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A quantitative and qualitative evaluation of the least burdensome provisions of the Food and Drug Administration Modernization Act of 1997

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A QUANTITATIVE AND QUALITATIVE EVALUATION
OF THE LEAST BURDENSOME PROVISIONS OF THE
FOOD AND DRUG ADMINISTRATION MODERNIZATION ACT OF 1997
by
Monica Dominique Ferrante
A Dissertation Presented to the
FACULTY OF THE SCHOOL OF POLICY, PLANNING,
AND DEVELOPMENT
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PUBLIC ADMINISTRATION
August 2004
Copyright 2004 Monica Dominique Ferrante
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UMI Number: 3145197
Copyright 2004 by
Ferrante, Monica Dominique
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TABLE OF CONTENTS
LIST OF TABLES............................................................................................... v
LIST OF FIGURES............................................................................................. vi
ABSTRACT ................................................................................................. viii
Chapter
I. INTRODUCTION AND SUMMARY................................................... 1
Regulation—Concepts and Issues.................................................. 2
Purpose of this Research................................................................ 10
Significance of this Study............................................................... 12
Research Plan................................................................................. 15
Delimitations.................................................................................. 17
Plan of the Dissertation.................................................................. 17
II. LITERATURE REVIEW....................................................................... 19
Regulatory Regimes....................................................................... 20
Capture Theory of Regulation........................................................ 24
External Signals Theory................................................................. 25
Public Choice Theory..................................................................... 27
History of Regulation..................................................................... 27
III. FDA AND MEDICAL DEVICE REGULATION.................................. 73
IV. LEAST BURDENSOME REGULATORY MODEL............................ 83
Events Contributing to Political Support of Regulation................. 86
Traditional 510(k) Process............................................................. 98
The New 510(k) Paradigm............................................................. 101
Special 510(k)...........................................................................102
Abbreviated 510(k)................................................................. 103
The Traditional IDE Process.......................................................... 104
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The New IDE Process......................................................................106
Traditional Premarket Approval (PMA) Process.............................107
PMA Process under FDAMA...........................................................110
Least Burdensome Provisions of FDAMA..................................... 113
Least Burdensome Pros and Cons.............................................116
Least Burdensome Activities....................................................118
Informal Activities.............................................................118
Early Collaboration Activities......................................... 119
Lease Burdensome and the 510(k) Program......................120
Least Burdensome and the PMA Program.........................122
Key Points for the FDA.................................................................. 123
V. RESEARCH PROBLEM.........................................................................125
The Research Hypothesis.................................................................127
Specific Hypotheses for Analysis................................................... 127
Delimitations.................................................................................. 128
Limitations........................................................................................129
VI. DATA ORGANIZATION AND METHODOLOGY........................... 130
510(k) Research Phase 1 ..................................................................131
Description of Variables............................................................131
Target Population......................................................................132
Production of Data....................................................................133
Methodology........................................................................... 135
IDE/PMA Research Phase 2........................................................... 137
Description ofVariables.......................................................... 137
Target Population......................................................................138
Production of Data....................................................................140
Methodology.............................................................................143
Summary...........................................................................................145
VII. DATA FINDINGS AND ANALYSIS....................................................147
510(k) Research Phase 1 Introduction..............................................147
Least Burdensome Provisions for 510(k) Premarket Notification
Process—Analysis of Timeliness Hypothesis...........................148
The Effect of the Special 510(k)............................................. 152
The Effect of the Abbreviated 510(k).......................................155
Resources Applied to the Review Process................................158
The Effect of Guidance Documents..........................................159
Use of Recognized Standards....................................................163
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Least Burdensome Provisions for Investigational Device
Exemptions and Premarket Approval Process
Introduction............................................................................. 169
Demographic Information.........................................................170
Informal Pre-IDE Process Assessment................................... 172
Informal Pre-IDE Process and Communication—
Analysis of Communication Hypothesis...................... 173
Informal Pre-IDE Process and Resolution of Significant
Issues—Analysis of Issue Resolution Hypothesis 174
Early Collaboration Activities—Formal Pre-IDE Meetings.... 176
Early Collaboration Program and Communication............179
Early Collaboration Program and Resolution of
Significant Issues...........................................................180
Significant Factors Addressed by Pre-IDE and Early
Collaboration......................................................................181
Randomized Controlled Trials...........................................181
Surrogate Endpoints...........................................................181
Predictability of the IDE/PMA Process....................................185
Perception of Cultural Change..................................................186
“Time, Effort and Money” as Factors in Decision-Making 189
Benefits of the Least Burdensome Provisions...........................192
Recommendations to the FDA for Improvement......................193
Summary of Research Findings........................................................195
Timeliness Hypothesis Findings...............................................195
Communication Hypothesis Findings.......................................196
Issue Resolution Hypothesis Findings......................................197
VIII. SUMMARY AND CONCLUSIONS......................................................199
Regulatory Regime.......................................................................... 204
Regulatory Capture.......................................................................... 205
External Signals................................................................................207
Public Choice................................................................................... 208
Conclusions..................................................................................... 209
Future Research Implications.......................................................... 210
Closing Conclusion......................................................................... 215
SELECTED BIBLIOGRAPHY............................................................................ 217
APPENDICES
A. Glossary of Acronyms..................................................................... 224
B. Traditional PMA Submission Requirements....................................227
C. Interviewee Letter............................................................................ 235
D. Interview Guide............................................................................... 238
iv
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LIST OF TABLES
1. 510(k) Performance Data............................................................................ 80
2. 510(k) Performance by Submission Type..................................................... 149
3. Number of 510(k)s by Type........................................................................ 150
4. Total 510(k) Review Time Average by Year............................................... 151
5. FDA 510(k) Review Time Average by Year.............................................. 153
6. Percentage of Change in Average 510(k) Review Times............................. 157
7. FDA Full-Time Employees by Year........................................................... 158
8. Percentage of 510(k)s Found Deficient........................................................ 159
9. 510(k) Average Review Times—Guidance.................................................. 161
10. Percentage of 510(k)s Found Deficient—Standards................................... 164
11. 510(k) Average Review Times—Standards.................................................166
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LIST OF FIGURES
1. Regulatory Reform Legislation Timeline................................................... 34
2. 510(k) Average Review Time..................................................................... 78
3. Number of 510k)s by Type...........................................................................150
4. Total 510(k) Review Time Average by Year............................................. 152
5. FDA 510(k) Review Time Average by Year.............................................. 154
6. FDA Full-Time Employees......................................................................... 158
7. Percentage of510(k)s Found Deficient........................................................ 160
8. 510(k) Average Review Times................................................................... 162
9. Percentage of 510(k)s Found Deficient...................................................... 165
10. 510(k) Average Review Times..................................................................... 166
11. Perceptions of Pre-IDE Program................................................................ 173
12. Pre-IDE Communication.............................................................................. 174
13. Pre-IDE Significant Issue Resolution........................................................... 175
14. Perceptions of Formal Meetings................................................................. 177
15. Early Collaboration Program Has Improved Communication..................... 179
16. Early Collaboration Program Has Identified and/or Resolved
Significant Issues........................................................................... 180
17. Perceptions on Use of Surrogate Endpoints................................................ 183
18. Improvement in Predictability.................................................................... 185
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19. Perceptions of Cultural Change....................................................................187
20. Consideration of Time, Effort and Money.................................................. 190
21. Change in FDA Culture.............................................................................. 191
22. Recommendations for Improvement........................................................... 193
23. Findings in Support of Review Time..........................................................196
24. Findings in Support of Communication Improvement............................... 197
25. Findings in Support of Issue Resolution Improvement..............................198
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ABSTRACT
Federal, state and local government agencies are active in almost all areas of
our lives to influence behavior and to protect individuals and businesses from abuse
(including dangerous products). Regulation of some aspects of behavior, both
individual and corporate, arose because of abuses and the public outcry that they be
addressed. There are, however, valid issues regarding the scope, implementation and
effectiveness of the regulatory models employed today as technology and its
implications become increasingly complex and difficult for “non-experts” to grasp.
This dissertation deals with the problems of how a regulatory agency
balances their mission to protect the public with processes that are both efficient and
effective. How do they prevent harm while not hindering progress?
This research focuses on the Food and Drug Administration Modernization
Act of 1997 that established a framework for process changes in the activities
associated with medical device clearance to market. The performance of these
processes, as well as the perceptions of the medical device industry, is explored to
determine whether these changes have been effective.
Specifically, the purpose of the research is to evaluate the Least Burdensome
provisions of the Modernization Act through both quantitative and qualitative
methods and to draw conclusions regarding its effectiveness. The research examines
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two pre-market approval processes for medical devices, 510(k) Pre-market
Notification and Pre-market Approval (IDE/PMA). The 510(k) submissions were
quantitatively evaluated with respect to average review times. The IDE/PMA
process was qualitatively evaluated through elite interviews of several prominent
industry professionals in regulatory processes.
The findings of the research show that 510(k) review times are modestly
improved as a result of FDA process changes permitted by the legislation. In the
IDE/PMA process, the interviewees were consistent in their perception that the
approval process had improved. While they also agree that there is room for more
improvement, the consensus among them was that the open communication and
other activities have improved issue resolution and, thus, the predictability of the
process. This study concludes that the Least Burdensome provisions appear to have
been effective in improving the pre-market approval process for medical devices.
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CHAPTER I
INTRODUCTION AND SUMMARY
Although all democratic peoples are instinctively drawn toward the
centralization of power, this attraction is uneven. It depends on
particular circumstances which may promote or restrain the natural
effect of the state on society.1
Alexis de Tocqueville
Federal, State and Local government agencies are active in almost all areas of
our lives, with power exercised and purpose defined by large bureaucratic entities.
Regulation of some aspects of behavior, both individual and corporate, arose because
of abuses and the public outcry that they be addressed. Many, however, have valid
issues with the scope, implementation and effectiveness of the regulatory models
employed today as technology and its implications become increasingly complex and
difficult for “non-experts” to grasp. Herein lies the dilemma inherent in the
regulatory process. Most businesses can safely and effectively manage their core
competencies. These businesses are ethical and honest and strive to do their best.
Regulation is bom of those events where the few businesses that are not so
concerned about delivering safe and effective products or are unethical or
uninformed in their management cause harm.
Alexis de Tocqueville, Democracy in America, ed. Jay Mayer (New York: Doubleday &
Co., 1969).
1
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How does a regulatory agency balance their mission to protect the public
with processes that are both efficient and effective? How do they prevent some from
causing harm while not hindering the progress of others with over burdensome
processes? How can regulation be balanced within the ever-changing political
landscape? How can regulators learn to live in a world full of risk and uncertainty?
The following discussion outlines “regulation” in a general sense and
describes concerns with the overall concept and attributes of regulatory systems.
The focus is then narrowed to the specific case of the Food and Drug
Administrations (FDAs) regulatory processes as applied to medical device
technology.
Regulation—Concepts and Issues
The term “regulation” defines a broad array of policies governing economic
and industrial activities.
Regulatory policies address firms’ entry into and exit from
particular markets; prices; rates of return; and modes of
competition; as well as the characteristics of the goods being
produced, the quantities being produced, the means of
production, and the negative externalities (such as pollution)
arising from the production process.2
These policies are intended to control the behavior of corporations and in many
cases, can result in significant cost to the corporation and subsequently the
consuming public. Regulation may affect economic development by influencing
2 Marc Allen Eisner, Regulatory Policies in Transition (Baltimore: Johns Hopkins University
Press, 2000), xiii-xiv.
2
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investment and production decisions. The corporation must internalize the costs
associated with compliance to regulatory requirements on production processes.
Regulatory policies affect the performance of American firms in domestic and
international markets. Given the effects of regulation and the growing concerns with
U.S. economic performance, it should not be surprising that much of the recent
literature on regulation addresses its economic effects and the question of whether
these costs are justified.
For many politicians and policy analysts, regulation has been the “villain of
choice” for many years.
Critics of regulation, seeking to ignite traditional American
fears of big government, have decried the “regulatory time
bomb” and “social engineering” based on the imposition of
“command and control” policies. This specter can easily be
contrasted with “the market,” an institution that promotes
individual choice, entrepreneurial initiative, and business
efficiency.4
This over simplified contrast is ideologically charged and has been politically
convenient.
This tends to overshadow an important fact about regulatory policies. It is a
major misconception that regulation is the product of an oppressive elite or of a
partnership between monopolies and the state. In reality, the major regulatory
initiatives of the past hundred years originated in popular demands that were
stimulated, in most cases, by the perceived threats of economic and social change.
3 Ibid., xiii-xiv
4 Ibid.
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These demands were not simply translated into policy but
have been linked to prevailing political-economic theories and
administrative doctrines. Thus, regulatory change has often
taken the form of a unique synthesis of policy change and
institutional reform.5
“Regulatory agencies are bureaucratic institutions entrusted with the
implementation, management, and administration of public policy.”6 Regulation, as
defined by Kenneth Meier, is “an attempt by the government to control the behavior
of citizens, corporations or sub-governments.”7 Regulations are requirements,
standards and procedures that are intended to govern, modify and direct the behavior
of public and private entities and are empowered by punitive remedies, penalties and
sanctions, administered by the governing body. For those who oppose regulation, it
is seen as an undue burden to the regulated activity and a violation of the basic
principles of a capitalistic society. Their belief is the market should be allowed to
“regulate” itself; and that those activities not in the best interest of the public will
eventually go by the wayside or certainly face vigorous litigation for
mismanagement.
Others believe that regulation is necessary, particularly in areas where the
results of failure could manifest in hazardous situations that may go unmitigated in
pursuit of quick profits. Regulation is a reaction to occurrences where some subset
5 Ibid.
6 George Thomas Kurian, ed., A Historical Guide to the U.S. Government (New York: Oxford
University Press, 1998), 504-510.
’Kenneth Meier, Regulation & Consumer Protection: Politics, Bureaucracy and Economics,
3d ed. (Houston, TX: Dame Publications, 1998), 1.
4
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of society has by intent, ignorance, or inattention, caused harm to the general public.
It is the result of market failure in an area where failure is not acceptable but
potential financial gains are significant given the value placed on human life, health
and well-being.
Wilson has said that regulatory agencies operate in a world of powerful
lobbyists, high priced attorneys and manipulative experts. We also presume that the
ambitions of bureaucrats are reinforced by the electoral needs of Congressmen and
the private claims of interest groups. This is illustrated through the concept of the
regulatory agency being “captured” by the interests they are supposed to regulate.8
Why then, if agencies are captured, do businesses complain of the excessive
burden of regulation? There are several possibilities to explain this behavior. First,
the industry may disguise benefits it may be receiving. The regulatory process may
be insignificant compared to the benefits derived from competition-reducing
regulation. Differing agencies may have differing effects—benefiting some
industries while imposing standards requiring significant resources for compliance
on others, or requirements of one agency conflicting with the requirements of
another. Finally, business may suffer fiscal harm, but possibly to the benefit created
for the public.9 In general, the politics of regulation include how goals are
determined, conflicts resolved or managed, standards set and policy enforced. There
8 James Q. Wilson, The Politics of Regulation (New York: Basic Books, Inc., 1980), ix.
9Ibid.
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is no clear consensus on the value of regulatory programs or on the value of
government intervention in market transactions.
Regulation can take many different forms. Rigid and prescriptive regulation
is the most widely known where the entity is told with what it must comply and how
it should achieve that compliance. This model is typically enforced using adversarial
processes. There are other models that simply define the requirements to be met and
allow the entity to achieve the desired results as it chooses. This model typically
employs the use of policies, guidance documents, memos and manuals. This model
is also more cooperative in nature with education and negotiation as major
components.
The first notable efforts towards national regulatory legislation came at the
turn of the century. “The tremendous economic changes of the latter half of the
nineteenth century forced the mobilization of diverse interests demanding a policy
response to the growing concentration of economic and political power and the
elimination of decentralized local market systems.”1 0 This regulatory legislation was
intended to control corporate organization and practices in a number of industries
including rail transportation, finance, meatpacking, and pharmaceuticals. “This
regulatory regime took form only after the turn of the century, when the demands
were linked with Progressive arguments regarding state-economy relations and
administrative reform doctrines.”1 1
1 0 Eisner, 27-29.
"Ibid.
6
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When looking at the policies of the period it is clear that each is based on the
use of the market as a benchmark. In the specific case of antitrust policy Congress
passed the Sherman Act, the Clayton Act and the Federal Trade Commission Act.
These Acts were designed to eliminate or prevent industrial organization from
undermining market mechanisms. Policy-makers were committed to preserving the
markets and a decentralized industrial structure. However, in some cases the type of
industry itself, such as those requiring large capital investment, or where there were
significant benefits in economies of scale, precluded a return to the market. “Thus,
in the case of railroads and public utilities, policies were created to compensate for
the lack of markets by producing market-like results through administrative means.
This regulatory regime was, in essence, market corrective.”1 2
The Granger movement promoted the creation of local cooperative
organizations that brought farmers together for purposes of purchasing and
marketing and provided a basis for political mobilization. Farm groups, often
working with small merchants, focused on the clearest symbol of the new economic
order, successfully demanding laws regulating the railroads. In the early 1870s
depressed farm prices gave the larger economic-structural changes new
t ^
significance. And so regulation began in the late 1800s with the Interstate
Commerce Commission (ICC).
l2Ibid., 27-28.
ljMorris P. Fiorina, “Flagellating the Federal Bureaucracy,” Society 20, no. 3 (1983): 66-74.
7
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Since that time this has expanded into areas including health, safety and the
environment. In each case, the reason for regulation was based on different issues.
In all cases the process was reactive-responding to some event or public pressure.
One additional aspect of regulation is that it is forced to consider equity and
fairness—a balanced playing field for all participants. It is said, “In this sense,
regulations are designed to protect the powerless against the powerful.”1 4 This is the
very reason why the American public accepts the curtailing of the capitalist, profit
driven activities of industry in order to protect the public’s welfare. “The common
thread running through economic, environmental, technological and social
regulations is the elusive concept of public good. A government’s ultimate authority
in issuing regulations is as the guardian of this public good.”1 5
There are some areas of regulation that have additional responsibilities; areas
where there is a risk and a benefit associated with controls. Technology is one such
area where the reason for regulation relates more to the adverse consequences that
may result from failure. Regulatory agencies that deal with technology (i.e., medical
device regulation by the FDA) establish standards to prevent unintended
consequences, when possible. These regulatory agencies fulfill the government’s
role in controlling technology because Congress is not capable of dealing with the
rapidly changing technological world. The risk associated with this control is that it
1 4 Kurian, 504-510.
1 5 Ibid.
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may inhibit exploration in new technologies or improvements in existing technology
because of regulatory burden and uncertainty.
Regulation presents a unique challenge to both the public and private sector.
The challenge is simply stated: How do we provide sufficient regulation and
oversight to protect the public while ensuring that those regulations are not crippling
the ability of the private sector to be innovative? This lack of advancement may be
detrimental to that same public those regulations were intended to protect.
In the estimation of venture capitalist Robert Daly, “The new
regulations and delays mean adding $10 million to $20 million
to a company’s budget, and several years until the device gets
to market. At that rate, most [venture capital] deals don’t
make sense.” Increased costs mean that some investments are
no longer expected to generate a satisfactoiy return, some
innovations are no longer worthwhile to develop, and
ultimately some patients will suffer and die as a result.1 6
Regulatory program effectiveness is based on three key outcomes. First, it
may be necessary to regulate an entity and that regulatory effort may be effective.
Second, regulation may be necessary but the regulatory effort may be ineffective due
to poor implementation or inadequate resources. The third possibility, the flip side
of regulation, is not that regulation is ineffective but that it is overly effective—
eroding economic efficiency and national competitiveness. This third scenario
generally results from (1) politicians bending to advocacy groups and enacting
Robert Higgs, Hazardous to Our Health (Oakland, CA, The Independent Institute, 1995),
73.
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unreasonable regulations1 7 and (2) rent-seeking—where business pressures
politicians to promulgate regulations to “keep the other guy at a disadvantage.”
The net effect of “over regulation” is that it costs the regulating agency time
and resources with no value added to their mission and to the detriment of other
activities that could provide benefit. It costs industry time and resources, again with
no value added to their business objectives and to the detriment of other activities
such as new product development, job retention, etc. Over regulation may also cost
the public. Those individuals protected by regulation can suffer from delayed access
to new technologies. Additional costs can be passed on to them by industry. Even
loss of jobs could result as national competitiveness wanes.
Purpose of this Research
Since the Medical Device Amendments to the Food Drug and Cosmetic Act
were enacted in 1976, there have been several evaluations that demonstrate a failure
of the Agency to fully implement the regulations.1 8 In addition, between 1993 and
1995, it became quite clear that the manner in which the amendments were codified
into regulations were bureaucratic, not necessarily science based and unduly
burdensome. The net effect was a protracted regulatory process that protected the
1 7 David H. Rosenbloom and Richard D. Schwartz, eds., Handbook of Regulation and
Administrative Law (New York: Marcel Dekker, Inc., 1994). (See also Weaver, 1978.)
1 8 “The Temple Report” Subcommittee on Oversight and Investigations, Less Than the Sum
o f Its Parts (Washington, DC: U.S. Government Printing Office, May 1993); The Wilkerson Group,
“Forces Reshaping the Performance and Contribution o f the US Medical Device Industry, (New
York: The Wilkerson Group, June 1995); and FDA Reform Legislation, Hearings Before the
Subcommittee on Health and Environment of the Committee on Commerce on HR. 3199, 3200, and
3201, U.S. House of Representatives, 104t h Cong. 2d sess., May 1s t and 2n d , 1996, Serial No. 104-99.
10
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public health from harm, and at the same time denied it technological advances that
could save lives. In other words, the mission of the FDA was to protect the public
health rather than promote the public health.
After several years of privately funded studies, Congressional investigations,
formal hearings before Congress, and three more amendments to the Act, Congress
enacted the Food and Drug Administration Modernization Act (FDAMA). This
legislation was a bipartisan effort and sought to reduce regulatory burden without
lowering the statutory requirements for establishing the safety and effectiveness of
medical devices. To that end, Congress provided the agency with the latitude to seek
alternative methods to achieve this goal. The results of this effort have been defined
as the Least Burdensome Provisions of the Act.
Efforts to reform the process by which federal administrative
agencies carry out the laws passed by Congress are grounded
in implicit and only loosely constructed hypotheses about the
regulatory process. Further, attempts to test alternative
hypotheses have been largely unconvincing because the
approaches—primarily case study and anecdotal—yield
insights that cannot be confidently generalized.1 9
The Food and Drug Administration Modernization Act was legislated to
reform the processes used to bring new drugs and devices to the American Public.
The objective of the Act was to streamline the regulatory process while maintaining
or improving the protections afforded by such regulation. Least Burdensome
provisions of the Act were written to change the regulatory process for medical
1 9 Wesley A. Magat, Alan J. Krupnick, and Winston Harrington, Rules in the Making A
Statistical Analysis o f Regulatory Agency Behavior (Washington, DC: Resources for the Future,
1986), xi'.
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devices to be more efficient without lowering the standards for safety and
effectiveness. Greater efficiency tends to lead to better predictability in the process.
The purpose of this research is to evaluate implementation of the Least Burdensome
provisions of the Modernization Act through both quantitative and qualitative
methods and draw conclusions regarding whether these provisions have been
effective.
The specific questions to be answered are:
OA
• What effect have the provisions had on 510(k) review times?
• What effect have the provisions had on communication between the FDA
and industry?
• What effect have the provisions had on resolution of significant issues?
Significance of this Study
Regulatory agencies, especially social ones like the FDA, receive tremendous
amounts of information that they must process through a series of complicated steps
to reach decisions. These decisions generally affect a particular industry category
and take place in an agency setting constrained by Congressional, executive, and
judicial oversight.
The Least Burdensome provisions are incremental policy reform within the
context of FDA modernization. It is important to understand whether this
2 0 Section 510(k) of the Medical Device Amendment to the Food Drug and Cosmetic Act
describes the regulatory review process for currently marketed established medical device clearance to
market. These devices are described as “me too” in that there are no significant new technologies or
clinical indications claimed, rather they are improvements of existing technologies for similar
indications.
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incremental regulatory policy change is successful or not. This would be evidenced
by changes in communication, the 510(k) process, guidance documents being issued
and used. Another important factor is whether this change has been implemented
through tactical activities or whether there is also an organizational change seeking
to modify the culture of the organization to think in a manner consistent with the
Least Burdensome philosophy.
This research is important in many different respects. From the perspective
of healthcare providers and consumers a change to the regulatory process that makes
it faster and more predictable could result in access to new and improved
technologies without sacrificing safety or quality. For the taxpayer who foots the bill
for government processes, the prospect of more getting done faster with same
resources would be considered a worthy goal. For the medical device industry less
work/cost to get approvals leads to more improvement and innovations. This leads
to more jobs retained in research and development and manufacturing in the United
States. For the politicians increasing U.S. competitiveness through medical device
exports improves the economy.
For the FDA, as with other social regulatory agencies, regulatory policy is
influenced by fear that a mistake will let something bad happen and this is to be
avoided at all cost. It begins with Congress and the fact that for many of these
procedural agencies, Congress cannot say how safe is safe enough. So, they pass
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broad powers and force the agency to deal with this ambiguity, and then criticize
0 1
when implementation is not good enough.
In a regulatory agency the expectation for regulatory policy is zero errors.
There are accolades when the public is saved from something bad such as tainted
grapes from Chile or Tylenol bottles that had been tampered with. In these types of
events there is no concern for how remote the probability of harm might be.
On the other hand, if the public perceives that the FDA is not adequately
providing protection from devices that can cause harm, they are severely criticized.
This was the situation with the failure of heart valves or breast implants. The
question asked was what failure in FDA process allowed these harmful devices to
enter the market. Finally, the agency is also considered to have failed their job if a
life saving drug or device is delayed or not allowed to be placed on the market if
there is a perceived benefit that the public desires. In these cases the agency is
considered to be too conservative.
This research will help us learn about regulatory policy with in the context of
Least Burdensome to better understand the balance between risk and benefit.
Demonstrating that there are activities and administrative processes that work
effectively to manage the risk while allowing the benefit, could open the possibility
for Least Burdensome to be extended to other social regulatory agencies and
improve their processes as well.
2 1 James Q. Wilson, Bureaucracy: What Government Agencies Do and Why They Do It (New
York: Basic Books, Inc., 1989), 246.
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Regulation is a major area in the academic field and practice of Public
Administration. The expectation that government will protect us requires the
administration of public resources to develop policies to meet those expectations.
How public policy is used to achieve the goals of regulation without creating
problems is a delicate balance.
This research is of substantive value to regulators seeking knowledge about
regulatory processes. With this expanded knowledge, better decisions can be made
with regards to regulatory policies leading to a common goal. That goal would be
continued protection under the regulations without burden that has no added value to
the process.
The significance of this research lies in the knowledge gained by
understanding whether this change to the regulatory process achieved those goals
and objectives set out by President Clinton’s administration and carried on by
President Bush.
Research Plan
The intent of the provisions are to reduce the burden on both agency
resources as well as industry resources by allowing alternate means of establishing
compliance to regulatory requirements. If the Least Burdensome provisions result in
reduced resource requirements while continuing to achieve regulatory compliance,
the public continues to be protected and may not be denied access to life saving new
technologies. In addition, those unused resources can be applied to more value-
added work. The concept of Least Burdensome regulation has been demonstrated to
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be effective, and could potentially be extended to other regulatory agencies and their
processes.
This research is accomplished through analysis of two specific programs
implemented under the Least Burdensome regulations. The first analysis involves
the assessment of the Least Burdensome provisions directed at the Pre Market
Notification or 510(k) process. This analysis compares review times of traditional
510(k)s before and after the implementation of the Least Burdensome provisions, as
well as those for Special and Abbreviated 510(k)s. The goals of the Least
Burdensome provisions are to establish “fast track” processes for simple devices or
device modifications and to ensure that clinical data was only requested for devices
requiring such studies to establish equivalence and finally, the use of recognized
standards.
The second area of analysis addresses the provisions related to the Pre-
Market Approval (PMA) process. The issues with the PMA process involve the
clear communication and common understanding between the FDA and the industry
sponsor regarding the appropriate clinical endpoints necessary to establish safety and
effectiveness of a particular device to achieve market approval for a new technology.
The Agency initiated formal meetings with criteria by which determinations would
be made and agreed upon. Measurement of the success of this program is not
achievable by evaluating review time for PMAs because the technologies are
extremely complex. Also, the variables that affect time for completion of clinical
trials and PMA review and approval are numerous.
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An analysis of the success of this aspect of the program is accomplished
through the use of elite interviews. Those selected for interview have experience
under the FDA PMA regulatory process prior to the enactment of the Least
Burdensome provisions as well as experience with the Least Burdensome programs.
The objective is to understand whether the industry representatives perceive a change
in the process and in what direction that change is moving.
Delimitations
The scope of this research is limited to the evaluation of a specific program
(Least Burdensome) within a particular aspect (content, review and predictability of
pre-market submissions) of a regulated industry (medical devices) to minimize the
effect of external variables. It is also limited to the data resident on the FDA Web
site for 510(k) submissions, and to the medical device industry perspective with
regards to the IDE and PMA processes. This focus allowed sufficient time to
execute a true elite interview process with stakeholders and analyze the data, while
maintaining the reliability and validity of the information.
Plan of the Dissertation
Chapter 2 is a review of the literature relevant to understanding the regulatory
process and how regulation plays a role in the larger field of Public Administration.
Chapter 3 describes the specifics of FDA Regulation of Medical Devices. Chapter 4
follows with a detailed explanation of the Least Burdensome regulatory model. This
model is the basis for the dissertation research and so a significant amount of
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information is provided about the legislation and subsequent implementation within
the Center for Devices and Radiological Health (CDRH) of the FDA. Chapter 5
describes the research problem with detailed description of limitations of the study.
Chapter 6 then addresses the population to be studied, how the data is generated and
the methodological approach used in designing and then executing the study.
Chapter 7 is the heart of the research findings with the analysis of the data and
results. Finally, Chapter 8 concludes with a summary of the effectiveness of the
Least Burdensome provisions and how this research might be expanded into future
studies.
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CHAPTER II
LITERATURE REVIEW
There has been considerable research on the subject of regulation and the
various theories and models that have been employed throughout that history. The
majority of this literature describes the negative effects of regulation to include both
burden on the industry and agency as well as the potential for causing harm either by
error or omission. The many areas where regulation has benefited the public, averted
danger and even saved lives have not been as thoroughly evaluated. It is not
uncommon for a lack of assessment to exist where the process is working; rather the
literature tends to focus on areas for improvement.
Regulation is an emotional issue because many of the regulated believe that
they are being punished for someone else’s failure to do the right thing. This
frustration and resentment is a consistent thread through much of the literature in the
medical device area and very evident in the Congressional hearings. Particularly the
performance issues of the FDA that brought about the needed changes in the Medical
Device Review process.
This literature is selected as the basis for this research because the FDA
Modernization Act calls for a regulatory model that addresses the issues of the past
and looks towards a more global, harmonized process. These goals can only be
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achieved through methodologies that stem from the very core of regulatory theory
and models. These theories are the foundation from which to ask the question
whether the Least Burdensome provisions of the Modernization Act initiated by the
FDA contribute to the goal of an improved regulatory process.
