MANAGING THE RISKS
`FROM MEDICAL PRODUCT USE
`
`CREATING A RISK
`MANAGEMENT FRAMEWORK
`
`REPORT TO THE FDA COMMISSIONER
`FROM THE TASK FORCE ON RISK MANAGEMENT
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`May 1999
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`MANAGING THE RISKS
`FROM MEDICAL PRODUCT USE
`
`Table of Contents
`
`Executive Summary ...................................................................................................................1
`Findings...........................................................................................................................................................2
`Conclusions, Recommendations, and Options .........................................................................................12
`Introduction .............................................................................................................................16
`Legislative and Management Initiatives Have Helped Speed Review Time ........................................16
`Concerns Have Been Raised About the Effects of PDUFA ....................................................................17
`The Commissioner Asked the Task Force to Look Into Public Concerns About the Risk
`Management System ...................................................................................................................................18
`Part 1: Background — What Are the Risks and What Is FDA's Role in Managing Risk? ....20
`Goals Are to Maximize Benefit, Minimize Risk .......................................................................................21
`What ARE the Risks Involved With Using Medical Products? .............................................................23
`What Is FDA's Role in Minimizing Risk?.................................................................................................29
`Conclusions...................................................................................................................................................31
`Part 2: Is the FDA Maintaining the Quality of Its Premarketing Reviews? ...........................33
`Has the Rate of Serious Adverse Events Increased? ..............................................................................33
`How Well Is the Agency’s Quality Control System Working?..............................................................37
`What Factors in the Development Process Could Affect Risk Identification?.....................................43
`Conclusions and Recommendations ..........................................................................................................49
`Part 3: How Does FDA Conduct Postmarketing Surveillance and Risk Assessment?............51
`Overall Postmarketing Risk Assessment Is Complex .............................................................................52
`FDA Uses a Number of Approaches to Assess Risk..............................................................................54
`Initiatives Underway to Expand Postmarketing Risk Assessment........................................................63
`Other Efforts Being Considered to Expand FDA's Risk Assessment...................................................65
`Conclusions, Recommendations, and Options .........................................................................................69
`Part 4: Managing the Risks From Medical Product Use........................................................71
`Current Risk Management for Medical Products...................................................................................71
`Federal Risk Management Framework ....................................................................................................73
`Is the Current Risk Management System Working? ..............................................................................76
`
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`The Time Is Right for a New Systems Framework .................................................................................77
`FDA’s Overall Risk Management Activities ............................................................................................79
`Conclusions, Recommendations, and Options .........................................................................................90
`Members of the Task Force .....................................................................................................98
`Bibliography...........................................................................................................................100
`Acronym List..........................................................................................................................103
`Appendices .................................................................................................................................1
`Table of Contents .......................................................................................................................1
`Appendix A.............................................................................................................................A-1
`Appendix B.............................................................................................................................B-1
`Appendix C.............................................................................................................................C-1
`Appendix D ............................................................................................................................D-1
`Appendix E.............................................................................................................................E-1
`Appendix F.............................................................................................................................F-1
`Appendix G ...........................................................................................................................G-1
`Appendix H ...........................................................................................................................H-1
`Appendix I.............................................................................................................................I-1
`
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`EXECUTIVE SUMMARY
`
`As one of her first initiatives after being sworn in as FDA
`Commissioner, Dr. Jane Henney established a Task Force to
`evaluate the system for managing the risks of FDA-approved
`medical products, focusing particularly on FDA’s part in the
`system. This report is the result of that review.
`
`Briefly, the Task Force assessed risk management practices within
`the overall healthcare delivery system, focusing on the roles and
`responsibilities of each participant. The Task Force applied a risk
`management model used in other Federal sectors. We also
`examined the various risks from medical products and their sources.
`The Task Force then evaluated FDAªs role in the current system.
`First, we reviewed the Agency’s premarketing risk assessment and
`approval processes to determine if serious adverse events are
`occurring at a higher rate now than they have in the past. Next, the
`Task Force evaluated FDAªs postmarketing surveillance and risk
`assessment programs to see if they are doing the job they were
`intended to do. Finally, the Task Force analyzed all of FDA’s risk
`management activities to evaluate the Agency’s role in the overall
`system for managing medical product risks. Our findings are
`summarized here.
