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7 Regulation and Contraceptive Development This chapter briefly reviews the process of contraceptive development and examines the U.S. Food and Drug Administration (FDA) requirements and procedures for approving new contraceptive drugs and devices. It then compares them with those of regulatory bodies in other countries and those of the World Health Organization. Some analysts contend that the regulatory climate in the United States has impeded the U.S. pharmaceutical industry's willingness to pursue innovations in contraceptive development (Isaacs and Holt, 1987a; Greep et al., 1976; Djerassi, 1987, 1981~. Reports of the regulatory problems associated with contraceptive development tend to be anecdotal and not based on a systematic analysis of the regulatory environment. Nevertheless, a good deal is known about the impact of FDA and the patent and tax laws implemented and overseen by other U.S. government bodies on innovation in the pharmaceutical field. Some of what we know clearly applies to contraceptive development. The FDA is a reviewer, not an initiator, of new products. Pharmaceutical or device firms, research groups, or government agencies conduct research and test new contraceptives and present their results to FDA for review. Drugs and medical devices are regulated separately and are reviewed by different units of the FDA, although the requirements are similar. A contraceptive vaccine would be regulated differently from a contraceptive drug or medical device; like other vaccines, it would be regulated as a biological product under 351 of the Public Health Service Act (42 U.S.C. 262 [1982 & Supp. 19881; 21 C.F.R. pt. 600 [1988]). FDA's requirements help protect people from potentially harmful products. 89

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90 DEVELOPING NEW CO=RACEPTIVES Yet the time, costs, and data required to gain approval of a new product reduce the incentives to undertake innovative research and may also reduce effective patent life and, thus, the profitability of new products. The balance between allowing ample opportunity to develop useful new products and protecting the safety of consumers is at the heart of the debate about the FDA's safety and effectiveness requirements for new drugs generally and for contraceptives in particular. For some, the FDA is regarded as a significant barrier to better contraceptive methods and therefore to fewer unwanted pregnancies and abortions. For others, the FDA's standards and procedures are seen as being not rigorous enough and too easily influenced by pressures from private industry. THE DEVELOPMENT PROCESS i] Contraceptive development involves identifying possible avenues to intervening En the reproductive process, eliminating those that are ineffective, infeasible, or unlikely to be acceptable because of side effects or for other reasons, then testing the remaining drugs or devices for safety and efficacy. Throughout this process, changes may be made in a method's composition, dosage, or mode of administration. Some changes may necessitate additional testing, and some tests may need to be replicated in different populations. The development of a new contraceptive, like the development of other drugs and therapeutic devices, is a complex, multifaceted process involving a wide variety of scientific disciplines. Successful contraceptive development requires millions of dollars, takes years to complete, and may involve the testing of thousands of different chemical compounds. Many drug formulations are discarded during the development process because of concern about safety, efficacy, feasibility of delivery, or marketability. In drug development generally, FDA approval is sought for only 1 out of every 10,000 new chemicals synthesized in the laboratory. One study found that, of 20 new chemical entities identified as potential antifertility agents between 1963 and 1976, 17 were placed into human trials, but only 3 were submitted to FDA for approval, of which 2 were actually approved (Harper, 1983~. It is difficult to estimate the cost of developing a new contraceptive or any other new product because of the problems involved in incorporating the costs of false starts and opportunity costs in the calculations. One recent study (Wiggins, 1987) estimates that it cost $125 million to successfully bring a new chemical entity to the market in 1986 compared with $54 million in 1976. Although the estimate may not be precise, it does indicate the approximate level of investment required and how that has changed over time. Figure 7.1 summarizes the drug development process in the United States. The text below describes the steps outlined in the figure. When basic research on human reproduction provides a lead for contraceptive development by identifying a possible point for the contraceptive intervention,

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RECULATION AND CONTRACEPTIVE DEVELOPMENT 91 CONCEPTUAL WORK l_J AND INITIAL SYNTHESIS I PRECLINICAL 1-3 years I TOXICOLOGICAL to complete I TESTI NO ON ANI MALS INVESTIGATIONAL ~ 30 days NEW DRUG ~ to process I APPLICATION (I ND) A FDA ACCEPTANCE \/ OFIND I PHASE I includes <100 people, to establish safety CLINICAL I I PHASE II includes1 TRIALS* 1,000 people, to establish effectiveness Fertility and Maternal Health Drugs Advisory Committee makes recommendations to FDA ~ 6 months-1 year | 1 to complete ~ | 6 months-2 years l to complete | t'~L~UIIbII ~ll~liv~ll~ '4 PHASE lil includes > 1,000 people, to confirm safety, effectiveness, 1-4 years and dosage; trials often continue to complete during NDA evaluation NEW DRUG APPLICATION (NDA) 2 months-7 years to process | ~ FDA APPROVAL FOR MARKETING I HI POSTMARKETI NG SURVEI LLANCE O drug sponsor activity O drug sponsor application O FDA activity & FDA evaluation technical trials require approval by the Institutional Review Board (IRB) of participating institutions FIGURE 7.1 Me drug develo~xnent process in the United States.

