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7
Federal Laws and Regulations
This chapter and the next discuss the issue of federal and state laws and
regulations and the disincentives in developing new anti-addiction medications
to the industry. This chapter includes a discussion of the drug-development
process, focusing on the multiple interactions between the private sector and
federal regulatory agencies, specifically the Food and Drug Administration
(FDA) and the Drug Enforcement Administration (DEA), necessary to develop
and bring to market an approved anti-addiction medication. This chapter also
presents recommendations aimed at accelerating drug discovery and development
by removing obstacles to the private sector.
CREATION OF A DRUG BY THE
PHARMACEUTICAL INDUSTRY
More than 90 percent of new drugs are discovered by scientists in the
pharmaceutical industry (Kaitin et al., 1993; PMA, 1993b). With rare exceptions,
the remainder are derived from the work of academic or government scientists
(Kaitin et al., 1993~. Even for drugs discovered outside the industry, a
partnership or licensing agreement with a drug firm is ultimately necessary for
development, manufacturing, and marketing. The process used by the pharmaceu-
tical industry to turn a compound into an agent that can be used by patients (e.g.,
a tablet or an injectable medicine) can be divided into three stages (Figure 7.1~:
discovery, development, and marketing (Knoop and Worden, 1988; Spilker and
Cuatrecasas, 1990; Agersborg, 1993~.
154
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FEDERAL LA US AND REGULATIONS
.
155
Drug discovery consists of a complex set of laboratory research activities,
conducted mainly by chemists and pharmacologists (or molecular biologists in
the case of the biotechnology industry), from which emerges a compound or a
set of related compounds with a specified biological activity, e.g., inhibition of
a key enzyme or receptor. The hope is that such a compound, when subjected to
further testing (the process called drug development), will prove to be a useful
therapeutic agent for a disease in which, e.g., that enzyme or receptor plays a
role. New compounds are identified through such approaches as screening large
numbers of compounds for the desired biological activity, optimizing molecular
structures, using computer-assisted molecular modeling, and testing active
compounds in animal models of the relevant disease, when such models exist
(Spilker and Cuatrecasas, 1990; PMA, 1993a; Rapaka and Hawks, 1993~.
Scientists engaged in drug discovery use the scientific techniques of basic
biomedical research, but the goals of the enterprises are different. The purpose
of basic research is to advance knowledge and to make it available to the
scientific community at large. Basic research is usually funded by government
and conducted by academic or government scientists, and its product is public
information in written, visual or electronic form. In contrast, the purpose of drug
discovery is to identify new substances of potential value in the treatment or
prevention of disease. Drug discovery makes use of basic biomedical knowledge,
but its end products are a new chemical entity and information on what it does;
much of this information is considered proprietary, and new chemical entities are
patentable as inventions. Drug discovery as an organized enterprise takes place
almost exclusively in the pharmaceutical industry. When a new drug is discov-
ered outside the pharmaceutical industry, it is usually a biotechnology product
that is an outgrowth of basic research (an event that is likely to become more
common) or a product of a collaborative government-industry or university-
industry partnership.
Drug development consists of studies on a potential new drug to determine
what it does in humans, whether it is safe and effective for the treatment or
prevention of a disease, and whether it is properly labeled. The studies include
toxicity studies in animals and clinical studies in humans that are customarily
divided into three phases:
Phase I clinical trials in which healthy volunteers receive the drug,
and tests are conducted to determine pharmacological information including
absorption, blood concentrations, metabolism, initial side effects and, if
possible, mechanism of action and efficacy.
· Phase II clinical trials involve several hundred patients in which
evidence on efficacy and dose-response relationships are obtained.
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156
DEVELOPMENT OF MEDICATIONS
· Phase Ill clinical trials involve several hundred to several thousand
patients in which efficacy and safety are demonstrated in hospital and
outpatient settings.
During drug development, the formulations to be marketed (e.g., tablets,
capsules, injections) are also developed, and the manufacturing process is scaled
up progressively and optimized (Figure 7.1) (Spilker and Cuatrecasas, 1990~.
When a compound is ready for the first clinical study in humans (Phase b,
it falls under the regulatory authority of FDA and an investigational new drug
(IND) application is submitted to the agency. During the remainder of the drug-
development period, there is extensive interaction with FDA that includes
consultation on the development plan and protocols, the submission of data on
serious and unexpected adverse events, and the submission of periodic reports.
When the manufacturer has completed the drug-development program, all the
information on the formulations, the manufacturing process and plant, toxicity
in animals, and clinical effects in humans is submitted in a new drug application
(NDA). An important document in the NDA is the proposed package insert,
which states that the drug has been shown to be safe and effective and provides
directions for use. The NDA is then reviewed by FDA, often with considerable
interaction between the agency and the manufacturer; the process might include
open review by an advisory committee. If all parts of the NDA are judged to
meet the standards prescribed by federal law and regulations, it is approved.
