2
Natural History of a Drug

This chapter describes some key steps in reviewing potential new therapies and monitoring drugs once they are in the marketplace, with an emphasis on how safety considerations are handled throughout the process. The elements of the drug regulatory system have been well described elsewhere (Lipsky and Sharp, 2001; Randall, 2001; Meadows, 2002; FDA, 2006c). The committee also reviewed some of the factors that shape how the understanding of a drug’s safety and efficacy profile evolves during the lifecycle and what regulatory action is taken. Those factors include scientific uncertainty; resources at the Food and Drug Administration (FDA); statutory requirements, including both limitations in authority and deadlines that shape the timing and scope of regulatory activities; and workload and staffing.

This discussion is intended to provide a reference point for subsequent chapters that provide the committee’s findings about the strengths and weaknesses of the drug safety system and recommendations for strengthening it. A number of the points addressed in this chapter are related directly to the committee’s recommendations. The material in this chapter is drawn largely from Center for Drug Evaluation and Research (CDER) documents—both guidance documents for sponsors and internal manual of policies and procedures that describe a wide variety of official policies—and from conversations with current and former FDA staff.

CDER reviews various types of drug applications and supplements. This chapter focuses on New Drug Applications (NDAs), although some of the processes also apply to supplemental NDAs, which are most often submitted for new indications of approved drugs. The chapter traces the



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The Future of Drug Safety: Promoting and Protecting the Health of the Public 2 Natural History of a Drug This chapter describes some key steps in reviewing potential new therapies and monitoring drugs once they are in the marketplace, with an emphasis on how safety considerations are handled throughout the process. The elements of the drug regulatory system have been well described elsewhere (Lipsky and Sharp, 2001; Randall, 2001; Meadows, 2002; FDA, 2006c). The committee also reviewed some of the factors that shape how the understanding of a drug’s safety and efficacy profile evolves during the lifecycle and what regulatory action is taken. Those factors include scientific uncertainty; resources at the Food and Drug Administration (FDA); statutory requirements, including both limitations in authority and deadlines that shape the timing and scope of regulatory activities; and workload and staffing. This discussion is intended to provide a reference point for subsequent chapters that provide the committee’s findings about the strengths and weaknesses of the drug safety system and recommendations for strengthening it. A number of the points addressed in this chapter are related directly to the committee’s recommendations. The material in this chapter is drawn largely from Center for Drug Evaluation and Research (CDER) documents—both guidance documents for sponsors and internal manual of policies and procedures that describe a wide variety of official policies—and from conversations with current and former FDA staff. CDER reviews various types of drug applications and supplements. This chapter focuses on New Drug Applications (NDAs), although some of the processes also apply to supplemental NDAs, which are most often submitted for new indications of approved drugs. The chapter traces the