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92 DEVELOPING NEW CONTRACEPTIVES scientists must then determine what mechanism is best suited to take advantage of the potential point of intervention and how it can be delivered. Prototype delivery systems may then be prepared, which may be modified in light of the results of further research. Once a drug is identified as a potential contraceptive, it must be carefully screened to establish its full range of effects. Animal studies are conducted initially to screen drugs. If the results have merit, additional animal studies and small-scale human trials follow. These early studies focus on the chemical breakdown of the drug in the body and on absorption and excretion rates. Scientists assess the drug's potency, its pharmacological effects, the onset and duration of action, chemical stability, and probable toxicity (Pasquale, 1980~. At this stage the delivery system and the expected difficulty of production and formulation are also starting to be considered. Manufacturing processes would typically be designed and tested at this stage to ensure that the drug can be produced in a . ~ . . . . uniform c dosage m . arge quantities. Following initial synthesis and preliminary animal testing, the developer of a new contraceptive drug submits an application for claimed Investigational New Drug exemption (IND) to the Food and Drug Administration. The 1ND is an exemption from the statutory restriction against interstate shipment of an unapproved new drug. The IND includes information on the drug's composition, source, synthesis, and possible benefits. It also includes a detailed protocol for human testing. Human trials of the new drug may begin after a 30 day waiting period, if the FDA has not objected. If the FDA requests clarifications or more data, the drug company must respond to the FDA's satisfaction and wait another 30 days from the last response before beginning human trials. Human clinical testing of new contraceptive drugs is divided into three phases: Phase I studies are usually conducted on a small number of volunteers and are used to determine the safe dose range, the absorption process, and possible levels of toxicity; Phase II studies provide more information about the drug's safety as well as efficacy in carefully selected subjects; and Phase III studies, which may involve several hundred or more participants, are used to establish the drug's safety and efficacy in actual clinical use. Clinical trials for new drugs take an average of five years, but they may continue for as many as 10 years (FDA, 1988~. When testing has been completed, and assuming no unacceptable problems have been discovered in the process, the developer would submit a New Drug Application (NDA) to the FDA to obtain approval to market the drug. Each NDA consists of between 2 and 15 volumes of material summarizing all the research the developer has conducted or sponsored on the drug, and 10 to 100 volumes of raw data collected during the development process (Isaacs and Holt, 1987b). The NDA for the NOR PLANT contraceptive implant, which was submitted to FDA in August 1988, contained over 19,000 pages in 53 volumes. The average review rime for an NDA is two years, but it can take as long as seven years (FDA, 1988~. IUDs, which have a systemic effect because they contain copper or a hormone,

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RECU~TION^D CONTRACEPTIVE DEVE~PMEV 93 are classified as drugs in the United States and must meet the premarketing requirements for drugs. The FDA approval process for new contraceptive devices, such as diaphragms and inert IUDs, is similar to that for drugs (Isaacs and Holt, 1987b), although the approval time for devices is often shorter, in part because there is usually no backlog of Premarketing Approval Applications (PMAs) for FDA review of devices (see below for more details on the regulation of devices). The Fertility and Maternal Health Drugs Advisory Committee, a panel of outside experts who serve 4-year terms, acts as an adviser to the FDA on safety and efficacy issues related to new contraceptives and other drugs. It makes recommendations to the FDA regarding sponsors' applications to market new drugs. These recommendations, although not binding, are usually adopted by the FDA. Once a drug is approved, the manufacturer can begin to promote it to the medical community and to the public. The FDA requires periodic reports following NDA approval and may require postmarketing studies to determine the incidence of serious adverse reactions. A major objective of contraceptive researchers is to reduce the incidence and severity of side effects associated with systemic contraception. After more than two decades of use by millions of women, most of the risks and health benefits of oral contraceptives are known. There may, however, be adverse and beneficial effects yet to be identified that are associated with the new oral contraceptive formulations used in the past decade. (Almost all of the existing studies of oral contraceptives are based on women using high-dose pills; one hypothesis is that the newer low-dose pills will have fewer side effects, but also fewer health benefits than the high-dose pills.) Replicating this experience of widespread, long-term use of oral contraceptives in clinical trials for other methods is not yet possible. Long-term safety issues related to new systemic contraceptive methods will not be completely resolved until they have been in general use for many years. THE REGULATION PROCESS As a mirror of Americans' concerns and attitudes about consumer protection and the safety of drugs, Congress exerts an important influence on the FDA through legislation, hearings, and other less formal mechanisms, such as inquires into the FDA's activities. Congress has established standards of safety and effectiveness for all drugs and medical devices marketed in the United States. These standards are contained in the Federal Food, Drug and Cosmetic Act (FFDCA) (21 U.S.C. 301 et seq. [1982 & Supp. III 19851~. The FDA is the agency responsible for the administration of the FFDCA and is empowered to promulgate regulations to aid in its enforcement. The current FFDCA has undergone substantial legislative revisions since the original Pure Food and Drugs Act (Pub. L. No. 59-384, 34 Stat. 768 t19061) was

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94 DEVELOPING NEW CO=RACE"IVES passed in 1906 to prevent the misbranding or adulteration of foods and drugs. In 1938, Congress added safety testing requirements to the FFDCA in response to deaths caused by a drug that had not been tested for toxicity. The 1962 amendments, drafted in response to the thalidomide tragedy, required proof of effectiveness, including "adequate and well controlled trials," prior to approval of a new drug (Pub. L. No. 87-781, 76 Stat. 780 [1962]). With the 1976 Medical Device Amendments to the PPL,CA (Pub. L. No.94-295,21 U.S.C. 360b-360k [1976]), Congress required scientific evidence of safety and effectiveness prior to marketing new medical devices including IUDs, many of which were not adequately regulated prior to that time. Most recently, Congress passed the Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. No. 98417, 98 Stat. 1598, codified principally in 21 U.S.C. 355 and 35 U.S.C. 156), which accelerates FDA approval of generic drugs and allows restoration of up to five years of patent time lost in FDA's approval of pharmaceuticals. Congressional oversight of FDA's activities has played an important role in the approval of new contraceptives. Members of Congress have frequently responded to public concern about product safety by publicly questioning FDA officials regarding the agency's approval processes and decisions. This creates an environment of caution, in which Congress, representing public opinion, is seen to want little or no risk without significant therapeutic advantage. In 1983, for example, FDA officials were required to defend their approval of the Today contraceptive sponge (U.S. Congress, 1983~. Worries about congressional reaction are also widely believed to have helped determine the nonapproval of the injectable contraceptive, Depo-Provera. The FDA receives little public credit for the timely approval of a new contraceptive, but it may suffer a serious loss of public esteem for not identifying even small risks associated with new products. As stated above in the section on the development process, a developer of a new contraceptive does not need approval from the FDA to initiate conceptual work, laboratory testing, or preclinical research on animals. However, preclinical research is reviewed by the FDA when a contraceptive developer submits an application for FDA approval (21 C.F.R. 314.125,314.126 [19881~. Submission of an application to the FDA (21 U.S.C. 355(i), 360j~g) [1972 & Supp. 19881) and approval by an institutional review board (IRB), which is an oversight committee at the hospital or research institution (21 C.F.R. 312.66, 56.103 [19881), are required before the initiation of clinical seals of a drug or device on humans, and detailed regulations apply to the design and conduct of such trials (21 C.F.R. pt. 312 [19881~. Approval by the FDA is also needed before a new drug or device may lawfully be marketed (21 U.S.C. 355, 360e [19821; Buday, 1987~. Following FDA approval for marketing, a drug or device remains subject to numerous regulatory requirements with respect to manufacturing, labeling, and reporting of adverse experiences associated with it (21 U.S.C. 351-53, 360j~f) t19821~; 21 C.F.R. 314.80, 314.81 [19881~.

