3
The FDA Advisory Committee System

This chapter describes the current advisory committee system of the Food and Drug Administration. It first provides an overview and then considers the official purposes of such committees. It also examines their actual uses, including the variations in use among the different centers and the complementary ways that the agency obtains expert advice. The chapter also discusses the ''goldfish bowl" environment within which FDA advisory committees function.

THE PRODUCT EVALUATION PROCESS

The three units of the Food and Drug Administration that concern us in this report are the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH).The work of the three centers is mainly but not exclusively related to the evaluation of new therapeutic and diagnostic products. The discussion in this chapter is frequently organized around the three different categories of medical technologies—that is, drugs, biologics, and devices.

The Drug Evaluation Process

When, after in vitro testing and animal studies of toxicity, a new chemical entity appears promising enough to consider clinical trials in humans, the sponsor must notify the FDA of its intention to conduct such trials.1 The investigational new drug (IND) application that the sponsor files contains both current data and details of the study design. The FDA, on receipt of an IND, has 30 days within which to review the submission. If the agency judges that no safety problems bar the initiation of the trial, it may allow the IND to become effective and the trial to go forward. If problems exist, it may place a "clinical hold" on the trial until the sponsor corrects



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 70
Food and Drug Administration Advisory Committees 3 The FDA Advisory Committee System This chapter describes the current advisory committee system of the Food and Drug Administration. It first provides an overview and then considers the official purposes of such committees. It also examines their actual uses, including the variations in use among the different centers and the complementary ways that the agency obtains expert advice. The chapter also discusses the ''goldfish bowl" environment within which FDA advisory committees function. THE PRODUCT EVALUATION PROCESS The three units of the Food and Drug Administration that concern us in this report are the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH).The work of the three centers is mainly but not exclusively related to the evaluation of new therapeutic and diagnostic products. The discussion in this chapter is frequently organized around the three different categories of medical technologies—that is, drugs, biologics, and devices. The Drug Evaluation Process When, after in vitro testing and animal studies of toxicity, a new chemical entity appears promising enough to consider clinical trials in humans, the sponsor must notify the FDA of its intention to conduct such trials.1 The investigational new drug (IND) application that the sponsor files contains both current data and details of the study design. The FDA, on receipt of an IND, has 30 days within which to review the submission. If the agency judges that no safety problems bar the initiation of the trial, it may allow the IND to become effective and the trial to go forward. If problems exist, it may place a "clinical hold" on the trial until the sponsor corrects

OCR for page 70
Food and Drug Administration Advisory Committees the problem or withdraws the application. If the FDA does not respond within the 30-day period, the sponsor may begin the clinical trial. Drug development involves three stages of clinical trials. In a Phase I trial, a relatively small group of healthy volunteers take the drug for several months to provide initial data on safety and the drug's action in humans. If Phase I results are acceptable, one or more Phase II trials will be initiated. Phase II trials assess the effectiveness of the drug, with continued attention to safety and noncritical side effects, and define the clinical endpoints for the assessment of Phase II and III data. Phase II studies may involve up to several hundred participants who have the disease under study, compared with 20 to 100 healthy individuals in Phase I trials, in which subjects are often randomized. If Phase II results are promising and the substance is not being evaluated for the treatment of a life-threatening or serious disease—and therefore being considered for expedited approval (e.g., technologies to treat cancer or AIDS)—then Phase III trials are undertaken.* These trials are both larger (several hundred or even more patients) and longer (one to four years). Often, initiation of Phase III trials occurs after a meeting between the FDA and the drug company sponsoring the trial and the FDA to clarify and agree on the basis for evaluating the drug. The results of Phase III, because of the larger pool of patients and longer duration of use, provide the detailed information necessary for use of the drug in clinical practice—appropriate dosage levels, less frequent side effects, and so forth. The manufacturer submits the data from all three clinical trial phases and from the preclinical studies to the FDA in a new drug application (NDA) to market the substance for specific indications. An NDA also contains detailed information on the laboratory formulation and chemistry of the drug, the manufacturing process, quality control procedures, the proposed labeling of the drug, and samples of the drug in its proposed dose and form.** The data from all three phases, but particularly those from Phase III, form the basis for the FDA's decision on approval, including its specification of indications and other parts of the official label. *   The FDA issued proposed regulations in April 1992 for the accelerated approval of drugs for serious or life-threatening illnesses (57 Federal Register 13234, April 15, 1992). At the same time, the Public Health Service announced a final policymaking promising investigational drugs for AIDS and other HIV-related diseases more widely available under "parallel track" procedures (57 Federal Register 13250, April 15, 1992). **   In general, only prescription drugs go through the NDA process.