The final step in the creation of a new drug is marketing. This ordinarily
lasts many years unless (as happens rarely) the drug must be withdrawn because
of a safety problem. An important characteristic of the marketing period, not
widely recognized by the public, is that new uses for a drug are often found after
initial marketing as the result of serendipitous discovery by an astute clinician or
planned studies by clinical investigators in new patient populations. Sometimes
such a new use is more important medically than the use for which the drug was
originally developed. The discovery of new uses after initial marketing has
proved to be a particularly powerful route to innovation for psychoactive drugs,
inasmuch as their effects are not easily predicted from animal models and must
usually be identified and proved in humans. Indeed, most of the drugs now in
use or in the later stages of evaluation by NIDA for the treatment of opiate or
cocaine addiction were originally developed for other medical indications (Wes-
son and Ling, 1991; NIDA, 1990~.
The total cost of creating (discovering, developing, and marketing) a new
drug has been analyzed in several studies (Wiggins, 1987; Grabowski and
Vernon, 1990; DiMasi et al., 1991) and recently reviewed by the Office of
Technology Assessment (OTA, 1993~. OTA concluded that "in 1990 dollars, the
mean cash outlay required to bring a new drug to market (including the costs of
failures along the way) was approximately $127 million for drugs first entering
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FEDERAL LA US AND REGULATIONS
157
human testing in the 1970s." If capitalized costs (the so-called "cost of time")
and tax deductions are considered, the after-tax cost per marketed drug estimated
by OTA was "somewhere between $140 and $194 million (in 1990 dollars)." A
little more than half the total cost went to preclinical activities such as drug
discovery, chemical synthesis, formulation development, and toxicology and the
remainder went to clinical development. The mean time to create a successful
drug was about 12 years. Corresponding figures for the biotechnology industry
are not available.
To assess the adequacy of the budget of the NIDA Medications Development
Division (MDD), it is most useful to consider actual cash outlays by pharmaceu-
tical companies, inasmuch as the capitalizing of expenditures and tax deductions
do not apply to MDD. In this context, the cash outlay for Phase III studies of
marketed drugs was estimated by DiMasi and co-workers (1991) to be $14.3
million in 1990 dollars; that figure was supported by OTA (1993~. Those costs
r~r`^ri~ril`' romeo r~ni~llv_fz~ct~r then the rate of general inflation- during the
1 ~l)V1 ~1] 1 V ~- ~ ~ AM ~ } ^ ~ ~_^ ~ ~ _ _ _
1980s and presumably continue to do so.
On the basis of those figures and informal estimates given by the pharma-
ceutical executives who met with the committee, the committee believes that
$10~0 million is a reasonable estimate for the average cash outlay to develop
a major new indication for an already-approved drug. The cash outlay for the full
development of a new compound would presumably be near the industry average,
i.e., in the range of $100-200 million. For a shared development pro-
gram MDD in partnership with a private organization in which the govern-
ment supported clinical development, the cash outlay of public funds would be
about half the total cost.
Individual pharmaceutical and biotechnology companies have continuing
research programs searching for new psychoactive chemicals; some might also
have marketed drugs that could be useful in treating one aspect or another of
addiction in addition to their primary uses. Individual firms also have the
technology for developing, manufacturing, and marketing such drugs. NIDA has
research funds to support the development of improved animal models and
screening techniques, an operating clinical investigator network, funds to support
the clinical development of new drugs and new indications, and a relationship of
trust with FDA. Given the enormous amounts of time and money required for
pharmaceutical research and development, a collaborative approach between the
government and the private sector that pulls complementary resources together
appears to be highly desirable.
Chapter 3, in its assessment of MDD, considered the interactions between
the private sector and NIDA. The remainder of this chapter addresses the ways
in which FDA and DEA interact with the private sector and provides committee
recommendations to remove federal regulatory disincentives.
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Representative terms from entire chapter:
controlled substances
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FEDERAL LAWS AND REGULATIONS
FOOD AND DRUG ADMINISTRATION
159
Complaints that the traditional FDA drug-approval process is too slow and
discourages drug development are not new. In recent years, however, the tradi-
tional process has undergone changes designed to expedite FDA review and to
expand the use of experimental treatments under some circumstances. The User
Fee Law was passed in 1991 to expedite review and approval of new drugs. In
addition, the federal Food, Drug, and Cosmetic Act (FDCA) provides special
incentives to manufacturers of particular categories of drugs. These incen-
tives such as accelerated approval, treatment INDs, and orphan exclusivity are
also available to manufacturers of new anti-addiction drugs. For example, LAAM
(levo-alpha-acetylmethadol), which on July 9, 1993, became the first narcotic
maintenance drug approved since methadone, was granted orphan exclusivity for
use in the treatment of heroin addiction suitable for maintenance with opiate
agonists. LAAM also was given an expedited final review by FDA (see LAAM
case study in Chapter 84.