`
`Executive Summary 1
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`FINDINGS
`
`Managing the Risks From Medical Product Use
`
`The time is right for a new framework
`The key finding of our review is that the time is right to apply a
`systems framework to medical product risk management. The FDA
`plays only a part in the complex system of risk management.
`Numerous other groups participate in decision making related to
`the use of medical products. A systems framework for risk
`management should enable a better integration of the efforts of all
`the involved parties. Such a framework also should facilitate a
`better understanding of both the risks involved in using medical
`products and the sources of those risks. A better understanding of
`risks and a more integrated risk management system will enable
`more effective risk interventions.
`
`The current risk management system has evolved over time
`At the turn of this century, healthcare in this country was generally
`provided by a family practitioner who treated patients from cradle
`to grave. As illustrated in the following figure, medical products
`today are developed and used within a complex system involving a
`number of key participants: (1) manufacturers who develop and
`test products and submit applications for their approval to the FDA;
`(2) the FDA, which has an extensive premarketing review and
`approval process and uses a series of postmarketing surveillance
`programs to gather data on and assess risks; (3) other participants
`in the healthcare delivery system, including healthcare practitioners;
`and (4) patients, who rely on the ability of this complex system to
`provide them with needed interventions while protecting them from
`injury.
`
`Executive Summary 2
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`Executive Summary 3
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`

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`Managing the Risks From Medical Product Use
`
`assessment. The FDA approval/nonapproval decision is the
`Agency's central risk management action. FDA must ensure that
`beneficial medical products are available and labeled with adequate
`information on their risks and benefits while protecting the public
`from unsafe products or false claims. The figure below is a
`snapshot of FDA’s role in the current risk management system.
`During premarketing review, the Agency assesses the evidence
`demonstrating the benefits and describing the risks of medical
`products.
`
`F D A R o le in M e d ic a l P ro d u c t s
`F D A R o le in M e d ic a l P ro d u c t s
`R is k M a n a g e m e n t
`R is k M a n a g e m e n t
`( R x P r o d u c t s )
`
`Executive Summary 4
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`

`

`Managing the Risks From Medical Product Use
`
`FDA
`evaluates
`benefits/risks
`for the population
`
`Provider
`evaluates
`benefits/risks
`for a patient
`
`Patient
`evaluates
`benefits/risks
`in terms of
`personal values
`
`RRR
`
`BBBB
`BBBB
`
`Executive Summary 5
`
`

`

`Managing the Risks From Medical Product Use
`
`within the Federal Government.1 This model encompasses the basic
`processes that are used to identify and assess the risks of specific
`health hazards, implement activities to eliminate or minimize those
`risks, communicate risk information, and monitor and evaluate the
`results of the interventions and communications. The Task Force
`found that the processes identified in the Federal model are
`consistent with the activities the Agency and many of the other
`involved participants currently undertake as part of their approach
`to risk management. Under the current system, however, these
`activities are fragmented, rather than part of an integrated systems
`effort. The Task Force easily adapted the Federal model to create a
`proposed model for managing the risks associated with using
`medical products.
`(See the proposed model below.) This new
`framework encourages a much greater integration of risk
`management efforts than the current system.
`
`P r o p o s e d R i s k
`M a n a g e m e n t M o d e l
`
`Executive Summary 6
`
`

`

`Managing the Risks From Medical Product Use
`
`One activity often missing from other risk management models that
`is implicit in risk-benefit assessment and is critical in a system that
`would manage healthcare risks involves engaging healthcare
`partners and other stakeholders in risk-benefit analyses. This
`activity is characterized by others as risk confrontation:
`community-based problem solving that actively involves relevant
`stakeholders in the decision-making process. 2 This is one area of
`activity that traditionally has had lower priority in the Agency than
`its pre- and postmarketing scientific risk assessment responsibilities.
`The Task Force believes that risk confrontation is a key process
`that needs to be a part of any new risk management framework.
`
`FDA should engage stakeholders to examine the current risk
`management system
`The Task Force recommends that FDA take the opportunity to
`engage all stakeholders to reexamine the current system for
`managing the risks associated with the use of medical products.