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The Future of Drug Safety: Promoting and Protecting the Health of the Public work of the NDA review process in CDER’s Office of New Drugs (OND) and its offices of drug evaluation which conduct premarket reviews, and in CDER’s Office of Drug Safety (ODS) (which is now called the Office of Surveillance and Epidemiology, OSE, because of a restructuring of CDER in May 20051) and its Division of Drug Risk Evaluation (DDRE), which monitors postmarket risks and undertakes risk assessments. (Other divisions and offices of ODS/OSE address safety issues, such as medication errors and drug names.2) The chapter does not address Abbreviated NDAs for generic drugs that go through CDER’s Office of Generic Drugs. Nor are drugs that are on special tracks, such as accelerated approval or orphan-drug status, specifically addressed in this general description of how a new drug moves through the system. Economic Impact of Drugs Prescription drugs play a major role in American health and economy. For example, prescription drugs for controlling blood pressure and blood cholesterol levels were partly responsible for one of the ten great public health achievements of the 20th century: the 5 percent decline in death rates for coronary heart disease since 1972 (CDC, 1999). Prescription drugs are among the innovations that have replaced some highly invasive measures (such as surgery) with less invasive preventive and health maintenance therapies (DHHS, 2002). Prescription drugs also can help reduce health care costs by decreasing hospitalization. National survey data show that 44 percent of Americans take at least one prescription drug in any given month (NCHS, 2004). In economic terms, the investment and return on investment of drug discovery and development are vast. Although methodologies used for estimating the cost of bringing a drug to market are a matter of some controversy, some estimates are provided here as an illustration (Epstein, 2004). The cost of drug development has been estimated at approximately $800 million and at between $500 and $2,000 million (DiMasi et al., 2003; Adams and Brantner, 2006). The Bain report provided the estimated cost of development at $1.7 billion (Gilber et al., 2003). In 2005, the biopharmaceutical industry spent approximately $51.3 billion in drug discovery and development (PhRMA, 2006). A great deal is spent on prescription drugs. Due to cost-containment strategies, the rate of increase of spending on prescription drugs has slowed down, but still totaled $179.2 billion in 2003, and comprised 11 percent of national health spending (Kaiser Family Foundation, 2005; Smith et al., 2005). 1 For the remainder of this chapter, we will refer to this office as ODS/OSE. 2 Division of Surveillance, Research and Communication Support and Division of Medication Errors & Technical Support.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public THE INVESTIGATIONAL NEW DRUG As discussed in Chapter 1 and throughout the report, FDA has initiated or is initiating many changes related to drug safety in its internal procedures and organization. Some of the changes may supersede the descriptions in this chapter. Also on the horizon is FDA’s Critical Path Initiative, announced in 2004, which is intended to stimulate the development and use of new scientific tools to better assess the safety and effectiveness of drugs under study (FDA, 2004a; DHHS/FDA, 2006). Investigational New Drug Submission and Review The vast majority of chemical molecules and candidate drugs screened for therapeutic potential and toxicity never show sufficient promise to enter human trials (PhRMA, 2006). But when preclinical data indicate that a compound is reasonably safe for initial testing in humans, shows promising pharmacologic activity, and has commercial prospects, the sponsor submits an Investigational New Drug (IND) Application to FDA, and the agency’s oversight begins (FDA, 2006c). IND sponsors can be companies, research institutions, or individual investigators. Often the sponsor has been in frequent contact with FDA throughout the development process prior to submission of the IND, and has participated in FDA’s pre-IND consultation program (FDA, 2006c). FDA produces numerous guidance documents to steer sponsors through the regulatory process. Those documents are prepared and updated continually. Some are very specific, for example, describing appropriate methods for a specific type of study; others provide more general guidance about preparing submissions to the agency (FDA and CDER, 2006b). Some reflect international harmonization efforts among European, Japanese, and US regulators. The average new commercial IND submission totals about 28 volumes of about 500 pages each—about 14,000 pages (Henderson, 2006). It contains manufacturing and chemical information about the drug and the results of animal tests, toxicology studies, and other preclinical tests. The IND also contains protocols for small phase 1 human studies intended to document the drug’s metabolism and excretion, determine a safe dose, and identify acute side effects (FDA and CDER, 2006b). Local institutional review boards (IRBs) must review the protocols to ensure protection of human subjects. If a sponsor has already begun human trials outside the United States, it also includes their results. By law, FDA has 30 days from the date an IND is received to place a hold on the proposed human trials (FD&C Act, SEC. 505(i)(2)) if it deems it to be necessary. CDER can take up to about 2 weeks of that period to process the IND, assign it to a review division within OND on the basis of

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The Future of Drug Safety: Promoting and Protecting the Health of the Public the drug’s likely indication, and assemble a review team. The team includes a project manager and several scientific reviewers from OND and other CDER offices as required (CDER et al., 1998). The reviewers then have the remainder of the 30-day period to determine whether safety concerns justify placing a hold on the human trials. In the absence of FDA action to delay or prevent a trial, the sponsor can begin testing the compound in humans on day 31 (FDA and CDER, 2006b). FDA typically allows human trials to proceed if no serious safety concerns have surfaced (FDA and CDER, 2001a). As occurs throughout the review process, safety assessments and regulatory actions are influenced by evidence of the potential benefit of the product. For example, reviewers are likely to tolerate a higher threshold of toxicity for a drug that will be used to treat life-threatening cancer than for a new antihistamine similar to those on the market. Early Clinical Trials and Related Studies The sponsor typically begins phase 1 trials by testing several increasing dosages in healthy volunteers (see Box 2-1 for definitions of all phases of clinical trials). About 20–80 subjects are usually involved in one or more of these trials (FDA, 2006c). Animal and other toxicology studies and phase 1 studies may be concurrent. If the initial phase 1 results do not show unacceptable toxicity, the sponsor moves to larger, phase 2, trials which involve from a few dozen to hundreds of patients who have the condition for which the drug is being studied (CDER et al., 1998; FDA, 2006c). Efficacy and safety are evaluated by continuing to test various dosages of the compound in patients (FDA, 2006c). Clinical trials are conducted under the sponsor’s auspices by commercial, academic, or other entities in the United States or, increasingly, overseas. In trials, an active product is compared with a placebo or occasionally with an existing drug for the condition (FDA, 2006c). Sponsors increasingly include genetic studies in the premarket period as part of a personalized-medicine approach to identifying target populations for a drug. The developing science of pharmacogenomics is generating strong interest and attention in and outside FDA as a way to improve drug safety through predictive techniques, but any widespread use of these techniques in clinical practice is well into the future. Sponsors develop study protocols and undertake, fund, and oversee studies. The OND review team and sponsor consult as the trials and studies are under way, new protocols are developed, and new data emerge. The review team can play a critical role in how the studies proceed. The extent of consultation varies among drugs and sponsors. The sponsor is required to notify FDA and all investigators in written safety reports of “any adverse