The recent changes to the traditional drug-approval process might provide
additional opportunities for encouraging and expediting the development of anti-
addiction medications.
Recent Initiatives to Expedite Availability of New Drugs
Of particular importance is a series of initiatives intended to expedite the
availability of drugs to treat serious and life-threatening diseases for which no
adequate therapeutic alternatives exist. The acquired immune deficiency
syndrome (AIDS) crisis was the driving force behind these efforts, but products
intended to treat a variety of other conditions including drug addic-
tion properly qualify for treatment under these initiatives. The first such
initiative was the treatment-IND mechanism, established in 1987, which allows
expanded access to some experimental treatments before they are approved.
Under the treatment-IND regulations, FDA may approve the distribution of an
investigational drug outside the context of controlled clinical trials to treat
patients with serious or immediately life-threatening diseases for which no
comparable or satisfactory alternative therapy is available [21 CFR § 3 12.34a.
For this purpose, FDA defines a disease, including a stage in the progression of
a disease, to be immediately life-threatening if "there is a reasonable likelihood
that death will occur within a matter of months" or "if premature death is likely
without early treatment" [21 CFR § 312.34(b)~3~(ii)~. Whether a disease or a
particular stage of a disease is serious depends on "its impact on such factors as
survival, day-to-day functioning, or the likelihood that the disease, if left
untreated, will progress to a more serious one" (FDA, 1992a). The standard for
160
DEVELOPMENT OF MEDICATIONS
FDA approval of a treatment IND in the case of a "life-threatening disease," in
turn, is whether the "available scientific evidence, taken as a whole," provides
a "reasonable basis" for concluding that the drug "may be effective for its
intended use in the intended patient population" and would not expose patients
to an "unreasonable and significant additional risk of illness and injury" t2 1 CFR
§ 312.34(b)~3~(i)~. For a "serious disease," the standard is whether there is
sufficient evidence of safety and effectiveness to support treatment use [21 CFR
§ 312.34(b)~2~.
Most of the customary IND procedural requirements apply to treatment
INDs, including informed-consent requirements and prohibitions on proapproval
promotion or other commercialization of experimental treatments (although
companies normally may charge to cover costs) [21 CFR §§ 312.34(c),
312.7(d)~2~. In addition, the drug sponsor is expected to continue conventional
clinical trials and to pursue marketing approval of the drug with "due diligence"
[21 CFR § 312.34(b)(iv)~. Among the products that FDA has approved for
treatment-IND status are drugs for the treatment of hairy-cell leukemia, AIDS
and AIDS related conditions, Alzheimer's disease, multiple sclerosis, respiratory
distress syndrome in infants, Gaucher's disease, obsessive-compulsive disorder,
Parkinson's disease, and ovarian cancer (FDA, 1993c).
Although the treatment-IND program was designed primarily for patients
who could benefit from earlier access to promising experimental drugs, it
theoretically offers potential benefits from a sponsor's perspective as well. It
allows recovery of developmental costs earlier in the process than might
otherwise be possible. It also offers the chance to familiarize patients, prescribers,
and payers with a product earlier in the process, and this can facilitate the formal
introduction and initial marketing of the product (as long as the sponsor keeps
applicable restrictions on proapproval promotion and commercialization in mind).
Given that drug addiction should qualify as a serious, and even a life-threatening,
disease for treatment-IND purposes,
The committee recommends that the FDA make the treatment-IND
route available for anti-addiction medications.
A second mechanism, known as parallel track, also extends the availability
of investigational treatments. Although it is now limited to AIDS patients,
parallel track might be adapted to a program tailored to meet the needs of drug-
addicted patients in combating addiction. Under parallel track, "promising"
investigational agents may be provided to AIDS patients who are not able to take
standard therapy or for whom standard therapy is no longer effective and who
are not able to participate in clinical trials (U.S. DHHS, 1992~. Parallel-track
drugs are thus distributed entirely outside the controlled clinical-trial framework,
although they must be under a study protocol and data on safety and side effects
FEDERAL LA US AND REGULATIONS
161
must still be collected (U.S. DHHS, 1992~. The evidence of effectiveness needed
for a parallel-track drug is less than that generally required for a treatment IND;
the parallel-track standard is "promising evidence of efficacy" combined with
evidence that the drug is "reasonably safe" (U.S. DHHS, 1992~. In reviewing a
parallel-track proposal, FDA looks at such factors as evidence of a lack of
satisfactory alternative therapy and the possible impact of the parallel-track study
on the controlled trials that will be the primary source of evidence of the drug's
efficacy (U.S. DHHS, 19921.'