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RECULATION AND CO=RACEPTIVE DEVELOPMEV 95 FDA's Regulation of Drugs As described above, a party seeking to conduct clinical research (i.e., research on human subjects) on an unapproved new drug, known as the "sponsor," must submit to FDA's Center for Drug Evaluation and Research an Investigational New Drug (~D) application. The FDA requires preclinical studies before a designated new drug is tested in humans; the nature, scope, and duration of these studies depend on the nature and intended use of the drug. As the research, and therefore the use of the drug, expand in duration and/or number of subjects, the requirements for preclinical studies become more demanding. The sponsor of the research must also obtain approval from the internal review board affiliated with the institution at which the research will be conducted. The FDA has recently revised its regulations for the investigation of new drugs with a view to reducing regulation of the early phases of human trials (U.S. Department of Health and Human Services, 1987~. The FDA will seek to reduce reviews that were previously conducted solely to assess the scientific quality of the data produced by a particular protocol, but it will not reduce reviews conducted for the purpose of protecting the safety of research subjects. It has been argued that FDA has overregulated the early phases of research and unduly inhibited scientific flexibility (a criticism intended to be met by the revised regulations), and that its protections of human subjects are unduly costly and drive research abroad. Our society is unlikely to accept less demanding protection of research subjects, and it is not known how much FDA's regulations diminish the amount of pharmaceutical research done in the United States. The United States remains the most profitable single market for most kinds of drugs, and clinical trials serve not only to develop and confab scientific knowledge, but also to introduce a drug to physicians and the potential consumer market. The FDA's regulation of research on contraceptives has been controversial, particularly with respect to its requirements for testing for long-term carcinogenicity in dogs and monkeys. The questions raised relate to the appropriateness of using these animals as experimental models for humans. Changes in toxicological and clinical testing requirements for contraceptive steroids implemented in 1987, however, have eliminated some of the controversial dog and monkey testing requirements. Standards of Approval: Safety The FEDCA requires that an application for approval of a new drug "include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof . . ." (21 U.S.C. 355(d) t19821~. Approval is to be denied if"the results of such tests show that such drug is unsafe or do not show

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96 DEVELOPING NEW CO=RACE~IVES that such drug is safe for use under such conditions" (21 U.S.C. 355(d) [19821~. Any doubts about safety are to be resolved by denying approval. There has been little public argument that the statutory requirements for proof of safety or that FDA's interpretation and implementation of them have been unduly demanding. Indeed, the most frequent and persistent criticism of FDA's administration of the requirements for proof of safety has been expressed in congressional hearings called to chastise the agency for being insufficiently demanding. Yet FDA's requirements for proof of safety have been a principal and highly controversial obstacle to the introduction of new contraceptive steroids. The controversy over regulatory aspects of the safety of steroidal contraceptives focuses on two sets of issues: risk characterization and assessment and risk management (National Research Council, 1983~. The first set of issues relates to the identification and quantification of the risks presented by contraceptive drugs and, in particular, the scientific appropriateness of FDA's requirements for the toxicological screening of such drugs. That set of issues is considered in this section. The second set of issues relates to the judgment of what level of risks in a new contraceptive should, for purposes of FDA approval, be acceptable in light of the benefits provided by the contraceptive. That set of issues is considered later in this chapter. Toxicological Testing of Contraceptive Drugs Since the introduction of the fast oral contraceptives in the 1960s, the FDA's requirements for toxicological testing of proposed contraceptive drugs have been much more demanding than its requirements for the testing of other drugs. The rationale for the more severe requirements is that contraceptive drugs are intended for long-term use by millions of healthy women, most of whom have alternative contraceptive options. Given the assumed pattern of use, rigorous requirements to ensure a high degree of safety are justified. Controversy has focused, not on the FDA's objective, but rather on its strategy for achieving it. FDA requirements for toxicological testing in animal subjects have been revised over the past 20 years. In 1968 the deputy director of the FDA's Office of New Drugs summarized the agency's requirements for toxicological testing of new contraceptive drugs (Goldenthal, 1968:14~: We are currently requiring, as a minimum, a one-year toxicity study conducted in a rodent and the dog prior to initial clinical evaluation of [oral contraceptives] which usually consists of a three-cycle study in the human. We have also recommended, but not insisted, that a concurrent chronic study in the monkey be initiated. We have not stipulated any further toxicity requirements for continuation of these clinical pharmacology studies (Phase 2) as long as the chronic toxicity studies are ongoing. However, prior to the beginning of the large scale clinical trial (Phase 3), we have insisted that studies of up to 7 years duration in the dog and up to 10 years in the monkey be commenced.... The results of studies of 2 years duration in the rat, dog and monkey should be submitted in consideration for our approval of an oral contraceptive for marketing.