`We encourage a public policy discussion that focuses on defining
`more clearly the roles and responsibilities of all participants of the
`risk management system (cid:221) FDA, industry, healthcare provider
`organizations, healthcare practitioners, patients, and the public.
`Only by examining the roles of these various participants can gaps
`and misallocation of efforts be identified and improvements made.
`
`Understanding the types of risks and their sources is critical
`To evaluate the current system, it is critical that the stakeholders
`also consider what is known about the sources of risk from medical
`products and what is not yet completely understood. As discussed
`in detail in Part 1 of the report, risks from medical products
`generally fall into four categories.
`
`2 Leviton, L.C., C.E. Needleman, and M.A. Shapiro, Confronting Public Health
`Risks: A Decision Maker’s Guide, SAGE Publications, Inc., 1998.
`
`Executive Summary 7
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`S o u rc e s o f R i sk F ro m M e d ic a l P ro d u c t s
`
`K n o w n S ide Effects
`
`Un avoidable
`
`Avoidable
`
`M edication and
`Device Error
`
`Product
`Defects
`
`Preventable
`Adver se
`Events
`
`Injury or
`Death
`
`Re ma in in g
`Uncert ainties:
`- Unexpe cte d
`side effects
`- Unstudied uses
`- Unstudied
`popula tions
`
`Most injuries and deaths associated with the use of medical
`products result from their known side effects. Some side effects
`are unavoidable, but others can be prevented or minimized by
`careful product choice and use. It is estimated that more than half
`of the side effects from pharmaceuticals are avoidable.3 Other
`sources of preventable adverse events are medication or device
`errors. Injury from product defects is unusual in the United States
`because of the great attention paid to product quality control and
`quality assurance during manufacturing. The final category of
`potential risk involves the remaining uncertainties about a
`product.
`
`Knowledge about a product will always be limited to some extent at
`the time of approval by factors in the product development process.
`For example, rare side effects and long-term outcomes (both
`positive and negative) may not be known when a product is
`approved because of the relatively small size and short duration of
`clinical trials. And because of the populations not studied in clinical
`trials (e.g., pregnant patients, children, people with other diseases)
`or minimally studied (e.g., geriatric patients), side effects may be
`discovered if these groups are treated with a product after it goes
`
`3 Bates, D.W., L.L. Leape, and S. Petrycki, “Incidence and Preventability of
`Adverse Drug Events in Hospitalized Adults,” J Gen Intern Med., 8:289-294,
`1993.
`
`Executive Summary 8
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`on the market. Even after long use of a product, uncertainties will
`remain.
`
`One problem for discussion is the lack of adequate data about the
`causes, incidences, preventability, and relative contribution of the
`various types of risk. Currently, no group has the role of collecting
`and analyzing these types of data. Systematic approaches to risk
`management require the use of such data to plan and evaluate the
`success of risk interventions. It is unlikely that major improvements
`in risk management can occur without better data.
`
`All participants in the risk management system, including the FDA,
`have a role to play in minimizing the risks from using marketed
`medical products. The Task Force believes that the stakeholders
`should collaborate to determine how better data on risks can be
`collected — so that efforts and interventions can be targeted to the
`most serious problems, and the effects of interventions can be
`evaluated.
`
`FDA’s current role in risk management
`Turning to FDA’s role in overall risk management, the Task Force
`examined the Agency’s premarketing and postmarketing risk
`assessment activities, evaluating their quality and effectiveness.
`The Task Force also looked at FDA’s efforts in other aspects of
`risk management such as risk communication, confrontation, and
`overall evaluation.
`
`As discussed in detail in Part 2 of this report, the Task Force
`evaluated whether the heightened sense of time pressure on Agency
`review teams has reduced the quality of FDA’s premarketing
`reviews or caused poor decision making. We studied how often
`previously unanticipated serious adverse events4 were identified
`after approval in drugs reviewed since the implementation,
`beginning in 1990, of several legislative (e.g., PDUFA) and
`managerial initiatives to speed the Agency’s review process.5 We
`
`4 A number of terms are used to describe an adverse event, including adverse drug
`reaction (ADR), adverse experience, and adverse effect. In this report, the term
`adverse event is used in most cases to avoid confusion.