With its goals of reaching patients beyond the scope of standard therapy or
conventional clinical trials, parallel track provides a prototype for expanding
access to treatment to addicted patients, who share some general characteristics
with AIDS patients. For example, it is often difficult to find drug-addicted
individuals who qualify as subjects for controlled clinical trials. Both population
groups include members who might take other drugs that confound the
interpretation of controlled clinical trials. For AIDS patients, the issue is
exposure to other treatments; for drug-addicted patients, the issue is polydrug
use. In addition, as with AIDS, there can be important ethical and recruitment
issues with respect to placebo (or no-treatment) controls. Furthermore, a parallel-
track procedure that would reach addicted individuals who might otherwise fall
outside the system (at least at the testing stage) might further the important
public-policy goals of preventing and treating drug addiction. Therefore,
The committee recommends that FDA include medications for drug
addiction in the parallel-track mechanism.
Another important development aimed at speeding the drug-approval process
is FDA's accelerated-approval program. Adopted in its final forth in December
1992, accelerated approval is available for drugs that offer "meaningful therapeu-
tic benefit compared to existing treatment" for "serious or life-threatening
illnesses" and whose approval is to be based on evidence of the drug's effect "on
a surrogate end point that reasonably suggests clinical benefit or . . . on a clinical
'In addition, some formal IND requirements do not necessarily apply, most notably
supervision by an institutional review board. However, the parallel-track policy statement
contemplates a national panel of"human subjects" to protect patients in parallel-track
programs. At least in theory, individual patients seeking access to parallel-track treatments
must satisfy a fairly detailed and stringent set of entry criteria designed to exclude patients
who could take standard approved treatments.
162
DEVELOPMENT OF MEDICATIONS
end point other than survival or irreversible morbidity" (FDA, 1992b).2 Such
approval will be conditioned on completion of postmarketing clinical studies to
"verify and describe [the drug's] clinical benefit and to resolve remaining uncer-
tainty about the relationship of the surrogate end point to clinical benefit" (21
CFR § 314.51 0~. Drugs approved under the accelerated procedure are also subject
to a streamlined procedure for withdrawal of approval, e.g., if a postmarketing
clinical study fails to verify clinical benefit (21 CFR § 314.530~. Thus,
The committee recommends that, to the extent that a valid end
point for the effectiveness of an anti-addiction medication might be
established, accelerated approval be available.
The committee is impressed that these newer administrative mechanisms for
drug distribution under INDs and for more rapid approval are properly applicable
to anti-addiction medications, but it notes that FDA has not included anti-addic
tion medications in its public statements or written examples in the Federal
Register related to these new policies.
We encourage the commissioner of FDA to announce clearly (in
public statements and the Federal Register) that treatment IND,
parallel track, and accelerated approval are applicable to anti-
addiction medications as an incentive to private investment in this
field.
Market Exclusivity and Orphan Drug Status
Other potential sources of incentives for anti-addiction drug development are
the various statutory exclusivity provisions. The 1984 Drug Price Competition
and Patent Term Restoration Act (DPC-PTR Act, Public Law 98-417), which
amended the FDCA, gives a sponsor of a drug that is a new chemical entity 5
years of market exclusivity after NDA approval, during which time no other
sponsor may submit an abbreviated application for a generic version of the same
drug [FDCA §§ 505(c)~31(D)(ii), 505(j)~41(D)(ii)~. Manufacturers of drugs
approved for a new indication are granted 3 years of exclusivity for the new
indication if new clinical tests were "necessary" to support the approval [FDCA
§§ 505(c)~3~(D)(iv), 505(j)~4~(D)(iv)~. In addition, the DPC-PTR Act allows a
Surrogate end points are clinical or laboratory measurements that correlate with
patient benefit, such as CD4+ blood-cell counts as a basis for assessing the efficacy of
AIDS drugs or reduction in blood pressure as a predictor of decreased mortality or
morbidity due to hypertensive cardiovascular disease (e.g., stroke, heart failure, and
myocardial infarction).
FEDERAL LAWS AND REGULATIONS
163
manufacturer to obtain an extension to its patent term for a portion of the term
lost while the product was in regulatory review if the sponsor pursued its market-
ing application with due diligence (35 USC § 156~.
A separate basis for exclusivity is the Orphan Drug Act (Public Law 97-414,
FDCA §§ 525-528~. This law, enacted in 1983 and amended several times, is
intended to encourage the development of drugs needed to treat rare diseases
whose potential sales might not justify funding of the animal and clinical trials
needed to bring products to approval. The standard for orphan status is whether
a drug is intended to treat a "rare disease or condition," i.e., a disease or
condition that affects fewer than 200,000 persons in the United States or that
affects more than 200,000 but for which there is no reasonable expectation of
recovering development costs from sales in the United States.
To obtain orphan exclusivity, a sponsor must first request and obtain FDA
designation of its drug as an orphan drug. The request, which must be filed
before the sponsor submits its marketing application for the product and be
granted before the marketing application is approved, must include a description
of the rare disease or condition for which the drug is being investigated, the
reasons why the drug is needed for the disease or condition, a description of the
drug arid a discussion of its scientific rationale, and documentation of the rarity
of the disease or condition within the meaning of the statute (21 CFR § 3 16.201.