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REGULATION AND CO=RACEPTIVE DEVE~PME ~97 In the 1970s, FDA added a requirement that, prior to the initiation of large- scale Phase III clinical trials, two-year toxicity studies in rats, dogs, and monkeys be completed. Analysis of data from these animal studies can take up to two additional years, which are added to the overall time necessary for new drug development. These requirements remained substantially unchanged until August 1987, when FDA's Advisory Committee on Fertility and Maternal Health Drugs considered the "Guidelines for the Toxicological and Clinical Assessment and Post- Registration Surveillance of Steroidal Contraceptive Drugs," which had been adopted by the World Health Organization in July 1987. The advisory committee recommended several changes in FDA's requirements, which would have made them similar both to the WHO guidelines and to the FDA's requirements for noncontraceptive drugs. In October 1987, after concluding that the required tests on animals had not been proven to have relevance to human beings, the FDA made some of the recommended changes. The testing requirements before and after the 1987 changes are shown in Table 7.1. The testing requirements for 10-year monkey studies were completely eliminated. The 7-year testing period in beagles has been reduced to an interim testing period of 3 years, pending the release of a WHO study of the relevance of testing in beagles and its assessment by the FDA. FDA testing requirements for contraceptive steroids now conform more closely to the requirements for other drugs, with the exception of the 3-year dog studies required for contraceptive drugs. The former requirements for 7-year beagle and 10-year monkey studies were particularly burdensome for sponsors of new contraceptives. In addition, many scientists thought the beagle studies inappropriate from a scientific point of view because of the breed's high risk of breast tumors. Together with the other chronic toxicity testing required, these tests substantially increased the cost of developing new contraceptive drugs (Djerassi, 1970~. They also produced results that were interpreted as casting doubt on the safety of new contraceptives. The most dramatic case of such doubt has been Depo-Provera. The Case of Depo-Provera The process that resulted in the disapproval of Depo-Provera illustrates how the FDA reviews new drugs and the agency's concern for the safety of consumers. It also reveals the impact of congressional oversight as well as the impact of the legislative decision to place the burden of proof of safety on the drug sponsor. Depo-Provera (depot-medroxyprogesterone acetate) is an injectable contraceptive administered every three months. The drug's sponsor, the Upjohn Company, sought approval of Depo-Provera for contraceptive purposes in 1967; the drug has been approved by the FDA for noncontraceptive purposes since 1960. In 1968 a 7-year study in beagles and a 10-year study in rhesus monkeys were initiated. In 1972 a second 7-year beagle study was initiated due to high mortality (attributed to pyometra) in the first study. In 1974 the FDA initially

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REGULATION ID CO=RACEPT~E DEVE=PME ~99 decided to approve Depo-Provera as a contraceptive for a limited patient population, but, under congressional pressure resulting from concerns about cervical cancer, the agency deferred further action. In 1975, results from the first beagle study showed mammary tumors, including carcinomas, in treated dogs. In 1978 the FDA formally determined that Depo- Provera had not met the agency's safety standards. The FDA's reasons included the results in the first beagle study, its finding that there was no patient population in the United States that needed the drug, and its doubts about the feasibility of postmarketing surveillance in the United States to assess the risks of the drug. Upjohn sought review of the FDA's decision by a public board of inquiry, a "science court" composed of three nongovernmental scientists appointed by the Commissioner of Food and Drugs and acceptable to Upjohn; the board for the Depo-Provera proceeding was appointed in 1981. Id 1979, results of the 10-year rhesus monkey study showed endometria1 cancer in two monkeys in the high- dose group. In 1982 the results of the second beagle study were reported: a high incidence of mammary nodules and carcinomas was found. The public board of inquiry, after holding hearings and receiving reports from its own consultants, issued its report on October 17, 1984. It upheld the denial of approval of the contraceptive indication for Depo-Provera in the United States. The board concluded that the second beagle study was well designed and well conducted, that it showed a dose-response relationship, and that in the study the observed carcinogenic effects were attributable to Depo-Provera. It also concluded that the monkey study was poorly designed and conducted; that it did not show a dose-response relationship; but that uterine carcinomas in rhesus monkeys are unexpected and not known to occur spontaneously; and, therefore, that there was reason to assume that the carcinomas were related to the drug. The board concluded that, until proven otherwise, the endometrial carcinomas in the monkeys should be viewed as related to Depo-Provera This result was, in effect, an allocation of a burden of proof: in the face of a currently unexplainable adverse result, the burden is on the sponsor of the drug to show to the satisfaction of qualified scientists that a given result is not related to the drug in question, rather than on the regulatory agency to show that a result is related to the drug. This allocation of the burden is required by the FFDCA. Richard and Lasagna (1987) have analyzed how differences in drug regulatory philosophy and clinical requirements in the United States and the United Kingdom resulted in the approval of Depo-Provera for contraceptive purposes in the United Kingdom but not in the United States. The U.S. public board of inquiry and the U.K. review panel both reviewed the available scientific data, but their assessments and recommendations were quite different. In Great Britain, the panel reviewing Depo-Provera found that the evidence did not show that it was unsafe and therefore approved it. The U.S. board of inquiry found that the available evidence did not prove that Depo-Provera was safe, however, and therefore did not recommend approval. The difference in outcomes seems to have resulted not