While there is much in the research regarding the FDA regulation of drugs,
there is very little in the way of medical devices. There are some similarities
between the two regulatory processes; however, the issues are significantly different
with regards to changing technologies, risk benefit assessments, and the shear
duration of the approval processes. To that end, this research will deal specifically
with the area of pre-market approval of medical devices and those processes, before
and after the Least Burdensome provisions. At this time there appears to be little in
the literature that addresses the specific issue of changing regulatory policy to reduce
the burden of compliance and not give up on the safety net provided by the standard
processes.
Regulatory Regimes
The history and evolution of regulation has been theorized to be a series of
regimes. The majority of regulatory initiatives of the past 100 years began with
popular demands that were stimulated by perceived threats of economic and social
change.2 2 These demands have threads that reach not only through regulatory policy,
but also political-economic theories and administrative doctrines. Thus, regulatory
change has many times been a combination of policy change and institutional
2 2 Eisner, xiv.
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reform. The theory of regulatory regimes is based in the following definition.
“Policy is purposeful pattern of action rather than a mere expression of intent or
proclamation of goals.”2 3
Regulatory legislation is often imprecise and policy is
routinely defined through implementation.. . . Regimes are
political-institutional arrangements that define the relationship
between social interests, the state, and economic actors such as
corporations, labor unions, and agricultural associations 2 4
Economic changes create concern and that uncertainty drives the demand for better
definition of government role in the economy. Those in power and those who have a
great deal to lose use their influence to initiate changes in government that will
protect their interests.
This driving force can be seen throughout the four primary regulatory
regimes that have occurred since the late 1800s. The four regimes to be described
are the market regime, the associational regime, the societal regime and the
efficiency regime.2 5 The regulatory regime of the Progressive Era is termed the
Market Regime because it used the market as a benchmark. This regime was a
response to the development of large corporations. Its purpose was to establish rules
around anti-trust and force a return to a market economy and also to set rates
equivalent to those that would have existed under market conditions for things such
as electric power and rail transportation where there was no competition.
2 3 James E. Anderson, Public Policy-Making, 3d ed. (New York: Holt, Rinehart & Winston,
1984), 3.
2 4 Eisner, 2.
2 5 Ibid.
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The era of the New Deal, in response to the economic collapse of the Great
Depression, brought the next regime into play, the Associational regime. This
regime was all about recovery, the creation and expansion of regulatory subsystems
was intended to achieve one objective. To promote industrial stability and
redistribute national income to certain regulated groups. Government promoted the
idea of economic associations playing a role in defining and implementing regulatory
policy. They effectively created a system of government-supervised self-regulation.
“By integrating interest groups into the regulatory process through quasi-corporatist
arrangements, they promoted economic stability, allowed regulators to draw on the
expertise and resources of the regulated, and minimized confrontations.”2 6
The regulatory initiatives of the 1960s and 1970s are completely contrasting
to those of the Progressive Era and the New Deal. “Deep skepticism about the
distribution of economic power in society and about the excesses of capitalist
production contributed to a rejection of the earlier goals of regulation.”2 7 The
regulatory policies of this period were intended to protect the public from the
environmental and health hazards that came from such large-scale industrial
production. This “social regulation” expanded regulatory authority all the way into
the production process itself. Where previously regulation had to do with finance
and economics and the business entity as a whole, this new regulatory policy
affected how things were done inside the entity. This was the era of the
2 6 Ibid., 5.
2 7 Ibid.
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Environmental Protection Agency (EPA) and the Occupational, Safety and Health
Administration (OSHA), the FDA and the regulation of medical device
manufacturing processes through GMP. This regime is described as the Societal
Regime.
Finally, during the late 1970s and early 1980s policy was shaped by attempts
to address the failing economy. High inflation rates, sluggish growth and
international competitiveness all caused the legislators to look for “culprits.” One of
those culprits was identified as regulation. Successive presidents initiated programs
to evaluate the cost and benefits of the regulations imposed. At the same time they
were asking for new regulations to be rationalized, they were initiating deregulation
in several areas. The message became efficiency. These initiatives extended
throughout the 1990s under the auspices of “government reinvention.” The goals
were to increase flexibility and reduce the cost of compliance, hence the name
Efficiency regime.
Regulatory change has not stopped, although there is not yet a new regime.
The continuation of the programs and policies initiated in 1990s under the
reinvention flag are for the most part ongoing. The question is have they been
effective?
The literature on how regulatory agency processes work or their effectiveness
is very limited. In one overview of regulatory literature, Joskow and Noll concluded
that “Extensive attempts at modeling the behavior of regulatory agencies and
regulatory processes have not as yet been forthcoming.. . . Very little research is
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available on the comparative outcomes of different regulatory institutions.”2 8 Most
of the literature addresses the causes of regulation and not the regulatory processes
themselves. Theories on regulatory origins try to explain why agencies make
decisions to regulation or deregulate industries or economic activities. These
theories include capture theory where the regulators are captured by those industries
that they regulate,2 9 external signals theory where third parties are monitoring and
speaking out on the regulatory process, and public choice theory where regulators are
seeking to satisfy their own desires and those of the elected officials that oversee
them.3 0
Capture Theory of Regulation
The capture theory of regulation proposes that employees of single industry
agencies, over time, begin to identify the interests of the agency with the interests of
the industry. This “capture” results from the repeated contact of agency and industry
employees as they work towards fulfilling regulatory requirements. Capture can also
occur when key employees either worked for industry and moved to government or
more typically worked for government and would like to work for industry. This is
the so-called “revolving door” practice. The final major component contributing to
2 8 Paul Joskow and Roger G. Noll, “Regulation in Theory and Practice: An Overview,” in
Studies in Public Regulation, ed. Gary Fromm (Cambridge, IM A : MIT Press, 1981).
2 9 George J. Stigler, “The Theory of Economic Regulation,” Bell Journal of Economics 2, no.
1 (1971): 3-21.
,0Barry M. Mitnick, The Political Economy of Regulation: Creating, Designing and
Removing Regulatory Forms (New York: Columbia University Press, 1980).
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regulatory capture is where the industry is expert, holds all of the information or data
and can thus exercise a significant amount of influence over the agency.3 1
The whole issue of regulatory capture presents a dilemma when compared to
the lack of communication from the FDA. If there is capture or too close a
relationship between the agency and industry, this will lead to ineffective protection
of the public interest. The alternative has been clearly demonstrated through
Congressional and industry studies as resulting in paralysis.3 2 Nothing gets done,
which is just as harmful to the public. Therefore, regulatory policy must consider
appropriate controls to address the potential for capture while at the same time not
tying the hands of those executing the process.
External Signals Theory
Within the context of the societal and efficiency regulatory models External
Signals Theory plays a significant role in explaining not only the origins of
regulatory policy, but in their implementation. External signals as defined by Noll3 3
are those from groups external to an agency who measure its success and provide
feedback both within the agencies process and outside of it. In general, the agency
will seek outcomes that balance conflicting demands. In the case of medical device
3lMagat, Krupnick, and Harrington, 13.
3 2 “The Temple Report” Subcommittee on Oversight and Investigations; and The Wilkerson
Group.
j3Roger G. Noll, ‘ '‘ 'Government Administrative Behavior and Private Sector Response: A
Multidisciplinary Survey,” Social science working paper 62 (Pasadena, CA: California Institute of
Technology, 1976).
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regulation, protect the public without adversely affecting access to new technologies.
The objective is to “minimize conflict and criticism which appear as ‘signals’ from
the economic and social environment from which they operate.”3 4
Within the medical device industry there are many external groups
monitoring the performance of the regulatory process, both from the perspective of
the healthcare consumer and the perspective of the industry that provides these
products and services. The consumer advocates include the Public Citizen Health
Research Group headed by Dr. Sidney Wolfe, and Congressional oversight
committees. The industry advocates include AdvaMed (formerly Health Industry
Manufacturers Association HIMA) and independent research companies to include
the Wilkerson Group.
In addition to these advocate groups there is also Emergency Care Research
Institute (ECRI). This group provides information about device performance to the
hospital community. This information covers everything from side to side
comparisons of products to potential hazards from device failures. Each of these
groups observes and then reports on FDA and industry performance through their
own publications, as well as in the trade press and general media. Congress, in
particular, is sensitive to issues from constituents or the media where there appears to
have been a failure of the FDA to protect the public. This type of feedback triggers
corrective action leading to behavioral changes in both the legislators and the
regulators.
3 4 Mitnick, 138.
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Public Choice Theory
Public choice is based on the actions of individuals. These actions are made
on their own preferences and are generally better informed than would a decision
made for them by a government agency. For example, voters choose candidates
whose positions reflect their own opinions. The public employee pursues strategies
that lead to promotion and increasing the size and budget of the organization.
Elected officials deal with constituency requests that enhance the probability of
35
reelection. In a sense this simply means that we do what we are rewarded for, and
the reward is that outcome we desire most.
The Food Drug and Cosmetic Act as amended is not well defined and gives
broad discretion to the FDA to implement regulations to protect the public from
harm. Public choice theorists would argue that an agency with such powers would
promote its own self interest and those of the government officials they seek to
please, rather than the public interest.
History of Regulation
The Interstate Commerce Commission (ICC) was established in 1887. It was
the first regulatory commission in U.S. history and was established as a result of
mounting public indignation in the 1880s against railroad malpractices and abuses.
The railroad price wars of the late 1800s nearly destroyed the transportation system
in this country and triggered the regulatory process in the United States. This
5 Jack Rabin, W. Bartley Hildreth, and Gerald J. Miller, Handbook o f Public Administration
(New York: Marcel Decker Inc., 1989), 1002.
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regulation began at the request of farmers, union leaders, muckrakers and writers in
the nineteenth century. These people were socially conscious and wanted the
government to defend them from the robber barons and industrial cartels. Thus,
regulation was intended as a tool to help ensure a decent quality of life for the
American public by not only fighting monopolies, but destructive forms of
competition as well. With the creation of the ICC there was a shift in regulatory
powers to the Federal Government.
Until President Theodore Roosevelt’s administration, the ICC’s effectiveness
was limited by the failure of Congress to give it enforcement power, by the Supreme
Court’s interpretation of its powers, and by the vague language of its enabling act.
Beginning with the Hepburn Act (1906), the ICC’s jurisdiction was gradually
extended beyond railroads to all common carriers except airplanes by 1940. Its
enforcement powers to set rates were also progressively extended, through statute
and broadened Supreme Court interpretations of the commerce clause of the
Constitution, as were its investigative powers for determining fair rates of return on
which to base rates. In addition, the ICC was given the task of consolidating railroad
systems and managing labor disputes in interstate transport. In the 1950s and 60s the
ICC enforced U.S. Supreme Court rulings that required the desegregation of
passenger terminal facilities.
This shift in regulatory powers to the Federal Government continued through
the Wilson era with the Coast Guard in 1915, and the Tariff Commission in 1916.
Subsequent administrations followed with the Commodities Exchange Authority in
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1922, Customs Service in 1927, Federal Radio Commission in 1927, Federal Power
Commission in 1930 and the Food and Drug Administration in 1931.3 6
Chronology of Regulatory Powers and Agency Creation
Regulation is founded in the Constitution in the commerce clause (Article 1,
Section 8) that reads: “To regulate commerce with foreign nations, and among the
several states, and with the Indian tribes... .”3 7 This clause is where government is
granted the legal authority to regulate commerce for the first time. Regulatory
powers were originally granted for the purposes of trade and as a result were
established as part of the executive branch. “In each case the executive was
responding to rather than anticipating industrial and economic changes.”3 8
There were numerous agencies and even more regulatory legislation that
touched every aspect of American business. In 1931 the Bureau of Chemistry, that
had been a part of the Department of Agriculture, was established as the Food and
Drug Administration under the Department of Health and Human Services.
Additional legislation included the National Industrial Recovery Act of 1933.
This act gave authorization to create the Code of Federal Regulations (CFR) and the
Federal Register in 1934. The Federal Register recorded the activities of the
legislature. Regulations and executive orders were published in the Federal Register.
In addition to the Federal Register the regulatory agencies were bound by the
3 6 Kurian, 504-510.
,7 The Constitution of the United States, Article 1, Section 8.
,8 Kenneth Meier, Regulation: Politics, Bureaucracy and Economics (New York: St. Martin’s
Press, 1985).
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definitions and implementations of regulation they codified in the CFR. Finally, in
1946, the Administrative Procedures Act defined standard operating procedures for
regulatory programs.3 9
1798, Marine Hospital Service Act
During the same period of regulatory development, a much older
organization evolved; it was eventually integrated into the Department of Health and
Human Services. This organization was the Public Health Service. Between 1800
and 1850 the United States experienced incredible growth while the public health
activities did not. As a result, there were many epidemics that reduced the average
life expectancy in U.S. cities to less than life expectancy in London. At that time,
London had the reputation for the most unsanitary living and working conditions in
the “civilized” world. “... the average age at death in large English cities was only
36 years for the gentry, 22 years for trades-people, and 16 years for the laboring
class.”4 0
The Public Health Service in the United States actually began in 1798 with
the Marine Hospital Service Act that provided healthcare for sick and disabled
seamen. Most of the work of the Public Health Service, up until 1935, was carried
out under the Treasury Department. It was not until 1870 that a Surgeon General
was appointed for the Public Health Service. In 1878 the port quarantine legislation
3 9 Fredrick V. Mosher, Basic Documents of American Public Administration, 1776-1950
(New York: Holmes & Meier Publishers, 1976), v.
4 0 John J. Hanlon and George E. Pickett, Public Health Administration and Practice (St.
Louis, MO: The CV Mosby Company, 1979), 2.
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was passed, which authorized the Public Health Service to investigate disease and
disease prevention.
The rapid growth of cities tended to out run the forces of law
and order and to smother under the weight of numbers any
attempts at civic reform. Before public health measures could
be adopted or enforced, other more pressing problems had to
be solved. An effective police force, the first requisite of
community life, did not make its appearance in the Atlantic
seaboard cities until 1853, and satisfactory fire prevention
came even later. Protection against the dirt and filth of human
aggregation, which threatened the life of every man, woman
and child, had to wait upon the adequate enforcement of law
and order.4 1
Endemic disease was fed by the dirt and overcrowding of cities. People
became frightened by smallpox, diphtheria, typhoid and yellow fever. These
epidemics were said to be caused by “Miasma,” this idea that the fumes in the air
filled with the stench or garbage, excrement, and disease could somehow infect you.
Rich or poor, a person could be well in the morning and dead by nightfall4 2 Even
minor afflictions often meant weeks of suffering because old-time medicine was so
inept. The medical care in the face of these diseases was largely limited to
disinfection and quarantine. “Public health officials splashed disinfectant about the
slums to demonstrate vigorous action against pestilence—a measure that proved to
be more a public relations measure than a success in improving sanitation.”4 3
4 1 John J. Hanlon and George E. Pickett, Public Health Administration and Practice (St.
Louis, MO: The CV Mosby Company, 1979). (See also Newsholme, 1925, 21.)
4 2 Otto L. Bettmann, The Good Old Days—They Were Terrible (New York: Random House,
1974), 135.
4 3 Ibid„ 138.
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1860, The Shattuck Report
The low quality of medical care is summed up in the following statement by
Holmes “if the whole materia medica as now used, could be sunk to the bottom of
the sea, it would be all the better for mankind - and all the worse for the fishes.”4 4
American public health in the mid-nineteenth century is best illustrated in the Report
o f the Sanitary Commission o f Massachusetts 1850, by Lemuel Shattuck (1793-
1859)4 5 The Shattuck Report, presented on April 25,1860, included the following
recommendations:
• establishment of state and local boards of health;
• a system of sanitary police or inspectors;
• the collection and analysis of vital statistics;
• a routine system for exchanging data and information;
• sanitation programs for towns and buildings;
• studies on the health of school children; studies on tuberculosis;
• the control of alcoholism;
• the supervision of mental disease;
• the sanitary supervision and study of problems of immigrants;
• the erection of model tenements, public bath houses;
• the control of smoke nuisances;
• the control of food adulteration;
4 4 Hanlon and Pickett; and O. W. Holmes, Writings XI, Medical Essays (Boston: Houghton
Mifflin Co., 1891), 22.
4 5 Holmes.
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• the exposure of nostrums;
• the preaching of health from pulpits;
• the establishment of nurses’ training schools;
• the teaching of sanitary science in medical schools; and
• the inclusion of preventive medicine in clinical practice, with routine
physical examinations and family records of illness.
This report presented the principal concepts and modes of action that
ultimately formed the basis of much of today’s public health policy and practice.
However, the report was not considered until some twenty-five years later.
Figure 1 illustrates the legislative history of FDA regulation from the FD&C
Act in 1938 to the Medical Device Amendments in 1976 through to the most recent
legislation in 2002 the Medical Device User Fees Modernization Act.
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Medical Device
Regulatory Reform
Legislation
tr
1993
National Performance Review
1982-1988
Congressional
Investigations and
Hearings
TheVUIksrsonStLKfy
Hiird Party
Review Pilot
rr
1938 1975
Food Drug
and
Cosmetics A3 1975
Medical Device
Anencfcnentto
FD&C A3
1985
1984
M ecfical Deuce
Reporting Regulations
1978
Good Manufacturing
Practices Regulations
21CFR820
1990
SafeMscfcd
Devices A t
1995
1993
Temple Report 1906
Export Reform
2000
2002
Mecfcal DeMoe
Amendments
MDUFMA
1992
Mecfcal Device
Amendments
1997
FDA Modernization Act
(Least Burdensome
Provisions)
I l l I I 1
1 Forel 1
Carter 1 Reagan I Bush I Clinton
I Bush
: m :
1 1
D(D) R(D) ! m I
! j
D(D)/D(R)
j m
* R(D) indicates Republican Administration and Democratic Congress
Figure 1. Regulatory Reform Legislation Timeline.
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1906, Federal Food and Drug Act
The Federal Government had shown little interest in food and drug laws until
1906 when public opinion underwent a radical change. Dr. Harvey Wiley, a
visionary public servant, fought for passage of the Federal Food and Drug Act of
1906, one of the nations first consumer protection laws.4 6 Dr. Wiley, who was the
zealous and colorful head of the Bureau of Chemistry at the Department of
Agriculture, championed a movement for reform. In 1897, Dr. Wiley instigated the
Association of Official Agricultural Chemists to promote the new food and drug law.
Dr. Wiley was concerned with the “bilking of consumers through adulteration of
food.”4 7 In addition, Dr. Wiley was concerned about the hazards to consumers
health as well, particularly such hazards posed by patent medicines. Dr. Wiley’s
Congressional testimony created a public following for food and drug legislation.
This following included several concerned groups, such as the American Medical
Association, the American Pharmaceutical Association, and the Ladies Home
Journal and Colliers magazines.
At the same time Dr. Wiley was championing his cause, writer Upton
Sinclair took his place in the ranks of the “Muckrakers.” President Theodore
Roosevelt coined this term in 1906 to refer to a group of journalists who devoted
themselves to exposing the ills of industrialization. Sinclair published a book
entitled The Jungle. This novel described the conditions in the meatpacking
4 6 David Kessler, A Question o f Intent (New York: Perseus Book Group, 2001), 121.
4 7 Wilson, The Politics of Regulation (New York: Basic Books, Inc., 1980), 193.
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industry from the perspective of an immigrant laborer. The story provided
descriptions of how diseased cattle were processed into corned beef and how a
worker who fell into a rendering vat was “reincarnated” as pure lard. A public
outcry against the unhealthy standards in the meatpacking industry was heard. This
book illustrated for the government and the American public, the dangers of
unregulated meat processors. Theodore Roosevelt and many members of Congress
read this book and were adamant that legislation be implemented. Before the end of
the year the Meat Inspection Act and the Federal Food and Drug Law (known as the
Wiley Act) were enacted and enforced by the Bureau of Chemistry.4 8
On June 30,1906, the Pure Food and Drugs Act was signed into law. The Act
was legislated despite great opposition from canning companies, drug and whiskey
interests, and those who sold proprietary medicines. The legislation resulted in a
program to control the manufacturing process, labeling and sale of food and was
given to Dr. Wiley to implement. In 1927, the FDA was established as the agency
intended to administer this ever-growing program. In 1938, the Federal Food Drug
and Cosmetics Act was signed and the FDA was subsequently transferred from the
Department of Agriculture to the Department of Health and Human Services. This
bill made more than 40 significant changes to the Wiley Act while retaining key
components. Some of these improvements include extension of the law to
cosmetics, requiring pre-distribution safety clearance for new drugs, establishment of
4 8 Les Schnoll, The Regulatory Compliance Almanac (Chico, CA: Patton Press, 2000), 4.
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standards for food packaging, inspections, and added the power of court injunctions
to the previous authority for seizure and prosecution.4 9
1976, Medical Device Amendment to the Food, Drug, and Cosmetic Act
Over the next four decades the focus of the FDA was on foods and the
regulation of drugs. As technology advanced and medical devices for diagnosis,
monitoring and therapy were becoming more complex, it became evident that this
was an area with serious implications for public health. In addition to the
complexities of these new devices was the opportunity for “quack” devices to make
clinical claims and provide no therapeutic effect for the patient. Once again, the
combination of a potential public health issue combined with a consumer protection
concern led to the expansion of the Food Drug and Cosmetic Act. In May of 1976,
the Medical Device Amendments5 0 to the Act were implemented, with provisions for
the classification and regulation of medical devices.
A medical device is defined as:
Any instrument, apparatus, appliance, material, or other
article, whether used alone or in combination, including the
software necessary for its proper application, intended by the
manufacturer to be used for human beings for the purposes of
diagnosis, prevention, monitoring, treatment, or alleviation of
disease; diagnosis, monitoring, treatment, or alleviation of, or
compensation for an injury or handicap; investigation,
replacement or modification of the anatomy or of a
physiological process; or control of conception and which
does not achieve its principal intended action in or on the
4 9 Ibid.
S 0 Medical Device Amendments of 1976, 21 USC 301, Public Law 94-295, May 28, 1976.
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human body by pharmacological, immunological, or
metabolic means, but which may be assisted in its function by
such means.5 1
Medical devices traditionally include three categories of action. There are
diagnostic devices, therapeutic devices and monitoring devices. An example of
diagnostic devices would include imaging such as ultrasound, magnetic resonance
imaging (MRI); in vitro diagnostic tests such as blood analysis, urinalysis, and drug
tests. Examples of therapeutic devices include internal and external defibrillators,
pacemakers, and infant radiant warmers. Monitoring devices include multi
parameter patient monitors that measure ECG, temperature, blood pressure,
respiration, EEG; fetal monitors that measure maternal contractions and fetal heart
rate; and oxygen saturation monitors. There are also general use medical devices
such as hand held surgical instruments, hospital beds, bandages, thermometers,
examination gloves and lights, etc.
1978, Good Manufacturing Practices Regulation
The regulation established in the Code of Federal Regulations (CFR) 21 CFR
820 describes current good manufacturing practices for methods used in, and the
facilities and controls used for the following: manufacture, packing, storage, and
installation of all finished devices intended for human use. This regulation is
intended to assure that these devices will be safe, effective and in compliance with
the Federal Food, Drug, and Cosmetic Act. Part 820 establishes basic requirements
applicable to finished devices, including additional requirements for critical devices.
5 1 Schnoll, 426.
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Part 820 is established and promulgated under authority of
sections 501, 502, 518, 519, 520(f), and 701(a) of the act (21
U.S.C. 351, 352, 360h, 360i, 360j(f), and 371(a)). The failure
to comply with any applicable provisions in Part 820 in the
manufacture, packing, storage, or installation of a device
renders the device adulterated under section 501(h) of the act.
Such a device, as well as the person responsible for the failure
to comply, is subject to regulatory action.5 2
Good Manufacturing Practices were added to the list of General Controls along with
Registration and Listing. These General Controls apply to all medical devices.
1984, Medical Device Reporting Regulations5 3
The Good Manufacturing Practices regulations included requirements for
complaint processing as a means of understanding device performance in the clinical
environment. This source of post-market data was intended to drive product
improvements and detect any potential safety issues with the device. Legislation
further extended this requirement and a formal process for adverse event reporting
was established. This process would serve two functions. First, it would provide
early access to adverse events facilitating timely investigation and/or notification;
this would help mitigate any further adverse events and further reduce the potential
for harm.
The data were also necessary for the agency to understand the clinically
established risk-benefit status for a particular type of medical device. In other words,
5 2 Code of Federal Regulations, 21 CFR Part 820—Good Manufacturing Practice for Medical
Devices, 1996, available from www.gpoaccess.gov/cfr/index.htral.
5 3 Code of Federal Regulations, 21 CFR Part 803—Medical Device Reporting, September
1984, available fromwww.gpoaccess.gov/cfr/index.html.
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with the existing state of technology, it showed what could reasonably be expected
with regards to safety of a device for a particular intended use. In addition, the data
would help to establish some baseline for device types with regards to potential
adverse events. These data could then be monitored for changes in trends as an
indication that further investigation may be warranted. The results of this
investigation might lead to corrective action, such as a safety alert or product recall.
1982-1988, Multiple Congressional Investigations and Hearings
During this timeframe, a series of Congressional hearings established that the
FDA had not met the statutory requirements of the 1976 legislation. The
deficiencies noted were in two areas. First, the agency was required to assess all
devices that were determined to be Class III when the Medical Device Amendment
was enacted. These devices were already in the market place but met the criteria for
a new technology or technologies with significant risk. An example would be
implants. These devices were referred to as Pre-Amendment Class III devices. The
regulations required the FDA to gather data regarding these devices and determine
whether there was sufficient clinical information to support a conclusion that the
device could be adequately controlled through use of a safety and/or performance
standard. If this criteria were met then a reclassification petition could be submitted
and the device classification changed. If this criteria could not be met, meaning that
there were still significant questions regarding the safety or effectiveness of the
device for its intended use, then the FDA was required to “call for PMAs” for that
device family. A PMA or PreMarket Approval submission is provided to the FDA
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for their review and approval for any new technology or new clinical application of
an existing technology that may have implications for safety or effectiveness. A call
for PMAs meant that the FDA would request all manufacturers of a particular device
type to perform clinical studies and submit PMAs for each of their respective
products. This assessment and call for PMAs was never accomplished.
The second major finding had to do with the 510(k) process. The 510(k)
Premarket Notification submission is provided to the FDA for their review and
clearance for devices that are known technologies and indications for use, so called
“me too” devices. This process is predicated on the fact that the safety and
performance of the device is controlled through compliance to standards. Therefore,
the FDA was required to develop performance standards for each family of devices
under the Class II designation for use by industry in the design of products and for
use by FDA reviewers to confirm equivalence in the 510(k) submission review. It
took more than 10 years for the FDA to create its first draft standard for apnea
monitoring devices (devices intended to detect when the patient is not breathing).
No others had been developed. The findings from these investigations brought about
the Safe Medical Devices Act of 1990.
1990, Safe Medical Devices Act (SMDA)
The SMDA5 4 introduced several major changes in medical device
regulations. These changes were focused on (a) compliance (giving the FDA better
tools for enforcement issues); (b) reporting requirements for improved
5 4 Safe Medical Devices Act, Public Law 101-629, October 1990.
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communication of adverse events; and (c) flexibility for the agency to gather safety
and effectiveness data on devices that were pre-amendment Class III.
Flexibility—Class II device regulation was now augmented with Special
Controls. Special Controls affect clinical data requirements for 510(k)s, use of
performance standards, post-market surveillance and patient registries. The FDA
was granted the authority to re-classify devices from Class III to Class II if Special
Controls were deemed adequate, and Class II devices to Class I if General Controls
were deemed adequate. Industry could submit a Petition for Reclassification of a
device and the FDA could ‘down classify’ based on this data. Class III devices
cleared via 510(k) would now be required to provide a summary of all adverse safety
and performance data, manufacturers could be required to comply with performance
standards, and, finally, an approval could be suspended if the device could cause
harm if distribution continued.
Monitoring—In the area of Medical Device Reporting (MDR) there were
major changes. Legislation requiring device user facility reporting was enacted by
Congress to increase the amount of information the FDA and device manufacturers
receive about problems with medical devices. Numerous reports have shown there is
widespread underreporting although manufacturers and importers of medical devices
have been required since 1984 to report to FDA all: device-related deaths, serious
injuries, and certain malfunctions. A 1986 General Accounting Office (GAO) study
showed that less than 1% of device problems occurring in hospitals were reported to
FDA and the more serious the problem with a device, the less likely it was to be
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reported. A GAO follow-up study in 1989 concluded that despite full
implementation of the MDR regulation, serious shortcomings still existed. To that
end, the FDA expanded the mandatory reporting requirements to user facilities and
distributors. A requirement for annual summaries was added for confirmation of
reports. And finally, specific definitions for serious injury/illness were provided.
FDA requirements for reporting recalls were also expanded. Specific
requirements on manufacturers responsibilities regarding reporting of Corrections
and Removals were also defined. The FDA could further require distribution to be
ceased and/or users to be notified. The agency also incorporated the assessment of
what happens if the device is removed from service and which option constitutes the
greater risk to public health.
Enforcement—The agency was given the authority to levy civil and criminal
penalties on companies that had significant, repeated violations of the Good
Manufacturing Practices regulations. A Center for Biologies was created to address
biologic products (blood banks, tissue engineering, etc.) and combination
drug/biologic products. The investigations leading to SMDA and the expanded
enforcement tools also led the way for expansion of the Good Manufacturing
Practices to include Design Controls.
Specifically, in January 1990, the FDA published the results of an evaluation
of device recalls that occurred from October 1983 through September 1989, in a
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report entitled “Device Recalls: A Study of Quality Problems.”5 5 The FDA found
that approximately 44% of the quality problems that led to voluntary recall actions
during this six-year period were attributed to errors or deficiencies that were
designed into particular devices. The problems may have been prevented by
adequate design controls. These design-related defects involved both non-critical
devices (e.g., patient chair lifts, in vitro diagnostics, and administration sets) and
critical devices (e.g., pacemakers and ventilators). Also in 1990, the Department of
Health and Human Services Inspector General conducted a study entitled “FDA
Medical Device Regulation From Premarket Review to Recall”'5 6 that reached
similar conclusions. With respect to software used to operate medical devices, the
data were even more striking. A subsequent study of software-related recalls for the
period of fiscal year (FY) 1983 through FY 1991 indicated that over 90% of all
software-related device failures were due to design-related errors, generally the
failure to validate software prior to routine production.5 7
The SMDA also added a new section 803 to the Act (21 U.S.C. 383), which,
among other things, encourages the FDA to work with foreign countries toward
mutual recognition of Current Good Manufacturing Practices (CGMP) requirements.
5 5 FDA, Center for Devices and Radiological Health (CDRH), Device Recalls: A Study of
Quality Problems, HHS Publication FDA 90-4235 (Rockville, MD: CDRH, January 1990).
5 6 0ffice of Inspector General, FDA Medical Device Regulation from Premarket Review to
Recall, HHS Publication OEI09-90-00040 (Washington, DC: Office of Inspector General, February
1991).
5 7 FDA, Center for Devices with Radiological Health (CDRH), Software-Related Recalls for
Fiscal Years FY 83-FY 91 (Rockville, MD: CDRH, May 1992).
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FDA undertook the revision of the CGMP regulation to add the design controls
authorized by the SMDA. The agency believed that it would be beneficial to the
public and the medical device industry for the CGMP regulation to be as consistent
as possible, with the requirements for quality systems contained in applicable
international standards. They are the International Organization for Standardization
(ISO) 9001:1994 “Quality Systems—Model for Quality Assurance in Design,
f a
Development, Production, Installation, and Servicing”' and the ISO committee
draft (CD) revision of ISO/CD 13485 “Quality Systems—Medical Devices—
Supplementary Requirements to ISO 9001.”5 9
1992, Medical Device Amendment6 0
In 1992, several provisions established in the 1990 SMDA were removed;
these provisions were related to the adverse event reporting system. The user and
distributor reporting was made voluntary rather than mandatory, and the requirement
for an annual summary report was removed. These were changed because the
Agency did not have the enforcement power, authority or resources necessary to
ensure that user and distributor facilities comply with reporting requirements. The
annual summary report was found to be redundant on the part of industry. In
addition, the Agency did not feel that resources should be applied to the task of
5 8 ISO 9001:1994, Quality Systems—Model for Quality Assurance in Design, Development,
Production, Installation, and Servicing (Geneva, Switzerland: International Organization for
Standards).
5 9 ISO Draft Revision of ISO/CD 13485, Quality Systems—Medical Devices—Supplementary
Requirements to ISO 9001 (Geneva, Switzerland: International Organization for Standards).
6 0 Medical Device Amendments of 1992, Public Law 102-300, May 1992.
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reconciling individual reports from a company to their summary report. It was felt
that these resources would be better used in a more value added activity.
May 1993, “Less Than the Sum of Its Parts”—The Temple Report
The Temple Report was based on an investigation performed by the
Subcommittee on Oversight and Investigations of the Committee on Energy and
Commerce, U.S. House of Representatives. The primary findings of the report are
summed up as follows:
The FDA’s efforts at implementing all of the major provisions
of the 1976 Amendments have been closely scrutinized and
highly criticized over the years. Some provisions, such as
performance standards for Class II devices, have never been
implemented; others, such as the regulations governing the
Premarket Approval (PMA) process have taken years to
implement. These failures have been attributed to the
impracticality of some of the provisions, the Agency’s
bureaucratic inefficiency, and, depending on how the statute is
interpreted, to Congressional vagueness and/or overspecificity.
But the end result has been that the provisions of the 1976
Amendments requiring the regulation of devices that were
already in the market prior to passage of the 1976
Amendments (the Preamendment devices), the premarket
notification provisions, and the Good Manufacturing Practices
(GMPs) provisions have been late in coming, have never
occurred, or have been implemented incompletely. Thus, the
assurances of safely intended by the 1976 Amendments have
not been realized.6
slThe Temple Report, 7.
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The Temple Report begins with a programmatic review of the approval
processes used by the Agency. Interviews with reviewers at the Agency revealed
several areas of concern.
• Resource management was a significant factor. (Are the right people
assigned to the right tasks?)
• There was more work than the staff could complete within the statutory
time requirements. (The volume and complexity of work exceeded the
number of people available to do the work in the timeframes required.)
• Expertise was another area where reviewers felt deficient. They lacked
training and time to take courses to keep up on technology advancements.
• The efficiency of reviews was another area for investigation. This
included delays caused by poor quality submissions from many
manufacturers, and a suggestion to screen submissions, allowing
communication with industry and Advisory Panel experts.
• Communication was the key factor described by all. Absence of
communication made reviewers work more difficult and time consuming.
The reviewers demonstrated that use of the phone and fax requests rather
than written requests saved time (hours versus weeks) resolving questions
and concerns.
Interviews with Agency management added that inefficiencies were caused
by other factors as well. These factors included loss of key reviewers and lack of
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direction from the Program Management Staff. Agency management expressed their
desire for the following changes:
• recommendations for 510(k) assessment for completeness;
• stratification and alternate process for 510(k)s;
• better use of guidance documents;
• establishing some level of predictability in the process; and
• use of Office of Science and Technology resources as experts.
This phase of the assessment formulated the rudimentary beginnings of the Least
Burdensome provisions regarding 510(k) submissions.
In the areas of IDE/PMAs, the findings were based on the study of a small
sample of device applications conducted by Dr. Robert Temple with an ad hoc
committee. His findings are described as follows:
. . . certain patterns of deficiencies in the design, conduct and
analysis of clinical studies were present in enough of the
applications to suggest that these deficiencies represent a
common problem, one regularly encountered by CDRH in
reviewing PMAs and 510(k)s.
In most of the applications reviewed by the committee, it
appeared that clinical trials, even large ones, were carries out