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 2-1 Phases of Clinical Trials and Medicine Development Phase 1 Clinical pharmacology studies in healthy volunteers (sometimes subjects) to determine the safety and tolerability of the drug/product, other dynamic effects, and the pharmacokinetic profile (absorption, distribution, metabolism, and excretion). Phase 2 Clinical investigation studies in subjects with the target disease, to determine efficacy, safety, and tolerability in carefully controlled dose-ranging studies. Phase 2 studies are typically well controlled and closely monitored. Phase 3 Formal clinical trials. Large-scale placebo controlled and uncontrolled studies in subjects to gather further information on efficacy and on the safety and tolerability of the drug or product. Phase 4 Postmarketing surveillance to expand safety and efficacy data in a large population, including further formal therapeutic trials and comparisons with other active comparators. SOURCE: Adapted from 21 CFR 312.21 (2005). experience associated with the use of the drug that is both serious and unexpected” or “any finding from tests in laboratory animals that suggests a significant risk for human subjects including reports of mutagenicity, teratogenicity, or carcinogenicity” (21 CFR 312.33). The sponsor also submits annual progress reports on the IND to FDA. The regulators may direct the sponsor to undertake specific studies or laboratory evaluations in studies to look for possible markers of safety problems (such as liver toxicity or cardiovascular changes) on the basis of previous experience or questions about the class of drugs or the mechanism of action. End of Phase 2 Meeting and Phase 3 Trials If the results of the early trials are promising, the sponsor and the review team typically meet for an “end of phase 2 meeting” to discuss the upcom-