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REGULATION ED CONTRACEPTIVE DEVELOPMENT 107 Health. Although the regulatory forms and terminology applicable to devices differ from those applicable to drugs, and the specific issues of safety vary between drugs and devices (as they do, of course, among drugs and among devices), substantially similar general requirements for the demonstration of safety and effectiveness and a favorable ratio of benefits to risks apply to both categories of products. The system for regulation of medical devices is more complex than that for regulation of drugs, and a full exposition is beyond the scope of this chapter (see Munsey and Samuel, 1984~. A brief summary is sufficient, however, for an understanding of how the FDA regulates contraceptive devices. Under the 1976 medical device amendments to the FFDCA, all categories of devices are classified by the FDA into one of three classes. Class I devices, the simplest and the least regulated, are subject to the statute's general controls: prohibitions of adulteration and misbranding; registration of manufacturers and listing of specific devices in submissions to the FDA; vulnerability to being banned if they are deceptive or present an unreasonable and substantial risk of illness or injury; vulnerability to an order by the FDA requiring notification to health professionals and others of a risk to the public health or an order by the FDA requiring repair, replacement, or refund; record-keeping and reporting obligations; vulnerability to an order by the FDA restricting the distribution of the device; and good manufacturing practice requirements. Facilities in which any device is manufactured, processed, packed, or held in the course of interstate commerce are subject to inspection by the FDA. There are no contraceptive devices categorized as Class I; examples of Class I devices include adhesive bandages and toothbrushes. Class II devices are subject to all the general controls that apply to Class I devices and are also, in theory, subject to performance standards developed or adopted by the FDA. Condoms and diaphragms are examples of Class II devices. In principle, Class II devices are ones for which the general controls "are insufficient to provide reasonable assurance of the safety and effectiveness of the device [and] for which there is sufficient information to establish a performance standard to provide such assurance...." (21 U.S.C. 360c~a)~1~(B) (1972 and Supp. 1989~. Thus far, however, the FDA has not established any performance standards, and there is no prospect that it will. This aspect of the statute has simply proven unworkable. The FDA's position is that, for Class II devices, the general controls, together with the FDA's general rulemaking authority, compliance programs, and enforcement actions provide adequate assurance of safety and effectiveness. Both Class I and Class II devices may be introduced into commercial distribution without prior approval by the FDA. Class III devices are subject to all the general controls that apply to Class I and Class II devices and are also subject to specific device-by-device premarketing approval by the FDA. Examples of Class III devices include tubal occlusion plugs, sterilization clips, and inert IUDs. The factors that determine whether a

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]08 DEVELOPING NEW CONT~CE~~ES

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RECULATIONkDCO~RACEPTIVEDEVELOPME ~109 The next stage in the FDA approval process for Class III contraceptive devices is the Premarket Approval Application (PMA), which is comparable to an NDA for a new drug (21 U.S.C. 360e [19821~. Once the PMA is received by the FDA, the agency attempts to respond to the applicant within six months. The product must be evaluated by an obstetrics and gynecology advisory panel that makes recommendations to the FDA regarding the approval of the device. For a new device that is claimed to be equivalent in safety and effectiveness to a pre-1976 device already on the market (e.g., condoms and diaphragms) and that FDA has classified as Class I or II (i.e., not requiring premarketing approval), the manufacturer must submit to the FDA a notice demonstrating equivalency to the already marketed product but does not have to submit a PMA (21 U.S.C. 360~) [19821~. The FDA review period for such applications is 90 days, but the actual review period may be longer due to incomplete applications from the manufacturer and requests for clarifications and additional evidence by the FDA. Impediments to FDA Approval A number of factors may cause delay in the approval of new drugs and devices. A 1980 study by the General Accounting Office (GAO) found the following problems: (1) FDA guidelines were imprecise; (2) reviewers of NDAs changed; (3) scientific and professional disagreements between the FDA and the industry were slow to be resolved; (4) the FDA's feedback to industry about deficiencies was slow; (5) chemistry and manufacturing control reviews were especially slow; and (6) the industry submitted incomplete NDAs. In recent years, however, the FDA has made significant efforts to eliminate or reduce some of these problems. For contraceptive products approved between 1962 and 1987, it is possible to calculate the mean duration between the date an NDA was received by the FDA and the date it was approved for marketing. For oral contraceptives (96 different formulations), the average time was 19 months; for intrauterine devices (5 products), it was 26 months; for vaginal contraceptive products (3 products), it was 13 months (FDA, 1988~. The recent changes by the FDA in toxicological testing requirements for new contraceptive steroidal drugs may help to speed up the approval process for new contraceptive drugs by reducing the amount of data the FDA must review. It should be mentioned, however, that the NDA review period is only a small fraction of the total time necessary to develop and obtain approval of a new contraceptive drug or device. Although claims have been made that the FDA is making progress in speeding the approval process, analysis of NDA approval trends for contraceptives shows mixed results. For example, of oral contraceptive NDA applications received in the 1960s (36 formulations), the average time to approval was 27 months; of oral contraceptive NDA applications received in the 1970s (37 formulations), the average time to approval had dropped to only 12 months. However, of oral contraceptive NDA applications received in the 1980s (23 formulations), the average time to approval had risen to over 16 months.

