MANAGING THE RISKSFROM MEDICAL PRODUCT USECREATING A RISKMANAGEMENT FRAMEWORKREPORT TO THE FDA COMMISSIONERFROM THE TASK FORCE ON RISK MANAGEMENTU.S. Department of Health and Human ServicesFood and Drug AdministrationMay 1999
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`iMANAGING THE RISKSFROM MEDICAL PRODUCT USETable of ContentsExecutive Summary...................................................................................................................1Findings...........................................................................................................................................................2Conclusions, Recommendations, and Options.........................................................................................12Introduction.............................................................................................................................16Legislative and Management Initiatives Have Helped Speed Review Time........................................16Concerns Have Been Raised About the Effects of PDUFA....................................................................17The Commissioner Asked the Task Force to Look Into Public Concerns About the RiskManagement System...................................................................................................................................18Part 1: Background — What Are the Risks and What Is FDA's Role in Managing Risk?....20Goals Are to Maximize Benefit, Minimize Risk.......................................................................................21What ARE the Risks Involved With Using Medical Products?.............................................................23What Is FDA's Role in Minimizing Risk?.................................................................................................29Conclusions...................................................................................................................................................31Part 2: Is the FDA Maintaining the Quality of Its Premarketing Reviews?...........................33Has the Rate of Serious Adverse Events Increased?..............................................................................33How Well Is the Agency’s Quality Control System Working?..............................................................37What Factors in the Development Process Could Affect Risk Identification?.....................................43Conclusions and Recommendations..........................................................................................................49Part 3: How Does FDA Conduct Postmarketing Surveillance and Risk Assessment?............51Overall Postmarketing Risk Assessment Is Complex.............................................................................52FDA Uses a Number of Approaches to Assess Risk..............................................................................54Initiatives Underway to Expand Postmarketing Risk Assessment........................................................63Other Efforts Being Considered to Expand FDA's Risk Assessment...................................................65Conclusions, Recommendations, and Options.........................................................................................69Part 4: Managing the Risks From Medical Product Use........................................................71Current Risk Management for Medical Products...................................................................................71Federal Risk Management Framework....................................................................................................73Is the Current Risk Management System Working?..............................................................................76
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`iiThe Time Is Right for a New Systems Framework.................................................................................77FDA’s Overall Risk Management Activities............................................................................................79Conclusions, Recommendations, and Options.........................................................................................90Members of the Task Force.....................................................................................................98Bibliography...........................................................................................................................100Acronym List..........................................................................................................................103Appendices.................................................................................................................................1Table of Contents.......................................................................................................................1Appendix A.............................................................................................................................A-1Appendix B.............................................................................................................................B-1Appendix C.............................................................................................................................C-1Appendix D............................................................................................................................D-1Appendix E.............................................................................................................................E-1Appendix F.............................................................................................................................F-1Appendix G...........................................................................................................................G-1Appendix H...........................................................................................................................H-1Appendix I.............................................................................................................................I-1
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`Managing the Risks From Medical Product UseExecutive Summary 1EXECUTIVE SUMMARYAs one of her first initiatives after being sworn in as FDACommissioner, Dr. Jane Henney established a Task Force toevaluate the system for managing the risks of FDA-approvedmedical products, focusing particularly on FDA’s part in thesystem. This report is the result of that review.Briefly, the Task Force assessed risk management practices withinthe overall healthcare delivery system, focusing on the roles andresponsibilities of each participant. The Task Force applied a riskmanagement model used in other Federal sectors. We alsoexamined the various risks from medical products and their sources.The Task Force then evaluated FDA
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` role in the current system. First, we reviewed the Agency’s premarketing risk assessment andapproval processes to determine if serious adverse events areoccurring at a higher rate now than they have in the past. Next, theTask Force evaluated FDA
` postmarketing surveillance and riskassessment programs to see if they are doing the job they wereintended to do. Finally, the Task Force analyzed all of FDA’s riskmanagement activities to evaluate the Agency’s role in the overallsystem for managing medical product risks. Our findings aresummarized here.