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The Future of Drug Safety: Promoting and Protecting the Health of the Public ing phase 3 trials. The phase 3 trials can involve fewer than 100 patients in some cases or many thousands in others, depending on the target population and the endpoints being evaluated (on the average, they involve about 600–3,000 patients). The drug is tested against a placebo or sometimes against another drug (FDA, 2006c). The trials are designed and powered to evaluate selected efficacy outcomes, not safety end points, although they can generate safety signals to pursue. The “end of phase 2 meeting” can be an important early point in the lifecycle of the drug to identify and track potential safety issues and to ensure that the sponsor’s protocols address key questions. Roles of the Office of New Drugs and the Office of Drug Safety/Office of Surveillance and Epidemiology Premarket Period OND is responsible for premarket reviews, makes approval decisions, and retains authority for regulatory decisions after a drug is marketed. OND clinical reviewers typically are physicians, some with epidemiology training, who are skilled in review of clinical trials. DDRE staff are mostly pharmacists and epidemiologists whose expertise tends to be in observational studies and whose primary focus has been on monitoring and evaluating postmarket data. Traditionally, the OND review team has drawn on ODS/ OSE, and particularly DDRE, as safety consultants when they determined a need for a specific safety review. DDRE staff routinely participate in a limited number of premarket activities; they have historically functioned in a consultation capacity to OND, called on to perform specific safety reviews. In a recent report on postmarketing drug safety, the Government Accountability Office characterized ODS/OSE as a consultant to OND in the postmarket period and described a problematic working relationship between the two offices (GAO, 2006). In its official response to that report, FDA asserted that the “consultant” term understates the importance of ODS/OSE and referred to the agency’s efforts to “foster a partnership” between ODS/OSE and OND that makes them equals in the postmarket identification and timely resolution of drug safety issues (GAO, 2006). FDA’s recent efforts to integrate the work of the two offices better may also extend to the premarket period. Chapter 3 discusses the challenges in the OND and ODS/OSE relationship and recent efforts to address them. One of the 17 drug-evaluation divisions (see organization chart), the Division of Neurology Products (DNP),3 has a safety team in the unit. The 3 DNP and the Division of Psychiatry Products were combined in the past and were separated in the 2005 reorganization of OND. They both continue to use the safety team, which now officially reports to DNP.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public safety team’s role is to quantify and set priorities among potential risks posed by the drug they are reviewing. They do not make recommendations on a drug’s approvability (Racoosin, 2006). The committee was told that discussions have occurred in FDA about including a full-time safety officer in the other ODS/ODE divisions. Two possible explanations for why that has not occurred were offered: shortage of safety officers and the fact that some divisions do not review enough applications to support a full-time safety officer. Completion of Clinical Trials and Their Limitations Clinical trials typically take 2–10 years to complete (PhRMA, 2006), depending on such factors as the rate of the event of primary interest, the length of patient followup, the staging of trials, and the difficulty of accruing patients. When data from phase 2 trials seem extremely promising, particularly in the context of serious or life-threatening diseases or conditions, an NDA may be filed without proceeding to or completing phase 3 trials.4 For example, azidothymidine (AZT) was approved for treatment of HIV infection on the basis of phase 2 trials (Grassley et al., 2004). Only about 20 percent of drugs that enter phase 1 trials go on to be approved and marketed (lower estimates have been provided by others so the true percent is unknown) (DiMasi et al., 2003; PhRMA, 2006). A sponsor may decide to halt trials for various scientific or commercial reasons. A recent study found that the number of clinical trials being conducted in the United States leveled off in 2000 and then started to decline in 2002. The author attributes the decline to cancellation of late-stage trials (Kaitin, 2005). Even when a sponsor completes its trials and submits the resulting data in support of an NDA, important safety information about the drug is not yet available. That point is essential for an understanding of the drug regulatory system and the incomplete safety profiles of the drugs that enter the marketplace. The gaps in critical information, such as safety data, are due to a number of factors, including the limited number of subjects studied and the ways in which the subjects and the research setting differ from the conditions of use when the drug is marketed (CDER et al., 1998). Preapproval trials typically are too small to detect even significant safety problems if they are rare. An adverse event (even a serious one) that occurs in less than one in 1,000 patients cannot be reliably detected except in the largest premarket trials but can pose a serious public health problem when hundreds of thousands 4 FDA may grant accelerated approval on the basis of surrogate endpoints, but approval is conditional on sponsors’ undertaking or completing validation trials.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public or millions of people use the drug (GAO, 1990; Okie, 2005; Racoosin, 2006). For example, bromfenac, a non-steroidal anti-inflammatory drug (NSAID) marketed for 11 months in 1997–1998, was found to have serious and sometimes fatal liver toxicity in about one in 20,000 people who used the drug (Friedman et al., 1999); the NDA clinical trial base would have had to include 60,000 patients to detect such an effect before marketing (Friedman et al., 1999). Preapproval clinical trials also have little information on the effects of long-term exposure to the drug due to their often short duration. Furthermore, clinical trials usually do not represent the full array of patients who will use the product once it is approved. Trials often exclude patients with comorbidities or those taking other medications, although both may be common among future users of the marketed drugs. Elderly patients, ethnic and racial minorities, and the very sick are underrepresented, and pregnant women are generally excluded from trials. Drugs generally have not been tested in children as part of the NDA, although patent-extension incentives are aimed specifically at encouraging pediatric testing in children (Meadows, 2003). Those limitations are inherent in the system and cannot be changed without adding considerably to the time and expense of drug approvals, which would delay patient access to potentially beneficial drugs. It is generally understood that it is not routinely realistic to require premarket trials on tens or hundreds of thousands of subjects. Thus, inherent in the fundamental design of the drug approval system is the delayed availability of important safety data until a drug is used in larger and more diverse populations after marketing. That approach means that the initial postmarket period is a critical time for developing a fuller understanding of a drug’s safety profile. Premarket clinical trials are designed primarily with efficacy. Safety issues sometimes surface, but the challenge is the possibility of unusual, unexpected, undocumented risk. If sponsors and CDER reviewers are not vigilant about identifying and pursuing safety signals in the trials, the opportunity to evaluate safety in the premarket trial period may be lost. In the premarket period there usually is a shortage of information on how a new drug compares with other treatments for the same indication. Sponsors are not routinely required to submit such comparative trials to obtain approval. Once a drug is on the market, it can be difficult to compel sponsors or others to undertake appropriate comparative trials. Sponsors usually do not initiate such trials unless they believe that their product has a readily identified or demonstrable advantage. A postmarket comparative trial of newer hypertension agents—angiotensin-converting enzyme (ACE) inhibitors—against older diuretic drugs, for example, found the older drugs to be more effective in reducing blood pressure (Appel, 2002). In addition, comparative trials are expensive, and cost-benefit considerations are not