with little planning or attention to the purpose of the study,
and ignored a number of basic principles of experimental
design.
There were also significant deficiencies in study reporting and
analysis. Perhaps because of inadequate attention to study
design and endpoints before the study began, reporting of
results was often chaotic with inappropriate analyses, or with
inadequate comparisons to historical controls.
The deficiencies found by the committee were sufficiently
serious to impede the Agency’s ability to make the necessary
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judgments about the safety and effectiveness, or substantial
equivalence of the devices covered by the applications.
Although such deficiencies can be overcome in some cases,
they have negative consequences for both sponsors and users.
In an interview with the subcommittee staff following his
team’s review of an assortment of applications, Dr. Temple
criticized ODE’s failure to conduct, as a matter o f practice,
preliminary discussions between a medical device application
and the ODE review staff. He considered this failure to be a
hindrance to both the Agency and the industry in developing
an understanding of what would be needed in an application,
whether it be IDE, 510(k), or PMA. There is little, if any,
guidance on the kinds and quantity of data desired, the number
of patients that should constitute a study, when
biocompatibility data is necessary, or how much detail should
be provided.6 2
It is evident that these findings are the basis for the IDE/PMA provisions in
the Least Burdensome activities that specifically target these issues. The ideas
presented included meeting with the FDA, documenting the meeting and the
information discussed, and finally establishment of conclusions that are agreed upon.
The report continues with: identification of other issues in the area of enforcement,
the subsequent impact of these issues on the medical device industry and, finally, a
summary of recommendations for reform.
September 1993, National Performance Review (NPR)
In September of 1993, Vice President A 1 Gore released the results of an
intensive six-month study of the Federal Government. The report was a summary of
ideas and advice from Federal workers, state and local government officials,
6 2 Ibid„ 58.
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management experts, business leaders and private citizens. The purpose was to
recommend reforms that would change government from .. red tape to results to
/ • I
create a government that works better and costs less.” The principles of NPR
included cutting unnecessary spending, serving customers, empowering employees,
helping communities solve their own problems, and fostering excellence. NPR was
intended to drive change that would guarantee effective, efficient and responsive
government. The goal of these reforms was to “close the trust deficit,” by proving
that tax dollars were being well spent. The team that performed this study was made
up of Federal employees. What they found as the root cause of the problem was that
government operated as an industrial era bureaucracy in an information age.
There were four recommendations that came from the Gore report
specifically aimed at Health and Human Services (HHS) of which the FDA is a part.
• HHS02—Re-engineer the HHS process for issuing
regulations. HHS should improve the timeliness and
quality of regulations issued and should involve
stakeholders in the development of regulations.
• HHS 10—Institute and collect User Fees on FDA’s
inspection and approval processes. Food, drug and
medical device manufacturers, processors and suppliers
should be required to pay for FDA services.
• HHS 12—Strengthen department-wide management. The
department should conduct a review of its organizational
structure and management systems to determine an
appropriate balance between centralized and decentralized
functions.
• HHS 13—Review the field and regional office structure of
the HHS and develop a plan for shifting resources to
6 3 Albert Gore, The Gore Report on Reinventing Government (New York: Random House,
Inc., September 1993), 7.
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match workload demands. The review should emphasize
customer service, results and increased accountability.6 4
These recommendations at a higher level are consistent with the more detailed
findings of the Temple Report and earlier Congressional investigations of the FDA
and the regulatory processes used to manage medical devices.
1995, UCSD and Price Waterhouse
In 1995, findings of a study conducted on the FDA’s inability to meet
statutory obligations under the Medical Device legislation was published. There
were 4 primary findings. First, there were clearly elements of the FDA process that
slowed approvals.
These elements were lack of guidance documents, changing clinical
endpoints, requests for additional information, and changes in personnel, technical
competencies and overall submission quality. Communications policies were an
issue, with memoranda prohibiting communication between the reviewers and
industry. Recommendations to allow FDA/Industry communication, contacting
reviewers to clarify questions and verify responses and pre-submission meetings to
improve submission quality were offered. FDA process impact on device
availability was demonstrated through the process analogy. A faster review leads to
earlier market introduction and revenue generation. Understanding the impact of
timely approvals shows the economic realities that drove the pervasiveness of plans
to move medical device development offshore. In summary, conclusions reached by
“ ibid., 141.
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the report were that process improvements could be made by improved
communications and publication of guidance documents. By improving
communication and guidance documents, submissions to the agency would be
improved and the process expedited.6 5
1995 June, The Wilkerson Group Study
In June of 1995, an independent research organization was tasked with
examining what the current sentiment within the medical device industry regarding
the regulatory environment and determining if any changes were being made to their
business as a result. A report entitled “Forces Reshaping the Performance and
Contribution o f the U.S. Medical Device Industry”6 6 was prepared by The Wilkerson
Group, Inc., for the Health Industry Manufacturers Association (HIMA). The
purpose of the study began with an assessment of the industry supporting U.S.
medical technology. They described the industry in its modem form beginning in
the 1960s with the adaptation of technologies such as lasers, information processing
and imaging to the clinical community. The study also demonstrated that in
achieving these advances, the industry also created jobs for U.S. citizens and made a
significant contribution to the U.S. balance of trade.
6 5 UCSD and Pricewaterhouse, Improving America Health: A Survey of the Working
Relationship Between the Life Science Industry and the FDA (New York: Pricewaterhouse Coopers,
1995).
66The Wilkerson Group.
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The report then identifies several “challenges” that serve to threaten the
ability of the industry to continue with such innovative development of products.
The challenges they list included:
• managed care;
• payment policies for new technology;
• cuts in public financing of health care at academic medical
centers and teaching hospitals;
• product liability; and
• the increasing stringent regulatory environment making
new development and commercialization more difficult,
time consuming and costly.
The Wilkerson study followed a 4-step analytical approach: (1) Gather
preliminary evidence and identify prevailing forces as noted above; (2) Develop
initial hypotheses about the likely impact of these forces; (3) Analyze the impact of
these forces on the industry and supporting infrastructure; (4) Draw conclusions
concerning the long term effects on patient access, technological leadership and the
economy.
The report revealed a major issue through the survey and interview process.
The single
. . . most damaging element of device regulation was an
overwhelming sense of un-predictability... Increasing FDA
oversight decreases investment attractiveness, but at least
when oversight is consistent and predictable, investors and
industry managers can adjust planning accordingly. Today,
consistency is lacking in many areas raising numerous
questions... ”6 7
67
Ibid., 76.
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The findings and conclusions of the study summarized the strategies employed by
companies to adapt to the increased regulatory burden and un-predictability. These
strategies were necessary for growth and continued profitability and in some cases
economic survival.
Many companies adapted by expanding their presence in foreign markets and
moving device-related activities overseas, particularly new product development.
Other companies restructured operations to cut cost and through forming alliances,
sought to preserve growth and profitability. In other words, larger organizations
were able to withstand the cost and resource impact of increased regulation—a start
up company could not. The survey showed that 50-60% of companies were
increasing clinical studies in Europe. One third of these were increasing R&D in
Europe as well, due largely to the uncertainty and delays associated with FDA
regulation.
These decisions were based on simple economics. Increased requirements
and review times resulted in increased investments needed to commercialize a
product. This, in turn, delays the time to positive cash flow. The cost impact is then
two-fold. First, the increased investment needed to meet additional regulatory
requirements and second the loss of revenue due to delays in bringing the product to
market. These adaptive practices have allowed some companies to maintain their
growth and profitability; however, there are significant undesirable effects in the
U.S. There are three specific areas identified:
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• Patient access
• Industry structure and innovation;
• Economic contribution of the industry.
“US patients are gaining access to most breakthrough technologies and
important product improvements months or even years later than patient in other
countries.” Some companies are abandoning development of new technologies
because the regulatory demands make it difficult to justify product development
aimed at markets of limited scope and size. A common scenario to illustrate this
effect would be modification of devices and technologies from use in the adult
patient population to use in the pediatric and neonatal patient population. These
applications are at risk because the regulatory costs are well in excess of the costs for
the adult devices. For example, an adult oxygenator cost $50,000.00 to bring the
technology to market. The same oxygenator for pediatric use would cost more than
$1 million to bring to market. The total expected market capacity for this type of
device is about $9 million.6 9
1996 May, Congressional Hearings on FDA Reform Legislation
On May 1,1996, Mr. Bilirakis, Representative from Florida and Chairman of
the Subcommittee on Health and Environment, began the hearings on FDA reform
legislation. He stated:
We all want products to maintain, and I underline that, to
maintain our high standards for safety and effectiveness and to
68Ibid., xxix.
6 9 Ibid., 91.
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have an effective regulatory system. In my view, the goal for
FDA reform can be summed up in a single word, and that
word is access, access to new safe and effective products,
access to experimental products, access to information about
medical treatments, access to leading edge science and
technology, and access to high technology jobs in America.7 0
Many of the proposals in the bills presented during the hearings were not new
ideas. Some had come from both the Bush and Clinton administrations. The
problem had not been getting good reform ideas, but rather getting them
implemented. The following excerpts are from various Congressmen on the
committees that sponsored the reform bills under discussion. Their positions fall on
both sides of the FDA reform question, some stating that the reform is needed, but
care must be taken not to lower the statutory requirements that have so far kept the
American public safe. Many others have taken the position that the agency is
neglecting its duties to promote public health by delaying or denying access through
bureaucratic red tape.
Mr. Waxman (D), Congressman from California, urged caution in the process
by stating:
Changing the authority and practices of the Food and Drug
Administration is an activity which will affect every single
American.. . . We cannot make changes in the laws governing
FDA on the basis of general theories or vague intent to make
the Agency work better and approve things faster, however
well motivated those intentions may be. We have to look at
the specifics of the legislative proposals. We have to be sure
they are drafted to reflect our intent and we have to have
sufficient time to do the job right.7 1
7 0 FDA Reform Legislation, 1.
7 1 Ibid., 2.
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Mr. Bliley (R), Chairman of the Committee on Commerce, provided the most
comprehensive commentary regarding the reform process and its objectives.
We all want to stimulate innovation and development of life
saving new medicines and devices and we all want them
brought to the patients who need then as quickly as possible,
and we all want to continue consumer confidence in the safety
of those products, and we all want doctors and medical
researchers to effectively communicate, to disseminate
information so patients can benefit from the experience of
others.
Those goals are not achieved by the current regulatory
structure.. . . An essential element is that the regulatory
program for each category of product is suitable for the
particular product involved. Issues of safety and effectiveness
are different, after all, for each category of product and the
regulation of each should be no greater and no less than what
is reasonably required. We should always strive to eliminate
unnecessary regulatory burdens and that means a level of
Federal regulation no greater than is appropriate given the
circumstances.7 2
Mr. Greenwood (R), Congressman from Pennsylvania:
Two months ago, more than 300 individuals and patient
groups signed an open letter to Congress, patients suffering
from AIDS and cancer, relatives of those stricken with
Alzheimer’s disease and sickle cell anemia. Their message
was powerful. Americans are dying of red tape.
Consumer protection, they told us, means more than keeping
unsafe and ineffective products off the market. It is just as
important that safe and effective products are made available
to people who need them as quickly and as efficiently as
possible.. . .
7 2 Ibid„ 4.
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It’s not happening when it takes twice as long for approval of
the average new medical device as it did just 6 years ago. And
it’s not happening when, if your child needs the most
advanced medical treatment available, the first thing you have
to do is get that child a US passport.7 3
Mr. Burr (R), Congressman from North Carolina:
Someone once said “Only a fool is one that continues to do the
same thing, expecting a different result.” . . . Thomas
Jefferson said “I’m not an advocate for frequent change in
laws and constitutions, but laws and institutions must go hand-
in-hand with the progress of the human mind, as that becomes
more developed, more enlightened, as new discoveries are
made, new truths discovered and manners and opinions
change. With the changes o f circumstances, institutions must
advance also to keep pace with the times.7 4
Mr. Upton (R), Congressman from Michigan:
Unlike some of my colleagues, I do not believe that these bills
are somehow going to undermine the FDA’s prime mission
and threaten the health and safety of the American public.
The facts are that current FDA regulations and policies are
stifling innovation and those rules are threatening the health
and safety of our citizens. We must make sure that the
regulations fit the products and needs in question. This means
that the government may not have a comer on the market of
expertise and knowledge.7 5
And finally, Mr. Bilbray (D), Congressman from California:
Mr. Chairman, you will hear people speak today attacking the
FDA’s existing system and defending it, but I think that the
proof is in the pudding when you look at the fact that the FDA
recognizes that they have and have had problems that needed
to be addressed. I think you’ve seen the FDA try to internally
be very aggressive about trying to change some of their
7 3 Ibid, 5.
7 4 Ibid„ 6.
7 5 Ibid., 14.
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procedures. But, frankly, there are limits to the ability of a
bureaucracy to reform itself.7 6
During these hearings there were many who testified from industry and
academia. The following are selected excerpts from those statements that further
support the need for reform as well as some recommendations for change.
Mr. James Benson, Health Industry Manufacturers Association (HIMA) and
former FDA acting Commissioner:
The main problem that I see is FDA’s current leadership is
meandering from what I have always considered to be its
primary role of truly promoting the public health. Promoting
the public health doesn’t mean just stopping risky products.
That’s certainly important. It also involves promoting both
prompt patient access to safe and effective devices and a
sensitivity to the product development process which is our
avenue to new and innovative products of the future....
We must never loose sight of the fact that a life saved by a
new product is just as valuable as a life saved by blocking a
potentially risky product.. . . FDA sometimes insists that data
in support of new products demonstrate the precise or absolute
degree of risk that those products pose. Having been on the
hot seat, in fact this seat, on many complex issues during my
FDA years, I can fully understand the desire for absolute
certainty. But even the most vigorous testing cannot yet yield
absolute certainty about risks because science itself rarely, if
ever, yields absolute answers.
For this reason, Congress directed the Agency in 1976 to use a
standard of reasonable safety and effectiveness. Not absolute,
not perfect, but reasonable. Yet today the Agency veers from
this Congressional intent by seeking absolutes that science can
never intend.
That concerns me, Mr. Chairman, because in pursuing this
quest the Agency imposes new policies that are lengthening
7 6 Ibid„ 15.
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the product development process. Clearly, these FDA efforts
to expand effectiveness requirements and to seek more and
more specific data do not promote the public health. Instead,
they threaten it by reducing access you and I and every
American patient has to new treatments and, if the US industry
can’t get its products approved in a timely way, then we will
lose our innovative edge, our jobs, and, most importantly, our
quality health care in this country in the future.7
Mr. Richard Beebe, Hewlett Packard Medical Products Group:
Hewlett Packard believes that it is vital to increase regulatory
efficiency. In an ideal world there would be one regulatory
system worldwide. Progress is actually being made towards
this with the FDA’s new Good Manufacturing Practices
regulation. What I would like to propose today is that we take
another step along this road, in this case learning from where
we have already been.
HP proposes that Congress reaffirm its original intent for
regulating Class II medical devices. Class II devices are those
which Congress originally believed could be effectively
regulated by performance standards. FDA never promulgated
any performance standards for Class II devices required by the
1976 Medical Device Amendments, presumably because the
statute of required rulemaking, which is inefficient and too
costly a method for developing standards and keeping them
current.
. . . Nonetheless, over the last several decades, consensus
process of international experts which includes the FDA have
developed hundreds of standards which are currently being
used to evaluate device performance. This is a body of work
that should not be overlooked.
. . . What I am proposing is that the FDA identify which
standards it accepts and publish them in the Federal Register
to resolve product review issues.
If the FDA were to accept a manufacturer’s certification of
compliance to these standards, the Agency could focus its
effort on the remaining issues that really need an
7 7 Ibid., 315.
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individualized review, thus consuming significantly less
resources in the process.7 8
Mr. Beebe went on to state that use of consensus standards in review of
510(k) submissions would facilitate possible third party review of submissions. This
use of standards could also be extended to the Quality System Certification process.
Inspections based on the same standards could be done by several different entities,
not just the FDA. And, finally, standards could be the cornerstone for a global
harmonization effort.
1996, The FDA Export Reform and Enhancement Act, Third Party
Review Pilot
In 1996 there was an additional amendment to the FD&C Act, specifically
regarding the import and export of component parts of medical devices. At the same
time a very important pilot program was initiated. The idea of privatization of some
Federal Government activities was implemented and the FDA was expected to
investigate and propose a pilot program for the third party review of medical devices.
This Third Party Review program was implemented in a series of phases. Devices of
a simple nature were first to be tried. Devices with performance standards to govern
their safety and effectiveness were next. Third parties had to be qualified by the
FDA with regards to having the skill set, the integrity and the willingness to commit
to the process the FDA identified. The key to making this third party work and
ensuring that the third party review was equivalent to the FDA was in the application
of standards. The Third Party Pilot program began in August of 1996.
7 8 Ibid„ 357.
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This program of third party review is very familiar to the medical device
industry. The European Community regulates medical devices through third parties
in a manner that is very similar to the Underwriters Laboratories (UL) in the United
States. UL is a third party test laboratory that has published basic safety standards
for medical devices as well as many other consumer products such as hair dryers,
toasters, power tools, and so on. UL is a private entity that a company can enlist to
test their products to these standards, and if they pass, the company can apply the test
house mark of approval. In this case it is the UL symbol generally located on the
backside or bottom of the product. This test mark indicates that the product was
tested to basic safety standards. In some cities such as Los Angeles and Chicago,
and some states such as North Carolina, this mark is a requirement for the purchase
and use of such products.
The Clinton administration had made it clear through the NPR that the
expectation was to privatize where possible, for government to work more like a
business and to put customers (the American people) first. This Third Party Pilot
program was FDA’s attempt to privatize the review process for low risk 510(k)s to
improve review times for industry and free up resources for the FDA once the
program was implemented.
1997, FDA Modernization Act, HR 3201
On November 21,1997, the President of the United States signed into law the
“Food and Drug Administration Modernization Act of 1997” which amended
provisions of the Federal Food, Drug and Cosmetic Act relating to all products under
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FDAs authority. The changes to device law are probably the most pervasive and
address all aspects of device regulation. The theme of the device amendments is
efficiency through simplification, clarification, collaboration and streamlining. Pre
market review processes have been clarified and simplified. For PMAs and the most
risky Class II devices, these submissions have been made more efficient through a
series of collaborative meetings. Post-market reporting and tracking authorities have
been streamlined and have now been made to reflect how the FDA has been
implementing them since the enactment of The Safe Medical Devices Act of 1990.
Additionally, the new law creates authority by which the FDA can increase
regulatory efficiency on the pre- and post-market processes through the recognition
of national and international consensus standards. Through certification to FDA-
recognized standards, regulated entities can satisfy many requirements under the Act.
To the extent this amendment increases the reliance on standards, the opportunity of
achieving some degree of harmonization with international regulatory requirements
is increased.7 9
The significant provisions of the legislation are summarized below:
• Use of “FDA Approved” in Labeling—a manufacturer
may use the statement that FDA has approved a PMA or
IDE application in their labeling. This was previously
prohibited. While the FDA is allowing this statement, they
have not decided whether this may be used in the
promotion of a device.
• Dissemination of Information about New Uses—a
manufacturer may disseminate published journal articles
about a new use or other information about the safety and
7 9 Mark Heller and Stephanie Philbin, The Medical Device Provisions of the Federal Food,
Drug, and Cosmetic Act (Washington, DC: Food and Drug Law Institute, 1998).
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effectiveness of unapproved indications if certain criteria
are met.
• Medical Device Reporting—MDRs are reports of potential
adverse events resulting from use of a medical device.
Manufacturers are no longer required to certify the number
of MDRs filed. User facility reporting requirements have
also been reduced.
• Class I and Class II Device Exemptions—nearly all Class I
devices are exempt from FDA review and many Class II
devices will be evaluated for exemption from 510(k) pre
market notification requirements.
• 510(k) Intended Use Guidelines—FDA will provide
guidance for determining when general ‘intended use’
statements are not sufficient for determining substantial
equivalence.
• Recognition of Standards and Use of Declaration of
Conformity—FDA can recognize national or international
standards instead of developing their own performance
standards. Manufacturers can provide a Declaration of
Conformity to demonstrate conformance to standards.
This declaration describes the device, the standards to
which the device conforms, a signature and date that the
declaration was made.
• Changes to an Approved IDE or PMA Device—minor
changes can be made to an approved device without prior
FDA review within specific guidelines. FDA must be
notified within a specified timeframe for these changes.
• PMA Applications—FDA is required to meet with
applicants 100 days after the document is received. The
purpose of the meeting is to review deficiencies and
information required to complete the application. After a
specified time the FDA can use PMA data to approve
other products.
• Practice of Medicine—nothing shall “limit or interfere
with the authority of a health care practitioner to prescribe
or administer any legally marketed device to a patient for
any condition or disease within a legitimate health care
practitioner-patient relationship.”8 0
8 0 Food and Drug Administration Modernization Act of 1997, Public Law 105-115,
November 1997.
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• Product Classification—a manufacturer may request a
product classification from the FDA, who must respond
within 60 days
• Device Tracking and Post market Surveillance—
mandatory tracking and surveillance are eliminated and
required on a case-by-case basis. Surveillance is limited to
a maximum duration of 36 months.
2002, H.R. 3580, Medical Device Amendments of 2002
The Medical Device User Fee and Modernization Act of 2002 (MDUFMA),
Public Law 107-250 was enacted on October 26, 2002. The provisions of this act are
summarized as follows:
• Identify a single point of contact within the Agency to
ensure consistency and coordination of review efforts
resulting in the reduction of delays in the review of hybrid
technologies.
• Expand FDA use of outside experts in review of
breakthrough technologies. This allows technical experts
to be used by the Agency to review technologies that are
beyond the scope or capabilities of FDA personnel. This
allows for more timely reviews and a better assessment of
the potential safety and effectiveness issues.
• Authorize FDA to accredit third party inspectors to do
Quality Systems inspection of companies with a good
record, and use of outside experts to conduct overseas
inspections. This authorization follows on the coat tails of
the Third Party Review program for 510(k) submissions.
The previous pilot demonstrated the capabilities of
establishing and managing third parties to maintain the
statutory requirements, while reducing the workload at the
agency. In addition, the harmonization o f the Quality
System Regulations with international Quality System
Standards further facilitated this effort.
• User fees for medical device review is an extension of a
program piloted in the review of pharmaceuticals. User
fees that are directly applied to the review process have
facilitated faster, more thorough reviews through the
ability to add more resources and improve the skill set and
knowledge base of the reviewers.
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This legislation is recently enacted. The FDA is in the early stages of
implementation of some aspects and still in the development stage with regards to
other aspects. It has taken some time to codify these requirements into programs and
regulations that could be implemented.
In summary, the performance of the FDA in implementing the Medical
Device Amendment of 1976 has been shown to be lacking. The success of these
Amendments has been limited at best, as evident in the continual revisiting of the
issues. From the Amendment of 1976 until the mid 1980s the FDA and the industry
they regulated worked together to establish best practices for regulatory compliance.
The FDA defined the intent of the regulations and the industry educated the FDA
with respect to how these regulations could be complied with. From the mid 1980s
and more specifically with the advent of the Generic Drug Scandal in 1989, the
regulatory process turned adversarial. The FDA had instructed their submission
review staff to relegate all communications to formal letters that were subject to
management review. No phone calls or faxes were permitted. This remained the
case until the Temple and Wilkerson studies demonstrated the damage caused by this
arms length, zero communication behavior on the medical device industry and access
for the American public to breakthrough technologies. The Food and Drug
Modernization Act of 1997 was the cornerstone for re-establishing a more
cooperative environment by creating a foundation for the Least Burdensome
philosophy. The Least Burdensome activities are designed to facilitate this
cooperation in a structured manner to avoid the potential for regulatory capture. This
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research will attempt to determine whether these provisions have facilitated
successful change in the regulatory process.
Common perceptions regarding party platforms as they relate to regulation
are not always supported by the actions of those parties. There are numerous articles
and studies published by a variety of research institutes reporting that while the
Administrations strive for better efficiency and improved service by government
entities, the number of regulations and the scope of application are continually
increasing. A study from the Center for the Study of American Business finds that
Federal regulatory agencies experienced significant expansion in their authority
throughout 1997.
It is hard to escape the conclusion that the Republican
Congress has been a willing handmaiden to Bill Clinton in re
regulating the American economy. This follows the almost
complete reversal of Ronald Reagan’s deregulatory efforts by
George Bush, who hired more than 21,000 additional
regulators in just four years, and increased real spending on
regulatory activities by more than 21%. Apparently, the
Republican Party is no longer the party of deregulation.8 1
The Reagan and Bush years 1981 to 1993 resulted in three major medical
device legislative activities in addition to several Congressional investigations and
hearings. During the Clinton administration there were two completed legislative
agendas and a third one in process, the Bush administration that followed Clinton
completed the legislative activities related to the third item. The two most recent
legislative activities, the FDA Modernization Act of 1997 and the Medical Device
8 1 Bruce Bartlett, CSAB Study: Regulatory State Advancing (Washington, DC: National
Center for Policy Analysis), August 25,1997.
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User Fees Modernization Act (MDUFMA) of 2002 are both aimed at improving the
efficiency of the medical device regulatory process. It would seem that both
Republican and Democratic administrations sought to improve the way government
works and Congress irrespective of what party dominates, plays a role in increased
regulatory burden. What is different in the Republican administration regulations as
compared to the Democratic administration is the tone or intent behind the
legislation. The legislation passed in the late 1980s and early 1990s is clearly
adversarial and enforcement related. As noted earlier, the legislation of the late
1990s and 2002 is more cooperative in nature.
The issue of a cooperative process as described by the Least Burdensome
provisions, versus adversarial, which was the case in the past, is at the core of this
analysis. A cooperative process is defined as purposeful interaction between the
agency, industry and the clinical community that includes open communication. For
example, a description of concerns and expectations through public notification and
guidance documents. In general, expression of a philosophy that working together
improves efficiency and effectiveness and in the end results in a benefit to public
health.
The adversarial behaviors that were prevalent from the mid 1980s through the
early 1990s were heavily based in the philosophy that the agency could not be
effective in protecting public health if it was perceived to be “working for the
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industry it is suppose to regulate” as opposed to “working objectively for medical
advances in the best interests of those who pay FDA salaries, the American
taxpayer.” The American public had become very distrustful of government and big
business and were concerned that the agency was “captured.” Public sentiment that
they were not being adequately protected drove Congress and subsequently the FDA
to distance themselves from activities that could be perceived as a conflict of
interest. The effect of the “gag rule” implemented by the FDA along with the added
enforcement tools given to the agency created an environment of antagonism and
confusion. The results of these actions are clearly documented in the Temple and
Wilkerson studies previously described. The interaction between the public and
private sector has a significant bearing on our success as a nation in the global
economy. This issue has been hotly debated with regards to the broader question of
what role, if any; government should play in improving the international
competitiveness of American industry. When the FDA moved from a somewhat
cooperative model to a very adversarial, arms length, zero communication mode, the
impact on industry was so significant that Congress became involved.
As previously noted, in May of 1993 a report entitled “Less than the sum of
its Parts” by the Subcommittee on Oversight and Investigations was issued. It
described the Agency as having failed to implement the 1976 Medical Device
Amendment as intended by Congress. The review showed a need for change in
8 2 James P. Carter, Racketeering in Medicine—The Suppression of Alternatives, The Attack
Dog: The Role of the FDA (available from The CATO Institute, www.cato.orgA.
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organizational structure, management methods and controls with a belief that there
were systemic weaknesses in the regulatory program. Since that time there have
been many changes implemented. There have also been many initiatives to improve
the process by which medical devices are regulated. The goal in every change
strategy was to improve the health outcomes for the public, and economic outcomes
for the device industry.
While it might appear that these goals are potentially in conflict, good
engineering practices as well as good business practices support both objectives.
Standard business models require that products or services satisfy the need of the
customer. In the medical device industry the end customer is the patient and
intermediate customers are the physicians and caregivers that use these devices in
their work. Devices are marketed for a specific indication for use. If the device does
not adequately perform its functions, the physician or caregiver will purchase a
product that better meets their needs and the needs of their patients. Many device
purchases are based on product comparisons, either side-by-side use, or a review of
published literature to include clinical study publications and/or competitive analysis
conducted by third parties such as Emergency Care Research Institute (ECRI).
Hospitals now include biomedical engineers, infection control personnel and risk
managers on their staffs and they participate in purchasing decisions. These
individuals are knowledgeable in safety and performance standards and are informed
with regards to health alerts, recalls, FDA enforcement activities, etc. One medical
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device manufacturer stated that if you provide a quality product that does what it is
intended to do and is reliable, they sell themselves.
If the products are designed to meet the needs of the clinical community,
addressing issues in the care of patients, then the results presumably lead to
improved health outcomes. For example, improved diagnostics allows for early
detection and treatment of disease, less invasive procedures reduce potential side
effects and recovery time.
However, there are always those few companies that do not fulfill their
regulatory obligations and in rare instances this results in harm to the public. In
these cases, the costs to the company on an individual level with criminal
implications, on a financial level with fines and penalties and the loss in customer
confidence are enormous.
For the vast majority of companies, non-compliances are typically a result of
oversight or misunderstanding of the regulatory requirements. For these companies
process improvements may increase awareness and understanding thereby reducing
non-compliances. The improvement efforts described include: adding resources,
providing training for personnel, exempting low risk devices from the review
process, producing criteria to determine when to submit for a product change,
allowing abbreviated submissions for specific changes to devices, and establishing
activities related to the Least Burdensome regulatory approach. These
recommendations were legislated in HR 3201 and entitled the FDA Modernization
Act (FDAMA). The specific provisions of the Act that pertain to the issues and
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subsequent recommendations above are implemented in the Least Burdensome
Provisions of the Act.
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CHAPTER III
FDA AND MEDICAL DEVICE REGULATION
The Food and Drug Administration is chartered with protecting public health
as legislated in the Federal Food, Drug and Cosmetic Act of 1938 (as amended).
This Act was amended several times for various food and drug issues. In 1976, the
Act was amended to include regulation of Medical Devices. There are two primary
components to medical device regulation: (1) regulation of the manufacturer to
ensure compliance to the Quality System Regulations (QSR) and (2) regulation of
the devices themselves through the pre-market review process.8 4
The FDA facility inspection process verifies a manufacturer’s compliance to
the QSR. The Quality System Regulation requires a structured, documented set of
processes, (similar to those outlined in the International Standards Organization
(ISO) 9000 series of standards) to help ensure that each product is designed and
manufactured to meet the specifications for the stated intended use.
The premarket review of medical devices is based on the device
classification. In the United States, there are three classes of medical devices. Class
I devices are low risk and are subject only to the general controls that apply to all
8 3 Food and Drug Administration Quality System Regulation, 21 CFR 820.
8 4 Medical Device Amendment of 1976 to the Food Drug and Cosmetic Act, Public Law 94-
295.
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medical devices. General controls include registration of manufacturers, record
keeping requirements, leveling requirements, and compliance with QSR
requirements noted above. Class II devices are those with moderate risk and for
which general controls are not sufficient to ensure safety and effectiveness. For
these devices special controls apply including compliance to performance standards,
post-market surveillance, patient registries, guidelines and other appropriate actions.
For these devices the Agency believes that standards can or have been written to
assure a minimum level of safety and effectiveness. Manufacturers of Class II
devices are subject to inspection by the FDA to verify compliance with the QSR. In
addition, manufacturers of many Class II devices must submit a 510(k) Notification
to the FDA to request permission to market the device by establishing substantial
equivalence. The manufacturer provides documentation that demonstrates the device
is substantially equivalent (i.e., as safe and effective as) a device already marketed
for the same intended use.
Class III devices are typically high-risk new technology or existing
technologies being applied in a unique manner to a new problem. Thus, the
technology may be a completely new approach for treatment or diagnosis of a
particular disease state, such as the introduction of Magnetic Resonance Imaging
(MRI) a decade ago or the application of a known treatment modality in a new way.
An example of the latter would be Transmyocardial Revascularization (TMR), which
uses application of laser energy to create channels in the heart to relieve severe
angina.
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These Class III devices require clinical data to establish the safety and
effectiveness for the intended use of the product. These clinical studies must
demonstrate statistical significance and typically require an Investigational Device
Exemption (IDE) from the FDA to allow human clinical trials to proceed. In the
IDE process, the FDA reviews the pre-clinical data to determine the potential risk to
the patients in the study as well as a preliminary assessment of effectiveness. The
agency then compares the risks associated with the technology to the potential
benefit. There must be a clinical benefit that appears to outweigh the risks associated
with the new technology in order for the FDA to approve the clinical study.
Once the clinical studies are complete, the device sponsor prepares a Pre-
Market Approval (PMA) submission. This submission is intended to provide the
agency with the data necessary to establish safety, effectiveness and clinical utility of
the technology. PMA review and approval has been a significant area of contention
in the medical regulatory arena, because the belief is that new technologies, which
could be saving lives or significantly improving outcomes, are delayed or made
unavailable to the U.S. public due to inefficiencies in the system. These
inefficiencies include approval of IDE clinical study protocols that may not lead to
an “approvable” clinical endpoint once the PMA has been submitted to the agency.
Approval of a PMA is also contingent on the facility undergoing a Quality System
Regulation inspection with no significant non-compliances.
Within all submittal types there are issues that consistently plague the
process. This would include multiple review cycles caused by unclear expectations
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and on occasion inconsistent requirements from reviewer to reviewer or division to
division. Another issue has been a lack of predictability in the timeliness of the
reviews. Many manufacturers believe that they could manage additional
requirements and the timeframes needed for review if they had a clear understanding
of how long the process would take.