OCR for page 70
Food and Drug Administration Advisory Committees The Biologics Approval Process The approval process for biologics is quite similar to that for drugs,2 in part because the FDA merged the two Bureaus of Drugs and Biologics from 1982 to 1987 into the Center for Drugs and Biologics. Biologics, however, are regulated under a regime based on the Public Health Service Act of 1944 rather than the Food, Drug, and Cosmetics Act. Although the evaluation process parallels the drug evaluation process, manufacturers submit a product license application (PLA) rather than an NDA. They do so on a "rolling submission" basis beginning before the end of Phase III clinical trials, submitting pieces of the application as they are completed without waiting to assemble a complete application. In addition, manufacturers also submit an establishment license application (ELA). If the FDA approves the product, both the product and the manufacturing establishment receive licenses. The Device Approval Process For regulatory purposes, the FDA classifies medical devices for human use into one of three risk-related categories, as required by the Medical Device Amendments of 1976. All three classes of devices are subject to "general controls," which are "sufficient to provide reasonable assurance of safety and effectiveness" of a device. General controls empower the FDA to: prohibit adulterated or misbranded devices; require domestic and foreign device manufacturers and initial distributors to register their establishments annually and list their devices; ban certain devices; demand notification of risks and require repair and replacement of refund for defective products; restrict the sale, distribution, or use of certain devices; and require conformance with regulations pertaining to Good Manufacturing Practices, records and reports, and inspections.3,4 Class I devices are regulated solely through general controls. The statute defined Class II devices as those devices that could not be designated as Class I but for which sufficient information existed to establish a "performance standard." Standards were visualized as a more stringent form of regulation; however, the FDA has promulgated no performance standards between 1976 and the present. Consequently, the Safe Medical Devices Act of 1990 provides for regulation under "special controls." In addition to potential regulation by performance standards, Class II devices are subject

OCR for page 70
Food and Drug Administration Advisory Committees to the general controls listed above, including Section 510(k) of the Food, Drug, and Cosmetic Act. Section 510(k) requires that for any device brought to market after May 28, 1976—the date of enactment of the 1976 amendments—the sponsor must provide ''premarket notification" to the FDA of its intent to market the device.* To be eligible for immediate marketing, the device must be judged by the FDA to be substantially equivalent to a device in use before that date. The FDA is required to rule on a 510(k) notification within 90 days of receiving it; if the agency does not respond, the company may proceed with marketing. If the FDA determines that a device is not substantially equivalent to one that has been marketed previously, it automatically places the device in Class III. The pre-market approval (PMA) route for a Class III device is analogous to the NDAs and PLAs of drugs and biologics. The manufacturer must present data from "well controlled investigations" or other appropriate tests to provide "reasonable assurance" of the device's safety and effectiveness. Before the initiation of human clinical trials on a device, the Institutional Review Board (IRB) of the institution at which the trials are to be conducted must decide whether the device poses a "significant risk" to patients. If it does, the manufacturer must apply for an investigational device exemption (IDE) from the FDA in order to conduct the trial. If it does not, the FDA's permission is not required, and the manufacturer must only adhere to the sections of the IDE regulation that pertain to nonsignificant-risk devices. AGENCY WORKLOAD AND ADVISORY COMMITTEES The three centers vary in their workload for new product evaluations, with the CDER having the heaviest workload, the CDRH having the next heaviest, and the CBER having the lightest. Figures 3-1 and 3-2 indicate the budget and the total number of personnel for each center for fiscal year 1991. A quantitative indication of the work of the three centers is presented in the following tables. Table 3-1 indicates the number and type of submissions or applications that were received by CDER for the years 1986 *   Medical device manufacturers are required to submit a premarket notification if they intend to introduce a device into commercial distribution for the first time or to introduce, or reintroduce, a device that will be significantly changed or modified to the extent that its safety or effectiveness could be affected...." Premarket notification [510(k)] is not required for preamendment devices, devices under the IDE regulation, most transitional devices [devices previously regulated as drugs or antibiotics], and custom devices. In addition, a number of class I devices have been exempted by regulation from 510(k) requirements.