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The Future of Drug Safety: Promoting and Protecting the Health of the Public part of FDA’s statutory purview. (Chapter 4 addresses this topic in greater detail.) Thus, premarket studies typically do not answer questions of great concern to health care providers, patients, and payers: Which drug in a class works work best for most patients? Which is the best first line of treatment? Which is most cost-effective? By definition, premarket trials do not address the implications of expansive off-label use, that is, use for conditions in which the given compound was not studied (or not approved) in tests submitted to FDA (Beck and Azari, 1998). A recent study found that 21 percent of the 725 million prescriptions written in 2001 were for off-label uses (Boodman, 2006). Pre-New Drug Application Submission Meeting As trials are completed and analyzed, the sponsor meets with the review team to go over the impending NDA submission; it is in the sponsor’s and FDA’s interest to anticipate issues so that the NDA is complete when submitted. For example, a 2006 report indicated that when sponsors met with CDER staff before submitting an NDA, there was a greater likelihood that the drug was approved on the first cycle (FDA News, 2006b). According to FDA documents, the discussions include development of strategies to manage known risks (CDER, 2005b). ODS/OSE staff sometimes participate in the meetings; it may be the first time that ODS/OSE staff become involved in the IND. (When OND is reviewing a supplemental NDA for new labeling or manufacturing, ODS/OSE may be active in reviewing available postmarket data on the approved indication.) NEW DRUG APPLICATION In the last couple of years, FDA has received 110–120 NDAs per year (FDA and CDER, 2005). The average size is 235 MB with 250 files, the equivalent of almost 400 volumes of 500 pages each, or about 200,000 pages (Henderson, 2006). Often, an NDA does not arrive all at once—FDA allows gradual submission for fast track5 studies (rolling review). Sponsors are also required to provide additional data that become available during the review process. Data management is a critical task with a project of this size. Scientific reviewers need sophisticated knowledge of and access to programs for managing and analyzing the data. In addition, because sponsors have some 5 “Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases” (FDA, 2006c).

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The Future of Drug Safety: Promoting and Protecting the Health of the Public leeway in how they present their summary safety and efficacy data and where in this massive file they are found, reviewers must sometimes devote considerable time to finding the critical safety data needed for the review. ODS/OSE involvement is typically limited to meeting attendance and providing consults at this point in the process. The arrival of data on a rolling basis can further complicate the process. Sponsors can submit materials to the NDA fewer than two dozen times, as was the case with cinacalcet hydrochloride6 (Meyer, 2004), or as many as 70 (or even more) times, as occurred with sibutramine7 (Bilstad, 1997). Prescription Drug User Fee Act Timetables and Performance Goals Triggered When FDA receives the final piece of an NDA the Prescription Drug User Fee Act (PDUFA) clock begins ticking (FDA, 2005f). PDUFA was enacted in 1992 and reauthorized in 1997 (PDUFA II) and 2002 (PDUFA III). It is up for reauthorization in 2007. The law provides for the pharmaceutical industry to pay user fees to FDA to be used primarily to staff and resource new drug (and biologic) review divisions, in exchange for which FDA agrees to expedite drug reviews according to specific timetables. PDUFA has also established deadlines to expedite the premarket review process, to schedule meetings requested by industry, resolve disputes, to respond to questions about study protocols, and develop guidances (see Box 2-2 and Appendix C for the goals, and see Chapter 3 for additional discussion of PDUFA). The PDUFA II and III goals call on FDA to review and act on 90 percent of standard original NDAs within 10 months and 90 percent of priority NDAs in 6 months. A priority NDA review is intended for drugs that “represent significant improvements compared with marketed products” (FDA and CDER, 2005). PDUFA has resulted in a dramatic decline in new drug review time. For standard NDA reviews, the median FDA review time was 11.9 months in 2004, down from 20.8 months in 1993 (FDA, 2005d; CDER, 2006). For priority NDA reviews, the median review time was 6.0 months in 2004, down from 16.3 months in 1993 (Weiss Smith, 2006). Initial Filing Review CDER does an initial review of an NDA to determine whether it is acceptable for review. Within 60 days, CDER informs the sponsor if there are 6 Sponsor submitted data to FDA 19 times from September 8, 2003, through March 5, 2004. 7 Sponsor submitted data to FDA 85 times from August 7, 1995, through November 22, 1997.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public substantive deficiencies in the file that cause FDA to “refuse to file” the application (CDER et al., 1998). That occurs when the NDA has such critical deficiencies that it clearly is not approvable as submitted. When submitted, the NDA is also designated as a standard (10-month timetable) or priority (6-month timetable) review by the division office or office director. A minority of NDAs have been designated as priority reviews. In 2004, for example, 29 of the 119 NDAs submitted were priority reviews, and the remaining 90 were standard reviews. Most priority reviews involve new molecular entities (NMEs). An NME is defined as “a medication containing an active substance that has never before been approved for marketing in any form in the United States” (FDA and CDER, 2001b). Of the 119 NDAs submitted in 2004, 36 were for NMEs, and 21 of these were assigned priority status. (See Table 2-1 for past NME priority and standard approval numbers.) Assembly of Review Team and Beginning of Review Within about 2 weeks of receiving an NDA, CDER names a review project manager and primary scientific reviewers. Although reviewers who were involved with the IND are strong candidates for the review, the team does not necessarily include all those involved earlier. Some members of the original team may be too busy with other work, may have moved on to other positions, or may have left FDA. Reviewers’ workloads typically include premarket reviews and supplemental NDA reviews and issues arising with marketed drugs that they previously reviewed. They may also be involved in writing guidance documents or may be participating in other CDER or FDA initiatives; in the wake of highly publicized concerns about safety, CDER has launched a number of initiatives in the last year to evaluate, articulate, and improve procedures. Obstacles in hiring new staff due to a change in Department of Health and Human Services human resources policies have placed added strain on the workforce. The review team includes OND staff with expertise in various medical and scientific specialties—including clinical medicine,8 pharmacology, and toxicology—and CDER reviewers from outside OND with expertise in such fields as chemistry, manufacturing and controls, microbiology, and statistics. In some cases, outside experts (special government employees) may participate in reviews (CDER et al., 1998; FDA, 2006c). In consultation with the clinical team leader and perhaps other team members, the primary clinical reviewer will ultimately be responsible for 8 There are inconsistencies in CDER documents in the use of medical review or clinical review. They appear to be interchangeable terms. It has been suggested that use of clinical review indicates that a primary reviewer need not necessarily be a physician, although most of them are. In this report, we will use the more inclusive term clinical review or clinical reviewer.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public BOX 2-5 Adverse Event Reporting in 2004 In 2004, FDA received 422,889 reports of suspected drug-related adverse events: 21,493 MedWatch reports directly from individuals (patients or providers). 162,107 manufacturer 15-day (expedited) reports. 89,960 serious manufacturer periodic reports. 149,329 nonserious manufacturer periodic reports. SOURCE: FDA and CDER (2005). Union, where electronic reporting to the European Medicines Agency has been mandatory since November 2005, over 90 percent of adverse reactions involving European-authorized medicines have been electronically reported by manufacturers. ODS/OSE safety officers are expected to review the “15-day reports” when they arrive. They continually review incoming reports from MedWatch, redirecting those related to other regulated products, and contractors enter all the MedWatch reports into AERS. Some adverse events (AEs) from companies, such as those in periodic reports for drugs that have been approved for more than 3 years or those considered non-serious, are not are routinely entered into AERS. The structure of the AERS database complies with a guidance issued by the International Conference on Harmonisation (ICH E2B). FDA codes AEs with a standardized international terminology, the Medical Dictionary for Regulatory Activities (MedDRA). AERS allows for the on-screen review of reports, the use of searching tools, and various output reports. FDA is making limited use of data mining software to identify early drug safety signals in the AERS database via automated searching. AERS is an important component of the postmarket surveillance system, particularly for identifying unexpected and rare adverse events (Rodriguez et al., 2001). For example, aplastic anemia and the rare skin disorder Stevens-Johnson syndrome have been linked to drugs through AE reporting (FDA, 1994). However, AERS is not efficient in distinguishing between signal and noise from adverse events, such as heart disease, which has a high background rate in the population (see Chapter 4 for a more comprehensive discussion). Some of the limitations of AERS data are the lack