A major issue emerging from the Wilkerson Group survey and
interviews is that the most damaging element of device
regulation is an overwhelming sense of unpredictability. ...
uncertainty about what is required as a critical factor in
increasing product review complexity.. . . The predictability
and complexity of regulation dramatically affect decisions for
innovators, manufacturers and investors. When regulatory
demands, time frames, and costs are predictable, companies
can make informed decisions about product development
priorities.8 5
Over regulation and unclear expectations in the medical device regulatory
process have been documented in industry studies and Congressional
investigations.8 6 The issue of a prescriptive over-bearing model versus a model that
employs judgment and flexibility between the public and private sector has a
significant bearing on our success as a nation in a global economy. It has been hotly
debated with regard to the broader question of what role, if any; government should
play in improving the international competitiveness of American industry. When the
FDA moved from a somewhat cooperative model to a very adversarial, arms length,
zero communication model, the impact on industry was so significant that Congress
8 5 The Wilkerson Group, 57, 76.
8 6 The Temple Report.
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£ 7
became involved. In May 1993, a report entitled “Less Than the Sum of its Parts”
by the Subcommittee on Oversight and Investigations was issued and described the
agency as failing to implement the 1976 Medical Device Amendment as Congress
had intended. The results demonstrated a need for change in organizational
structure, management methods and controls, and a belief that there were systemic
weaknesses in the regulatory program.
The Wilkerson Group, Inc., conducted a survey of medical device
manufacturers to better understand the impact of the regulatory process on industry.
The report, entitled “Forces Reshaping the Performance and Contribution of the U.S.
Medical Device Industry,” concluded that patient access to new medical technologies
were months and even years behind other countries. Delayed access is reflected in
lost opportunities to (1) save lives, (2) reduce hospitalization and recovery time,
(3) lower infection rates, and (4) improve patient quality of life. They also
concluded that companies were abandoning product development efforts due to the
effects of regulatory policies, new medical device start-ups were declining, and the
U.S. competitive position was slipping. High technology jobs were also on the
decline. The trend they found in the medical device industry was for companies to
introduce medical technology outside the United States. In some cases they even
87-
Ibid.
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moved their factories outside the U.S. This resulted in a significant economic impact
due to loss of domestic jobs and the supporting infrastructure for those positions.8 8
510(k) Average Review Time
250
200
«, 150
> >
n >
° 100
50
0
Figure 2. 510(k) Average Review Time.
The performance of FDA in the 510(k) pre-market notification process is
clearly illustrated in the figure above. The data show a significant and steadily
increasing trend in the time the agency was taking to review new product
submissions and providing clearance to market. The critical point for the industry in
this regard was the loss of predictability in the submissions process. This lack of
predictability was the primary driver for the resulting actions taken by companies
described previously.
8 8 The Wilkerson Group, xxxi.
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Industry was not alone in recognizing the untenable state of affairs within the
Office of Device Evaluation. From 1991 to 1994 there was more than a 100%
increase in average review time from 102 days to 216 days and the backlog of
submissions was growing to nearly 4000 documents.8 9 During the same timeframe,
the number of submissions had increased nearly 12% making the problem even
worse. In early 1993 the Wall Street Journal published data on 510(k)s pending for
more than 90 days, the statutory limit. This report supported the experiences of many
companies whose submissions had been languishing for months before even being
looked at. The buildup of the huge backlog in 1992 and 1993 was the development
that led these applicants to speak of a “black hole” and “eternal limbo.”
By 1994 the situation had reached a point where the Agency had to take
action. They responded by creating an army of FTEs detailed to ODE to achieve
three goals. First to eliminate the 510(k)s older than 90 days, next to eliminate the
backlog, and finally to reduce the overall review time to meet the statutory
requirements.
8 9 0ffice of Device Evaluation, Annual Report, Fiscal Year 1996.
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Table 1
5100c) Performance Data
Year
510(k)
Received
510(k)
Completed
Full-Time
Employees
Greater
Than 90
Days
Backlog
(active and
overdue
only)
1990 5831 6197 276 0 1174
1991 5770 5367 251 2 1402
1992 6509 4862 263 331 2599
1993 6288 5037 273 1894 3822
1994 6434 7135 340 460 2414
1995 6056 7948 368 9 1486
1996 5298 5563 368 0 1408
1997 5049 5155 356 0 1287
1998 4623 5229 340 0 1057
1999 4458 4593 330 0 943
2000 4202 4397 359 0 850
2001 4248 4150 353 0 934
2002 4320 4376 354 0 935
Table 1 illustrates the increasing number of submissions more than 90 days
under review as well as the growing backlog of submissions waiting for review at its
most severe in 1993. It also shows improvements made in each of these areas. The
corrective actions put in motion by the FDA resulted in a dramatic improvement by
1995, well before the FDA Modernization Act was legislated. These corrective
actions included adding resources and selecting the less complex submissions to
work on first.
This “army” of borrowed resources from other Offices within the FDA
increased the number of reviewers by an unknown number. However, their
contribution to the effort is clearly reflected in the demonstrated improvements
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shown in the table above. There are potential dangers in this strategy of reallocation
of resources in that the results may not be maintainable. This was addressed by other
activities that would reduce the workload to what was manageable by the permanent
staff when the other resources returned to their respective tasks.
Finally, there seems to be a well-founded assertion that the improvements are
also partly attributable to “cherry picking” or processing of the easy submissions to
reduce the backlog.9 0 This was most likely the case by virtue of the fact that the
additional reviewers would be new to the process and necessarily would be given the
easier submissions to gain experience with the process. This would leave the
experienced ODE reviewers to address the submissions that were greater than 90
days.
As impressive as the improvements from 1994 to 1995 were, they had been
achieved by a reallocation of resources that was temporary. They had reviewed all
of the “easy” submissions, leaving the more complex submissions still to be
addressed. The Agency had a legal requirement to review all submissions within 90
days and to continue to improve the average review times until they met the intent of
the legislators. The Agency had also committed to elimination of the backlog of
submissions that were past due. This could not be achieved and then maintained
without significant changes to the process.
9 0 Higgs, 67.
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The approval slowdown was at its worst in 1993 and 1994 and industry
sought relief from Congress. While improvements had been made, without real
change in organizational effectiveness, there was little confidence that these
improvements would continue or even be sustained. This was the driving force
behind the Congressional hearings in 1996 that then led to the FDAMA legislation in
1997.
The interesting question about enforcement of protective
regulation, therefore, concerns the sources of variance in
regulatory agency behavior and social impact. Under what
conditions is regulatory enforcement forceful and effective?
When is it not? When is regulatory enforcement economically
inefficient? When socially beneficial? What methods of
enforcement contribute to effective and efficient results?9 1
The Temple Report and the Wilkerson studies were key factors driving the
Hearings Before the Subcommittee on Health and the Environment in May of
1996. The hearings included testimony from industry, academia, the clinical
community, and public health advocacy groups.
Since that time, many changes have been implemented and many initiatives
started to improve the process by which medical devices are regulated. The intended
results of these efforts are improved health outcomes for the public and improved
economic outcomes for the device industry. This was culminated in the Food and
Drug Administration Modernization Act (FDAMA) of 1997.
9 1 Rosenbloom and Schwartz. (See also Kagan, 1994, 385.)
9 2 FDA Reform Legislation.
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CHAPTER IV
LEAST BURDENSOME REGULATORY MODEL
President Carter is credited with being the originator of the Least
Burdensome philosophy, as we know it today. In 1979, he charged “regulatory
agencies to pay more attention to the costs (as well as the benefits) of their rules,
thereby implementing a presidential order to choose the Least Burdensome way of
achieving regulatory goals.” In the mid 1980s, Ronald Reagan took this concept
even further and implemented widespread deregulation in telecommunications,
securities, trucking, railroads, buses, cable television, etc. He did not, however,
venture into the areas related to public health.
Public Health came to the forefront with the visibility brought by Hillary
Clinton. Under President Clinton, the Executive Order 12866 “Regulatory Planning
and Review” established a number of guidelines for the development of
regulations—one of these guidelines was to adopt the principle of the least burden on
society in tailoring regulations.9 4 More specifically, the Clinton White House
emphasis on health care ensured that this regulatory philosophy was also directed
towards those entities involved in the health care process.
9 3 Wilson, The Politics of Regulation, 391.
9 4 Kurian, 504-510.
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The Least Burdensome provisions of the FDAMA of 1997 are defined in a
draft guidance document released for comment in May of 2001. The purpose of the
FDAMA is “to ensure the timely availability of safe and effective new products that
will benefit the public and to ensure that our Nation continues to lead the world in
new product innovation and development.”9 5 The goal of Congress was to
streamline the regulatory process to improve patient access to breakthrough
technologies. They did not lower the statutory thresholds for substantial
equivalence or reasonable assurance of safety and effectiveness through the
reduction of unnecessary regulatory burdens associated with the pre-market
clearance and approval processes. The challenge for the FDA was to implement
programs that would reduce burden, speed the process and still maintain at least the
same level of public protection. The Agency has accomplished this through alternate
approaches that require the same scientific demonstration of safety and effectiveness
thus the statutory thresholds are maintained. These alternate approaches are
described in guidance documents published by the Agency for implementation of the
various Least Burdensome activities. For example, the guidance document entitled
The New 510(h) Paradigm Alternate Approaches to Demonstrating Substantial
Equivalence in Premarket Notifications, describes use of guidance documents,
special controls and consensus standards. In this guidance the Agency states:
Since design control requirements are now in effect and
require the manufacturer to conduct verification and validation
9 5 Senate Report No. 105-43, 1997.
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studies of a type that have traditionally been included in
510(k) submissions, the Agency believes that it may be
appropriate to forgo a detailed review of the underlying data
normally required in 510(k)s.9 6
As a result of the additional controls under the Quality Systems Regulations for
design, the data that is generated through the design control procedures must be
maintained by the manufacturer and be available for FDA inspection. This illustrates
how the same statutory requirements for data are fulfilled in a potentially less
burdensome manner for the Agency and the manufacturer.
The Food Drug and Cosmetic Act was amended in 1997 with the addition of
two sections 513(a)(3)(D)(ii) and 513(i)(l)(D) to capture the intent of the legislation.
These two sections of the law contain the Least Burdensome provisions of the act.
Since the enactment of this legislation the FDA has been developing an accurate
interpretation of those provisions that would reflect the intent of Congress. It would
also structure regulations that could be uniformly implemented. The Least
Burdensome concept touches nearly all aspects of the pre-market regulatory process.
It includes pre-submission meetings, the actual submissions, and guidance
documents to facilitate the process. Although the Least Burdensome provisions are
relatively recent, the approach has been used in the past to resolve regulatory issues
and in some circumstances bring new devices to market.
9 6 FDA, Center for Devices and Radiological Health (CDRH), The New 510(k) Paradigm
Alternate Approaches to Demonstrating Substantial Equivalence in Premarket Notifications, Section
A (Rockville, MD: CDRH, March 1998).
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The FDA defines Least Burdensome as:
. . . a successful means of addressing a pre-market issue that
involves the most appropriate investment of time, effort and
resources on the part of industry and FDA. This concept
applies to all devices and device components of combination
products regulated by FDA, and when conscientiously applied,
will help ensure scientific integrity in the decision making
process, while affording a high degree of public health
protection and expediting the availability of new device
technologies.9 7
The basic principles of the Least Burdensome provisions are:
• The spirit of the law, as well as sound science, should be
the basis for all regulatory decisions.
• Information unrelated to the regulatory decision should not
be part of the decision making process.
• Alternative approaches to regulatory issues should be
considered to optimize the time, effort, and cost of
reaching resolution of the issue within the law and
regulations.
• All reasonable measures to lessen review times and render
regulatory decisions within statutory timeframes should be
used.
Events Contributing to Political Support of Regulation
To this point the general nature of regulatory processes has been described.
In addition the specifics of how the Food and Drug Administration regulations
medical devices is also described. In order to understand the evolution of medical
device regulation we must explore the changing political environment and specific
9 7 FDA, Center for Devices and Radiological Health (CDRH), The Least Burdensome
Provisions of the FDA Modernization Act o f1997: Concept and Principles: Draft Guidance for FDA
and Industry (Rockville, MD: CDRH, May 2001).
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events that have affected the legislation passed for the FDA and how those
regulations were implemented. Although the general consensus across
administrations has been that regulation of medical devices is necessary, the
politically appointed leadership of the agency significantly affects the interaction
between the agency and the regulated industry. The legislative history of medical
device regulation through Republican and Democratic administrations and
Congressional majorities is illustrated in Chapter 2, Figure 1. The reaction to events
in each administration has been to give the FDA additional powers and or discretion
on application of the regulations to industry.
There is considerable literature regarding how the FDA gained and exercised
greater authority over the pharmaceutical industry and continuing controversy over
the potential adverse consequences of FDA regulation. Medical device regulation
has attracted little to no attention from scholars. The FDAs powers have been
described as a process of “punctuated politics” with the primary actors, the FDA,
members of Congress, interest groups and trade associations and the public
OR
conducting their affairs in a more or less stable policy environment. The FDA has
fixed statutory authority, regulates in a fairly consistent manner, and the public
generally plays a passive role. From time to time the “normal condition” changes
dramatically and the Congress gives the agency sweeping new authority or, less
frequently, the agency markedly alters the conduct of its regulation.
9 8 Higgs,2.
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Past history has however, illustrated true cases of public harm, and in each
significant instance, there has been a political and then regulatory response. Once
again, the news media provides shocking investigative reports about the danger, or
less often, the ineffectiveness of a medical product. The revelations about unsanitary
meatpacking plants in Upton Sinclair’s novel The Jungle catalyzed passage of the
Food and Drugs Act of 1906. The Elixir Sulfanilamide tragedy—more than 100
persons died after taking a medicine—provoked passage of the Federal Food Drug
and Cosmetic Act of 1938. The Thalidomide tragedy—babies were bom deformed
because their mothers had taken a dangerous sedative—gave rise to the Kefauver-
Harris Drag Amendments of 1962.
In the history of device regulation, the most significant issues were those
related to faulty intrauterine contraceptive devices (IUDs) and cardiac pacemakers in
the early 1970s, which stimulated passage of the Medical Device Amendments of
1976; those related to fractures of the Bjork-Shiley convexo-concave heart valve,
which hastened enactment of the Safe Medical Devices Act of 1990; and those
related to diseases and injuries allegedly caused by leaking silicone gel-filled breast
implants, which prompted the FDA to undertake an aggressive enforcement
campaign in the early 1990s. Such revelations produce public clamor that prompts
Congress to create new statutory authority for the FDA or leads the FDA to
undertake more stringent enforcement of existing regulations.
The previous discussion clearly describes the foundation for the primary
focus of medical device regulation, to protect the public health. However, there can
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be a detrimental effect with excessive regulation. This over regulation results from a
reaction to a real or perceived threat. Several real tragedies have been described that
resulted in expanded regulatory jurisdiction that was justified on the basis of offering
true protections. The following example is one where over regulation was caused by
a perceived threat. This case was so extreme that it nearly destroyed one company
and had a major effect on all of the manufacturers of those types of products as well.
One of the most effective triggers for causing change to the “normal
condition” is an outcry from the public. These outcries are generally the result of a
sensationalistic report by the news media that profess to be consumer advocates. An
example from the recent past involved Physio-Control Corporation. In 1990 this
company was the market leader in pre-hospital resuscitation equipment. They
manufacture defibrillators used to treat cardiac arrest." Defibrillators are unique
medical devices in that they are used to revive a patient who is effectively dead.
These patients either have no heartbeat or ventricular fibrillation a fatal condition
where the heart simply quivers rather than pumps. No blood flow means no oxygen
delivered to the brain, heart and other vital organs. The defibrillator delivers an
electrical shock through the heart. This stops the heat from fluttering allowing the
heart to resume a normal cardiac rhythm.
Physio-Control was the subject of a program broadcast by WRC-TV an NBC
affiliate in Washington DC. This program was titled “Fatal Flaws” and highlighted
medical device reports (MDRs) filed by the company and drawing the conclusion
"Ibid., 61.
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that the products must be defective. The program was broadcast in 1990 and a
follow up in 1992. After the airing on the “Today Show” in 1992, Jim Page editor of
Journal of Emergency Medical Services stated that the public had been exposed to “a
scurrilous ‘hit piece.’”1 0 0
The sequence of events that unraveled from this program began with
overwhelming public anxiety about defibrillators and whether they would work
when needed. The political process then kicked into motion. While this news was
being spread across the nation, consumer advocate Dr. Sidney Wolfe (the Ralph
Nader of public health) was demanding that the FDA take action. The broadcast was
as much an indictment of the Agency as it was the company and Congressman
Dingell with record gathering already initiated clearly lay the blame on FDA “not
doing its job.”1 0 1
The FDA responded to this frenzy of media, public sentiment and
Congressional outrage by proceeding to make an example of Physio-Control. The
company stopped all shipments and signed a consent decree and proceeded to
resolve their issues with the FDA. The company was out of the marketplace for
nearly two years causing a significant financial burden. In addition, all new projects
and innovations were put on hold so that all the company’s resources could be
focused on resolving the issues surrounding the consent decree.
1 0 0 lbid.,61.
1 0 1 Ibid„ 62.
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In this situation one has to consider that the patients these devices are used on
are effectively being brought back to life, which is different than preventing someone
from dying. These people are found in their homes, in lakes or pools, on sidewalks,
and any other place that one might have a heart attack. The time it takes for
emergency medical teams to respond, whether or not anyone is performing CPR, the
overall physical condition of the patient, etc., are all factors in whether the
resuscitation effort will be successful. In addition, the care and maintenance of the
device is key. How often is it checked, are the batteries properly charged, are there
extra batteries available, and so on. Were the products really defective or was this an
incredible misunderstanding of the data? Defibrillators are used tens of thousands of
times a day and successfully resuscitate the patient. Were the failures noted in the
medical device reports where the patient was not revived a result of the device, the
user, the care of the equipment or simply equivalent to the number of patients that
would have died under any circumstances?
The FDA between 1990 and 1992 inspected nearly every defibrillator
manufacturer to ensure that each facility was complying with the Good
Manufacturing Practices (GMP) regulations. Further investigation into the medical
device reports for defibrillators showed that lack of proper maintenance was the
primary cause of device failures in the field. To that end the FDA and defibrillator
manufacturers developed a detailed checklist for device maintenance and fitness for
use checks. These checklists are provided to users of the products as part of the
device labeling.
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It is clear from this example that the political process had severe adverse
consequences for Physio-Control. The actual issue was significantly smaller than the
media made it out to be and the root cause was industry wide. Corrective action by
the Agency could have been taken through a much less adversarial process.
The example of Physio-Control is a fairly recent one where the device issues
were not related to a failure of the industry or the FDA. A misunderstanding of data,
a desire to protect the consumer, and reaction before investigation from the political
side, triggered the events.
The most significant detrimental effect of over regulation is when the public
is denied access to technologies that may help them. In many of these cases the
technologies are new and there may be risks. But for many patients the benefits are
well worth the risks. While the FDA has improved the process for regulating drug
trials in cases where there is no satisfactory alternative, the same is not always true
for devices. Particularly in cases where the treatment is palliative and the clinical
endpoints are less concrete. The following is an example where regulatory burden
has been overwhelming because of difficulties in designing clinical studies that
would support a clear, scientific, statistically significant endpoint.
Patients who suffer from emphysema have difficulty breathing and are at
some point relegated to a sedentary life tied to an oxygen tank. A surgical procedure
using a medical laser to remove damaged alveoli from the lung, much like pruning a
tree, allows the remaining alveoli more space to expand and perform gas exchange.
For these patients, the procedure is palliative, but also significantly improves their
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quality of life, returning many to an active lifestyle for some period of time. This
procedure referred to as Lung Volume Reduction, and the devices used to perform
the procedure, were in regulatory limbo for years. Questions about how the clinical
study should be structured, what was the clinical benefit, and so forth were never
truly resolved. As long as the device manufacturers could not make a medical claim
for this procedure, many insurance providers (primarily Medicare), considered the
procedure experimental and would not provide coverage. Therefore, only those
patients who could afford to pay for such a procedure would have access.
Congress and the FDA have recognized the effect of over regulation. This
recognition is expressed in the refinement of the Agency mission. Protection of the
public health does not consider the negative consequences of delaying or denying
access to potentially life saving technologies. To reflect the understanding that this
is a key consideration in medical device regulation, the FDA has publicized a new
focus of promoting public health. Promoting public health expands the scope of the
agencies responsibility to include preventing adverse events as well or better than the
past and in addition, facilitating access through improved regulatory processes that
encourage innovation rather than stifle it. The goal for the agency was to get new
technologies and improvements to the market faster and with less effort while at the
same time maintaining the same high standards for safety and effectiveness. The
difficulty with this goal is that there will be situations where they may conflict. In
these cases, it is clear from the legislation that safety and effectiveness will always
come first.
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Congressional investigation and private research through several
administrations both Republican and Democrat demonstrated that the Agency had
not met its objectives. The events leading to the Amendment of 1976 began with the
recognition that devices since World War II had become much more sophisticated
and complex. New materials and technological advances gave rise to pacemakers,
surgical implants, artificial vessels and heart valves, intrauterine devices,
replacement joints and many others. Along with complexity came more severe
consequences if these devices were poorly designed, had inadequate workmanship or
operated improperly. Consequences could include permanent impairment or death
and since many of these devices were implanted into the body inspection of the
device and its performance over time was impossible.
At the same time that device complexity was increasing and potential for
adverse events to be increasingly severe, the public was becoming less and less
tolerant of any risk. We entered an era where the standard was perfection. Zero risk
was the only acceptable risk and the public demanded strict regulation of medical
devices. Their expectation was that medical devices should operate perfectly and that
if they did not Congress and the FDA should do something to make them operate
perfectly.1 0 2
Unfortunately, medical devices cannot be made to operate perfectly. They
can be made to operate more safely, at greater cost, and at some point the benefit
derived is negligible in terms of safety and huge in terms of cost. These are
1 0 2 Ibid., 78.
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inversely proportional characteristics. Devices can become so “safe” that no one can
use them due to excessive cost and in some cases shear size of the device. Consider
multiple battery backups, their weight, and size and maintenance requirements to
address a user not following routine device care.
The FDA wanted the power to require pre-market testing of devices for
safety and effectiveness in the same manner as was employed at the time for new
drugs. Dr. Theodore Cooper conducted a study that documented evidence of
significant medical device issues in the early 1970s with pacemakers and IUDs. The
legislation, with the evidence shown by the study, began to generate momentum.
Since the Amendment in May of 1976 the Executive and the Congress have clearly
recognized the importance of regulation in the area of public health and have
supported such regulation. This Amendment was legislated during the Ford
administration and subsequently expanded on during the Carter administration. The
political climate during this time was significantly affected by the Watergate scandal
and other events that lead the public to mistrust government The FDA at that time
was trying to codify the Medical Device Amendment into regulations. In order to
complete this task, they first had to understand the industry that they were now
responsible for regulating. The subsequent regulations regarding Good
Manufacturing Practices and Medical Device Reporting were a result of that
learning.
The Democratic Congress ensured that the regulatory process for medical
devices was initiated and closely monitored. Congressional Investigations and
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Hearings during the Reagan administration demonstrate the concern on the part of
Congress that the FDA was not implementing the device legislation as it was
intended. The FDA was working with deliberateness and speed with the emphasis
on deliberateness. At the same time the administration was working very hard to
regain the confidence of the American people when yet another event changed the
political landscape. The advent of the Generic Drug Scandal in 1989 was just
another case demonstrating that government and business could not be trusted.
The Generic Drug Scandal shook public confidence in the FDA. A small
number of generic drug companies provided falsified data and offered illegal
gratuities to FDA employees. This resulted in the Agency removing more than 200
products from the market. In addition, each generic drug maker was investigated and
nine were referred to Federal grand juries. The investigations by the FDA did not
reveal any potential for harm to the public, but officials involved were referred to the
Justice Department and charged with fraud and reckless disregard for the health of
consumers.1 0 3
This scandal had two effects on the FDA and the regulatory process. One
effect was to make the Agency more adversarial. This behavior was intended to
demonstrate distance between the regulator and the regulated to address any
concerns of potential conflict of interest. The second effect was to increase the
documented evidence needed in submissions upon which market entrance would be
1 0 3 Carolyn Poirot, What Consumers Need to Know About Generic Drugs (PersonalMD Your
Lifeline Online, available fromwww.PersonalMD.com, May 14,2004).
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based. This was intended to ensure that the Agency had all of the necessary
information to evaluate new applications. This expansion of regulatory authorities
and the concept of “creeping regulatory augmentation” soon resulted in the slowing
and sometimes total elimination of new technologies from the market place.
A majority of Congressional investigations have been in response to failures
of the Agency to adequately protect the public health. Many of these presumed
failures have been instigated by over zealous media who cause a panic. Congress
responds accordingly and the result is a renewed intensity of regulatory scrutiny.
However, with the advent of AIDS, and other diseases, new and promising
technologies coming to the attention of the public there comes a recognition that we
are dying waiting for perfection. A better answer might be to accept some level of
risk, especially in cases where there are no other alternatives. When the public takes
this viewpoint, demands for strict regulation quickly turn to criticism for being
prevented access to “potentially” life saving technologies. Now the public outcry is
over regulation is a problem.
This change in public rhetoric was then supported by the medical device
industry in the early to mid 1990s when the “approval slowdown” occurred. The
argument was the same. Over burdensome regulation was preventing industry from
bringing the best new technologies to bear on the human medical condition. The
public was being denied access to technologies that were available in other parts of
the world. With the public and the medical device industry on the same bandwagon,
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Congressional investigations turned from criticizing the Agency for not being tough
enough to criticizing them for being over burdensome.
Doctors, hospitals, and emergency medical services
increasingly find that devices available elsewhere in the world
are not available in the United States, and thousands of
patients are suffering as a result. The cause of those woes is
evident: perplexing, costly, and time-consuming regulations
promulgated and enforced by the U.S. Food and Drug
Administration. Kshitij Mohan, an industry executive and
former FDA official, recently observed that “the pendulum
may swing back eventually, but the pendulum at FDA is more
like a wrecking ball.1 0 4
Congress and the FDA subsequently responded to these issues. Each aspect
of the regulatory process that has been identified as “broken” or ineffective has been
evaluated and through the Congressional hearing process, spoken to by the Agency,
the medical device industry, consumer advocates and health care providers. The
FDAMA legislation directly addresses many of these issues with requirements that
the process be changed. Specifically with regards to over regulation of medical
devices, the “Least Burdensome” provisions of the Act were legislated.
Traditional 510(h) Process
A 510(k) Notification is a submittal to the FDA requesting clearance to
market a device that may be substantially equivalent to a currently marketed device.
In other words, there are no new questions regarding the safety or effectiveness of
1 0 4 Robert Higgs, Wrecking Ball: FDA Regulation of Medical Devices, Policy Analysis No.
235 (Washington, DC: CATO Institute, August 7, 1995).
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this device for its intended use. The traditional 510(k)1 0 5 process requires the
manufacturer to prepare a document that includes the following information:
Table of Contents
Cover Letter
Indication for Use Statement
Premarket Notification Truthful and Accurate Statement
Substantial Equivalence Flowchart
Labels and Labeling
Product and Package Labeling
User Manual
Product Brochure
Photo
Voluntary Standards
Declaration of Conformity
Device Description
Theory of Operation
Engineering Drawings
Indications and Controls
Intended Use
Physical Specifications and Descriptions
Biological Specifications
Chemical Specifications
Descriptive Comparison to a Legally Marketed Device
Comparison Chart
Predicate Device Labeling
Similarities and Differences
Performance Data Supporting Substantial Equivalence
Risk Assessment
Safety, Performance, EMI Testing
Biocompatibility
Materials
Color Additives
Clinical Performance*
Software
Level of Concern
Description
Device Hazard Analysis
Software Requirements Specification Architecture
1 0 5 FDA, Center for Device and Radiological Health (CDRH), Premarket Notification 510(k):
Regulatory Requirements for Medical Devices, HHS Publication FDA 95-4158 (Rockville, MD:
CDRH, August 1995).
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Software Design Specification
Traceability Analysis
Development Process
Verification, Validation Test Plan and Results
Revision History
Unresolved Anomalies
Released Version Number
Sterilization Information
510(k) Summary of Safety and Effectiveness
* Clinical data is generally not required for devices regulated
under 510(k) if the performance characteristics can be
evaluated through verification activities. If clinical data is
required the manufacturer must also comply with the
Investigational Device Exemption (IDE) requirements.
The complexity of the device and whether or not clinical data is required are
important factors affecting the resources and costs associated with preparing the
submission. It is important to note that all of the items listed above are considered
necessary elements of a good product development process and are required under
the Quality Systems Regulations (QSR) previously described. The difficulty for
most manufacturers is with regards to the timing of the 510(k) submission with the
product development process. In order for the data required in a traditional 510(k) to
be available the product must be virtually ready for market. In this case the time for
510(k) clearance is translated into time that the product could be in commercial
distribution. If the 510(k) process were consistent and reviews were completed
within the statutory 90 days and requests for additional information minimized, the
manufacturer could plan for this regulatory review time in their project and business
plans. However, lack of predictability, multiple review cycles (generally of 90 day
durations), requests for additional information that may not have been generated as
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part of the development process are all factors that have significantly extended the
time to market for these devices. Most businesses describe this time between the
product ready for commercialization and receipt of clearance to market from the
FDA in terms of lost revenue and potential market share. The secondary
repercussions of this lost revenue include reduced funding for future research and
development. In the end the health of the American public may be adversely
affected.
The New 510(h) Paradigm
“The New 510(k) Paradigm—Alternate Approaches to Demonstrating
Substantial Equivalence in Premarket Notifications—Final Guidance”1 0 6 was
published in March of 1998 in keeping with the Least Burdensome philosophy of
FDAMA. This Final Guidance document described two alternative approaches that
may be used under the proper circumstances to demonstrate substantial equivalence.
This guidance established procedures regarding the use of consensus standards,
reliance on post market controls, use of guidance documents and special controls.
The intent of this paradigm was to streamline the preparation and review of 510(k)
submissions thus conserving industry and Agency resources while still protecting the
public health.1 0 7
m The New 510(k) Paradigm.
1 0 Tbid.
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Special 510(k)s
The Safe Medical Devices Act of 1990 (SMDA)1 0 8 provided the FDA with
the authority to expand the scope of the Good Manufacturing Practices regulations to
include pre-production design controls. This requirement became effective in June
of 1997. Since design control requirements were in effect and require the
manufacturer to conduct verification and validation testing equivalent to what is
required in a traditional 510(k) submission, the Agency believes that, for some
510(k) submissions they may forgo a detailed review of the data in the 510(k)
because this data, under design control requirements must be maintained by the
manufacturer and be available for FDA inspection. Thus a manufacturer of a device
will conduct risk analysis, verification and validation to demonstrate that the design
output meets the design input requirements. The documentation of this
demonstration will be filed in the Design History File and will be inspected during
subsequent FDA inspections. The 510(k) will no longer be required to contain this
information rather a “Declaration of Conformity” to the design control requirements
is submitted instead. In addition, the manufacturer must provide a concise summary
of how design controls are implemented, the methods used for risk assessment and
identification of verification and validation activities used. This type of 510(k)
submission is referred to as a “Special 510(k): Device Modification.” As indicated
by the name the Special 510(k) only applies to submissions for modifications to
already cleared devices. The modification must not affect the intended use of the
1 0 8 Safe Medical Devices Act, Public Law 101-629, October 1990.
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device, nor alter the fundamental scientific technology of the device. The Agency
has committed to review these 510(k)s within 30 days of receipt.
Abbreviated 510(k)s
The FDA has created numerous guidance documents intended to
communicate to manufacturers the regulatory and scientific expectations for device
submissions. Since the inception of Good Guidance Practices1 0 9 device specific
guidance documents are developed with public participation. The Safe Medical
Devices Act of 1990 (SMDA) introduced the concept of special controls; defined as
use of performance standards, post market surveillance, patient registries, and
guidance documents, as an appropriate means to assure device safety and
effectiveness. Finally, under the FDA Modernization Act, the FDA has amended
section 514 of the Act to specifically authorize recognition of national and
international standards.
Therefore, a device manufacturer may submit an Abbreviated 510(k) when an
FDA device specific guidance document exists, a special control has been
established, or when FDA has recognized a relevant consensus standard. In lieu of
this information the manufacturer will provide a summary report describing how
guidance, special controls and/or consensus standards have been used to address
risks associated with the device. If a submission relies on use of a consensus
1 0 9 FDA, Center for Devices and Radiological Health (CDRH), CDRH Manual for the Good
Guidance Practices (GGP) Regulations; Final Guidance for FDA Staff (Rockville, MD: CDRH,
February 2001).
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standard then a Declaration of Conformity must be provided. While the FDA has not
committed to a shorter review cycle for Abbreviated 510(k)s, the Agency does
believe that reliance on summary reports describing use of standards and guidance
will be more efficient than the data intensive review of a traditional 510(k)
submission. Thus, resources can be used for more complicated issues and should
expedite the overall process.
The Traditional IDE Process1 1 0
Investigational Device Exemptions are submitted when a medical device
requires clinical data to support either a claim of substantial equivalence to a
currently marketed device or to establish the safety and effectiveness of a new
device. These studies are most often conducted in support of a Pre Market Approval
(PMA) where the technology is new or a known technology is being applied in a new
way. The contents of an IDE submission include:
Device description
Intended use
Reports of any prior investigations
Laboratory, animal and clinical studies performed
Bibliography of all publications relevant to the evaluation of
the device
Adverse event information
Investigational Plan
Purpose of the study
Protocol
Risk Analysis
Description of the Device
Monitoring procedure for the study
Manufacturing of the device
U 0FDA, Center for Devices and Radiological Health (CDRH), Investigational Device
Exemptions (IDE) Manual (FDA 96-4159) (Rockville, MD: CDRH, 1996).
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Investigator information
IRB (Investigational Review Board) information
Sales information
Labeling
Informed Consent
Environmental impact
The IDE submission is prepared by the study sponsor and submitted to the
FDA for review. The statutory timeframe for review of IDEs is 45 days. This
process is open loop in that the submission is prepared based on the general guidance
for IDEs. The sponsor independently determines the study parameters and clinical
endpoints. The FDA then reviews the document for completeness. The clinical
protocol and endpoints are reviewed to ensure that the study will establish the safety
and effectiveness of the device for its intended use and thus achieve the market
approval desired by the sponsor. As with each of the review processes, if the FDA
finds deficiencies in their review then a letter requesting additional information is