OCR for page 70
Food and Drug Administration Advisory Committees Figure 3-1 Fiscal year 1992 operating budgets for CDER, CBER, and CDRH. Source: FDA/CDER/CBER/CDRH. Figure 3-2 Allotment of full-time-equivalent positions in CDER, CBER, and CDRH. Source: FDA/CDER/CBER/CDRH.

OCR for page 70
Food and Drug Administration Advisory Committees through 1991. Although the figure for original new drug applications (NDAs) fluctuates somewhat from year to year, in general, it reveals a steady pattern. Investigational new drug (IND) applications have reached the 2,000 level, of which nearly 20 percent are commercial. Table 3-2 shows the same data on submissions to CBER for the years 1987 through 1991. Although the number of original product licensing applications (PLAs) fell back sharply in 1990 and 1991 from the three preceding years, it is expected that they will rise again as the biotechnology revolution generates an increasing number of new therapeutic products. This expected increase in demand can be seen in the doubling of original INDs from 1987 to 1991. Table 3-3 reveals the level and nature of CDRH submissions. The number of original PMA applications appears relatively stable at fewer than 100 per year. However, the 510(k) applications have consistently run above 5,000 each year, indicating the high volume of medical device submissions that claim "substantial equivalence" to a pre-1976 device. Table 3-4 indicates the stream of CDER approvals during the years 1986 through 1991. The criteria for "refusal to file" an application are currently being tightened up, and these figures may show an increase in the immediate future. CBER approvals are shown in Table 3-5. The number of PLA approvals reveals a steady and significant increase during the five years from 1987 through 1991. Table 3-6 shows a stable pattern for original PMA approvals for the 1987 through 1990 period. However, adding 1986 and 1991 to these data presents a picture of declining PMA approvals. Again, approvals of 510(k) applications run very high, consistent with the volume of such applications received. Approvals of IDEs (originals, amendments, and supplements) is stable and high. Table 3-7 lists all standing FDA technical advisory committees as of July 1,1992.

OCR for page 70
Food and Drug Administration Advisory Committees Table 3-1 Submissions Received by the Center for Drug Evaluation and Research, Calendar Years 1986–1991 Submission Type 1986 1987 1988 1989 1990 1991 Original NDAs received 120 142 126 118 98 112 NDA resubmissions 18 24 30 33 16 12 Major amendments 344 286 408 455 474 435 NDA supplements NA 1,889 1,857 1,867 2,006 1,670 Original ANDAs & AADA rec'd. NA NA NA 784 312 311 Major amendments NA NA NA 2,846 1,125 1,302 Original INDs 1,596 1,346 1,337 1,345 1,530 2,116 Commercial INDs 330 302 363 308 376 374 Note: NDA, new drug application; NA, not available; ANDA, abbreviated new drug application; AADA, abbreviated antibiotic new drug application; IND, investigational new drug. Source: "Selected Calendar Year 1991 Information and Accomplishment Data," DHHS/PHS/FDA/CDER/OMB.

OCR for page 70
Food and Drug Administration Advisory Committees Table 3-2 Submissions Received by the Center for Biologics Evaluation and Research, Calendar Years 1987–1991 Submission Type 1987 1988 1989 1990 1991 Original PLAs 92 98 99 63 48 PLA amendment 379 421 445 458 552 Original ELAs 33 36 39 24 15 ELA amendment 93 162 198 192 148 Original INDs* 266 294 277 379 504 Note: PLA, product license agreement; ELA, establishment license agreement; IND, investigational new drug. * INDs are reported by fiscal year. Source: Center for Biologics Evaluation and Research/Office of Management.

OCR for page 70
Food and Drug Administration Advisory Committees Table 3-3 Submissions Received by the Center for Devices and Radiological Health, Fiscal Years 1986–1991 Submission Type 1986 1987 1988 1989 1990 1991 Original PMAs 69 81 96 84 79 75 PMA supplements 478 700 727 810 660 593 Original IDEs 206 218 268 241 252 213 IDE amendments 365 265 316 271 288 283 IDE supplements 2,884 2,836 3,391 3,038 3,043 3,647 510(k)s 5,063 5,265 5,536 7,022 5,831 5,770 Note: PMA, pre-market approval; IDE, investigational device exemption. Source: "Office of Device Evaluation Annual Report(s) Fiscal Years 1986–91," DHHS/PHS/FDA/CDRH.

