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Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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4
The Science of Safety

The deliberation and decisions of a science-based regulatory agency depend on the quality of the scientific data that it obtains and reviews to make valid scientific judgments. The science underlying drug development is complex and multidisciplinary. As Chapter 2 describes briefly, the early phases of drug development involve basic in vitro and in vivo research to characterize general attributes of a drug. The staff of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER), particularly in Office of New Drugs (OND) review divisions, works with the industry sponsor of a drug to guide the design and the collection and analysis of those data. The FDA Critical Path Initiative is designed to foster the development of innovative scientific approaches to drug discovery and development. (Critical Path also includes some effort to develop methods for predicting safety problems better, for example, biomarkers of QT prolongation and indicators of liver toxicity; see Chapter 1.) This report of the Committee on the Assessment of the US Drug Safety System focuses on data generated and reviewed further along the development spectrum, so Critical Path will not be addressed in detail, but the committee recognizes Critical Path’s importance and the potential for better tools for the prediction and early detection of the safety of pharmaceuticals as biomedical knowledge increases (FDA, 2004). Enthusiastic as the committee is about the potential of new biology and personalized medicine to contribute to the development and use of safe drugs, the promise of the “right drug for the right person at the right time” is not likely to be realized for most patients for some time.

There will always be a need for clinical trials and postmarket, population-based studies to fully understand the risks and benefits associated with

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

drugs, especially to identify rare or unsuspected safety problems. Controlled phase 4 studies will remain important for verifying that drugs approved on the basis of limited exposures and surrogate end points actually have health benefits and for assessing whether common adverse events can be attributed to a drug when such events (such as heart attacks in older adults) emerge as a potential safety signal. This chapter underscores the importance of generating strong science to support regulatory decision-making about the risks and benefits associated with drugs and the importance of ensuring that the decisions made throughout a drug’s lifecycle are credible and transparent.

GENERATING THE SCIENCE

Understanding Risk and Benefit for Approval Decisions

As has been described in Chapter 2, a New Drug Application (NDA) and the reviews of an NDA by CDER staff contain thousands of pages of information about the effects of a drug. CDER clinical reviewers are expertly trained to analyze the efficacy and safety data from clinical trials. Individual case reports of adverse events from the trials are reviewed, as are comparisons of event rates of many safety outcomes in the overall product database, including those in uncontrolled safety studies. The reviewers also consider the statistical methods used by the company to generate the results. CDER has issued many guidances and documents of policies and procedures outlining the best ways to review and analyze such data (DHHS et al., 2005; FDA, 2005c). Clinical trials are designed to test hypotheses that are the agreed-on bases for determining efficacy. Trials designed to test hypotheses about serious safety outcomes would in most cases require many more subjects than are needed for an efficacy endpoint. For some conditions, the efficacy outcomes may be surrogate endpoints, which are expected to capture the information about efficacy but are usually not informative about safety.

Safety information can emerge from clinical trials, but rare events may not surface at all; if they do, it is at a rate so low that one cannot distinguish a drug-caused event from one expected by chance (background incidence). Safety information is usually limited to reports of common adverse events, the relation of which to drug exposure can be assessed by comparing rates between study treatment groups, or adverse events already predicted by results of animal studies or in connection with other drugs in the same class. Safety information also includes abnormalities in clinical laboratory test values seen during preapproval trials that may portend occasional clinically significant events. That set of suspected adverse events serves as a starting point for decisions about postmarket surveillance and drug safety research. The safety profile of a new molecular entity (NME) is especially uncertain, because of a lack of information on similar drugs already on the market.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Murglitazar, a drug for diabetes that activates both alpha- and gamma-peroxisome proliferator-activated receptors, was reviewed by FDA for approval during the committee’s work. In the preapproval trials, compared with the other arms of the trials (some compared the drug with a placebo, others with another diabetes medicine), murglitazar improved sensitivity to insulin and the control of blood lipids in patients with type 2 diabetes. Those efficacy outcomes are examples of surrogate endpoints because they are expected to predict the occurrence of cardiovascular events. In the same preapproval trials, however, patients randomized to murglitazar had a significantly higher incidence of the combined outcomes of death, heart attack, stroke, and heart failure. The reason for the discrepancy between surrogate endpoints and health outcomes is not clear, but the case of murglitazar illustrates the importance of verifying the assumed health benefits of new drugs and of conducting more complete risk-benefit analyses (Nissen et al., 2005).

As described in Chapters 2 and 3, OND clinical reviewers are primarily responsible for assessing the safety information in an NDA, and interactions and involvement of the Office of Drug Safety/Office of Surveillance and Epidemiology (ODS/OSE)1 staff vary among OND offices. A recent time-accounting exercise by CDER reports that OND devotes 51 percent of total scientific and technical staff effort on safety-related activities (FDA, 2005a). Despite that large investment of time and effort, the safety profile of a drug at the time of NDA review is necessarily uncertain at the time of approval. The only certainty at the time of approval is that the CDER official who signed the approval letter has not identified safety problems that in his or her best judgment outweigh the potential benefit of the drug for the specific indication and population studied. However, to expect that premarket studies or FDA review of these studies can reveal all the information about the risks and benefits of new drugs that is needed to make optimal treatment decisions would occasion unreasonable delay in approval.

Reducing Uncertainty About Risk and Benefit After Approval

As described in other sections of this report, important new information about a drug’s effectiveness2 accumulates after approval, although effectiveness is extremely diffcult to assess outside the context of a randomized trial. The committee has chosen to describe the major components essential to as-

1

In May 2006, CDER renamed the Office of Drug Safety (ODS) the Office of Surveillance and Epidemiology (OSE). The committee will refer to this office as ODS/OSE in the report in recognition that some statements refer to actions of the office in the past and some statements refer to the present.

2

Efficacy refers to effects in controlled clinical trials; effectiveness refers to effects in the “real world.”

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

sessment of drug safety after approval as the generation of hypotheses based on early safety signals, the strengthening of safety signals, the conduct of confirmatory studies to identify and quantify new or hypothesized risks and benefits, the evaluation of risk management programs to minimize known safety risks, and the continuing evaluation of risks and benefits in light of new risk or new benefit information to ensure that the known benefits of a drug continue to outweigh the known risks. The committee concludes that although CDER is involved in a variety of activities to generate and assess postmarket safety information, the current approach is not as comprehensive and systematic as is needed to serve drug safety and public health objectives optimally. The committee offers specific recommendations to CDER and other federal departments and agencies for improving postapproval assessment of drug-related risks and benefits.

Signal Generation

Although some safety signals are generated in laboratory tests and clinical trials conducted in the preapproval setting or from known or suspected biologic actions of a drug, the primary method by which FDA documents new adverse events in the postmarket setting is monitoring of suspected adverse drug reaction reports entered into the Adverse Event Reporting System (AERS). AERS combines the voluntary adverse drug reaction reports from MedWatch, such as direct reports from healthcare practitioners and consumers, and the required reports from manufacturers—15-day expedited reports of serious3 and unexpected adverse events and manufacturer periodic reports. The information provided by this part-voluntary, part-mandatory system of reporting forms the basis of detection of many safety signals and has been useful in identifying rare adverse events.

Spontaneous AERSs have many limitations, but they offer the possibility of identifying rare serious adverse events in a timely manner among all persons across the entire region to which the system applies. For example, if there is a one-in-a-million serious adverse event applicable to those exposed to a drug used in 10 million people per year in the United States, it might never be observed in a database of several hundred thousand, or even several million people in which the number exposed to the drug might be only a few thousand per year. But in the entire United States it is not so unlikely that at least one such event would get reported. Even a small number of reports of events that are commonly caused by drug exposure, such as liver or kidney failure, aplastic anemia, anaphylaxis, Stevens-Johnson syndrome,

3

A serious adverse event is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect (CFR 312.32).

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

and so on, can constitute an important safety signal. Spontaneous reporting is subject to certain limitations, including underreporting, the influence of bias in reporting, lack of denominator data, and difficulties in attribution of association between reported event and drug exposure.

Little has been done to optimize the usage of AERS for drug safety signal detection until recently. The work of DuMouchel and others raised the real possibility of doing automated searches of AERS to identify possible associations worthy of further followup. These “data mining” techniques greatly increase the value of AERS data, and that of other spontaneous reporting systems. Developing more rigorous systems in which to investigate AERS signals or any other possible risks of interest is warranted and long overdue; such systems have the potential to improve the ability to develop safety information in a more rapid and more reliable manner. The Centers for Education and Research on Therapeutics (CERTs) are assessing the potential use of health care databases for enhanced identification of adverse drug events. But the addition of new tools such as the use of health care databases does not mean we should abandon the old, especially now that we have methods to substantially enhance the value of these older tools.

In 2004, FDA received 422,889 reports of suspected drug-related adverse events. Of those reports, 21,493 were MedWatch reports directly from individuals (about 15 percent of which came directly from consumers), 162,107 were manufacturer 15-day (expedited) reports, 89,960 were reports of serious events included in manufacturer periodic reports, and 149,329 were reports of other events included in manufacturer periodic reports. As described in Chapter 2, safety evaluators in ODS/OSE review case reports in their drug-class portfolios. That is necessarily very time-consuming. Electronic submission of adverse event (AE) reports makes the system more efficient and timely, although it is reported that only half of the AE reports are submitted electronically, so the AERS contractor must spend time in performing data entry before the information can be reviewed by the safety evaluators.

A safety evaluator receives about 650 electronic reports per month. Review of AE reports can sometimes identify rare or unusual events that require additional research to understand. The following are some drugs for which AEs were identified through AERS: terfenadine (torsade de pointes and sudden death), cisapride (torsade de pointes and sudden death), troglitazone (hepatic failure), infliximab (tuberculosis and opportunistic infections), and cerivastatin (rhabdomyolysis) (Wysowski and Swartz, 2005). Statistical approaches available for the analysis and display of AERS data (such as the WebVDME program) have received only limited use by CDER until recently. CDER staff have recently described how the use of a Bayesian statistical analysis would have confirmed the cerivastatin, rhabdomyolysis, and renal failure association after 6 months of postapproval use if it had

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

been available (Szarfman et al., 2002). Other systematic methods of screening for AEs have also received little attention, although their use appears to be increasing. The committee is aware of the criticisms of AERS, but the committee believes that the planned update known as AERS-2 will useful. The committee supports a focused improvement in how CDER uses passive-surveillance reports as a tool in drug safety research.