prepared and sent to the sponsor and the cycle begins again. Many companies have
had the impression that submissions coming up to the statutory time limit will get a
quick review, and a letter will be generated asking questions to “stop the clock.”
This practice is possible with all of the pre-market processes, and can usually be
detected when the reviewer is requesting information that has already been provided
in the original submission. It is unclear whether this is an infrequent occurrence or
something more prevalent. In any event, the sponsor must interpret the request for
information and prepare changes to the submission or the clinical protocol and
resubmit to the FDA. This is a serial open loop process with the potential for
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delaying implementation of a study or ending in a stalemate and the technology
abandoned.
The New IDE Process
In January of 1998, the FDA published a guidance document regarding the
general policies for the IDE process.1 1 1 This guidance document describes a pre-IDE
process intended to facilitate the initiation of clinical trials under the IDE regulation
by encouraging sponsors to begin communicating with the ODE reviewing division
prior to submission of the original IDE application. The guidance describes a pre-
IDE meeting and/or a pre-IDE submission.
The pre-IDE meetings may be formal or informal where the formal meeting
is described under section 201 of the FDA Modernization Act of 1997. The informal
meetings are intended to provide a forum for discussion regarding pre-clinical data
or the investigational plan being developed for the formal IDE submission. These
meetings may take place via conference call, videoconference or face-to-face. The
meetings are documented by the FDA and include a summary of any
recommendations or guidance provided by the agency. Formal guidance meetings
may be requested in writing by the sponsor to reach an agreement with the FDA
regarding the FDA review of a particular investigational plan. This “Agreement
Meeting” must occur within 30 days of the request by statute. The information the
FDA requires for such a meeting includes a detailed description of the device, a
m FDA, Center for Devices and Radiological Health (CDRH), Guidance on IDE Policies
and Procedures (Rockville, MD: CDRH, January 1998).
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proposed clinical plan, intended use and expected performance of the device. If an
agreement is reached between the FDA and the sponsor the terms are recorded as
part of the administrative record.
Pre-IDE submissions may be submitted for early review so that the FDA can
identify potential problem areas with the protocol design, pre-clinical testing, test
results, etc. These submissions are reviewed while the sponsor completes
preparation of the formal IDE submission. The documents are logged into the pre-
IDE tracking system and the FDA is committed to a timely response, usually within
60 days of receipt.
Interactive IDE review encourages the FDA reviewers to communicate often
with the sponsor during the IDE review process, rather than only at the end of the
review. This facilitates resolution of deficiencies within fewer review cycles. ODE
reviewers, with supervisory concurrence “should feel free to use the telephone or
\\1
telefacsimile to aid in the interactive review process.”
Traditional Premarket Approval (PMA) Process1 1 3
The PMA process is required for any product with new technology or
application of an existing technology for a new indication. This process is meant to
establish the safety and effectiveness of the technology for its intended use. In this
process there is also an element of clinical utility within the effectiveness
1 1 2 Guidance on IDE Policies and Procedures.
1 1 3 FDA, Center for Devices and Radiological Health (CDRH), Premarket Approval (PMA)
Manual (FDA 93-4214) (Rockville, MD: CDRH, April 1993).
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assessment. The process is risk based where the net benefit to the patient must
outweigh any risk occurring as a result of the technology or its use. A PMA
submission contains the following:
The summary section must contain the following information:
Indications for use. Give a general description of the disease
or condition that the device will diagnose, treat, prevent, cure,
or mitigate and include a description of the patient population
for which the device is intended.
Device description. Explain how the device functions, the
basic scientific concepts that form the basis for the device, and
the significant physical and performance characteristics of the
device. A brief description of the manufacturing process
should be included if it will significantly enhance the readers
understanding of the device. The generic name of the device
as well as any proprietary name or trade name should be
included.
Alternative practices and procedures. Describe any alternative
practices or procedures for diagnosing, treating, preventing,
curing, or mitigating the disease or condition for which the
device is intended. Include a statement such as "other
commercially available devices" if similar class III products
are available. Do not include any treatment practices or
procedures that are considered investigational.
Conclusions drawn from the studies. Discuss how the data and
information in the application constitute valid scientific
evidence, and provide reasonable assurance that the device is
safe and effective for its intended use. A concluding
discussion must present benefit and risk considerations related
to the device, including a discussion of any adverse effects of
the device on health, and any proposed additional studies or
surveillance that the applicant intends to conduct following
approval of the PMA.
The original PMA is submitted to the FDA upon completion of the pre-
clinical and clinical studies. The PMA is received by the FDA and assigned a lead
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reviewer. Typically an informal team is used to review the document for
completeness. This team includes an engineer or technical representative, a clinical
reviewer, and a statistician at a minimum. Once it is determined that the submission
is “fileable” the formal review can begin. The filing determination is made within 45
days. If the submission has deficiencies this is documented to the sponsor in writing
depending on the significance of the deficiencies the submission may be considered
not fileable.
Once the submission passed this preliminary review, the reviewer’s attention
is turned to the technical aspects of the submission. Detailed information about the
device design from an engineering perspective is reviewed to determine whether
basic safety requirements are met. The clinical indications for use are reviewed
along with the labeling and any contraindications. Finally, the results of the clinical
study are reviewed and an independent statistical analysis performed on the raw data
to verify the sponsor’s findings.
During the time when the internal FDA review is proceeding, the submission
is forwarded to the members of the FDA Advisory Panel for their assessment. The
advisory panel includes independent physicians and researchers with expertise in the
clinical areas indicated for the device under review. This panel also includes an
industry representative and a consumer representative. Once all of the required
reviews are complete a formal, open public meeting of the advisory panel is
scheduled. At this meeting the results of the clinical study as well as the product
labeling and any adverse events are discussed. The panel members then make a
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recommendation with regards to the submission as to whether it is approvable or not.
The recommendations can include requirements for changes to the product labeling,
post-market surveillance for additional data gathering, or even limitations on the
scope of device applicability (e.g., adult use only).
The FDA then completes the summary of safety and effectiveness data and
makes a final determination based on their review and the recommendations of the
advisory panel. In parallel with this panel process the FDA field investigators must
conduct a pre-Approval Quality Systems Inspection of the facility where the devices
are to be manufactured to ensure compliance with the Quality Systems Regulations.
The results are then provided to the sponsor in the form of an Approval or
Approvable letter with the appropriate conditions stated.
This process, by statute, is intended to take 180 days. This can be the case
for devices that are low in complexity or where there is some level of experience
with similar modalities within the agency. However, due to the complexity of many
of these new technologies, the process is more typically on the order of two to three
years.
PMA Process under FDAMAlu
Under the Least Burdensome provisions, the PMA process itself and the
statutory requirements have not changed. The focus of the FDA and the industry is
still the statutory criteria for approval of the Pre market Application. This is defined
lu The Least Burdensome Provisions of the FDA Modernization Act o f1997.
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as the determination of reasonable assurance of safety and effectiveness based on
valid scientific evidence. What has changed is the manner in which this is achieved.
The Agency has been tasked in the provisions to consider alternative sources
and methodologies to satisfy the statutory requirements. First, any information
unrelated to the pre market approval decision should not be submitted to nor
requested by the FDA. Where clinical outcomes can be predicted from non-clinical
data, well-designed bench and/or animal testing can be the basis for approval of the
PMA Conditions where non-clinical data may meet the threshold for approval would
be devices where information is available in the public domain.
Where clinical data is needed, alternatives to Randomized Controlled clinical
trials where biases can be controlled should be evaluated. This could include
reliance on valid non-US data where the application is appropriate for the U.S.
patient population demographics. Paper PMAs may be used where the bench testing
and/or results from peer reviewed scientific literature and meta analysis addresses the
issues of safety and effectiveness. Study designs may also employ non-concurrent
controls such as historical (literature or patient records), objective performance
criteria to measure against, or using the patient as their own control such as pre- and
post-treatment characteristics.
In addition, when clinical data is needed, the use of a scientifically valid
surrogate endpoint may be used as well as non-traditional statistical methods such as
Bayesian analyses. Bayesian techniques allows for combining studies to reduce the
overall sample size needed for the experimental and/or control device. As each of
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these alternatives is employed in the study design, early submission may also be
appropriate.
When possible, the FDA and industry should rely on information available
from earlier versions of the device, and market experience with similar devices. This
may reduce the need for new data if the performance throughout a similar product
life cycle can be evaluated. Also, post market study information should be evaluated
in the context of how it might guide the requirements for pre market data in addition
to the intended use of assuring long-term device safety and effectiveness.
Finally, the effective use of FDA-recognized consensus standards can also be
used to streamline the submission with respect to the engineering evaluation of the
product. Declarations of conformity to the applicable standards provide the FDA
with a baseline for safety and performance characteristics of the device.
In each area of the pre-market process for bringing medical devices to the
marketplace there is a common theme with Least Burdensome. The statutory
requirement for safety and effectiveness of the device is not changed; and, therefore,
the public continues to be protected. However, the regulatory burden associated with
the pre market processes is lessened by early interaction and communication to
ensure everyone is on the same page and reducing the duplication of information and
relying on existing data to fulfill the requirements for valid scientific evidence.
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Least Burdensome Provisions of the FDAMA
Section 205 of the FDAMA amended the Food Drug and Cosmetic Act to
incorporate two references to the “Least Burdensome” decision threshold. The first
reference is found in Section 513 (a) (3) (D) (ii), which states:
Any clinical data, including one or more well-controlled
investigations, specified in writing by the Secretary for
demonstrating reasonable assurance of device effectiveness
shall be specified as the result of a determination by the
Secretary that such data are necessary to establish device
effectiveness. The Secretary shall consider, in conjunction
with the applicant, the Least Burdensome appropriate means
of evaluating device effectiveness that would have a
reasonable likelihood of resulting in approval.1 1 5
The second reference also in Section 513 (i) (1) (D) states:
Whenever the Secretary requests information to demonstrate
that devices with differing technological characteristics are
substantially equivalent, the Secretary shall only request
information that is necessary to making substantial
equivalence determinations. In making such requests, the
Secretary shall consider the Least Burdensome means of
demonstrating substantial equivalence and request information
accordingly.1 6
There are two key aspects of this initiative. The first relates directly to the
health of the American public—access. The purpose of the Least Burdensome
provisions is to remove inefficiencies from pre-market processes to facilitate
bringing new technologies to patients. It is not intended, nor will it have the effect of
lowering the statutory requirements that must be fulfilled in the process. This is
U 5Food and Drag Administration Modernization Act of 1997.
U 6Ibid.
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accomplished through alternate approaches that require the same scientific
demonstration of safety and effectiveness thus the statutory thresholds are
maintained. These alternate approaches are described in guidance documents
published by the Agency for implementation of the various Least Burdensome
activities. Thus, the bar has not been lowered and public health will continue to be
protected.
The second aspect, which is critical to the successful implementation of these
provisions, is that the Least Burdensome provisions will require a change in the
culture of the Agency. The FDA must:
• recognize that there are multiple approaches to satisfying regulatory
requirements;
• communicate, collaborate and compromise in the interest of public
health;
• understand not only the letter of the law, but also the spirit of the law; and
• factor “time, effort and money” as considerations in decision-making.
These are significant paradigm changes for the Agency. Those who work at
the FDA have been repeatedly reminded that they are to avoid situations that could
be perceived as a conflict of interest. The relationship the FDA had with industry
prior to the Modernization Act was structured such that the American public would
have no concern regarding whose interests were being served. The FDA would
protect the public from industry. The FDA had been prevented from thinking
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“outside the box” because discretion, acceptance of multiple approaches,
communication and collaboration were considered open to favoritism.
The required “level playing field” can only be accomplished and
demonstrated by forcing everyone to comply with the same rules in the same way
each and every time the situation occurred. This was the case even when there was
new knowledge to be applied ensuring that whether you were the first or the last to
participate the rules stayed the same. Allowing the FDA any discretion or
interpretation of the spirit of the law could lead to different requirements for different
companies or devices. And, certainly in the past no regulatory agency was allowed
to consider “time, effort and money” when making a determination that impacts
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something so important as public health.
In assessing the Least Burdensome provisions, the FDA aligned this concept
with maintaining scientific integrity. They recognized that all scientific endeavors
are affected by the availability of resources. Good science can include consideration
of cost-effectiveness. Compromise is a necessity for successful research. Finally,
lessening regulatory burden can serve to enhance scientific progress and advance
medicine.
The FDA initiated this process by developing “Evidence Models for the Least
Burdensome Means to Market.” This model included a decision algorithm to
determine the need for clinical data. The focus is on two questions: (1) Does
1 1 7 Center for Devices and Radiological Health (CDRH) Staff College, “The Least
Burdensome Provisions of the FDA Modernization Act of 1997,” slide presentation.
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available valid scientific evidence provide a basis for clearance when the device is
used as indicated in target population? (2) What is the most appropriate and
reasonable way to obtain these data? The “Interim” FDA definition for Least
Burdensome is “a successful means of addressing a pre-market issue that involves
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the smallest investment of time, effort and money on the part of the submitter.”
The Agency believes time, expense and effort are all regulatory indicators of burden.
They define time as time to market reflected in cumulative review days and number
of review cycles; expense as cost associated with obtaining FDA marketing
authorization; and effort as resources required to meet the regulatory requirements.
Least Burdensome Pros and Cons
The FDA was tasked with the implementation of the Least Burdensome
provisions. This was a daunting task in that they were to reduce regulatory burden
without decreasing the statutory requirements for medical device manufacturers to
design and produce safe and effective products for their specified intended use. The
FDA believes that the following “Least Burdensome” activities1 1 9 benefit the
program while maintaining the historical protections in the FDA process:
• Application of appropriate risk/benefit criteria in decision
making rather than blanket rules to be followed with no
regard to the specific situation, this would include
consideration of different ideas
• Acceptance of historical data as demonstration that a
device may be safe and effective in lieu of new clinical
U 8Ibid.
,,9Ibid.
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studies that can be costly and may not provide any new
learning
• Pre-market/post-market balance, particularly when
addressing long-term safety and effectiveness issues. Not
every question regarding long-term safety and
effectiveness can be answered before the device is released
to the market. However, if data demonstrate there is a
benefit in the short term that outweighs the risk, and some
assessment of potential long-term issues can be provided,
it may be reasonable to require post-market surveillance.
This serves as an early detection system, if any long-term
issues arise.
• Acceptance of “state of the art” scientific principles and
methods (including clinical study design)
• Consistent use of guidance documents and standards
• Consistent requirements for manual methods versus
automated methods
• Application of a hierarchical approach to Least
Burdensome
• Consideration of “accepted medical practice” in decision
making
• Communication across FDA regarding Least Burdensome
approaches
The following are issues that the FDA believes can become obstacles to the
19H
“Least Burdensome” concept:
• Necessity of submission in question (i.e., is the submission
even required)
• Ineffective communication regarding what information is
needed in a submission which leads to prolonged decisions
and delays, if everyone is not on the same page regarding
implementation
• FDA requirements exceeding expectations in guidance
documents and recognized standards. This is an issue that
results in long, protracted testing for compliance, and, in
some cases, redesign of devices to comply. Additional
requirements may not result in any measurable
improvement in safety or effectiveness, but can be costly
with regards to time, expense and resources.
1 2 0 Ibid.
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• Human Clinical studies to provide data for 510(k) review
when engineering laboratory testing can demonstrate
substantial equivalence. Clinical testing should be limited
to those features and functions that cannot be verified
through other means.
• Unclear justifications for Not Substantially Equivalent
decisions. This refers back to the communication issue.
Clear rationale for Not Substantially Equivalent
determinations allows the submitter to evaluate next steps
with some measure of whether there are other options that
will result in a positive outcome. The alternative is an
open loop where the device is resubmitted with changes
that may or may not address the FDA’s concerns.
• Lack of reviewer familiarity with new technology. This
issue is not addressed through the Least Burdensome
provisions; however, more recent legislation allows the
agency greater latitude in use of experts to resolve this
issue.
• Lack of clarity for FDA rejection of industry approach or
proposal. The Least Burdensome provisions allow for
alternatives to be considered. If the FDA is not accepting
or unclear about their issues it can extend the process for
the same reasons noted previously.
Least Burdensome Activities
The Least Burdensome provisions are grouped into activities. There are
formal and informal activities. There are activities within each of the device
submission processes and activities on the part of FDA during the review process.
Pre-submission activities in the Pre-Market Approval and 510(k) processes include
the following:
Informal Activities
• Simple information inquiries can be requested from the Division of Small
Manufacturer’s Assistance and Office of Device Evaluation.
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• Guidance Document Development activities are to be expanded so that
there are documents for all types of submissions. This facilitates the
manufacturer preparing a complete document.
• The Pre-IDE Program, although already initiated, is further formalized in
the Least Burdensome provisions. The objective is to aide in the
development of appropriate clinical studies with achievable and
acceptable clinical endpoints for the device prior to study initiation.
■ 1995 Guidance. Informal advice on pre-clinical testing and/or
clinical protocol; letter, phone, fax, meetings.
■ 1999 Guidance. Goal is to benefit sponsor; not a pre-requisite
for an IDE; striving for single cycle.
■ Pre-IDE is appropriate during testing or protocol development
or for Non-Significant Risk studies.
■ Pre-IDE is not appropriate if the device or Indications for Use
are not well characterized. It is not appropriate for complete
IDEs nor an in-depth review of data.
Early Collaboration Activities
Determination meetings are intended to establish appropriate clinical
validation objectives so that the PMA review is without major issues. Determination
meetings:
• Are described in Section 520(g)(7)(A);
• Can be requested by any Pre Market Application sponsor;
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• Provide agreement on what valid scientific evidence is needed to
demonstrate effectiveness;
• Focus on clinical trial design;
• Result in documentation of discussions and determinations; and
• Produce binding results unless they are found to be contrary to public
health.
Agreement meetings are intended to achieve consensus on the actual study
design. Agreement meetings:
• Are described in Section 513(a)(3)(D)(i);
• Are applicable to Class III devices and implants;
• Enable agreement on Investigational Plan;
• Result in documentation of discussions and determinations; and
• Produce binding results unless a substantial scientific issue essential to
determine Safety or Effectiveness is identified. This would not be
finalized without an additional opportunity to meet.
Least Burdensome and the 510(h) Program
The 510(k) decision-making process was evaluated and it was confirmed that
a new device is substantially equivalent if: (1) it has the same intended use and the
same technological characteristics or (2) the same intended use and different
technological characteristics, without raising different questions of safety and
effectiveness, and with data that demonstrate it is safe and effective.
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This assessment resulted in ideas for changing the process. Mechanisms to
lessen the burden of 510(k) review were proposed and include the following:
• Use of standards, guidance documents, special controls {Federal Register
Notice February 19,1998, “Recognition and Use of Consensus
Standards”): A modified guidance on the use of standards was issued.
• Use of design controls: Design controls are the Quality Systems
Requirements that apply to the engineering design process for
development of new products. “The New 510(k) Paradigm” guidance
issued March 20,1998 Special 510(k)s that discussed the following
changes: summary of design control activities, use of a Declaration of
Conformity to design controls, reliance on Quality System Regulation
requirements, and a statutory timeframe resulting in a final decision
within 30 days.
• Use of the “de novo” classification process: The original device
legislation ruled that any device that could not be found equivalent to one
already on the market would automatically be classified as Class III and
require a PMA to be brought to market. This classification allows for a
risk-based evaluation to determine if a “de novo” process is appropriate.
It is defined in Section 513(f)(2) of the FD&C Act and is a risk-based
classification process. It is used when a device cannot be found
substantially equivalent and it is less burdensome than PMA.
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In addition, areas outside of the scope of 510(k) review were also clearly established
and include the following:
• Verifying conformance with standards (Section 514, voluntary
standards): The submitter should provide a Declaration of Conformity to
standards and not be required to submit the actual test report results. The
FDA has successfully used a similar certification process for software
validation. In these cases where the agency depends on declarations or
certifications, compliance is assured through the facility inspection
process. The agency performs both routine and risk based inspections of
medical device manufacturers and during this inspection records of
standards compliance can be reviewed in the same manner as software
validation records.
• Ensuring adherence to quality systems requirements, e.g., special 510(k)s:
Special 510(k)s are not withheld when there is pending Quality Systems
issues between the agency and the manufacturer as is the case with
standard 510(k)s.
• Claims substantiation activities.
Least Burdensome and the PMA Program
The FDA evaluated the PMA process and confirmed that PMAs must
demonstrate reasonable assurance of safety and effectiveness. This must be
accomplished through use of valid scientific evidence. Of the studies supporting
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PMAs, 45% were Randomized Controlled Trials (RCT), 48% were not RCT and 7%
had no controls.
The evaluation of the PMA process yielded the following mechanisms to
lessen burden: use of a Declaration of conformity to standards, use of surrogate
endpoints in clinical studies, reliance on non-clinical testing, and reliance on
literature and/or non-active controls.
Key Points for the FDA
The FDA is now required to factor Least Burdensome concepts into all pre
market activities, such as development of guidance documents, acceptance of
consensus standards, and greater reliance on the controls that exist in the Quality
Systems Regulations. To satisfy this requirement the Agency has delineated specific
behaviors that include the following. Prior to making requests of industry, the FDA
has agreed that their review staff should discuss the need for additional studies with
colleagues and agency management. The FDA is committed to remaining open-
minded to alternative proposals for satisfying regulatory requirements.
With regards to 510(k)s, the Agency will now consider what information the
statute, to demonstrate Substantial Equivalence, envisioned. The Agency is
committed to learn from previous 510(k) decisions and consider whether additional
studies are necessary for decision making. The Agency is also using the tools
provided by FDAMA and re-engineering, such as special and abbreviated 510(k)s,
exemptions and other FDA guidance.
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With regards to PMAs the Agency is now factoring recognized standards into
the decision-making processes. They also consider non-clinical alternatives for low
risk devices or device modifications. If clinical data are needed, consideration is
given to alternatives to Randomized Clinical Trials.
The FDA is challenged through the Least Burdensome provisions to make a
conscious effort to factor in all relevant publicly available information to reduce
regulatory burden. In this way, data that already exists can be put to use and efforts
are not duplicated. In each case where a device is reviewed for safety and
effectiveness, the data to demonstrate this must be available. In devices that require
clinical data to demonstrate the safety and effectiveness the process improvements
suggested in Least Burdensome are pre-submission meetings, modular review of the
data and use of existing clinical data when appropriate. These improvements do not
change the burden of proof regarding the device performance, but help to ensure that
resources are not wasted, and clinical subjects are not needlessly investigated in
pursuit of questionable clinical endpoints. The goal envisioned is that the process
becomes more efficient and wastes less time and effort. The benefits derived are
reduced burden on industry that can lead to improvements in access to new medical
technology for the American public.
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CHAPTER V
RESEARCH PROBLEM
The literature clearly describes the regulatory theories, policies and
methodologies used in the regulation of medical devices. In addition, the studies
cited have demonstrated a failure of the FDA to fully implement the medical device
amendments to the Federal Food Drug and Cosmetic Act. The practices employed
by the Agency to regulate devices were inconsistent and unpredictable. The
regulatory burden on industry was so significant that development and
commercialization of new technologies were pursued outside of the United States.
This resulted in delayed access or no access to these technologies for the American
public.
This review of the relevant literature regarding the issue of regulatory burden
demonstrates the potential effect on public health. Regulatory burden is a function
of how controls are implemented through policies and procedures. The question of
how to reduce regulatory burden without reducing the protection of the public is of
critical importance to the field of Public Administration. Changes to the regulatory
process that successfully reduce burden can improve timeliness and access to the
latest technologies. If these types of changes are found to be effective in the
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regulation of medical devices, the concept of Least Burdensome may be applied in
other regulatory arenas, as well.
The FDA believes time, expense and effort are all regulatory indicators of
burden. They define time as the time to market reflected in cumulative review days
and number of review cycles. Expense is cost associated with obtaining FDA
marketing authorization to include clinical studies, product testing, consultants, etc.
Effort is resources required to meet the regulatory requirements. This definition is
based on the results of Congressional investigations, hearings, industry studies and
surveys.
Increased requirements and a lack of predictability make it virtually
impossible for a business to remain solvent while addressing regulatory
requirements. Decisions regarding commercialization of devices outside of the
United States to generate revenue while the domestic process is ongoing have
become the norm rather than the exception. The importance of this research is that it
is of substantive value to regulators seeking knowledge about regulatory processes.
With this expanded knowledge, better decisions can be made with regards to
regulatory policies leading to a common goal. That goal would be continued
protection under the regulations without burden that has no added value to the
process.
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The Research Hypothesis
The question to be answered is whether the implementation of the Least
Burdensome provisions of the FDA Modernization Act has resulted in a reduction in
regulatory burden in the areas of time, expense and effort in the medical device
submittal process.
Specific Hypotheses for Analysis
Null Hypothesis for Timeliness: Implementation of the Least Burdensome
provisions has made no substantial improvement in the timeliness of 510(k) reviews.
If 510(k) review times are improved, then the Least Burdensome provisions for
510(k)s may be effective in reducing the time component of regulatory burden as
defined by the FDA.
Null Hypothesis for Communication: Implementation of the Least
Burdensome provisions has made no substantial improvement in the perceived
quality of communication between the FDA and industry. If communication is
improved, then the Least Burdensome provisions for IDE/PMA may be perceived as
effective in reducing the time, expense and/or effort components of regulatory
burden, as defined by the FDA.
Null Hypothesis for Issue Resolution: Implementation of the Least
Burdensome provisions has made no substantial improvement in the timeliness of
issue identification and resolution. If early identification and resolution of
significant issues occurs, then the Least Burdensome provisions for IDE/PMA may
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be perceived as effective in reducing the time, expense and/or effort components of
regulatory burden, as defined by the FDA.
Delimitations
This study is limited to the Food and Drug Administration Medical Device
Regulatory clearance/approval process. In addition, the study has been limited to the
industry perspective with regards to the Least Burdensome provisions. Specifically,
the research evaluates the 510(k) Pre-market Notification process through
quantitative analysis of 510(k) review times. The research also qualitatively
addresses the IDE/PMA Pre-market Approval process with respect to
communication and guidance. This facilitates understanding of the provisions affect
on the more difficult to quantify measures of expense and effort. The study focuses
on comparing performance in these processes prior to the 1997 implementation of
the Modernization Act and subsequent to implementation of the Least Burdensome
provisions of that Act. Expense can be evaluated by comparison of the number of
510(k)s requiring clinical data before the implementation of the provisions as
compared to after. Effort can be evaluated by the average number of submissions
per reviewer before and after the provisions. However, these two parameters are
more difficult to quantify and are not included in the scope of this research.
Restated, the scope of this research is limited to the evaluation of a specific
program (Least Burdensome) within a particular aspect (content, review and
predictability of pre-market submissions) of a regulated industry (medical devices) to
minimize the effect of external variables. In addition, this focus allowed sufficient
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time to execute a true elite interview process with stakeholders and analyze the data,
while maintaining the reliability and validity of the information.
Limitations
There are a few limitations with this research as presented. The 510(k)
review time assessment may benefit from a formal statistical analysis, possibly a t-
test or analysis of variance. Currently only the individual records for 510(k)
submissions are publicly available. These statistical tests require computation of the
standard deviation. Without access to the 510(k) database this would be an
untenable task and is beyond the scope of this research. This may, however, be an
interesting assessment for policy analysts within the agency who have access to this
data.
The data presented for the IDE/PMA process is qualitative and gives a
general perception regarding the effectiveness of the Least Burdensome provisions.
It may be that if quantitative performance metrics were available, then a more
concrete assessment could be performed. There is also very little experience with
two aspects of the provisions, one is the Abbreviated 510(k) process and the second
is with the formal Agreement and Determination meetings. While there is data to
suggest that both of these areas are not working as well as expected, it is not clear
that there is sufficient experience to render a conclusion to that effect. There are
some thoughts presented as to why those two aspects of the provisions are not
working. However, investigating this further was beyond the scope of this research.
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CHAPTER VI
DATA ORGANIZATION AND METHODOLOGY
The Agency believes time, expense and effort are all regulatory indicators of
burden. They define time as the time to market reflected in cumulative review days
and number of review cycles. Expense is the cost associated with obtaining FDA
marketing authorization; and effort is defined as the human resources needed to meet
the regulatory requirements.
The process comparison is as follows: When there is no definition of
requirements, what is submitted has a much lower probability of being correct and
the Agency can make request for additional information. Any information is fair
game. This would include information to increase the security of the reviewer,
satisfy curiosity or to expand the knowledge base. While these may be legitimate
requests for information, they should not be used to hinder the device approval
process. If requirements are not defined then the submitter is taking an educated, or
maybe not so educated guess as to what the Agency’s concerns might be.
Information is provided, then reviewed and found to be lacking, questions are asked,
responses submitted, and this information raises more questions. If this submission
is an IDE or PMA then clinical studies may have to be modified, etc., at great
expense and delays. The cycle can be quite long with multiple iterations taking the
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time and energy of the submitter and the reviewer as well. This process model is
open loop in engineering terms and by nature is very unpredictable. This is the basis
for the definition of unnecessary regulatory burden from the perspective of
industry,1 2 1 Congress1 2 2 and the FDA.1 2 3
An alternative process model, that is the model based on a Least Burdensome
philosophy would look more like the following: FDA defines the requirements for
submissions, the proper information is provided by the submitter, the FDA has what
they need to complete a thorough review and assessment and the submission can be
completed. In this case process requirements definition, proper communication,
effectively a close-loop process, significantly increases the probability that a get it
right the first time event will occur. Close-loop systems are inherently more efficient
for all involved and very predictable.
510(h) Research Phase 1
Description of Variables
The independent variables in Phase 1 of the study are the provisions that
apply to 510(k) submissions. These provisions include use of the special and
abbreviated 510(k) processes, certifying conformity to recognized standards, and use
of design controls. These provisions change the inputs to the 510(k) review process.
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The Wilkerson Group.
1 2 2 FDA Reform Legislation, 4.
l2’Center for Devices and Radiological Health (CDRH) Staff College.
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The dependent variable is the 510(k) review time where the value is actually the
number of days it takes to review these submissions.
The processes do not appear to be systematically different with regards to all
other aspects with the exception of the independent variables, i.e., the regulatory
requirements. The process steps, responsibilities, resources, etc., are control
variables. Should a variable such as resources be changed, there would be an
expected change in the dependent variable. This would make it difficult to
determine which independent variable, provisions or resources, contributed to the
change. Therefore, these variables should be inspected to understand whether they
are influencing the results of the study.
The 510(k) study assesses data on the timeliness of 510(k) reviews. The data
demonstrates whether the review times prior to the implementation of the Least
Burdensome provisions are the same or different from the review times post
implementation. As described previously, a longitudinal analysis of review time data
before and after implementation is compared using Histogram analysis to illustrate
variation.
Target Population
In the 510(k) phase of the study there are no subjects to be derived. In this
phase a case is defined as a 510(k) submission. The class of cases to which this
investigation applies is that of medical device pre-market notifications. The
sampling design and decision rules include analysis of data over time as well as
performing an interrupted time-series analysis to draw causal inferences. This
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design was chosen because the time-series data facilitates trend analysis and can be
used to support or refute hypotheses.
Production of Data
This research for Phase 1 involves a longitudinal study collecting and
comparing data from several distinct time periods. Time series analysis is used
because it measures variables at regular intervals over several years. Time series
facilitates establishment of a baseline measure, reflects changes over time and can
potentially forecast future trends. Time series analysis generally has four types of
variations: long term trends, cyclical variations, seasonal variations, and irregular
fluctuations.1 2 4 The variation anticipated in this research is limited to long-term
trends.
The required information from this 510(k) database is the unique 510(k)
identifier, the date the submission was entered, the date the submission was
completed and the type of 510(k) (Special, Abbreviated or Traditional). This
information is publicly available from the FDA Web site under the Databases
heading. The data is limited to individual record-by-record accessibility. It is not
possible to manipulate the data from this database in the manner necessary to
perform this analysis. However, the FDA also publishes an Annual Report, a
document containing detailed summary evaluations of 510(k) review times. In
addition to the data from the Annual Reports, the Program Operations Staff of the
1 2 4 Elizabeth Ann O’Sullivan and Gary R. Rassel, Research Methods for Public
Administrators, 2d ed. (New York: Longman Publishers, 1989), 30.
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FDA Office of Device Evaluation provided the remaining data items needed for this
study as well as results from their own data analysis. The information gathered for
each 510(k) represents a case. The data analysis is performed on results prior to and
post implementation of the provisions. Cases are placed along a time continuum
with the process change delineated.
The validity associated with a time-series research design is excellent. The
researcher can draw inferences from the data to support or refute the claims of the
Least Burdensome provision objectives. The data in the FDA 510(k) database are
relatively stable and consistent. The data in the system also extends far enough into
the past to provide an adequate sample of pre-FDAMA performance. The issue with
the FDA 510(k) database is that while the data needed for the study are public, the
access is available to the public on a record-by-record basis. This does not facilitate
a direct analysis of the raw data. Annual reports by the Agency have reported on the
very top-level summary of 510(k) review performance. The Annual Report
information alone is not detailed enough to demonstrate change as a result of the
Least Burdensome provisions without the additional data provided by the FDA.
However, because the performance measures are straightforward and have been
database driven for more than 10 years, the data quality and objectivity is not in
question. The data is qualitatively measured and thus does not require any
