lung cancer (small cell
and non-small cell)

• Pembrolizumab (KEYTRUDA) approved on 10 May 2017 for first
line therapy
• Pembrolizumab (KEYTRUDA)approved on 24 October 2016
• Atezolizumab (TECENTRIQ) approved on 18 October 2016
Ovarian cancer (non-germ
cell)
• Olaparib (LYNPARZA) approved on 17 August 2017
Pancreatic cancer
Prostate cancer
• Cabazitaxel (JEVTANA) modified dose approved on 14 September
2017
Renal cell cancer/
urothelial carcinoma

• Pembrolizumab (KEYTRUDA) approved on 18 May 2017
Durvalumab (IMFINZI) approved on 01 May 2017 Nivolumab
(OPDIVO) approved on 02 February 2017
• Atezolizumab injection (TECENTRIQ) approved on 18 May 2016
• Lenvatinib capsules (LENYIMA) approved on 13 May 2016
• Cabozantinib (CABOMETYX) approved on 25 April 2016
Uterine cancer Niraparib (ZEJULA) approved on 27 March 2017
Note: Endometrial cancer, hairy cell cancer, and oropharynx cancers (squamous cell) are included in the list
but no products were approved for these indications during the timeframe of January 2016 to October 2017.
In order to supplement the information that was available in the literature, I conducted a search of
the keyword, “orphan designation” under the FDA’s website on October 2017. A total of 374
products were listed under the search term of “cancer”, and over 800 products under other
relevant search terms including carcinoma (187), melanoma (107), multiple myeloma (74),

53
glioma (80), lymphoma (172), tumor (90), sarcoma (1), and leukemia (271). Some of the adult
cancers may have a prevalence of more than 200, 000 cases a year so technically would not be
considered as orphan drugs according to the US FDA definition of orphan drugs. However, some
have different subforms based on genomic phenotype and could be designated as potential
orphans. These thousands of products that were designated as orphan drugs have been exempted
from conducting pediatric clinical research. Table 5 below lists recent oncology approvals that
have been granted with an Orphan Drug Designation and therefore are not subjected to PREA.
Table 5: Recent Adult Oncology Drugs Approvals Granted with Orphan Drug
Designation (January 2016 to October 2017)
Products Approved between January 2016 to
October 2017
Overview of Approved Indications Granted
with an Orphan Drug Designation (Exempted
from PREA)
Acalabrutinib (CALQUENCE), approved on 31
October 2017
Mantle cell lymphoma (MCL)
Avelumab (BAVENCIO) approved on 23 March 2017 Merkel cell carcinoma (MCC)
Axicabtagene ciloleucel (YESCARTA), approved on
18 October 2017
RITUXAN HYCELA approved on 22 June 2017
Diffuse large B-cell lymphoma (DLBCL)
Dabrafenib and trametinib approved on 22 June 2017

Certinib (ZYKADIA) approved on 26 May 2017
Brigatinib (ALUNBRIG) approved on 28 April 2017

Osimertnib (TAGRISSO) approved on 30 March 2017
Non-small cell lung cancer (NSCLC) with RAF
V600E mutation
NSCLC with ROS-1 positive
NSCLC with anaplastic lymphoma kinase
(ALK)-positive
NSCLC with EGFR T790M mutation
Lenalidomide (REVLIMID), approved on 22 February
2017
Daratumumab (DARZALEX) approved on 21
November 2016
Multiple myeloma
Olaratumab (LARTRUVO), approved on 19 October
2016
Soft tissue sarcoma (STS)
Inotuzumab ozogamicin approved on 17 August 2017
Blinatumomab (BLINCYTO) approved on 11 July
2017

B-cell precursor acute lymphoblastic leukemia
(ALL)
Ibrutinib (IMBRUVICA) approved on 02 August 2017 Chronic graft versus host disease (cGVHD)
Gemtuzumab ozogamicin (MYLOTARG) approved on
01 September 2017
VYXEOS approved on 03 August 2017
Enasidenib (IDHIFA) approved on 01 August 2017

Midostaurin (RYDAPT) approved on 28 April 2017
Acute myeloid leukemia (AML): CD33 positive

Acute myeloid leukemia (AML): with IDH2
mutation
Acute myeloid leukemia (AML): with FLT3+
mutation

54
Products Approved between January 2016 to
October 2017
Overview of Approved Indications Granted
with an Orphan Drug Designation (Exempted
from PREA)
Pembrolizumab (KEYTRUDA) Gastroesophageal junction adenocarcinoma
approved on 22 September 2017
Classical Hodgkin lymphoma (cHL) approved
on 15 March 2017
Nivolumab (Opdivo) Hepatocellular carcinoma (approved on 22
September 2017)
Classical Hodgkin lymphoma (cHL) on 17 May
2016
Copanlisib (ALIQOPA) approved on 14 September
2017
Obinutuzumab (Gazyva Injection) approved on 26 Feb
2016
Follicular lymphoma (FL)
Everolimus (AFINITOR) approved on 26 February
2016
Neuroendocrine tumors (NET)
Eribulin (HALAVEN) approved on 28 February 2016 Unresectable or metastatic liposarcoma
Regorafenib (STIVARGA) approved on 27 April 2017 Hepatocellular carcinoma (HCC)
Avelumab (BAVENCIO) approved on 09 May 2017 Urothelial carcinoma
Niraparib (ZEJULA) approved on 27 March 2017
Rucaparib (RUBRACA) approved on 19 December
2016
Ovarian cancer
Ovarian cancer with deleterious BRCA mutation
Venetoclax (VENCLEXTA) approved on 11 April
2016
Ofatumumab (Arzerra Injection) approved on 19
January 2016
Chronic lymphocytic leukemia (CLL) with 17p
deletion
Recurrent or progressive chronic lymphocytic
leukemia (CLL)

As discussed earlier, some adult cancers do not have a similar pediatric subtype(s); nonetheless, a
recent review of cancer types by the FDA Pediatric Subcommittee noted that several tumor types
in children were similar to those of adults based on appropriate genetic or biomarker evidence. In
the July 2016 FDA Status Report to Congress, the FDA Commissioner at the time, Robert Califf,
noted that,
…expanding the scope of PREA to require pediatric studies based on a
pediatric tumor’s expression of a molecular target or the known molecular
mechanism of a new drug could significantly increase the number of pediatric
studies conducted under PREA...Because PREA does not apply to drugs for
indications for which orphan designation has been granted even when the
same cancer types occur in the pediatric population, there are substantial
delays in the evaluation of highly effective cancer drugs in children. (FDA,
2016c)

55
However, the regulatory environment may be changing. The Research to Accelerate Cures and
Equity (RACE) for Children Act signed into law as part of the 2017 FDARA now requires
companies to apply PREA to any treatment with a molecular target that is relevant to both an
adult and a childhood disease. Despite having an orphan designation (21 USC 355a), original
new drug applications (NDAs) and biologic licensing applications (BLAs) for a novel active
ingredient submitted three years after the law was enacted would have to include reports on a
"molecularly targeted pediatric cancer investigation" if the drug or biologic were intended for
treatment of an adult cancer whose molecular target was determined by FDA " to be substantially
relevant to the growth or progression of a pediatric cancer". The expansion of PREA to certain
types of pediatric cancers also removes the “inadvertent loophole” (Gottlieb, 2017) seen to exist
because many adult cancers occur in organs different than those of genotypically similar
childhood cancers.
The FDA acknowledged that the new requirement could be challenging for sponsors. Thus, they
also provided more opportunities for sponsors to interact with FDA as they developed their
pediatric strategy. Sponsors with drugs for serious or life-threatening diseases can now have a
meeting to discuss preparations of an initial PSP not later than End-of-Phase 1 or within 30 days
of the request. Additional meetings can be scheduled to discuss any deferrals or waivers from
such trials. As part of FDARA, FDA was required to issue additional guidance to the sponsors.
Within the first year, after the law was enacted, the FDA was to post a list of molecular targets
relevant to pediatric cancers and to develop a list of those targets that will get automatic waivers.
Such material is not yet available at time of writing.
The Carrot: Best Pharmaceuticals for Children Act (BPCA): Another way to gain insight into the
effectiveness of the recent rules to foster pediatric trials is to analyze the 40 approved products for

56
adult cancers that were granted pediatric exclusivity (PE) as of 31 March 2017. These are posted
on the FDA website (www.fda.gov) (Appendix B). Of the 211 pediatric exclusivities that were
granted across all indications, 18 (8.53%) had a pediatric cancer indication (Appendix C). For
these 18 drugs, the average time from first adult approval to pediatric exclusivity was 87 months
(range: 39 to 166 months). This verifies the perceived “lag” in pediatric development compared
to the adult indications.
A few factors may explain the prolonged timeframe between the initial adult approval to the
availability of information for pediatric treatment of the same drug. First are the challenges
imposed by the number of pediatric subjects required for each study demanded in the Written
Request (WR). In addition, many sponsors still do not initiate pediatric studies until the adult
indication has been approved. Finally, it might be the case that a lengthy period of consultation is
needed to reach an agreement with the health authorities on study design. Only 5 of the 18
products (clofarabine, imatinib mesylate, premetrexed, ixabepilone, and temsirolimus) had been
issued a WR prior to the initial adult approval (Appendix C). In most cases, that WR was not
issued until years after the initial approval in adult indication(s). A recent Status Report to
Congress (FDA, 2016c) noted that, from 1998 to July 2012, FDA issued 54 WRs for pediatric
studies of oncology products. Since the enactment of 2012 FDASIA to the date of the report,
FDA issued 12 WRs for oncology drug and biological products, plus 4 additional WRs under
discussions at the time of the report. The significant increase in the rate of issued WRs was
attributed to the proactive approach within the FDA, including their quarterly interactions with
representatives of the pediatric oncology investigator community.
Creating Hope Act: Rare Pediatric Disease Priority Review Voucher (RPDPRV): One of the
specific “carrots’ for some companies to conduct a pediatric program is the ability to gain a

57
priority review voucher that can be used in future or even sold to another company (Section
2.2.1.2). As of October 2017, a total of 11 RPDPRVs have been awarded (Table 6). Only two of
these, UNITUXIN (dinutuximab) and KYMRIAH (tisagenlecleucel) were approved as a
“reward” for treating pediatric cancers.
Table 6: Listing of Rare Pediatric Disease Priority Review Vouchers Awarded (as of
October 2017)
Drug Name Date Voucher
Awarded and
Drug Sponsor
Indication Received
RPDPR Voucher
Endpoints of
Approval
Comments
VIMIZIM
(elosulfase alfa)
14 February
2014
BioMarin
Mycopolysaccharidosis
Type IV (Morquio A
Syndrome)
Significantly
improves
patients’ ability
to walk
Sold to Sanofi at
$67.5 million,
excised in
November 2014
for a new
cholesterol drug
UNITUXIN
(dinutuximab)
10 March 2015
United
High-risk
neuroblastoma
Improves the
overall survival
rates of affected
children
Sold to AbbVie
($350 million)
CHOLBAM
(cholic acid)
17 March 2015
Asklepion
Bile acid synthesis
disorders due to single
enzyme defects, and
peroxisomal disorder
Improved liver
functions,
increase body
weight by 10%
and survival > 3
years
Sold to Sanofi at
$245 million in
May 2015
XURIDEN
(uridine triacetate)
4 September
2015
Wellstat
Hereditary orotic
aciduria
Stable pre-
specified
hematologic
parameters
during the 6-
week trial period
Sold to
AstraZeneca
STRENSIQ
(asfotase alfa)
23 October
2015 Alexion
Hypophosphatasia
(genetic, rare
metabolic disorder)
Increase overall
survival and
alleviated
symptoms
Unsold
KANUMA
(sebelipase alfa)
8 December
2015
Alexion
Lysosomal acid lipase
deficiency
Increase overall
survival
Unsold
EXONDYS 51
(eteplirsen)
19 September
2016
Sarepta
Duchenne muscular
dystrophy
Accelerated
approval of
Exondys 51 is
based on the
surrogate
endpoint of
dystrophin
Sold to Gilead
for $125 million
in February 2017

58
Drug Name Date Voucher
Awarded and
Drug Sponsor
Indication Received
RPDPR Voucher
Endpoints of
Approval
Comments
increase in
skeletal muscle
observed in
some Exondys
51-treated
patients.
SPINRAZA
(Nusinersen)
23 December
2016
Ionis
Pharmaceuticals
Spinal muscular
atrophy (SMA)
Improvement in
motor
milestones, such
as head control,
sitting, ability to
kick in supine
position, rolling,
crawling,
standing and
walking
Unsold
EMFLAZA
(deflazacort)
9 February 2017
Marathon
Pharmaceuticals
Duchenne muscular
dystrophy (DMD)
Improvements in
a clinical
assessment of
muscle strength
across a number
of muscles
Unsold
BRINEURA
(cerliponase alfa)
27 April 2017
BioMarin
Batten disease (To
slow loss of walking
ability (ambulation) in
symptomatic pediatric
patients 3 years of age
and older with late
infantile neuronal
ceroid lipofuscinosis
type 2 (CLN2), also
known as tripeptidyl
peptidase-1 (TPP1)
deficiency)
Demonstrate
fewer declines in
walking ability
Unsold
KYMRIAH
(Tisagenlecleucel)
30 August 2017 B-cell precursor acute
lymphoblastic
leukemia (ALL) that is
refractory or in second
or later relapse
Overall
Remission Rate
(Complete
remission +
complete
remission with
incomplete
hematological
recovery)
Unsold
(Gaffney, Mezher, & Brennan, 2018; http://priorityreviewvoucher.org/ accessed on 01 March 2018)

59
The effectiveness of the RPDPRV program has been controversial. As shown in the table above,
the vouchers have gained notice in the pharmaceutical industry because of their value. Some
vouchers have been sold to other drug sponsors for prices of up to $350 million; two companies,
BioMarin and Alexion, have already developed and received more than one RPDPRV. As
identified by both the GAO and certain patient advocacy groups, sales of a voucher can fuel
reinvestment in further research.
Four of five sponsors that were awarded or transferred and later sold
vouchers told us that they plan to reinvest a portion of the proceeds they
received into additional research and development of drugs to treat other rare
pediatric diseases…
Patient advocacy groups also generally favor the program. For example, one
group we spoke to said that the program has stimulated a transfer of cash
from larger drug sponsors to smaller ones through the sales of the vouchers,
and that these smaller drug sponsors may reinvest a portion of the proceeds
to continue developing drugs for rare pediatric diseases. A few groups also
indicated that the program could lead to the development of much-needed
pediatric drugs without costing the government resources (GAO, 2016).
On the other hand, the FDA has had concerns with the program because it obligates the Agency
to review an application under Priority Review that does not have priority status. It sees this
requirement as running counter to its public health mandate of giving precedence for drugs with a
high impact on disease (GAO, 2016). From the FDA’s perspective, some programs started
pediatric development before FDASIA was enacted so the fact that they qualified for a voucher is
insufficient evidence to argue the program has been effective (FDA, 2016c). The GAO report
also expressed similar concerns about premature conclusions on the usefulness of the program.
Given that the typical drug development process often exceeds a decade,
insufficient time has elapsed to gauge whether the 3-year-old pediatric
voucher program has been effective at encouraging the development of drugs
for rare pediatric diseases.

60
Nevertheless, industry and patient advocacy groups typically view this program as an important
incentive for pediatric drug developments for rare pediatric diseases (GAO, 2016).
So far, only two vouchers have been awarded for a rare pediatric cancer. Nevertheless, those
cases point to the potential importance of incentives to probe issues associated with the
development process. For example, the approval of dinutuximab (UNITUXIN) has been
showcased as a “lesson learned in expediting the development of rare pediatric cancer drugs”
(ASCO, 2016). Dinutuximab is the first FDA-approved treatment for patients with high-risk
neuroblastoma. In the US, there are 250 to 300 such patients. The tumor develops predominantly
in children; the median age at diagnosis is 19 months, and 90% of patients with neuroblastoma
are diagnosed before the age of 5 (ASCO, 2016). The approval was based upon a clinical
program designed specifically for this pediatric cancer and was conducted in a randomized study
of 226 patients by the Children’s Oncology Group (COG) (Study ANBL0032) (FDA, 2015).
FDA explained the two major challenges, illustrated in Figure 7, that appeared to account for the
lengthy period between the early evaluation of anti-GD2 antibodies in neuroblastoma (early
1990s) and FDA approval (2015) in a 2016 interview conducted by ASCO.

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Figure 6: Timeline of Dinutuximab Development (Clinical to US BLA Approval)

First, they noted that it took 7 years to enroll the required participants. Second, an additional
multi-year period was needed to scale up and supply commercial volumes of drug and to conduct
comparability trials of the commercial product against drug used in the pivotal clinical trial.
However, some time was gained by leveraging regulatory incentives. The FDA’s Office of
Orphan Products Development designated neuroblastoma a “rare pediatric disease.” in 2013 and
granted priority review to its BLA to shorten the review time from 10 months to 6 months. In
addition, the manufacturer, United Therapeutics, received a RDPRPV as permitted under the
Creating Hope Act. This drug sets a precedent of a program specifically designed to secure a
pediatric cancer indication. Its success and receipt of financial incentives show how
public-private partnerships and regulatory acceleration can facilitate the drug development for
pediatric cancers.