4.1: The committee recommends that in order to improve the generation of new safety signals and hypotheses, CDER (a) conduct a systematic, scientific review of the AERS system,4 (b) identify and implement changes in key factors5 that could lead to a more efficient system, and (c) systematically implement statistical-surveillance methods on a regular and routine basis for the automated generation of new safety signals.


The committee does not intend that review of AE reports, whether submitted by manufacturers as mandatory under federal regulation or submitted by patients or their providers through the MedWatch program, be the primary tool used by CDER for postmarket safety analysis. The committee does not support making AE reporting mandatory. Enforcing mandatory reporting is difficult and the committee’s goal is to have better reporting and better use of what is reported, not to increase the workload of CDER safety evaluators with unhelpful information. The passive reporting system in place today is capable of, and has made, important contributions, and the committee hopes that CDER will work to make the current system more efficient. In the next section, the committee offers recommendations for tools that will supplement and complement the AERS system and provide better data for regulatory and public health purposes.

Signal Strengthening and Testing

The development and implementation of a lifecycle approach to the evaluation of the risks and benefits related to drugs will require expanded efforts in signal strengthening and signal testing in the postmarket setting. Once safety evaluators in ODS/OSE or clinical reviewers see sufficient numbers of similar case reports, they have to decide whether apparent signals are real—that is indicative of a problem—or just “noise” in the system. That determination should begin with the application of available tools, such as sector maps and empirical Bayes reporting ratios for analyzing spontane-

4

The committee is aware that CDER is beginning to undertake an information-technology upgrade of AERS.

5

Such as data sources, coding, quantity, quality of reports, and best use of CDER staff.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

ous reports and should continue with more active methods of evaluating signals.

Sometimes, the need for signal-strengthening studies is anticipated at the time of approval. Just before approval, CDER negotiates about phase 4 studies that the company commits to conducting. Chapter 2 includes information about the number of those studies that are not completed. An exception to the inability of CDER to compel the studies is the case in which a drug is approved under accelerated approval. Postmarketing studies range from simple pharmacokinetic studies through analysis of data in administrative databases to controlled trials. The current approach, leaving the negotiations of plans for postmarket studies to the late stages of the pre-approval process, is not optimal and may lead to studies that are not well designed. That is one of the reasons why a large proportion of postmarket commitments are not started or completed. Another factor that could contribute to suboptimal design is uncertainty of OND clinical reviewers about the types and designs of postmarket studies that might be developed, particularly observational studies. It is unusual for CDER to bring in outside experts for independent review and advice about the hypotheses and design of phase 4 studies committed to at the time of approval, but such advice might be useful. As described in Chapter 2, input from advisory committees is often not sought because of committee meeting schedules.

A strong postmarket safety system requires a wide array of data resources that permit continuing evaluations. Some may be directed at tracking patterns of drug use, the indications for the use of a drug in the population, and a general description of the types and frequencies of various AEs. Others may be directed at signal generation. For instance, as electronic medical-records databases are further developed, it may be possible to incorporate real-time reporting of AEs that can be made available to FDA for analysis. Such an effort would require considerable development.

Signals or hypotheses about safety issues may arise from other sources, including known or suspected biologic drug effects that become evident through animal and human studies. Once a potential signal is identified, followup studies are likely to involve the use of a variety of study designs and data sources, including large electronic administrative databases. ODS/ OSE has four task-order contracts6 for access to administrative databases for epidemiologic research. The contractor sites are the HMO Research Network, Ingenix Inc., the Kaiser Foundation Research Institute, and Vanderbilt University (Seligman, 2005). Cumulatively, those organizations cover 23.5 million people, and each has characteristics that make it particularly useful. For example, the Vanderbilt site uses Medicaid data from Tennessee and Washington and thereby obtains information about high-risk and eth-

6

This program had previously been funded through a cooperative agreement mechanism.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

nically diverse populations. The Ingenix site has access to some laboratory data in addition to claims data, and the HMO Research Network and the Kaiser Foundation Research Institute sites have access to electronic medical records. Study designs for the contracted studies often are presented to the Drug Safety and Risk Management Advisory Committee or involve other outside experts through the special government employee mechanism for review and comment as a form of scientific peer review.

The funding for the cooperative agreement program is severely limited and the program has always been small. In 1985, the funding level was $1.2 million; since then, resources have varied. Despite inflation in the interim, funding for FDA drug safety cooperative agreements reached a low of $900,000 in 2000 (personal communication, Gerald Dal Pan, FDA, March 30, 2006). In fiscal year (FY) 2006, funding for FDA drug safety contracts totals only $1.6 million, and it is scheduled to decrease to $900,000 in FY 2007. According to an ODS annual report, the contract program in 2004 supported five feasibility7 studies and three in-depth studies, but in FY 2006 the program will have sponsored feasibility studies for two drug safety questions and will not have sufficient funds to execute one high-priority in-depth study fully—on the cardiovascular risks posed by drugs prescribed for attention deficit hyperactivity disorder (ADHD) (IOM Staff Notes, 2005–2006). In contrast, a similar program funded by the Centers for Disease Control and Prevention (CDC) to study safety problems associated with vaccines, the Vaccine Safety Datalink (VSD), included data on more than 7 million people covered by eight managed-care organizations. CDC supported the VSD with $13 million and eight full-time staff persons in FY 2004 (Davis, 2004).

FDA also works with the CERTs that have access to large healthcare databases, including the HMO Research Network and the Department of Veterans Affairs (VA). CDER has internal access to the General Practice Research Database (GPRD)8 and to proprietary databases9 that house extensive information on drug use. Access to the GPRD was expected to provide valuable information to CDER for drug safety purposes, but ODS/OSE has struggled to get sufficient computer resources and staff trained to use it. Four full-time safety evaluators now work with those databases, and two staff epidemiologists work part-time with them in their research.10 CDER staff presented their first findings from the GPRD at the 2006 summer meeting of the International Society of Pharmacoepidemiology.

7

A feasibility study involves preliminary assessments of whether a database contains sufficient exposures or outcomes in appropriate populations to answer the study question.

8

A computerized database of longitudinal medical records from primary care practices in the United Kingdom and a source of data for many epidemiologic studies around the world.

9

Verispan, LLC; IMS Health; and Premier.

10

Personal Communication, G. Dal Pan, FDA (ODS/OSE), 2006.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

VA serves an enrolled population of 7.7 million veterans, their family members, and survivors through its more than 1,300 sites of care, including 154 medical centers. The presence of automated databases and a prescription drug benefit makes VA a promising setting for postmarket drug studies. There are some examples of the use of data from the VA system for studies of the prevalence of AEs (Nebeker et al., 2005) and case-control studies of possible adverse effects of drugs (Shannon et al., 2005). VA and CDER would like to work together to use this resource more broadly, but resource limitations prevent more extensive collaboration. VA populations are included in the research of a few of the CERTs (CERTS, 2006; UI Health Care News, 2006).

There is near-unanimous agreement that the Medicare Modernization Act and the Medicare Part D benefit offer potential new resources for post-marketing drug studies. As of January 2006, an estimated 43 million people on Medicare were eligible to sign up for prescription drug coverage through Part D plans, and the Department of Health and Human Services (DHHS) indicates that 19.7 million beneficiaries were enrolled as of April, 2006 (Kaiser Family Foundation, 2006). Because the elderly are frequent users of multiple medications for concomitant diseases, data from Medicare Part D could play an important role in postmarket drug studies, particularly given the opportunity to create linkages among pharmacy, outpatient, inpatient, physician office, and emergency-department claims. FDA has endorsed a proposal, lacking in detail, to establish a postmarketing surveillance system for prescription drugs that would use billing data and health care information collected from Medicare beneficiaries (Kaiser Family Foundation, 2005). Through the Agency for Healthcare Research and Quality (AHRQ) Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) Network, investigators are developing a methodologic toolbox and data-analytic framework for using population-based claims and administrative data sources in pharmacoepidemiologic and pharmacovigilance research (DHHS and AHRQ, 2006).

This kind of research is labor-intensive, and specialized knowledge is required to use some of the databases. A small number of ODS/OSE epidemiologists and safety evaluators are trained to use the databases directly or to collaborate with other researchers to design and analyze data, and they have limited time to conduct research because of their other responsibilities (such as responding to OND consults, working to develop needed CDER guidances, and preparing for meetings).

The advantages of research using health care databases include the ability to conduct studies of uncommon diseases or understudied populations with respect to drug exposures, minimization of study costs, reduction in the time required to complete a study, and the opportunity to study large numbers of patients. Those systems can also provide valuable information

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

on the background incidence of AEs, which is helpful in understanding the significance of findings in passive-surveillance systems. The disadvantages include missing data and misclassification of key data on outcomes (Hripcsak et al., 2003), drug use, or potential confounding factors. Information on severity of illness or functional status is often uniformly missing (Jackson et al., 2006) and selection bias cannot be prevented from influencing results. The large samples in administrative databases can provide considerable power to assess associations; however, precise but biased estimates of risk are not generally useful. Other disadvantages are difficulties in gaining access to primary medical records (and access to patients themselves), either entirely or on more than just a sample basis; dependence on diagnostic coding systems, which can be problematic for some conditions or topics; and drug-formulary restrictions in some health plans that limit the ability to study newer drugs if they are not on the formulary. Finally, much of the useful clinical information, such as descriptions of adverse reactions, exists only in narrative form, which makes automated analysis difficult (Jollis et al., 1993). There are strategies for correcting for some of the limitations of the databases (such as chart review to find missing data or to improve the accuracy of information), but they are sometimes resource-intensive. Consideration must be given to the strengths and limitations of the data in setting priorities within the program and between research methods for addressing a specific safety problem.

In some instances, active surveillance to generate safety signals and resolve other knowledge gaps is useful. Active surveillance is the regular, periodic collection of case reports from health care providers or facilities. CDER has been involved in developing a limited number of active-surveillance strategies. One example is an emergency room-based surveillance project for drug-induced injury, the National Electronic Injury Surveillance System– Cooperative Drug Adverse Event Surveillance System (NEISS–CADES), jointly funded by the Consumer Product Safety Commission, CDC, and FDA. FDA recently issued a request for information that stated its interest in this regard. In addition, FDA has cosponsored pilot development of a drug-based surveillance system that explores the feasibility of using data-mining techniques to identify safety signals in automated claims databases (DHHS, 2005). NEISS-CADES was used very recently to document AEs associated with stimulant medications used for ADHD (Cohen et al., 2006).