OCR for page 70
Food and Drug Administration Advisory Committees Table 3-4 Application Approvals by the Center for Drug Evaluation and Research, Calendar Years 1986–1991 Application Type 1986 1987 1998 1989 1990 1991 NDAs approved 98 69 67 87 64 63 NDAs approvable 71 39 31 48 41 46 NDAs refusal to file 14 22 17 10 14 23 NDAs not approvable 109 116 114 69 81 77 NDAs withdrawn 36 34 53 59 55 48 ANDA & AADA approvals NA NA NA 265 80 193 ANDA & AADA not approvables NA NA NA 1,899 828 1,080 Note: NDA, new drug application; ANDA, abbreviated new drug application; AADA, abbreviated antibiotic new drug application; NA, not available. Source: "Selected Calendar Year 1991 Information and Accomplishment Data," DHHS/PHS/FDA/ CDER/OMB.

OCR for page 70
Food and Drug Administration Advisory Committees Table 3-5 Application Approvals by the Center for Biologics Evaluation and Research, Calendar Years 1987–1991 Submission Type 1987 1988 1989 1990 1991 PLAs approved 33 44 52 70 60 PLAs withdrawn 6 19 14 19 17 PLAs inactive 3 2 4 0 0 PLAs denied 0 0 0 1 0 ELAs approved 15 16 24 29 19 ELAs withdrawn 2 4 4 5 5 ELAs inactive 2 2 2 0 0 ELAs denied 0 0 0 1 0 Note: PLA, product license agreement; ELA, establishment license agreement. Source: CBER/OM.

OCR for page 70
Food and Drug Administration Advisory Committees guidelines with the help of advisory committees, professional societies, and consultants to the drug industry. These guidelines consisted of "generally accepted principles for reaching valid conclusions about the safety and effectiveness of drugs, and [the] views of recognized experts about appropriate methods for studying specific classes of drugs." The preamble also noted that FDA used individual advisory committee members as consultants in several ways. For example, the FDA included them in meetings with sponsors to discuss specific scientific issues, to participate in "end-of-Phase II" conferences that helped to plan Phase III studies (as noted in the "IND Rewrite proposal"),8 and on an ad hoc basis as technical consultants or expert reviewers, especially in cases in which the agency lacked resources or expertise. "In summary," the preamble stated, "FDA believes that the primary goal of the advisory committee (and outside consultant) system should be to help the agency make sound decisions based upon the reasoned application of good science." Medical Device Statutes In the case of medical devices, the law requires the use of advisory committees. The Radiation Control Act of 1968, which amended the Public Health Service Act, directed the Secretary to establish a Technical Electronic Product Radiation Safety Standards Committee (TEPRSSC) "to provide consultation before the Commissioner prescribes any performance standards for an electronic product." In advising the Commissioner, the TEPRSSC may propose standards for his consideration, consult on standards he has proposed, and recommend action on "any other matter" related to the act. Authority to act on the advice of the TEPRSSC is explicitly vested in the Commissioner. The FDA has always administered this provision of the law, currently through the CDRH, and it is the first instance of the agency being required by statute to establish and maintain an advisory committee. The Medical Device Amendments of 1976 directed the Secretary to use advisory committees in two ways. First, they directed him to establish "panels of experts" for classifying medical devices intended for human use "according to the various fields of clinical medicine and fundamental science" in which these devices were to be used. Second, they required him to establish advisory committees (other than classification panels) to review proposed regulations for medical device performance standards, to review all PMA applications, and to make recommendations on Good Manufacturing Practice regulations. For the purposes of this study, the use of advisory committees for premarketing approval is the most important concern.