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Paediatric (Pediatric) Regulatory Framework in the European Union (EU)
Europe has shared the concerns of the US regarding the need to increase pediatric research and
product development. By the early 2000s, about 50 to 75% of approved medications still had not
undergone adequate pediatric study (Vassal, 2009). In December 2000, the EU Parliament voted
to address the need for better medicines for children, and six years later, approved the Paediatric
Regulation (EU 1901/2006) that entered into force on 26 January 2007. Its objective, like that of
the FDA, was to improve the development and availability of medicines for children without
subjecting the children to unnecessary clinical trials.
Pursuant to the Paediatric Regulation, companies were required to submit a Paediatric
Investigation Plan (PIP) for any medicinal product with a new or changed indication as soon as
the adult pharmacokinetic studies of the drug program were completed. Under article 7, this PIP
would have to be approved and included in the marketing authorization application unless an
exemption has been granted. That exemption typically took the form of a waiver, granted by
EMA’s Paediatric Committee (PDCO). The PDCO was also given the role of reviewing and
reaching an agreement with the sponsoring companies on the nature of studies to be carried out as
part of their PIPs. To reward companies for carrying out the pediatric studies, a 6-month
extension would be granted by awarding a Supplementary Protection Certificate (SPC) when the
product was authorized in all Member States. Supplementary protection certificates (SPCs) are
an intellectual property right that serves as an extension to a patent right. The extension was
contingent only on carrying out the paediatric studies. It would be granted whether those trials
showed efficacy in children or whether the drug was authorized for commercialization. Table 7
below summarizes the EU Paediatric Regulations in terms of obligations versus incentives.

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Table 7: EU Paediatric Regulation: Obligations Versus Incentives
Type of Medicine
Product
Obligation Incentives (If
Compliance with the
Agreed PIP)
Comments
New PIP or Waiver 6 months extension of
SPC
An agreed PIP is
required for validation
of a MAA
One Patent and Already
Approved/Authorized
PIP or Waiver 6 months extension of
SPC
An agreed PIP is
required for validation
of the variation
application of new
indication or new route
or new pharmaceutical
form
Products Granted with
Orphan Designation
(Orphan Medicine)
PIP or Waiver 2 additional years of
market exclusivity
This is added to the
original 10 years = a
total of 12 years of
exclusivity
Off Patent Medicine None (voluntary PIP
possible for PUMA
10 years of data
protection
no addition to
exclusivity or patent as
both have expired for
off-patent medicine
MAA = marketing authorization application. PIP = Paediatric Investigational Plan. PUMA = paediatric-use
marketing authorization. SPC = supplementary production certification. It is an intellectual property (IP)
right that extends the duration of certain rights associated with a patent. (EMA, 2013b)

Key Differences Between the US and EU Pediatric Regulations
Most drugs are developed with the intent of marketing them at least in the EU and the US if not
globally. However, efficient drug development can be hampered by dissonance in the legal and
regulatory requirements in these two constituencies (Storm, 2018). Even differences in
definitions or patient classifications can be present. For example, the US FDA considers pediatric
patients to be those from birth up to the 16th birthday, and subdivides them into four age groups
including neonates (0-1 month), infants (1 month to 2 years), children (2 years to 12 years) and
adolescents (12 years to 16 years). The EU Pediatrics Regulation does not define the different
age groups in the pediatric population that it identifies as ranging from birth and 18 years.
Instead, it follows the definitions in ICH Guidance E11 that groups pediatric patients into five

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categories: preterm newborn infants; term newborn infants (0 to 27 days); infants and toddlers (28
days to 23 months); children (2 to 11 years); and adolescents (12 years to 16-18 years). Table 8
below outlines the key differences between the US and EU pediatric regulations.
Table 8: Differences in Pediatric Regulations: EU Versus US
US BPCA US PREA EU Paediatric
Regulation
Requirement or Not Voluntarily Mandatory Mandatory
Documentation Written Request (issue by FDA)
(initiated by FDA or by request
from the Sponsor via
submission of a Proposed
Pediatric Study Request)
Pediatric Study Plan
(submit by Sponsor,
agreement from
FDA)
Pediatric
Investigation Plan
(submit by Sponsor,
agreement from
EMA PDCO)
Waiver Not applicable Allow Allow
Timing of Initial
Plan Discussion
Not specified (FDA suggested
early discussion, end of phase
2, or earlier for oncology
products)
End of Phase 2 End of Phase 1
Reward/Incentive 6 months addition to existing
patent and exclusivity
No reward 6 months addition to
SPC/Patent
Conditions Covered FDA may request a pediatric
study to evaluate the same
indications intended or
approved for adults, but it may
also request that a sponsor
conduct a pediatric study for a
different indication, including
one not approved for adults
Same indications
intended or approved
for adults
Same disease
condition intended or
approved for adults
Orphan Designation
Product
Applicable/Included Exempted from
requirement under
2012 FDASIA
Required/Included
Transparency of
Pediatric Plan to
Public
Written Request not made
public by the FDA until
Pediatric Exclusivity is granted
PSP (issued to the
Sponsor’s
Investigational New
Drug Application)
not made public by
the FDA and not
available via
Freedom of
Information Act
Agreed Plan and
PDCO
Recommendations
are made public by
the EMA PDCO

These differences impose different pediatric research obligations for the same drug product.
They also provide different incentives or similar-sounding incentives that nevertheless differ in

65
certain details. Thus, it is useful to examine the degree to which the rules in the two regions
result in similar outcomes for the drug manufacturer. One area, for example, is that of pediatric
waivers.
Pediatric studies may be waived under both PREA and the EU Pediatrics Regulation as a partial
waiver (study is not feasible or appropriate or safe for a specific age group; hence, waving a
specific age group from pediatric study requirement) or as a full waiver for all age groups. Under
PREA, the FDA assesses a waiver for the same indication that is planned in adults based on
established criteria, for some or all pediatric age groups. FDA grants a full or partial waiver
specific to the drug product based on the adult indications. In contrast, the EU PDCO assesses
waivers for a condition, but the full waiver can apply for any indication of a specific product.
Waivers can also apply to a class of products. The EMA (but not the FDA) publishes a class
waiver list that identifies classes of drugs/biologics that are waived from the pediatric study
requirement.
The need for a paediatric development may be waived for classes of
medicines that are likely unsafe or ineffective in children, that lack benefit for
paediatric patients or are for diseases and conditions that only affect the
adult population. (EMA, 2017b)
Nevertheless, the reasons for waiver requests are similar between the EU Pediatric Regulation
and US PREA (Table 9).
Table 9: Grounds for Waiver Request for Pediatric Studies
PREA Pediatric Regulation

Partial waivers for specific age groups or full waiver
for the indication:

Class waivers – for specific medicinal products or
classes of medicine products that:

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PREA Pediatric Regulation
● Necessary studies are impossible or highly
impracticable (due to small number of patients)
● There is evidence strongly suggesting that the
drug or biologic product would be ineffective
or unsafe in that age group
● The product does not present a meaningful
therapeutic benefit over existing therapies (and
not likely to be used by a substantial number of
pediatric patients in that age group)
● The applicant can demonstrate that reasonable
attempts to produce a pediatric formulation for
that age group have failed.

● Are likely to be ineffective or unsafe in part or
all of the pediatric population
● Are intended for conditions that occur only in
adult populations;
● Do not represent a significant therapeutic
benefit over existing treatments for pediatric
patients.

A recent retrospective comparison of product-specific pediatric full waivers granted by FDA and
EMA across all therapeutic areas between 2007 and 2013 (Egger et al., 2016) shows that their
waiver decisions were consistent in most cases (66 of 80, 83%). The authors attributed the
converging approaches to the monthly meetings held between two agencies. The cases of
divergent requirements appeared to be associated with two issues. First was the occasional
difference in the definition of indication vs. condition. In the US, PSPs are for the exact
indications for which the company intends to develop the product in adults, whereas PIPs take
into account the whole of the corresponding condition. The condition may include one or more
indications falling below/within the condition (EMA, 2012). For example, the PSP was waived
for pembrolizumab in the NSCLC indication but a PIP was issued to cover pediatric solid tumors
including CNS tumors. Second was a difference in the weight given to potential therapeutic
benefits for children or considerations for study feasibility, resulting in a difference of assessment
between PDCO and PeRC regarding potential benefit versus risk. Understanding the factors
leading to the misaligned outcomes would help the applicant to assess the timing and the need for
joint-discussion with FDA and EU on the pediatric development program, based on the

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perception of therapeutic needs in the respective region and the potential of broader condition
consideration per examples above.
2.2.3.1 Difference in US and EU Pediatric Oncology Study Requirement: Recent Example
Differences in the US and EU approaches to pediatric oncology programs can also be discerned
from an examination of certain types of drugs currently in development. A case in point are the
immune checkpoint inhibitors that have shown efficacy in some chemotherapy-resistant adult
cancers Four agents acting through the programmed cell death-1 (PD-1) pathway (nivolumab,
pembrolizumab, atezolizumab, and durvalumab) have recently been approved for adults and may
have promise for certain refractory pediatric malignancies such as sarcoma, neuroblastoma, and
high-grade glioma. Table 10 summarizes the US and EU pediatric regulatory status based on
publicly available information as of October 2017. This reflects the following differences in
pediatric regulatory status in the US and EU of all 4 products:
1) There were no PSPs in the US either because they had PREA orphan drug exemption or
had a pediatric waiver
2) There were PIPs requirement and the studies outlined within the agreed PIPs of the same
class of medicine product are consistent,
3) There were important differences between the decisions of the two agencies, particularly
with regard to regulatory decision-making outcomes based on the pediatric data (further
explained in the paragraph after Table 10).

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Table 10: US and EU Pediatric Status of Approved Anti-PD1/L1 Agents (as of
October 2017)
Anti-PD1/L1
Agents
US Regulatory (Pediatric Status) EU Paediatric Status (PIP)
including PIP
Condition/Indication(s)
Nivolumab Written Request Issued, but not made
public
Approved indication (MSI-H) included
pediatric
● Malignant neoplasms excl. nervous
system, hematopoietic and lymphoid
tissue / Melanoma & solid tumors
● Malignant neoplasms of lymphoid
tissue & CNS / rrHL; rrNHL; glioma
● No inclusion of pediatric in the
SmPC
Pembrolizumab Pediatric study conducted (PK and
Safety) in ped. ST pts
Approved indications (cHL and MSI-
H) included pediatric
Written Request not issued
● Malignant neoplasms excl. nervous
system, hematopoietic and lymphoid
tissues / Melanoma & PD-L1(+)
solid tumors.
● HL / 2L cHL & rrHL
● No inclusion of pediatric in the
SmPC
Atezolizumab Written Request issued, but not made
public
Held Ped. ODAC in 2016 with FDA
Malignant neoplasms excl. nervous
system, hematopoietic and lymphoid
tissue / 1L PD-L1(+) solid tumors
Durvalumab Written Request not yet issued ● Malignant neoplasms excl. nervous
system, hematopoietic and lymphoid
tissue; awaiting PIP decision
● Malignant neoplasms of
haematopoietic and lymphoid tissue:
awaiting PIP decision
Source: list of WR issued as of 31 Oct 2017
(https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm050002.htm)
SmPC = Summary of Product Characteristics.
CNS=central nervous system;MSI-H=microsatellite instability-high;rr=relapsed/refractory;HL=hodgkin's
lymphoma;cHL=classic hodgkin's lymphoma;SmPC=Summary of Product
Characteristic;ODAC=Oncologic Drugs Advisory Committee; PK=pharmacokinetics; ST=solid tumors.

The toxicities of these compounds are nearly similar, with autoimmune adverse events being most
common and concerning (Wagner & Adams, 2017). The similar agreed-upon PIPs across all four
agents in the same class of therapy (see a summary in Appendix D) may have raised concerns
about requiring companies to complete for the rare pediatric cancer patients to meet regulatory
obligations, rather than assigning patients to more promising studies based on scientifically and
medically available data. It points to a need for effective collaboration between stakeholders,

69
including sponsors, in the broader plan to target the development of related drugs, especially if
they all targeting the same disease pathway or disease.
The US FDA and EMA have had differing perspectives on data supporting their regulatory
decisions. Recent (2017) FDA approvals of nivolumab and pembrolizumab in microsatellite
instability-high cancer (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal
cancer (mCRC) that included pediatric patients (12 years and older) were based on a tissue-
agnostic approach that used a biomarker, rather than an organ to define the disease across.
Inclusion of the adolescent population in the approved indication was based on data extrapolation.
As of October 2017, these indications were not reflected in the marketing authorization for the
same drugs in the EU Summary of Product Characteristics; instead, their approved indications
have only been based on organ types.
Framing the Study of Pediatric Oncology Drug Development
The goal of pediatric regulations in the US and the EU is to encourage and accelerate the
development of new therapies for pediatric diseases. In the pediatric oncology arena, the health
authorities (FDA and EMA), academia, and patient advocacy groups encourage early clinical
evaluation of targeted drugs developed for adult cancers in children with relapsed/refractory
cancers. Both the FDA and EMA now require pediatric investigations of drugs directed at
molecular targets considered substantially relevant to pediatric cancer even when the adult cancer
indication does not occur or is biologically different in the pediatric population. Both agencies
express the hope that targeted amendments to PSP/PIP and issuance of WRs in the US under
BPCA earlier in product development would improve the timeliness of pediatric evaluations and
ultimately market introductions. Thus, at this point, the views and motivations of the regulatory
agencies appear quite clear.

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Workshops on pediatric oncology drug development usually included representatives from the
industry; however, the few industry representatives selected to provide the industry’s perspective
on specific regulatory initiatives were mainly from major pharmaceutical companies and their
discussions at the workshops usually focused on a specific regulatory regulation or new initiative.
What is not clear is the views of industry across company sizes, the sector most affected by these
efforts, and most able to translate these incentive-based intentions into actionable activities,
outputs, and outcomes with regard to the broader regulatory landscape. In this current research, I
explored the perspectives and experience of industry stakeholders, through the eyes of regulatory
experts from small to large companies, who I consider to be the subset of personnel best placed to
describe the experience, outcomes, and views related to pediatric incentive programs advanced by
regulatory agencies. Their experience in adapting, planning and implementing drug development
programs may provide insights into the issues that they have encountered with the staging of
trials and the impact that incentives and regulatory requirements have had on their strategies.
This study used a systematic approach based on the conceptual framework outlined in the
National Implementation Research Network’s (NIRN) publication, “Improving Programs and
Outcomes: Implementation Frameworks” (Bertram, Blase & Fixsen, 2014). This framework
provided refinements to the initial iteration of the implementation constructs and frameworks by
Fixsen and coworkers in 2005 (Fixsen, Naoom, Blasé, Friedman & Wallace, et al., 2005). The
NIRN implementation framework was utilized for this research because it has been applied over
the last three decades to study gaps and challenges in the implementation of diverse programs,
from education to human service initiatives. It has also been applied in other studies of
implementation in the regulatory sector (Church, 2017; Pire-Smerkanich, 2016).

71
The four stages basing the Implementation Framework described by Bertram et al served as the
platform of this research (Figure 7).
Figure 7: Four Stages of Implementation Framework

(Copied from Bertram et al., 2014)
The evolving pediatric regulations and scientific knowledge impact the way that industry makes
its decisions about staging and implementing a pediatric trial. As they force change on the
clinical trial strategy, the experiences gained from the practice level have educational value by
giving feedback to inform the policymakers about the effectiveness of their policies (NIRN,
2018). The Practice-Policy Communication Cycle, outlined in Figure 8, illustrates one goal of
implementation research, to provide information bidirectionally to both the industry and health
authorities regarding implementation barriers and opportunities to encourage better alignment of
goals and capabilities to support effective pediatric drug development.

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Figure 8: Feedback Loop: Practice-Policy Communication Cycle

Copied from (NIRN, 2018), aiHUB: http://implementation.fpg.unc.edu
By considering the Practice to Policy Feedback Loops into each stage of the implementation, the
framework was used as a practical guide to constructing appropriate survey questions that
explored all stages of the implementation process (Table 11). It provided a systematically staged
method to explore where challenges were faced with respect to the adoption and implementation
of programs that attempt to respond to drug development regulations focused on pediatric
cancers.
Table 11: Outline of Implementation Stages: Industry’s Feedback of the
Practice-Policy Loop
Exploration
“Get Ready”
Internal:
• Are the regulations clear for the company?
• Does everyone involved embrace the new regulatory directions
regardless of whether opportunity or challenge may result?
External:
• Does the company take part in policy shaping discussion related to
pediatric rules and staging?

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Installation
“Get Set”
Internal:
• Do companies have an organizational structure to address pediatric
drug development per current policy?
• How does the company decide at what point a pediatric development
plan will be introduced?
• Who leads the pediatric trial initiatives and how do they interact with
the teams pursuing adult trials?
• Are pediatric waivers explored as an option and at what point are they
pursued?
• Have the company applied or proposed innovative study design?
External:
• How satisfactory are the channels to get feedback from health
authorities about pediatric plans? What have been areas of challenge
or disagreement with the pediatric development plan?
• Have the health authorities been receptive to innovative study design
to meet PIP/PSP requirement?
Initial Implementation
“Go”
Internal:
• Did the company have the relevant expertise? any anticipated
constraining factors?
• Are sufficient resources made available to implement the plan
effectively?
• Any resistance to organizational or process adjustments?
• How did the development of a pediatric plan affect the timelines of
other ongoing programs and why?
External:
• Were there any issues that require external alignment/collaborations,
i.e. nonclinical advancement?
• Were modifications needed and did those require extensive regulatory
interactions? If yes, what was the experience with those interactions?
Full Implementation
“Keep Going”
Internal:
• Is there a metric in place to measure the effectiveness of pediatric
program?
• Is the process in a sustainable manner for all applicable programs?
• Did the program follow intended milestones/ If no why not?
External
• Did regulators move the goalposts during the implementation of the
program?
• Were reporting structures for program progress and completions
handles smoothly?