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1 10 DEVELOPING NEW CO=RACE~IVES Postmarketing Surveillance Some risk is inevitable with all contraceptives, whether it is a health risk or the risk of pregnancy because of contraceptive failure. It is impossible to know what the long-term risks or benefits of a new contraceptive will be until many years after the product has been in use and many thousands of person-years of use have accumulated. Increases in scientific knowledge of risks and benefits does not come in steady increments. The risks of oral contraceptives, for example, were known before many of their beneficial health effects were discovered. At present, postmarketing surveillance systems for contraceptive products are not adequate. No long-term epidemiological studies of the health risks and benefits of the new oral contraceptive formulations that have been introduced during the past two decades in the United States are under way. To evaluate the impact of oral contraceptives on diseases such as breast cancer, scientists must rely on data on higher-dose contraceptives, some brands of which have been taken off the market. In the past, consumers have carried the bulk of the burden of inadequate or nonexistent postmarketing surveillance in the form of higher prices for products or in the form of excessive injuries. Although the need for more postmarketing surveillance is clear, there are a number of obstacles to a successful surveillance system. These include the problems of confidentiality of medical records, development of appropriate data bases and methodologies, and financing these often very costly studies. Furthermore, there is often a long lag time between the actual experience of users and the final results of the analysis of postmarketing surveillance studies. Discussion of the details of this complex topic is beyond the scope of this report. As noted above, however, the assumption is that contraceptives are used for long periods of time by millions of healthy people and that there is a long latency period for the potentially most important and most worrisome risks. Thus, although we do not wish to make detailed recommendations on improvements in postmarketing surveillance systems, we believe such improvements are necessary. CONTRACEPTIVE REGULATION: AN INTERNATIONAL PERSPECTIVE Like the FDA, national drug regulatory agencies in other countries have requirements for the approval of contraceptives that exceed the requirements for other drugs (Rowe, 1983~. These additional requirements exist because (1) prevention of unwanted pregnancy is not considered to be a curative therapy or prophylaxis; (2) recipients of contraceptive drugs are still exposed to the risk of pregnancy because no contraceptive is 100 percent effective; and (3) contraceptive drugs are taken for longer periods than most other drugs. Regulatory standards for drugs and medical devices vary among countries with respect to: (1) product development, (2) effectiveness, (3) safety, (4) packaging

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REGULATION AND CO~RACEPTIVE DEVELOPME ~ ~ ~ and quality control, (5) instructions for use, (6) consumer protection, (7) product availability, and (8) pricing (Cook et al., 1982~. Although differences among countries in regulatory requirements are probably related to international differences in contraceptive development efforts, broader social and economic factors play a much more important role in determining the extent to which contraceptive development takes place in particular countries. A 1980 study by the General Accounting Office identified several key differences in the regulatory processes in the Netherlands, Norway, Sweden, the United Kingdom, and Canada compared with the United States (GAO, 1980~. The GAO concluded that the regulatory processes in these countries were generally faster and more flexible. Among the key differences between the countries studied and the United States were: (1) greater use of expert committees, (2) greater acceptance of foreign data, (3) less politicizing of the drug approval process, and (4) greater cooperation between regulators and industry (GAO, 1980; National Academy of Engineering, 1983~. The mean number of months from the NDA application for marketing a new drug to the date when regulatory approval was granted varied widely among the countries: the United Kingdom, 5 months; Canada, 16 months; Norway, 17 months; the United States, 23 months; and Sweden, 28 months (GAO, 1980~. It should be pointed out, however, that the period from the filing of the NDA to the date of approval is only a very short segment of the total time required for new drug development. Furthermore, these figures include applications with very minor changes or modifications that are included as NDAs. Regulation in Europe European pharmaceutical firms generally follow the European Economic Community (EEC) directives for new drug applications when submitting new contraceptives for approval in Western Europe. Following approval in one EEC country, a drug company may expect expeditious reviews in other EEC countries. Nevertheless, simultaneous submissions to several countries are frequently made to circumvent possible delays in the review procedure in the first country. This approach is viewed by the drug industry as superior to the establishment of a complex supranational European regulatory agency. Some European drug industry experts view the FDA's revision of its toxicological and clinical testing requirements for new contraceptive steroids as a very positive development. Moreover, although a 3-year beagle study is still required by the FDA and none is required by EEC countries, the FDA has indicated that this requirement will be reviewed in light of the findings of a study currently being completed. Although toxicological requirements for testing new contraceptive steroids in Europe and the United States are now much more similar than they have been, European drug companies are still concerned about such issues as whether approval will be granted on the basis of European clinical data

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~ 12 DEVELOPING NEW CO==CE~~ES only, the FDA's monitoring requirements for clinical studies conducted outside the United States, and FDA requirements for availability of raw data on the subjects of clinical research. The lack of price control makes the United States an attractive country for the introduction of new contraceptive products. In Europe, the prices of contraceptives are normally controlled by governments, and companies claim that low profit margins barely allow recovery of R&D costs. Because of the size of the U.S. market, as well as its potential for higher profits than Europe, regulatory changes in the United States may affect contraceptive development activities in Europe as well as in the United States. The United States is not the only country that has seen a decline in the effective patent life of contraceptives and other pharmaceuticals. No patent life restoration legislation exists in Europe. However, the United States and the EEC both have legislation that protects the exclusive marketing rights of a pharmaceutical company that submits a file for regulatory approval, regardless of the patent situation. In Europe, fees of new products remain inaccessible (and therefore cannot be used by competitors to gain marketing approval for generic copies) for up to 10 years from the time the first EEC country approval has been granted; in the United States the FFDCA grants up to 5 years of exclusive marketing rights from the time of FDA approval. Formal patent life in the United States is 17 years, while in Europe it is 20 years. Regulation in Developing Countries Because of limited resources and limited expertise, many developing counties base their regulatory decisions on the status of drugs or devices in the developed countries where they are produced or marketed. For example, the Zimbabwean government, through its Drugs Control Council, will not approve any drug that is not approved for public use in its country of origin (Mutambirwa, 1988~. A number of developing countries, such as Bangladesh and Nepal, do not rely on the status of a product in the exporting country; in those countries, the ministries of health oversee the approval of new drugs and medical devices (including contraceptives). A special medical review panel is often established to perform this function (Cook et al., 1982~. A few developing countries have well-established drug registration agencies, whose principal concern is the introduction and sale of new drugs (Rowe, 1983~. In those countries, import and export restrictions, tariffs, laws governing manufacturing, and corporate and university research could have an important effect on the development and introduction of new products. This is the case in India, where research on new contraceptives is well advanced. The current government of India has made several changes in the domestic regulatory environment that are encouraging greater growth and development of a private pharmaceutical industry (e.g., exempting venous pharmaceutical products from