4.2: The committee recommends that in order to facilitate the formulation and testing of drug safety hypotheses, CDER (a) increase their intramural and extramural programs that access and study data from large automated healthcare databases and (b) include in these programs studies on drug utilization patterns and background incidence rates for adverse events of interest, and (c) develop and

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

implement active surveillance of specific drugs and diseases as needed in a variety of settings.

Other federal partners in the drug safety system (VA and the Centers for Medicare and Medicaid Services, CMS, in particular) also use automated databases and should work with CDER, as appropriate, to accomplish the goal of improved formulation and testing of drug safety hypotheses for the entire drug safety system. As will be described in Chapter 7, CDER and its federal partners in the drug safety system will need increased resources to accomplish these goals.

Confirmatory Studies

Passive surveillance, epidemiologic research with administrative databases, and active surveillance can be used to answer many drug safety questions. When they do not provide definitive answers, they can sometimes provide guidance for the development of further studies or provide sufficient information to narrow the uncertainty about drug-related risks and benefits and guide regulatory actions and the decisions of patients and providers. In some instances, full-scale observational studies or clinical trials will be required to answer key questions, particularly if the outcome of interest is common in the patients taking a drug. Such studies are often expensive and time-consuming, but they provide valuable information that less rigorous studies cannot provide. For example, the Women’s Health Initiative (WHI) and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) cost an estimated $725 million and $125 million, respectively, but provided valuable evidence about efficacy and safety.

Although $125 million seems like a lot of money, 28.4 percent of the adult population, or about 65 million men and women, of the United States have high blood pressure (Fields et al., 2004), and more than half of them are taking medications for it (Hajjar and Kotchen, 2003). The annual costs of two of the blood-pressure medications used in ALLHAT are about $547 for amlodipine (a calcium-channel blocker) and $83 for chlorthalidone (a low-dose diuretic) (The Medical Letter, 2004). Demonstration that low-cost and older drugs, such as diuretics, are the most effective first-line treatment for high blood pressure can improve health outcomes and save money. ALLHAT also helped to resolve uncertainty about the safety profile of the calcium-channel blockers.

There is no realistic mechanism to ensure that important phase 4 clinical trials are done. As discussed in Chapter 2, some phase 4 studies to be conducted by the drug sponsor are agreed on at the time of drug approval, but for various reasons, many of those studies are never completed. FDA has no authority to compel the completion of these studies, and industry could

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

be reluctant to conduct them because of high costs and the possibility that unfavorable results would negatively influence market share.

A significant impediment to the successful completion of studies is that they are typically negotiated between CDER and the industry very late in the approval process. The study designs can be inadequate, and there is little opportunity given time constraints imposed by the Prescription Drug User Fee Act (PDUFA), for CDER to bring in outside experts when they are needed to help with study design. Experts who are in the pool of potential special government employees (including advisory committee members) can be consulted, but they must be screened for conflicts of interest, and only one can be brought in at a time to comply with the Federal Advisory Committee Act. Although there may be legitimate reasons for abandoning some of the phase 4 study commitments, many could be useful, especially with study-design improvement.

Once a drug is approved, unless the industry sponsor is looking for a new indication for the drug, CDER has no leverage to require further studies by the company. Pharmaceutical companies continue to conduct clinical trials of their drugs, and there is an emerging recognition that these are often marketing-driven and their designs may be inadequate for any reliable assessment of safety or efficacy (Psaty et al., 2006), may underreport AEs, may lead to selective publication of favorable results and non-publication of studies whose findings are unfavorable for marketing (Psaty and Rennie, 2006), and therefore can be misleading. The concept of these “seeding” trials, performed primarily for marketing purposes, is not new (Kessler et al., 1994).

CDER does not have the resources to fund large randomized clinical trials, nor was it ever intended to do so. The drug safety system is currently dependent on the industry, the National Institutes of Health (NIH), or foundations to fund such studies. Other groups have a strong interest in reducing the uncertainty about therapeutic risks and benefits—health care payers, for example—but they have not typically conducted large and expensive phase 4 trials. No entity is responsible for helping to set priorities among the drug safety and drug efficacy questions that need to be examined, particularly with resource-intensive controlled trials. Some studies are necessary for answering questions for regulatory purposes (such as whether risks outweigh benefits and what regulatory action should be taken); others are important for public health purposes and are not likely to be funded by industry (such as head-to-head trials of drugs approved for the same indication).

The potential cost of large safety trials has been a concern for many. A model for “large, simple trials” was established in the United Kingdom in the 1970s; a series of increasingly large randomized trials was conducted to examine regimens for treatments to prevent cardiovascular mortality in

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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those at elevated risk. Those trials were conducted with very modest budgets. Although the costing of trials in the United Kingdom and the United States is admittedly very different due to differences in the way health care and biomedical research are supported in the two countries, there may be ways to conduct trials in the United States with substantially smaller budgets than has been assumed. The increasing computerization of medical data and move toward electronic medical records may facilitate the implementation of more efficient trials with fewer personnel needs. Research into methods for conducting simpler, less expensive trials that might be suitable for answering straightforward but important safety questions is warranted, and represents a logical area for FDA scientific involvement, even leadership.

4.3: The committee recommends that the Secretary of HHS, working with the Secretaries of Veterans Affairs and Defense, develop a public-private partnership with drug sponsors, public and private insurers, for-profit and not-for-profit health care provider organizations, consumer groups, and large pharmaceutical companies to prioritize, plan, and organize funding for confirmatory drug safety and efficacy studies of public health importance. Congress should capitalize the public share of this partnership.


The program for confirmatory studies should focus on the conduct of large, long-term phase 4 clinical trials to evaluate the health risks and benefits associated with chronic-disease medications approved on the basis of short-term trials of surrogate endpoints—such as blood pressure and lipid and hemoglobin A1c concentrations—and on comparative safety and effectiveness studies. The public-private partnership could also consider studies of cost-effectiveness, particularly comparative cost-effectiveness, which is unlikely to be studied by industry and would be very important for those members of the public-private partnership who are insurers and provider organizations, including the VA, CMS, and Department of Defense (DoD). The randomized clinical trial is the optimal method of assessing the efficacy and safety of a drug therapy, but there are other approaches, including analyses of physical or electronic medical records, patients, and specimens identified in the large automated databases and analyses of data from observational studies.

DHHS agencies with an interest in drug safety include FDA, NIH, AHRQ, CDC, and CMS. VA already partners in a limited way with FDA in some drug safety studies, and both agencies express an interest in expanding that collaboration. With a system of 7.7 million veterans and over 100 million prescriptions filled every year and with excellent electronic records, VA would provide valuable data as well as insight and expertise to this partner-

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

ship. The committee is not aware of any collaborations with DoD on such studies,11 but DoD provides health care coverage to over 9 million persons and has excellent epidemiologic research capacity, easily accessible research subjects, and a national interest in the safest and most effective use of drugs for troop readiness and cost containment for the largest health care system in the country. That is why the committee included DoD in the partnership. NIH has supported many important such trials, and the committee expects it will continue to do so. Each agency in the collaboration will need staff dedicated to this work in addition to information-technology upgrades and administrative support.

Discussions about needed confirmatory studies should include regulatory findings and related advisory committee input, should address major study-design issues, and should lead to studies that supplement and complement those being done by industry sponsors as part of their postmarket study commitments. The committee urges industry to use the expertise of the proposed public-private partnership for comment on the design of studies and for oversight of study conduct and analysis of results. Proposals for all confirmatory drug safety studies, whether funded or conducted by public or private entities, should be subject to a peer-review process modeled after NIH study sections to ensure scientific excellence.

An important outcome of the partnership should be that federal agencies provide FDA access to all administrative databases12 (under conditions consistent with the protection of patient privacy) managed by the federal government for purposes related to postmarketing surveillance, safety monitoring and analysis, and risk-benefit assessment of approved drugs.

Funding for the studies planned by the partnership would come from different sources, including congressional appropriations, depending on the questions to be addressed. Some studies planned under this partnership would have been conducted absent the partnership; therefore, the resources needed are not all additional costs to the system. It is hoped that the partnership would help prioritize questions and advise on important study design issues. The partnership might also facilitate collaborations that otherwise would not occur. The committee believes that industry bears the responsibility for paying for clinical trials and other observational studies which support a product’s approval and its safe and effective use (e.g., specific

11

DoD and other agencies have collaborated in planning and analyzing complementary studies of the safety of the smallpox and anthrax vaccines.

12

This could be accomplished by training CDER staff to use the databases directly or to work with staff in the other agencies. In either arrangement, new staff will be needed to implement this recommendation. Access to the databases could be obtained through an interagency task force (either existing or to be created) including representatives of FDA, representatives of federal agencies that manage medical databases, and other members to coordinate and ensure effective use by FDA of such medical databases for postmarketing drug safety.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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postmarket study commitments) and that both government and industry, in collaboration with others, bear the responsibility for funding other clinical trials or observational studies performed for broader public health objectives rather than specific regulatory purposes. Industry also has a social responsibility to make sure that its products are safe and effective, so it should contribute to these trials of public health importance. The secretary of DHHS should provide funding for the administrative management of the partnership, but funds for the research will need to come from a variety of sources. CDER will need support from the FDA commissioner and from the secretary of DHHS to use the information from the studies for the best regulatory policy-making. The committee understands that priority-setting and collaboration will not be easy, but they are necessary for advances in drug safety.

Risk Minimization Action Plans

As described above, some drug safety problems are suspected, some are unknown and unsuspected, and others are known at the time of approval. Risk management is an iterative process that encompasses the assessment of risks and benefits, the minimization of risks, and the maximization of benefits. The committee views with concern the CDER statement that the “cornerstone” of risk management encompasses “efforts to make FDA-approved professional labeling clearer, more concise, and better focused on information of clinical relevance” (FDA, 2005b). There is widespread acknowledgment that product labeling has not been a very effective means of communication to prescribers about risk management.