verification of the research design.
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Methodology
Phase 1 of the research focuses on the 510(k) process and the Least
Burdensome provisions intended to reduce regulatory burden as defined by the FDA.
The parameters described by the FDA include time, expense and effort. In the
510(k) process, the provisions establish a streamline process for 510(k) submissions
for modifications to already cleared devices that have a statutory review time of 30
days compared to the standard 90 days. Thus, the effect of the Least Burdensome
provisions with regard to time is reflected in the review times, before and after
implementation, for submissions. Expense associated with obtaining FDA marketing
authorization and effort required to meet regulatory requirements become an issue
when clinical studies are required. In the 510(k) area, one of the provisions is to
minimize the occasions when clinical data are needed in the submission, thereby
reducing the expense and effort of meeting the regulatory requirements. Expense
can be evaluated by comparison of the number of 510(k)s requiring clinical data
before the implementation of the provisions as compared to after. Effort can be
evaluated by the average number of submissions per reviewer before and after the
provisions. However, these two parameters are more difficult to quantify and are not
included in the scope of this research. The question for the 510(k) process is
whether use of standards, design controls, “de novo” classification, and “Special
510(k)s” have had an effect on the submission review times.
The data organization takes the form of a Histogram analysis of 510(k)
review times. The data is presented for each year from 1997 to 2002. The data is
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presented as “Number of Review Days” on the Y-axis versus “Year” on the X-axis.
Review times will be grouped for each year by 510(k) type. The groupings are:
Total 510(k)s, Traditional, Abbreviated and Special. The data is analyzed to see if
there is any change in the overall average review times in the year prior to the
FDAMA Least Burdensome provisions of 1997 as compared to the review times
after implementation.
Histogram analysis is one component of Process Capability analysis as
defined by Joseph M. Juran. Process capability is the measured, inherent
reproducibility of the product turned out by a process. In the process capability
model process is defined as some unique combination of machine, tools, methods,
materials and people engaged in production. The output of the process may be a
physical good or a service. With respect to the FDA process this includes the tools,
methods and people needed to review 510(k) notifications for medical devices.
Capability is defined as competence based on tested performance of the process to
produce quality products. For the FDA this would be the number of review cycles
needed for a 510(k) submission to clear. Measured is defined as output or work
performed by the process. This is the overall time to review a 510(k) in the FDA
process. Inherent reproducibility is product uniformity resulting from a process that
is in a state of statistical control, i.e., the absence of assignable causes of variation.
FDA review times appear to be in a state of statistical control in the absence of the
1 2 5 Joseph M. Juran and A. Blanton Godfrey, Juran’ s Quality Handbook (New York:
McGraw-Hill, 1999), 22.11-22.24.
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following known causes of variation: inconsistent submission requirements,
reviewer expertise and whether clinical data is required. Measurements are made on
the product (a good or a service) because product variation is used to quantify
process capability. Process capability is defined as reproducibility over a long period
of time with normal changes in people, tools and other process conditions. Thus
process capability is the ability of the process to produce the desired results in a
consistent manner even during normal perturbations in the process.
IDE/PMA Research Phase 2
Description of Variables
The independent variables for Phase 2 are the IDE/PMA provisions,
specifically implementation of the Pre-IDE Program and the early collaboration
Determination and Agreement Meetings. This phase of the study is qualitative;
therefore, the dependent variable results are subjective. The results are experiences
and perceptions rather than concrete measures.
The IDE/PMA data is extracted from a series of elite interviews with
professionals who have experience in these processes both before and after
implementation of the provisions. This data is reviewed for common themes and
experiences to try and determine whether there is agreement with regards to the
perception that the Least Burdensome provisions have affected the IDE/PMA
process. In addition, through the interview process there has been opportunity to
discuss concrete examples. This may lead to variables that would lend themselves to
a more quantitative analysis in the future. For the purposes of this study, the
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qualitative information stands on its own as a method to discover the perspectives
and feeling of industry with regards to this program.
Target Population
The IDE/PMA phase does involve a target population. The characteristics of
this population include: (1) medical device manufacturer regulatory affairs
professionals, (2) device classification of III requiring IDE/PMA submission, and
(3) experience with submission processes prior to and subsequent to Least
Burdensome provision implementation. The sample has been developed through a
request for volunteers, with the help of AdvaMed (the medical device industry trade
association, formerly Health Industry Manufacturers Association HIMA). The
interviews continued until it was possible to reliably anticipate what the interviewee
was likely to say, while at the same time trying to ensure representative coverage of
regulatory professionals in the industry. In the elite individual interview, this
typically occurs within five interviews in a very homogeneous population and the
population of medical device regulatory professionals is quite homogeneous. In
qualitative research the number of interviews is much less important than the quality
of information gained. This type of research is intended to ensure that the qualitative
analysis will accomplish what it does best—to discover (not measure) potentially
important insights.
The population of regulatory professionals involved in the IDE/PMA process
with the FDA is both very small and very homogenous. The average number of
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PMAs submitted over the last five years is 40 per year. In the five years from 1998
to 2002, 130 different companies submitted a total of 221 PMAs. In order to
understand the total population that would meet the study criteria the data was
reviewed to determine the number of companies with more than two PMA
submissions. This would help identify companies that may have adequate
experience. The total number of companies with more than two PMAs over the five-
year period is 12 or 9% of the total PMA company population. This data was
extracted from the Annual Reports for each year.
In order to further verify the population the PMA database was searched by
year and by the company sponsoring the PMA for submissions that had been
approved in that year. The database limited records to 500 per year. This sample
was all or nearly all of the records, but a consistent sample. Analyses of this data
showed an average of 40 PMAs per year were approved. In the sample taken over
the six year period from 1996 to 2002 there were 238 PMAs approved by a total of
140 applicants. Of those applicants, eight companies had more than two PMAs with
at least one PMA preceding the FDAMA. These eight companies are responsible for
22% (52) of all the PMAs submitted, and 132 companies were responsible for the
remaining 186 applications. Also, of those eight companies who met the criteria,
two companies (or 25%) are responsible for 10% of all the PMAs approved. Both of
these companies are represented in the elite interviews conducted for this research.
This assessment further confirms that the population of companies that could be
interviewed who met the study criteria is quite small.
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Given the resultant small population and the anticipated difficulties in
gaining access to the regulatory professionals in these 12 companies it was
determined that further investigation into possible candidates be performed.
There were 100 companies over the five-year period that submitted PMAs to
the FDA for review. The vast majority of these companies were startups or very
small. These types of companies typically do not hire a regulatory professional into
their company, but rather use either regulatory consultants or law firms who
specialize in regulatory submittals for this work. This allows the company to take
advantage of regulatory expertise without the cost of permanent employment. To
that end, elite regulatory professionals who provide their services through consulting
or representation could meet the study criteria. Therefore, a sample size of 10 was
selected. By targeting all 12 major corporations that met the study criteria, as well as
consultants and medical device law firms who perform these services for small
companies, the sample size of 10 became both reasonable and adequate.
Production of Data
The IDE/PMA phase of the study also employs descriptive research in the
form of elite interviews. Elite interviews are used to gain an understanding of what
the belief systems, activities, roles in decision-making processes and relationships
are of leaders and experts in a particular field or profession. To the extent that these
individuals exercise power and influence in their organizations their perceptions
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should be subject to empirical examination.1 2 6 These individuals in the medical
device area are expected to have a broad view of the regulatory environment well as
knowledge of how the FDAMA legislation affects their ability to bring new products
to market. A semi-structured interview approach has been taken. In this approach,
qualitative data are generated. However, a specific agenda was followed and the
relevant topic areas and themes to pursue were determined in advance. The
interview was loosely structured around an interview guide with key questions. This
guide facilitates some degree of comparability in the resultant data. In this
methodology the interviewer is free to follow up on ideas, ask for clarification, or
seek elaboration. The interviewees can answer the questions in terms of what they
see as important. They may also determine the scope and depth of the answers they
provide. Analysis of the qualitative data gained in this interview process has been
evaluated for trends and patterns that repeat among the various participants. The
analysis is systematic and follows a prescribed process; that yields a verifiable
conclusion. In addition to common themes, the data is evaluated for the range and
diversity of results. The information analyzed is then interpreted. The quality of this
interpretation is dependent on the analyst’s capabilities in this area and with this
methodology of research.1 2 7
The interview process resulted in the documenting of the beliefs and
perceptions of the interviewee with regards to the affect of the Least Burdensome
1 2 6 Hilary Arksey and Peter Night, Interviewing for Social Scientists (London: SAGE
Publications, Ltd., 1999), 122.
1 2 7 0 ’Sullivan andRassel, 175.
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provisions on the IDE/PMA process. To obtain this information, the key questions
in the interview guide focused on the issues related to the provisions such as
communications, use of early collaboration meetings, and experience with FDA
during these interactions. The data gathered was analyzed for trends and patterns to
determine if there is a common perception among those most intimately involved
with the process. Data reliability is a function of accurate recording so that analysis
is performed on the true data set, and consistency of responses. A combination of
tape recording (if acceptable to the interviewee) and note taking was used. With
regards to the consistency of response, the purpose of trending and patterning the
results is to elicit this consistency to the degree that it exists. This consistency is
effectively the equivalent of reliability in the positivist world of quantitative analysis.
The question of the validity of this qualitative data was addressed through the
assessment of the data. The value of the outcomes may be used for action, program
development, or for the policy or research community in general. In simpler terms,
validity is addressed through the ability of the research to answer the question, “what
is the value added by this information?”
Qualitative research is not looking for principles that are true
all the time and in all conditions, like laws of physics; rather
the goal is understanding of specific circumstances, how and
why things actually happen in a complex world. Knowledge
in qualitative interviewing is situational and conditional.1 2
1 2 8 H. J. Rubin and I. S. Rubin, Qualitative Interviewing: the Art of Hearing Data (London:
Sage Publications, 1995).
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Methodology
Phase 2 of the research focuses on the IDE/PMA processes and the Least
Burdensome provisions intended to reduce regulatory burden as defined by the FDA.
As noted above, the parameters described by the FDA include time, expense and
effort. In the IDE/PMA process, the provisions establish a series of pre-submission
activities intended to increase the success rate of clinical studies and PMA approvals.
The specific activities include the Pre-IDE program, part of which was implemented
in 1995 to include informal advice on pre-clinical testing and clinical protocols, and
communication through multiple means including face-to-face meetings. Guidance
in 1999 to the FDA staff emphasized that the purpose of the program was to benefit
the sponsor (industry) and to facilitate a single cycle review and approval rather than
multiple iterations. The programs for PMA focused primarily on communication
and interaction in the early stages of the PMA. The provisions establish formalized
meetings to determine and document binding agreements between the Agency and
industry regarding the existence of valid scientific evidence, clinical trial design, and
investigational plans.
The process change might be described as follows for the IDE example.
Prior to Least Burdensome the process was open loop. The sponsor would develop a
clinical study protocol with specific endpoints and submit to the FDA. The FDA had
45 days to respond to the submission with an approval to proceed with the study, or
request for additional information. The vast majority of IDE submissions were
followed by a request for additional information. The industry would interpret the
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request and respond, and the FDA would review and ask more questions. The result
could be multiple review cycles for the Agency and the industry to get on the same
page. In a paper approach it is exceedingly difficult to convey clear understanding of
the product to be developed, the rationale for why the particular endpoints in the
clinical study were chosen, and why the agency had issues. The early collaboration
meetings allow for the discussion of the issues addressed above, education, and
explanation to occur. Consensus should be achieved in a more rapid, efficient
manner. The potential for misinterpretation should also be reduced. Thus the affect
of the Least Burdensome provisions with regard to time may be reflected in the
review times for submissions. Expense associated with obtaining FDA marketing
authorization, and effort required to meet regulatory requirements may also be
reduced.
This phase of the research is qualitative for several reasons. The most
significant reason is that there is great variability in clinical study requirements
(IDE) and PMA development, review and approval. Therefore, assessment with
regards to time, expense and effort are not homogenous, or predictable outside the
specific case being evaluated. Comparison of the following parameters would not be
valid under these conditions: review times, expense of clinical trials or effort
required to achieve product approval. The regulatory burden in the IDE/PMA
process is greatly affected by the complexity of the technology, the frequency and
severity of the disease process to be addressed, and many other variables associated
with the device in question. Clinical utility and what may be needed to demonstrate
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it is also another significant variable. These sources of regulatory burden are not a
result of FDA process and would not be possible to mitigate with process changes.
For these reasons the research in the IDE/PMA area focuses on industry’s perception
of the utility of the early collaboration activities and their effect on the overall
process.
The data was gathered using the Elite Interviewing methodology.1 2 9 This
methodology is intended to capture beliefs and perceptions through the use of open-
ended questions about a given topic. The interview guide for this research includes a
few quantitative questions regarding the nature, size and complexity of the sponsor’s
company. This is followed by eight or nine open-ended questions related to the
provisions and the interviewee’s assessment of the effect of these provisions on their
regulatory processes. Out of this interview process comes some sense of the
perceived validity of the Least Burdensome provisions and some concrete examples
of successes and failures of the provisions to meet the objective of reduced
regulatory burden. These examples include events both before and after the
implementation of the provisions.
Summary
The purpose of using this two-phased approach is to produce research that is
complete and methodologies that would confirm the consistency of any conclusions
1 2 9 Lewis Dexter, Elite and Specialized Interviewing (Evanston, IL: Northwestern University
Press, 1970); and Arksey and Night.
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that are drawn. This technique is described as “triangulation.”1 3 0 Data triangulation
means the use of a research design involving diverse data sources to explore the
same phenomenon. Therefore, the quantitative 510(k) data with statistical inference
combined with the qualitative data from interviews leads to some conclusion
regarding the effectiveness of the Least Burdensome provisions of the FDAMA. Use
of quantitative and qualitative data serves to improve the reliability and validity of
the data. The internal validity of this study is based on the evidence gathered,
regarding the change in the dependent variables, (510(k) review times, early
collaboration and communication) as a result of the change in regulatory process by
implementation of the Least Burdensome provisions. External validity applies to the
interview methodology and whether the sample selected is truly representative of the
experience in the general population affected by this regulatory process change.
The limitations in the interview phase of the study lie in having access to
experts. In addition, there must be a sufficient number of experts who meet the
criteria of experience pre and post implementation of the provisions. Finally there
must be consistency across the various experiences to derive conclusions from the
interview data.
1 3 0 E. J. Webb, D. T. Campbell, R. D. Schwartz, and L. Sechrest, Unobtrusive Measures:
Nonreactive Research in the Social Sciences (Chicago: Rand McNally, 1966).
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CHAPTER VII
DATA FINDINGS AND ANALYSIS
This research study is comprised of two major components identified as
Phase 1 and Phase 2. Phase 1 of the study involved gathering quantitative data on
the 510(k) Pre-market Notification process from the FDA 510(k) Annual Reports
and Web site 510(k) Database. One of the objectives of the Least Burdensome
provisions for the 510(k) process was to improve the timeliness of the pre-market
clearance process.
Phase 2 of the study involved gathering qualitative data on the IDE/PMA
processes through a series of elite interviews with Regulatory professionals
intimately involved with these processes and the FDA. One of the objectives of the
Least Burdensome provisions for the IDE/PMA process was to improve
communication and resolution of significant issues early in the process rather than
later when extensive time and resources had already been expended.
510(k) Research Phase 1 Introduction
The following sections outline the data collected in each phase of the study as
well as analyzing the information and providing a statement of findings. Phase 1
begins below with a restatement of the first question and a description of the changes
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the provisions made within the 510(k) process. Then the data for each change is
described in the following sequence:
• Effect of Special 510(k) process
• Effect of Abbreviated 510(k) process
• Resources Applied to the Review Process
• Effect of Guidance Documents
• Use of Recognized Standards
Least Burdensome Provisions for 510(h) Premarket Notification
Process—Analysis of Timeliness Hypothesis
Restating the Null Hypothesis for Timeliness: Implementation of the Least
Burdensome provisions has made no substantial improvement in the timeliness of
510(k) reviews. If 510(k) review times are improved, then the Least Burdensome
provisions for 510(k)s may be effective in reducing the time component of
regulatory burden as defined by the FDA.
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Table 2
510(h) Performance by Submission Type
Year Full-Time
Employees
Type of
Submission
Number
Submitted
Total Review
Average
Days
FDA Review
Average Days
Traditional 5049 130 97
1997 356 Abbreviated 0 0 0
Special 0 0 0
Total 5049 130 97
Traditional 4528 120 95
1998 340 Abbreviated 7 62 62
Special 66 22 21
Total 4623 114 89
Traditional 3985 108 85
1999 330 Abbreviated 75 99 80
Special 361 29 24
Total 4458 102 80
Traditional 3471 115 87
2000 329 Abbreviated 118 103 83
Special 583 32 27
Total 4202 102 77
Traditional 3394 110 86
2001 353 Abbreviated 174 99 82
Special 685 32 28
Total 4248 96 75
Traditional 3525 115 90
2002 353 Abbreviated 165 119 91
Special 776 33 28
Total 4320 100 79
Table 2 provides summary data over the five-year timeframe from just prior
to implementation of the Least Burdensome provisions and for four years post
implementation. This data illustrates several important findings to be discussed in
further detail in the following paragraphs. In order to set the stage a few points
should be made. First, over the five-year period resources available for 510(k)
review was relatively flat. Second, the total number of original submissions over the
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five-year period decreased by 14%. Finally, the average days to review all 510(k)s
for the FDA decreased by 18.5%.
Table 3
Number o f 510(k)s by Type
Total #
510(k)s Traditional Abbreviated Special
1997 5049 5049 0 0
1998 4623 4528 7 66
1999 4458 3985 75 361
2000 4202 3471 118 583
2001 4248 3394 174 685
2002 4320 3525 165 776
Number of 510(k)s by Type
6000
4000
3000
2000
1997 1998 1999 2000 2001 2002
Year
ITotal#510(k)s ■Traditional DAbbrev ■Special
Figure 3. Number of 510(k)s by Type.
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The Least Burdensome provisions of the FDA Modernization Act included a
new 510(k) paradigm. This paradigm provided for two new types of 510(k)
submissions; Abbreviated and Special. As previously described, Abbreviated
510(k)s allowed the use of a Declaration of Conformity to consensus standards in
lieu of safety and performance test data. The Abbreviated 510(k) carried the same
statutory timeframe of 90 days and was expected to reduce the overall review time.
Special 510(k)s provided for an expedited review for straightforward changes where
labeling review is adequate for determining substantial equivalence. This Special
510(k) type carried a 30-day statutory timeframe. Figure 3, illustrates the fairly
constant flow of 510(k) submittals to the Agency. It also shows a steady increase in
the number of 510(k)s submitted under these newly defined categories since 1997.
By the end of 2002, 23% of all 510(k)s received were identified as Special (18%) or
Abbreviated (5%). It is clear that this program within the Least Burdensome
provisions has been accepted and has had significant participation in the case of
Special 510(k)s.
Table 4
Total 510(h) Review Time Average by Year
Year Total Traditional Abbreviated Special
1997 130 130 0 0
1998 114 120 62 22
1999 102 108 99 29
2000 102 115 103 32
2001 96 110 99 32
2002 100 115 119 33
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Total 510(k) Review Time
(FDA and Industry Combined)
140
1997 1998 1999 2000 2001 2002
Year
U Total M Traditional DAbbrev ■ Special
Figure 4. Total 510(k) Review Time.
The Effect of the Special 510(k)
The intent of the New 510(k) Paradigm and the Abbreviated and Special
510(k)s was to reduce the regulatory burden of 510(k) submissions and at the same
time streamline the process to achieve a reduction in overall review time. Figure 4
illustrates the total 510(k) review time from submission to substantial equivalence.
This includes both the FDA review time as well as the time taken by the
manufacturer to respond to requests for additional information. The data begins in
1997 to show the review times prior to implementation of FDAMA. The data is
presented annually with each of the 510(k) types and the total shown individually.
From this histogram there are several observations that can be made. First, the
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average review time for all 510(k) types in aggregate have improved by 23% from
130 days in 1997 to 100 days in 2002. The review times for traditional 510(k)s has
also decreased by 14% which may be attributed to the increased time available to
review these submissions. The increase in available review time for traditional
510(k)s comes from the time freed up through implementation of the Special 510(k)
process that calls for a review time of 30 days or less. This improvement is
achieved in spite of the fact that average Abbreviated 510(k)s review times have
continually increased from 62 days in 1997 to 119 in 2002. The data clearly
demonstrate that implementation of the Special 510(k) process has had a positive
effect on submission review time.
Table 5
FDA 510(k) Review Time Average by Year
Year Total Traditional Abbreviated Special
1997 97 97 0 0
1998 89 95 62 21
19 99 80 85 80 24
2000 77 87 83 27
2001 75 86 82 28
2002 79 90 91 28
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FDA 510(k) Review Time
(FDA Review Time Only)
120
1997 1998 1999 2000 2001 2002
Year
| M Total M Traditional DAbbrev ■ Special)
Figure 5. FDA 510(k) Review Time.
FDA review time, as shown in Figure 5, is defined as that time taken by the
FDA alone in reviewing submissions. To provide a confirmation of the results from
the Total 510(k) Review time evaluation, an assessment of the FDA 510(k) review
time was also performed. This data is analyzed to ensure that the improvements are
not primarily the result of industry improving turn around times but true
improvements in the FDA process. It is important to note that the improved turn
around time for requests for additional information is largely attributed to the
communication between reviewers and industry.
The average FDA review time for all 510(k) types in aggregate have
improved by 18.5% from 97 days to 79, which now complies with the statutory
timeframe of 90 days. The FDA review times for traditional 510(k)s has also
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decreased by 7% from 97 days to 90 days. As noted above, this may be attributed to
the increased time available to review these submissions. The Special 510(k)s have
an average FDA review time of 28 days which meets the statutory time frame of 30
days or less. Once again, this improvement is achieved in spite of the fact that the
FDA Abbreviated 510(k)s review times have continually increased from 62 days to
91.
The Effect of the Abbreviated 510(k)
The Abbreviated 510(k) Process is shown in both the Total 510(k) review
times(Figure 4) as well as the FDA 510(k) review times (Figure 5) to have had a
negative effect. Not only do the review times now exceed the statutory timeframes
of 90 days, they also exceed the total average review times as well. The effect on the
total review time is negligible, primarily because there are very few submissions that
follow this path (see Figure 3).
The very small number of submissions in the Abbreviated 510(k) program
speaks to two issues. First, the statutory timeframe is the same 90 days as for a
traditional 510(k), so there is no time incentive for a manufacturer to attempt the new
paradigm and take a risk that their submission will be questioned. Also, it became
clear to those in industry that the FDA did not have sufficient exposure to the
European Standards based regulatory process upon which the Abbreviated 510(k)
submission was based. Their discomfort was twofold. They had not had the
opportunity to become knowledgeable with the content of the safety and
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performance requirements defined in the international standards. They were also not
accustomed to accepting a certification that testing had been performed. Prior to the
Abbreviated 510(k) the applicant would have provided the data for the FDA to
review. In the section titled Use of Recognized Standards there is further discussion
as to why the performance of the Abbreviated 510(k) process is so poor.
The data thus far demonstrates that the improvements in review times are
largely attributable to the implementation of the Special 510(k) process component
of the Least Burdensome provisions. Traditional 510(k)s are still the vast majority
of the submissions and in both the total review time and FDA review time there were
improvements within the Traditional 510(k) process itself. This, however, does not
account for the whole improvement seen in the data. The Abbreviated 510(k)
process does not support such an improvement. There were no significant changes
in resources during this timeframe. And while the total number of 510(k)
submissions decreased by 14% this does not account for the total improvement in
review time.
There was also an important factor that may have counteracted this
improvement. This was the exemption of over 118 product types from 510(k)
submission in 1998. This exemption eliminated products that were low risk, and
quick to review. This left the submissions that were more complex and required
more analysis, collaboration and subsequently more time to review. It would seem
logical that elimination of the quick reviews, that tend to bring the average review
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time down, and leaving the complicated reviews, that tend to bring the average
review time up, would result in an increase in review time. But this was not the case.
Table 6
Percentage o f Change in Average 510(k) Review Times
510(k) Type Total Review Time FDA Review Time
% Improvement All
510(k)s
23% 18.5%
% Improvement
Traditional 510(k)s
14% 7%
% Difference 9% 11.5%
Another important finding is that while the manufacturer turn around time
has also improved the majority of the improvement has come from the FDA. The
FDA improvement in review time is 18.5% and the total improvement is 23%. The
difference would be the improvement contributed by the manufacturers. The FDA
has then contributed 80% of the improvement and manufacturers 20% with regards
to total review time.
In summary, the Special 510(k) process, with increasing numbers of
submittals and consistent review times of less than 30 days suggests a potential
causal relationship between overall review time improvement and this program.
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Resources Applied to the Review Process
Table 7
FDA Full-Time Employees by Year
Year Full-Time Employees
1997 356
1998 340
1999 330
2000 329
2001 353
2002 353
FDA Full-Time Employees
400
350
. 300
§ 250
o 200
E 150
m 100
50
0
1997 1998 1999 2000 2001 2002
Year
Figure 6. FDA Full-Time Employees.
Questions regarding other potential independent variables must be asked. For
example, if the numbers of resources available to review 510(k) submissions are
constant, then the change could be attributed to the implementation of the provisions.
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If resources were not constant, an increase in resources could result in improved
review times whether or not the provisions had been implemented; or the effect of
one might outweigh the other. Figure 6 illustrates the change in available resources
over the time period of interest. While there is some variability in the number of
full-time employees, the trend indicates fewer resources have been applied rather
than more. This further supports the findings that the Special 510(k) process has had
a positive effect on the average review time of 510(k)s.
The Effect of Guidance Documents
Table 8
Percentage o f 510(k)s Found Deficient
With Guidance 33
Without Guidance 46
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% 510(k)s Found Deficient
With Guidance Without Guidance
Submissions
Figure 7 . Percentage of 510(k)s Found Deficient.
Least Burdensome provisions included a recommendation that guidance
documents and recognized standards be used as a means to reduce regulatory burden
and reduce review times by improving the quality of the original submission to the
FDA. The Agency conducted a study to determine the impact of guidance and
standards on 510(k) review times and cycles.1 3 1 In this study the FDA found that
submissions for devices without guidance had higher first-cycle deficiency rates
requiring a request for additional information from the submitter and longer review
times. These findings were based on 510(k) submissions for approximately 617
different Class II device types that were found substantially equivalent during 2002.
ljlEric Rechen, Impact o f Guidance and Standards on 510(h) Review Times and Cycles,
PowerPoint presentation, May 2003.
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This sample contained 1644 Traditional or Abbreviated 510(k)s, excluded were
Special 510(k)s and submissions reviewed by third parties. Figure 7 illustrates the
findings for submissions with deficiencies on the first review cycle. There is a 13%
increase in the number of submissions found with deficiencies in the first review
cycle for 510(k) submissions where no guidance document exists. There was a 33%
deficiency rate in devices with guidance (n=1021) and a 46% deficiency rate in
devices without guidance (n=623).
Table 9
510(h) Average Review Time—Guidance
With
Guidance
Without
Guidance
FDA Time 88 106
Manufacturer Time 18 34
Total Time 106 140
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510(k) Average Review Time
160
> > 140
c o
0 120
1 100
1 80
a > 60
s i
2 40
a >
> 20
0
With Guidance Without Guidance
I FDA Review Time B Manufacturer Response Tim e
Figure 8. 510(k) Average Review Time.
Furthermore, the review times for devices without guidance documents were
longer than those devices with guidance documents available. There is a 24%
increase in average review time found in the 510(k) submissions where no guidance
document exists. There was a significant increase in the FDA review time of 17%
and the manufacturers response time increased much more dramatically by 47%.
This would indicate that the guidance document provides important information to
both the submitter and the reviewer regarding what information is required and in
what format. This may facilitate improved submission quality as well as consistency
and ease of review, both of which could lead to reduced review time. Sample size
for this analysis is the same as for Figure 8.
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The FDA concluded that the results of this in depth study correlated well to
previous analysis. They suggested that the device specific guidance documents help
to reduce the occurrence of multiple 510(k) review cycles and expedite 510(k)
clearance. They believe that use of guidance could yield an additional 25%
improvement in these performance measurements. The FDA states that these
findings are consistent with other analysis and support a causal relationship.1 3 2
Use of Recognized Standards
The FDA continued their investigation into the use of consensus standards in
the review of 510(k)s. Consensus standards are those standards applicable to
medical devices that are developed by an independent organization such as the
International Standards Organization (ISO), Association for the Advancement of
Medical Instrumentation (AAMI), or International Electro-technical Commission
(IEC). These organizations have committees established for each major medical
device specialty. The committees are typically comprised of members from the
parent organization, industry representatives, the medical community and academia
if appropriate and in most cases representatives from the regulatory bodies (FDA,
Ministry officials, etc.). Examples of international consensus standards and their
U.S. equivalent include:
• IEC 60601-1 / UL 2601 General Requirements for Safety of Electro
Medical Equipment
• IEC 60601-2-19/ AAMI Particular Standard for Infant Incubators
,3 2 lbid.
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• ISO 9000 / FDA Quality Systems Regulation
The Abbreviated 510(k) process is the one that relies most heavily on the use
of standards and Declarations of Conformity as the process improvement driver. The
statutory timeframe for Abbreviated 510(k)s is the same as Traditional 510(k)s
because of the potential complexity of the devices. Use of standards to help
demonstrate safety and effectiveness is the basis for this 510(k) category.
Abbreviated 510(k)s may also employ use of special controls to ensure safety and
effectiveness.
Table 10
Percentage o f 510(k)s Found Deficient—Standards
Traditional Abbreviated
Guidance No Guidance Guidance No Guidance
33% 46% 26% 55%
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% 510(k)s Found Deficient
60%
50%
40%
30%
20%
10%
0%
Guidance No Guidance Guidance No Guidance
Traditional 510(k)s Abbreviated 510(k)s
Figure 9. Percentage of 510(k)s Found Deficient.
Figure 9 illustrates two points. First, in both Traditional and Abbreviated
510(k)s use of guidance reduces the deficiencies found during the first review cycle
as was illustrated in Figure 7. It also shows that when no guidance is available the
reliance on consensus standards may actually impede the process. In this case 46%
of Traditional 510(k)s without guidance required additional information as compared
to 55% of Abbreviated 510(k)s without guidance. It is important to note the very
large disparity in sample size because of the infrequent use of the Abbreviated
510(k) process. The Traditional sample included with guidance n=949 and without
guidance n=603. The Abbreviated sample included with guidance n=72 and
without guidance n=20.
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Table 11
510(k) Average Review Times—Standards
Trac itional Abbreviated
Guidance
No
Guidance Guidance No Guidance
FDA Time 88 105 83 124
Manufacturer Time 18 34 21 35
Total Time 106 139 104 159
510(k) Average Review Time
150
« 200
£
Q
*
0 )
1 100
v
2 50
v
>
< 0
Guidance No Guidance
Traditional 510(k)
Guidance No Guidance
Abbreviated S10(k)
■ FDA Review Time ■ Manufacturer Response Time
Figure 10. 510(k) Average Review Time.
The average 510(k) review times shown in Figure 10 illustrate two points.
First, in both Traditional and Abbreviated 510(k)s use of guidance reduces the
average review time as was illustrated in Figure 8. It also shows that when no
guidance is available the reliance on consensus standards may actually impede the
process. Standards have what has been described as an “iffy” knowledge base within
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the Agency. There is a lack of experience and training, few people get to participate,
there is no mentoring, and no cross-fertilization. In the opinion of one ex-FDA
official, the Abbreviated 510(k) process has had far more modest improvements than
expected for two reasons. First, the agency recognized many standards and guides
that do not really assist in the determination of safety or effectiveness. Second, the
agency has not educated the public, or their own reviewers with respect to what
standards are and how they should be applied to the process. The reviewers do not
want to get caught in an error, they do not trust the standards process, so they ignore
the law and ask for data anyway.
In Figure 10, the average review time of Traditional 510(k)s without
guidance is 139 days as compared to the average review time of Abbreviated 510(k)s
without guidance of 159 days. The sample size for this average review time
assessment is the same as that described above in the discussion of Figure 9. The
effect of Abbreviated review times is not carried through to the total population due
to the very small number of Abbreviated submissions as compared to the total
submission quantity processes each year.
In summary, the FDA has found that if guidance exists, explicit conformity
with the guidance or with a recognized standard in the Abbreviated 510(k) may
result in improved review times. However, in the absence of guidance, use of a
Declaration of Conformity to a recognized standard appears to delay the 510(k)
process. The FDA surmises that guidance on how conformity to recognized
standards addresses 510(k) requirements for safety and performance might be needed
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to facilitate the Abbreviated 510(k) process.1 3 3 This premise is supported by
anecdotal feedback from both reviewers within the agency as well as those
regulatory professionals interviewed for this research. Their feedback suggests that
there is inconsistency within the Agency with regards to the reviewers experience
and understanding of consensus standards, their content and how they apply to the
510(k) process. It is the opinion of one interviewee that reviewers who have had the
opportunity to participate on standards committees or who have been exposed to
these standards in their work are more knowledgeable in their application with
regards to safety and performance. In these cases the Abbreviated 510(k) with
Declaration of Conformity to standards is of benefit in their review and may reduce
the overall review time. In cases where the reviewer is not familiar with these
standards, there is a learning curve associated with the process. This generally
involves additional time on the part of the reviewer as well as requests for additional
information by the reviewer to address questions or issues arising from this
knowledge gap. Another point that was raised by this interviewee is that
manufacturers do not always know what standards are applicable to their devices, or
they claim partial compliance to standards, or compliance to multiple standards. It
does not appear that the implementation of consensus standards has had sufficient
time to overcome these hurdles. This has resulted in the extended review times
shown in the data analysis above.
Ibid.
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Least Burdensome Provisions for Investigational Device Exemptions
and Premarket Approval Process Introduction
Phase 2 describes the results of the elite interview beginning with a
description of the interviewees and followed by a data analysis structured to the
interview guide found in Appendix D. The major category headings discussed are:
• Demographic Information
• Informal Pre-IDE Process Assessment
• Informal Pre-IDE Process and Communication (Question 2)
• Informal Pre-IDE Process and Resolution of Significant Issues
(Question 3)
• Early Collaboration Activities Formal Pre-IDE Meetings
• Early Collaboration Program and Communication
• Early Collaboration Program and Resolution of Significant Issues
• Significant Factors Addressed by Pre-IDE and Early Collaboration
• Predictability of the IDE/PMA Process
• Perception of Cultural Change
• “Time, effort and money” as factors in decision-making
• Benefits of the Leas Burdensome Provisions
• Recommendations to the FDA for Improvement
The Least Burdensome provisions of the FDA Modernization Act included
new practices for the IDE program that involve early interaction and involvement
between the FDA and the manufacturer of the device. There are multiple aspects of
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the IDE/PMA programs to try and facilitate a Least Burdensome approach. The
research in this area was conducted through an elite interview process with the use of
an Interview Guide. The data is analyzed using a Likert1 3 4 scale for those questions
where a range of attitudes can prevail. The qualitative information has also been
reviewed for trends and patterns. To the degree that they exist, they are grouped and
described by theme for respondents with the same or similar perceptions.
Demographic Information
As previously noted, the population of regulatory professionals involved in