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CHAPTER 3. METHODOLOGY
Introduction
The research was conducted in 5 steps: 1) Literature review and analysis of current product
landscape, presented in Chapter 2; 2) Development of a survey instrument to solicit industry
inputs; 3) Critical review of the survey instrument by a focus group of experts; 4) Revision and
dissemination of the final survey; and 5) Analysis of the results.
Survey Development and Focus Group Feedback
A draft survey was developed based on the foundational framework outlined in Chapter 2. Some
questions had multiple-choice, Likert or scaled choice formats; others had open text fields that
allowed respondents to enter written comments. Questions were designed to solicit industry’s
inputs on the challenges that they face as they develop and implement programs that attempt to
respond to regulations relevant to the development of drugs to treat pediatric cancers.
The draft survey was provided to a focus group who were tasked with giving critical feedback on
the survey questions and identifying any gaps in the content of the survey. The focus group
included 9 participants from industry and academia. Certain members of the focus group were
selected because they had extensive knowledge and/or previous experience in the field of
pediatric cancer drug development from a clinical and/or regulatory perspective. Others were
chosen to contribute their extensive expertise with survey preparation and development. The
focus group members are described in Table 12. An additional participant provided comments on
the questions related to European pediatric regulation and experience via electronic
correspondence.

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Table 12: List of Focus Group Participants
Participant Name Affiliation
Frances Richmond, PhD USC Regulatory Science (Chair of Focus
Group)
Nancy Smerkanich, DRSc USC Regulatory Science
Florence Houn, MD, MPH Former FDA Review Division Director.
Executive Regulatory Affairs Professional in
Pharmaceutical Industry
Jennifer Wiley, MS Senior Regulatory Affairs Professional in
Pharmaceutical Industry
Neal Storm, DRSc Senior Regulatory Affairs Professional in
Pharmaceutical Industry
Michael Jamieson, DRSc USC Regulatory Science
Patricia Duchene Senior Regulatory Affairs Professional in
Pharmaceutical Industry
Gilbert Burckart, Pharm.D. Pediatric Expert at the US FDA Office of
Clinical Pharmacology
Julien Rongere

(Provided feedback via e-mail)
Senior Regulatory Affairs Professional in
Pharmaceutical Industry in Europe

Prior to the focus group meeting, all participants were provided with an electronic copy of the
survey. The meeting was held on 11 June 2018, in person for the attendees close to the Health
Sciences campus of the University of Southern California and via an online web conference link
for those who could not attend in person. The meeting was approximately 90 minutes long. It
started with a short presentation of the intended research, the framework used to structure the
survey, and the purpose of the study. Following the presentation, the group reviewed each survey
question in order and discussed possible improvements in the wording and/or structure, for
example, by combining certain questions into groups or removing questions that might yield
duplicate responses, to improve clarity and to assure that data would be collected in a way that
facilitated effective statistical description and data display.

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Based on feedback from the focus group, the survey was revised and sent for final review to three
individuals to ensure that all comments and action items from the discussion had been addressed
appropriately. The final survey consisted of 37 questions (see Appendix D).
A validation test run was conducted by sending a preliminary copy of the survey via the Qualtrics
system to two individuals in the focus group. They ensured that the survey was delivered as
intended, could be filled out appropriately, and would provide data in a form suitable for the
intended analyses.
Survey Dissemination and Analysis
The survey was disseminated via the Qualtrics system between 12 September 2018 to 10 January
2019 to 113 participants working in the industry who had experience in cancer drug development
and held positions in clinical or regulatory affairs. Potential participants were solicited through
industry working groups focusing on pediatric initiatives (i.e. BIO Pediatric Working Task
Group), industry lists of companies with oncology programs, or individuals whose contact
information could be obtained via LinkedIn Premium and contacted by in-mail. Potential
respondents were also asked to refer/recommend other individuals or contacts who might be
qualified to address this research topic. No financial compensation or incentive was offered to
participants of this research. Email reminders were sent to individuals who had not completed the
survey 3 weeks after receipt. Because limited numbers of individuals have experience in pediatric
oncology drug/biologic development, a link to the survey was also posted on LinkedIn under the
Regulatory Affairs Professional Society page to solicit potential qualified respondents from
additional sources.

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Survey results were collected electronically and analyzed graphically when possible. Because the
numbers of respondents in this exploratory survey were predictably small, statistical analyses
were mainly descriptive. Open-ended questions and written inputs from participants were
reviewed and examined for content and grouped according to identified categories of information.
A preference index was established for those questions that solicited degrees of agreement,
importance or preference regarding certain statements. To identify overall levels of preference or
importance, individuals who identified that they could not answer were removed, and then the
number of respondents with a particular level of preference was multiplied by the score assigned
to that level of preference. The most positive level of preference was assigned a score of 1 and
progressively lower preferences were assigned progressively higher scores. For example, a
question asking to rate a statement on a 3-point scale of “very important”, “somewhat important”
and “not important” would be scored 1, 2 and 3 respectively. The multiplied scores were then
summed and divided by the number of individuals who expressed a view. The preference index
could then be used as an additional metric of positivity or agreement - a low resulting number
meant that respondents as a group felt a statement to be more important or were more than a
higher number would indicate.

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CHAPTER 4. RESULTS
The survey was disseminated from mid-September 2018 through early January 2019 to
113 individuals via email. Twenty additional individuals were also identified by a search on
clinicaltrials.gov that lists companies with recent pediatric oncology studies. Two clinical and
regulatory professionals from the respective companies were identified and contacted via
LinkedIn in-mails. The survey period closed on 10 January 2017, after 46 of the contacted
individuals had completed the survey, reflecting a participation rate of 41%.
Profiles and Background of Participants
As shown in Figure 9, most respondents were at the Director level (56%, 26/46). The remaining
respondents self-identified as Vice Presidents (15%, 7/46), Managers (15%, 7/46), and
Specialists/Associates (4%, 2/46). Four respondents (8%) self-identified as “Other” and provided
titles of “Associate Director” (1), “Consultant” (1), “Senior Vice President” (1), and “Owner” (1).
Figure 9: Current Job Title of Respondents
What title best describes your current responsibilities in your company/organization?

79
As shown in Figure 10, most of the survey participants worked in Regulatory Affairs (63%,
29/46), but 20% (9/46) worked in Clinical Development, 9% (4/46) in Project Leadership/Project
Management and 9% (4/46) in other types of positions. The four identified as “Others” identified
roles in Business Development (1), Pharmacovigilance (1), Product Late Stage Development (1),
and Quality Assurance (1).
Figure 10: Functional Areas of Respondents Within the Company
Which statement best describes your department's activities? (If you are a consultant, please
select the primary service that you provide):

80
As shown in Figure 11, almost half of the respondents (41%, 19/46) worked for large companies
with 10,001+ employees and about a quarter (26%, 12/46) were in small companies
(1-500 employees). Smaller proportions of respondents were employed by mid-size companies,
with 13% (6/46) from companies with 501-2,500 employees and 20% (9/46) from companies
with 2,501-10,000 employees.
Figure 11: Size of Company by Number of Employees
Which statement best describes the size of your overall company/organization? (If you are a
consultant, please select one organization for which you provide service and estimate its size):

Experience in Pediatric Oncology Development for Drugs/Biologics
Because this survey aimed to understand the industry’s experience in pediatric oncology drug
development, a discriminatory question was included to identify the respondent’s familiarity with
either the US or the EU pediatric regulations. Two respondents identified that they had “no”
familiarity with either set of regulations. These respondents were directed to the end of the survey
and therefore did not answer any of the subsequent questions. Thus, results were based on the
answers of 44 of the 46 respondents who replied “Yes” to indicate experience in pediatric
oncology drug development.

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Most respondents were familiar with the pediatric oncology development plan across the US and
EU. However, 5% (2/44) respondents identified no experience with development plans for the
US and 11% (5/44) respondents were not familiar with those for the EU. The personal
experiences ranged across the categories of very knowledgeable and somewhat knowledgeable as
shown in Table 13. Under the category of “knowledgeable”, more respondents were familiar with
or had personal experiences with development plans for the US (39%) than the EU (27%)
(Table 13).
Table 13: Personal Experience in Pediatric Oncology Drug/Biologic Development in
the US and in the EU
Which of the following best describe your personal experience in pediatric oncology development
for drugs and/or biologics?
Very
Knowledgeable
Knowledgeable Somewhat
Knowledgeable
None Total
Pediatric Oncology
Drug/Biologic
Development Plan
in the US
14 (32%) 17 (39%) 11 (25%) 2 (4%) 44
Pediatric Oncology
Drug/Biologic
Development Plan
in the EU

13 (30%) 12 (27%) 14 (32%) 5 (11%) 44
Respondents were asked to indicate the functional area that best described their role related to
pediatric oncology drug/biologic development. Table 14 demonstrates that the respondents had
overlapping responsibilities/involvement across multiple functional activities. Thus, the number
of selections made across all of the offered areas of responsibility were much higher than the
number of respondents. Almost half of the respondents participated as the lead responsible party
in regulatory strategy. Many also participated in clinical development but there they more
commonly played a role as team members than lead. A smaller number had ancillary roles in

82
specialized areas including statistics, nonclinical development, formulation or translational
development. The 9 responses listed under “others” included functional areas not captured in the
choices- Project Leadership, Project Management, and Regulatory Affairs Vice President with
supervisory roles.

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Table 14: Roles in Pediatric Oncology Drug/Biologic Development Within the Organization
Which of the following best describe your role related to pediatric oncology drug/biologic development in your organization?
Lead Party Team Member Ad Hoc
Member
for
Input
No Involvement Total
Regulatory Strategy (including
coordination with Health Authorities)
15 (47%) 8 (25%) 7(22%) 2 (6%) 32
Clinical Development 4 (15%) 13 (48%) 7 (26%) 3 (11%) 27
Clinical Pharmacology 0 8 (33%) 10 (42%) 6 (25%) 24
Statistics 0 4 (17%) 14 (58%) 6 (25%) 24
Nonclinical/Translational Development 0 4 (17%) 11 (48%) 8 (35%) 23
Formulation and CMC 0 5 (21%) 11 (46%) 8 (33%) 24
Other (please specify) 5 (56%) 0 0 4 (44%) 9

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The FDA has issued detailed guidance and provided different mechanisms to communicate
pediatric regulations/guidance to applicants/sponsors. Respondents were asked to identify the
degree to which they had used certain of these FDA guidance documents as they prepared a
pediatric study plan (PSP) or proposed pediatric study request (PPSR) (Figure 12). Using a
preference index calculated from a 4-point scale that included “Always”, “Most of the time”,
“Sometimes”, and “Never”, the most utilized document appeared to be the “Guidance for
Industry – Pediatric Study Plan”, with an average score of 1.6. Both the “Guidance for Industry –
How to Comply with the Pediatric Research Equity Act” (average score of 2.1) and the
“Guidance for Industry - Qualifying for Pediatric Exclusivity” (average score of 2.1) were the
next most commonly used. Both the “Guidance for Industry – Rare Pediatric Disease Priority
Review Vouchers” (2.5) and the guidance governing “Pediatric Information Incorporated into
Human Prescription Drug and Biologic Products Labeling” (2.3) were typically identified to be
consulted less commonly. Two text responses provided “other” resources, that included the FDA
Reauthorization Act of 2017 (FDARA) and “Consideration for the Inclusion of Adolescent
Patients in Adult Oncology Clinical Trials”.

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Figure 12: Utilization of FDA Guidance Documents
In the US, which of the following FDA guidance documents have you used when preparing a
pediatric study plan (PSP) or proposed pediatric study request (PPSR) for oncology
drug/biologic development?

The use of other forms of assistance was also explored. These resources included the templates
posted by FDA explaining the specific information and format needed for the proposed pediatric
plan; the link to Written Requests (WR) and any amendments associated with approved drugs for
which a pediatric exclusivity determination was made; workshops; Q&A documents; and the
established Pediatric Mailbox. Using a 4-point scale, respondents most commonly selected the
PSP and Written Request (WR) templates as the tools always utilized (average score of 1.7),
followed by the publicly available information of WR/PSPs from other sponsors (2.2), “General
Clinical Pharmacology Consideration for Pediatric Studies” (2.4), and FDA Workshop/public
meetings (2.4). Only a few respondents identified that they utilized the Pediatric Mailbox on the
FDA website (3.6).

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Figure 13: Utilization of Other FDA Information and Mechanisms
In the US, which of the following information/mechanisms have you used when preparing a
pediatric study plan (PSP) or proposed pediatric study request (PPSR) for oncology
drug/biologic development?

When asked about the clarity of the FDA’s guidance documents, respondents noted that most of
the types of information provided as options were very clear. Using a 3-point scale, respondents
seemed to rate the timing of the requirement (average score of 1.5) and the incentive/reward
system (1.5) as especially clear. In comparison, more respondents regarded as “somewhat clear”
the information and details needed for the pediatric plan (1.8) and whether such a plan was
required (1.7).

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Figure 14: Clarity of FDA Guidance Documents and Information on Pediatric Study
Plan Development
Are the US FDA guidance and statutory requirements related to pediatric oncology drug/biologic
development clear to your organization?

A similar question was also included to characterize the respondents’ experience with regard to
the use of EMA guidelines related to pediatric oncology drug/biologic development. As shown in
Figure 15, most respondents utilized the guideline on the format and content of application
(average score of 1.8), followed by publicly available agreed PIPs (1.9), and templates related to
the format and content of the applications (2.0) as the resources that they consulted most.
However, the majority of respondents who answered the question used all of the identified
documents at least “most of the time”. Very few (1-2) respondents identified that they never used
these documents.

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Figure 15: Utilization of EMA Guideline and Information on Pediatric Investigational
Plan Development
In the EU, which of the following EMA guidelines and mechanisms have you used to prepare the
paediatric investigational plan (PIP) for an oncology drug/biologic development program?

Respondents were asked to express their views about clarity of guidance related to EU pediatric
oncology drug development using a 3-point scale. Most respondents found that the guidance
related to the timing of the requirement was very clear (average score of 1.4). Somewhat less
clear for most respondents were the guidances related to waiver/deferral qualification (1.7),
incentives/reward (1.7), and levels of details required in PIP (1.8) (Figure 16). Very few (1-3)
respondents characterized the EU documents as unclear.

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Figure 16: Clarity of EU Guidance Documents and Information
Are the EMA guidelines and regulation/legislation related to pediatric oncology drug/biologic
development clear to your organization?

Respondents were asked to identify the usefulness of other sources of publicly available
information from 7 listed choices (Figure 17). Most respondents considered these resources to be
helpful. However, two sources, “the agreed PIPs that were publicly posted” and “the pediatric
study notes on FDA approval letters” were characterized as “very helpful” (average scores of 2.0
and 2.1, respectively, on a 3- point scale) more often than the other choices. Written Requests
posted by the FDA were also found to be helpful (2.2). Notably, 6 respondents were unaware of
the EPARs on pediatric variations, but only 1-3 respondents were unaware of the listed sources
on FDA’s public information on pediatric studies.

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Figure 17: Helpfulness of Publicly Available Information
Do you find the following sources of publicly available information helpful when preparing a
pediatric oncology drug/biologic development plan?

In the US, pediatric study designs submitted under an Investigational Drug Application are
considered to be proprietary so it cannot be made publicly available by the FDA until pediatric
exclusivity is granted or until the product is approved (when the pediatric required study becomes
part of the approval letter). Respondents were asked whether they believe that this information
should be publicly available earlier in the US. Two-thirds of the respondents (66%, 21/32)
expressed the view that it should be made available earlier, nearly a quarter (22%, 7/32) that it
should not, and 15% (4/32) could not answer. Certain respondents who felt that the information
should NOT be released earlier provided the reasons for that view:

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Reveals too much confidential information that should not be released early in development
(especially since PIPs are expected to be completed earlier in development).
Written Requests are voluntary and therefore are not binding. Given this they should never be
made public. The EC has received considerable pushback that their disclosure of certain data
related to PIPs in early stage jeopardize CCI as PIPs are agreed in early stage development.
Trial disclosure requirements bind all study sponsors (including academia) to post trial designs
in reality/
Strategic advantages
High likelihood of revealing trade secrets before marketing authorization.
Companies that take the initiative should get the reward. Not companies that notice a
competitor is doing it, then finish sooner.
Competitive reasons

Organizational Structure for Pediatric Oncology Development
The timing of pediatric studies appeared to vary with respect to studies in adults. A minority of
respondents identified that they have always positioned their trials in a certain order. In some
cases, this was after Phase 1/2 studies in adults had efficacy results (8/28), or less frequently,
once data was available from nonclinical pediatric models (3/27), at the time that phase 3 trials in
adults had been initiated (6/23) or completed (4/26). However, more respondents appeared to
introduce those discussions at different times, by answering “sometimes” to most of the choices.
Thus, the number of chosen answers exceeded the number of respondents. One respondent noted
in the associated text box that the timing depended on the program, for example, due to the
mechanism of action of the product, and another respondent gave the added choice of the
availability of proof-of-concept in adults. Nine respondents identified that they never introduced
those discussions “after phase 3 adult studies were completed”, and 7 never discussed them “once
data is available from a nonclinical pediatric model”, but a few identified “never” for the
remaining choices (Table 15).