PDUFA III required FDA to issue guidances to industry on risk management. The preceding sections of this chapter describe tools to assess and clarify drug risks and benefits. Risk minimization is the effort to minimize risks already identified. Risk minimization action plans (RiskMAPs) constitute a relatively new approach to minimizing known risks of a drug beyond the standard industry responsibilities related to routine risks, such as labeling and reporting of AEs. According to the guidance entitled “Guidance for Industry, Development and Use of Risk Minimization Action Plans,” “RiskMAP means a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. A RiskMAP targets one or more safety-related health outcomes or goals and uses one or more tools to achieve those goals” (FDA, 2005b). The guidance describes the following possible RiskMAP tools:

  • Targeted education and outreach to communicate risks and appropriate safety behaviors to healthcare practitioners or patients.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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  • Reminder systems, processes, or forms to foster reduced-risk prescribing and use.

  • Performance-linked access systems that guide prescribing, dispensing, and use to target the population and conditions of use most likely to confer benefits and to minimize particular risks.

NDAs for NMEs are required to include RiskMAPs, but at the time of approval most non-NMEs will not need RiskMAPs. Known risks can be addressed through standard industry and CDER activities. Information about possible risks can be sufficiently uncertain that appropriate minimization strategies are not obvious.

RiskMAPs can also be developed or modified after marketing. Every RiskMAP should be viewed as a “living document” that evolves throughout the lifecycle of a drug. One of the best examples is the case of isotretinoin, a teratogenic drug indicated for severe cystic acne. The risk minimization activities for this drug have increased in complexity. The Pregnancy Prevention Program (PPP) was established in 1988 in an attempt to prevent exposure of pregnant women to isotretinoin. The PPP asked female users of isotretinoin to enroll voluntarily in a survey administered by Boston University’s Sloane Epidemiology Unit and enrolled 45 percent of women of reproductive age who were using the drug. Of these women, 36 percent did not have any type of pregnancy test before beginning treatment, and about 900 pregnancies occurred among enrollees during 1989–1998 (No Author, 2000). A new program, SMART (System to Manage Accutane Related Teratogenicity), was implemented in 2002 (Levine A, 2002; Honein et al., 2004). SMART retained the voluntary registration of PPP and

  • Added a requirement for two negative pregnancy tests before the first prescription with the second pregnancy test occurring during menses.

  • Added qualification stickers on each prescription to confirm that the patient had agreed to use contraception and had signed an informed consent about the teratogenic risks posed by isotretinoin and to verify that the physician had confirmed the negative pregnancy tests and had counseled the patient about participation in the voluntary followup survey.

  • Added a requirement that prescriptions not be filled without a qualification sticker.

  • Added a requirement that prescriptions not be filled more than 7 days later than the qualification date on the sticker.

  • Added a restriction that limited all prescriptions to a 30-day supply.

  • Disallowed automatic refills and telephoned-in prescriptions.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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  • Increased incentives for survey participation.

The first-year evaluation of SMART found that 127 pregnancies were reported among isotretinoin users in the year before SMART (April 1, 2001, to March 31, 2002) and 120 during SMART’s first year (April 1, 2002, to March 31, 2003) (Avigan and DalPan, 2004; Pitts and Karwoski, 2004; Ackermann Shiff et al., 2006).

The ineffectiveness of SMART led to a more aggressive approach. iPLEDGE, the risk management program instituted in March 2006, drew praise for its comprehensiveness but criticism that the complicated responsibilities for patients, prescribing physicians, and dispensing pharmacists would discourage use. Key components of iPLEDGE are registration of patients and pharmacists, documentation by female patients of child-bearing potential of two forms of contraception and a laboratory-confirmed negative pregnancy test, verification by the pharmacist that the prescription is valid, and distribution of a medication guide.

RiskMAPs are a fairly new development, and an FDA guidance acknowledges the need for evaluation of plan performance (FDA, 2005b). PDUFA III gave ODS/OSE a role in the review and evaluation of risk management plans. The PDUFA III goals call for ODS/OSE participation in pre-NDA meetings and pre-biologic license application meetings to discuss preliminary risk management plans and proposed observational studies and, in the period 2–3 years after approval, to evaluate risk management plans after implementation.

4.4: The committee recommends that CDER assure the performance of timely and scientifically-valid evaluations (whether done internally or by industry sponsors) of Risk Minimization Action Plans (RiskMAPs). This review should include determining whether an individual RiskMAP is effective and overall evaluations of the strategies used and the processes of CDER staff and industry sponsors for planning and implementing RiskMaps. Evaluations should consider burdens and consequences in addition to design and effectiveness.

Risk-Benefit Analyses Throughout the Lifecycle

The regulatory decision to approve a drug requires the determination that the benefits of the drug outweigh the risks associated with it when used for the indication for which the drug is approved. That is, the drug must demonstrate a favorable risk-benefit profile. As a country we have chosen to place a significant degree of decision-making about the availability and potential use of medicines in the hands of a science-based regulatory body.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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The FDA is the first gatekeeper regarding access to drugs in exercising approval authority. Some drugs, perhaps even many, will not and should not be permitted to be used by patients who expect their medicines to be safe and effective. Some believe that drugs should be made much more freely available on the market for anyone who wishes to use them, particularly if the patient has a fatal disease for which they are willing to take the chance that a drug will have little benefit and possibly many serious risks (Burroughs and Walker, 2006). For many of these situations, accelerated approval was developed as a mechanism to make selected promising drugs available early in their evaluation.13 However, it is widely accepted that the FDA has the authority to determine whether the risk-benefit profile for a drug is appropriate to release the drug on the market. Whether the “bar” for approval is too high or too low for particular drugs has not been the focus of this committee’s efforts. In practice, once a drug is approved, health care providers and patients make many decisions about use of a drug. In this section we discuss ways that the regulator can make those decisions easier, by being more explicit about what is known and not known about the sum total of a drug’s benefits and its risks.

As described elsewhere in this report, there are many uncertainties at the time of approval. Eliminating all those uncertainties prior to approval would require an unreasonable number of premarketing studies and would have serious implications not only for pharmaceutical companies in terms of research and development but also for patients awaiting new and important medicines. What regulators and drug sponsors know about the drug at approval will change over time. Some of that new information will pertain to the benefits of potential new indications for the drug and other new information will pertain to the risks or adverse effects of the drug. For example, the results of additional studies completed during a drug’s postapproval period can alter our understanding and perception of the risk-benefit profile and result in new actions on the part of FDA, clinicians, and the public.

FDA reviews a drug for benefits and risks from the perspective of its intended use (the indication in a population), but in most instances, the drug will not have been evaluated for so-called off-label use. Spontaneous reports of adverse events may indicate a potential safety problem and warrant a safety study. Safety and effectiveness data from studies on uses other than the approved indication are gathered if the sponsoring company is studying the drug in clinical trials for a supplemental NDA for a new indication or if sufficient off-label use occurs. Formal studies of safety and/or effectiveness can also be undertaken. There is a “rolling” or incremental increase in information about the risk-benefit of most drugs after licensure and the

13

Other mechanisms to increase access to drugs include compassionate use protocols and enrollment in clinical trials.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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committee is interested in formalizing the accumulation, integration, and communication of that increased and improved knowledge.

In both the preapproval and the postmarketing setting, the risk-benefit analysis that currently goes into regulatory decisions appears to be ad hoc, informal, and qualitative. For preapproval, review divisions work relatively autonomously under general guidance on how to review applications in the absence of clear guidelines about how to make the final decision regarding approval (FDA, 2005c). Some variability is necessary, due to the very nature of the drugs themselves. Considerations regarding the balance of efficacy and safety for a new drug to treat a fatal condition are different from those for the tenth drug in a therapeutic category to treat minor symptoms. However, variability in how review divisions operate is of concern to industry (Tilson et al., 2006) and to CDER. CDER leaders have expressed interest in standardizing their means of analyzing risk and benefit and in doing so, when possible, in an integrated way. A recent study by Boston Consulting Group performed for Pharmaceutical Research and Manufacturers of America (PhRMA) confirms that CDER lacks standard approaches to this important responsibility (Tollman, 2006). Consistency in the approval process will benefit the drug sponsors in preparing their NDA packages and in planning postmarket study commitments.

In addition, increased efforts at risk-benefit analysis will help support postapproval decision making by regulators, drug sponsors, physicians, and patients. More robust risk-benefit analyses can provide quantitative estimates that may be useful to clinicians and patients in deciding whether to use a medicine. For example, a recent publication summarizing safety outcomes from the WHI used a relatively simple table to present results from that study (see Table 4-1). The WHI was three large clinical trials in one, and the major interventions were hormone replacement therapy, low-fat diets, and calcium plus vitamin D. The main outcomes for the comparison of estrogen plus progestin with placebo are summarized in the table (Women’s Group for the Women’s Health Initiative Investigators, 2002). When all types of outcomes are treated as equal, hormone replacement therapy is associated with an overall increase in adverse health events of about 20 per 10,000 women per year. Women will vary in their baseline risk of these types of disease conditions; however, they will also vary in the preferences for avoiding one type of disease condition or another as well as in their views about the value of symptomatic relief from menopausal symptoms. The information from the WHI trial provides patients and physicians with a useful empirical basis for the discussion of risks and benefits relating to the use of combined hormone therapy. Moreover, risk-benefit analyses can help to identify what key questions remain to be answered and thus generate the most important issues or hypotheses that require additional study.

Integrated comprehensive quantitative assessments and weighing of

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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TABLE 4-1 One-Year Increase or Decrease in the Number of Major Health Outcomes Among 10,000 Women Taking Estrogen Plus Progestin Compared with Women Taking Placebo

Event Type

Number*

Coronary heart disease

+7

Stroke

+8

Pulmonary embolus

+8

Invasive breast cancer

+8

Colorectal cancer

–6

Hip fracture

–5

Total

+20

*A plus sign means that, compared with placebo, there were more events in the women taking hormone therapy, and a minus sign means that there are fewer events in the women taking hormone therapy.

SOURCE: Adapted from Women’s Group for the Women’s Health Initiative Investigators (2002).

risks and benefits are far from perfect. Some misleading analyses (with resulting inappropriate regulatory or clinical decision making) are likely because of imperfect information. Nevertheless, the potential advantages of having a systematic approach to risk-benefit analysis for prescription drugs include increasing consistency of approach to approval decisions among the review divisions; a growing common understanding about the criteria for approval and other regulatory actions; increased transparency for the industry, health care providers, patients, and researchers; increased credibility of FDA and CDER; and direct assessments of comparable drugs. Ideally, the weighing of a product’s risks and benefits will be both transparent and reproducible.