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`Managing the Risks From Medical Product UseExecutive Summary 2FINDINGSThe time is right for a new frameworkThe key finding of our review is that the time is right to apply asystems framework to medical product risk management. The FDAplays only a part in the complex system of risk management.Numerous other groups participate in decision making related tothe use of medical products. A systems framework for riskmanagement should enable a better integration of the efforts of allthe involved parties. Such a framework also should facilitate abetter understanding of both the risks involved in using medicalproducts and the sources of those risks. A better understanding ofrisks and a more integrated risk management system will enablemore effective risk interventions.The current risk management system has evolved over timeAt the turn of this century, healthcare in this country was generallyprovided by a family practitioner who treated patients from cradleto grave. As illustrated in the following figure, medical productstoday are developed and used within a complex system involving anumber of key participants: (1) manufacturers who develop andtest products and submit applications for their approval to the FDA;(2) the FDA, which has an extensive premarketing review andapproval process and uses a series of postmarketing surveillanceprograms to gather data on and assess risks; (3) other participantsin the healthcare delivery system, including healthcare practitioners;and (4) patients, who rely on the ability of this complex system toprovide them with needed interventions while protecting them frominjury.
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`Sponsor
`Risk/Benefit
`Assessment
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`FDA
`Premarket
`Risk/Benefit
`Assessment
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`FDA
`Approval
`Decision
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`Risk
`Managers
`(Prescribers)
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`Patients
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`Risk ConfrontationEfforts
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`Crisis
`Management
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`FDA Risk
`Intervention
`Labeling
`Restrictions on Use
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`Postmarket Phase
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`Nurses
`Pharmacists
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`Complex System for Managing the Risks of Medical Products(Rx Products)
`Premarket Phase
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`Managing the Risks From Medical Product UseExecutive Summary 3
`MarketWithdrawalPostmarket Risk/Benefit AssessmentAncillary Risk Managers:FDA Healthcare Delivery SystemsManufacturers Professional SocietiesOther Federal Groups Risk Communications Dear Doctor Letters Warnings Label Changes Risk Management Intervention Formulary Restrictions Restrictions to Specific Professionals Practice GuidelinesRisk CommunicationAdvertisingPatient InformationInternetReportingReportingNot everyone’s role is clearly definedAlthough medical products are required to be safe, safety does notmean zero risk. A safe product is one that has reasonable risks,given the magnitude of the benefit expected and the alternativesavailable. All participants in the medical product development anddelivery system have a role to play in maintaining this benefit-riskbalance by making sure that products are developed, tested,manufactured, labeled, prescribed, dispensed, and used in a waythat maximizes benefit and minimizes risk.In some cases, roles are clearly defined. For example, FDA’scurrent efforts, which are laid out in the Federal Food, Drug, andCosmetic Act, are largely devoted to pre- and postmarketing risk
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`S p o n s o r
`R i s k / B e n e f i t
`A s s e s s m e n t
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`F D A
`P r e m a r k e t
`R i s k / B e n e f i t
`A s s e s s m e n t
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`F D A
`A p p r o v a l
`D e c i s i o n
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`Managing the Risks From Medical Product UseExecutive Summary 4assessment. The FDA approval/nonapproval decision is theAgency's central risk management action. FDA must ensure thatbeneficial medical products are available and labeled with adequateinformation on their risks and benefits while protecting the publicfrom unsafe products or false claims. The figure below is asnapshot of FDA’s role in the current risk management system. During premarketing review, the Agency assesses the evidencedemonstrating the benefits and describing the risks of medicalproducts.FDA Role in Medical ProductsFDA Role in Medical ProductsRisk ManagementRisk Management(Rx Products)
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`The Agency approves a product when it judges that the benefits ofusing a product outweigh the risks for the intended population anduse. A major goal of the premarketing review is to ensure thatproducts are truthfully and adequately labeled for the populationand use. Labeling is given considerable emphasis because it is thechief tool the Agency uses to communicate risk and benefit to thehealthcare community and patients.Once medical products are on the market, however, ensuring safetyis principally the responsibility of healthcare providers and patients,who make risk decisions on an individual, rather than a population,basis. They are expected to use the labeling information to selectand use products wisely, thereby minimizing adverse events.