OCR for page 70
Food and Drug Administration Advisory Committees FDA Advisory Committee Charters The charters of specific FDA advisory committees indicate that their purpose is to advise the Commissioner on the safety and effectiveness of the product in question. The typical CDER advisory committee charter reads as follows: [The committee] reviews and evaluates available data concerning the safety and effectiveness of marketed and investigational human drug products for use in [specified disease treatments] ... and makes appropriate recommendations to the Secretary, the Assistant Secretary, and the Commissioner of Food and Drugs. The charges of two CDER committees are couched in slightly different language. The Generic Drugs Advisory Committee is to advise on the safety and effectiveness of human generic drug products for use in treating "a broad spectrum of human diseases." The Drug Abuse Advisory Committee, with a broad charge, advises the FDA Commissioner on "the scientific and medical evaluation of all information gathered by the Department of Health and Human Services and the Department of Justice with regard to safety, efficacy, and abuse potential of drugs or other substances and recommends actions to be taken by the Department of Health and Human Services with regard to marketing, investigation, and control of such drugs or other substances." The charters of the four CBER advisory committees also focus on the evaluation of data related to safety and effectiveness. In addition, the charges to the Biological Response Modifiers Advisory Committee and the Vaccines and Related Biological Products Advisory Committee require them to consider "appropriate use," and those to the Allergenic Products Advisory Committee and the Blood and Blood Products Advisory Committee to consider labeling issues.* Yet the scope of CBER advisory committees extends beyond these functions in one important respect, in which they differ from CDER and CDRH committees. With its origins in the biologics program of the NIH, the CBER also uses its advisory committees to review the quality and relevance of the center's intramural research program, which provides scientific support to its product regulation responsibilities, and the quality and performance of its research personnel. *   The Blood and Blood Products Advisory Committee also functions as a device advisory committee for blood-related devices, examining issues related to classification, safety and effectiveness, formulation of product development protocols, review of PMAs, and the "reclassification, exemption, and banning of devices."

OCR for page 70
Food and Drug Administration Advisory Committees The CDRH, as noted in Chapter 2, used advisory panels to classify pre-1976 medical devices into one of three risk-related categories; it terminated these classification panels once their responsibilities had been carried out. The center also used approximately 16 separately chartered advisory committees for product evaluation purposes. In 1990, the CDRH formally terminated its existing advisory committees, established a single Medical Devices Advisory Committee, and reconstituted the previous committees as 16 "panels" of the new committee. The center did so to enable it to bring needed expertise to bear on a given product review and to meet the requirement for a quorum of voting members more easily. The single committee consists of a maximum of 148 members, of whom 114 are standing voting members and 34 are nonvoting members (16 consumer representatives and 18 industry representatives); the members are distributed to panels as before. Under this arrangement, the device panels function as they did before as committees, except that the responsible FDA official can invite committee members from other panels, as well as designated consultants, to serve as voting panel members at a particular meeting. This can occur under two circumstances: first, "when expertise is required that is not available among the current voting standing members of the panel," and second, to meet the need for a quorum when one is lacking.9 The CDRH describes the purposes of its rechartered advisory committee structure as follows: Reviews and evaluates available data concerning the safety and effectiveness of [specified devices] currently in use and advises the Commissioner regarding recommended classification of these devices into one of three regulatory categories; recommends the assignment of a priority for the application of regulatory requirements for devices classified in the standards or premarket approval category; reviews classification of devices to recommend changes in classification as appropriate; recommends exemption of certain devices from the applications of portions of the Act; advises on the necessity to ban a device; and responds to requests from the Agency to review and make recommendations on specific issues or problems concerning the safety and effectiveness of devices. Some variation exists within the CDRH panels. For example, the Dental Products Panel functions at times as a nonprescription drug advisory panel. In addition, the Radiologic Devices Panel is to advise on "a coordinated program" for the medical application of radiation that maximizes diagnostic information and therapeutic benefits per unit of exposure.

OCR for page 70
Food and Drug Administration Advisory Committees About the same time that this rechartering occurred, Congress enacted the Safe Medical Devices Act of 1990.10 Section 16 of that act required that regulations be issued to determine the primary mode of action of a product that combined a drug, device, or biological product and to assign primary jurisdiction to the responsible FDA center. The FDA, in implementing this requirement, expanded it to include all product jurisdiction issues. The results of this were new regulations; three new intercenter agreements, and the rechartering of CDER and CBER advisory committees to permit the use, when expertise is needed or a quorum is lacking, of any FDA technical advisory committee member (and designated consultants) as a voting member on any other committee. The implications of this rechartering are discussed in Chapter 7. The CDRH has two committees that are not engaged in product evaluation. The Device Good Manufacturing Practice Advisory Committee is responsible for reviewing proposed regulations for "good manufacturing practices governing the methods used in, and the facilities and controls used for, the manufacture, packing, storage, and installation of devices, and . . . the feasibility and reasonableness of those proposed regulations." The TEPRSSC, as mentioned earlier, advises the Commissioner "on the technical feasibility and reasonableness of performance standards" to control radiation emission from electronic products. THE USES OF ADVISORY COMMITTEES The above discussion indicates the range of official purposes of FDA advisory committees in the area of drugs, biologics, and medical devices. Not surprisingly, then, the agency—or, more accurately, its program units—uses such committees in a number of different ways. These variations derive from the following sources: the three separate centers—their histories, technical and regulatory responsibilities, workloads, and their organizational "cultures"; the stage of product development and evaluation—prelicensing, licensing, postmarketing approval; the means by which the centers seek external advice—advisory committees, Special Government Employee (SGE) consultants, primary reviewers, and workshops; and other factors. The "other factors" may comprise: the class of therapeutic products under consideration; the stage of scientific development of the pertinent clinical field or area; the specific tasks of a given advisory committee; the different