The barriers to moving pharmaceutical risk-benefit assessment toward a more systematic and scientific endeavor include those related to data and to methods. Data are a primary rate-limiting factor in the evaluation of risks and benefits. Information on a drug’s risks and benefits comes from preclinical and clinical studies, but it is phase 3 clinical trials that provide the bulk of the data used to make risk-benefit determinations at the time of approval. Risk or safety assessment is limited by what is missing. Most important for risk assessment is the lack of information that would enable estimation of event rates, their comparison across treatment groups, and evaluation of causality. Findings from preapproval clinical trials may suggest safety signals, but the numbers of events tend to be small and may not lend themselves to precise statistical analyses. The trials lack the ability, both because of their size and because of the relative homogeneity of the typical clinical trial population, to yield confident statements about the plausible

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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range of risks that would affect the populations who would actually take the drug if it were approved. Therefore, when a safety signal is apparent but uncertain, in some cases additional studies should be designed to reduce the uncertainty about potential risk. Benefit data may also be limited by what is missing, namely, information on health benefits if the approval was based on surrogate endpoints rather than health outcomes. Also typically lacking is information on risk-benefit relationships in important subgroups of patients (such as those with severe disease or comorbidities), or large numbers of patients exposed to the drug for long durations, or results of other treatments (head-to-head trials), and on long-term health outcomes.

Regarding methods, a growing set of tools can be used to attempt to quantify the value of research. Because the results of a research program are intrinsically uncertain, the tools are based on a “value of information” approach that identifies the value of research as the expected value of the improvements in outcomes that would be generated by a research project (Meltzer, 2001; Claxton et al., 2005b). The techniques to guide research priorities are beginning to be used in other countries to assess when additional research on a drug should be required as part of a regulatory decision. For example, in the United Kingdom the National Institute for Health and Clinical Excellence has begun to explore the use of the approaches to evaluate research priorities (Claxton et al., 2005a). Quantitative measures of treatment benefits and the application of risk-benefit analysis should consider such factors as the seriousness of a disease, its chronicity, and the effect of a drug on quality of life or the disease process.

Metrics that have been used to measure benefits include absolute differences in event rates, mortality, number of lives saved, and quality-adjusted life years (QALYs) (the relative differences are not nearly as helpful as the absolute ones in this setting). Quantifying benefits in terms of those metrics is difficult or impossible if efficacy is assessed only in terms of surrogate endpoints. Risks can be summarized in terms of incidence, risk difference, excess risk, severity, and duration. Rates and risks are quantitative, but only the more common events that occur with enough frequency in premarket clinical trials can be incorporated into the metrics with any precision. As the comittee learned in its workshop (see Appendix D for the workshop agenda), the science and the acceptance of approaches to simultaneously and explicitly considering multiple benefits and risks for pharmaceuticals and their preferences is evolving (Weiss Smith, 2006).

4.5: The committee recommends that CDER develop and continually improve a systematic approach to risk-benefit analysis for use throughout the FDA in the preapproval and postapproval settings. The systematic approach should have the following characteristics:

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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  • Use the most rigorous possible scientific methods to provide guidance about what information should be collected and how that information should be analyzed and used for decision making.

  • Help assure that the studies required to conduct risk-benefit analyses are properly designed to answer key public health questions and completed in a timely fashion.

  • Make the product of these analyses available to patients, physicians, policy makers, and researchers in terms that will aid their decision making. Information on the specific consequences (such as treatment benefits and adverse effects) of therapeutic options, and the level of uncertainty about those consequences should be provided for all drugs.

  • Provide when possible population-level measures of effectiveness and cost-effectiveness using standard measures that aggregate across domains of health (such as QALYs) to help inform approval and coverage decisions.14

  • Calculate when possible the expected value of research to guide recommendations about when to perform additional studies.

  • Provide guidance about what new data are needed and how those data should be analyzed.

  • Be updated as new information becomes available.

  • Be described in publicly available documents that are appropriate for all stakeholders.

The benefits of the effort will be harmonization of the work of different review divisions, a growing understanding of the criteria for approval and other regulatory actions, and increased transparency for the industry, healthcare providers, patients, and researchers. The committee believes that with the tools described above, the evidence base on the risks and benefits associated with drugs will be more complete and will serve the health of the public better. In addition to generation and evaluation of data, the drug safety system must be viewed by the public and the prescribing community as credible. The next section describes some concrete steps that will reassure the public that the science on which FDA makes regulatory decisions about risks is credible.

CREDIBILITY OF THE SCIENCE

As has already been discussed extensively, uncertainty about benefits and risks is common throughout much of a drug’s lifecycle. Once safety

14

FDA does not make coverage decisions or consider cost-effectiveness, but other partners in the drug safety system do, and this information will be valuable.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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signals begin to emerge, unless observational studies or controlled trials are done to examine safety endpoints, difficult judgments about the meaning of data that are less than perfect data must be made. As Chapter 3 describes, CDER’s functioning is stressed when there is disagreement about the best course of action in the face of uncertainty. It is important that CDER staff—and industry sponsors, healthcare providers, and patients—believe that the best decisions possible have been made. Confidence in the judgments depends on the expertise of those informing the decisions, their wisdom and leadership ability, and the transparency of the information itself.

Expertise in the Center for Drug Evaluation and Research

The committee has made several recommendations to expand the data on drug risks and benefits to improve decisions. However, appropriate expertise must be brought to bear to plan research and use the resulting data. That expertise comes from the CDER staff and their advisory committees and other non-governmental experts. The committee believes that there is a need to expand the available expertise to take on the new responsibilities described in recommendations made in this report. CDER will need more expert staff, deeper expertise in the staff it already has, and different kinds of expertise.

4.6: The committee recommends that CDER build internal epidemiologic and informatics capacity in order to improve the postmarket assessment of drugs. In recognition of the human resource limitations in the current employment market to meet this role, a combination of advancing professional skills through continuing education and support for academic training programs is needed.


Informatics experts should track progress on the national health-information infrastructure, look for opportunities to gather information about drug safety and efficacy after approval, coordinate partnerships with external groups to study the use of electronic health records for AE surveillance, participate in FDA’s already strong role in setting national standards and track the development of tools for data analysis in industry and academe, and encourage the incorporation of the tools into FDA practice where appropriate.

Expanded epidemiologic expertise will allow ODS/OSE to apply more sophisticated methods in extracting information from the case reports from the passive-surveillance system and information from administrative databases. ODS/OSE staff could serve as principal investigators for some research projects in the expanded epidemiology-contracts program; this could help in recruitment and retention of staff. In addition, the increased sophisti-

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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cation regarding epidemiologic methods could lead to more productive and respectful interactions with other CDER staff, advisory committee members, and industry scientists. The recommendation in the preceding chapter that would give ODS/OSE staff more responsibilities in both preapproval and postapproval settings will require increased capacity in numbers of staff and in the expertise that ODS/OSE staff contribute.

However, expanding epidemiologic capacity in CDER staff may be challenging. Few academic centers are capable of providing appropriate training in pharmacoepidemiology. That has led to a national dearth of adequately trained personnel in drug safety and risk management (Lo Re and Strom, 2006). A recent commentary from the International Society of Pharmacoepidemiologists echoes the concern for Europe as well (ISPE, 2006).

Options for improving training in drug safety and risk management have recently been proposed to the committee (Lo Re and Strom, 2006). The federal government has never offered career-development awards in pharmacoepidemiology, except to those whose interests matched the interests of categorical institutes of NIH, which allowed them to apply to those institutes for mentored career development awards, such as the K01, K08, and K23 Awards. The only federal funding now available for training in pharmacoepidemiology is in the CERTs program (see below). The National Institute of General Medical Sciences is about to award its first pharmacoepidemiology training grant in its clinical pharmacology training program. However, it will contain only two slots per year—this is far too few to meet the needs of FDA alone, much less those of the field in general.

Increasing the epidemiologic capacity of CDER, focusing on ODS/OSE but also in OND if desired, could take the form of hiring new staff with training in epidemiology in addition to their professional medical, nursing, or pharmacy training or could be accomplished through targeted programs of training of existing ODS/OSE staff. That could range from short courses, to the support of degree programs at either the master’s or the doctoral level, to a formal training program, such as the Epidemic Intelligence Service program at CDC.15 A first step in laying out the options for increasing training opportunities could be a committee of ODS/OSE and OND staff with input from epidemiologists from CDC, NIH, AHRQ, and other FDA centers. Priority should be given to training programs with direct links to advancing the scientific work that underpins CDER’s regulatory mission.

With expanded expertise and resources, CDER could be a more effective steward of postmarket safety and a more credible scientific partner with industry and academe by actively participating in defining important

15

The committee has not done an independent assessment of how those options are used but understands that they are all viable options.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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research questions and designing appropriate studies. More details about increasing CDER resources is presented in Chapter 7.

Increasing the scientific sophistication of the CDER staff should not take place in isolation. The goal is to support good science-based regulatory decision-making, and a corollary goal is to support the research infrastructure of the agency. There is a small research program in CDER and in other FDA centers, but history shows a slow decline in that capacity. The committee notes with satisfaction the recent decision of the FDA Science Board to look into ways to expand the research capacity in FDA.

FDA depends on research conducted by the regulated industry and by academic scientists who are financially dependent on the industry. The committee believes that the scientific reviewers in CDER would be well served by having opportunities to engage in scientific research that complement but do not conflict with their regulatory duties. There is little opportunity in CDER for OND and ODS/OSE reviewers (and possibly other offices as well) to engage in research (DHHS and OIG, 2003). For example, the ODS annual report for 2004 states that ODS staff were coauthors of three papers in the peer-reviewed literature (all of which were with coinvestigators in the cooperative agreement program). The FDA Center for Biologics Evaluation and Research, CDER’s sister center, has a long history of research publication in many areas, including postmarket surveillance, as do epidemiologists at CDC, and the committee urges that CDER encourage such efforts.

The progenitor of FDA, the Bureau of Chemistry established in the Department of Agriculture in 1906, created at its inception the Food Research Laboratory to underscore its commitment to science-based regulation, and for over 50 years special advisory committees to the department secretary or the FDA commissioner have repeatedly affirmed the central importance of intramural scientific research to the functioning of the agency (see Box 4-1).

Since 1955, at least six committees have consistently asserted the centrality of high-quality scientific research to the regulatory missions of FDA and called for major changes in the organization and management of the agency’s scientific endeavors.