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`P r e s c r i b e r s
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`Patients
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`F D A
`P o s t m a r k e t
`S u r v e i l l a n c e
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`Managing the Risks From Medical Product UseExecutive Summary 5FDAevaluatesbenefits/risksfor the populationProviderevaluatesbenefits/risksfor a patientPatientevaluatesbenefits/risksin terms ofpersonal valuesB B B BB B BBRRRBenefitsBenefitsRisksRisksTo assist with postmarketing risk management, the Agencymaintains a system of complex postmarketing surveillance and riskassessment programs to identify adverse events that are notidentified during medical product development and premarketingreview. FDA monitors suspected adverse events associated withthe use of an approved medical product. The Agency uses thisinformation to initiate labeling updates and, on rare occasions, toreevaluate the marketing decision.Although the FDA’s role is fairly clear, the roles of some of theother participants are less clear. This is because what began asindividualized care by one practitioner has evolved into a complexsystem of risk management that now involves manufacturers, theFDA, practitioners, many other elements of the healthcare deliverysystem, and patients. With the flood of new products reaching themarketplace, an increasingly complex healthcare environment, andthe emerging global market, the Task Force believes that a newconceptual framework for risk management activities is needed. The new framework should help define the roles of those involvedand better integrate their efforts.How would a new systems framework look?As discussed in Part 4, a specific model has been developed formanaging the risks associated with other health and safety issues
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`Managing the Risks From Medical Product UseExecutive Summary 6within the Federal Government.1 This model encompasses the basicprocesses that are used to identify and assess the risks of specifichealth hazards, implement activities to eliminate or minimize thoserisks, communicate risk information, and monitor and evaluate theresults of the interventions and communications. The Task Forcefound that the processes identified in the Federal model areconsistent with the activities the Agency and many of the otherinvolved participants currently undertake as part of their approachto risk management. Under the current system, however, theseactivities are fragmented, rather than part of an integrated systemseffort. The Task Force easily adapted the Federal model to create aproposed model for managing the risks associated with usingmedical products. (See the proposed model below.) This newframework encourages a much greater integration of riskmanagement efforts than the current system.Proposed RiskManagement Model
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`Engage Partners
`and Other
`Stakeholders
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`Identify Issues
`and Put Them
`into Context
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`Evaluate Results
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`Assess Risks/
`Assess Benefits
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`Implement
`the Strategy
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`Identify and
`Analyze Options
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`Select a Strategy
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` 1 Presidential/Congressional Commission on Risk Assessment and RiskManagement, Framework for Environmental Health Risk Management — FinalReport, Vol. 1, 1997.
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`Managing the Risks From Medical Product UseExecutive Summary 7One activity often missing from other risk management models thatis implicit in risk-benefit assessment and is critical in a system thatwould manage healthcare risks involves engaging healthcarepartners and other stakeholders in risk-benefit analyses. Thisactivity is characterized by others as risk confrontation: community-based problem solving that actively involves relevantstakeholders in the decision-making process. 2 This is one area ofactivity that traditionally has had lower priority in the Agency thanits pre- and postmarketing scientific risk assessment responsibilities.The Task Force believes that risk confrontation is a key processthat needs to be a part of any new risk management framework. FDA should engage stakeholders to examine the current riskmanagement systemThe Task Force recommends that FDA take the opportunity toengage all stakeholders to reexamine the current system formanaging the risks associated with the use of medical products. We encourage a public policy discussion that focuses on definingmore clearly the roles and responsibilities of all participants of therisk management system
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`FDA, industry, healthcare providerorganizations, healthcare practitioners, patients, and the public. Only by examining the roles of these various participants can gapsand misallocation of efforts be identified and improvements made.Understanding the types of risks and their sources is criticalTo evaluate the current system, it is critical that the stakeholdersalso consider what is known about the sources of risk from medicalproducts and what is not yet completely understood. As discussedin detail in Part 1 of the report, risks from medical productsgenerally fall into four categories. 2 Leviton, L.C., C.E. Needleman, and M.A. Shapiro, Confronting Public HealthRisks: A Decision Maker’s Guide, SAGE Publications, Inc., 1998.