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Table 15: Timing of Pediatric Planning Initiation
In your company/organization, when is pediatric planning initially discussed for an oncology
drug/biologic program?
Always Sometimes Never Do Not
Know
Total
After Ph1/2 Studies in
Adults with Efficacy
Results
8 (29%) 17 (61%) 1 (3%) 2 (7%) 28
Once Data is Available
from a Nonclinical
Pediatric Model
3 (11%) 14 (52%) 7 (26%) 3 (11%) 27
At the time that Ph3 in
Adults is Initiated
6 (23%) 16 (62%) 3 (11%) 1 (4%) 26
After Ph3 in Adults has
been completed
4 (15%) 12 (46%) 9 (35%) 1 (9%) 26
Other (Please Specify) 2 (33%) 1 (17%) 0 3 (50%) 6
Reasons provided under Other:
• This is entirely dependent on the mechanism of action
• Once Proof-of-Concept data is generated in adults

Historically, pediatric development has been tied to an adult clinical program, but some
stakeholders have encouraged the industry to develop therapies that are not linked to an adult
study. Respondents were asked if the organizations for which they worked had ever considered or
implemented stand-alone pediatric oncology programs without a tie to an adult program. The
majority of respondents (63%, 17/27), stated “No”, but approximately 30% (8/27) stated “Yes”,
and 7% (2/27) stated, “Cannot answer”.
Respondents were also asked to indicate if they or their company/organization had taken part in
discussions related to policy-setting opportunities or in industry discussions related to pediatric

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oncology drug development. About half participated in FDA/CHMP meetings or health
authorities/industry workshops, respectively (50%,14/28; 54%,15/28). Others have provided
comments to those discussions; a few only followed webcasts of announcements from those
meetings or not participate at all. Relative breakdowns are shown in Table 16. Two did not know
the answer to the question.
Table 16: Participation in Meetings and Workshops
Do you or does your company/organization take part in influencing policy or industry working
group(s) discussions related to pediatric oncology drug/biologic development regulation?
We
Participate
in
Workshops
/
Meetings
We Provide
Review
Comments
We do not
Participate but
Attend
Webcasts/
Follow
Announcements
We have never
participated
Do not
Know
FDA or CHMP
Organized
Meetings (e.g.
Pediatric ODAC,
ACCELERATE)
14 (50%) 4 (14%) 6 (21%) 2 (7%) 2 (7%)
Health Authorities/
Industry Workshops
15 (54%) 5 (18%) 4 (14%) 2 (7%) 2 (7%)
Provision of
Review Comments
7 (25%) 9 (32%) 5 (18%) 4 (14%) 3 (11%)
When asked how their pediatric teams are organized to support oncology drug development,
relatively few identified that internal resources were dedicated to pediatric programs only (40%,
11/28) and this appeared to be more typical in clinical development than other divisions of the
company, i.e. regulatory affairs (23%, 6/26). Instead, most identified that their internal resources,
such as nonclinical development, translational medicine, safety, clinical pharmacology, and
formulation development worked both on pediatric and non-pediatric programs. The use of

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external consultations appeared to be rare, reported by only 1-3 individuals regardless of job
function (Figure 18).
Figure 18: Resources Within Organizations for Pediatric Oncology Development
In your company/organization, how is the pediatric team organized to support oncology
drug/biologic development?

Text provided under Other:
• Cross-functional Project leadership
• Pharmacometrics

Respondents were asked if the development of a pediatric oncology plan or pediatric requirement
has affected the timelines and planning of other ongoing programs in the organization. A few of
the individuals who chose to answer this question (11%, 3/27) identified that they could not
answer. Most (63%, 17/27) responded “No”, whereas 26% (7/27) responded “Yes” with the
following reasons:

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Allocation of limited resources
Peds is now considered much earlier in development and across more indications than ever
before
All portfolio
Obtaining regulatory agreement
In Europe, the PIP activities remain a high risk, rate limiting procedure for expedited filing
plans due to a ‘late’ start to the procedure. This is partly because our development plans were
expedited, and we inherited a Phase 3 program from an academic institution.

Respondents were asked to identify if they faced one or more of five offered challenges when
planning for pediatric oncology drug/biologic development (Figure 19). Most participants
strongly agreed or agreed (44%, 12/27 and 25%, 7/27, respectively) that competing for resources
with other programs was a challenge; only 4% (1/27) somewhat disagreed. Respondents also
somewhat agreed that limited understanding of requirements within the organization (41%,
11/27) and limited internal expertise in the pediatric field (33%, 9/27) also posed challenges.
Limited support from management on pediatric programs had mixed responses, including 29%
(8/28) who “somewhat disagreed”. Using the 5-point scale to describe the listed elements, most
challenging appeared to be “competition for resources” with a score of 2.0 compared to limited
internal expertise (2.8), limited understanding of requirement (2.9), and limited support from
management (3.2).

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Figure 19: Challenges in Pediatric Oncology Development Plan
What would best describe the challenges your team has encountered within the
company/organization when planning for pediatric oncology drug/biologic development?

Other included:
• Applicability of adult drug targets to pediatric populations (science).
• Limited appropriate pediatric targets for our agents.
As a follow-up question, respondents were also asked to rank the challenges offered in Figure 27.
Consistent with the results described above, “competition of resources with other programs” was
rated as most challenging (average score of 1.9, with 1 representing the most challenging)
(Table 17), followed by “limited internal expertise in pediatric clinical science” (2.4). “Support
from management” (3.4) and “understanding of regulatory requirements” (3.5) had immediate
scores and “logistics related to submissions” had lowest scores (4.3).

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Table 17: Ranking of Challenges Within the Company/Organization in Pediatric
Oncology Development Planning (n =26)
Please rank the challenges that your team has encountered within the company/organization
when planning for pediatric oncology drug/biologic development, where 1 represents most
challenging and 5 least challenging.
1
Most
Challenging
2 3 4 5
Least
Challenging
Average
Score
Competition for
Resources With Other
Programs
14 7 2 1 2 1.9
Limited Internal
Expertise in Pediatric
Clinical Science
7 8 6 3 2 2.4
Limited Support from
Management for
Pediatric Program
2 5 6 8 5 3.3
Limited
Understanding of
Regulatory
Requirements
0 6 8 7 4 3.5
Limited
Understanding of
Logistics Related to
Submissions
1 0 4 7 13 4.3

Respondents were asked about the degree of challenge or disagreement related to certain key
elements of their pediatric development plans (Figure 20). “Timing of the study” stood out as a
challenge that was rated most often as “always” (18%, 5/28) or “most of the time” (39%, 11/28);
However, 7 respondents identified this challenge “sometimes” (25%, 7/28) and two identified it
as “never” happening (7%, 2/28). Other challenges/disagreements that were most commonly
identified “most of the time” was “dosing” (33%, 9/27) and “pediatric study endpoints” (32%,
9/28). The remaining elements were most commonly selected “sometimes”: age group inclusion
(32%, 9/28), formulation development (29%, 8/28), animal study planning (35%, 10/28), and

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safety follow-up (50%, 14/28). When applying a 4-point scale, “timing of study” had the highest
average score (2.2) as a disagreement compared to other listed elements: pediatric study
endpoints (2.7), dosing (2.8), age group inclusion (2.8), and formulation development (2.9). Both
safety follow-up and animal study planning had an average score of 3. About 20-30% of the
respondents could not give an answer to each of the choices.
Figure 20: Challenges/Disagreements in Key Elements of Pediatric Oncology
Development Plan
When working within the company/organization, what have been the areas of challenges or
disagreement in the key elements of a pediatric oncology drug/biologic development plan? Select
all that apply.

Note: Total of 28 responses for each listed element, except for “dosing” with a total of
27 responses, and “Others” with 6 responses.
Text reported under “Others”:
• Patient criteria
• Decision-making criteria (Go/No-Go)
• Patient Population
• Overall trial design

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Respondents were also asked to identify the extent to which they had experienced challenges
related to five listed external factors that had previously been mentioned in the literature
(Figure 21). The two factors considered extremely challenging by most respondents were both
related to recruitment, including “enrollment delays related to small participant pool” (extremely
challenging: 50%, 14/28; very challenging: 32%, 9/28) (average score of 2.0 in a 4-point scale);
and “competing enrollment with trials for drugs in the same class” (extremely challenging: 44%,
12/27; very challenging: 18%, 5/27) (average score of 2.3). “Study conduct challenges” were
identified most frequently as a “slightly challenging” (43%, 12/28) (average of 2.9) but several
participants found study conduct to be extremely (11%, 3/28) or very challenging (25%, 7/28).
“Ethics board negotiations” and “lack of interest from investigators” appeared to be the less
significant challenges, ranked by most as “slightly challenging” (46%, 13/28) (average of 3.2) but
several participants found ethics board review as extremely challenging and very challenging
(14%, 4/28 and 7%, 2/28, respectively). “Lack of interest from investigators” was mostly viewed
as “slightly challenging” (36%, 10/28) and rated most commonly as “not challenging at all”
compared to the other provided choices. About 15-25% of the respondents could not answer these
questions.

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Figure 21: External Factors Contributing to Challenges in the Implementation of the
Pediatric Oncology Development Plan
How serious are the following types of challenges when implementing the pediatric oncology
drug/biologic development plan?

Note: Total of 28 responses for each listed element, except for “competing enrollment with trials
for drugs in the same class” with a total of 27 responses, and “Others” with 4 responses

Respondents were asked to rank by frequency the approaches to pediatric oncology drug
development that their organization has taken from 5 options, with 1 being most frequent to 5
being least. As shown in Table 18, respondents identified “full waiver request” approaches or
“orphan drug exemption” approaches as most frequent (10/25 and 8/25 respectively) (average
score of 2 and 2.7 on a scale of 1 to 5). “Full deferral post adult approval” also had a relatively
similar score (2.9) to that of orphan drug exemptions, but the distribution of answers related to
full deferrals was weighted toward intermediate rankings whereas the choices related to orphan

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product designations were more bimodal. Least frequent approaches included “written request in
the US” (3.5) and “early pediatric study in parallel with Phase 2 in adults” (3.8).
Table 18: Ranking of Frequency of Approaches Taken by Organizations for
Development Programs
Please rank by frequency the approaches that your current company/organization has taken with
regard to the approach in your oncology drug/biologic development programs (with 1 as the
most frequent approach, 5 as the least).
1
Most
Frequent
2 3 4 5
Least
Frequent
Preference
Rating
Full Waiver Request (n = 25) 10 8 3 4 0 2.0
Early Pediatric Study in Parallel
with Phase 2 in Adults (n = 25)
2 3 4 4 12 3.8
Full Deferral Post Adult
Approval (n = 25)
4 5 9 4 3 2.9
Orphan Drug Exemption in the
US (n = 25)
8 5 2 6 4 2.7
Written Request in the US
(n = 25)
1 4 7 7 6 3.5

Experience with FDA and EMA Interactions
Respondents were asked whether their organizations have proposed any of the four study design
elements encouraged by the health authorities in their pediatric development plan (Table 19).
Approximately one-third of respondents have proposed the inclusion of adolescents as part of the
adult program in either the US (36%, 16/44) or the EU (33%; 14/42) proposals. Relatively
common as well as the use of extrapolation, modeling, and simulation in both US and EU
proposals (30%, 13/44; 29%, 12/42 respectively). A smaller number of respondents used
real-world evidence as a comparator (US, 14%, 6/44; EU, 17%, 7/42) or the use of a master
protocol design (US, 18%, 8/44; EU, 21%, 9/42).

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Table 19: Experience in Inclusion of New Study Design Elements in Proposals to
Health Authorities
Has your company/organization proposed any of the following design elements in the pediatric
oncology drug/biologic development plan? If yes, please select all that are appropriate.
Proposal Included in US
(PSP/PPSR)
n=44
Proposal Included in EU
(PIP)
n=42
Inclusion of adolescents as
part of adult program
16 (36%) 14 (33%)
Master Protocol Design 8 (18%) 9 (21%)
Real World Evidence as
Comparator
6 (14%) 7 (17%)
Use of Extrapolation,
Modeling and Simulation
13 (30%) 12 (29%)
Other 1 (2%) 0
Text provided under “Other”
• Every early development program is different

As a follow-up question, respondents were asked to rate the degree to which health authorities
were receptive to the novel study design elements listed above (Figure 22 and Figure 23). The US
FDA appeared most receptive when respondents proposed the inclusion of adolescents as part of
the adult program (48%, 12/25 as very receptive and 36% and 9/25 as somewhat receptive) or
proposed the use of a master protocol approach (32%, 7/22 as very receptive and 32%, 7/22 as
somewhat receptive). On a scale of 1-3 from very receptive to not very receptive, “inclusion of
adolescents as part of adult program” and “master protocol design) had very similar average
scores, 1.4 and 1.5, respectively. No respondents selected “not very receptive”. The use of
“Extrapolation, Modeling and Simulation” was also somewhat acceptable to the US FDA (1.9)
with most respondents selecting “somewhat receptive” (43%, 12/28). “Using real world evidence
as comparator” elicited more mixed responses (average of 2.4) with only 5% of respondents

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(1/22) selecting “very respective”, 32% (7/22) as somewhat receptive and 27% (6/22) as not very
receptive. About 25-30% of the respondents selected “do not know”.
Figure 22: Receptivity of the US FDA to Novel Study Design Elements
From your experience, how receptive are the health authorities to the following design elements
for pediatric oncology PSP/PPSR/PIP?

Note: Total of 28 responses for “Inclusion of Adolescent as part of the adult program” and “Use
of Extrapolation, Modeling & Simulation”. Total of 22 respondents for “Master Protocol Design”
and “Real World Evidence as Comparator”. Three respondents selected “Other”.
One text statement provided under “Other”:
• “we have an orphan exemption in the US so do not have PSP obligations, however, at a
recent conference I spoke with an FDA official who endorsed our plans to include
children of any age in our pivotal study, which has no upper or lower age range. In
Europe, we are still in the midst of PIP negotiations, but they were fine with the approach
though of course they want to see a minimum number of pediatric subjects”
Overall, respondents considered the EMA to be less receptive than the FDA to most of the listed
selections (Figure 23), except for “use of extrapolation, modeling and simulation” (very
receptive: 22% (5/23); somewhat receptive: 45% (10/23). None selected “not very receptive”
(average score of 1.7). The EMA was identified to be very or somewhat receptive to “inclusion of
adolescents” [very receptive: 22% (5/23); somewhat receptive: 48% (11/23); average score of

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1.8]. When ranking “Master protocol design”, most respondents selected “somewhat receptive”
(45%, 9/20) but a few selected “very receptive” and “not very receptive” (2/20 each, 10%). More
respondents answered “do not know” (36%, 32/89) of all the answers when asked about the
experience with the EU than the US on these study design elements.
Figure 23: Receptivity of the EU CHMP to Novel Study Design Elements
From your experience, how receptive are the health authorities to the following design elements
for pediatric oncology PSP/PPSR/PIP?

Note: Total of 23 responses for “Inclusion of Adolescent as part of the adult program” and “Use
of Extrapolation, Modeling & Simulation”. There were 20 respondents for “Master Protocol
Design”, 21 respondents for “Real World Evidence as Comparator”. Two respondents selected
“Other” but no details were provided.

The respondents were asked to share their levels of satisfaction with the current mechanisms to
obtain feedback about their development plans from the US FDA and/or EU PDCO (Table 20).
More than half of those who offered an assessment were satisfied with each of the 4 listed
mechanisms from the US FDA. With respect to the “Initial Pediatric Study Plan”, 63% (17/27)
were satisfied, 15% (4/27) had a neutral view and 11 % (3/27) were dissatisfied. The rest could
not answer. With respect to “US Pediatric Study Plan Amendments”, 56% (14/25) were satisfied,

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12% (3/25) were neither satisfied nor dissatisfied and 16% (4/25) were dissatisfied. With respect
to “US Written Request Amendments”, 52% (14/27) selected “satisfied”, 30% (8/27) selected
“neither satisfied nor dissatisfied” and only 1 respondent (4%) selected “dissatisfied”. With
respect to “US Proposed Pediatric Study Plan”, 50% (13/26) selected “satisfied”, 23% (6/26)
selected “neither satisfied nor dissatisfied”, and 11% (3/26) selected “dissatisfied”. A somewhat
different experience was typical for the EU PDCO process. Only approximately 30% (8/27) of
respondents were satisfied with the PIP and PIP modification processes, compared to 41%
(11/27) who were neither satisfied or dissatisfied and 19% (5/27) who were dissatisfied.

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Table 20: Satisfaction with Current Mechanisms for Development Plan Feedback
from the US FDA and/or EU PDCO
From your experience, how satisfied are you with the mechanism in obtaining feedback from the
US FDA and/or EU PDCO about pediatric oncology drug/biologic development plan?
Notes from respondents:
• The CHMP SCA Working Party was not on the listed mechanism – their input on
paediatric programs is more important than PDCO
• All have been orphan, so no FDA interaction
* “Cannot Comment” removed in the preference scale
Satisfied Neither
Satisfied
nor
Dissatisfied
Dissatisfied Cannot
Comment
Total Preference
Rating*
US FDA on
initial Pediatric
Study Plan
(iPSP)
17 (63%) 4 (15%) 3 (11%) 3 (11%) 27 1.4
US FDA on PSP
Amendment
14 (56%) 3 (12%) 4 (16%) 4 (16%) 25 1.5
US FDA on
Proposed
Pediatric Study
Plan (PPSR)
13 (50%) 6 (23%) 3 (11%) 4 (15%) 26 1.6
US FDA on
Written
Request (WR)
Amendment
14 (52%) 8 (30%) 1 (4%) 4 (15%) 27 1.4
EU PDCO on
Paediatric
Investigational
Plan (PIP)
8 (30%) 11 (41%) 5 (19%) 4 (15%) 27 1.9
EU PDCO on PIP
Modification
7 (26%) 11 (41%) 5 (19%) 4 (15%) 27 1.9
Other 0 0 0 5 (100%) 5 3

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Respondents were also asked to share the approaches that they have taken regarding the timing of
PSP and PIP coordination (Figure 24). The most common approach taken by the companies was
to obtain the PIP first and the PSP/PPSR second as reflected by the fact that more respondents
selected this sequence was the approach that was always (18%, 5/27) or sometimes taken (59%,
16/27). Somewhat less frequently taken was the approach in which the PIP and PSP were pursued
in parallel but not under the Parallel Scientific Advice pathway (always taken: 7%, 2/27;
sometimes taken: 52%, 14/27; never: 26%, 7/27). Companies pursued PIP and PSP submission
under parallel advice much less frequently. Three (11%) respondents selected “always” and 5
(8%) selected “sometimes”, but most selected “never” (52%, 14/27). This pattern of frequency
was consistent with that assessed by examining the preference rating using a 3-point scale. The
selection, “obtained PIP agreement followed by PSP/PPSR” had an average score of 1.9,
compared to “pursued PIP/PSP in parallel but not under Parallel Scientific Advice” (2.2), and
“Parallel Scientific Advice” (2.5). About 20% of respondents selected “do not know” to the
offered choices.

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Figure 24: Respondents’ Experience on Timing of PSP and PIP Coordination
Regarding timing of PSP and PIP coordination for pediatric oncology drug/biologic planning,
how often have you taken the following approaches?