In response to those committees’ recommendations, FDA has established (and then disestablished) multiple new research organizations (centers, bureaus, and at least one institute) and repeatedly recreated the senior management position of scientific director under various names. History indicates that those repetitive efforts all failed, and although the reasons for failure are not self-evident, the record points to the common problem of discordance among well-intentioned scientific aspirations, ever-increasing regulatory mandates and complexities, and annual budgets that were chronically insufficient to accommodate the desired objectives.

The admonition of the 1991 advisory committee that the agency “avoid

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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BOX 4-1

History of Reports Regarding Research at FDA

In 1955, the report of the Citizen’s Advisory Committee on the Food and Drug Administration to the secretary of health, education, and welfare, stated: “Research is the heart of any scientific operation. Although the FDA is primarily a regulatory agency, it must engage in research of the sort that leads to more accurate scientific methods for determining whether a food or drug is safe. Such research in scientific methodology, and perhaps a limited amount of what might be termed ‘random research,’ can do much to upgrade the professional competence, elevate the morale of scientific workers, and contribute to the general effectiveness of the FDA.”

In May 1991, the final report of the Advisory Committee on the Food and Drug Administration, convened by the secretary of health and human services asserted: “In an era of rapid technological advancement, the FDA must reaffirm its commitment to research as an integral component of its activities. The FDA’s intramural and extramural research projects must be linked to the Agency’s primary functions … High levels of scientific expertise are required to review product applications and to respond to public health crises … FDA scientists who are actively engaged in research help build a vital foundation of Agency understanding and expertise. Without that foundation, the Agency’s ability to address emerging regulatory problems is hampered. It is essential that the FDA avoid being blind-sided by rapid advances in biomedical science and technology.”


For more information see: Science Board to the Food and Drug Administration. 1955. Appendix D, An Abbreviated History of at Least Four Decades of Efforts to Upgrade the Quality of Science in the FDA.

being blind-sided by rapid advances” in biomedical and other sciences and technologies resonates with the present committee, which reaffirms the importance of a robust program of intramural scientific research to inform FDA’s regulatory deliberations and actions. Such an intramural program would provide an excellent interface with the agency’s relatively modest investments in extramural research conducted by CERTs and other contractors. The committee applauds those extramural investments and does not intend that they be threatened by the recommended strengthening of the intramural research program. On the contrary, the committee believes that there is an abundance of extraordinary research opportunities that could substantially enhance the agency’s regulatory processes with respect to both the efficacy and the safety of new therapeutics. Many of the opportunities

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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involve the creation and application of new algorithms and methods to improve the processes of preclinical and clinical drug development and new processes to enable effective safety and efficacy monitoring and evaluation over the entire lifecycle of a therapeutic. If FDA is to take advantage of the many research opportunities, research must be recognized as critical to its core mission and be adequately funded. Opportunities for research bring opportunities for real and perceived conflicts of interest, and the committee urges that these be watched carefully. The committee urges that the research opportunities be linked explicitly to FDA’s regulatory mission. The committee affirms that a strong program of intramural scientific research provides an essential foundation for sound, science-based regulatory policy and performance.

4.7: The committee recommends that the Commissioner of FDA demonstrate commitment to building the Agency’s scientific research capacity by:

  1. Appointing a Chief Scientist in the office of the Commissioner with responsibility for overseeing, coordinating, and ensuring the quality and regulatory focus of the agency’s intramural research programs.

  2. Designating the FDA’s Science Board as the extramural advisory committee to the Chief Scientist.

  3. Including research capacity in the Agency’s mission statement.

  4. Applying resources to support intramural research approved by the Chief Scientist.

  5. Ensuring that adequate funding to support the intramural research program is requested in the Agency’s annual budget request to Congress.

Advisory Committees

Chapter 2 describes some basic characteristics of FDA drug-product advisory committees. Those experts and their input constitute an important resource for FDA in tackling particularly difficult or challenging questions related to its regulated products. Scientific advances, changing technology, and the increasing complexity of new drug products have necessitated the establishment of a strong advisory committee system. Through its advisory committees, FDA can seek advice experts from outside the agency who serve as “special government employees”. The system enables FDA to tap into critical expertise at major research institutions.

Advisory committees are used as a source of independent advice about questions raised by the agency regarding new drugs in the review process,

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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safety or efficacy issues that emerge after drug approval, methodological approaches in study design, conduct or analysis, and policy issues. Committees may be asked to comment on whether there are sufficient data to support product approval. They may be asked to comment on some aspect of safety, effectiveness, or clinical development peculiar to a product. They may also be asked to recommend whether additional studies are needed for some products or whether changes should be made to a drug’s label in response to new risk information. Typically, after presentations by the sponsor, agency representatives, and a public comment period, advisors will vote on the questions posed to them. Advisory committee recommendations are not binding, but the agency usually abides by them.16

FDA uses its advisory committees selectively because of time and cost considerations. Typically, advisory committees are involved in decisions involving new or complex technologies or issues that involve some element of controversy. Advisory committees tackle issues that do not have simple answers. Soliciting the advice of an advisory committee is usually at the discretion of the division director of one of FDA’s five product centers.

Advisory committees promote several goals of the agency. They contribute to the quality of agency decisions and ensure that important public health decisions are based on informed and expert advice. They also increase the transparency of those decisions in that the transcripts of all meetings and the material presented at the meetings are made public, and the meetings receive much mass-media attention. The use of such critical outside expertise to inform agency decision-making lends credibility to the agency’s decisions. In addition, because advisory committees always include a consumer or patient representative to provide insight or feedback about the public’s or patient’s perspective, those meetings are among the few opportunities for the public to play an active role in FDA decisions. Participation in the public comment period is another such opportunity.

The present system has served the agency well, but several factors have made the use of advisory committees more challenging. Review deadlines adopted as part of PDUFA have made it increasingly difficult for the agency to convene advisory committees for questions related to product approval. With review deadlines for priority-rated drugs set at 6 months (10 months for standard-rated drugs), the agency is hard pressed to complete its review, formulate its questions for the advisory committee, and then schedule the meeting within a timeframe that permits these 6-month deadlines to be met. Such committees typically must be scheduled 2 months in advance, so regulators cannot fully anticipate the questions or problems that they will encounter in the review process (DHHS and OIG, 2003; IOM Staff Notes,

16

It is precisely the practice of following advisory committee recommendations that makes the Plan B controversy so notable.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

2005–2006). The problem is mainly one of logistics, timing, and complying with the regulations for using special government employees, including the process for considering conflict of interest.

Some in the agency have suggested that the review deadlines have forced them to plan for advisory committee input too early in the process, before the questions to be presented have been fully developed and the appropriate expertise is fully recognized, and hence reduced the effectiveness of this important agency resource. Data also show that from 1998 to 2001 there was a 50 percent reduction in the agency’s use of advisory committees for approved NMEs and priority drugs (DHHS and OIG, 2003). NMEs and in particular priority-rated drugs are the most innovative and complex new drug products and have been shown to be associated with increased drug risks (Olson, 2004). Although reduction in product submissions has contributed in part to the decline in use of advisory committees, FDA managers indicate that they have little time to hold advisory committee meetings within the current review deadlines (DHHS and OIG, 2003:11–12). The reduction in the use of the committees has important implications for the agency. Reduction in input from informed independent experts may reduce the quality of the decisions and thereby lead to a reduction in public confidence in the agency. Reduction in use of advisory committees also reduces the public’s role in FDA decisions and reduces the transparency and perhaps the credibility of the regulatory decisions in the public’s mind.

4.8: The committee recommends that FDA have its advisory committees review all NMEs either prior to approval or soon after approval to advise in the process of ensuring drug safety and efficacy or managing drug risks.


The committee recognizes that it might be impossible for all NMEs to be reviewed by an advisory committee before approval, because of the time constraints described elsewhere. However, it believes that such review is important and allows for review of the drug after approval if preapproval review is not possible. If FDA is granted the authorities that the committee believes it should have (as described in Chapter 5), there will ample opportunity for useful input even after approval. Careful review of phase 4 study designs by advisory committees and/or by the public-private partnership should obviate concerns that giving CDER more control over phase 4 studies could be wasteful and inefficient. The goal is for better-designed studies that will be conducted and answer needed questions.

The committee has concerns about the composition of product-specific advisory committees. Traditionally a statistician serves on these committees, but other than Drug Safety and Risk Management (DSaRM) Committee, there is no guidance related to epidemiology or other public health expertise.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Because consideration of risk and benefit often depends on understanding the population perspective and review of observational studies and because drug safety problems are not reviewed only by DSaRM, the committee would like to ensure that the recommendations of advisory committees are based on a broad spectrum of disciplinary expertise.

4.9: The committee recommends that all FDA drug product advisory committees, and any other peer review effort such as mentioned above for CDER-reviewed product safety, include a pharmacoepidemiologist or an individual with comparable public health expertise in studying the safety of medical products.


In addition to concerns about advisory committee expertise and appropriate review, the committee shares concerns about the appearance of independence of advisory committees as it is affected by financial relationships of members with pharmaceutical or other private interests. In making the determination of whether a financial interest poses a conflict, FDA applies the terms of two statutes, 18 U.S.C. § 208, and 21 U.S.C. § 505(n). Under both, FDA may grant a waiver of any conflict of interest provided that some criteria are met. In addition, both statutes provide for public disclosure of financial interest information when a waiver has been granted (see 18 U.S.C. § 208(d)(1) and 21 U.S.C. § 355(n)(4)).