`
`5 Through the Prescription Drug User Fee Act of 1992 (PDUFA) and the Food and
`Drug Administration Modernization Act of 1997, Congress has encouraged the
`FDA to act more rapidly in making decisions on whether new medical products
`may enter the marketplace.
`
`Executive Summary 9
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`then compared the numbers to those collected by a 1990 General
`Accounting Office (GAO) report on serious adverse events for
`drugs reviewed prior to 1990.6 We also examined FDAªs quality
`control systems for premarketing review and marketing decisions to
`see if adequate systems are in place.
`
`Rates of withdrawals and adverse events remain low
`We found that FDA’s premarketing review processes are
`successfully identifying the serious risks associated with using
`medical products at least as well as in previous decades. Despite
`shortened FDA review time, comparisons of drugs reviewed and
`approved during the 1990s to those approved previously show that
`the rate of market withdrawals for safety reasons has remained
`relatively unchanged over the decades. As the graph below shows,
`the rate of safety-based market withdrawals of new molecular
`entities (NMEs) has ranged from approximately 1 to 3.5 percent
`over the past several decades.7
`
`Number
`
`200
`
`150
`
`100
`
`50
`
`0
`
`Safety-Based NME Withdrawals
`Based on Year of Approval
`
`113
`
`127
`
`95
`
`172
`
`3.2%
`
`3.5%
`
`1.6%
`
`1.2%
`
`1979-1983
`(3)
`
`1984-1988
`(4)
`
`1989-1993
`(2)
`
`1994-1998*
`(2)
`
`5-Year Approval Period (number withdrawn in calendar years)
`
`4.0%
`
`3.0%
`
`2.0%
`
`1.0%
`
`0.0%
`
`Percentage
`
`Percentage of cohort withdrawn
`
`Number of NMEs approved in calendar years
`
`*PDUFA years
`
`6 Government Accounting Office, FDA Drug Review — Postapproval Risks 1976 -
`1985, GAO/PEMD-90-15, April 1990.
`
`7 FDA, Center for Drug Evaluation and Research, 1998 Report to the Nation, May
`1999.
`
`Executive Summary 10
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`With advances in scientific knowledge, safety problems may be
`identified for long-marketed products. For example, of the five
`drugs withdrawn for safety reasons after 1992, two were approved
`before PDUFA was implemented.8 In addition, comparisons also
`showed that unexpected serious adverse events resulting in
`revisions to product labeling after approval are occurring
`proportionately less often than in the past.
`
`The Task Force also found that the key elements of an International
`Standards Organization (ISO)-modeled quality assurance/quality
`control program for premarketing review are in place and being
`used. FDA has consistently used supervisory rereview, conducted
`by subject matter experts, for 100 percent of the marketing
`decisions as the cornerstone of its quality control function. These
`quality control reviews are conducted typically at three supervisory
`levels before a final approval decision is made.
`
`Some factors limit the identification of adverse events
`The Task Force analysis identified several factors in the medical
`product development process that limit the Agency’s ability to
`observe some kinds of adverse events before marketing. Factors
`include the relatively small size and short duration of clinical trials
`and the representativeness of the patients studied. For example, as
`discussed in Part 2, rare side effects are often not observed before
`marketing because of the limited number of patients exposed to a
`product before approval. And, most trials do not last long enough
`to enable identification of potential long-term side effects. In
`addition, patients in clinical trials are often not representative of the
`types of people who will be exposed to a product once it goes on
`the market. Changing these aspects of medical product
`development could increase the manufacturers’ and the Agency’s
`ability to identify serious risks before marketing. However, such
`changes would increase development costs and slow product
`availability.
`
`Finally, the Task Force believes that in the case of some new
`medical products, consideration should be given to how rapidly
`they are made available in the marketplace for widespread use.
`Slowing a rapid market rollout for some products when time-tested
`
`8 Redux, Pondimin, Seldane, Duract, and Posicor were withdrawn from the market
`in 1997 and 1998; Seldane and Pondimin were approved prior to PDUFA. For a
`full discussion, see, Friedman et al., “The Safety of Newly Approved Medicines,”
`JAMA, Vol. 281, No. 18, May 12, 1999.
`
`Executive Summary 11
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`alternatives are available could limit the impact of unexpected
`serious adverse events.