OCR for page 70
Food and Drug Administration Advisory Committees reviewing divisions, including the relationship between the review organizations and the advisory committees; the personalities of different review officials; and the absence of sustained FDA-wide policy guidance. How these factors interact to affect variation in the use of advisory committees can be addressed by taking each center in turn. Variations Among Centers The CDER, which is the oldest FDA user of advisory committees and the center with the most complicated history of use, brought them into existence in the decade following the 1962 drug amendments. That legislation required that, in addition to safety, the effectiveness of drugs be established for all old drugs—prescription and over the counter—marketed between 1938 and 1962 on the basis of safety alone; all new drugs were to be evaluated for both safety and effectiveness as well. The agency thus had both an immediate need, to acquire expertise that it did not have on its staff, and a long-term need, to recruit personnel with greater medical and scientific expertise than it then had. The legislation also reinforced the adversarial relationship between the agency and the regulated industry. Not surprisingly, among the three centers considered in this report, agency-industry relations have been most confrontational for drugs. The CDER advisory committee system that developed is organized along the lines of therapeutic agents or product lines, from an industry perspective, as indicated in Table 3-7. This organization parallels the drug evaluation units of the center—the two Offices of Drug Evaluation and their respective divisions, the Pilot Drug Evaluation Office, the Office of Generic Drugs, and the Office of Over-the-Counter Drugs. In biologics, vaccine development has been justified by a public health rationale and embedded in a public health institutional framework. The need for government regulation of safety is not subject to dispute. The economic incentives for commercial vaccine developers have been weaker historically than for drug manufacturers, and agency-industry relations are less confrontational than for drugs. The CBER advisory committee system is organized according to therapeutic categories or product lines, as Table 3-7 makes clear. The reviewing offices of the CBER, however, do not correspond directly to the advisory committee structure. Instead, several units may review a given PLA, depending on the biologic under consideration. The CBER system, unlike those of the CDER and CDRH, extends beyond product evaluation to the review by the four advisory committees of CBER intramural research programs and research personnel. One question raised by this practice is whether four advisory committees, each reviewing

OCR for page 70
Food and Drug Administration Advisory Committees a portion of the intramural research program, fragment the oversight of that effort. It is possible that a single "board of scientific counsellors," charged with reviewing all CBER intramural research, might be a more appropriate structure. Many observers have viewed the CDRH's implementation of the 1976 amendments as sensitive to the needs as to the device industry and favorable to product innovation, of well as to the physicians and other health professionals who use the devices. Although the Safe Medical Devices Act of 1990 imposed a number of new requirements on the FDA that may affect its relations with manufacturers, it gave the agency greater discretion in the use of advisory committees, as noted earlier. The CDRH advisory committee system, like the CDER system, is organized along the lines of therapeutic agents or product lines. Internal organization of the Office of Device Evaluation parallels these advisory committees. One feature that differs between the CDRH and CDER, however, is that executive secretaries and division directors play different roles in product evaluation. The CDRH executive secretary is typically a medical review officer to whom additional executive secretarial functions have been assigned, whereas the division director may be mainly a manager. A major tension in the CDRH system, not found in those of the CDER and CBER, is that advisory committees have been the primary means to obtain expert clinical advice for product reviews that are conducted by a professional staff composed predominantly of engineers. Consequently, CDRH usually designates one member of an advisory committee as a "primary reviewer" for each PMA that comes before it, and the committee member receives additional compensation for such work.* Center Workload and Stage of Advisory Committee Use The CDER workload of INDs, NDAs, and other applications is the greatest of any of the three centers, as reflected in Tables 3-1 through 3-4. This workload has led the CDER to focus its use of advisory committees on issues that arise in the product evaluation stage, rather than on earlier or later stages. The evaluation stage involves (1) review of specific NDAs and (2) consideration of scientific and technical policy issues related to the review of a class of products. Although the CDER devotes some committee time to the preapproval (e.g., clinical trial) and postmarketing stages of drug *   FDA regulations authorize payment to advisory committee members for homework on an hourly basis for assignments that require "a definitive study" and "tangible end product," such as a written report, provided that this end product does not represent the end product of the advisory committee [21 CFR Part 14.95(c)]. See ''Compensation'' in Chapter 8.