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The Future of Drug Safety: Promoting and Protecting the Health of the Public of denominator data on number of users to delineate the frequency of an event, lack of control groups, recall bias of patients and reporters, poor case documentation in the reports (critical details that could contribute to an understanding of an event are missing), and substantial underreporting of AEs (Ahmad et al., 2005). Other Postmarket Data Although AERS data may provide the initial signal of a safety problem, other studies and databases are typically needed to investigate associations. Those data include results of clinical trials and epidemiologic studies that are conducted, or whose results are available, after a drug is approved. The sponsors’ phase 4 trials are intended to expand the understanding of the safety and efficacy profile, of selected drugs. However, many of these studies are not completed (or even begun), for various reasons described above. FDA lacks the regulatory tools to adequately compel sponsors to complete appropriate studies (see Chapter 5 for more information). According to a March 2006 report, out of 1,231 agreed-on (by the sponsor) open postmarket commitments of drugs and biologics, 797 (65 percent) have yet to be started12 (FDA, 2006d). Another source of postmarket safety data is studies of marketed drugs designed to investigate new or expanded indications. Sponsors may include these studies in an efficacy supplement submitted to FDA seeking expanded label indications. Sometimes these studies may yield important data. For example, the APPROVe (Adenomatous Polyp Prevention on Vioxx) trial was designed to identify a new application for rofecoxib and showed an increased risk of serious cardiovascular events with rofecoxib compared with placebo—this cardiovascular impact was a secondary consideration (FDA, 2004b). Post-marketing safety information may also be generated by sponsors through the establishment of active surveillance systems, such as pregnancy-exposure registries (Ackermann Shiff et al., 2006). The National Institutes of Health (NIH) or other agencies may also sponsor trials to gain new information about marketed drugs. Examples are the NIH-funded randomized controlled primary prevention trial, the Women’s Health Initiative, which reported on adverse health effects of and benefits from use of combined estrogen and progestin (Rossouw et al., 2002). An earlier NIH-funded study, the cardiac arrhythmia suppression trial, found that drug treatment for asymptomatic ventricular arrhythmia in patients who had a heart attack did not prevent—and in fact substantially increased the risk of—sudden cardiac death. FDA had used a drug’s effect on 12 231 (19%) are ongoing; 28 (2%) are delayed; 3 (1%) have been terminated; 172 (14%) have been submitted.