`
`Postmarketing surveillance and risk assessment are performing as
`designed
`
`We found that the postmarketing surveillance programs currently in
`place are good at rapidly detecting most unexpected serious
`adverse events that occur during the postmarketing period. As
`described in more detail in Part 3 of this report, the Agency relies
`principally on a passive adverse event reporting system, depending
`to a great extent on voluntary reporting by the healthcare
`community. The system rapidly alerts the Agency to the
`occurrence of rare, serious adverse events not previously identified.
`
`The system also provides an increased understanding of the range
`of severity in known product-associated adverse side effects. We
`found that the Agency’s postmarketing surveillance and risk
`assessment programs are performing well for the goals they were
`designed to achieve. However, FDA’s programs were not designed
`to evaluate the rate, or the impact, of known adverse events.
`
`The Task Force has presented some options for expanding the use
`of automated systems for reporting, monitoring, and evaluating
`adverse events and product defects and increasing the Agency’s
`access to data sources that would supplement and extend its passive
`reporting systems. These would enhance the Agency’s ability to
`evaluate reports of serious adverse events. Examples of such
`sources include broad-based health information databases and data
`from sentinel user facilities where staff are trained to rapidly
`recognize and accurately report adverse events. Implementing
`some of these changes would require increased funding.
`
`CONCLUSIONS, RECOMMENDATIONS, AND OPTIONS
`
`Conclusions
`
`Medical products provide great benefit to the public, but they can
`also cause injury. FDA and the many other participants in
`healthcare delivery act to maximize the benefits and minimize the
`risks associated with using medical products, but often the actions
`of the participants are insufficiently integrated. The Task Force
`believes that the common goal of maximizing benefits and
`
`Executive Summary 12
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`minimizing risks could be greatly advanced if the participants in the
`system worked together to gain an understanding of these activities
`within a systems framework. To achieve such a framework, we
`need a better understanding of the risks involved and their sources,
`and we need to clarify our individual roles and ensure that our
`individual roles are well integrated. Only then can we plan effective
`risk management strategies.
`
`The Task Force also examined in detail FDA’s role in the overall
`system. We find that the Agency's pre- and postmarketing risk
`assessment systems are performing well. Nonetheless, we believe
`that additional emphasis should be placed on the quality assurance
`of our premarketing review programs. In addition, the Task Force
`finds that program expansion is needed to ensure that our
`postmarketing programs are able to meet the challenges of the
`current regulatory and healthcare environment.
`
`Recommendations
`The Task Force is making a number of recommendations as a result
`of its review. Most recommendations center around ways that
`FDA, within the confines of the current system, can further improve
`its risk management activities. The Agency intends to implement
`these recommendations. Many of these improvements already are
`underway, and the Task Force recommends that ongoing
`enhancements be aggressively pursued. Specifics can be found at
`the end of Parts 2, 3, and 4 of the report, but these
`recommendations generally include:
`
`•
`
`Initiate steps to have each Center establish separate quality
`assurance/quality control units.
`
`• Ensure and document ongoing professional education and core
`competency training for all reviewers.
`
`• Complete the good review practice documents and keep them
`current.
`
`• Rapidly complete AERS and enhance MAUDE adverse event
`reporting systems for pharmaceutical products and medical
`devices.
`
`•
`
`Integrate existing postmarketing systems so analytical tools,
`data entry, and editing can be uniformly applied, and all
`
`Executive Summary 13
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`information is readily available to every reviewer.
`
`• Enhance and intensify surveillance of newly marketed products.
`
`• Develop new methodological tools for inference from available
`datasets.
`
`The Task Force also identified a number of options for
`consideration, which, if adopted, might contribute to improved risk
`management. These ideas need full public policy analysis and
`review to understand their potential value, costs, and acceptability
`to the various stakeholders in medical product risk management.
`Some of the options would require significant new resources and
`legislative changes. Input from stakeholders on these options and
`their prioritization is needed. For these reasons, the Task Force’s
`key recommendation is that:
`
`• FDA join in or convene a meeting, or series of meetings, with
`stakeholders to discuss the current system for managing risks.
`As part of this meeting, FDA should consult stakeholders about
`the options identified in detail in the report and summarized
`below.