OCR for page 70
Food and Drug Administration Advisory Committees development, the CBER, in contrast, is involved earlier, more deeply, and on a more sustained basis with the development of a specific biologic, such as a vaccine, in part because of its lower volume of work. Until recently, the CBER has had the smallest workload of the three centers. Coupled with the public health character of its purview and its less confrontational relationship with industry, this has meant that the CBER has been involved in product development and evaluation earlier and more extensively than is true for either drugs or devices. Consequently, CBER advisory committees also have been engaged in the evaluation of biologics at earlier stages than is usual for drugs. The biotechnology revolution, however, is generating an increasing stream of new therapeutic biological products. This trend has led the FDA to increase the number of professional medical and scientific personnel on its staff. New biological therapeutics now drive the growth occurring in the CBER's work, the impact of which is felt largely by the Biological Response Modifiers Advisory Committee. As these developments unfold in the coming decade, the CBER workload will continue to increase, and the pressures of scarce professional personnel resources may impel the center to focus more on the licensing, rather than the prelicensing, stage. The CDRH workload is complicated; unlike drugs and biologics, it is based on risk-related classification of devices. For Class II medical devices, the FDA must determine whether a device is the substantial equivalent of one marketed before the 1976 amendments. As described earlier, some Class III devices have been on the market since before 1976, while others have reached the market since then through the 510(k) procedure and still others by the PMA route. The PMA workload that advisory committees now face is substantial and growing; rechartering of multiple advisory committees into a single committee with multiple panels presumably has made this workload easier to manage. The law requires the sponsor of a Class III device marketed before the 1976 amendments to submit a PMA application when the agency calls for safety and effectiveness data on all devices in that category. The Safe Medical Device Amendments of 1990 required the FDA, by December 1, 1995, to call for PMAs or to reclassify as Class II approximately 130 such devices. Although the agency claims that it lacks the resources to fulfill this statutory requirement completely, it is calling for PMA applications for some of these devices. It is likely that the resulting PMAs will be reviewed by advisory panels. For example, the two meetings of the General and Plastic Surgery Advisory Panel that considered the safety and effectiveness of silicone gel breast implants in November 1991 and February 1992 were reviewing one of these pre-1976 devices.

OCR for page 70
Food and Drug Administration Advisory Committees Other Means of Seeking Advice In addition to the use of advisory committees, the three centers formally seek external expert advice through Special Government Employee (SGE) consultants and workshops. Consultants: The FDA appoints all voting members of its technical advisory committees as Special Government Employees to permit them to be paid and reimbursed for expenses. All FDA consultants are also SGEs, but not all SGE consultants are advisory committee members. Conversely, a scientist can be both a consultant and a committee member. The SGE status is mainly used to pay or reimburse scientific expertise. The CDER uses consultants, some of whom are advisory committee members and some of whom are not, throughout the drug evaluation process. For example, it may bring an advisory committee member, as a consultant, into an "End of Phase II Conference" with a drug sponsor. Or it may use an SGE consultant who is not an advisory committee member for that purpose. The FDA may also use a nonmember SGE consultant as a consultant to an advisory committee. All three centers use consultants in these various ways. In some situations, the CDER may draw on the expertise of consultants who have been engaged by product sponsors. If the FDA has a problem with a sponsor's application, the agency may ask the firm to come to a meeting to discuss the problem and to bring with it one or several of its principal consultants. The agency thus may extend its access to external expertise, when it deems it useful, to consultants to the industry. Formal Workshops: The three centers differ in the extent of their use of workshops. The CDER often uses this approach, describing a meeting as a minisymposium and organizing it in conjunction with an advisory committee. An example of this kind of activity was a one-day meeting on dose-response measurement of angiotensin-converting enzyme inhibitors that was organized by the Cardiovascular and Renal Drugs Division. The second day was a formal Cardio-Renal Drugs Advisory Committee meeting, focused on specific submissions. Perhaps because of the public health linkage with vaccine development, the CBER sponsors or cosponsors a number of workshops each year devoted to scientific issues that bear on its regulatory responsibilities. The distinctions between an advisory committee meeting and a workshop are several: workshops are generally called to explore the state of the science in relation to a given issue and not to advise the FDA; the workshops, including all technical presentations, are open to the public, especially the relevant

