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OCR for page 89
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
OCR for page 98
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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.
Representative terms from entire chapter:
contraceptive development