`
`The Task Force identified a number of options that we believe may
`improve the FDA’s risk management activities as well as improve
`the overall system of managing the risks from medical products.
`These options should be evaluated in the context of the stakeholder
`risk confrontation meeting(s) recommended above. Only by
`working with all other participants in the overall risk management
`system for medical products can the Agency arrive at the most
`effective approach for managing those risks.
`
`Details of the options for public consideration can be found in the
`relevant chapters of this report. In summary, these options might
`include:
`
`• Examine and evaluate mechanisms designed to address the
`inherent limits of premarketing development (e.g., wider use
`of large, community-based simple trials, restricting exposure
`during the early postmarketing period).
`
`• Design and implement additional mechanisms to obtain
`
`Executive Summary 14
`
`Options
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`postmarketing information (e.g., sentinel sites, prospective
`product use registries, enhanced links to external
`databases).
`
`• Enhance Agency epidemiological and methodological
`research activities.
`
`• Enhance the Agency’s role and responsibilities in risk
`communication.
`
`•
`
`Increase the number of postmarketing risk interventions for
`products with special risks, such as restricting distribution
`of products or requiring mandatory educational programs
`for healthcare professionals and patients.
`
`• Seek legislative changes for other types of risk intervention,
`such as suspension authority for drugs.
`
`Executive Summary 15
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`INTRODUCTION
`
`As set forth by Congress in section 406 of the Food and Drug
`Administration Modernization Act of 1997 (Modernization Act),
`the mission of the U.S. Food and Drug Administration (FDA) is, in
`part, to (1) promote the public health by promptly and efficiently
`reviewing clinical research and taking appropriate and timely action
`on the marketing of regulated products and (2) protect the public
`health by ensuring that human drugs, including biologics, are safe
`and effective and that there is reasonable assurance of the safety
`and effectiveness of medical devices intended for human use. FDA
`is charged with pursuing this mission through consultation with
`experts in science, medicine, and public health, and through
`cooperation with consumers, users, and industry. The
`Modernization Act also instructs FDA to maximize the availability
`and clarity of information concerning new products for consumers
`and patients.
`
`During the 1980s and the early 1990s, critics talked of a drug lag in
`the United States. They claimed that long review times were
`denying the American public the benefits of new products that were
`available in other developed nations many months or years earlier.
`
`LEGISLATIVE AND MANAGEMENT INITIATIVES HAVE HELPED SPEED
`REVIEW TIME
`
`To address concerns about the timeliness of reviews, the
`pharmaceutical industry, consumer groups, FDA, and Congress
`worked together to develop new legislation. Through the
`Prescription Drug User Fee Act of 1992 (PDUFA) and the
`Modernization Act of 1997, Congress has encouraged the FDA to
`
`Introduction 16
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`act more rapidly in making decisions on whether new medical
`products may enter the marketplace. PDUFA provides FDA with
`additional funds from user fees, permitting FDA to employ a larger
`workforce to handle review workloads. The fees are paid by the
`sponsors of new drug and biological products and can only be used
`in support of the new pharmaceutical product review process.
`PDUFA did not change FDA's standard for drug and biologics
`safety and effectiveness.
`
`These legislative initiatives have been successful. Since its
`enactment, PDUFA user fees have paid for a 60-percent increase in
`staff assigned to the review of new pharmaceutical applications.
`The average time from submission of an application to approval has
`dropped from about 30 to 12 months. Along with this
`improvement in review times has come an increase of almost 40
`percent in the number of new products approved per year, from an
`average of 70 to 97 applications per year.
`Industry negotiated
`strict administrative accountability and aggressive review time
`performance goals in exchange for its support of PDUFA. FDA
`has established an excellent record of meeting, or exceeding, these
`goals. FDA's faster review is not just the result of more FDA staff,
`but is also due to improvements in program management and
`efforts to streamline the review process.
`
`Unlike the Center for Drugs and the Center for Biologics, the
`Center for Devices did not benefit from user fees. However, the
`medical device program received a budget increase in 1994. This
`increase, along with a reallocation of funds from other activities,
`management changes, and program reengineering improved results
`for the device program. For example, the review time for device
`premarket applications (PMAs) has decreased from 27 mont