the IDE/PMA process with the FDA is very small. The average number of PMAs
submitted over the last five years is 40 per year. The total number of companies with
more than two PMAs over that same period is 12 or 9% of the total PMA company
population.
There were 10 interviews conducted; of which two were small start up
companies that used seasoned regulatory professionals in their application process.
There were three members of law firms who practice in the area of medical device
regulation and submissions. The remaining five were large companies where the
regulatory professionals interviewed had corporate responsibility for multiple
businesses with a variety of devices covering many of the FDA device families.
These individuals had a broad range of experiences and opinions regarding the Least
Burdensome provisions and their effectiveness.
l340 ’Sullivan and Rassel, 273.
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All interviewees had experience with the IDE process pre and post FDAMA.
Eight of the interviewees had multiple experiences with the PMA process, one
device was concluded to be a 510(k) submission with clinical data and the last PMA
is under preparation for filing.
A summary of the job functions of those interviewed include three Corporate
Vice Presidents who are responsible for multiple business units across several
medical specialties submitting multiple original PMAs to nearly every Division of
the FDA Office of Device Evaluation on an annual basis. Also included are three
Vice Presidents or Directors of Regulatory and Clinical Affairs for startup companies
dealing with one product area and one original PMA and one FDA review team at a
time, but with job experience covering multiple submissions. And finally,
Consultants, two private and two through law firms that specialized in medical
device submissions and regulation, are also part of the sample group.
The sample of three major corporations of the 12 corporations meeting the
criteria equates to 25% of the total population available. Of the remaining
companies that had only one submission, the sample was comprised of seven
executives with experience across multiple submissions. This sample represented
6% of the small company population. The percentage is probably much higher, but
there is no way of determining how many professionals have submitted applications
for more than one company. The 6% is based on the worst-case assumption that the
remaining 118 companies, rather than some smaller subset, comprised the total
population. In addition to the statistics presented, the consistency in experiences
171
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across all of the interviewees was notable. This supports the sample size as valid and
further demonstrates the homogenous nature of the total population.
The following data is summarized from the interview transcripts and is
organized according to the structure of the interview guide. The summary responses
as well as specific comments are noted for each area discussed.
Informal Pre-IDE Process Assessment
The interview began with a discussion of what each company’s experience
with the IDE process was prior to the Pre-IDE program and after. The information
below summarizes the feedback from the interviewees with regards to their
perceptions.
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All interviewees had multiple interactions with the FDA.
All concluded that access to the agency for informal meetings is vastly
improved.
Pre FDAMA—“we were banned from even trying to communicate
with the FDA and they us”
Post FDAMA—“not pleasant, but not negative”
All had discussions about clinical protocols and proposed clinical
endpoints.
All sought and achieved communication through voicemail, email,
meeting and the consensus among most was that the results were
successful.
Early interaction forced issues to be raised, discussed and eventually
resolved earlier in the process. There was a mixed review on whether
they would call these interactions “successful.” Some took several
meetings, some were delayed because the agency did not have a position
or clear understanding on a particular issue, and in some cases the
reviewers simply were not responsive.
Figure 11. Perception of Pre-IDE Program.
Informal Pre-IDE Process and Communication—Analysis o f
Communication Hypothesis
Restating the Null Hypothesis for Communication: Implementation of the
Least Burdensome provisions has made no substantial improvement in the perceived
quality of communication between the FDA and industry. If communication is
improved, then the Least Burdensome provisions for IDE/PMA may be perceived as
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effective in reducing the time, expense and/or effort components of regulatory
burden, as defined by the FDA.
Pre-IDE program has improved communication.
& 6
® IT
■ o 5
c
° A
Q . 4
(0
a > o
Q £ 3
a >
XI
E
Strongly Agree Neutral Disagree Strongly
Agree Disagree
Figure 12. Pre-IDE Communication.
As shown in Figure 12, there was an overwhelming consensus that the
Agency has become much more open and responsive with regards to early
communication and early collaboration. There is varied experience with regards to
how successful these interactions have been.
Informal Pre IDE Process and Resolution o f Significant Issues—Analysis
o f Issue Resolution Hypothesis
Restating the Null Hypothesis for Issue Resolution: Implementation of the
Least Burdensome provisions has made no substantial improvement in the timeliness
of issue identification and resolution. If early identification and resolution of
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significant issues occurs, then the Least Burdensome provisions for IDE/PMA may
be perceived as effective in reducing the time, expense and/or effort components of
regulatory burden, as defined by the FDA.
J3
S 6
c 5
o
SM
3
o 2
■ _
0) 1
S3 '
| o
Pre-IDE program has identified and/or resolved significant
issues.
Strongly
Agree
Agree Neutral Disagree Strongly
Disagree
Figure 13. Pre-IDE Significant Issue Resolution.
For those that agreed there was a sense that issues were resolved because
communication forced these issues much earlier in the process. The issues resolved
had to do with sample size for clinical studies and data requirements. For the neutral
respondent their experience reflected a lack of sufficient resources in the agency to
work on issue resolution in a timely manner once the issue was identified. The
respondent who disagreed described their interactions as reaching the conclusion that
they would agree to disagree and nothing was really resolved. The interviewees
suspect that access to clinical experts will further facilitate the resolution of issues in
the IDE process. This data is presented in Figure 13.
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Early Collaboration Activities—Formal Pre-IDE Meetings
The whole basis for the Least Burdensome provisions evolves around
establishment of these formal meetings, both Determination and Agreement. The
intent of Least Burdensome was to limit PMA and 510(k) reviews to that which was
statutorily necessary for an approval or clearance and to provide applicants the
opportunity to try to hold the agency from being excessive in the extra data requested
in a PMA. These formal binding meetings are the means by which requirements can
be agreed upon and then upheld over the duration of the clinical studies and
subsequent approval process. Applicants have benefited from the formal meetings
by negotiating and reaching agreement for what their specific data requirements are
going to be and testing the Agency’s resolve in making further requests for
information and data for PMA. The primary concern here is that if the company
does not push for these formal meetings then nothing will change from the process
prior to Least Burdensome.
The following are perceptions regarding the formal Determination and
Agreement meetings based on the interviewees experiences.
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FDA considers formal meetings a “big deal.”
FDA prefers to be informal, don’t like to make commitments on the fly.
FDA “avoids this like the plague” several commented.
Considered of limited utility—most think the informal process is better.
FDA considers a manufacturer who uses Least Burdensome as a rationale
to be somewhat threatening (i.e., we have a legislative tool and we are
going to use it).
Protracted process to get to agreement, but very successful most of the
time.
Figure 14. Perceptions of Formal Meetings.
These formal meetings are intended to be binding on the part of the industry
as well as the FDA. To the extent that the agreements made are reasonable and meet
the statutory requirements for ensuring safety and effectiveness the decisions are
binding. Agency has a hard time binding itself to anything because of insecurity that
results if a wrong decision is made. Formal meetings are found to be binding except
in the cases where the initial decision was incorrect. If there is some concern about
protection of health then the agreement is invalidated. It is expected that if the
foundation for agreement is incorrect or an error is made then the meetings would
not be binding.
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One company gave an example where the agreements reached were not
upheld. In this case the reviewing statistician was replaced and the new statistician
did not agree with the determination made. It was not clear that there was an issue
other than the new statistician was not comfortable with the decisions made by the
prior reviewer. While in one sense this is understandable, no one likes to be held
accountable for someone else’s decision, it is not in keeping with the Least
Burdensome philosophy. In this type of situation, where a reviewer makes a change
to the agreement and there is no basis for the change, management has been enlisted
to uphold the Least Burdensome intent. Changes in requirements once the
agreement has been made, is where the power of these provisions are evident. This
process has made visible problems with individuals at the review and division levels
with regards to both reaching and upholding agreements.
Four interviewees had participated in Determination meetings, and three in
Agreement meetings. The general sense amongst half of the interviewees was that
the meetings were successful—eventually. Much of this process of meeting is to get
the agency comfortable with what they are agreeing to. In most cases it took a series
of meetings before an actual agreement was reached.
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Early Collaboration Program and Communication
Early Collaboration program has improved
communication.
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Neutral Disagree Strongly
Disagree
Figure 15. Early Collaboration Program Has Improved Communication.
The experience of companies with regards to the formal Early Collaboration
meetings (Agreement and Determination) and communication, the results are mixed,
see Figure 15. Some interviewees agreed that communication was improved and that
they found the Agency open and willing to work to achieve consensus. The other
interviewees felt that the meetings were long and arduous and that the results were
unimpressive and non-binding. One interviewee also made the point that limited
resources played a role in that timeliness of responses did not meet their
expectations. This lack of timeliness in response has been attributed to several
factors. Resources as noted above were discussed by FDA reviewers as an issue
because the number of FTEs remained the same and yet these same reviewers were
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expected to reduce 510(k) review time, meet with companies on IDEs and PMAs to
resolve issues and at the same time work on development of guidance documents,
etc., to meet the implementation timelines for FDAMA.
Early Collaboration Program and Resolution o f Significant Issues
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Early Collaboration program has identified and/or
resolved significant issues.
Strongly
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Agree Neutral Disagree Strongly
Disagree
Figure 16. Early Collaboration Program Has Identified and/or Resolved
Significant Issues.
Three interviewees agreed that the formal meetings helped identify problems
early and bring them to resolution. Based on experiences prior to Least Burdensome,
they stated that under the old process these issues would not have been raised until
much further along in the process after much more time and resources had been
expended. Three interviewees felt that the process dragged on and that there was
hesitation on the part of FDA to raise their concerns and this resulted in a much
longer process of identification and resolution of issues. (See Figure 16.)
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Significant Factors Addressed by Pre-IDE and Early Collaboration
Randomized Controlled Trials
Randomized controlled Trials was a topic discussed in the majority of formal
and informal meetings, in two cases a blinded Randomized Controlled Trial (RCT)
was required, in two cases it was not possible to blind the study and in one case the
study was non-randomized due to the fact that safety was being evaluated not a
clinical endpoint regarding efficacy. The interviewees agreed that FDA has come a
long way and they will entertain new trial designs. They also indicated that for new
therapies where little is known, the reviewers would gravitate to the security of a
randomized trial. This enables a direct comparison to the current standard of care.
One interviewee commented that the FDA at least listens. They want the gold
standard blinded RCT, and the manufacturer comes in with a proposal that is the bare
minimum. Before, Least Burdensome the FDA would accept nothing less than the
gold standard—today, they consider something in the middle that addresses the
public health issues without requiring work that has no value added.
Surrogate Endpoints
1
Prentice defined a “surrogate endpoint is a response variable for which a
test of null question of no relationship to the treatment group under comparison is
also a valid test of the corresponding null question based on the true endpoint.” For
example, cholesterol levels are a surrogate endpoint for coronary artery disease.
mR. L. Prentice, “Surrogate Endpoints in Clinical Trials: Definition and Operational
Criteria,” Statistics in Medicine 8 (1989): 431-440.
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Surrogate endpoints are a hot topic with the medical research community for
a number of reasons. First is to facilitate determination of effectiveness with the
least amount of invasiveness to the patient. Second, use of surrogate endpoints can
also allow assessment of effectiveness without waiting years. The following
comments describe experiences with the FDA when discussing use of surrogate
endpoints:
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Use of surrogates is attempted but generally results in severely limited
labeling for the device.
Surrogate endpoints are not applicable to many device types.
Surrogate endpoints have been used in post market surveillance and have
lessened the expense of the study.
FDA considers surrogate endpoints but requires validation of the
surrogate and may ask for traditional follow up on a lesser number of
patients.
Consideration of surrogates has been evolutionary, it is still not where it
needs to be, the FDA is still out of sync with where the practice of
medicine is heading.
The FDA has improved its willingness to accept surrogate endpoints, the
company just needs to demonstrate the applicability of the surrogate
endpoint to the clinical effect that is expected for the device.
Secondary endpoints versus post market trials—cost is the same, but the
process is front loaded and if the product is cleared, revenues can help
fund the post market studies.
Figure 17 . Perceptions on Use of Surrogate Endpoints.
Both Randomized Controlled Trials and Surrogate Endpoints have significant
impact on the design of a clinical study. This includes the number of patients to be
enrolled, the process by which enrollment is determined and patient follow-up
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requirements. Each of these factors into the cost, resource requirements and duration
of the study. This in turn may affect the total time, effort and money it takes to bring
a new technology to the market.
CenterWatch estimates that the medical device industry spends about $100
million annually on clinical grants (a clinical grant is defined as the portion of the
clinical research budget paid to an investigator). Manufacturers estimate that they
typically spend $1.5 million on grants to test IDE devices, and 342 IDEs were
submitted over the past five years. This comes to roughly $500 million total, or $100
million annually.1 3 6
NORCROSS, Ga.—(BUSINESS WIRE)—Feb. 25,2004—
SpectRx, Inc. (OTCBB: SPRX) today announced that it is
initiating U.S. Food and Drug Administration (FDA) pivotal
clinical trials of its non-invasive cervical test by submitting
final protocols to hospitals participating in the multi-site study.
The protocols, under review by each site's Institutional
Review Board (IRB), were developed in consultation with the
FDA and leading physicians from around the nation. After the
review process is completed, formal testing of patients begins.
"Submission of these protocols is a milestone event in the
development of this non-invasive test," said Keith D. Ignotz,
chief executive officer of Guided Therapeutics, Inc., the
SpectRx subsidiary company commercializing the non-
invasive cervical cancer device. "We believe that this fast,
point-of-care technology has the potential to detect disease
earlier, thereby reducing unnecessary and painful procedures
and decreasing the cost of cervical disease management."
Development of the non-invasive cervical cancer test is
supported by a $1.4 million grant from the National Cancer
1 3 6 “Medical Device Trials: A Market in Flux,” CenterWatch (December 1, 1995).
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Institute (NCI), $767,000 of which will go toward completing
the clinical trial this year.1 3 7
Predictability of the IDE/PMA Process
There is a perceived Improvement in Predictability.
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Agree Disagree
Figure 18. Improvement in Predictability.
Two interviewees stated that the focus on resolving issues up front and
interaction during the process makes each step more predictable. Formal Agreement
and Determination meetings are particularly helpful in this regard. It seems to take a
very long time to reach an Agreement, but once done, things move smoothly. Three
of the interviewees agreed that the predictability is improving, but still not as good as
it could be. It was also noted if the submission is a “no brainer” then there is
1 3 7 Bill Wells, SpectRx Inc. Begins Initial Phase of FDA Pivotal Clinical Trial for Non-
invasive Cervical Cancer Detection Test, available from Business Wire, www.businesswire.com.
February 25,2004.
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predictability, if it is difficult, complex, or extremely new then there is no
predictability.
There was one interviewee who does not believe that Least Burdensome has
improved predictability. This interviewee stated that use of guidance documents,
another component of the provisions, provided the most benefit. In addition, it was
stated that there is still a culture among some reviewers to ask multiple iterations of
questions. Finally, in one instance the interviewee stated that predictability is
definitely not better. In this case the statistician was replaced and changed the
requirements of the clinical study. This happened to two different companies;
however, in one case, the study was already underway. The FDA has no “corporate
history.” Once the trial parameters are set, it can be a year or two before a clinical
study is complete. The objective of the provisions is to prevent a rejection by the
Agency sending the process back to square one. Figure 18 illustrates these findings.
Perception of Cultural Change
There were several themes that came out of this part of the interview having
to do with whether behaviors and philosophy in the Agency are changing in response
to the expectations of the Least Burdensome provisions. The first and most
significant comments have to do with experience. The following are the opinions of
interviewees with regards to the experience levels of the reviewers in their jobs as
well as direct experience with aspects of the Least Burdensome provision programs.
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Entertaining alternatives is a 90/10 proposition. 90% of the time you get
reviewers who are willing to listen and 10% of the time you get one of the
“old timers” who don’t want to change.
Entertaining new processes and ideas / they are avoided because it is
outside the comfort zone of the people involved.
New personnel / many changes—one company brought meeting minutes
from previous meetings with the Agency and helped educate and bring up
to speed the new reviewers. This was successful.
There is variation based on the experience level within the divisions, a
comment made by every interviewee. The opinion of one interviewee is
that people have been trained in Least Burdensome but choose not to
comply—the sense of several others is that while trained, there has not
been sufficient time to understand what the provisions really mean in their
day to day work.
It is a function of experience for the divisions that do few IDEs or PMAs.
They are not really getting repeated experience within a reasonable
timeframe.
There is nothing in the way of mentoring from the divisions that have
more experience to the ones who have less—no lessons learned,
guidelines for implementation, etc.
Some experiences have demonstrated that timeliness and consistency
improves with device familiarity.
Figure 19. Perceptions on Cultural Change.
The use of technical experts is another area that was discussed by several
interviewees. Use of experts, particularly those who are members of the FDA
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Advisory Panels, is an area where both the industry and the FDA agree that more
would be better. The Least Burdensome provisions extend to the Advisory Panel
members in that (1) determinations regarding acceptability of clinical results and
(2) whether post market studies are needed, are recommended by these panel
members. With the advent of User Fee legislation1 3 8 there is now a means for
funding part time, or temporary technical experts to help bring knowledge regarding
current standards of care to the pre-market approval process. The FDA is trying to
implement and expand this program, they are even asking for resumes to try and
create a pool of resources to draw from. A significant issue with no real resolution
occurs when the technology is extremely unique and innovative. In these cases it is
hard to find experts without running into people involved in the research area and
this becomes a potential conflict of interest.
FDA use of Advisory Panel experts, falls more in the realm of looking for
protection. The Advisory Panel members provide recommendations regarding the
technologies they review and whether they believe that the safety and efficacy of the
device has been demonstrated by the clinical studies. They are seeking specific
answers to specific questions. Use of experts also helps the reviewers gain technical
knowledge. To the extent that the reviewers can learn and incorporate this technical
knowledge into the regulatory framework the use of experts should work well. A
potential downside of this lies in the situation where there is too much dependence
1 3 8 The Medical Device User Fee and Modernization Act o f2002 (MDUFMA), Public Law
107-250, October 26, 2002.
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on experts who are typically clinicians and academics. These professionals tend to
have a much higher threshold for data and information than may be needed to
demonstrate safety and efficacy. This is in direct conflict with the philosophy of
Least Burdensome.
For many of the interviewees, the major obstacle to changing the culture and
behaviors of the FDA lies squarely on the issue of resources. Things will not change
if there are not adequate resources to allow time for learning, time for exploring
alternatives, time for mentoring and cross fertilization of experiences. Lack of
adequate resources causes the same old behaviors to appear. There is a sense that
documents are reviewed in a rush to meet the statutory timeframes. Questions are
asked and in many cases are already answered in the document. This cursory review
and request for information causes delays and results in both the lack of
predictability as well as extension of the time, cost and resources needed to complete
the process.
“Time, Effort and Money” as Factors in Decision-Making
It has been the experience of several interviewees that the FDA reviewers do
not (and they agree should not) have any consideration for economics. In upper level
management there is sensitivity in the context of whether the requirements that were
agreed to are being changed. Economic concern is generally limited to where the
reviewing division has shifted the success criteria. If the original criteria were wrong
then there would be no consideration. If the changes are unfounded, the company
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small and the technology novel, then there is a better chance that the financial burden
on the company be considered.
There is Consideration of Time, Effort and Money.
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Agree Disagree
Figure 20. Consideration of Time, Effort and Money.
There were four interviewees that believe there has been no real change. One
of the interviewees stated:
There is no concept of the impact a request for 100 more
patients will have with respect to time, effort or cost. The
FDA does not really care if your business goes down the
tubes, they do not think about this, it is not where their heads
are.
There were two interviewees that found the FDA to be very sensitive to the
fact that they were a small company. This came through in discussions regarding
sample size and post market studies. The majority of interviewees, five, agreed that
factors affecting regulatory burden were considered after issues were escalated to
high level civil servants in FDA management. In these cases the reasons for
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escalation included inability to schedule meetings in a timely manner, inability to
come to resolution on areas of concern by the FDA, inability to come to conclusions
regarding endpoints and sample sizes, and the like. These interviewees also stated
that they feared escalation would alienate the reviewer. They “don’t want to piss
them off’ because the reviewer is responsible for the evaluation process and can
make recommendations to management regarding the quality of the information
provided. It was clear, however, in many of the meetings that the reviewers are not
the final decision makers with respect to policy. This was another reason for
escalating issues to management. Figure 20 illustrates these findings.
There is a perceived change in FDA Culture.
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Figure 21. Change in FDA Culture.
The general consensus among interviewees is that the culture of the Agency
has not changed because the philosophy is not fully understood and accepted and
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because the behaviors supporting the philosophy are not necessarily supported. The
Agency’s mission is to promote and protect the public health. If there is any
question that the Least Burdensome philosophy could result in a mistake in the
IDE/PMA process, the reviewer will ask for data even if the request is in violation of
the provisions. It is a very risk adverse organization just by virtue of what they do.
To change from extreme conservatism to a thought process where judgment and
reliance on non-standard methods are used will take time. Figure 21 illustrates the
industry’s perceptions in this regard very clearly.
Benefits of the Least Burdensome Provisions
Several interviewees agree that there are benefits. One stated that the agency
tends to follow what they have done in other matters, i.e., precedents are followed.
So, to the extent that constructive agreements are made others can follow. There is a
“spin-off’ effect beyond negotiating the agreement and the front end loading does
save time down the road, except in those few cases where the negotiated agreement
is not well founded. Some interviewees believe that there is not sufficient
experience to know yet. Others stated that it seems good so far, but institutions are
slow to change. The real benefits seen by one interviewee are in 510(k) area, real
time supplements, and modular PMAs but not in clinical trial design. And a final
observation is that there are pockets of reluctance, resistance to change, old
mentality, and again, cultural change is needed.
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Recommendations to the FDA for Improvement
Recommendations for improvement to the process were happily provided by
all of the interviewees. Their thoughts touched on areas such as education,
mentoring, management support, performance metrics, etc.
Institutional support on decision-making. PMA reviewers should be more
comfortable with the process. They seem to feel vulnerable—i.e., just hanging
out there. This would be the most important thing to facilitating and expediting
the review process and avoiding excessive data and information demands.
Assistance from Program Office for reviewers to help learn new processes.
Think of industry as a customer.
Improve communication within the Agency.
Keep an open mind.
Maintain and expand participation in Association for the Advancement of
Medical Instrumentation (AAMI), Regulatory Affairs Professional Society
(RAPS), and other regulatory and standards groups.
Consider re-instituting the Vendor Day program. The Vendor Day program was
coordinated by the Health Industry Manufacturers Association (HIMA, now
AdvaMed). The purpose was to have several manufacturers of a particular type
of device bring their products to a large conference room and effectively have a
trade show for the FDA. This allowed reviewers to come from their offices
during the day or two visit, speak with manufacturers and users of these devices
and see how they work first hand. The products included patient monitors,
ultrasound, defibrillators, etc. The information shared was both clinical and
technical with many design questions asked and answered.
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Figure 22 (continued)
Use Project Management as an approach to facilitate multiple reviews: controls
timeliness, quality and necessity of questions, pushes decision making from
management to team leader.
Facilitate cultural change—upper level of management understands and can get
results. The process should work without escalation.
Learn more about surrogate endpoints and their uses, learn more about novel
statistical techniques and put them to use.
If a new idea backfires don’t stop the whole process. Continue to pursue the idea
on a case by case so that issues can be addressed or mitigated.
Get more resources, this is the only way to improve predictability.
Address accountability in reviews to control outliers.
Consider better process for use of foreign data.
Train and require that clinical personnel stay in touch with clinical practice.
DeNovo process is not adequately defined or implemented.
People need to be managed and performance measured.
Panel members need to understand Least Burdensome as well. Post market
studies should not be designed during panel meetings, but offline and
collaboratively.
Figure 22. Recommendations for Improvement.
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Summary of Research Findings
Analysis of the data as described above will result in support of the premise
that the Least Burdensome provisions of the FDA Modernization Act of 1997 have
achieved their goal of reducing the regulatory burden on the medical device product
approval process. This evidence could lead to broader implementation of this type of
approach in other regulatory venues. If the data are not supportive of this premise
then the decision may be to investigate other strategies to reduce burden. In any
event, knowledge of the affect of these provisions provides a basis for further policy
analysis and regulatory reform.
Timeliness Hypothesis Findings
Null Hypothesis for Timeliness: Implementation of the Least Burdensome
provisions has made no substantial improvement in the timeliness of 510(k) reviews.
If 510(k) review times are improved, then the Least Burdensome provisions for
510(k)s may be effective in reducing the time component of regulatory burden as
defined by the FDA.
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The number of original 510(k) submissions has remained relatively
constant (approximately 4500 submissions per year).
The number of resources available for review of submissions has
remained very constant (approximately 353 FTEs per year)
There has been a steady increase in the number of submissions using the
Least Burdensome Special 510(k) process. From 0 in 1997 to 776 (or
23%) in 2002.
510(k) average review times have decreased. Total review time has
decreased 23%, FDA review time has decreased 18.5% since 1997.*
Figure 23. Findings in Support of Review Time Improvement.
*This improvement is in part due to the decrease in original submissions
from 1997 to 2002 of 14%. However, at the same time 118 devices were
exempted from submission, eliminating effectively all of the low risk “easy
to review” submissions and leaving the more complex submissions to be
addressed. While there is no way to quantify the effect of this exemption, it
is reasonable to think that the effect may have counteracted some of the
benefit derived from the reduction in original submissions.
Therefore, while the results may not be statistically significant, performance
measures for the Least Burdensome activities in the 510(k) process demonstrate that
timeliness of 510(k) reviews has improved.
Communication Hypothesis Findings
Null Hypothesis for Communication: Implementation of the Least
Burdensome provisions has made no substantial improvement in the perceived
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quality of communication between the FDA and industry. If communication is
improved, then the Least Burdensome provisions for IDE/PMA may be perceived as
effective in reducing the time, expense and/or effort components of regulatory
burden, as defined by the FDA.
9 of 10 or 90% of interviewees agreed that communication with the
Agency under the informal pre-IDE process was improved.
3 of 5 or 60% of interviewees agreed that communication with the
Agency under the formal Early Collaboration Agreement and
Determination meetings was improved.
5 of 10 or 50% of interviewees agreed that “time, effort and cost” were
considered in their interactions with the Agency and that this resulted in a
less costly process.
Figure 24. Findings in Support of Communication Improvement.
Data collected and analyzed with respect to Least Burdensome activities in the
IDE/PMA process demonstrate that communication between the FDA and industry
has improved.
Issue Resolution Hypothesis Findings
Null Hypothesis for Issue Resolution: Implementation of the Least
Burdensome provisions has made no substantial improvement in the timeliness of
issue identification and resolution. If early identification and resolution of
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significant issues occurs, then the Least Burdensome provisions for IDE/PMA may
be perceived as effective in reducing the time, expense and/or effort components of
regulatory burden, as defined by the FDA.
6 of 8 or 75% of interviewees agreed that issue resolution improved under
the informal pre-IDE process.
3 of 6 or 50% of interviewees agreed that issue resolution improved under
the formal Early Collaboration Agreement and Determination meetings.
5 of 10 or 50% of interviewees agreed that “time, effort and cost” were
considered in their interactions with the Agency and that this resulted in a
less costly process.
Figure 25. Findings in Support of Improved Issue Resolution.
Data collected and analyzed with respect to Least Burdensome activities in the
IDE/PMA process demonstrate that early identification and resolution of significant
issues between the FDA and industry has improved.
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CHAPTER VIII
SUMMARY AND CONCLUSIONS
Previous chapters have discussed the history of regulation, various regulatory
theories and the legislative frameworks from which medical device regulation is
bom. These first chapters also describe regulation in the context of the greater field
of Public Administration, and what makes regulatory processes of such importance
to study. Once this foundation was established, Chapter 5 then defines the research
question and specific hypotheses to be tested. Chapter 6 follows with data
organization, description of variables and the research design. In Chapter 7, the
analysis of the data and findings was provided with regards to the specific
hypotheses being tested. This chapter summarizes the dissertation’s major findings
based on the detailed information gathered and conclusions from these findings are
drawn.
Regulation of medical devices is the primary focus of this study. In
particular, this study explored the effectiveness of the Least Burdensome provisions
of the Food and Drug Administration Modernization Act. The study tested three
hypotheses to determine whether the programs and activities resulting from the Least
Burdensome provisions have had a positive effect on the medical device pre-market
approval processes.
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The data gathered in the 510(k) review process clearly demonstrates an
improvement in review time since the implementation of the New 510(k) Paradigm
program. The average review times for submissions have declined. The use of
guidance documents has also been demonstrated to have a positive effect on review
times for 510(k) submissions.
In summary, the FDA has found that if guidance exists, explicit conformity
with the guidance or with a recognized standard in the Abbreviated 510(k) may
result in improved review times. However, in the absence of guidance, use of a
Declaration of Conformity to a recognized standard appears to delay the 510(k)
process. The FDA surmises that guidance on how conformity to recognized
standards addresses 510(k) requirements for safety and performance might be needed
to facilitate the Abbreviated 510(k) process.1 3 9 This premise is supported by
anecdotal feedback from both reviewers within the agency as well as those
regulatory professionals interviewed for this research. Their feedback suggests that
there is inconsistency within the Agency with regards to the reviewers experience
and understanding of consensus standards, their content and how they apply to the
510(k) process.
It is the opinion of one interviewee that reviewers who have had the
opportunity to participate on standards committees or who have been exposed to
these standards in their work are more knowledgeable in their application with
regards to safety and performance. In these cases the Abbreviated 510(k) with
1 3 9 Rechen.
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Declaration of Conformity to standards is of benefit in their review and may reduce
the overall review time. In cases where the reviewer is not familiar with these
standards, there is a learning curve associated with the process. This generally
involves additional time on the part of the reviewer as well as requests for additional
information by the reviewer to address questions or issues arising from this
knowledge gap.
Another point that was raised by this interviewee is that manufacturers do not
always know what standards are applicable to their devices, or they claim partial
compliance to standards, or compliance to multiple standards. It also may be the
case that standards do not yet exist for the technologies under review. This is
typically the case for newer technologies that have the least known about them and
the least amount of clinical experience.
It does not appear that the implementation of consensus standards has had
sufficient time to overcome these hurdles. This has resulted in the extended review
times shown in the data analysis above.
Null Hypothesis for Timeliness: Implementation of the Least Burdensome
provisions has made no substantial improvement in the timeliness of 510(k) reviews.
If 510(k) review times are improved, then the Least Burdensome provisions for
510(k)s may be effective in reducing the time component of regulatory burden as
defined by the FDA.
Performance measures for the Least Burdensome activities in the 510(k)
process demonstrate that timeliness of 510(k) reviews has improved.
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In the IDE/PMA programs the most significant changes are a result of the
informal pre-IDE process. These changes include an overwhelming improvement in
communication and early detection and resolution to significant issue. With regards
to the Early Collaboration activities, the results are mixed. The formal Agreement
and Determination meetings require a binding agreement at the conclusion. There
appears to be a great reluctance on the part of the Agency to have these meetings and
when forced, the process becomes arduous and protracted. The end result has been
successful once an agreement is reached. In these cases the binding nature of the
agreement provides some level of predictability in the process. This is the goal most
desired by the medical device industry.
Null Hypothesis for Communication: Implementation of the Least
Burdensome provisions has made no substantial improvement in the perceived
quality of communication between the FDA and industry. If communication is
improved, then the Least Burdensome provisions for IDE/PMA may be perceived as
effective in reducing the time, expense and/or effort components of regulatory
burden, as defined by the FDA.
Data collected and analyzed with respect to Least Burdensome activities in
the IDE/PMA process demonstrate that communication between the FDA and
industry has improved.
Null Hypothesis for Issue Resolution: Implementation of the Least
Burdensome provisions has made no substantial improvement in the timeliness of
issue identification and resolution. If early identification and resolution of
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significant issues occurs, then the Least Burdensome provisions for IDE/PMA may
be perceived as effective in reducing the time, expense and/or effort components of
regulatory burden, as defined by the FDA.
Data collected and analyzed with respect to Least Burdensome activities in
the IDE/PMA process demonstrate that early identification and resolution of
significant issues between the FDA and industry has improved.
In summary, the objective of the Least Burdensome provisions of the Food
and Drug Administration Modernization Act was to improve access to new medical
device technologies to the public by reducing the regulatory burden in the pre-market
approval processes that regulate these devices. This study focused on performance
metrics for the 510(k) review process with regards to review time. With regards to
the IDE/PMA processes intended for new technologies the study focused on the
perceptions of experts in the regulatory field. The study illustrates their experiences
with regards to programs and activities intended to facilitate early and often
communication between the FDA and the manufacturer to bring early detection and
resolution of issues that might delay or even prevent product approval. Review time
and delays in product approvals directly affect time to market for medical devices
and can result in delayed access to medical device improvements and advances.
We can, therefore, conclude that the Least Burdensome provisions of the
FDAMA appears to be effective in improving the pre-market approval processes for
medical devices in both the 510(k) and IDE/PMA programs as demonstrated by the
data collected and analyzed in this research.
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These findings and conclusions are consistent with the regulatory theories
presented in the literature. In each of the theory areas described, the results of the
study demonstrate that the Least Burdensome provisions are clearly an outgrowth of
the efficiency regulatory regime. The issue of regulatory “capture,” or in FDA
terminology a perception of conflict of interest is stated as a concern by those
interviewed regarding issue resolution and use of new approaches in demonstrating
compliance to regulatory requirements. The industry trade press as well as hospital
and citizens advocacy groups continue to monitor the performance of the FDA and
report on various aspects of the implementation of the provisions. The FDA in turn
has taken corrective action based on this feedback as well as their own data analysis
on what is working and what is not. Finally, public choice theory states that we all
act in concert with how we are evaluated. The FDA has taken care to add