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The Future of Drug Safety: Promoting and Protecting the Health of the Public arrhythmia as a surrogate marker of efficacy, but although the drug reduced arrhythmia, it also increased cardiac death (NHLBI, 2005). Additional information on the safety of marketed drugs may come from large, automated databases. FDA purchases access to some of those databases as a resource for pharmacoepidemiologic studies designed to test hypotheses, particularly those arising from AERS. (Chapter 4 contains a more detailed discussion of relevant programs and agreements with academic research institutions.) FDA also obtains information from IMS Health, a provider of market research services to the pharmaceutical and health care industries. Among the services obtained from IMS Health are the National Disease and Therapeutic Index, which provides data on diagnoses, patients, and treatment patterns; Integrated Promotional Services, which measures professional and consumer promotional activity in the pharmaceutical industry; and the National Prescription Audit, which tracks pharmaceutical products dispensed in retail, mail-order, and long-term care channels. Trained staff and (often expensive) supportive technology are typically needed to use some of those databases fully. CDER’s limited resources for such activities have precluded taking full advantage of their potential contribution to understanding the safety of approved drugs (see further discussion in Chapter 4). Resources also severely constrain their external research program. DDRE has about 18 epidemiologists. They work with the safety officers (who are also referred to as safety evaluators and generally are pharmacists) on assessments, determining for example the background risk of a condition to determine whether reported rates may be above expected levels. They also oversee agency-sponsored epidemiologic research. Identifying and Evaluating Spontaneous Safety Signals As CDER receives new information related to a drug’s safety profile, it makes risk assessments and determines how risks can best be managed. For monitoring purposes, every marketed drug is assigned to a safety evaluator, usually a pharmacist in DDRE. Generally, one safety evaluator oversees all drugs in a class, such as statins, so he or she tends to work consistently with a specific OND division that handles those drugs. AE reports on a drug are automatically forwarded by e-mail to the appropriate safety evaluator and to the OND reviewer with responsibility for that drug. ODS/OSE employs about 25 safety evaluators, and each receives about 500–800 reports a month to monitor, including some that are designated as “serious” on the basis of criteria established by FDA. The committee was told that safety evaluators now have less time than before to keep up with their inboxes as they are spending more time on OND consultations, in developing complex postmarket risk assessments, and in such activities as

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The Future of Drug Safety: Promoting and Protecting the Health of the Public RiskMAP development and assessments required by the Best Pharmaceuticals for Children Act (FDA and CDER, 2005). Safety officers begin the process of building on initial reports either when requested by an OND reviewer to pursue a signal or on the basis of their own review of reports. Initial safety signal information is generally incomplete or uncertain; for example, a case report has few details, a patient is taking several drugs at once and a reaction could be related to the combination or to one of the drugs alone, could be related to the disease rather than to any of the drugs, or the effect may be so common in the population that it is difficult to determine whether it is associated with drug use. Only through additional investigations—including data mining searching with MedDRA codes, review of premarket studies, and analysis of available data from sources described above—might a picture begin to emerge. Increasingly, ODS/OSE is undertaking assessments not just regarding the drug that may have generated reports but regarding the class of drugs that it belongs to. Rare is the story that builds as clearly and completely as one would like for making scientific evaluations and regulatory decisions. Adequate information to quantify risk or to compare the safety of a drug with the safety of alternative therapies in its class may not be readily available. Not uncommonly, uncertainties and professional disagreements about the significance of signals persist. OND and ODS/OSE are expected to work together to assess risk and determine how to manage it, but OND has authority to make regulatory decisions related to the findings. A recent Government Accountability Office report noted problems in the relationship between ODS/OSE and OND staff, including lack of clarity about roles and responsibilities and communication barriers (GAO, 2006). As noted earlier, FDA’s official response to those findings cited its commitment to making ODS/OSE and OND “co-equal partners in the post-market identification and timely resolution of drug safety issues” (GAO, 2006) (see discussion in Chapter 3). Another challenge facing FDA is to decide when to alert the public and providers of AE reports that are under investigation. On one hand, reporting at the earliest stages could confuse and perhaps unduly alarm patients and providers and lead patients to inappropriately avoid or stop using a drug that they need. On the other hand, waiting too long to alert providers and users about potentially serious problems with a marketed drug can put patients at risk. FDA has been criticized for waiting too long and has proposed a Drug Watch Web site that would give the public and providers information about potential problems with marketed drugs earlier than in the past. The proposed Drug Watch program has been subject to criticism from the pharmaceutical industry. One reason given by industry against the program is that it is not useful to look at one study in isolation, as would be