A drug that has been designated an orphan is entitled to marketing exclusivity
for 7 years abler approval, during which time FDA may not approve another
sponsor's application for the same drug for the approved orphan indication, apart
from specified exceptions.3
In addition to market exclusivity, an orphan-drug manufacturer may apply
for special FDA orphan research grants and contracts and is eligible for tax
credits for the costs of clinical trials conducted in the United States. Also, FDA,
if asked, must provide the sponsor with written protocol recommendations, and
the statute instructs FDA to encourage open-label studies so that patients needing
the drug have access to it (FDCA §§ 525, 528; 26 USC § 44H).
Several sponsors of anti-addiction drugs already have taken advantage of the
orphan-drug provisions. For example, LAAM was granted orphan status for the
treatment of heroin addicted patients suitable for maintenance on opiate agonists,
as was Du Pont's Trexan~ (naltrexone) for maintenance of the opiate-free state
in detoxified formerly opiate-addicted persons by blocking the effects of
exogenously administered opiates (FDA, 1994~. In addition, Pharmavene Inc.
Obtained an orphan-drug designation for its product butrylcholinesterase, which
3These exceptions include inability of an orphan-exclusivity holder to ensure a supply
of the drug [FDCA § 528(b)~1~] and demonstration by a second sponsor that its version
of the product is clinically superior to the orphan-exclusivity holder's version [21 CFR
§ 316.3(b)~13~(ii)].
164
DEVELOPMENT OF MEDICATIONS
is in testing for increasing the clearance of toxic blood concentrations of cocaine
produced by a drug overdose (FDA, 1993a). Although the sponsors of LAAM
took advantage of the provisions of the Orphan Drug Act, the fact that other
manufacturers of anti-addiction drugs now in development have not obtained
orphan status might indicate that additional incentives are needed. Legislation
that would have granted orphan-drug incentives specifically to manufacturers of
anti-addiction drugs was proposed in 1989 and 1990 but was not enacted
[S. 171 1, 101st Cong., 1st Sess. (19891; S. 2649, 101st Cong., 2d Sess. (19901;
S 2650, 101st Cong., 2d Sess. (19901~. This issue is further explored in Chapter
9 and a recommendation is made.
FDA Guidelines on Evaluation of
Anti-Addiction Drugs
The FDA has written draft guidelines intended to assist manufacturers in
developing new anti-addiction drugs (FDA, 1 992c). The draft document entitled
"Guidelines for the Development and Evaluation of Drugs for the Treatment of
Psychoactive Substance Use Disorders" is circulating within FDA and is not yet
publicly available.4 The guidelines address such issues as appropriate clinical end
points, clinical-trial methods, the use of adolescents in clinical trials (an
important issue, given the age of the drug-addiction patient population), polydrug
abuse, and the greater potential for abuse of prescription drugs by drug users than
by the rest of the population (FDA, 1992c).
Several of those issues require special mention. The question of appropriate
clinical end points in establishing the effectiveness of anti-addiction drugs has
long been debated for a number of reasons, including the nature of the patient
population, the use of women and pregnant drug users in clinical trials, the ethics
of using placebo or no-treatment controls, and the difficulties of measuring absti-
nence and recidivism. In principle, the ideal clinical end point would be cessation
of drug addiction without the need for maintenance therapy with a treatment
drug. However, reduction in, rather than outright cessation of, use of the illegal
drug in question might also be a suitable end point. Cessation or reduction, in
turn, can be measured through biological tests, self-reporting of use, measure-
ment of money spent on drugs, or a challenge test. Other possible end points
might be: retention time in therapy, severity of dependence, withdrawal
symptoms or drug-abuse toxicities, patient craving for the drug, illegal activities
involvement related to drug use, employment or family status, and mortality or
morbidity.
4The committee received a copy of the guidelines for developing and evaluating anti-
addiction medications after the publication of the preliminary report (March 1994~.
FEDERAL LAWS AND REGULATIONS
165
Another guideline issue concerns the evidence required for evaluation of the
safety and effectiveness of anti-addiction drugs. For example, although LAAM
had been the subject of over 20 studies from 1969 through the early 1980s, FDA
required the completion of a "usage" study before approval (FDA, 1 993b). It was
concerned about the application of LAAM to the current drug-addict population
and whether the directions for use would ensure successful treatment, i.e., in
methadone (now narcotic) treatment clinics (FDA, 1992d). The study was an
uncontrolled "open-label" (unblinded) trial designed so that drug-addicted
individuals were permitted to come in directly and participate. Efficacy was mea-
sured by retention rate and "dirty urine" and safety by serious adverse reactions
(FDA, 1992d). To resolve the ethical questions raised by a placebo control, the
study used historical controls that were based on comparable data on methadone
use (FDA, 1992d). Thus although FDA is likely to require some clinical
information on "real-world" conditions of use for particular anti-addiction drugs,
it appears to be flexible in accepting nontraditional trial designs to obtain such
information.