OCR for page 70
Food and Drug Administration Advisory Committees technical community, without regard to organizational affiliation or conflict of interest; and workshops are not governed by the Federal Advisory Committee Act.*11 A central question about consultants and workshops is whether either of these mechanisms provides value equivalent to that of advisory committees? If so, in what contexts? The FDA wants to be able to say of advisory committees, "We assembled the best people in the country; they heard the evidence, debated its implications, and provided us with this advice." Consultants may provide detailed advice of great value on specific matters; however, their role does not provide a forum for public discussion, nor do they perform in a fashion that allows the FDA to make the above claim to the public and press. On the one hand, workshops allow the agency to generate a synthesis of the state of scientific development in an area. On the other hand, because they may not result in advice, workshops are unable to perform certain roles that advisory committees fulfill. The issue may be whether these other mechanisms are genuine alternatives to advisory committees or are more appropriately understood as adjuncts to them. Another question is whether these other methods for tapping the expertise of outside scientists escape the strictures of the Federal Advisory Committee Act? In this context, the conflict-of-interest restrictions do apply to agency consultants, but the regulations allow "two or more FDA consultants" to meet with the agency on an ad hoc basis.12 SUMMARY The FDA advisory committee system has been an integral part of the product evaluation process for drugs, biologics, and medical devices. The agency has made increasing use of these committees over time. Procedures for using advisory committees vary from center to center and often within centers. These variations have many explanations, some quite clearly justifiable in operational terms but others seemingly the product of neglect by the agency's central administration or the idiosyncratic preferences of agency officials directly responsible for their ongoing management. For much of the past decade, little attention appears to have been devoted to establishing and maintaining an optimum level of agency-wide uniformity in committee procedure and management. *   An example of a CBER-related workshop was a two-day meeting organized by the Institute of Medicine's Forum on Drug Development on the "microheterogeneity of biological macromolecules." The workshop considered the scientific issues underlying small changes in large biological molecules and the implications of these issues for FDA policies.

OCR for page 70
Food and Drug Administration Advisory Committees The primary purpose of FDA advisory committees, as stated in the NDA Rewrite, is to assist the agency in making "sound decisions based upon the reasoned application of good science." They do so by advising on the approvability of specific product applications based on an examination of the adequacy of the data supporting claims of safety and effectiveness. In addition, advisory committees provide technical advice on broader issues relating to product evaluation generally. Advisory committees are not the only ways by which FDA seeks external expert advice. The agency also makes use of consultants and workshops. These other mechanisms are best viewed as complementary to rather than alternatives to advisory committees. They reflect a natural response by a regulatory agency that depends on access to expert scientific and clinical information to fulfill its statutory responsibilities. The IOM committee was very conscious that the use of advisory committees by the FDA was embedded in this broader context of seeking and obtaining external expert advice. It has focused almost exclusively on the use of these technical advisory committees, however, because, by common judgment, that is the component currently most in need of attention. NOTES 1.   Food and Drug Administration, New Drug Development in the United States (Rockville, Md.: Food and Drug Administration, January 1988). 2.   Pharmaceutical Manufacturers Association, In Development: Biotechnology Medicines (Washington, D.C.: Pharmaceutical Manufacturers Association, 1991). 3.   Food and Drug Administration, Everything You Always Wanted to Know About the Medical Device Amendments and Weren't Afraid to Ask , HHS Pub. FDA 90-4173, 3rd ed. (Washington, D.C., August 1990). 4.   Ibid., pp. 12 and 15. 5.   21 CFR 14.1(a)(1), 1991. 6.   50 FR 7452, February 22, 1986. 7.   47 FR 46622, October 19,1982. 8.   48 FR 26732, June 9, 1983.

OCR for page 70
Food and Drug Administration Advisory Committees 9.   Food and Drug Administration, "Charter, Medical Devices Advisory Committee," (Washington, D.C., October 27, 1990). 10.   Public Law 101-629, November 28,1990. 11.   Institute of Medicine, Microheterogeneity of Biological Macromolecules: Report of a Workshop (Washington, D.C., 1991). 12.   21 CFR 14.1(b)(5)(ii).