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`Managing the Risks From Medical Product UseExecutive Summary 8Sources of Risk From Medical ProductsKnown Side EffectsUnavoidable AvoidableMedication andDevice ErrorProduct DefectsPreventableAdverseEventsInjury orDeathRemainingUncertainties:- Unexpected side effects- Unstudied uses- Unstudied populationsMost injuries and deaths associated with the use of medicalproducts result from their known side effects. Some side effectsare unavoidable, but others can be prevented or minimized bycareful product choice and use. It is estimated that more than half of the side effects from pharmaceuticals are avoidable.3 Othersources of preventable adverse events are medication or deviceerrors. Injury from product defects is unusual in the United Statesbecause of the great attention paid to product quality control andquality assurance during manufacturing. The final category ofpotential risk involves the remaining uncertainties about aproduct.Knowledge about a product will always be limited to some extent atthe time of approval by factors in the product development process.For example, rare side effects and long-term outcomes (bothpositive and negative) may not be known when a product isapproved because of the relatively small size and short duration ofclinical trials. And because of the populations not studied in clinicaltrials (e.g., pregnant patients, children, people with other diseases)or minimally studied (e.g., geriatric patients), side effects may bediscovered if these groups are treated with a product after it goes 3 Bates, D.W., L.L. Leape, and S. Petrycki, “Incidence and Preventability ofAdverse Drug Events in Hospitalized Adults,” J Gen Intern Med., 8:289-294,1993.
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`Managing the Risks From Medical Product UseExecutive Summary 9on the market. Even after long use of a product, uncertainties willremain.One problem for discussion is the lack of adequate data about thecauses, incidences, preventability, and relative contribution of thevarious types of risk. Currently, no group has the role of collectingand analyzing these types of data. Systematic approaches to riskmanagement require the use of such data to plan and evaluate thesuccess of risk interventions. It is unlikely that major improvementsin 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 marketedmedical products. The Task Force believes that the stakeholdersshould collaborate to determine how better data on risks can becollected — so that efforts and interventions can be targeted to themost serious problems, and the effects of interventions can beevaluated.FDA’s current role in risk managementTurning to FDA’s role in overall risk management, the Task Forceexamined the Agency’s premarketing and postmarketing riskassessment activities, evaluating their quality and effectiveness. The Task Force also looked at FDA’s efforts in other aspects ofrisk management such as risk communication, confrontation, andoverall evaluation.As discussed in detail in Part 2 of this report, the Task Forceevaluated whether the heightened sense of time pressure on Agencyreview teams has reduced the quality of FDA’s premarketingreviews or caused poor decision making. We studied how oftenpreviously unanticipated serious adverse events4 were identifiedafter approval in drugs reviewed since the implementation,beginning in 1990, of several legislative (e.g., PDUFA) andmanagerial initiatives to speed the Agency’s review process.5 We 4 A number of terms are used to describe an adverse event, including adverse drugreaction (ADR), adverse experience, and adverse effect. In this report, the termadverse event is used in most cases to avoid confusion.5 Through the Prescription Drug User Fee Act of 1992 (PDUFA) and the Food andDrug Administration Modernization Act of 1997, Congress has encouraged theFDA to act more rapidly in making decisions on whether new medical productsmay enter the marketplace.