The committee is impressed that the guidelines on efficacy end points and
approval requirements are valuable to drug sponsors in planning their drug-
development programs. Clinical guidelines diminish the uncertainty faced by
private sponsors and can serve as an incentive to develop anti-addiction medica-
tions. Therefore,
The committee recommends that FDA make publicly available the
draft guidelines for developing and evaluating anti-addiction
medications, seek open comment from the private sector and
academic experts, and then complete and publish those guidelines
in a timely way.
DRUG ENFORCEMENT ADMINISTRATION
Scheduling
FDA's approval of an anti-addiction drug does not necessarily end the
regulatory requirements for marketing the drug. If the drug is a narcotic itself or
is subject to abuse, as are methadone and LAAM, it is subject to regulation as
a controlled substance by DEA. For those drugs, there is another step before
marketing can occur. When FDA reviews a new drug product with a potential
for abuse, it must notify DEA (Controlled Substances Act § 201(f); 21 USC §
801(f); 21 CFR 314.104~. FDA requires that an NDA include a section assessing
the drug product's abuse liability (FDA, 1990~. During the review process, FDA,
with the assistance of the Drug Abuse Advisory Committee and input from
166
DEVELOPMENT OF MEDICATIONS
NIDA (FDA, 1985), makes a scheduling recommendation to DEA using the
criteria outlined in the Controlled Substances Act [CSA §§201 (b), (c); 21 USC
§§ 81 labs, (c)~.s Under the CSA, a drug with a potential for abuse is placed into
one of five schedules, depending on the magnitude of the potential for abuse,
whether the drug has accepted medical uses, and the extent to which abuse of the
drug will lead to physical or psychological dependence.6 The restrictions arid
requirements that apply depend on the schedule into which a particular drug
product falls. Congress made the initial scheduling determinations in the statute;
DEA has authority to make scheduling decisions for new drugs not covered in
the statute and to reschedule drugs under some circumstances (CSA §§ 201, 202;
21 USC §§ 811, 812~.
After receipt of FDA's recommendation, DEA makes its initial scheduling
determination and publishes it as a proposed rule in the Federal Register, waits
for comments, and then issues its final rule. This might occur before or after
FDA approval. In the mid-1980s, FDA routinely issued NDA "approvable"
letters for drugs proposed for scheduling. In 1986, FDA changed its policy
regarding NDA approvals for drugs pending scheduling and issued final "approv-
al" letters with the addition of a statement that the drug could not be marketed
until it was scheduled by DEA. The result was that the "clock" measuring time
before patent expiration, for DPC-PTR Act purposes, was started, even though
the drug was not able to be marketed. Under current FDA policy, issuance of a
5The criteria include the scientific evidence of the drug's pharmacologic effect, if
known; the state of scientific knowledge regarding the drug; the risk, if any, to the public
health; the drug's psychic or physiologic dependence liability; whether it is an immediate
precursor of a substance already controlled; the scientific and medical considerations
involved in the drug's actual or relative potential for abuse; its history and current pattern
of abuse; and the scope, duration, and significance of abuse.
Specifically, a Schedule I drug has a high potential for abuse, has no accepted
medical use in treatment in the United States, and there is a lack of accepted safety for
use of the drug under medical supervision; a Schedule II drug has a high potential for
abuse and has an accepted medical use in treatment in the United States or an accepted
medical use with severe restrictions, and its abuse might lead to severe psychologic or
physical dependence; a Schedule III drug has a lower potential for abuse than a Schedule
I or II drug and has an accepted medical use in treatment in the United States, and its
abuse might lead to moderate or low physical dependence or high psychologic
dependence; a Schedule IV drug has a lower potential for abuse than a Schedule III drug
and has an accepted medical use in treatment in the United States, and its abuse might
lead to less physical or psychologic dependence than a Schedule III drug; and a Schedule
V drug has a lower potential for abuse than a Schedule IV drug and has an accepted
medical use in treatment in the United States, and its abuse might lead to less physical or
psychologic abuse than a Schedule IV drug [CSA § 202(b)~.
FEDERAL LA US AND REGULATIONS
167
final approval letter seems to permit sale under the Food, Drug and Cosmetic Act
without restriction, and no provision of the CSA applies to a drug that is not
controlled under that Act.
Drug manufacturers have complained about the delay in DEA scheduling.
Typically, scheduling can take from several weeks up to 2 months after approval
of an NDA by FDA. For example, in the case of LAAM, DEA published its
proposed decision to transfer the product from Schedule I to Schedule II in April
1993, before the NDA was approved. A 30-day comment period was set, and the
final rule was issued on August 18, 1993, about 5 weeks after the NDA was
approved (DEA, 1993~.