Note: Total of 27 responses for each field except for 3 responses under “Other”.
Text input under “Other”:
• All have been orphan, so no FDA interaction

Respondents were asked to share the issues of challenge/disagreement that they had experienced
during their discussions with the FDA on the proposed pediatric development plan from a list of 7
options (Table 21). This was measured by assessing if more than one round of discussion is
required on any specific elements in the study design. Based on the feedback, the elements that
required more than one discussion were age group inclusion and dosing (48%, 12/25 and 46%,
12/26 respectively). More mixed experiences were evident for the timing of the study (46%,
12/26, agreement in initial discussion vs. 38%, 10/26, requiring more than one discussion); safety
follow-up (50%, 13/26 vs. 38%, 10/26); formulation development (35%, 9/26 vs. 38%, 10/26);
and pediatric study endpoints (same percentage: 42%, 11/26). “Animal study planning

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agreement” was least likely to require more than one discussion (50%, 13/26 agreement in initial
discussion vs. 27%, 7/26 requiring more than one discussion). About12% to 27% of respondents
could not comment on various elements presented in this question.
Table 21: Experience Regarding FDA Discussions on Selected Topics Related to
Pediatric Development Plans
What have been the areas of challenging or disagreement during the review of the proposed
pediatric oncology development plan (PSP/PPSR or PIP) with health authorities? Select all that
apply.
Reach
Agreement in
Initial
Discussion
Require More
Than One
Discussion
Cannot
Comment
Total
Timing of Study 12 (46%) 10 (38%) 4 (15%) 26
Dosing 9 (35%) 12 (46%) 5 (19%) 26
Age Group Inclusion 7 (28%) 12 (48%) 6 (24%) 25
Formulation
Development
9 (35%) 10 (38%) 7 (27%) 26
Animal Study Planning 13 (50%) 7 (27%) 6 (23%) 26
Pediatric Study
Endpoints
11 (42%) 11 (42%) 4 (15%) 26
Safety Follow-up 13 (50%) 10 (38%) 3 (12%) 26
Others 0 1 (20%) 4 (80%) 5

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A similar question was asked regarding respondents’ experience with discussions with the EMA
(Table 22). Based on the feedback, most of the study plan elements required more than one
discussion than reaching agreement in first round, i.e. “dosing” (32%, 7/22 vs. 41%, 9/22), “age
group inclusion” (29%, 7/24 vs. 41%, 10/24), and “animal study planning” (29%, 7/24 vs. 28%,
9/24). There were more respondents (25-38%) selected cannot comment than the previous
question on the US FDA experience. A relatively even split was seen for most topics between the
need for one discussion versus multiple discussions, including “timing of study” (33%, 8/24 vs.
27%, 9/24), “formulation development” (29%, 7/24 vs. 33%, 8/24), “pediatric study endpoints”
(25%, 8/23 vs. 39%, 9/23), but the topic “safety follow-up” more frequently required only one
discussion (46%, 11/24) .

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Table 22: Experience Regarding EMA Discussions on Selected Topics Related to
Pediatric Development Plans
What have been the areas of challenge or disagreement during the review of the proposed
pediatric oncology development plan (PSP/PPSR or PIP) with health authorities? Select all that
apply.
Reach
Agreement in
Initial
Discussion
Require More
Than One
Discussion
Cannot
Comment
Total
Timing of Study 8 (33%) 9 (37%) 7 (29%) 24
Dosing 7 (32%) 9 (41%) 6 (27%) 22
Age Group Inclusion 7 (29%) 10 (41%) 7 (29%) 24
Formulation
Development
7 (29%) 8 (33%) 9 (38%) 24
Animal Study Planning 7 (29%) 9 (38%) 9 (33%) 24
Pediatric Study
Endpoints
8 (35%) 9 (39%) 6 (26%) 23
Safety Follow-up 11 (46%) 7 (29%) 6 (25%) 24
Others* 1 (14%) 2 (28%) 4 (57%) 7
*Note from respondents:
• Scope of PIP condition/indication
• minimum number of pediatric subjects for study
• Patient Population, Go/No-Go criteria

Respondents were asked if they were able to reach an agreement with the FDA on a proposed
pediatric study plan (PPSR) for their pediatric oncology drug/biologic program within the
estimated timeframe (Figure 25). About two-thirds (66%, 18/27) of respondents identified that

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they were able to reach agreement within the estimated timeframe, only four respondents reported
that they could not, and five could not answer.
Figure 25: Experience in Reaching Agreement on PPSR with the FDA within the
Estimated Timeframe (N=27)
Based on your experience, have you been able to reach agreement with the FDA on the Proposed
Pediatric Study Plan (PPSR) in your pediatric oncology drug/biologic program within the
estimated timeframe?

Respondents were also asked whether delays have occurred in the initiation of a pediatric
oncology study that could be attributed to challenges in reaching an agreement on pediatric study
design with the US FDA or the EU PDCO (Figure 26). About one-third of respondents (33%,
9/27) reported no such delay. Amongst the respondents who had experienced delays, 4% (1/27)
were delayed by less than 3 months, 15% (4/27) between 3 to 6 months, and 22% (6/27) between
6 to 12 months of delay. Seven respondents were not able to answer this question.

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Figure 26: Experience on Timing and Delay in Reaching Agreement with the US FDA
or the EU PDCO
Based on your experience, has there been delay in the initiation of a pediatric oncology study due
to reaching agreement with the US FDA or the EU PDCO on pediatric study design elements? If
yes, please estimate the delay.

Respondents were asked if their organizations had received any pediatric reward/incentives
associated with their oncology drug/biologic development program (Figure 27). Only a few
respondents (11%; 3/26) had received a rare pediatric disease priority review voucher. About a
quarter of the respondents had received either a 6-month pediatric exclusivity/extension from the
FDA or from the EMA (26%, 7/27 for each). Most respondents received no pediatric
rewards/incentives, especially the rare pediatric disease priority review voucher (81%, 21/26).

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Figure 27: Experience in Receiving Pediatric Rewards/Incentives
Has the company/organization received the following for an oncology drug/biologic program?

In follow-up questions, respondents were asked why they did not receive a 6-month pediatric
exclusivity from the US FDA (Table 23) or a 6-month extension to SPC from the EU CHMP
(Table 24). The majority of the reasons (35%, 8/23 and a few reasons under “others” 30%, 7/23)
was because the company did not or has not submitted a PPSR, followed by Written Request
terms were not met (22%, 5/23). In the EU, as it is a requirement for PIP unlike the PPSR as
voluntarily, the most selected reason for not receiving the 6 months pediatric extension was the
timing of PIP completion (47%, 9/19), followed by “others” (42%, 8/19).

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Table 23: Reasons for Not Receiving 6-Months Pediatric Exclusivity from the US FDA
In your most recent experiences, if the organization has not received 6-months of pediatric
exclusivity from the US FDA on a pediatric oncology program, please select one of the following:
Reasons Total (N=23)
Did not submit a PPSR 8 (35%)
Submitted a PPSR, not received a Written Request 3 (13%)
Received a Written Request, not meeting terms in the
Written Request
5 (22%)
Others
• Did not apply for one
• We have not yet submitted
• In process of receiving WR
• Not completed yet and not meaningful for biologic
anyway
• Study ongoing
7 (30%)
Table 24: Reasons for Not Receiving 6-Months Pediatric Extension from EU CHMP
In your most recent experience, if the organization has not received the 6-months extension to
SPC with the completion of an agreed PIP on a pediatric oncology program, please select one of
the following reasons for not receiving the extension:
Reasons Total (N=19)
Timing of PIP completion 9 (47%)
Not meeting study elements in agreed PIP, other than the timing 1 (5%)
Non-compliant PIP as determined by PDCO 1 (5%)
Others
• Study ongoing
• Did not apply for one
• The SPC was already expired at the time of PIP
completion
• We have not yet submitted
• In progress
8 (42%)

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Respondents were asked about their organization’s view of the adequacy of the current incentives
(Table 25). When applying a weighted average using a 5-point scale (extremely adequate to
extremely inadequate), all listed US incentives had scores of about 2.0. Pediatric rare disease
priority voucher was viewed as marginally more adequate (average of 1.9; 30%, 8/27 extremely
adequate; 41%, 11/27 somewhat adequate, 22%, 6/27 neither adequate nor inadequate, and none
for somewhat or extremely inadequate) than the EU’s 2-year pediatric extension of orphan market
exclusivity (2.1), the 6-month exclusivity in the US (2.3 and 2.1 for orphan drug with small
market potential) and SPC extension in the EU (2.2). Only a small percentage (7-11%) of
respondents selected “do not know”.

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Table 25: Industry’s Perspective on Adequacy of Current Incentives for Pediatric
Oncology Drug Development
Does your organization view the current regulation as adequate in providing incentives to
stimulate pediatric oncology drug/biologic development?
Extremely
Adequate
Somewhat
Adequate
Neither
Adequate nor
Inadequate
Somewhat
Inadequate
Extremely
Inadequate
Do
not
know
Total
BPCA: 6-
months
Pediatric
Exclusivity
3 (11%) 17 (63%) 1 (4%) 3 (11%) 1 (4%) 2 (7%) 27
BPCA for
Orphan
Drug with
small
market
potential
5 (19%) 14 (52%) 3 (11%) 1 (4%) 1 (4%) 3 (11%) 27
Pediatric
Rare
Disease
Priority
Voucher
8 (30%) 11 (41%) 6 (22%) 0 0 2 (7%) 27
EU: 6-
months
SPC
Extension
3 (11%) 17 (63%) 0 3 (11%) 1 (4%) 3 (11%) 27
EU: 2-
years
Pediatric
Extension
of Orphan
Market
Exclusivity
5 (19%) 16 (60%) 0 2 (7%) 1 (4%) 3 (11%) 27

Respondents were also asked for their opinions on the key drivers to advance early pediatric
oncology drug development from a list of previously suggested drivers (Table 26). Using
weighted average for a 5-point scale from “extremely important” to “not at all important”,

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“harmonization of pediatric development plan across the FDA and PDCO” appeared to be the
most important factor overall (average of 1.7, with 63% (17/27) extremely important, 26% (6/27)
very important, and only 11% (3/27) as not at all important). It was followed by “a longer
exclusivity extension” (average of 2.0, with 37% (10/27) extremely important and very important
each, and none for not at all important) and “better knowledge to decrease high rate of failure”
(average of 2.0 with 40% (10/25) extremely important and very important each, 8% (2/25) as
moderately or slightly important each). “Cooperative efforts related to disease-specific working
groups” and “additional funding structure and partnerships” were also rated as very important
factors (average of 2.4 and 2.7, respectively), with more respondents selecting very important
(31-41%) versus slightly important. The least selected as important was “additional and specific
guidance” (average of 3.6, with only 1 respondent (10%) viewed this as extremely/very important
and most (40%, 4/10) noted this was not important at all.

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Table 26: Respondents’ Opinion on Key Drivers to Advance Early Pediatric Oncology Drug Development
In your opinion, what would be the key drivers to advance early pediatric oncology drug/biologic development?
Extremely
Important
Very
Important
Moderately
Important
Slightly
Important
Not at all
Important
Total Average
Score
Longer Exclusivity Extension 10 (37%) 10 (37%) 5 (18%) 2(7%) 0 27 2.0
Harmonization of Pediatric Study Plan
between US FDA and EU PDCO
17 (63%) 6 (26%) 1 (4%) 0 3 (11%) 27 1.7
Additional and Specific Guidance 1 (10%) 1 (10%) 3 (30%) 1 (1%) 4 (40%) 10 3.6
Disease Specific Working Groups with HAs,
Academies, and Industry
5 (19%) 11 (42%) 6 (23%) 3 (12%) 1 (4%) 26 2.4
Additional Funding Structure and Partnership 5 (19%) 8 (31%) 5 (19%) 6 (23%) 3 (12%) 26 2.7
Better Knowledge to Decrease High Rate of
Failure
10 (40%) 10 (40%) 2 (8%) 2 (8%) 1 (4%) 25 2.0
Other Incentives

1 (25%) 1 (25%) 1 (25%) 0 2 (40%) 5 3.2
Other 1 (25%) 1 (25%) 0 0 3 (60%) 5 3.6
Notes from respondents under “Other”
• Linked to driving innovative development
• Efficient trial design (platform trials/master protocols)

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At the end of the survey, respondents were given the opportunity to expand on what they believed
to be the key drivers to increase stand-alone programs specific for pediatric patients (Table 27).
Their multiple answers have a few themes: incentives for industry to compensate risks and
financial investment; appropriate clinical trial structure globally across partnerships; and
increased understanding of pediatric disease biology and science-driven study designs.
Table 27: Respondents’ Opinion on Key Drivers to Increase Pediatric Stand-Alone
Programs Specific for Pediatric Cancers
In your opinion, what would be the key drivers to increase pediatric stand-alone programs
specific for pediatric cancers?
They are not very relevant in the new area of targeted medicines and immune-oncology
For my company, we do this as it is essential to our mission. For other companies, it seems that
regulatory requirements are the only solution.
No comments – not aware
No application fee. Longer exclusivity. Use of novel study designs and surrogate endpoints.
More incentive to encourage companies to invest in pediatric research
A platform that evaluates scientific merit and relevancy of conducting the trial in a pediatric
population. If relevancy exists, then pediatrics should be introduced into the adult studies in a
stepwise manner (soon after relative safety is established in adults).
More focus on understanding pediatric disease biology and biomarkers (translational science)
rather than attempting to translate adult targets/data to pediatric disease.
Developing an appropriate clinical trial infrastructure (cooperative groups, industry,
investigators) to support the efficient design and conduct of trials with novel agents and
combinations (platform trials, umbrella and basket studies).
Connecting the regulators to the real-life challenges of conducting pediatric development and
setting pragmatic regulatory expectations that take into account data that has been generated
across a class of agents (meta-analyses), real work evidence and various sources of data
generation/exploration (investigator sponsored trials).
More incentives for the organization
Management/market drivers for the pediatric indication; absent market driver, more regulation
to mandate with incentives
While additional incentives would likely work, the bigger question is around understanding the
safety profile sufficiently in the absence of adult data and ethical issues

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In Europe, studies with children need to be reviewed by pediatric ECs, which adds a lot of
complexity to the inclusion of adolescents in adult trials.
A market driver – commercially there is limited to no real potential for ROI

Respondents were also asked if certain experiences with pediatric oncology programs were not
captured fully in this survey (Table 28). This question elicited only two responses:
Table 28: Other Experience with Pediatric Oncology Development Programs
Do you have certain experience with pediatric programs that we have not explored fully in the
survey above? If yes, we would value your additional comments.
Collaborating with NCI CTEP is helpful
While these studies are difficult, we just need to initiate, help patients, learn and re-adjust. We
have a shared responsibility with regulators and academia to address grievous diseases.

Exploratory: Cross Tabulations by Size of Organizations
To understand if the experience of respondents differs in relation to the size of the organization
with which they were associated, the size of the company (1-500 employees;501-2,500
employees; 2,501-10,000 employees; and 10,001+ employees) was cross-tabulated with
responses with other questions. Typically, no major differences appeared to be associated with
the size of the company with which respondents were associated. However, a few instances where
such relationships may exist are described below. Because the number of respondents in each size
category was small, results should be reviewed with caution.
Implementation Within the Organization: In your company/organization, how is the pediatric
team organized to support oncology drug/biologic development?

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As might be expected, larger companies more typically had dedicated resources and experts for
pediatric programs, particularly in clinical development and clinical pharmacology development
(Table E.1 in Appendix E). The largest companies (10,001+ employees) also appeared to have
dedicated resources in other areas, including regulatory affairs and translational medicine.
Experience in Pediatric Programs: What would best describe the challenges your team has
encountered within the organization?
The types and ratings of challenges were generally similar in companies of different sizes.
However, the largest companies typically appeared to have more support from management,
better internal expertise, and a better understanding of pediatric programs (Table E.2 in
Appendix E)
Long-term Implementation: Does your organization view the current regulation as adequate in
providing incentives to stimulate pediatric oncology drug/biologic development?
Most respondents from companies of large size (10,000+ employees) noted the existing US
pediatric incentives (6-months pediatric exclusivity and Pediatric Rare Disease Priority Voucher)
as extremely or somewhat adequate. Half of the respondents of small companies
(1-500 employees) rated the existing 6-month pediatric exclusivity as somewhat inadequate or
extremely inadequate (Table E.3 in Appendix E).