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`Managing the Risks From Medical Product UseExecutive Summary 10then compared the numbers to those collected by a 1990 GeneralAccounting Office (GAO) report on serious adverse events fordrugs reviewed prior to 1990.6 We also examined FDA
` qualitycontrol systems for premarketing review and marketing decisions tosee if adequate systems are in place.Rates of withdrawals and adverse events remain lowWe found that FDA’s premarketing review processes aresuccessfully identifying the serious risks associated with usingmedical products at least as well as in previous decades. Despiteshortened FDA review time, comparisons of drugs reviewed andapproved during the 1990s to those approved previously show thatthe rate of market withdrawals for safety reasons has remainedrelatively unchanged over the decades. As the graph below shows,the rate of safety-based market withdrawals of new molecularentities (NMEs) has ranged from approximately 1 to 3.5 percentover the past several decades.71979-19831984-19881989-19931994-1998*4.0%3.0%2.0%1.0%0.0%PercentageNumber200150100 50 0Safety-Based NME WithdrawalsBased on Year of Approval5-Year Approval Period (number withdrawn in calendar years) Percentage of cohort withdrawn Number of NMEs approved in calendar years*PDUFA years(3) (4) (2) (2)951131271723.2% 3.5% 1.6% 1.2% 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, May1999.
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`Managing the Risks From Medical Product UseExecutive Summary 11With advances in scientific knowledge, safety problems may beidentified for long-marketed products. For example, of the fivedrugs withdrawn for safety reasons after 1992, two were approvedbefore PDUFA was implemented.8 In addition, comparisons alsoshowed that unexpected serious adverse events resulting inrevisions to product labeling after approval are occurringproportionately less often than in the past. The Task Force also found that the key elements of an InternationalStandards Organization (ISO)-modeled quality assurance/qualitycontrol program for premarketing review are in place and beingused. FDA has consistently used supervisory rereview, conductedby subject matter experts, for 100 percent of the marketingdecisions as the cornerstone of its quality control function. Thesequality control reviews are conducted typically at three supervisorylevels before a final approval decision is made.Some factors limit the identification of adverse eventsThe Task Force analysis identified several factors in the medicalproduct development process that limit the Agency’s ability toobserve some kinds of adverse events before marketing. Factorsinclude the relatively small size and short duration of clinical trialsand the representativeness of the patients studied. For example, asdiscussed in Part 2, rare side effects are often not observed beforemarketing because of the limited number of patients exposed to aproduct before approval. And, most trials do not last long enoughto enable identification of potential long-term side effects. Inaddition, patients in clinical trials are often not representative of thetypes of people who will be exposed to a product once it goes onthe market. Changing these aspects of medical productdevelopment could increase the manufacturers’ and the Agency’s ability to identify serious risks before marketing. However, suchchanges would increase development costs and slow productavailability.Finally, the Task Force believes that in the case of some newmedical products, consideration should be given to how rapidlythey 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 marketin 1997 and 1998; Seldane and Pondimin were approved prior to PDUFA. For afull discussion, see, Friedman et al., “The Safety of Newly Approved Medicines,”JAMA, Vol. 281, No. 18, May 12, 1999.