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RECU~TION AND CO=RACEPTIVE DEVELOPME ~1 13 licensing requirements; easing of licensing requirements for additional capacity; and relaxing controls over foreign collaboration). The revised governmental policies have encouraged the private sector to begin to produce contraceptives. In 1987, the production of Copper T200 IUDs was initiated by both the public and the private sectors. The government is also encouraging private-sector involvement in the production of oral contraceptives and has recently removed price controls for oral contraceptives. The World Health Organization's Role In addition to its efforts to develop new contraceptives, the World Health Organization plays a role in the regulation of contraceptives. WHO works with governmental agencies, pharmaceutical companies, and nonprofit research organizations on the international harmonization of drug regulations; on updating official requirements for preclinical and clinical assessments of new fertility regulating agents; on postmarketing surveillance of contraceptives; and on the provision of advice and assistance, especially to developing countries, on the safety and efficacy of contraceptives. In recent years there has been increasing international cooperation among drug regulatory agencies in different countries, as well as between the international pharmaceutical fines and regulatory agencies Lasagna and Werko, 19863. The World Health Organization has helped bring about more international uniformity in the regulation and control of pharmaceutical drugs and other medical products. As of the early 1980s, 55 developing countries were participating in WHO's "Certification on the Quality of Pharmaceutical Products Moving in International Commerce Scheme" (Rowe, 1983~. This program provides information to importing countries about whether a given product has been authorized to be placed on the market in the exporting country and, if it has not been authorized, on the reasons why. There has been some discussion about establishing uniform international drug regulations, but to date little interest in this has been shown by pharmaceutical companies or national drug regulatory agencies (Rowe, 1983~. Since many countries do not have strong drug regulatory agencies and since the regulatory requirements and procedures of other countries vary widely, some have proposed that WHO regulate at least some products. In 1982, for example, representatives from the International Planned Parenthood Federation suggested that WHO become "an international drug regulatory mechanism for contraceptives" (WHO, 1984:1~. This idea was reiterated at the International Symposium on Research on the Regulation of Human Fertility in 1983. In fact, a review was undertaken by WHO to explore "the role WHO might play, the feasibility and the additional cost of becoming an international drug regulatory agency for contraceptives" (WHO, 1984:1~. WHO concluded that it did not have a mandate from its member states to establish itself as a regulatory authority. Whether or not WHO assumes formal

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1 ~4 DEVELOPING NEW CO=^CE~IVES regulatory responsibilities, increasing the role it plays internationally in providing advice, assistance, and information on the safety, effectiveness, and regulatory status of new contraceptive drugs and devices would probably help to facilitate international decisions regarding the approval of new contraceptive products. RECOMMENDATIONS The committee does not wish to reduce the safety requirements applicable to contraceptives. Instead, our objective is to add new criteria to the evaluation of safety to make it more meaningful and more specific to different groups of potential users. The committee recommends that the FDA increases the weight it assigns to contraceptive effectiveness and convenience of use. The effect of such a change is that a benefit-risk ratio that currently would be viewed as inadequate to support approval might be viewed as adequate. Such an approval should be subject to certain conditions intended to ensure that the approval will increase, rather than decrease, the long-term health of users of the new contraceptive. First, whenever appropriate such a contraceptive should be indicated only for a well-defined population that, in fact, is not adequately served by other contraceptives. Second, both the physician labeling (in professional language) and patient labeling (in lay terms) of the contraceptive should discuss the basis for the FDA's benefit-risk assessment and any and all significant risks to health presented by the contraceptive. The labeling should also suggest that a decision on whether or not to use the contraceptive should take into account the full array of risks presented by the contraceptive, the importance of avoiding pregnancy for health or other reasons, the effectiveness of this particular contraceptive, and the relative benefits and risks of other methods. The point of the labeling is that the patient, with advice from the physician, should make an informed choice. Third, approval should be followed by long-term studies of actual effectiveness in use and of adverse effects and any health benefits from use. The committee does not consider an increase in the weight ascribed to contraceptive effectiveness and convenience to be a major change in the FDA's regulation of contraceptives or a departure from the public policy that the FDA applies with respect to other drugs. Rather, we view it as an effort to make the FDA's regulation of contraceptive drugs and devices more similar to its regulation of other drugs and devices. The committee does not believe that the proposed change would justify, or would bring about, any reduction in public confidence in the effectiveness or safety of contraceptive products. The purpose of the change is to provide new contraceptives for particular groups in the population who are not adequately served by the current array of contraceptive products. For these subpopulations, we wish to encourage the FDA to consider new contraceptives that are effective and that- in light of their effectiveness and other qualities, and given the relative advantages and disadvantages of other contraceptive options and the needs of individual users have a risk profile that is acceptable socially,