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CHAPTER 5. DISCUSSION
The regulatory requirements for pediatric oncolytic drugs have evolved and continue to evolve,
even as this research project has progressed. As might be expected in a time of change,
considerable variation appears to be present in the ways that companies interpret and implement
regulatory recommendations into their pediatric programs. Their activities are particularly
important to understand because the current status quo is not seen to be adequate by many
stakeholders, such as academic and patient-advocacy groups. Those groups question why
pediatric studies are often delayed until one or more adult clinical trials have been carried out or
even until the drug has been marketed for adults. They argue that such delays deny children of
potentially effective new therapies and contribute to their unsafe use in the absence of pediatric
dosing and safety information. This study provides a more systematic analysis of industry’s views
with regard to incentives and challenges, including insights into their experiences when
interacting with health authorities and attempting to implement pediatric trials operationally. It
also provides information on the industry perspective related to the effectiveness of incentives to
stimulate pediatric oncology drug/biologic development.
Methodological Considerations
Delimitations
This research was delimited to regulatory and clinical professionals with experiences in pediatric
oncology drug and biologic development. Pediatric oncology has the special challenge that
pediatric cancers are most often dissimilar to cancers found in adults. Thus, it was important to
choose a homogeneous pool of respondents with experience in pediatric oncology development,

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so that the research could focus more specifically on experiences with FDA and EMA pediatric
processes.
The scope of this research was delimited to regulatory professionals in industry. The views of
other stakeholders, such as health authorities, investigators, or patient advocacy groups, are likely
to differ for the reasons outlined in Chapter 2. The research was also delimited to the examination
of experiences in two regulatory systems, those of the US and EU. The specialized group of
respondents surveyed here may also have had experience in other countries that were not studied
in this research. However, it is likely that those experiences will differ in some respects because
the foreign health authorities often interact with companies according to different conventions
(Thomsen, 2019). This could complicate the analysis. Further, it is likely that fewer of the
respondents would have sufficient information about these other regulatory regimes to provide a
sufficient picture of issues and implementation there. Regulatory interactions in other countries
are often conducted by local regulatory experts who have the linguistic and cultural capabilities to
operate more effectively in that specialized system. Even when comparing only two economies in
this study, it seemed that the level of expertise for each system was not identical. More
individuals in the respondent pool appeared to consider themselves to be knowledgeable or very
knowledgeable with regard to FDA regulations and submission practices than with EU practices,
despite the fact that these two markets often receive submissions for market approval for a single
product at or close to the same time (Downing et al., 2012).
This survey also focused on the regulatory environment in place as of Jan 2019 and thus will
reflect industry’s experience and thinking at that time. Since that time, additional guidance
documents (i.e. “Considerations for the Inclusion of Adolescent Patients in Adult Oncology
Clinical Trials Guidance for Industry – March 2019”; “Cancer Clinical Trial Eligibility Criteria:

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Minimum Age for Pediatric Patients; Draft Guidance for Industry – March 2019”) have been
issued. For this reason, the results presented here must be interpreted in light of the practices prior
to 2019; practices and opinions may change with the changing regulatory climate.
Limitations
This research was conducted using an online survey, an approach known to have certain potential
limitations. For this research, the most important of these potential limitations were seen to be the
availability of representative participants and the validity/reliability of the survey method.
5.1.2.1 Availability of Representative Participants
Survey validity is driven by the number and representativeness of its respondents (Fincham,
2008). Perhaps the largest potential limitation, then, was to assure the participation of a sufficient
number of engaged respondents who have had pediatric oncology drug/biologic experience. The
number of experienced clinical and regulatory professionals with such experience is relatively
small. Identifying appropriate regulatory and clinical professionals was particularly challenging
because they are not listed in a centralized database or registry from which their contacts could be
obtained. I, therefore, had to use a number of different methods to find experienced participants.
As a starting point to identify individuals with such specific experience, names were collected by
first collating the names of companies with pediatric oncology studies posted on clinicaltrials.gov
(a total of 54 as of 30 Apr 2019) or were correspondents on oncology drugs approved with a
pediatric indication (see Chapter 2). This approach was relatively unsuccessful because only a
small number of names could be identified using this process, and because the contact
information for those individuals was not listed. To locate contact information, the next step was
to invite, via the professional networking platform, LinkedIn, the regulatory and clinical
representatives from companies identified in those first searches. Additional sources, such as

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industry working groups or individuals known to me or my colleagues, were also added to the
roster of those approached to participate. To assure that only experienced participants were
included, a question at the beginning of the survey was used to filter out participants unfamiliar
with US or EU pediatric requirements. Thus, even though only 113 potential participants from
about 65 companies were approached, this group of individuals probably represented a significant
fraction of those working in the pediatric oncology field. Of those individuals, 46 (41%)
completed the survey. This response rate falls within a range of response rates typically
considered as reasonable for academic studies. For example, Baruch reported that studies
involving top management/organizational representatives had an average response rate of 36.1%,
with a standard deviation of 13.3 (Baruch, 1999). By identifying the companies to be approached,
it was possible to ensure that the search was relatively wide-ranging and inclusive across
companies, thus improving the representativeness and external validity of the results (Devroe,
2016).
Of those who responded, a majority were at the level of Director or above in regulatory or clinical
positions, suggesting that the responses were obtained from appropriate individuals at a level
sufficiently senior to have a good overall picture of the regulatory environment and its impact on
pediatric development plans. Although the sample size was too small to support sophisticated
statistical comparisons, the spread of responses from participants in companies of different sizes
suggested that a reasonable cross-section of the industry was engaged. Even though the variety of
companies might have been considered to introduce some degree of heterogeneity, cross-
tabulation of results for companies of different sizes yielded no apparent trends in views or
experiences, suggesting that the size of the company had little impact on the experience of the
practitioners (Section 4.5).

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5.1.2.2 Survey Methodology
There are advantages and drawbacks to the use of an online survey. Electronic dissemination is
convenient for the researcher because it ensured that all participants received the survey at a
specified point in time. In a field where regulations may be changing, such an approach would
reduce the variation that might be encountered if some respondents completed the survey before
an important regulation had changed whereas others completed it after. Electronic surveys are
also convenient for participants who can complete the survey at their own pace without having to
pick up documents at a particular street address and then mail the documents back. Convenience
was considered to be a particularly important consideration for busy professionals who are often
traveling because electronic surveys can be accessed at any location (Fincham, 2008).
In the past, electronic approaches have been criticized because they may deny access to
individuals who are uncomfortable with computerized documents. However, the types of
regulatory personnel in this study are likely to be well experienced with computerized approaches
to documentation and are required to submit drug applications in electronic format (FDA, 2019).
Thus, the electronic systems were seen to be better suited to this study than paper-based methods
to improve participation and thus external validity.
The designs of survey tools, as opposed, for example, to interview methods, can impose
limitations related to the numbers and format of questions that can reasonably be presented to the
respondents (Galesic & Bosnjak, 2009). A busy professional may fail to participate in a survey if
it is too lengthy (Galesic & Bosnjak, 2009). The draft survey for this research had 46 questions,
but some of these questions were combined or streamlined based on the advice of the focus
group. The fact that most respondents completed the survey suggests that the questions were not
too numerous. It is possible that it also reflects a high level of interest and engagement in this

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topic because it links directly to the professional experiences and concerns of the respondents.
However, by limiting the number of questions, certain topics could not be explored in any depth.
To reduce the likelihood that questions were focused too narrowly or were biased, a question was
included at the end of the survey to offer respondents the opportunity to address issues or topics
that might not have been covered sufficiently. Only two participants provided text responses, but
both noted that “collaborations” could be another topic to assess further if additional research
were to follow.
Consideration of Results
The present research attempted to answer the question, “Are the current regulatory and incentive
structures and support systems sufficient to stimulate and accelerate pediatric oncology drug
development?”. To systematize the research, a conceptual framework articulated by Bertram
(Bertram et al., 2014) was used to assess industry experiences at different stages of development
from conceptualizing the development strategy to planning and executing it. This framework
recognizes that implementing a program of any kind will typically involve stages. In this
discussion, the use of the framework helped to separate the experiences and challenges associated
with three specific stages- exploration, installation, and implementation.
From Exploration to Installation
5.2.1.1 Obtaining Information about Regulatory Requirements
The first stage of developing a pediatric strategy for any company would typically be to educate
the involved team members about the current regulatory and clinical considerations inherent to
pediatric oncology. Typically, it begins by consulting several types of educational materials,
including regulatory documents, materials documenting the experiences of precedent products,

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and other sources of input such as presentations at meetings or writings in trade journals. Of some
interest then were the opinions of the surveyed participants regarding not only the sources of
information that they consulted but also the perceived usefulness of those materials. It was clear
from their responses that companies were educating themselves broadly from not only the
regulations themselves but also guidance documents and associated FDA-published materials. It
was perhaps not surprising that almost all companies operating in the US used the draft guidance
on pediatric study plans all or most of the time, given that this guidance so directly addresses the
planning phase, compared, for example, to the guidance on labeling, which might be more
relevant at later stages of the program. In addition, US templates for PSPs and WRs were
consulted with the highest frequency. The key document consulted for PIPs in the EU was
comparable guidance on formatting and content of a pediatric plan. Thus, the most frequently
consulted guidance documents seem to be administrative in nature, focusing on formatting a
submission and completing the templates to support the adult marketing applications. Guidance
documents focusing on pediatric strategy, i.e. expansion of inclusion criteria to younger age
group, qualifying for pediatric exclusivity (BPCA), or obtaining a rare pediatric disease priority
review voucher, appeared to be resources seldom or never assessed by many survey respondents
at the exploration phase. However, some of the programs described in these less-consulted
guidance documents identify important incentives that could affect a go-no-go decision about the
timing and structure of a pediatric program. The fact that they were less commonly consulted
may support the often-advanced view that pediatric oncology planning is regarded by many
companies as a pro forma activity ancillary to their adult programs rather than a program with
potential strategic significance (Angelini, 2013).
A particularly interesting observation was the less frequent use of the “Rare Pediatric Disease
Priority Review Voucher” guidance in the US than might be expected. Given that cancer is rare in

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pediatric patients, one would expect that all companies would want to consider the business
aspects of seeking this kind of incentive and assessing the feasibility of embedding this goal early
into their strategies, even before commencing the clinical trials. Perhaps part of the reason relates
to the relatively limited experience with these voucher programs to date. In 2016, a GAO report
assessing the effectiveness of FDA’s pediatric voucher program (GAO, 2016) concluded that too
little time had passed (the program was only 3 years old at the time) to evaluate its effectiveness.
Most pediatric development programs will take more than 10 years to reach regulatory approval.
Our findings are consistent also with the evidence of others that voucher programs have not
provided sufficiently strong incentives for the development of pediatric drugs, at least for those
already advanced in the pipeline. For example, Hwang (Hwang et al., 2019) concluded, in a
study of clinical protocols listed in two commercial pharmaceutical research databases between
2008 to 2015, that the introduction of the voucher program had not caused rarer pediatric disease
treatments to move into the clinical development phase. These results are surprising because the
voucher program can be valuable. Vouchers are transferrable and can be sold at high prices to
other companies; four of the six pediatric vouchers awarded to date have been sold for prices
ranging from $67.5 million to $350 million (GAO, 2016). However, the decision to adopt this
strategy into an overall pediatric program must be taken early because specific upfront
nonclinical and clinical activities are required to support an original pediatric product application
that does not seek approval for an adult indication. It would be of interest to explore in the future
why these incentive programs are not considered by some companies and whether additional
guidance is required to encourage the use of this mechanism further.
Were the consulted documents sufficiently clear for the experts in this study? Most clear
appeared to be materials dealing with the timing of different requirements and incentive
structures. These elements are discussed using direct language several times throughout the

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regulations and guidance documents in both the EU and the US. Less clear appeared to be the
specific requirements and details needed to formulate a product-specific plan. One reason why
the requirements and expectations are less clear for product-specific submissions, however, is
probably because these rules are not generic, but rather can change according to differences in
preliminary safety concerns related to the product under consideration and the needs and severity
of the disease being studied. The need for more information on specific elements of a product
specific-plan may in part explain why health authorities have had to hold multiple public
workshops with specific industry groups. The FDA also conducted product-specific advisory
committee meetings to clarify expectations related to the use of modeling and simulation,
extrapolation, and master protocol study design. One example is the public discussion of the
atezolizumab pediatric development strategy held at the Advisory Committee in 2016 (FDA,
2016a). In that meeting, FDA advocated the use of a master protocol design based on mechanism
of action in the pediatric population across a range of age groups and cancer types.
What other method might educate regulatory teams as they explore the development of a pediatric
program? One way that has been identified anecdotally is enhancing public access to informative
information such as the study designs of similar drugs that have been shared with the health
authorities and/or the experiences of relevant precedents (FDA, 2017a). From the results here,
most regulatory departments seem already to be using the publicly available information
accessible to them when preparing a pediatric study plan. However, the FDA publishes many
potentially useful documents only after pediatric exclusivity is granted. Most respondents would
prefer the FDA to provide those documents for public access earlier in the regulatory approval
cycle. Their reports on experience with comparable EU documents suggest that the precedent
protocols published in the EU before product approval helped them to clarify the scope of
requirements acceptable by the PDCO. Nevertheless, a significant minority of companies did not

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support such release. When asked to explain their reluctance, main concerns centered on the
release of competitive and proprietary information, particularly for companies developing first-in-
class therapies. For those companies, details contained in a pediatric plan are usually tied to a
highly confidential overall development program. Their views are consistent with comments
previously raised in a public forum (FOCR, 2018), in which concerns were voiced about releasing
such information for first and second-in-class therapeutics because that release would put them at
a competitive disadvantage. The first-in-class company might be required to do pediatric studies
as a requirement of approval, but once the results of those studies are published, follow-on
products in the same class might be able to use their results to gain exemption from performing
similar studies. The concern is underlined by the frequently discussed experience with approvals
of immune checkpoint inhibitors PD-L1 products. In that case, the fact that three PD-1/PD-L1
products have now been approved may open the door for the seven or more follow-on products in
clinical development to apply for waivers. Those follow-on companies can argue that compounds
with the same mechanism of action have already been studied extensively in pediatric patients
and thus meet the waiver condition, “the medicinal product is not expected to represent a
significant therapeutic benefit over existing treatments for pediatric patients” (ACCELERATE,
2018).
From Installation to Implementation
The installation phase has a few key activities, including the formation of a pediatric development
team, the allocation of resources and the provision of management support. Results suggest here
that companies typically develop teams that draw on several different functional groups, a finding
that is consistent with approaches for other kinds of submissions (McNeely, 2019). What does
seem to differ, however, is the extent to which these teams have other responsibilities, usually in

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the adult programs for the same types of products. It was predictable, perhaps, that the members
of the team would have different levels of commitment to the pediatric program. Results suggest
that staff members from clinical development departments are more likely to be dedicated to the
pediatric program. This might be explained by the fact that the design and execution of such
clinical trials are time-intensive and likely to require specific expertise in trial conduct for both
the therapeutic area and the pediatric population. In contrast, other functional areas with more
modest contributions to the overall program more typically support both the adult and pediatric
programs.
It was interesting to compare the nature of team organization in small and large companies by
substratifying the responses of companies according to size. More large than medium/ small
companies identified that they had clinical and regulatory affairs personnel dedicated to pediatric
drug development activities. One likely interpretation is that the larger companies have more such
products in their portfolios and more resources to expend on their pediatric programs. However,
companies without a dedicated group could be more vulnerable to delays in pediatric
development, considering that respondents on average regarded competition for resources and
limited internal expertise in pediatric clinical science as the top challenges for their pediatric
programs. The fact that teams in many companies are drawn from personnel who are participants
in other adult programs would seem to create a situation in which team members are pulled in
different competing directions. The use of such a matrixed organization is well-known to
introduce challenges of competition for the time and energy of the team members (Davis, 1978).
This could threaten the efficient completion of the pediatric development program. About one-
quarter of the participants identified that the pediatric requirements affected the timelines and
planning of other programs. Nevertheless, most companies across company sizes, with or without
dedicated pediatric clinical resources, had no such delays. Perhaps the challenges associated with

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having competing responsibilities are offset by the learnings that come from having a broader
view of the overall strategy for the development of both adult and pediatric populations.
Alternatively, it may be that the installation stage involves only a few activities that can be slotted
easily into the overall responsibilities of the various team members. This would be particularly
the case if the company is considering to apply for a waiver or exemption for the pediatric clinical
trials. Results suggest that a full waiver request or orphan drug exemption continues to be the
most frequent approach to satisfy regulatory requirements in the US currently. In such a case, the
pediatric program might not have to progress to the installation phase, at least until the adult
product is approved and marketed, as commonly acknowledged in other literature (Bourgeois,
2019). However, reliance on such exemptions may be less common in future, because by August
2020, the RACE for Children Act ends an exemption from PREA requirements for cancer drugs
that have orphan status. That change will force many companies to make early plans for a robust
pediatric trial. Although the requirement is not yet in force, individual sponsors that expect to file
new drug/biologic applications in 2020 have already started to approach the FDA to clarify their
path forward (Sutter, 2019). In future, it will be useful to explore how companies approach these
early implementations and whether failure to plan early will result in delay for the adult
registration program.
Two positive findings were notable during this early implementation phase. First, gaining
support from management for the pediatric program was not seen to be problematic for most
companies, compared for example, to the challenges that they face when competing for resources
with other programs or finding internal expertise for such pediatric trials. Second, most
companies, regardless of size, appear to be incorporating pediatric strategy and assigning
resources within the company itself, instead of relying on ad hoc consultants. The reliance on

135
internal expertise may be challenging for some companies if companies have limited internal
expertise related to pediatric trials. One way to improve the level of expertise in a company is by
using consultants. Others who have studied various types of regulatory activities have reported
that external consultants are commonly utilized in the installation stage and identified to be useful
for short-term programs or programs that occur infrequently (Griffin, 2017); (Pire-Smerkanich,
2016). Further, the characteristics of pediatric cancers are often quite specialized, so outside
experts in translational medicine and nonclinical development could be quite helpful at the
installation stage to educate the team about scientific or regulatory aspects important, for
example, to the clinical design or selection of biomarkers and outcome measures (Saletta et al.,
2014). One reason why the team may prefer to depend on internal staffing may be that pediatric
planning requires longer-term involvement of key personnel and a thorough understanding of the
overall development program with which it must integrate across functional areas. These are not
activities easily done by short-term consultants.
When do companies begin to install and implement their pediatric programs? Results
demonstrated that the timing of pediatric planning varies based on certain attributes of the
programs such as the mechanism of action of the compound; only a minority of companies
position the trials in a particular epoch of development. The timing appears more often to be
determined by the availability of adult clinical data than the availability of nonclinical pediatric
data. However, the absence of appropriate preclinical models and deficiencies in the data to
confirm the relevance of molecular targets in pediatric patients have been identified as potential
barriers to early planning (Langenau et al., 2015). Further advances in preclinical testing and
model development may provide additional confidence for industry to move such planning to a
point before the adult program is advanced.