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`Managing the Risks From Medical Product UseExecutive Summary 12alternatives are available could limit the impact of unexpectedserious adverse events.Postmarketing surveillance and risk assessment are performing asdesignedWe found that the postmarketing surveillance programs currently inplace are good at rapidly detecting most unexpected seriousadverse events that occur during the postmarketing period. Asdescribed in more detail in Part 3 of this report, the Agency reliesprincipally on a passive adverse event reporting system, dependingto a great extent on voluntary reporting by the healthcarecommunity. The system rapidly alerts the Agency to theoccurrence of rare, serious adverse events not previously identified.The system also provides an increased understanding of the rangeof severity in known product-associated adverse side effects. Wefound that the Agency’s postmarketing surveillance and riskassessment programs are performing well for the goals they weredesigned to achieve. However, FDA’s programs were not designedto evaluate the rate, or the impact, of known adverse events.The Task Force has presented some options for expanding the useof automated systems for reporting, monitoring, and evaluatingadverse events and product defects and increasing the Agency’saccess to data sources that would supplement and extend its passivereporting systems. These would enhance the Agency’s ability toevaluate reports of serious adverse events. Examples of suchsources include broad-based health information databases and datafrom sentinel user facilities where staff are trained to rapidlyrecognize and accurately report adverse events. Implementingsome of these changes would require increased funding.CONCLUSIONS, RECOMMENDATIONS, AND OPTIONSConclusionsMedical products provide great benefit to the public, but they canalso cause injury. FDA and the many other participants inhealthcare delivery act to maximize the benefits and minimize therisks associated with using medical products, but often the actions of the participants are insufficiently integrated. The Task Forcebelieves that the common goal of maximizing benefits and
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`Managing the Risks From Medical Product UseExecutive Summary 13minimizing risks could be greatly advanced if the participants in thesystem worked together to gain an understanding of these activitieswithin a systems framework. To achieve such a framework, weneed a better understanding of the risks involved and their sources,and we need to clarify our individual roles and ensure that ourindividual roles are well integrated. Only then can we plan effectiverisk management strategies.The Task Force also examined in detail FDA’s role in the overallsystem. We find that the Agency's pre- and postmarketing riskassessment systems are performing well. Nonetheless, we believethat additional emphasis should be placed on the quality assuranceof our premarketing review programs. In addition, the Task Forcefinds that program expansion is needed to ensure that ourpostmarketing programs are able to meet the challenges of thecurrent regulatory and healthcare environment.RecommendationsThe Task Force is making a number of recommendations as a resultof its review. Most recommendations center around ways thatFDA, within the confines of the current system, can further improveits risk management activities. The Agency intends to implementthese recommendations. Many of these improvements already areunderway, and the Task Force recommends that ongoingenhancements be aggressively pursued. Specifics can be found atthe end of Parts 2, 3, and 4 of the report, but theserecommendations generally include:
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`• Initiate steps to have each Center establish separate qualityassurance/quality control units.
`• Ensure and document ongoing professional education and corecompetency training for all reviewers.
`• Complete the good review practice documents and keep themcurrent.
`• Rapidly complete AERS and enhance MAUDE adverse eventreporting systems for pharmaceutical products and medicaldevices.
`• Integrate existing postmarketing systems so analytical tools,data entry, and editing can be uniformly applied, and all
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`• Enhance and intensify surveillance of newly marketed products.
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`• Develop new methodological tools for inference from availabledatasets.The Task Force also identified a number of options forconsideration, which, if adopted, might contribute to improved riskmanagement. These ideas need full public policy analysis andreview to understand their potential value, costs, and acceptabilityto the various stakeholders in medical product risk management. Some of the options would require significant new resources andlegislative changes. Input from stakeholders on these options andtheir prioritization is needed. For these reasons, the Task Force’skey recommendation is that:
`• FDA join in or convene a meeting, or series of meetings, withstakeholders to discuss the current system for managing risks. As part of this meeting, FDA should consult stakeholders aboutthe options identified in detail in the report and summarizedbelow.OptionsThe Task Force identified a number of options that we believe mayimprove the FDA’s risk management activities as well as improvethe overall system of managing the risks from medical products. These options should be evaluated in the context of the stakeholderrisk confrontation meeting(s) recommended above. Only byworking with all other participants in the overall risk managementsystem for medical products can the Agency arrive at the mosteffective approach for managing those risks. Details of the options for public consideration can be found in therelevant chapters of this report. In summary, these options mightinclude:
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`Managing the Risks From Medical Product UseExecutive Summary 14information is readily available to every reviewer.
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`• Examine and evaluate mechanisms designed to address theinherent limits of premarketing development (e.g., wider useof large, community-based simple trials, restricting exposuredu