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The Future of Drug Safety: Promoting and Protecting the Health of the Public the case in Med Watch; they would prefer that similar studies be published together giving physicians and patients the opportunity to see the data in context (Agres, 2006). This has prompted FDA to rethink the program, so launch of that program has been delayed (FDA, 2005c,e). To help to resolve uncertainties, discuss issues publicly, or consider regulatory strategies to address a risk, an advisory committee meeting may be held. Members of the Drug Safety and Risk Management Advisory Committee and the committee with expertise in the specific class of drugs are typically involved. Regulatory Actions FDA’s regulatory authority is grounded in the FD&C Act and its amendments (21 USC 301). The historical origins of the act lie in the many 19th- and 20th-century incidents of widespread injury caused by ingestion of items that were either tainted versions of otherwise safe substances or unsafe substances marketed as something else entirely. Fundamentally FDA’s authority is limited to prohibiting the marketing of a drug that is adulterated or misbranded. With the middle-20th-century amendments came an expansion of the notion of misbranding, in which any failure to prove efficacy and safety before marketing would result in a finding of misbranding, because the marketing of the product would be a form of deception. Similarly, failure to adhere to agreed-on labeling or advertising requirements was viewed as a form of misbranding. The result is that FDA’s remedies for the marketing of dangerous or mislabeled drugs is limited largely to withdrawing them from the market. The threat of such an action (although for critical or popular therapies such a threat may not be credible) and the agency’s ability to use the mass media to call attention to the controversy give the agency some teeth in getting sponsors to comply with regulatory actions. Actions may include mandatory postmarketing surveillance, limitations on distribution, special education programs, or labeling changes, including use of a black box warning to call attention to serious risks. FDA also uses “Dear Health Practitioner” letters to inform providers of new information related to the safe and effective use of a marketed drug. Such actions have been taken numerous times although enforcement activities have varied over the years. Decisions about use of enforcement tools, especially such aggressive ones as seizing products deemed to be misbranded, are not CDER’s alone. The general counsel and the commissioner, both political appointees, are key to those decisions. FDA has come under criticism from some external stakeholders for not acting quickly enough or appropriately in the face of serious safety questions in specific cases (Wolfe, 2004; Curran, 2005). Some surveys also indicate concerns among CDER

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The Future of Drug Safety: Promoting and Protecting the Health of the Public staff respondents about how safety issues are handled (DHHS/OIG, 2003) although senior management has strongly defended controversial actions (IOM Staff Notes, 2005–2006). FDA does not routinely conduct “postmortems” of drug withdrawals as a basis for examining and possibly improving its procedures. Drugs withdrawn from the market have been reinstated by FDA for use with restrictions at the request of the sponsor (see Box 2-6 for summary of this case). One important issue for FDA and all other stakeholders in drug safety is the limited effectiveness of these regulatory warning tools in promoting drug safety. Although changes in the information provided in a label is a key tool for responding to and communicating new safety information, studies show that many patients are at risk because providers and the patients do not consistently heed labels, including the most serious black box warnings (Lasser et al., 2006). It is worth underscoring that the fundamental design of the drug approval system described above—separate from the quality of the data that sponsors generate in compliance with it—inevitably puts drugs on the market when safety information is incomplete. The obvious corollary is that the postmarket monitoring system, as well as the premarket review processes, must be as effective and efficient as possible. BOX 2-6 The Story of Alosetron (Lotronex) November 1999—FDA advisory committee recommends approval February 2000—FDA approves Alosetron for treatment of “diarrhea-predominant irritable bowel syndrome” in women June 2000—FDA advisory committee meeting discusses evidence of serious adverse events and votes to retain the drug on the market November 2000—FDA and the sponsor meet, sponsor withdraws Alosetron December 2001—sponsor proposes returning Alosetron to market with restrictions April 2002—FDA advisory committee recommends return to market with restrictions June 2002—FDA approves Alosetron’s return to market, with less rigorous restrictions than those recommended by the advisory committee SOURCE: Moynihan (2002).

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