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As new legislation (i.e. the FDARA RACE Act), and guidance (i.e. expansion of clinical trial
eligibility criteria) continue to emerge, it is helpful to understand if companies are playing an
active role in the development of those rules and policies. Results here underline differences in
the degree to which companies of different sizes participate in those activities. Not surprisingly,
medium-sized and large companies appeared to take a greater role in workshops/meetings
organized by health authorities and in providing comments on draft guidance. Most small
companies have not or have never participated in such activities. This supports the assumption
made even before the survey that the few selected industry representatives at workshops/meetings
were mainly from major pharmaceutical companies. These results raise a red flag that such
discussions may lack the perspective from smaller/start-ups companies where innovations often
take place (HBM Partners, 2019).
Full Implementation
The implementation phase of any program can be the most difficult as companies face the
logistical challenges of conducting the activities needed to satisfy the goals laid out during the
installation phase. This exploratory study was not designed to examine specifically the types and
level of complexity of pediatric study designs being implemented across companies but instead
was directed at understanding the experiences that those companies had with regulatory and
logistical implementation. The data suggested that most companies had similar challenges; a few
of the areas of particular concern were those of clinical trial development, interactions with global
health authorities, current incentive structures, and collaboration with other stakeholders.
5.2.3.1 Challenges in Clinical Programs
One of the major challenges identified by respondents was enrollment delay. Their experiences
are consistent with the analyses of Hwang and colleagues (Hwang, 2018) who also identified that

137
many pediatric studies required under the EU Paediatric Regulation and US PREA have been
delayed. Further, they found that pediatric studies that were conducted after marketing
authorization were less likely to be completed in a timely manner. Multiple factors undoubtedly
contribute to these delays (Rose & Senn, 2014). Children are a vulnerable population whose trial
participation often depends on a complicated set of permissions and assents from both the parent
and the child. Further, pediatric development is commonly based on a precedent or concurrent
adult development program for a superficially similar cancer, but in fact, may be targeting cancer
with a rare and different pathology for which the adult data may not be predictive. In addition,
because regulatory obligations mandate pediatric studies, multiple programs developed across
different companies compete for the same, limited patient pool.
The current system of mandatory requirements and financial rewards are not the solution for the
logistical challenges identified here. To address these more pragmatic concerns, US and EU
health authorities have encouraged industry to improve trial efficiency by harnessing regulatory
science and novel trial design. Some of the suggested steps are described in guidance documents
that discuss, for example, increasing the inclusion of pediatric patients as part of earlier adult
oncology trials, or using extrapolation, modeling, and simulation to reduce the numbers of
children who must be tested. The applications of master protocol design and real-world evidence
to replace experimental comparator groups have also been discussed in public fora between the
health authorities and industry (Former, 2017).
Are these ideas adopted by industry? Research here shows that about 1/3 of the respondents have
included adolescents as part of the adult program. A similar number has proposed the use of
extrapolation, modeling, and simulation to the US FDA and EU PDCO; they identify that the
regulatory agencies, and especially the US FDA, have been receptive to such proposals. These

138
findings suggest some level of welcome by regulators that hopefully will help to reduce
regulatory uncertainty and encourage more sponsors to consider the use of novel study designs.
Amongst the newest of the proposed options to modify study design are the use of master
protocols and real-world evidence. These have not yet been featured in programs that have
matured to the point of approval. Further, experience amongst regulatory and clinical
professionals with these approaches appears to be limited; fewer than 20% of respondents in this
survey had applied these approaches. They were also identified to be received with less
enthusiasm by both health authorities. Consequently, it remains unclear whether and when these
types of approaches will be acceptable to meet pediatric regulatory requirements or to satisfy
regulatory reviewers during NDA submission.
5.2.3.2 Interactions with Health Authorities
Often it is only during implementation that companies encounter concerns related to their
pediatric plans. At these points, they may find it necessary to seek the advice of regulatory
agencies. Most respondents in this study appeared to be relatively satisfied with the existing
mechanisms for obtaining feedback from the US FDA on their iPSPs, PSP amendments, PPSRs,
and WR amendments. However, only 1/3 of respondents rated the EU PIP and PIP modification
procedure as satisfactory. It is possible this reflects the differences in granularity required in the
PIP versus the PSP; PIPs require a complete investigational plan, from phase 1 to phase 3, when
only limited adult clinical data are available to inform such a plan or even the indication being
developed (Adamson et al., 2014). However, it is also important to note that majority of the
respondents who completed the survey were more familiar with the US procedures- 11% of the
respondents had no experience with EU procedure at all. Cross-tabulation analyses of respondents
knowledgeable with both the US and EU regulations also show more “dissatisfaction” with

139
mechanisms for PIPs and PIP amendments. Failure to reach a timely agreement with a health
authority can delay the start of the pediatric oncology study (Adamson et al., 2014). Such issues
may contribute at least in part to the finding in this survey that 30% of respondents have
experienced delays of 6 to 12 months because of challenges in reaching agreement on the
pediatric plan with the US FDA or the EU PDCO. Under the new rules in FDARA, a company
may find that it has to discuss its pediatric study plans with the FDA earlier than might have been
necessary in the past. This may help to align the timing of PSP in the US with the EU PIP.
Further, the US FDA included an explicit statement that the “sponsor may be able to meet the
requirements in sections 505A and 505B of the FD&C Act by including pediatric patients in adult
clinical trials” (FDA, 2019). This may reduce the amount of information needed for FDA
compared to the EMA even as it accelerates the timeline for the initiation of appropriate pediatric
studies (FOCR, 2018). As the FDA and the industry gain more experience with the new
requirements of FDARA, which impose deadlines in the summer of 2020, changes in the
approaches to pediatric planning should become clearer. It is likely, for example, that additional
types and timings of early interactions, such as face-to-face discussions different from those
typically scheduled at 210 days for PSP review, will be needed to facilitate timely agreements.
5.2.3.3 Current Incentive Structures
Previous research has described the clear benefits of incentives associated with pediatric trials in
the US (McKinsey, 2013). In particular, market exclusivity is often seen as a strong reward.
Accordingly, most participants seem to agree the current incentives offered by the US FDA or
EMA are adequate in advancing pediatric oncology drug development. A third of respondents
suggested that even longer exclusivity periods would be important to encourage early pediatric
development. However, the usefulness of such exclusivities may not be equally motivating across

140
different product lines. A review by McKinsey that analyzed 69 approved NDAs in 2001 showed
that 11 of the 69 were granted pediatric exclusivity between 2001 and 2006 and 10 of the 69
between 2007 and 2011. However, the remaining majority (48/69) had not received pediatric
exclusivity. The findings also showed that number of exclusivity extensions did not correlate
closely to the total number of ongoing pediatric clinical trials, with an emerging trend of
decreased exclusivity extensions after 2009. When comparing to sales from analyst estimates, the
finding also suggested that the benefits were more important to encourage the conduct of
dedicated pediatric trials for medications with blockbuster revenue (> $1 million) than for drugs
with annual sales below $100 million (McKinsey, 2013). The value of this incentive has also
been questioned by a study by Angelini and colleagues (Angelini, 2013), who showed that the
introduction of financial rewards by the FDA and EMA have not translated into an increase in the
number of pediatric clinical trials, or of drugs with pediatric indications.
What was the experience with pediatric incentives from the respondents in this research? Only a
few respondents in this survey had received a 6-month pediatric exclusivity extension and 3
received the rare pediatric disease priority review voucher. Most either did not submit a PPSR,
had not been issued with a Written Request in the US or did not complete the PIP on time in the
EU. In fact, as of the date of this research, only two oncology products have been rewarded with
the Rare Pediatric Priority Review Voucher (https://priorityreviewvoucher.org/). Other recent
research also finds a small increase of early (Phase 1 to Phase 2) rare pediatric-disease trials but
no significant difference in the number of rare pediatric-disease treatments starting post Phase 2
clinical development, when numbers before or after the Rare Pediatric Priority Voucher incentive
are compared (Gingery, 2019). Why the rare pediatric priority review voucher has not been more
effective in motivating companies could be an important future study.

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5.2.3.4 Global Collaboration and Knowledge Sharing
What else might encourage industry to launch earlier pediatric plans? The top two key drivers
identified by respondents here were not additional incentives but rather 1) advocating a change in
the degree of regulatory harmonization between the US FDA and EU PDCO, and 2) fostering a
platform for better knowledge to decrease the currently high rate of study failures.
The improvement in the convergence between regulators is particularly important to industry in
order to ensure efficient investigations. Although both the FDA and EU have frequent
interactions, adoption of a singular pediatric plan has often been difficult. The result can be
requirements to conduct duplicative or meaningless trials (Thomsen, 2019). The pathway of
Parallel Scientific Advice is considered by many to be convoluted and burdensome (Thomsen,
2019). Most respondents in this study have never taken the approach but rather had stepwise and
separate PSP/PIP interactions. FDA noted that both agencies have been attempting to engage in
regular communication to facilitate the implementation of international master protocols (Former,
2017). However, industry is asking for more clarification and transparency from the results of
these agencies' communications/meetings because understanding the rationale of any divergent
views may be important in reaching the best compromise for all stakeholders (FOCR, 2018).
Although many may believe that the development of standardized regulations and pediatric plan
is unlikely to be possible across the two regions, new initiatives might be able to reduce
bureaucratic and administrative burden on the industry. Global consistency would also be
important to reduce regulatory uncertainty for sponsors.
The second potential driver, noted from the respondents in the survey, would be to gain a better
understanding of pediatric cancers, and thereby reduce the high failure rate of pediatric studies.
As more is known about molecular targets, we might expect that already small pediatric cancer

142
populations will be subdivided further. These small subpopulations will be even harder to find so
streamlining clinical study designs based on a better understanding of disease biology (i.e.
identifying clinically meaningful pharmacodynamic (PD) endpoints) is essential to minimize
study failure in this vulnerable population. The success in translating this approach from
preclinical discoveries to clinical applications (i.e. utilizing specific clinical endpoints not
necessary mimicking the adult population study design) can only be achieved by public-private
partnerships of all appropriate stakeholders. In the preclinical space, discussions are underway to
establish a noncompetitive infrastructure that could be used to develop preclinical data needed to
prioritize decisions about new anti-cancer agents that could be relevant to the growth or
progression of one or more childhood cancers and to disseminate these data to all appropriate
stakeholders (FOCR, 2018). Knowledge sharing can be one of the key factors in decreasing the
high rate of failure of pediatric oncology studies. Some fear that more clinical studies under
FDARA requirements may not translate into successful studies (Terry, 2019) if there continues to
be a knowledge gap related to the underlying science. Thus, it is essential for companies to
collaborate with research facilities and cooperative groups to understand disease biology and
identify actionable targets in hard to treat childhood and adolescent cancers. Since health
authorities review PSP/PIP/PPSR from multiple sponsors potentially developing the same class of
therapy (i.e. with the same molecular target), it is also important for health authorities be engaged
in open-forum discussions, providing non-confidential/non-product specific information such as
statistics/experience of programs reviewed on a specific molecular target (i.e. via the
Transparency Initiatives at the FDA). Such knowledge sharing would help companies to select
the strongest candidates based on preclinical and early clinical data and to prioritize clinical
studies based on mechanisms of action underlying childhood cancers. One area of future research
may be to examine how stakeholders can work together most effectively in sustainable public-

143
private partnerships from precompetitive, preclinical science to effective and efficient protocol
design with agreements on disease-specific pediatric endpoints.
Conclusions and Future Directions
The results presented here paint a picture of a drug development process that is still in evolution.
Most companies that participated in this research are familiar with the requirements and have
allocated resources. They have also implemented a structure to initiate pediatric development
and, in some cases, are pursuing clinical trials. However, their responses suggest several
challenges with implementation. These are in some degree responsible for the persistent lag of
pediatric drug approvals and the high failure rate in pediatric oncology studies. Additional
pediatric requirements will not necessarily produce greater efficiencies in pediatric drug
development. As shown in the statistics (Chapter 2) and survey results (Chapter 4) presented here,
few companies have been successful in developing safe and effective cancer therapies in children,
and many are struggling to complete the studies that have been required by the regulations. The
results observed here are consistent with a recent survey conducted by the Tufts Center for the
Study of Drug Development (Yen, 2019) on industry’s perspective of progress in the area of
pediatric drug development in general. They align also with the industry comments collected by
Yen et al that evolution in the area of pediatric rare disease more generally was “slow but moving
in the right direction”. Moving forward, an ecosystem to increase the clarity and consistency
between global health authorities could assist in reducing regulatory uncertainty for sponsors.
Also, important may be better sharing of certain types of evidence- from preclinical and
translational discoveries to pediatric disease-specific clinical protocol/endpoints-, between
industry, governmental agencies, and academia. A concerted public-private effort will be
essential to improve timely access to innovative and effective therapies for children with cancer.

144
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153
APPENDIX A.
PHASE 1 AND PHASE 2 STUDY PROTOCOL REQUIREMENT OUTLINE
(from FDA Guidance for Industry: Pediatric Oncology Studies in Response to a Written Request)
Phase 1 Study Protocol
Requirement
Study Outcome Next Step
Includes:
• Rationale for the starting
dose (from adult or
nonclinical)
• Plan to gather
pharmacokinetic data
• Definition of maximal
tolerated dose (MTD)
• Stopping rules for toxicity
• Statistical plan based on
escalation scheme, cohort
size and stopping rules

Patient population: 18 to 25

If found unacceptable
toxicity and FDA
agrees with findings
after review of the
study report in the
application.
If FDA considers WR
met and no further
pediatric studies are
required.
Include information in
labeling.
FDA may grant PE.

If found acceptable
level of safety

Proceed to Phase 2
Study(-ies)

Phase 2 Study Protocol
Requirement
Next Step FDA Decision
Consider for a range of
potential indications

• Rational for the proposed
dose
• Design based on patients
benefit (i.e. add-on design
by adding the new drug to a
standard regimen and
compare to the standard
regimen alone)
• Statistical plan based on
cohort size, cohort phase
and stopping rules

If studies met WR

Submit reports to
application for review

Grant PE

Labeling changes upon
approval of application

154
APPENDIX B.
LIST OF FDA PEDIATRIC WRITTEN REQUEST ISSUED (ADULT CANCER TREATMENT)
As of 07 April 2017, FDA has issued a total of 429 approved active moieties with Written Request for Pediatric Studies under Section 505A of the
Federal Food, Drug, and Cosmetic Act.

The following list included the WR issued for active moiety approved for cancer treatment in the adult populations:

Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Atezolizuab Programmed death-ligand
1 (PD-L1) blocking
antibody
Locally advanced or metastatic urothelial carcinoma (2016) Genentech, Inc.
Bendamustine Alkylating drug Chronic lymphocytic leukemia (CLL) and Indolent B-cell non-Hodgkin
lymphoma (NHL) (2008)
Cephalon, Inc.
Bortezomib Proteasome inhibitor Multiple myeloma. Mantle cell lymphoma. (2003)

Millenium Pharm
Bosutinib Kinase inhibitor Ph+ chronic myelogenous leukemia (CML) (2012) Wyeth Pharmaceuticals, Inc.
Cabazitaxel Microtubule inhibitor Hormone-refractory metastatic prostate cancer (2010) Sanofi-Aventis

155
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Capecitabine Nucleoside metabolic
inhibitor with
antineoplastic activity
Adjuvant colon cancer. Metastatic colorectal cancer. Metastatic breast
cancer. (1998)
HLR
Carboplatin Platinum-based
chemotherapy
Ovarian carcinoma. (1989) Bristol-Myers Squibb
Carfilzomib Proteasome inhibitor Multiple myeloma (2012) Onyx Therapeutics, Inc.
Clofarabine Purine nucleoside
metabolic inhibitor
First approved indication: in pediatric acute lymphoblastic leukemia
(2004)
ILEX Products, Inc.
Crizotinib Kinase inhibitor Non-small cell lung cancer that is anaplastic lymphoma kinase (ALK)-
positive (2011)
Pfizer, Inc.
Cytarabine Cell cycle phase-specific
antineoplastic
agent, affecting cells only
during the S-phase of cell
division
Leukemias. Lymphomatous meningitis (1998) SkyePharma Inc.

156
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Dabrafenib Kinase inhibitor Melaoma with BRAF V600E mutation. (2013) Novartis Pharmaceuticals
Corporation
Darbepoetin Erythropoiesis-stimulating
agent (ESA)
Anemia due to chemotherapy (2001) Amgen, Inc.
Dasatinib Kinase inhibitor Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia
(CML). Ph+ acute lymphoblastic leukemia (2006)
BMS
Decitabine Nucleoside metabolic
inhibitor agent
Myelodysplastic syndromes (MDS) (2006) Eisai medical Research, Inc.
Denosumab RANK ligand (RANKL)
inhibitor
Increase bone mass of patients at high risk for fracture from cancer
treatment (2010).
Amgen, Inc.
Docetaxel Microtubule inhibitor Breast cancer. Non-small cell lung cancer. Hormone refractory prostate.
Gastric adenocarcinoma. Squamous cell carcinoma of the head and neck
cancer. (1996)
Sanofi-Aventis, U.S., Inc.
Eribulin Microtubule inhibitor Breast cancer (2010) Eisai, Inc.