The lag at DEA, if it becomes substantial, has practical implications for
anti-addiction drugs, with respect to lost marketing time. As stated above,
pioneer drug manufacturers might be eligible for patent-term extension to allow
them to recoup the time lost during regulatory review. In calculating the review
period for controlled substances, however, FDA does not count the time lost after
approval of an NDA through scheduling by DEA (FDA, 1988~; this time is unre-
coverable by the manufacturer.
The committee recommends that DEA review time be counted as
part of the regulatory process for purposes of patent-term extension
for controlled substances.
To accomplish this, any of the following three options could be
implemented:
· Amend the DPC-PTR Act.
· Concurrent DEA scheduling and FDA approval, in the final
stages of drug review.
· Unilateral FDA reversion to its earlier policy of issuing
NDA "approvable" letters for drugs proposed for scheduling.
The committee has reviewed the issue of scheduling at the state level in
Chapter 8 and offers an additional recommendation regarding this issue.
Quotas
If a drug is scheduled by DEA as a controlled substance, its manufacture is
heavily regulated by DEA. Specifically, DEA must set aggregate and individual
annual production quotas for Schedule I and II drugs (CSA § 306; 21 USC §
826), a process in which FDA also plays a role (21 CFR Part 1303~. In particu
168
DEVELOPMENT OF MEDICA TIONS
far, FDA must report to DEA the "results of studies and investigations of quanti-
ties of narcotic drugs or other drugs subject to control under [the CSA], together
with reserves of such drugs, that are necessary to supply the normal and
emergency medical and scientific requirements of the United States . . . not later
than the first of April of each year" [Public Health Service Act § 302(a); 42
USC § 242a. With FDA's recommendation in mind, DEA establishes yearly
aggregate production quotas for each Schedule I and II drug to meet "the
estimated medical, scientific, research, and industrial needs of the United States,
for lawful export requirements, and for the establishment and maintenance of
reserve stocks" [CSA § 306(a); 21 USC 21 826(a)~.
Although the purpose of the DEA quota system is to prevent inappropriate
diversion of controlled substances, it also has the effect of restricting a manufact-
urer's ability to manufacture and sell its product. Quotas may also affect manu-
facturing costs, because optimal batch sizes may exceed quota limits. Further-
more, the scheduling of a drug imposes substantial restrictions on the prescribing
of the drug by physicians. Those factors combine to make the scheduling of a
drug an important disincentive to developing a drug with addiction potential.
Regulatory Authority Over Anti-Addiction Drugs In Development
DEA's jurisdiction over a drug undergoing clinical investigation for an
anti-addiction indication depends on whether the drug is a controlled substance.
If the drug is a new chemical entity that has not been scheduled under the CSA,
it is not necessarily under DEA jurisdiction at the clinical-trial stage, even though
it might later be scheduled. FDA is not required to notify DEA about a new drug
that is not yet (but that ultimately might be) scheduled until it receives an NDA
for the drug, which will presumably be after clinical trials have been completed
[CSA § 201(f); 21 USC § 811(f)~. However, FDA could apprise DEA of the
drug at an earlier stage in the process if it thought that the drug had a potential
for abuse, in which case it is possible that the drug could be scheduled while still
in clinical trials or even earlier. If the investigational drug is already a controlled
substance (as was LAAM), then it will by definition be subject to DEA jurisdic-
tion while in clinical trials. Although holders of INDs for controlled substances
are exempt from some DEA requirements that parallel FDA requirements, DEA
still maintains substantial authority over the manufacture, distribution, and
research use of controlled substances, subjecting researchers of new anti-addiction
drugs to a dual regulatory scheme.
The CSA and !)EA's regulations require that persons conducting clinical
research with any controlled substance register with DEA [CSA §302(a)~1~; 21
USC §822 (a)(1); see also 21 CFR §§ 1301.21, 1301.22(a), 1301.22(b)~5~], keep
specific kinds of records [CSA § 307(a),~b); 21 USC § 827(a), (b)], and
FEDERAL LAWS AND REGULATIONS
169
periodically report to DEA [CSA § 307(d); 21 USC § 827(d)]. Holders of INDs
for controlled substances must register with DEA but are exempt from the CSA's
recordkeeping requirements (CSA § 307(c)(2)(A); 21 USC § 827(c)(2~(A); see
21 CFR Part 1304~. In particular, 21 CFR § 1304.03(e) provides that a DEA
registrant operating under an IND who "maintains records in accordance with
[the FDCA] is not required to keep records if he notifies [DEA] of the name,
address, and registration number of the establishment maintaining such records."
FDA requires, however, that a sponsor or investigator make its FDA-mandated
records pertaining to shipment, delivery, receipt, and disposition of the drug
available to DEA for inspection and copying at DEA's request [21 CFR §
312.58(b)~. In addition, FDA regulations mandate that investigators and sponsors
in clinical trials using controlled substances take special precautions, including
storage of the drug in a secure place with limited access, to prevent theft or
inappropriate diversion [21 CFR §§ 312.69, 312.58(b)~. This regulation is
consistent with Section 307(f) of the CSA, 21 USC § 827(f), which requires
FDA to promulgate rules to "insure the security and accountability of controlled
substances" used in clinical investigations.
There is, however, no corresponding exemption from the reporting require-
ments under the CSA [CSA § 307(d); 21 USC § 827(d)~. In addition, because
a DEA registration for research with controlled substances also authorizes the
manufacture and distribution of such substances (within defined limits) t21 CFR
§ 1301.22(b)~3) for Schedule I and (bus) for Schedules II-V] if a researcher
engages in either activity, he or she must comply with the recordkeeping and
reporting requirements for manufacturers and distributors [21 CFR § 1304.03a.
Thus, for example, the holder of an IND for a controlled substance that also
manufactures it must report data on the acquisition and reduction ofthe substance
from inventory monthly (unless it receives permission from DEA to report more
or less often) and data on the status of year-end inventory annually if the con-
trolled substance is in Schedule I or II, is a narcotic in Schedules III, IV, or V,
or is a listed psychotropic substance in Schedule III or IV (21 CFR § 1304.35~.
In addition, DEA requires that protocols for research with Schedule I
controlled substances be submitted to it for approval and requires researchers
using Schedule I substances to identify in their registration applications the extent
to which the research will also involve manufacture or importation (21 CFR §§
1301.32(a)~6), 1301.33~. This does not, however, apply to clinical investigations
under an IND. In those cases, the sponsor need only submit to DEA a copy of
its IND with a statement of the security provisions for storing and dispensing the
drug to prevent inappropriate diversion [21 CFR § 1301.33(b)~. In either case,
FDA has the ultimate authority to approve the study, either under the provisions
of the FDCA pertaining to INDs or, for research protocols not under an IND,
under 21 CFR § 1301.42, which requires DEA to forward applications for
registration for research with Schedule I substances to FDA. In making its
170
DEVELOPMENT OF MEDICATIONS
determination as to the merits of the study under the latter provision, FDA must
consult with DEA as to the adequacy of procedures to be taken to prevent
inappropriate diversion (21 CFR § 1301.42~. When art investigator warts to
increase the amount of a Schedule I controlled substance that it has received
approval to use, the sponsor first must submit a request to DEA, DEA then
forwards the request to FDA, which may grant or deny the request, taking into
account DEA's comments [21 CFR § 1301.33(c)~.
The practical consequence of this dual authority over clinical research,
particularly in the light of the additional complication of multiple state laws
patterned after the CSA (Chapter 8), is a clinical research environment for
scheduled drugs that is extraordinarily bureaucratic Tom the procedural point of
view arid unnecessarily difficult. That is especially true given the relatively small
amounts of any controlled substance used in research; thus the consequences of
diversion to public health would be small even if the diversion from research was
substantial. The administrative effort required to cope with this complex system
is discussed in Chapter 3. The difficulty of conducting clinical research is also
cited in the private sector as an important deterrent to R&D investment (Chapter
9~. Even if the new drug under study is not scheduled, the comparative agent in
positively controlled studies of the drug (which might well be the pivotal studies
for FDA approval) could be a controlled substance like methadone; this would
trigger the complex dual system of regulation. Finally, studies to optimize the
dose or dose schedule of a new drug and to extend the use to new patient
populations, such as pregnant women and adolescents, are typically done after
marketing, which means after the drug is scheduled. All studies of this type are
vastly more difficult on scheduled drugs and therefore, as a practical matter, tend
not to be done.
The committee recommends that action be taken to remove the
adverse effects of DEA requirements, under the Controlled
Substances Act (CSA), on clinical research investigations involving
controlled substances, by holders of active FDA INDs, either by
amending the CSA to exempt such investigations from applicable
DEA regulations or by the alternative administrative and regulatory
measures:
.
The development of a Memorandum of Understanding
between FDA and DEA governing the matter of dual authority over
clinical research to provide exemption from DEA reporting
requirements.
.
DEA revision of 21 CFR 1301.33 and parallel regulations
to provide that protocols, drug security, recordkeeping, production
controls, reporting, and other requirements would be governed by
FEDERAL LAWS AND REGULATIONS
the Fl)A regulations and monitored by FDA. This would require
parallel changes in FDA's IND regulations.
171
FDA's current provisions for control and recording the disposition of
controlled substances under an IND should be adequate to address concerns of
drug security and diversion.
CONCLUSIONS
Lee committee concludes that the complexities faced in the normal process
of drug discovery and development are made even more daunting arid costly by
the multitude of regulations arid clinical research constraints imposed by FDA
and DEA in the development of anti-addiction medications. Thus, the committee
has offered recommendations with the intent of easing the regulatory disincentiv-
es to the pharmaceutical industry and expediting the availability of new
phannacotherapies for heroin and cocaine addicts.
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