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REGULATION AND CONTRACEPTIVE DEVELOPMENT 115 medically, and to the value systems of users. If these limitations are adhered to, and if proper information is provided to physicians and patients, this proposed change (together with the other changes proposed by the committee) should have no effect on the rules of products liability that should otherwise be applicable to contraceptive products (see Chapter 8~. Contraceptive effectiveness helps women not only avoid unwanted pregnancy, but also avoid the medical risks that, for some women, would be associated with pregnancy and childbirth. Convenience is crucial to acceptability and actual use and therefore to effectiveness of use in a nonclinical setting. More generally, control of fertility itself is of very great value to many women and men; that value, even though unquantifiable, should be recognized in benef~t-risk evaluations. The FDA should also be prepared to approve, in some circumstances, a new contraceptive drug or device that presents a risk if it is shown that the new contraceptive offers a safety advantage for an identifiable group of users when compared with that group's current actual contraceptive practice (including nonuse). That is, in some circumstances a new contraceptive may, for some users, be safer than currently used contraceptives, even though the new product presents a risk that is nontrivial, and even though equally or more safe contraceptives are available but are not used by that group. In such circumstances, denial of approval of the new product on the ground that it presents a significant risk would be a disservice to the safety of users. Thus, although the committee strongly endorses the FDA's paramount concern for the safety of users of contraceptives, we believe that concern can be most effectively exerted by changing the current standard applied by the FDA for approval of new contraceptives. The proposed change would still impose on contraceptives a safety standard more demanding than that for other drugs and devices (which are not required to show a safety advantage compared with previously approved products). The committee also recommends that a comprehensive postmarketing surveillance system be established to provide systematic and timely feedback about positive and negative health effects of contraceptive products. Such a system of postmarketing surveillance would ensure that products that are later found to be unsafe are removed from the market or are more strictly controlled through product labeling and health warnings for subpopulations found to be at risk. Systematic and controlled postmarketing surveillance would help to avoid episodes that have occurred with certain intrauterine devices in the United States. The committee recommends that an international conference of drug regulatory officials be held to increase the priority that such officials give to contraceptive development, to harmonize the regulatory requirements of different countries to the extent possible, to discuss the need for greater postmarketing surveillance of new contraceptives, and to clarify the basis for regulatory decisions in individual countries. Such a conference, in the view of the committee, would make the need for new contraceptives and the opportunities of their development more visible. The Food and Drug Administration should complete its review of its

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~ 16 DEVELOPING NEW CO=RACE~IVES toxicological requirements for the evaluation of contraceptive products, especially its continued use of the beagle dog. The committee does not recommend any change in toxicological testing requirements that would significantly reduce confidence in the safety of contraceptives or the amount of relevant data that is useful in guiding prescribing decisions. The issue over the beagle dog has turned on whether that model is relevant to the assessment of safety, and whether studies of beagles provide data useful in prescribing steroidal contraceptives for humans. A decision to eliminate that testing requirement would be based on a scientific judgment that the requirement does not add to human safety. The elimination of the requirement on that basis would provide no justification for any change in the principles of products liability otherwise applicable to contraceptive products (see Chapter 8~. A report should be prepared by an independent body three to five years hence to assess FDA requirements with respect to contraceptives. The committee recommends that the FDA continue to evaluate ways to improve the toxicological and clinical trial requirements for contraceptive agents. Although the committee believes that it is too early to assess the effects of the Drug Price Competition and Patent Term Restoration Act, further study of effective patent life is needed and a report on the effects of the act, with particular reference to contraceptives, should be undertaken in the mid-1990s. CONCLUSION Congress and the Food and Drug Administration have made a number of important changes during the past few years, which are likely to influence the course of contraceptive research and development FDA has revised its regulations governing the early phase of drug research; because most research at this phase does not lead to marketed products or even to extensive additional research, the changes that the FDA has made are intended to reduce delays without reducing the protection of human subjects. The FDA has also reduced the toxicological testing requirements for new contraceptives, which were previously more rigorous than the requirements for most other drugs. The enactment by Congress of the 1984 Drug Price Competition and Patent Term Restoration Act also increases the incentives for new drug development, including development of new contraceptive products. Although the committee believes that considerable progress has been made in the FDA's regulation of contraceptive products, fundamental questions remain regarding standards of safety and effectiveness applied to contraceptive products. As argued in Chapter 2, the current array of contraceptives fails to meet the needs of a substantial number of men and women in the United States. Currently available contraceptives present significant risks, have significant failure rates in actual use, make demands on users that many cannot or do not in fact meet, or are inconsistent with the mores, practices, and deep-seated preferences of users or

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REGULATION AND CONTRACEPTIVE DEVELOPMENT 117 their sexual partners. The results, as discussed in Chapter 2, show that, even in the United States, there is substantial need for better and more varied contraceptive drugs and devices. In particular, some of the contraceptives that are most effective and intrude least in sexual practices for example, contraceptive steroids, however delivered~re also more risky than less effective methods and, for large groups of women (those over 35 who smoke), carry an added risk or are even contraindicated. Commissioner Hayes's statement of FDA's safety standard for contraceptives quoted earlier in this chapter does not adequately take into account the number of women who have health conditions for which existing methods are inappropriate or who for personal reasons find the existing methods unacceptable. In saying that contraceptives are used by healthy women, the commissioner does not recognize that a large number of women have contraindications for some available methods of contraception but are not sick as we ordinarily understand that term. For example, nursing mothers, women over the age of 35 who smoke cigarettes, and women with diabetes or hypertension have contraindications for the pill; nevertheless, we would not ordinarily think of these women as unhealthy. Equally important, in the case of contraceptives, effectiveness must be taken into account in calculations of safety. Methods with fewer side effects are not necessarily safer if they have higher failure rates. The risk of an unwanted or high-risk pregnancy must be weighed in the calculation of the safety of methods. The FDA needs to consider both effectiveness in clinical trials and effectiveness in general use in its approval process for contraceptive drugs. A contraceptive that has a low risk of unwanted pregnancy in actual use is an effective product. When considering the trade-off between benefits and risks, the benefits need to include gains in actual effectiveness when compared with existing methods. A range of contraceptives is essential to fit the needs of all potential users. Not all clinically effective drugs are effective for all people in actual use. The FDA therefore needs to consider the target population for any proposed drug to evaluate its effectiveness. In other words, a new contraceptive may offer no benefits in effectiveness compared with other methods under ideal conditions, but it may provide increased effectiveness to a particular population ill served by existing methods. This consideration should be given greater weight in the FDA's regulatory evaluations than it has been given in the past. It is important when evaluating a new contraceptive to compare its overall safety with that of already available methods. Account should be taken not only of new risks presented by the new method, but also of its advantage in not presenting risks known to be presented by the existing methods. For example, the fact that Depo-Provera did not affect coagulation or hypertension (whereas some contraceptive preparations do) was not generally considered in calculations of risks and benefits.