157
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Erlotinib Kinase inhibitor Non-small cell lung cancer (NSCLC) whose tumors have epidermal
growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R)
substitution mutations. Pancreatic cancer. (2004)
OSI Pharm
Everolimus Kinase inhibitor Hormone receptor-positive, HER2-negative breast cancer (advanced HR+
BC). Progressive neuroendocrine tumors of pancreatic origin (PNET).
Renal cell carcinoma (RCC). Renal angiomyolipoma and tuberous
sclerosis complex (TSC). Subependymal giant cell astrocytoma (SEGA)
associated with tuberous sclerosis (TSC). (2009)
Novartis
Fludarabine Antimetabolite,
chemotherapy
B-cell chronic lymphocytic leukemia (CLL). (1991) Berlex
Gefitinib Tyrosine kinase inhibitor Non-small cell lung cancer whose tumors have epidermal growth factor
receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution
mutations(2015)
AstraZeneca
Gemcitabine Nucleoside metabolic
inhibitor

Advanced ovarian cancer. Breast cancer. Non-small cell lung cancer.
Pancreatic cancer. (1996)
Lilly

158
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Imatinib Kinase inhibitor Ph+ CML. Ph+ ALL. myelodysplastic/myeloproliferative diseases
(MDS/MPD) associated with PDGFR (platelet-derived growth factor
receptor) gene re-arrangements. Aggressive systemic mastocytosis
(ASM) without the D816V c-Kit mutation. Hypereosinophilic syndrome
(HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-
PDGFRα fusion kinase (mutational analysis or FISH demonstration of
CHIC2 allele deletion). Unresectable, recurrent and/or metastatic
dermatofibrosarcoma protuberans (DFSP). Kit (CD117) positive
unresectable and/or metastatic malignant gastrointestinal stromal tumors
(GIST). (2001)
Novartis
Ipilimumab Human cytotoxic T-
lymphocyte antigen 4
(CTLA-4)-blocking
antibody
Melanoma. (2011) Bristol-Myers Squibb
Company
Irinotecan Topoisomerase inhibitor Metastatic carcinoma of the colon or rectum. (1996) Pharmacia & Upjohn
Ixabepilone Microtubule inhibitor Breast cancer. (2007) Bristol-Myers Squibb
Company

159
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Lenalidomide Thalidomide analogue Multiple myeloma (MM). Transfusion-dependent anemia due to low- or
intermediate-1-risk myelodysplastic syndromes (MDS) associated with a
deletion 5q abnormality. Mantle cell lymphoma (MCL). (2005)
Celgene Corporation
NAB-paclitaxel Microtubule inhibitor Breast cancer. Non-small cell lung cancer. Pancreas cancer. (2005) Celgene Corporation
Nivolumab Programmed death
receptor-1 (PD-1)
blocking antibody
BRAF V600 wild-type melanoma. BRAV V600 mutation-positive
melanoma. Non-small cell lung cancer. Advanced renal cell carcinoma.
Hodgkin lymphoma. Squamous cell carcinoma of head and neck.
Urothelial carcinoma. (2014)
Bristol-Myers-Squibb
Company
Oxaliplatin Platinum-based drug Advanced colorectal cancer (2002) Sanofi-Synthelabo, Inc.
Pemetrexed Folate analog metabolic
inhibitor
Nonsquamous non-small cell lung cancer (2004) Eli Lilly & Co.
Pomalidomide Thalidomide analogue Multiple myeloma (2013) Celgene Corporation
Sunitinib Kinase inhibitor Gastrointestinal stromal tumor (GIST). Advanced renal cell carcinoma
(RCC). pancreatic neuroendocrine tumors (pNET). (2006)
C.P. Pharm c/o Pfizer, Inc.
Temozolomide Alkylating drug Glioblastoma multiforme (GBM). (1999) Schering
Temsirolimus Kinase inhibitor Renal cell carcinoma. (2007) Wyeth-Ayerst

160
Active Moiety Drug Mechanism Adult Cancer Approval and Initial Approval Year Sponsor
Topotecan Topoisomerase inhibitor Small cell lung cancer (1996) SmithKline Beecham
Trametinib Kinase inhibitor Melanoma with BRAF V600E or V600K mutations. (2013) Novartis Pharmaceuticals
Corporation
Vinorelbine Vinca alkaloid Non-small cell lung cancer (NSCLC). (1994) Glaxo Wellcome
List: https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm077570.htm, assessed on 17 April 2017

161
APPENDIX C.
TIMING OF ADULT INITIAL APPROVAL TO PEDIATRIC EXCLUSIVITY GRANTED (ONCOLOGY INDICATIONS)
Of the total 211-pediatric exclusivity granted across therapeutic areas (as of 31 March 2017), 18, 8.53% had a pediatric cancer indication.

Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
Vinorelbine PPSR
submitted
on
11/15/2000
WR issued
on 1/9/2001
8/15/02 Leukemia/lymphoma 12/23/1994 First line treatment of
ambulatory patients with
unresectable, advanced
nonsmall cell lung cancer
7 years 8 mths = 92
mths
Temozolomide No PPSR
noted.
WR issued
on1/9/2001
11/20/02 Refractory/relapse
malignancies
08/11/1999 Treatment of adult patients with
142 refractory anaplastic
astrocytoma, i.e., patients at first
relapse who have experienced
disease 143 progression on a
drug regimen containing a
nitrosourea and procarbazine
3 years 3 mths = 39
mths

162
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
Topotecan PPSR note
noted. WR
issued
on5/16/2000
11/20/02 Refractory/relapsed
malignancies
05/28/1996 Treatment of metastatic
carcinoma of the ovary after
disease progression on or after
initial or subsequent
chemotherapy
mall cell lung cancer platinum-
sensitive disease in patients who
progressed after first-line
chemotherapy
combination therapy with
cisplatin for Stage IV-B,
recurrent, or persistent
carcinoma of the cervix which
is not amenable to curative
treatment
6 years 6 mths = 78
mths
Fludarabine PPSR
submitted
on
07/09/2001
4/3/03 Refractory/relapse
acute leukemia
04/18/1991 Treatment of patients with B-
cell chronic lymphocytic
leukemia (CLL) who have not
responded to or whose disease
has progressed during treatment
12 years = 144 mths

163
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
WR issued
on
11/09/2001
with at least one standard
alkylating-agent containing
regimen
Irinotecan PPSR
submitted
on
10/30/2000.
WR issued
on1/22/2001
3/10/04 Refractory tumors 06/14/1996 First-line therapy in
combination with 5-fluorouracil
and leucovorin for patients with
metastatic carcinoma of the
colon or rectum. (1) • Patients
with metastatic carcinoma of the
colon or rectum whose disease
has recurred or progressed
following initial fluorouracil-
based therapy.
7 years 9 mths = 93
mths
Carboplatin WR issued
on
4/11/2001
4/30/04 Refractory tumors 03/03/1989 Initial treatment of advanced
ovarian carcinoma in
established combination with
other approved
chemotherapeutic
agents.
15 years and 1 mths =
181 mths

164
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
Clofarabine No PPSR
recorded.
WR issued
on 3/7/2003
7/14/04 Refractory
Leukemias
12/28/2004
First approval in
pediatric, not adult!
Treatment of pediatric patients 1
to 21 years old with relapsed or
refractory acute lymphoblastic
leukemia after at least two prior
regimens. This use is based on
the induction of complete
responses. Randomized trials
demonstrating increased
survival or other clinical benefit
have not been conducted
Best example! First
approval was in
pediatric!
Gemcitabine PPSR
submitted
on
09/20/2000
WR issued
on1/9/2001
1/27/05 Refractory or
relapsed leukemia
and non-Hodgkin’s
lymphoma
05/15/1996

In ombination with cisplatin for
the first-line treatment of
patients with inoperable, locally
advanced (Stage IIIA or IIIB) or
metastatic (Stage IV) non-small
cell lung cancer.
s first-line treatment for patients
with locally advanced
(nonresectable Stage II or Stage
III) or metastatic (Stage IV)
8 years and 8 mths =
104 mths

165
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
adenocarcinoma of the
pancreas. Gemzar is indicated
for patients previously treated
with 5-FU.

Imatinib Mesylate PPSR:
01/21/2000
WR issued
on
9/20/2000
6/9/06 Philadelphia positive
(Ph+) leukemia
05/10/2001 Treatment of patients with
chronic myeloid leukemia
(CML) in blast 145 crisis,
accelerated phase, or in chronic
phase after failure of interferon-
alpha therapy
5 years 1 mth = 61
mths
Oxaliplatin PPSR
submitted:
07/29/2004;
WR issued
on
12/9/2004
9/27/06 Refractory tumors 08/09/2002 In combination with infusional
5-FU/LV, is indicated for the
treatment of 178 patients with
metastatic carcinoma of the
colon or rectum whose disease
has recurred or 179 progressed
during or within 6 months of
completion of first line therapy
4 years 1 mth = 49
mths

166
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
with the combination of 180
bolus 5-FU/LV and irinotecan
Docetaxel PPSR
submitted
on
01/31/2007
WR issued
on
06/11/2007
3/17/10 Solid Tumors 05/14/1996 Treatment of patients with
locally advanced or metastatic
breast cancer after failure of
prior chemotherapy
treatment of patients with
locally advanced or metastatic
non-small cell lung cancer after
failure of prior platinum-based
chemotherapy
13 years 10 months
= 166 mths
Pemetrexed PPRS
submitted
on 05/24/01.
WR issued
on 10/5/01

12/3/10 Refractory and
recurrent solid
tumors, including
osteosarcoma, Ewing
sarcoma/peripheral
PNET,
rhabdomyosarcoma,
and neuroblastoma
02/04/2004

In combination with cisplatin is
indicated for the treatment of
patients with malignant pleural
mesothelioma whose disease is
either unresectable or who are
otherwise not candidates for
curative surgery
6 years 10 mths
= 82 mths

167
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
Ixabepilone PPSR
submitted
on
11/20/2006
WR issued
on
6/22/2007
4/5/11 Solid Tumors 10/16/2007 In combination with
capecitabine is indicated for the
treatment of metastatic or
locally advanced breast cancer
in patients after failure of an
anthracycline and a taxane.
monotherapy is indicated for the
treatment of metastatic or
locally advanced breast cancer
in patients after failure of an
anthracycline, a taxane, and
capecitabine
3 years 6 mths = 42
mths
Temsirolimus No PPSR
noted
WR issued
on
1/12/2001
2/28/12 Treatment of
relapsed/refractory
solid tumors
05/30/2007

Treatment of advanced renal
cell carcinoma
4 years 9 mths = 57
mths
Bendamustine PPSR
submitted
5/24/12 Relapsed or
refractory acute
leukemia
03/20/2008 Treatment of patients with
chronic lymphocytic leukemia
(CLL)
4 yrs and 2 months =
50 mths

168
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
on
07/27/2009
WR issued
on
01/19/2010
Capecitabine PPSR
submitted
on
11/01/2004
WR issued
on
3/16/2005
8/28/13 Non-disseminated
intrinsic diffuse
brain stem gliomas
04/30/1998 Treatment of patients with
metastatic breast cancer
resistant to both paclitaxel and
an anthracycline-containing
chemotherapy regimen or
resistant to paclitaxel and for
whom further anthracycline
therapy is
not indicated
5 years 4 mths = 64
mths
Erlotinib PPSR
submitted
on
05/01/2009
3/18/15 Cancer (recurrent
ependymoma)
11/18/2004 Treatment of patients with
locally advanced or metastatic
non-small cell lung cancer after
failure of at least one prior
chemotherapy
regimen
10 years 4mths = 124
mths

169
Drug Written
Request
Date of PE
Granted
Indications Granted
with PE
First Adult Approval Indication in Adult From First Adult
Approval to PE
WR issued
on
05/07/2010
Bortezomib PPSR
submitted
on
10/21/2009
WR issued
on
04/27/2010
8/14/15 Acute lymphocytic
leukemia (ALL)
05/13/2003 Treatment of multiple
myeloma patients who have
received at least two prior
therapies and have
demonstrated
disease progression on the last
therapy
11 years 3 mths = 135
mths
PPSR = Proposed Pediatric Study Request. WR = Written Request. mths = months.
Source: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM514985.pdf, accessed on 05 April 2017

170

171
APPENDIX D.
FINAL VERSION OF PEDAITRIC ONCOLOGY DRUG DEVELOPMENT INDUSTRY
SURVEY

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186
APPENDIX E.
CROSS-TABULATIONS
Table E.1: Cross Tabulation of Company Size and Dedicated Resources on Pediatric
Programs

In your company/organization, how
is the pediatric team organized to
support oncology drug/biologic
What statement best describes the size of
your overall company/organization
1-500
employees
501-2,500
employees
2,501-
10,000
employees
10,000+
employees
Clinical
Development
Internal research dedicated
for pediatric programs only
0 1 4 6
Internal resource but also
working on non-pediatric
programs
6 2 2 4
External consultations 1 0 0 0
Do not know 1 1 0 0
Regulatory
Affairs
Internal research dedicated
for pediatric programs only
0 0 0 6
Internal resource but also
working on non-pediatric
programs
5 3 5 3
External consultations 2 0 1 0
Do not know 0 1 0 0
Clinical
Pharmacology
Internal research dedicated
for pediatric programs only
0 0 1 2
Internal resource but also
working on non-pediatric
programs
5 3 3 6
External consultations 1 0 2 0
Do not know 2 1 0 1

187
In your company/organization, how
is the pediatric team organized to
support oncology drug/biologic
What statement best describes the size of
your overall company/organization
1-500
employees
501-2,500
employees
2,501-
10,000
employees
10,000+
employees
Translational
Medicine
Internal research dedicated
for pediatric programs only
0 0 0 2
Internal resource but also
working on non-pediatric
programs
6 3 6 7
External consultations 1 0 0 0
Do not know 0 1 0 0

Table E.2: Cross Tabulation of Company Size and Internal Challenges on Pediatric
Programs
What would best describe the
challenges your team has
encountered with the
company/organization
What statement best describes the size of
your overall company/organization
1-500
employees
501-2,500
employees
2,501-
10,000
employees
10,000+
employees
Competing
for resources
with other
programs
Strong agree 4 3 2 3
Somewhat agree 1 0 3 3
Neither agree nor disagree 1 1 1 3
Somewhat disagree 0 0 0 1
Strongly disagree 0 0 0 0
Cannot answer 1 0 0 0
Limited
internal
expertise in
pediatric field
Strong agree 1 2 2 0
Somewhat agree 1 2 1 5
Neither agree nor disagree 3 0 2 2
Somewhat disagree 0 0 1 0
Strongly disagree 0 0 0 3
Cannot answer 2 0 0 0
Limited
support from
Strong agree 2 0 2 0
Somewhat agree 1 2 2 0

188
What would best describe the
challenges your team has
encountered with the
company/organization
What statement best describes the size of
your overall company/organization
1-500
employees
501-2,500
employees
2,501-
10,000
employees
10,000+
employees
management
on pediatric
programs
Neither agree nor disagree 1 0 1 3
Somewhat disagree 2 1 1 4
Strongly disagree 0 0 0 3
Cannot answer 2 0 0 0
Limited
understanding
of
requirements
within the
organization
Strong agree 2 1 1 0
Somewhat agree 2 3 3 3
Neither agree nor disagree 1 0 1 1
Somewhat disagree 1 0 0 2
Strongly disagree 0 0 1 4
Cannot answer 1 0 0 0

189
Table E.3: Cross Tabulation of Company Size and Views on Current Pediatric
Incentives in the US
Does your organization view the
current regulation as adequate in
providing incentives to stimulate
pediatric oncology drug
development?
What statement best describes the size of
your overall company/organization
1-500
employees
501-2,500
employees
2,501-
10,000
employees
10,000+
employees
BPCA: 6
months
Pediatric
Exclusivity
Extremely adequate 0 0 1 2
Somewhat adequate 4 3 5 5
Neither adequate nor
inadequate
0 0 0 1
Somewhat inadequate 1 0 0 2
Extremely inadequate 1 0 0 0
BPCA: 6
months
Pediatric
Exclusivity
for Orphan
Drug with
Small Market
Potential
Extremely adequate 0 1 2 2
Somewhat adequate 4 2 4 4
Neither adequate nor
inadequate
1 0 0 2
Somewhat inadequate 1 0 0 0
Extremely inadequate 0 0 0 1
Rare
Pediatric
Disease
Priority
Review
Voucher
Extremely adequate 2 1 3 2
Somewhat adequate 1 2 2 6
Neither adequate nor
inadequate
3 0 1 2
Somewhat inadequate 0 0 0 0
Extremely inadequate 0 0 0 0

Abstract (if available)

Abstract Drugs for cancer represent perhaps the largest and fastest source of new drug submissions in the last decade, accounting for 21% of new molecular entities (NMEs). Most of these drugs are for adults, for whom cancers are the second leading disease-related cause of death. However, drugs are often unavailable for children, for whom cancers are the leading cause of such deaths. This challenge has led both the Food and Drug Administration (FDA) in the United States (US) and the European Medicines Agency (EMA) to institute new pediatric regulations that include additional incentives and removal of pediatric study-requirement exemptions for companies that develop applicable targeted therapies. Both the US FDA and EMA are also attempting to encourage the earlier conduct of trials focused specifically on pediatric disease. The purpose of this research was to explore current industry views on the challenges and opportunities in pediatric cancer drug development under the existing regulations. Using a survey method, regulatory professionals and consultants with experience in pediatric drug development and/or design were provided with an electronic survey tool through a web-based interface. Data analysis was conducted on responses 46 participants from large and small companies undertaking pediatric oncology drug/biologic development. Results showed that most companies have allocated internal resources for pediatric oncology development and viewed the current pediatric incentives as at least “somewhat adequate”, yet they continued to face challenges with the implementation of pediatric planning and execution of innovative study designs. Factors that appear to inhibit uptake of early or dedicated pediatric oncology programs were difficulties in developing a globally harmonized regulatory plan and knowledge gaps in optimizing pediatric study designs.

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Asset Metadata

Creator Ng, Penny Wai Ping (author)

Core Title Regulation of pediatric cancer drug development: an industry perspective

School School of Pharmacy

Degree Doctor of Regulatory Science

Degree Program Regulatory Science

Publication Date 12/05/2019

Defense Date 09/20/2019

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

Tag drug development,EMA,OAI-PMH Harvest,oncology,pediatric,regulations,US FDA

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Richmond, Frances (committee chair), Bain, Susan (committee member), Smerkanich, Nancy (committee member), Storm, Neal (committee member)

Creator Email pennyng@usc.edu,pentom.cheng@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-244761

Unique identifier UC11674220

Identifier etd-NgPennyWai-8008.pdf (filename),usctheses-c89-244761 (legacy record id)

Legacy Identifier etd-NgPennyWai-8008.pdf

Dmrecord 244761

Document Type Dissertation

Rights Ng, Penny Wai Ping

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA