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



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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.”

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public 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.

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