The guidance “FDA Guidance on Conflict of Interest for Advisory Committee Members, Consultants and Experts” describes the type and amount of information that is considered in deciding whether a financial interest presents a potential conflict of interest that needs to be merely disclosed or needs to be reviewed by the ethics staff for consideration of a waiver regarding a topic to be discussed by the advisory committee whose meeting the special government employee is attending (FDA, 2000). Table 4-2 describes key information considered as a level of financial interest that is transmitted to the ethics staff in a memo but does not require a waiver although it is disclosed to the public. For interests that exceed such levels, FDA uses a “sliding scale” to decide whether levels of conflict of interest are acceptable. Levels are different for participation in a “general matter”17

17

A particular matter of general applicability is a matter that is focused on the interests of a discrete and identifiable class of persons but does not involve specific parties. For example, a guidance document that affects an entire class of products and all similarly situated manufacturers is a matter of general applicability. In addition, the use of a potential product solely as a model or example for general discussion whose results will apply to a class of products may be a matter of general applicability.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

TABLE 4-2 Conflicts of Interest That Lead to a “Cover Memo” Only (Disclosure Required, but Waiver)

Type of Conflict of Interest

Party Matters

General Matters

Any Matter

Stocks and Investments

Stock value is less than or equal to $5,000 in aggregate (5 CFR 2640.202(a) de minimis exemption)

Stock value is less than or equal to $25,000 per entity/$50,000 in aggregate (5 CFR 2640.202(b) de minimis exemption)

 

Primary Employment

SGE is a federal employee and his agency, not his organizational component, is conducting research on the product under review—funding from the sponsor is less than $500,000/per year

Matters will not have a special or distinct effect on the SGE or employer, the committee’s decision may affect SGE/employer only as a part of a class of product manufacturers (5 CFR 2640.203 (g) exemption for non-Federal employment interests of SGEs on advisory committees)

 

 

 

SGE is a federal employee, and his agency is conducting research for one or more firms with an interest in the general matter before the committee

 

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Type of Conflict of Interest

Party Matters

General Matters

Any Matter

Consultant/Advisor

SGE receives less than $10,000 per source per year and consulting on unrelated issue in the past or completed within the past 12 months (all monies paid)

SGE receives less than $10,000 per source per year and consulting on related or unrelated issue completed within the past 12 months (all monies paid)

 

 

SGE receives between $10,000 and $50,000 per source per year and consulting on unrelated issue in the past or completed within the past 12 months (all monies paid)

SGE receives between $10,000 and $50,000 per source per year and consulting on related or unrelated issue completed within the past 12 months (all monies paid)

 

 

 

SGE receives more than $50,000 per source per year and consulting on related or unrelated issue completed within the past 12 months (all monies paid)

 

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Type of Conflict of Interest

Party Matters

General Matters

Any Matter

Contracts/Grants/CRADAs

Remuneration is less than $100,000 per source per year to institution/$10,000 per source per year as salary support to the SGE and work on unrelated product is currently active or completed within the past 12 months

Remuneration is less than $100,000 per source per year to institution/$10,000 per source per year as salary support to the SGE and work on unrelated matter is current or completed within the past 12 months

 

 

 

Remuneration is less than $100,000 per source per year to institution/$10,000 per source per year as salary support to the SGE and work on related matter has been completed over a year ago

 

 

 

Remuneration is between $100,000–$300,000 per source/year to institution/$10,000–$15,000 per source/year as salary support to the SGE and work on unrelated matter is current or completed within past 12 months

 

Patents/Royalties/Trademarks

SGE receives less than $15,000 in royalties per affected source annually and SGE has a patent on an unrelated product, licensed by a competing firm, and receives royalties

 

 

Expert Witness

 

Remuneration is less than $5,000 per affected source per year and SGE makes no statement for or against any product of a sponsor or competitor

 

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Type of Conflict of Interest

Party Matters

General Matters

Any Matter

Teaching/Speaking/Writing

 

 

SGE receives less than $5,000 per source per year and topic is unrelated to the particular matter and SGE receives no compensation

 

 

 

SGE receives less than $5,000 per source per year and topic is unrelated and SGE is compensated

 

 

 

SGE receives less than $5,000 per source per year and topic is related but SGE receives no compensation (including travel)

 

 

 

SGE receives less than $5,000 per source per year and topic is related but not specific to the matter under discussion by the committee and SGE is compensated

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

Type of Conflict of Interest

Party Matters

General Matters

Any Matter

Department Heads—Contracts/Grants/CRADAs

Remuneration is less than $300,000 per source per year to SGE’s department and work on unrelated matter is current or has been completed within the past 12 months

Remuneration is less than $300,000 per source per year to SGE’s department and work on unrelated matter is current or has been completed within the past 12 months

 

 

Remuneration is less than $300,000 per source per year to SGE’s department and work on related matter has been completed within the past 12 months and SGE had only an administrative role

Remuneration is less than $300,000 per source per year to SGE’s department and work on related matter has been completed within the past 12 months, and SGE had only an administrative role

 

 

Remuneration is between $300,000–$600,000 per source per year to SGE’s department and work on an unrelated matter is current or has been completed within the past 12 months

Remuneration is between $300,000–$600,000 per source per year to SGE’s department and work on unrelated matter is current or has been completed within the past 12 months

 

 

 

Remuneration is between $300,000–$600,000 per source per year to SGE’s department and work on related matter has been completed within the past 12 months and SGE had only an administrative role

 

Exceptions for Institutional Directors

The interests reported are unrelated to the product at issue or to the competing products (up to $750,000 per source per year)

 

 

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

and in a “party matter.”18 Higher levels of conflicting financial interests require review by the DHHS ethics office and are balanced against the need for a member’s expertise and unique contributions. Waivers can be granted for the participation of members who have more than minimal financial conflicts. That information is disclosed on the FDA Web site and is read at the start of each advisory committee meeting. No policies limit the number of advisory committee members receiving waivers who are allowed to vote on any specific matter.

A recent analysis of over 200 CDER advisory committee meetings held between 2001 and 2004 shows a weak association between the presence of advisory committee members with conflicts of interest and the outcome of votes to approve or not approve a drug for marketing (Lurie et al., 2006), which supports a perception in some that advisory committee functioning is less than independent. However, Lurie et al. acknowledge that “excluding advisory committee members and voting consultants with conflicts would not have altered the overall vote outcome at any meeting studied.” FDA responded to the article with additional analyses of the data reviewed by Lurie19 concluding “… advisory committee members and consultants with financial ties to pharmaceutical companies tend to vote against the financial interest of those companies” (FDA, 2006). The committee notes that concerns about voting patterns by waivered advisory committee members presume that a vote by someone with a waivered conflict of interest is a “wrong” or “incorrect” vote, but concludes that there is no evidence to suggest that this is necessarily so.

Although some have proposed that there be a zero-tolerance policy regarding conflict of interest on FDA advisory committees (H.R.2744 Sec. 795), others express concern that such a policy could lead to severely underinformed advisory committees or leave a very small pool of potential advisory committee members. The committee recognizes that many leaders in academic medicine with experience designing and conducting clinical trials receive research support from the pharmaceutical industry and that they conduct their research in an unbiased manner. The committee also recognizes that researchers who consult for industry gain important insights that are needed in the review process. However, not all researchers with some of the relevant expertise necessary for these advisory committees have current or recent industry funding (of consultancies or the conduct of clinical

18

A particular matter involving specific parties focuses on a specific product application or other matter affecting a specific manufacturer and its competing products or manufacturers (such as NDA, PMA, PLA or BLA, or efficacy supplement for a new indication). That is, it focuses uniquely and distinctly on a given product/manufacturer.

19

Including votes by advisory committee members with conflicts of interest related to relationships with companies that would be considered competitors to the drug whose approval was being voted upon.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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trials). NIH, for example, funds clinical trials, and investigators associated with those would bring necessary practical expertise to a drug products advisory committee. The committee also recognizes that financial conflicts are not the only conflicts that could influence votes. It is hard to screen out or to waive positions of intellectual bias (Stossel and Shaywitz, 2006). The committee supports narrowing the policies in place today but acknowledges the difficulties of convening sufficient experts for the numerous advisory committees that review drug products. The committee supports a position of nonwaivable limits, but not a zero-tolerance policy, for financial conflicts of interest on FDA drug-product advisory committees.

4.10: The committee recommends FDA establish a requirement that a substantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee’s deliberations. The committee supports 60 percent as a reasonable definition of substantial majority and believes that a reasonable definition of free of significant financial involvement are those involvements that currently require only disclosure and do not require a waiver (see Table 4.2 for a summary). The committee urges that FDA issue waivers for the participation of the other 40 percent of advisory committee members very sparingly. The committee also urges that FDA routinely analyze the effect of their conflict-of-interest policies in protecting the objectivity and quality of committee activities. The committee further urges that each posting of an advisory committee transcript be accompanied by a list of waivers granted and that FDA publish a yearly summary of the number of waivers granted per advisory committee.


Most members of advisory committees work in academic institutions, particularly medical schools and teaching hospitals, and policies of those institutions can help to protect the integrity of those who serve. That is particularly important because the pool of experts in pharmaceutical policy who are free of financial conflicts appears to be shrinking. Pharmaceutical support of research and other academic and medical activities is widespread—a fact that the committee views with some concern. In that vein, it would be helpful if all universities and nonprofit academic healthcare institutions promulgate and enforce rigorous conflict-of-interest policies governing academe-industry relationships on the part of their faculty and their institutional leaders. At a minimum, such policies should require disclosure in all publications, speaking engagements, and consultations with government of any relationships with the pharmaceutical and device industries. Policies should also conform with recommendations concerning

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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conflicts of interest developed by the Association of American Medical Colleges. All universities and nonprofit academic health care institutions should have standing conflict-of-interest review committees that are independent of their technology-transfer functions and are staffed by professionals who are experienced in managing conflicts of interest.

Transparency

All stakeholders in the drug safety system have a legitimate interest in understanding the data on which drug availability in the marketplace depends. Not all people are interested in firsthand knowledge of the science and depend on the decisions of others (such as their physicians and regulator) to assure them that drugs they take are safe and effective. Others wish to have more knowledge of the data. Many data are made public in some form, at some time, and at some place on the FDA or another government or industry Web site, but the process is not systematic, comprehensive, or well organized. The committee believes strongly in the importance of increasing the availability to the public and to researchers of information about drug risks and benefits, whether specific study results or analyses of concerns by agency staff, and it provides several recommendations related to clinical trial registration and results reporting, Web-site posting of all NDA-review packages, and timely public release of all CDER summaries of emerging data relevant to the safety and effectiveness of a drug after approval.

As described in Chapters 2 and 3, information related to the efficacy of drugs approved for use in the United States is examined in extensive detail in the reviews prepared by CDER staff. Most of those review packages are posted on FDA’s Web site and summarize a significant amount of data supporting the approval of the drug, yet these postings do not include the entirety of what is known about a drug. A sponsor’s NDA is not made public (even in redacted form to protect proprietary interests), and FDA reviews of an NDA are not made public if approval is not granted. Those reviews of unapproved NDAs could provide valuable information about a drug if the application is a supplemental NDA or if it is for a new member of a class of products already on the market. Although pharmaceutical companies are required to submit to FDA information about all studies conducted under an IND, results of studies that are not submitted as part of a sponsor’s application package for approval or are finished after approval are not necessarily disclosed to the public. There is no way to know the results of clinical trials involving a drug if those results are not submitted to the FDA as part of an NDA or other review package or are not published in the scientific literature.