performance measures for these provisions to facilitate adoption of this philosophy in
all areas of the Agency.
Regulatory Regime
The regulatory regime of the past several years has been referred to as the
efficiency regime. After the great societal regulatory regime of the 1970s and 1980s
it became clear that while many of the regulatory policies that had been initiated
were most likely needed, the burden of compliance was having an untenable effect
on technology development and the economy. The efficiency regulatory regime
came about in response to this seemingly unnecessary burden. The theories and
subsequent policies abounding included the re-invention of government, National
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Performance Review, privatization of government tasks, and most directly the
Modernization of the FDA. The objective of the Modernization Act was to maintain
the safeguards that these regulatory policies had brought to bear, but to eliminate the
inefficiencies and redundancies in the processes that were not value added. The
objectives of the efficiency regime are clearly recognizable in the Least Burdensome
provisions of FDAMA and are in alignment with the goals and objectives of each of
the programs and policies noted above.
The methods used in this research produce concrete measures of efficiency
with regards to the 510(k) pre market notification process. The perception of
improvements in addressing major areas of concern and predictability are measured
through the elite interviews surrounding the IDE and PMA processes. In both areas,
improvements in these measures of efficiency support the benefits of a Least
Burdensome philosophy when making changes to regulatory processes.
Regulatory Capture
The regulations implementing the Least Burdensome provisions were
developed specifically with the concern of regulatory capture in mind. Capture
theory states that close, cooperative, and extended interaction between agency and
industry may establish relationships where the industry influence over the process is
substantial. This is also aggravated by the rapid development of technologies
leaving the agency, at times, dependent on the expertise and data resources of
industry to facilitate decision-making.
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Within the Least Burdensome activities, the FDA has established concrete
requirements and structured processes that tend to mitigate the potential for conflict,
or perceived conflict, of interest. Thus, while the provisions open the way for
judgment in handling of medical device approvals, those determinations are
consistently applied through process and management controls to continue to ensure
that the regulations are applied equitably. The perception of preferential treatment
must be avoided, particularly when rendering determinations regarding information
needed to meet the statutory requirements for medical device approval.
In the 510(k) process, the criteria for submissions that are streamlined and
have shorter statutory timeframes are well defined and may be used by any submitter
who meets this criteria. With regards to the IDE and PMA processes, the formality
of the meetings, the number of people involved, recording of the minutes of these
meetings, and management representation and review all serve to mitigate the
possibility that the reviewers may be “captured” or unduly influenced by the
manufacturer. In addition, this process allows for the FDA to access subject matter
experts of their own to level the technical playing field between the agency and
industry to further mitigate the potential for capture.
The analysis of both 510(k) data and the information extracted from the elite
interview process is used to confirm whether the descriptions of the activities
associated with Least Burdensome regarding controls are adequate to minimize the
potential for regulatory capture.
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External Signals
One of the sources of data used by external groups who monitor the
performance of the FDA programs is the Agency Web site (www.FDA.gov). This
Web site has all of the performance metrics with regards to submissions as well as all
of the Annual Reports that were used to extract the data analyzed in this research.
This Web site also has information prepared by the FDA policy analysts in their
desire to understand the effects of measurable aspects of regulatory policy as it is
implemented. These results, specifically in the area of use of guidance documents
and standards, have been further evaluated in this research.
It is important to note that the agency believes that criticism for being slow
and methodical is their burden to carry and although it is not pleasant, they believe it
is the nature of their job. On the other hand, criticism that they have not adequately
protected the public is something that they consider a significant failure. An analogy
might be the physician and patient outcome. If the patient is harmed as a result of a
failure on the part of the physician, this is an egregious event. If the physician tried
all of the standard treatments, but did not pursue the remotely possible and esoteric
treatments, is this also an egregious event, or a difficult judgment that is the nature of
their job?
Finally, the Agency is familiar with the types of public repercussions that can
and have occurred in the aftermath of a real or perceived failure, making the
tendency towards conservatism or even simply delaying decisions until more is
known a reasonable strategy.
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The elite interview data is analyzed for evidence of significant hesitation in
taking advantage of new methodologies given by the provisions for fear of making a
mistake.
Public Choice
The processes and activities associated with the Least Burdensome provisions
are structured and fairly well defined. Within each process there are timeframes for
particular activities as well as the expectation for binding agreements as outcomes
for meetings. Given that the employees at the FDA are motivated in the same
manner as other employees, their objective would be to meet the expectations of the
process and to avoid situations where this may not be possible.
The IDE/PMA processes have the most risk for the FDA because there may
be many cases where the technology is new or the proposed statistical assessment is
new, or the clinical protocol deviates from the standard randomized controlled trial
(RCT). In these cases, the Agency does not always have a similar situation to
emulate and there by reduce risk. In these cases it may be best to encourage the
informal communication path rather than the formalized process under Least
Burdensome. Use of the informal process may be the path where more time can be
taken without the accountability for keeping statutory timeframes or the fear of
making decisions that might ultimately be incorrect.
Public choice theory explains these behaviors as the Agency serving its own
self-interest before serving the interest of the general public. The elite interview data
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provides insight into the behaviors of the FDA with regards to IDE and PMA
activities under Least Burdensome.
Conclusion
Woodrow Wilson once said:
This is why there should be a science of administration which
shall seek to straighten the paths of government, to make its
business less unbusinesslike, to strengthen and purify
organization, and to crown its duties with dutifulness. This is
one reason why there is such a science.1 4 0
In this particular essay Wilson is evaluating why European countries do not have
such issues with their public administration process. He further states: “To answer
our purposes, it must be adapted, not to a simple and compact, but to a complex and
multiform state, and made to fit highly decentralized forms of government.. . . We
must Americanize it.”1 4 1
Wilson was arguing that the time had come for acknowledgement and
recognition of the field of public administration. He states that public administration
is controlled by the public “for wherever public opinion exists it must rule.” For the
scope of this study, the public wants to be protected, but yet still have access to
medical technologies. Their expectation is that regulatory policy should achieve
both. The Least Burdensome provisions of the FDAMA are an attempt to meet that
expectation. This study has demonstrated that there is a perception of improvement
1 4 0 Woodrow Wilson, The Study of Administration, in Basic Literature of American
Administration, ed. by Fredrick C. Mosher (New York: Holmes & Meier Publisher) 1981), 70.
1 4 1 Ibid.
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in the Agency’s ability to regulate medical technology and not only protect but also
promote the public health.
There are several lessons learned through this research regarding best
practices to be continued and potentially expanded. First, the Agency should
continue the abbreviated processes where safety is not a concern. They should
continue all activities that improve communication. Improved communication
means that issues are resolved; requirements are defined and understood by all
parties. These activities that improve communication with respect to the Least
Burdensome provisions include informal meetings, formal meetings, guidance
documents, etc.
Once the requirements are understood, industry will comply with them and
provide whatever information is deemed necessary to establish safety and
effectiveness of their device. Once requirements are understood, the process
becomes predictable for both the Agency and industry. In the final analysis,
predictability is the prize.
Future Research Implications
The research clearly demonstrates improvements in each of the major areas
studied. The study is focused on performance of the pre-market approval processes
with regards to meeting the objectives of the Least Burdensome provisions. The
study is conducted from the medical device industry perspective. A significant
contribution is anticipated if this study were to be extended to understand the
implications and the effectiveness of these Least Burdensome provisions from the
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perspective of the FDA and more specifically the reviewers who are tasked with
implementation.
This study taken from the FDA perspective, both at the reviewer level and
management level, would need to ask the same questions as presented here, but also
some additional questions. They might include questions around the issue of time
constraints for example. In the pre FDAMA environment, the reviewers were
shielded from interaction with the industry. It would be interesting to understand
whether the reviewers are feeling undue pressure from either industry or Congress as
a result of these changes.
The Least Burdensome provision activities are largely centered around direct
communication and meeting to discuss issues. Are these meetings a net benefit with
regards to time spent on a given application, or is the time it takes a further drain on
the resources available to complete work? It would be interesting to ask if the
reviewers believe that their process was as effective in protecting the public, as
efficient in accomplishing their tasks, or not. It would be very important to
understand these effects to gain a more completed assessment of the Least
Burdensome philosophy and whether it works in this environment.
With regards to the 510(k) process the data show that the Abbreviated 510(k)
process which involves Declaration of Conformity to recognized standards is not
providing the results expected by the Least Burdensome objectives, and as a result is
not widely used. An area for future research would be to understand why this
program is not working.
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In the IDE/PMA area, there are two potential areas for future research. First,
the research presented here is based on industry perception of the processes based on
their experiences before and after the provisions were implemented. To the extent
that more concrete performance metrics could be determined and then measured and
analyzed, the results of this study could possible be confirmed, further refined,
refuted, etc. Second, manufacturers are discouraged from participating in the Early
Collaboration Determination and Agreement meetings. Understanding why this is
the case would be another important evaluation for further improvements in the
process.
In both the cases of Abbreviated 510(k)s and in Determination and
Agreement meetings, a reassessment when there is sufficient participation to truly
understand the performance of these programs would appear to be a beneficial
endeavor. It seems in both cases that participation is limited because performance is
lacking. In other words, if it takes 90 days for a traditional 510(k) review and 100
days for an Abbreviated 510(k) review, the manufacturer may opt for the traditional
process rather than the Abbreviated. This is an issue because participation is needed
to further understand and gain experience that can be used to identify issues and
improve performance in review times, which will encourage greater participation—
the old catch 22.
Least Burdensome was intended to reduce the regulatory burden on industry
while maintaining the statutory requirements for safety and effectiveness. Studies
designed to evaluate whether safety and effectiveness have been maintained would
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be key to understanding the overall effect of the provisions. A longitudinal study on
adverse event rates might provide insight into whether this change to the regulatory
process had any affect on the potential to cause harm to patients or users of these
devices.
On the positive side, studies could be conducted to determine whether there is
greater access to new technologies, if lives have been saved, or quality of life
improved as a result of this change in the regulatory process.
In addition to extensions of this study, the newly legislated Medical Device
User Fees program may also have a significant effect on the Least Burdensome
activities. User fees are collected from manufacturers and are earmarked for use in
increasing resources for the medical device pre-market review process. Studying the
effects of user fees on implementation of Least Burdensome may also provide useful
information for those developing and implementing policy decisions within the FDA.
There is also a great potential for extending this research into broader reaches
of medical device regulation. For example, questions surrounding comparison of the
United States FDA regulatory model as compared to the European Medical Device
Directive. The regulation of medical devices in these two major geographies began
from very different philosophies and over the past several decades have grown to be
more and more similar in both intend and execution. This evolution has been
fostered by the Global Harmonization Task Force of the FDA that includes
representation from many of the world regulatory agencies. Evaluation of both
processes in their current state and their plans for the future can be performed. This
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assessment of what works and what does not could potentially lead to a regulatory
process that has the proper balance between protection and promotion of public
health while minimizing regulatory burden.
The relationship between the FDA and the industry it regulates exists as a
two-player system with Congress acting as mediator or instigator as the case may be.
Is there opportunity to explore strategies that might cause a shift towards a three
player construct; the FDA, the industry and those potential beneficiaries? Currently
the FDA Pre-market Approval process incorporates review of the submission and an
open public meeting of the clinical specialty advisory panel. This advisory panel is
comprised of physicians and academics independent of the FDA and the
manufacturer of the device under review. These panelists are experts in the
particular medical field that would make use of the device. In addition, the panel
membership includes a representative for the medical device industry and also a
consumer advocate. The role of the consumer advocate is to ensure that the interests
of the patient are represented. In addition, each public meeting provides the
opportunity for anyone to speak on the subject at hand. Could this forum be the
foundation for increasing the voice of the American public with regards to device
approvals? What would be the effect of introducing a third player with some ability
to change outcomes?
One of the questions asked in the elite interviews was whether there was a
sense that the culture at the FDA was changing with the implementation of Least
Burdensome. The responses indicated that the culture had not changed as a whole.
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There were some reviewers and managers that seemed to understand and were
supportive of change. The consensus was that changing culture is a slow and
difficult process and largely based on the individuals involved. How then can the
FDA begin to establish policies and engrain in the organization, the concept of risk
management in their work versus the current work ethic of risk prevention at any
cost? It is clear that risk management would be the responsibility of management
and the policy makers and not a responsibility borne by an individual device
submission reviewer or review team. Exploring use of new methodologies to change
organizational culture in light of this risk management framework could provide
significant benefit to the process.
The last two areas of inquiry, (1) shifting from a two-player model to a three
player with the expansion of the role of the American public and (2) moving to a risk
management philosophy from risk prevention, would both benefit from some
preliminary work. This work would begin with an evaluation of origins of the
current behavior. The Agency is clearly risk adverse because of the bad experiences
of the past. In addition, there are still those industry “bad guys” around that must be
addressed. In order to break out of this self-paradigm, the Agency will need strong
and effective leadership. This leadership may benefit from the knowledge gained by
such a historical assessment.
Closing Conclusion
In 1997, Congress enacted the Food and Drug Administration Modernization
Act. This legislation was an effort to reduce the regulatory burden without lowering
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the statutory requirements for safe and effective medical devices. The end goal was
to ensure the American public had access to the most advanced medical care the
medical device industry can offer.
This study has demonstrated a clear perception among a representative
sample of elite regulatory professionals that burden has been reduced, even though
the threshold for safety and effectiveness have not been lowered. Improvement in
the regulatory process for medical device market clearance is seen in a reduction in
510(k) submission review time. This improvement in review time is statistically
significant.
There was also sufficient data from the elite interviews to suggest a
consensus regarding the IDE and PMA processes. It is agreed that the provisions
have had a positive effect on communication and resolution of significant issues.
Therefore, we can conclude that the Least Burdensome provisions are
perceived to have achieved a decreased regulatory burden and an improvement in the
regulatory approval process for medical devices.
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(Winter 1978): 394
Webb, E. J., D. T. Campbell, R. D. Schwartz, and L. Sechrest. Unobtrusive
Measures: Nonreactive Research in the Social Sciences. Chicago: Rand
McNally, 1966.
Wells, Bill. SpectRx Inc. Begins Initial Phase o f FDA Pivotal Clinical Trial for Non-
invasive Cervical Cancer Detection Test. Available from Business Wire,
www.businesswire.com, February 25, 2004.
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The Wilkerson Group. Forces Reshaping the Performance and Contribution o f the
U.S. Medical Device Industry. New York: The Wilkerson Group, June 1995
Wilson, James Q. The Politics o f Regulation. New York: Basic Books, Inc., 1980.
________. Bureaucracy What Government Agencies Do and Why They Do It. New
York: Basic Books, 1989.
Wilson, Woodrow. The Study o f Administration. In Basic Literature o f American
Administration, ed. Frederick C. Mosher. New York: Holmes & Meier
Publishers, 1981.
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APPENDIX A
GLOSSARY OF ACRONYMS
510(k) - Pre-market Notification process described in section 510 (k) of the Medical
Device Amendments of May 1976 to the Food Drug and Cosmetic Act
AAMI - Association for the Advancement of Medical Instrumentation
CD - Committee Draft
CDRH - Center for Devices and Radiological Health
CFR - Code of Federal Regulations
CGMP - Current Good Manufacturing Practices
Class I - FDA classification of medical device with minimal risk
Class II - FDA classification of medical device where safety and effectiveness can
be controlled through application of a device standard with moderate risk
Class III - FDA classification of a medical device with new technology or
application of known technology for new indications where safety and effectiveness
must be demonstrated through clinical studies that establish risk/benefit, devices are
major risk
DoC — Declaration of Conformity to consensus standards
DSMA - Division of Small Manufacturer’s Assistance, FDA entity providing
information and assistance to industry
ECG - Electrocardiogram, a diagnostic device that measures the electrical activity of
the heart
EEG - Electroencephalogram, a diagnostic device that measures the electrical
activity of the brain
ECRI - Emergency Care Research Institute, private company providing information
on medical devices for hospital biomedical engineers, risk managers and purchasing
FDA - Food and Drug Administration
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FDAMA - Food and Drug Administration Modernization Act
FD&C - Food Drug and Cosmetic
FR - Federal Register, record of all activities of the U.S. Congress
FTE - Full-Time Equivalent (Employee)
FY - Fiscal Year
GAO - General Accounting Office
GMP - Good Manufacturing Practices
HIMA - Health Industry Manufacturer’s Association (now AdvaMed)
HHS - Health and Human Services
HP - Hewlett Packard
HR - House Rule
ICC - Interstate Commerce Commission
IDE - Investigational Device Exemption
ISO - International Standards Organization
MDR - Medical Device Report
MDUFMA - Medical Device User Fee Modernization Act
MRI - Magnetic Resonance Imaging
NPR - National Performance Review
ODE - Office of Device Evaluations
PMA - Pre-Market Approval
QSR - Quality System Regulations
R&D - Research and Development
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RAPS - Regulatory Affairs Professional Society
RCT - Randomized Controlled Trials
SMDA - Safe Medical Devices Act
TMR - Transmyocardial Revascularization, use of laser to drill micro channels in
ischemic areas of heart tissue to re-establish blood flow
UCSD - University of California San Diego
US - United States
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APPENDIX B
TRADITIONAL PMA SUBMISSION REQUIREMENTS
A PMA submission contains the following:
1. The name and address of the applicant.
2. A table of contents that specifies the volume and page number for each item
referred to in the table.
• The PMA must include separate sections on non-clinical laboratory
studies and on clinical investigations involving human subjects.
• Six copies of the PMA are required, each bound in one or more
numbered volumes of reasonable size. To facilitate review by the
advisory committee(s), additional copies may be requested by FDA.
• Trade secret or confidential commercial or financial information must
be included in all copies of the PMA. The applicant must identify in
at least one copy any information that they believe to be trade secret
or confidential commercial or financial information.
3. A summary section in sufficient detail to provide a general understanding of
the data and information in the application. Tip: The summary section should
contain brief statements of major points found elsewhere in the PMA and
should be approximately 10 to 15 pages in length.
The summary section must contain the following information:
Indications for Use. Give a general description of the disease or condition
that the device will diagnose, treat, prevent, cure, or mitigate and include a
description of the patient population for which the device is intended.
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Device Description. Explain how the device functions, the basic scientific
concepts that form the basis for the device, and the significant physical and
performance characteristics of the device. A brief description of the
manufacturing process should be included if it will significantly enhance the
readers understanding of the device. The generic name of the device as well
as any proprietary name or trade name should be included.
Alternative Practices and Procedures. Describe any alternative practices or
procedures for diagnosing, treating, preventing, curing, or mitigating the
disease or condition for which the device is intended.
Include a statement such as "other commercially available devices" if similar
class III products are available. Do not include any treatment practices or
procedures that are considered investigational.
Marketing History. Give a brief description of the foreign and U.S.
marketing history, if any, of the device known to the applicant. At a
minimum, include a list of all countries in which the device has been
marketed and a list of all countries in which the device has been withdrawn
from marketing for any reason related to the safety or effectiveness of the
device.
It would be appropriate to include dates of introduction into each country,
information about the quantity of product distributed in each country, a brief
description of any experience reporting mechanism, a summary of any
adverse experiences reported, and information about any withdrawals for any
reason related to the safety or effectiveness. Withdrawals because of poor
sales or physician disfavor should not be included. A U.S. marketing history
may occur if the device is marketed under 510(k) for a different intended use.
The description must include the history of the marketing of the device by the
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applicant and, if known, the history of the marketing of the device by any
other person.
Summary o f Studies. This section must contain a summary of the results of
technical data (non-clinical and clinical studies) under §814.20(b)(6) and an
abstract of any other data, information, or report described in the PMA under
§814.20(b)(8)(ii). The summary must include a description of the objective of
each study, a description of the experimental design of the study (or
hypothesis tested), a brief discussion of how the data were collected and
analyzed, and a brief description of the findings and conclusions, whether
positive, negative or inconclusive.
The summary must include a summary of non-clinical laboratory studies
submitted in the application and a summary of the clinical investigations
involving human subjects. The summary of the clinical investigations should
include a discussion of subject selection and exclusion criteria, study
population demographics, study period, safety and effectiveness data, adverse
reactions and complications, patient discontinuation, device failures and
replacements, tabulations of data from all individual subject reporting forms
and copies of such forms for each subject who died during a clinical
investigation or who did not complete the investigation, results of statistical
analyses of the clinical investigations, contraindications and precautions for
use of the device, and other information from the clinical investigations, as
appropriate. Any investigation conducted under an IDE must be identified.
Conclusions Drawn from the Studies. Discuss how the data and information
in the application constitute valid scientific evidence, and provide reasonable
assurance that the device is safe and effective for its intended use. A
concluding discussion must present benefit and risk considerations related to
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the device, including a discussion of any adverse effects of the device on
health, and any proposed additional studies or surveillance that the applicant
intends to conduct following approval of the PMA.
The applicant’s summary section should objectively link the medical claim(s)
for the device to the hypotheses tested and conclusions drawn from the
findings of all studies and investigations. Biased presentation of the study
data and inclusion of promotional claims are to be avoided. When preparing
the summary section, the applicant should be able to detect and correct any
accountability discrepancies, incomplete reporting and study design
deficiencies which an in-depth scientific review would discover. A properly
developed summary section by the applicant can serve as the basis for FDA
Summary of Safety and Effectiveness Data and will facilitate the FDA and
panel review process. A full and explicit account of the clinical investigations
and supporting data is needed to meet the legal requirements imposed by the
FD&C Act.
4. A complete description of:
• the device, including pictorial representations;
• each of the functional components or ingredients of the device if the
device consists of more than one physical component or ingredient;
• the properties of the device relevant to the diagnosis, treatment,
prevention, cure, or mitigation of a disease or condition;
• the principles of operation of the device; and
• the methods, facilities, and controls used in the manufacture,
processing, packing, storage, and where appropriate, installation of
the device in sufficient detail so that a person generally familiar with
current good manufacturing practices can make a knowledgeable
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judgment about the quality control used in the manufacture of the
device.
If complete manufacturing information is not available at the time the
PMA is submitted, its temporary omission may be justified.
5. Reference to any performance standard or voluntary standard.
Performance standard refers to those promulgated under Part 514 of the
FD&C Act or the Radiation Control for Health and Safety Act of 1968
(RCHSA) in effect or proposed at the time of the PMA submission.
A voluntary standard refers to one that is specifically applicable to any aspect
of the safety or effectiveness of the device and developed in accordance with
the FDA policy statement on standards development published in the Federal
Register of October 23,1985 (50 FR 43081).
The applicant must provide adequate information to demonstrate how the
device meets, or justify any deviation from, any of the mandatory
performance standards noted above and explain any deviation from a
voluntary standard.
6. Technical sections containing data and information in sufficient detail to
permit FDA to determine whether to approve or deny the application.
These sections and their contents are as follows:
Results o f Non-clinical Laboratory Studies. _ This section should contain the
results of the non-clinical laboratory studies with the device including the
microbiological, toxicological, immunological, biocompatibility, stress, wear,
shelf life, and other laboratory or animal tests, as appropriate. Information on
non-clinical laboratory studies shall include a statement that each study was
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conducted in compliance with Good Laboratory Practice for Non-clinical
Laboratory Studies. If the study was not conducted in compliance with this
regulation, provide a brief statement of the reason for the noncompliance.
Results o f Clinical Investigations Involving Human Subjects. This section
should include clinical protocols, number of investigators and subjects per
investigator, a discussion of subject selection and exclusion criteria, study
population demographics, study period, safety and effectiveness data, adverse
reactions and complications, patient discontinuation, patient complaints,
device failures and replacements, tabulations of data from all individual
subject reporting forms and copies of such forms for each subject who died
during a clinical investigation or who did not complete the investigation,
results of statistical analyses of the clinical investigations, contraindications
and precautions for use of the device, and other information from the clinical
investigations, as appropriate. The analysis and discussion should address the
impact, if any, on the safety and effectiveness measures. Additional
information such as an analysis and discussion of any potential biases related
to gender, race/ethnicity, etc., should be included. Any differences in safety
and/or effectiveness should be described in the labeling.
Information on clinical studies involving human subjects shall include the
following statements with respect to each study:
• It was conducted in compliance with the Institutional Review Board
regulations
• It was conducted in compliance with the Informed Consent regulation
• It was conducted in compliance with Investigational Device
Exemptions regulations concerning sponsors of clinical investigations
and clinical investigators.
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If the study was not conducted in compliance with these regulations,
include a brief statement of the reason for the noncompliance.
7. For a PMA supported solely by data from one investigator, a justification
showing why data and other information from a single investigator is
sufficient to demonstrate the safety and effectiveness of the device and to
ensure reproducibility of test results.
8. A bibliography of all published reports not already submitted, whether
adverse or supportive, that are known to or should reasonably be known to
the applicant and that concern the safety or effectiveness of the device.
Applicants should consider providing a copy of all of the key articles, a brief
summarization of the salient features of the article, and a brief discussion of
how the article relates to the safety and effectiveness evaluation for their
device.
An identification, discussion, and analysis of any other data, information, or
report relevant to an evaluation of the safety and effectiveness of the device
that are known to or should reasonably be known to the applicant from any
source, foreign or domestic. This includes information from investigations
other than those proposed in the application and from commercial marketing
experience.
Copies of such published reports or unpublished information should be in the
possession of, or reasonably obtainable by, the applicant, if an FDA advisory
committee or FDA requests.
9. One or more samples of the device and its components, if requested by FDA.
If it is impractical to submit a requested sample of the device, the applicant
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should name the location at which FDA may examine and test one or more
devices.
10. Copies of all proposed labeling for the device. Such labeling may include, for
example, instructions for installation and any information, literature, or
advertising that constitutes labeling under Part 201(m) of the FD&C Act.
11. An environmental assessment in accordance with 21 CFR 25 must be
included in the PMA application.
12. A financial certification or disclosure statement or both as required by 21
CFR 54.
13. Such other information as FDA may request.
Other Information. Such other information as FDA may request
Omissions. State any omissions and the rational for omission.
Updates. An applicant must periodically update its pending application with any
new safety and effectiveness information learned about the device from ongoing or
completed studies that may affect an evaluation of the safety and effectiveness of the
device or that may affect the statement of contraindications, warnings, precautions,
and adverse reactions in the draft labeling.
Color Additive. Information on color additives must be provided if applicable.
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APPENDIX C
INTERVIEWEE LETTER
Dear Regulatory Professional,
My name is Monica Ferrante. I am a Doctoral Candidate at the University of
Southern California doing research for my dissertation. I have worked for both the
public and the private sector in the regulatory field and I am currently employed by a
medical device manufacturer.
The reason for my letter is to request that you consider meeting with me to discuss a
very important public policy issue. I am investigating the effectiveness and/or
perceived benefit of the Least Burdensome Provisions of the FDAMA. I am doing
this because I believe it is imperative to the change process for regulatory entities to
evaluate improvement programs and act on the results. There is benefit to be derived
from this research by those inside and outside of the agency with regards to the
effectiveness of these provisions. If the study finds that these provisions are
effective, there may be opportunity for expanding this philosophy to further improve
the medical device regulatory process. This could benefit FDA resource utilization,
industry cost on the submittal preparation as well as the potential reduction in lost
revenue, and public health by improving access. If the study finds that the
provisions are ineffective, then further investigation could reveal why and a new
methodology or change to the current methodology could be pursued.
If you agree to participate, the interview will be confidential and take approximately
60 to 90 minutes of your time. We will discuss 7 or 8 open-ended questions
regarding the Least Burdensome provisions and your experience with these process
changes. Time permitting, we can also explore your relationship with the FDA and
whether these provisions have resulted in any changes in this regard.
The information gathered will be combined with other interview results to identify
any trends or patterns in the responses. If there are trends or commonalities
sufficient to support a hypothesis or draw a conclusion, this will be documented.
Additionally, any information that might provide topics of interest for future research
will also be documented. The results of the study will be made available to anyone
who participates and is interested in the outcome. The data analysis will provide
anonymity and any specific commentary will only be disclosed if it is clear that the
identity of the interviewee is not discemable. However, the interviewee may also
choose to be identified and given credit for their views. This will be determined
prior to initiation of any interviews.
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I hope that you will consider participation in this very important work and look
forward to meeting with you by phone or in person at your earliest convenience. I
can be reached by phone at 215-682-8691, fax at 215-682-8689 or email at
Monica_Ferrante@Hill-Rom.com. Thank you for your time and consideration in
this matter.
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* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
Reply form
I am interested in participating in this project.
Please contact me at ________________________ (phone or fax)
________________________ (date)
________________________ (time) to set up an interview.
Name/Title Company
Please return to Monica Ferrante
C/O Hill-Rom Air Shields
330 Jacksonville Rd
Hatboro, PA 19040
Phone 215-682-8691
Fax 215-862-8689
Email Monica_Ferrante@Hill-Rom.com
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APPENDIX D
INTERVIEW GUIDE
Demographic information
Name of firm: Name of Interviewee:
Size of firm:
Product Types:
Submissions:
510(k)s: pre FDAMA : post FDAMA:
IDEs: pre FDAMA : post FDAMA:
PMAs: pre FDAMA : post FDAMA:
Prior to getting started a few words on the general flow. The intent of this interview
is to understand your personal and your companies experience with the IDE and
PMA processes prior to implementation of the Least Burdensome Provisions of the
FDAMA as compared to submissions where these Least Burdensome activities were
used. The objective of the research is to determine whether there have been
improvements, if there have been improvements can be demonstrated in a concrete
manner and what do they show.
Questions:
1. What was your companies experience with the IDE process prior to the Pre-
IDE program? And after?
a. company/agency interaction,
b. discussions regarding protocols, clinical endpoints
c. How often was there interaction?
d. Were interactions successful?
e. Pre-IDE program has improved communication.
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Strongly agree Agree Neutral Disagree Strongly
Disagree
Why?
f. Pre-IDE program has identified and/or resolved significant issues
Strongly agree Agree Neutral Disagree Strongly
Disagree
Why?
2. Have you participated in the Early Collaboration activities? Which ones and
what was your experience?
a. Determination Meetings
b. Agreement Meetings
c. company/agency interaction
d. discussions regarding valid scientific evidence
e. clinical trial design, investigational plans
f. How often was there interaction?
g. Were interactions successful?
h. Were the results of these meetings binding?
i. Early Collaboration program has improved communication.
Strongly agree Agree Neutral Disagree Strongly
Disagree
Why?
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j . Early Collaboration program has identified and/or resolved significant
issues
Strongly agree Agree Neutral Disagree Strongly
Disagree
Why?
3. In your experience with the programs previously discussed, which of the
following were significant factors?
a. Use of existing valid scientific evidence
b. Randomized Controlled Trials
c. Surrogate endpoints
d. Use of non-clinical testing
e. Use of published literature
Please describe each factor and its significance.
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4. One of the most significant issues described by industry with regards to FDA
regulation has been “predictability.” Has this been an issue for your
company? Please describe.
Is it an issue today?
Strongly agree Agree Neutral Disagree Strongly
Disagree
Why?
5. What changes, if any, are perceived with regards to interactions with the
FDA? The FDA has described the following as their objectives with regards
to cultural changes:
a. Recognition of multiple approaches to satisfying regulatory
requirements
b. Communication, collaboration and compromise is acceptable in the
interest of public health
c. Understand the intent (spirit) of the law and not just the letter
d. Include “time, effort and money” as factors in decision-making
What is your experience with regards to these objectives defined by the
FDA?
Strongly agree Agree Neutral Disagree Strongly
Disagree
e. Are there other way that the FDA is demonstrating change?
Please give examples illustrating your experience.
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6. The FDA defines indicators of regulatory burden as Time, Effort and
Expense. They believe that the Least Burdensome provisions should reduce
regulatory burden. In your experience with the FDA processes and the Least
Burdensome activities, do you perceive a change? Is it with respect to time,
or effort or cost, or a combination?
Strongly agree Agree Neutral Disagree Strongly
Disagree
Please describe that change.
7. In your own estimation, has the effort put forth in these provisions resulted in
any benefit to your company? If so what would those benefits be? If not
what are the issues resulting from the implementation of this program?
8. If you could make any recommendations to the FDA for improvement in
these processes, what would they be?
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9. Are there any other questions that I didn’t think to ask?
10. Could you suggest anyone else that I might speak with?
Thank you for your participation in this survey, your responses will be kept
confidential and the data will be presented in aggregate. If you are not opposed to
being identified you may be cited as well. Prior to analyzing this information I
would be happy to provide you my notes for review and correction. In addition, the
summary information can be provided to you when the analysis is complete.
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Asset Metadata

Creator Ferrante, Monica Dominique (author)

Core Title A quantitative and qualitative evaluation of the least burdensome provisions of the Food and Drug Administration Modernization Act of 1997

School School of Policy, Planning and evelopment

Degree Doctor of Public Administration

Degree Program Public Administration

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

Tag health sciences, health care management,OAI-PMH Harvest,Political Science, public administration

Language English

Contributor Digitized by ProQuest (provenance)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-665681

Unique identifier UC11335841

Identifier 3145197.pdf (filename),usctheses-c16-665681 (legacy record id)

Legacy Identifier 3145197.pdf

Dmrecord 665681

Document Type Dissertation

Rights Ferrante, Monica Dominique

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 au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA