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Executive Summary
Pharmacotherapy for the treatment of drug addictions has received far too
little attention, despite the clinical success of methadone, which dates back to the
1960s. Over the last 30 years, only two additional medications have been
approved for the treatment of opiate addiction naltrexone and levo-alpha-
acetylmethadol (LAAM:and it is important to note that both those medications
were developed in the 1960s and early 1970s. There is still no approved
medication for the treatment of cocaine addiction. During the same 30 year
period, however, serious medical and social problems have evolved as drug
addiction has become a route for spreading the acquired immune deficiency
syndrome (AIDS) through the sharing of contaminated needles and the trading
of sex for drugs; multiple-drug-resistant tuberculosis has become common in
immunocompromised, human immunodeficiency virus (HIV) infected drug-
dependent individuals; an association between illicit drug use and increasing
violent crime has become clear; and the medical consequences for infants
exposed in utero to cocaine have become evident (Chapter 1~. It is for those
reasons and others (Chapter 3) that the committee focused its attention on
medications to treat opiate and cocaine addictions, although it recognizes that the
two addictive drugs that are most important with respect to morbidity, mortality,
and economic costs are alcohol and nicotine.
'Drug addiction is defined as the compulsive use of a drug despite adverse
consequences. This report focuses on opiate and cocaine addictions and does not address
alcohol and nicotine addictions.
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2
DEYELOPAJENT OF MEDICATIONS
Given the magnitude of the illicit-drug-use problem (there are an estimated
0.5-1 million heroin-dependent individuals and 2.1 million cocaine-dependent
individuals) and its economic and public-health consequences, addressing the
issue requires a dedicated effort not only to develop pharmacotherapies but also
to foster prevention, education, and the use of other treatment approaches. Yet,
pharmacotherapy, as a viable adjunct to other treatment modalities, has not
received widespread support from the federal government, nor has the private
sector been active in developing anti-addiction medications.
It was in-this climate of a near absence of private-sector and government
activity in the development of anti-addiction medications that Congress estab-
lished the Medications Development Division (MDD) in the National Institute on
Drug Abuse (NIDA). The division began in 1990 to coordinate and encourage
academic, private, and federal regulatory involvement in developing and bringing
to market new medications for the treatment of drug addiction. In 1992, the
Congress stipulated in the Alcohol, Drug Abuse, and Mental Health Administra-
tion (ADAMHA) Reorganization Act (P.L. 102-321) that the Department of
Health and Human Services contract with the National Academy of Sciences to
establish a committee in the Institute of Medicine (IOM) to examine the current
conditions for the development of anti-addiction medications. This report by the
IOM Committee to Study Medication Development and Research at the National
Institute on Drug Abuse responds to the Congressional mandate by examining the
progress of NIDA's Medications Development Division and exploring the
scientific, marketplace, regulatory, and other factors that adversely affect the
development of anti-addiction medications. The committee met with representa-
tives of the IOM Drug Forum, the pharmaceutical industry, and federal agen-
cies NIDA, the Food and Drug Administration (FDA), and the Drug Enforce-
ment Administration (DEA:conducted a survey ofthe pharmaceutical industry,
and sponsored a Workshop on Policies to Stimulate Private Sector Development
of Anti-Addiction Medications.
As a result of the committee's deliberations, meetings, and workshop, it
became evident that the major disincentives to pharmaceutical R&D for anti-
addiction medications include: an inadequate science base on addiction and the
prevention of relapse (especially for cocaine); an uncertain market environment
which includes such issues as: treatment financing, lack of trained specialists for
the treatment of drug addiction, federal and state regulations, market size, pricing
issues, societal stigma, liability issues, difficulties in conducting clinical research;
and a lack of sustained federal leadership.
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E9fECUTIl'E SUMMARY
STATE OF THE SCIENTIFIC KNOWLEDGE ON ADDICTION
3
The initiating event leading to drug addiction is the administration of an
agent, such as heroin or cocaine, to obtain a pleasurable effect. Addiction is
characterized as the compulsive use of a drug despite adverse consequences. Key
problems in addiction are how to prevent the onset of compulsive drug use and
how to prevent relapse and the craving that leads to relapse (Chapter 21. In the
past, much medical attention has been given to treatment (detoxification) for the
symptoms of acute abstinence. Yet, knowledge about the pathophysiology of the
syndromes of protracted abstinence and conditioned withdrawal or relapse is still
rudimentary and presents an important challenge to development of anti-addiction
medications.
Since the 1960s, it has become clear that the effects of opiate drugs are
mediated through interaction with opioid receptors and interference with actions
at those receptors presents a rational strategy for developing medications for
opiate addiction. The mechanism of cocaine addiction is not well characterized,
however, it is understood that the major pharmacological effect of cocaine is on
the dopaminergic system of the brain. Unfortunately, the potential involvement
of a wide range of neurotransmitter systems in cocaine's actions makes the
development of a treatment medication difficult because no single target site is
immediately apparent. In fact, an optimal strategy might require the use of
several drugs that have different mechanisms of action.
In response to the absence of a well-defined mechanism of action or a
compound for the treatment of cocaine addiction, MDD has developed the
Cocaine Treatment Discovery Program (CTDP) to screen candidate compounds
through a tiered strategy that uses both in vitro biochemical assays and in viva
behavioral tests. However, several factors limit the effectiveness of the screening
protocols and their predictive value in humans, including the lack of knowledge
of the mechanism of cocaine addiction; the lack of animal models for addiction,
craving, and relapse; and the small number of compounds supplied to NIDA for
screening. In its report, the committee makes several specific recommendations
to MDD regarding the CTDP program.
Because the state of scientific knowledge of addiction is rudimentary, the
committee believes that it is imperative to foster NIDA's basic-research efforts
in the mechanism of cocaine addiction and in the molecular, cellular, and
behavioral bases of chronic drug effects and the genetics of vulnerability to
addiction. There is also a need for basic research to develop laboratory models
of behavioral characteristics of the addictive process. The committee strongly
believes that unless basic research is supported at an appropriate funding level,
it will be difficult to make the necessary progress in the scientific knowledge
base. The lack of such knowledge would continue to hamper the private sector
and MDD in the development of a medication.
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4
DEVELOPMENT OF MEDICATIONS
In relation specifically to MDD, the committee recommends two mechanisms
to address the critical issue of supporting basic science:
The committee recommends that MDD be given a high priority for
funding. Although MDD was authorized at $95 million in FY 1994,
its appropriation of $40 million was considerably short of its
authorization and is far below what is needed for research and
development.
The committee is aware, however, of the budget constraints on the institutes
of the National Institutes of Health (NIH); as a possible mechanism for increased
support, the committee suggests the use of funds from the Special Forfeiture
Fund in the Office of National Drug Control Policy (ONDCP).2 Utilizing a
portion of those funds for basic research not only would provide additional
money to MDD, but would demonstrate executive-branch support.
The committee recommends that NIDA designate national drug
abuse research centers, subject to congressional appropriations, as
described in the ADAMHA Reorganization Act [P.L. 102-321,
Section 464N (a)l, "for the purpose of interdisciplinary research
relating to drug abuse and other biomedical, behavioral, and social
issues related to drug abuse." Those centers would be engaged in
and would coordinate all aspects of drug-abuse research, treatment,
and education.
The paucity of basic knowledge is best approached through a coordinated
effort, and the committee intends that such centers serve as focal points for all
2The ONDCP Special Forfeiture Fund results from the transfer of money from the
Federal Asset Forfeiture Fund (described below). In FY 1990, the Federal Asset
Forfeiture Fund transferred $117 million to federal law-enforcement agencies. Deposits
of $17 million were also made to the Special Forfeiture Fund to supplement ONDCP
program resources and of $115 million to support Federal prison construction. The use
of the Special Forfeiture Fund is at the discretion of the director of ONDCP.
The Federal Asset Forfeiture Fund is a sum of money resulting from the sale of
assets used in criminal activity that have been seized by the government. In 199O, DEA
seized assets valued at more than $1 billion. About two-fifths of the assets seized by
DEA was currency valued at almost $364 million. In addition, DEA seized $346 million
worth of real property, 5,674 vehicles worth over $60 million, 187 vessels valued at over
$16 million, and 51 airplanes worth over $25 million. Almost two-thirds of DEA's
seizures during 1990 resulted from cocaine investigations. DEA seizures that were
ultimately forfeited are valued at more than $427 million in 1990.
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EXECUTIVE SUMMARY
aspects of drug-abuse research and their designation would have the added
benefit of encouraging new investigators to enter the field; the centers would also
serve as sites for clinical trials and for training clinicians. With the designation
of such centers, the committee believes, progress will be made in basic and
clinical research on the treatment of drug addiction (Chapter 2~.
NIDA'S MEDICATIONS DEVELOPMENT DIVISION
In recognition of the need to stimulate the availability of medications to treat
drug addiction, the Anti-Drug Abuse Act of 1988 (P.L. 100-690) authorized
funds for a drug discovery and development program in NIDA. Beginning with
an appropriation of $8 million in 1988, NIDA launched a Medications
Development Program in its Division of Preclinical Research. Building on this
program, NIDA formally established the Medications Development Division in
1990. The primary strategy adopted by MDD is to work with industry to perform
the research and development necessary to secure FDA marketing approval for
new medications to treat drug addiction. MDD does not operate inhouse
laboratories or clinical-development programs to fulfill its mission. It manages
this work through multiple external instruments, such as contracts, grants, and
interagency and collaborative agreements (Chapter 3~.
While the current budget of $40 million and staff of 33 full-time equivalents
(FTEs) might be adequate to support the development of a small portfolio of
products based on drugs that are already in use, the committee believes that they
are insufficient to support basic research. Additionally, MDD has had difficulty
in stimulating private-sector interest, in acquiring industry partners, and in
obtaining a suitable number of compounds for screening. MDD had originally
developed a screening agreement in which a compound's structure is made public
after a 3-year period of confidentiality. That agreement has hindered MDD's
ability to acquire compounds and affected MDD's capability to develop its
screening program adequately because many companies did not want their
confidential data to be made public. Thus, in 1994 MDD revised their original
screening agreement and now all screening data from industry compounds will
remain confidential. That change in policy should have a beneficial effect on
MDD's screening program.
Although the committee commends MDD for the establishment of anti-
cocaine and anti-opiate screening programs, the lack of established in vitro
screening methods and validated animal models that are predictive in humans,
especially for anti-cocaine medications, limits the utility of the screening
program. The committee feels that there is a need for basic research to develop
laboratory models of critical behavioral characteristics of the addictive process.
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6
DEVELOPMENT OF MEDICATIONS
Improvement of such methods and models should be given a high priority for
grant and contract support by MDD.
It became apparent to the committee, during its review of MDD and
numerous meetings with industry representatives, that strong leadership is needed
in promoting pharmacotherapy as an important component of our national
strategy. Leadership must come from many sources, especially from the highest
levels of the federal bureaucracy. However, an important leadership role belongs
uniquely to NIDA and especially to MDD. MDD must view itself as the leader
in stimulating private-sector interest in developing anti-addiction medications.
The committee views this national leadership role as one of the key functions of
MDD. Consequently, it should be empowered to lead, as well as to fulfill, a
scientific and technical mission.
The committee recommends that NIDA and MDD, in determining
how to improve MDD's relationship with industry, evaluate the
applicability of the techniques already in use by the Developmental
Therapeutics Program of the National Cancer Institute, the
National Cooperative Drug Discovery Groups on Acquired Immune
Deficiency Syndrome of the National Institute of Allergy and
Infectious Disease, and the Anticonvulsant Drug Development
Program of the National Institute of Neurological Disorders and
Stroke.
Those are all programs (Appendix E) of similar mission within NIH that have
established effective working relationships among leading academic and
government scientists, FDA, and individual drug companies through a combina-
tion of scientific communication, mutual technical assistance, cooperative
agreements, and licenses. In the committee's view, the primary policy responsi-
bility of MDD should be to provide such leadership as a complement to its
scientific responsibilities (Chapter 31.
EFFECTIVENESS OF TREATMENT
There is strong consensus that methadone maintenance treatment is effective
for the treatment of opiate addiction (IOM, 1990; OTA, 1990; Anglin and Hser,
1992; Prendergast et al., in press). Treatment is effective in reducing opiate use,
criminal activity, and intravenous drug use. The evidence of treatment effective-
ness is not as strong for cocaine treatment, yet there is an accumulating body of
research pointing to the effectiveness of psychosocial treatment modalities. As
yet, there is not a pharmacologic agent for the treatment of cocaine addiction or
a medication to reduce cocaine craving.
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EXECUTIVE SUMMARY
7
Treatments for opiate and cocaine addiction are cost-effective (Chapter 41.
When the cost of opiate and cocaine treatment is compared to the benefits in
reduced crime, the result is unambiguous: every dollar invested in treatment
yields at least two and up to four dollars, and sometimes more, in societal
benefits (Gerstein et al., 19941. Treatment also averts other health care costs. In
short, current treatments for opiate and cocaine addiction, while variable in
nature and cost, are both effective and cost-effective. Clearly the federal
government should make every effort to expand the treatment capabilities of the
states. New medications, especially for cocaine addiction, do hold the potential
to reduce some of the need for counseling, which forms the largest share of
treatment charges. With lower overall treatment costs, treatment can prove to
become even more cost-effective.
The committee strongly recommends expanding the treatment
capabilities of the states for opiate- and cocaine-dependent individ-
uals to ensure that all those seeking treatment obtain it without
delay. The recommendation may be implemented by:
· Providing additional money to increase treatment in states
where there are waiting lists.
· Shifting money from supply control programs to treatment
programs.
TREATMENT FINANCING
The financing3 of treatment is often cited by the pharmaceutical industry as
yet another deterrent to the development of anti-addiction medications (Chapter
51. Prominent reasons are the fact that so few patients have private insurance and
there is a concomitant need to rely on direct public subsidy to pay for their
treatment (IOM Workshop, June 13, 1994~.
The annual payments for methadone maintenance treatment are estimated at
$480 million in PY 1993. There are an estimated 117,000 patients for whom
annual expenditures are about $4,100 each. Currently the financing of methadone
treatment is deeply dependent on the public sector, primarily in the form of
federal block grants and state alcohol and drug agency funds. Despite the sizeable
public role in financing, neither state agencies or the federal government have
3Financing is generally defined as the payment or reimbursement for the cost of
treatment made by private insurance, Medicaid, the patients themselves, or other sources.
Financing is important to pharmaceutical investment because it has a critical effect
treatment supply and the demand of treatment (Rogowski, 1993~.
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8
DEVELOPMENT OF MEDICATIONS
consolidated their potential market leverage to secure discounts on large volume
pharmaceutical purchases. Private insurance payment is almost insignificant.
Patients are willing to pay their share, but were treatment to become more costly,
patients are not likely to have the resources to absorb increased costs.
State financing has been and is expected to be a major impediment to the
sale of LAAM, according to both BioDevelopment and clinic operators. State
financing practices can be so rigid that they effectively block the introduction
and adoption of a new medication. The flow of funds to clinics is dictated by the
policies and regulations of two separate state agencies: the state alcohol and drug
agency, which administers state funds and federal block grants, and the state
Medicaid agency, which administers state and federal Medicaid dollars. There is
widespread variation in funding practices (IOM, 1995), but either state agency
can erect financial barriers to the adoption of a new medication. New York set
a flat daily or weekly fee per patient (which usually includes all services without
specifying the amount for medication and dispensing), and other states have set
a flat fee for a "dosing visit," the dispensing of one dose of medication.
California, authorizes ceilings on the number of publicly funded patients that can
be treated at each clinic (Goldstein, 1989~. Under these funding practices, LAAM
is at a disadvantage because it is more expensive than methadone, the medication
for which reimbursement rates have been structured over the past 20 years. To
obtain better reimbursement, clinics must petition the appropriate agency for
more favorable rates.
Financing and regulatory obstacles are contributing to the stalled market
penetration of LAAM. LAAM's higher price may have exacerbated the problem,
but the rigidity of the financing and regulatory structure antedates its introduc-
tion. This is unfortunate as LAAM is potentially more effective therapeutically.
Even one of LAAM's selling points for public health the prospect of increasing
clinic patient loads- has become a disincentive for state alcohol and drug
authorities struggling to find additional funding not just for LAAM, but for the
higher costs of counseling and comprehensive treatment for possibly more
patients. If BioDevelopment Corporation succeeds in securing adequate financing,
that will serve as an incentive to other pharmaceutical companies. If not, the
fixture for other opiate medications does not appear encouraging. Therefore, the
committee strongly urges state and federal agencies to work together, not only
to provide an incentive to pharmaceutical companies, but in the interest of public
health, to facilitate the availability of newly approved anti-addiction medications.
Possible mechanisms that the states and federal government might consider
include requiring all Substance Abuse Block Grant recipients to offer those
medications to patients and assuring appropriate financing of new medications
by state alcohol and drug agencies and their counterpart Medicaid agencies.
Those actions would have the additional benefit of providing a strong signal to
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EXECUTIVE SUMMARY
9
pharmaceutical companies demonstrating state and federal commitment to the
development of ar~ti-addiction medications (Chapter 5~.
TRAINING AND EDUCATION
Although the limited availability of scientists and clinicians specializing in
drug abuse research and treatment has direct consequences for the delivery of
health care services and research on new treatments, it has a less obvious, but
equally important, effect on pharmaceutical R&D investment. Pharmaceutical
companies traditionally market their products to health care professionals and
promote their products through personal visits by sales representatives, through
journal and mail advertising, and through support of scientific symposia and
continuing medical education. Pharmaceutical companies distribute their products
through hospital and community pharmacies, pharmacy chains, and distributors.
To the extent that the treatment of drug dependence is often delivered outside
that system by specialized clinics (e.g., narcotic treatment programs, typically
with part-time physicians and limited marketing opportunities for pharmaceutical
companies), and to the extent that drug abuse treatment involves many fields of
medicine (e.g., family practice, internal medicine, psychiatry), pharmaceutical
companies see greater difficulty in marketing anti-addiction medications than in
marketing other products. Pharmaceutical firms also rely on academic clinical
investigators and practicing clinicians to advise them on drug development issues
such as current therapeutic trends, the role of drugs in the overall treatment
strategy, unmet medical needs, indications to be evaluated, clinical trial design,
and appropriate therapeutic endpoints.
The committee believes that a long-term national effort is needed to
strengthen the substance abuse education and training of both specialists and
primary care physicians. That effort will strengthen the infrastructure needed for
research arid treatment arid will encourage pharmaceutical investment in this field
(Chapter 61.
The committee recommends that the federal government increase
its efforts to attract researchers and clinicians to the field of drug
addiction treatment. That may be accomplished by implementing
one or all of the following options:
· NIDA's training budget could be increased, but not at the
expense of their research programs. Requests from NIDA for large
increases in its training budget have not been filled in FY 1993 or
FY 1994, and NIDA has received a lower percentage of training
funds than several other institutes. Increasing NIDA's training
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10
DEVELOPMENT OF MEDICATIONS
budget such that it will enable NIDA to offer fellowships that are
competitive with private sector salaries, and therefore, more
attractive to potential candidates would "jump-start" the expansion
of the field of drug addiction treatment and research; it could have
nationwide impact by increasing the numbers of scientists and
physicians recruited, trained, and working in the field of drug
addiction.
· An educational loan repayment program in return for work
in drug abuse-related clinical research could attract young physi-
cians with substantial educational debt into careers as clinical
investigators.
.
Mid-career programs could be developed to encourage a
cadre of practicing physicians and scientists to enter the field of
drug addiction treatment and research.
The committee recommends an increased emphasis on drug abuse
education throughout medical school and primary care residency
programs. To accomplish this, the following could be implemented:
· Drug abuse education could follow a systematic, integrated
approach to coordinate the curriculum across specialty depart-
ments.
· Training institutions could develop affiliations with
community-based treatment centers, where feasible, to provide
student access to multiple treatment settings.
· The National Board of Medical Examiners4 and the
primary care specialty boards of the American Board of Medical
Specialties (ABMS) could pay increased attention to drug abuse
issues, skills, and knowledge on their examinations for certification.
· Faculty development programs could receive increased
federal support. The Center for Substance Abuse Prevention's
Faculty Development Program which trains medical school faculty
members to serve as role models, educators, and mentors in the
field of drug abuse research and treatment is a good model.
The committee recommends that comprehensive drug abuse centers
be developed to engage in and coordinate all aspects of drug-abuse
research, treatment, and education. Further, the committee recom
4The National Board of Medical Examiners prepares and administers to medical
students a two-part examination that is accepted by individual states as part of licensing.
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EXECUTIVE SUMMARY
mends that NIDA and the Substance Abuse and Mental Health
Services Administration (SAMHSA) work together to coordinate the
effective and efficient use of existing centers by adding, where
feasible, research, training, and/or treatment components.
FEDERAL REGULATORY ISSUES
Food and Drug Administration
11
Clinical testing and market approval of any new medication requires
compliance with the regulatory requirements of FDA. In recent years, the
traditional approval process has undergone changes designed to expedite FDA
review and to expand the use of experimental treatments under some circum-
stances. The recent changes to the traditional drug-approval process might
provide additional opportunities for encouraging and expediting the development
of anti-addiction medications. Of particular importance are three initiatives
intended to expedite the availability of drugs to treat serious and life-threatening
diseases for which no adequate therapeutic alternatives exist (Chapter 7~. First,
under the treatment-IND (investigational new drug) 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. A second mechanism, known as parallel track, also extends the
availability of investigational drugs. Under parallel track, "promising" investiga-
tional agents may be provided to 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. The third important development is FDA's
accelerated-approval-program. Adopted in its final form in December 1992,
accelerated approval is available for drugs that offer "meaningful therapeutic
benefit compared to existing treatment" for serious or life-threatening illnesses.
As an incentive to the pharmaceutical industry and because drug addiction should
qualify as a serious and life-threatening disease,
The committee recommends that FDA make the treatment-IND
route, the parallel-track mechanism, and accelerated approval
available for anti-addiction medications.
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EXECUTIVE SUMMARY
15
the federal level is prolonged for all newly approved drugs that are controlled
substances (Chapter 71; this regulatory delay can become years when the
rescheduling process requires both state and federal action and cannot begin until
NDA approval, e.g., LAAM. The committee believes that the public health
would be best served by an interpretation of the "currently accepted medical use"
clause in the Controlled Substances Act that would recognize the use in humans
under an IND and permit the scheduling process to begin at the time of NDA
submission. The information required for scheduling a drug is already required
to be in a self-contained section of the NDA. That section could be reviewed on
a fast-track basis by FDA, and a scheduling recommendation could be sent to
DEA well ahead of NDA approval. Scheduling could be done contingent upon
final FDA approval. That approach would permit states to reschedule schedule
I drugs closer in time to final FDA approval, minimizing delays such as the one
now affecting LAAM, and have no negative drug control implications.
Furthermore, it would remove a significant regulatory disincentive at the federal
level that affects all scheduled drugs, not just schedule I substances. The
committee concludes that if the current situation continues unchanged, it will
have a chilling effect on private sector investment for any medication that may
potentially meet the legal definition of a narcotic.
The committee recommends that the Office of National Drug
Control Policy (ONDCP) direct DEA, in consultation with FDA and
NIDA, to revise its policy on determining when a drug has a
currently accepted medical use in treatment so that, for new
therapeutic drugs that are also controlled substances, the process of
scheduling can begin as soon as possible after submission of the
NDA.
The committee believes that additional steps should be taken by federal
agencies within the existing system to reduce future state obstacles. The
committee proposes a two-step set of actions, interim and long-term. There are
two interim steps federal agencies (ONDCP, FDA, SAMHSA, NIDA, and DEA)
should take under existing authorities to ameliorate the delays, complexity, and
lack of uniformity at the state level.
Interim Actions
The committee recommends that federal agencies (ONDCP, NIDA,
SAMHSA, FDA, and DEA) work more closely and actively with
state regulatory authorities early in the drug development process
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DEVELOPMENT OF MEDICATIONS
to prepare the path for new anti-addiction medications. That
recommendation can be implemented as follows:
· Identification cf a regulatory point of contact in each state;
· Basic information could be given to the state contact early
in the drug development process (preferably no later than the sub-
mission of an NDA) about the medication, with emphasis on
characteristics that would be of most interest to state regulatory
authorities (diversion potential, target populations, or any special
characteristics that would affect how the drug would be dispensed,
such as dosing frequency). To the extent that any of the information
is proprietary and confidential, the developer's permission for such
disclosure would have to be obtained.
As the medication moves closer to FDA approval, federal
agencies could ensure that the necessary state regulatory processes
begin immediately after approval, or, if state regulations permit,
even before, such as upon the issuance of an approvable letter.
· Federal agencies could work with the state contact, as the
product moves through the state regulatory process, to correct any
problems as they arise.
.
The committee recommends that ONDCP, in cooperation with FDA,
DEA, SAMHSA, and NIDA, take an active role in compiling
relevant information about state regulatory processes for anti-
addiction medications that are categorized as narcotics and educat-
ing state regulators and pharmaceutical company representatives
about the processes and their practical consequences. To implement
that recommendation, the following steps may be taken:
· Conduct a comprehensive study of state laws and regula-
tions pertinent to the development of anti-addiction medications
that are controlled substances, and develop a step-by-step manual
for pharmaceutical companies explaining the mechanisms involved
in launching an anti-addiction medication.
.
Establish and maintain on-line access to the comprehensive
study, as well as to state regulatory information of a practical
nature (for example, a directory of relevant state officials) to facili-
tate pharmaceutical company access.
· Sponsor nationwide or regional educational meetings for
state authorities and clinic administrators to disseminate infor-
mation about potential anti-addiction medications.
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EXECUTIVE SUMMARY 17
Long-Term Actions
Ultimately, close attention should be given to reforming the current
patchwork of state regulations. The committee considered total federal preemp-
tion of state controlled-substance laws and regulations insofar as those authorities
affect the development of anti-addiction medications, but it concluded that such
a proposal would go beyond what is strictly necessary, and could also be
politically unrealistic. The committee does believe, however, that the initiative
for reform must come from the federal government, and will have to involve
some form of legislative change.
The committee recommends, on the basis of the comprehensive
study recommended above, that ONDCP, in coordination with other
relevant federal agencies, develop a series of specific actions
encouraging states to reform their laws and regulations to facilitate
the availability of new anti-addiction medications that are con-
trolled substances.6 Those actions should give particular attention
to:
· Modifying state laws and regulations for narcotic treatment
programs to remove the need to reopen and amend the laws or
regulations to accommodate each new product.
· Imposing specific deadlines for state regulatory action in
response to FDA approval of a new anti-addiction medication that
requires state action to be dispensed to patients.
· Developing flexible, alternative means of controlling the
dispensing of anti-addiction narcotic medications that would avoid
the "methadone model" of individually approved treatment centers.
Finally, the committee urges that Congress, in cooperation with the National
Conference of Commissioners on Uniform State Laws, draft legislation requiring
states to implement needed changes, rather than preempt outright the relevant
state laws or regulations. The legislation could establish regulatory benchmarks
(such as the length of time allowed after FDA approval for the state to take
legislative or other action; types of alternative dispensing controls). That
legislation could be freestanding or as an amendment to NATA.
60NDCP as previously drafted and put forth model state legislation on numerous
topics, thus there is a precedent for model legislation on research and development of anti-
addiction medications.
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DEVELOPMENT OF MEDICATIONS
If the federal government wishes to remove regulatory obstacles to the
development of anti-addiction medications, then significant changes in current
policies, laws, and regulations are necessary (Chapter 8~.
MARKET OBSTACLES AND CREATING INCENTIVES
Size of the Market
From the pharmaceutical industry's point of view the size of the potential
market for determining investment in research and development (R&D), is not
estimated simply from the absolute number of patients with a given condition.
For example, there are about 2.1 million cocaine-dependent individuals and
500,000 to 1 million opiate-dependent individuals in the United States (Hunt and
Rhodes, 1992; Kreek, 19921. Those numbers are high enough to be attractive, yet
there is significantly more pharmaceutical activity in other areas with comparable
or much smaller patient populations. Approximately 25,000 individuals have
amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), for which several
pharmaceutical companies have compounds in various stages of clinical
development (Samotin, 19941. Similarly, the market for medications to treat the
2.1 million epilepsy patients is well established at $400 million to 500 million,
and three new products have been or are about to be approved (Samotin, 19941.
The pharmaceutical industry appears willing to invest in R&D for markets that
are smaller in size or approximately the same size as the cocaine user market, yet
reluctant to enter the field of anti-addiction products. There are several reasons
for this apparent paradox.
First, there is a perceived lack of a market, by the pharmaceutical industry'
in terms of true medical demand, access to patients, and motivation of patients.
It is believed that a portion of the population is either not interested in treatment
or erratic in compliance. Second, one segment of treatment providers is
committed to a "drug-free" concept. Third, any particular medication is likely to
be useful for a particular indication (such as reducing the craving for cocaine)
and not for treating the entire drug-dependent population. The result is greater
uncertainty in predicting the demand or true market size for new anti-addiction
medications than for drugs intended for more established markets (Samotin,
19941. However, those niches represent opportunities, especially for small
pharmaceutical companies, biotechnology companies, and those already involved
in the development of central nervous system (CNS) compounds, that have not
been fully explored by the industry. Furthermore, an uncharted market coupled
with the limits in the basic science of addiction present a significant obstacle in
the discovery and delivery of anti-addiction medications.
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The Orphan Drug Act (P.L. 97-414) was enacted to stimulate the market in
the development of medications for rare diseases by granting market exclusivity
to companies who developed those compounds (Chapter 7~. The standard for
orphan status is whether a drug is intended to treat 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. Since the passage of the
Orphan Drug Act in 1983, the pharmaceutical industry has marketed 60
medications for orphan diseases, and FDA has granted 488 orphan drug
designations (Sanders, 1993~. The Orphan Drug Act could similarly be used as
a mechanism to provide market exclusivity to companies with FDA approved
anti-addiction medications. The committee believes that the FDA should consider
the actual patient population likely to be treated, rather than that potentially
treatable, as there is probably a large segment of the drug-dependent population
that will never present for pharmacotherapy. It is illogical and counterproductive
to the purposes of the Orphan Drug Act to count those patients against the
200,000 threshold.
The committee recommends that FDA interpret the Orphan Drug
Act broadly with the intent of granting orphan drug status to FDA-
approved anti-addiction medications whose potential market can
reasonably be judged to meet the 200,000 patient criterion stipulat-
ed by law. Alternatively, new legislation similar to the Orphan Drug
Act could be drafted specifically for FDA-approved anti-addiction
medications.
The committee believes that the designation of orphan or orphan like status for
approved anti-addiction medications is necessary to stimulate market investment
because the financial return is limited, given the nature of the anti-addiction
market (Chapter 9~.
Drug Pricing and Intellectual Property Rights
In 1986, the Congress passed the Federal Technology and Transfer Act (P.L.
99-502) to encourage private companies to commercialize federal inventions. The
statute authorizes federal laboratories to enter into cooperative research and
development agreements (CRADAs) with nonprofit institutions and private
companies. CRADAs enable government agencies to negotiate exclusive
commercialization licenses with industry partners. In 1989, NIH made an
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DEVELOPMENT OF MEDICA TIONS
administrative decision to adopt a reasonable (or fair) pricing clauses into its
CRADAS in response to complaints about the introductory price of AZT
(zidovudine), an AIDS medication, which was deemed excessive at $10,000 per
patient per year. AZT was developed through a cooperative agreement. Such
pricing provisions are also included in NIH exclusive licensing agreements.
The potential impact of CRADAs on pricing of products aIld patent rights
has been an important issue of concern for the pharmaceutical industry. Industry
representatives have noted that the "reasonable pricing clause" is an important
deterrent to a long-term, effective partnership between the government and the
private sector. It views the provisions as too broad and too threatening to
proprietary interests (U.S. DHHS, 19931.
The committee also heard from industry that the CRADA process is lengthy
and complex, often taking about a year for final approval and requiring many
layers of review (Chapter 9~. Industry officials noted their frustration with the
process required to establish a CRADA which, rather than encourage innovative
research, acts as another disincentive. NIH is fully aware of the controversy, and
is currently reassessing its CRADA policy. There have been two public meetings
(July 21 arid September 8, 1994) on the issue.
Inasmuch as the language of the "reasonable pricing clause" was adopted by
administrative action within NIH and is not legislatively required, NIH could
resolve the controversy by administrative action, and, at the same time protect
the interests of the public.
The committee recommends that administrative action be taken by
NIH to resolve the issue of reasonable pricing in CRADAs. Howev
er, if NIH is unsuccessful in stimulating the industry to form
cooperative agreements, then the committee recommends legislative
action to remove or modify the reasonable pricing clause.
In the absence of a definition of "fair or reasonable price" and in light of
NIH's lack of expertise to undertake meaningful analyses of private-sector
pricing decisions (OTA, 1993; U.S. DHHS, 1993), the committee believes that
this obstacle should be removed. Additionally, NIH should take steps to
streamline the CRADA process. NIH could assign additional staff members or
establish a centralized committee, to eliminate the need for multiple levels of
Section 8.3 of the NIH Patent Policy Board's Model CRADA states, "NIH have a
concern that there be a reasonable relationship between the pricing of a licensed product,
the public investment in that product, and the health and safety needs of the public.
Accordingly, exclusive commercialization licenses granted for NIH intellectual property
rights may require that this relationship be supported by reasonable evidence."
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21
review and provide a single site for negotiating and approving CRADAs (IOM
Workshop, June 13, 1994).
Societal Stigma
The societal stigma of developing and marketing a medication for the
treatment of drug-dependent patients is a concern for pharmaceutical companies.
They fear that, once a medication is approved for use in the treatment of drug
addiction, the market for other indications will diminish or disappear. Eli Lilly's
experience with methadone illustrates the point. Methadone was developed as an
analgesic, but its use for pain relief significantly diminished once it became
widely used as a treatment for heroin addiction. Patients do not want to take a
medication associated with drug addiction. Thus, the pharmaceutical industry is
understandably reluctant to develop compounds specifically for drug addiction,
if other medical uses for the compound are possible.
There is no easy solution to the problem of stigma associated with drug
addiction and its treatment. However, the committee stresses the need for
national leadership in support of pharmacotherapy and continued emphasis on
prevention and treatment. The sense of stigma is most likely to diminish as a
result of public education and broader acceptance of addiction as a treatable
disease (Chapter 9~.
NEED FOR FEDERAL LEADERSHIP
The committee has considered and attempted to bring clarity to the multiple
components involved in the development of anti-addiction medications. Such
development depends critically on cooperation between the public and private
sectors. Yet the number of federal agencies involved, current agency funding and
staffing levels, regulatory requirements, remaining scientific questions, and other
issues present difficult challenges to successful partnership and cooperation.
Although many of the challenges are addressed in this report, it is important to
recognize that government policies have not provided a strong emphasis on
pharmacotherapy for the treatment of drug addiction. This lack of federal
leadership represents an additional disincentive to industry, in that it affects the
public sector's ability to establish clear guidelines, enhance interagency
cooperation, and provide research programs with the stability necessary for
medication discovery and development (Chapter 9~. In addition to its role in
developing medications for drug addiction, the government is likely to be the
major purchaser of those medications. Thus, government policies are critical in
determining the environment in which such medications are developed and are
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DEVELOPMENT OF MEDICATIONS
necessary for supporting pharmacotherapy as an important and accepted form of
treatment.
The committee applauds the current emphasis on treatment in the 1994
National Drug Control Strategy and suggests an additional action to underscore
the importance of treatment and strengthen federal leadership.
One option might be for the President to issue an executive order
assigning a high priority to the development of medications for
drug-abuse treatment. This, or some other explicit action, would
enhance cooperation among the government agencies involved, focus
their activities, and aid in the removal of existing institutional
barriers.
Explicit action at the Presidential or cabinet level would have the added
benefit of signaling to the private sector that the development of anti-addiction
medications is a matter of high national priority. The committee further believes
that progress in this area should be monitored. Thus, any action taken should
include a provision for reporting by the involved agencies regarding their efforts
to coordinate with other agencies and remove barriers identified. Examples of
specific ways in which cooperation could expedite development of anti-addiction
medications are formalization of agreements between NIDA and the Department
of Veterans Affairs for support of clinical trials, and encouragement of all
agencies to promote cooperation with the private sector. Other strategies,
including the use of executive-level task forces and commissions, may also be
options to strengthen federal leadership and give the issue high priority in the
eyes of both the public and private sectors.
CONCLUSIONS
In reviewing the obstacles presented to the pharmaceutical industry for the
development of anti-addiction medications, it is clear that, the disincentives
outweigh the incentives. The formidable scientific and marketing issues,
regulatory complexities, and financial uncertainties add up to an unattractive
picture to the pharmaceutical industry, which tends to enter R&D investment
from a high risk-high reward perspective.
Although it is possible to envision incentives that would interest some
pharmaceutical companies (e.g., small pharmaceutical companies, biotechnology
companies, or those companies already involved in the development of CNS
compounds) without strong federal leadership, in establishing the role of
pharmacotherapy and a long-term federal commitment to research, the committee
believes all other efforts are likely to falter. As the federal government considers
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EXECUTIVE SUMMARY
23
policies that will remove obstacles, the committee suggests a tiered approach of
incentives, allowing each tier of incentives time to produce the desired effect
(Chapter 9~. For example, the first action may be the removal of disincentives,
then the creation of modest incentives, and finally the development of extraordi-
nary incentives.
The removal of disincentives includes many of the committee's administra-
tive recommendations: use of orphan drug and fast track mechanisms for anti-
addiction compounds; removal of adverse effects on clinical research of DEA
requirements under the Controlled Substances Act; and counting DEA review
time as part of the regulatory process for purposes of patent term extension for
controlled substances.
The creation of modest incentives should include broad interpretation of the
Orphan Drug Act to include anti-addiction medications or similar legislation to
stimulate the market in the development of anti-addiction medications; a strong
federal leadership role in support of treatment of drug-dependent patients;
funding of basic research and training; adequate funding of treatment; and a
modification or elimination of the "reasonable pricing clause" in CRADAs.
Finally, the committee considered two extraordinary incentives that the
executive branch and the Congress may wish to consider. They are presented
below as options for consideration, and they are not committee recommendations.
OPTIONS FOR FURTHER CONSIDERATION
The committee discussed whether the overall strategy (i.e., strong federal
leadership, regarding drug abuse treatment and support of research) coupled with
removal of obstacles to anti-addiction medication R&D would be likely to result
in activity by the pharmaceutical industry. Additionally, the committee
considered whether a considerable economic incentive specifically intended to
reward the development of new anti-addiction medications was needed. The
committee did not reach a consensus on that issue and has no formal recommen-
dation for such an extraordinary incentive.
Nevertheless, the committee wishes to include in this report a brief
description of two incentives that were supported by a majority of its members,
recognizing that the committee has not provided details for implementation of
those incentives (Chapter 9~. Both of the following proposals are limited to
medications developed for cocaine addiction and are intended to create a
guaranteed market in view of the limited potential for return on investment of
anti-addiction medications as perceived by the pharmaceutical industry.
Option I would offer developers of the first few (e.g., two or three) FDA-
approved medications for the treatment of cocaine addiction for 3 years after
approval a federal subsidy of a maximum of $50 million for purchase of the
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DEVELOPMENT OF MEDICATIONS
drug. The subsidy could be given, for example, through reimbursement of the
copayment portion of medications for patients with health insurance and the full
cost of medications for those patients without medical insurance.
Option 2 would allow for standing federal purchase orders for prearranged
quantities and at art adequate price of one or more new cocaine treatment
medications to begin at the time of FDA approval. The purchase orders would
establish unambiguous confirmation of a market demand for those products,
thereby stimulating investment and commercialization.
The options presented above were favored by a majority of the committee.
Most committee members also favored implementation of those extraordinary
incentives only if the first two tiers of recommendations fail to stimulate progress
in the anti-addiction medications market. A majority of the committee agreed,
however, that the above options should be deliberated by the executive branch
and Congress as they develop policies to stimulate this area of research and
development (Chapter 9~.
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Representative terms from entire chapter:
drug addiction