Several important efforts in recent years are aimed at increasing the availability of at least a minimum of information about current or complet-

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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ed clinical trials. A recent Institute of Medicine (IOM) workshop provided a summary of the major initiatives by DHHS, the pharmaceutical industry, international medical journal editors, and the World Health Organization (WHO) (IOM, 2006). The requirement in the Food and Drug Administration Modernization Act of 1997 (FDAMA) that the federal government develop a way to register clinical trials of drugs intended to treat serious or life-threatening diseases led to the creation of ClinicalTrials.gov in the National Library of Medicine. Section 113 of FDAMA specifically requires companies to register a trial conducted under an investigational NDA if it is for a drug to treat a serious or life-threatening disease or condition and is a trial to test effectiveness (42 U.S.C. 282(j)(3)(A)). The trial must be registered no later than 21 days after enrollment is opened. Companies can register nonrequired trials in the databank as well. As of July 1, 2006, more than 30,000 trials have been registered on the site. PhRMA encourages its members to do so voluntarily for all hypothesis-testing20 studies required for the condition being studied.

This registry, which in recent years has won broad acceptance by industry, requires the completion of 20 data fields, developed by the WHO as a “minimum required dataset” for full registration, and provides regularly updated information about federally and privately supported clinical research in human volunteers. The minimum required dataset provides information about a trial’s purpose and the therapeutic agent being tested, its primary and secondary hypotheses and prespecified endpoint(s), who may participate, locations, and contact information for more details. It does not, however, include the results of the trials, nor does the registry program have the resources to do so.

In 2002, pharmaceutical companies that are members of PhRMA committed to voluntary disclosure of the results of hypothesis-testing clinical trials for marketed and investigational drugs; and in 2004, PhRMA launched the Web site ClinicalStudyResults.org for this purpose. A review of the site shows great variability in the ease of accessibility and completeness of the information. In addition, in the past few years many drug sponsors have created their own “registries” on company Web sites, which list their clinical trials, and may list summaries of trial results. These voluntary commitments may signify good intentions for increasing transparency, but the history leading to their introduction may, on the other hand, suggest that they may rather represent efforts to avoid mandatory disclosure of results.

20

“Also known as “confirmatory” clinical studies, hypothesis-testing studies are always well-controlled and are intended to provide meaningful results by examining pre-stated questions (i.e., hypotheses) using predefined statistically valid plans for data analysis, thereby allowing firm conclusions to be drawn to support product claims. Hypothesis-testing studies may occur at any stage of drug development and include all phase III studies, some earlier-phase studies, and many studies of marketed products” (Clinicalstudyresults.org, 2006).

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
×

4.11: To ensure that trial registration is mandatory, systematic, standardized, and complete, and that the registration site is able to accommodate the reporting of trial results, the committee recommends that Congress require industry sponsors to register in a timely manner at clinicaltrials.gov, at a minimum, all phase 2 through 4 clinical trials, wherever they may have been conducted, if data from the trials are intended to be submitted to the FDA as part of an NDA, sNDA, or to fulfill a postmarket commitment. The committee further recommends that this requirement include the posting of a structured field summary of the efficacy and safety results of the studies. The committee does not offer specific details regarding this summary, preferring that NIH and FDA, in consultation with the pharmaceutical industry, should work together to agree on a reasonable plan.21 However, the committee suggests that mandatory fields could include, but are not limited to, (1) primary hypothesis, (2) experimental design, (3) primary predefined outcome measure(s), (4) planned and actual sample size per treatment arm, (5) number and type of serious AEs, (6) overview of results, and (7) risk-benefit summary. The company should have the responsibility of submitting the structured field summary to the FDA, who should review it for completeness and accuracy. The information should then be posted either on an easily accessible Web site at FDA with linkage to the trial’s registration on clinicaltrials.gov, or posted directly on the latter.


For those clinical trials covered by this recommendation, every completed trial would have to comply with this mechanism of results reporting, regardless of trial outcomes. For every covered trial that is stopped before prespecified completion, the sponsor would have to submit a summary describing the reasons for termination (Drug Safety Management Board action, economic considerations, etc.) to FDA/NIH for review and posting. The committee did not attempt to resolve what to do about postmarket studies conducted by investigators independent of industry. If these studies are federally funded, the funding agency could require as a condition of award that the lead investigators prepare and submit the structured summary to clinicaltrials.gov after publication of the study. Enforcement mechanisms for studies not conducted under federal grant/contract support are less clear. The committee believes that to ensure that results to be posted

21

Because the committee is not suggesting that raw data be posted, this recommendation should provoke no concerns regarding patient privacy. The committee recognizes that this recommendation will require significant additional resources to NIH, which runs clinicaltrials.gov, and to FDA, for their role in developing the results format and vetting the submissions.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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that are not vetted by the FDA are described completely, accurately, and in an unbiased manner, clinicaltrials.gov would have to establish some form of editorial review process. The National Library of Medicine, which runs clinicaltrials.gov, will need to be provided the necessary authorization and resources to accommodate results posting.

The format of clinical trial registration and results reporting should be done in a way that harmonizes with emerging international standards (such as those specified by WHO, for example, the minimum required dataset for registration, and the requirements for results reporting, in the ICH E3 Summary of Clinical Trial Results). The committee notes with interest the recent WHO call for registration of all interventional trials. The committee strongly urges the Congress to consider the status and benefits of harmonization with international standards when drafting legislative language to implement this recommendation.

The committee also encourages further steps to make drug safety and effectiveness information available to the public. The committee believes that CDER is the appropriate body to assume the responsibility for sharing important safety and efficacy information promptly and dependably with patients, providers, and researchers. One important source of this information at the time of approval is the NDA review package.

In response to the Electronic Freedom of Information Act Amendments of 1996, which were designed to broaden public access to government documents in electronic form, CDER posts NDA review packages22 on its Web site (at the “drugs@fda” portion of the site http://www.accessdata.fda.gov/scripts/cder/drugsatfda/). As of April 2006, review packages for NMEs approved from 1998 to the middle of February 2006 and non-NMEs approved in 1998–2001 are posted. There is a backlog for posting review packages for non-NMEs approved after 2001.23 All other NDA approval documents (that is, for drugs approved before 1998 and for all supplements) are posted on completion of a Freedom of Information Act (FOIA) request for that information (D. Henderson, personal communication).

4.12: The committee recommends that FDA post all NDA review packages on the agency’s Web site. Regardless of whether they were disclosed in response to a FOIA request, FDA should post all supplemental-NDA review packages and continue to work to post reviews for drugs approved before 1998 in a timely manner and as

22

Review packages are described in Chapters 2 and 3 and refer to the set of documents prepared by CDER staff. These packages provide the summary judgment that leads to decisions regarding approval.

23

Of 531 non-NME NDA approvals since 2001, 397 had been posted on the Web as of March 31, 2006, as had all the non-NME NDAs approved in 1998–2001.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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resources allow. High priority should be given to posting all review materials related to any product for which there are emerging safety concerns, particularly if they have been discussed at an advisory committee meeting.


OND and ODS/OSE staff prepare reviews or summaries of RiskMAPs and other postmarket safety information and, if discussed at an advisory committee meeting, these reviews are made public in accordance with the Federal Advisory Committee Act; however, reports of general ODS/OSE consultations are not, as a rule, made public. In 2005, ODS/OSE completed 439 reviews of postmarket safety issues (generated in ODS/OSE or as a result of consultations for OND). Materials from advisory committees are found on a portion of the CDER Web site distinct from that where the NDA reviews are posted. There is no one place where every public document regarding a specific drug is posted.

The committee recognizes that public disclosure of every internal document discussing a potential safety problem has drawbacks. Any one document likely describes only one aspect of a complicated topic. Full disclosure of those documents in real time could be confusing to the public and does not necessarily contribute to reducing the uncertainty about the risks and benefits associated with a drug. However, there is a marked imbalance between the disclosure of data accumulated before approval (the CDER discipline reviews) and disclosure of data summarized and presented after approval. The synthesis by CDER of postmarketing information that is made public about risks and benefits is minimal. The committee believes that CDER has a role to play in putting forth the views of the regulatory agency about emerging information and should not leave that task in the hands of the pharmaceutical industry or the academic community.24 Periodic and regular review by CDER of risk and benefit information is consistent with a lifecycle approach to drug regulation.

4:13: The committee recommends that the CDER review teams regularly and systematically analyze all postmarket study results and make public their assessment of the significance of the results with regard to the integration of risk and benefit information.


Drug regulation must follow scientific advances; as science progresses, so must regulation. The role of the regulator is not to impede the develop-

24

Product safety specialists from the Center for Biologics Evaluation and Research routinely develop reviews of the postmarket safety experience with a new vaccine within 2–3 years of the time the vaccine is licensed. These reviews are published in journals and are available on the FDA Web site’s VAERS (Vaccine Adverse Event System) page.

Suggested Citation:"4 The Science of Safety." Institute of Medicine. 2007. The Future of Drug Safety: Promoting and Protecting the Health of the Public. Washington, DC: The National Academies Press. doi: 10.17226/11750.
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ment of innovative medicines, but to ensure that needed drugs are available to patients and that risk-benefit information is accurate and widely available. The regulator must be the gatekeeper of the scientific foundation on which regulatory decisions are made. CDER must have the best data to review and an expert scientific staff to review them. Patients and their physicians must be assured that the scientific foundation on which CDER regulates drugs is credible.

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In the wake of publicity and congressional attention to drug safety issues, the Food and Drug Administration (FDA) requested the Institute of Medicine assess the drug safety system. The committee reported that a lack of clear regulatory authority, chronic underfunding, organizational problems, and a scarcity of post-approval data about drugs' risks and benefits have hampered the FDA's ability to evaluate and address the safety of prescription drugs after they have reached the market. Noting that resources and therefore efforts to monitor medications' risk–benefit profiles taper off after approval, The Future of Drug Safety offers a broad set of recommendations to ensure that consideration of safety extends from before product approval through the entire time the product is marketed and used.

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