|
Items in cart [0] |
Questions? Call 888-624-8373 |
| Copyright © 2009. National Academy of Sciences. All rights reserved. Terms of Use and Privacy Statement |
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 74
Assessment of the
Medications Development Division
This chapter describes and assesses the activities of the National Institute on
Drug Abuse (NIDA) Medications Development Division (MDD), which was
established in 1990 to bring new medications for the treatment of drug addiction
to market. This assessment is based on written materials supplied by MDD and
meetings between the Institute of Medicine committee and representatives of
MDD, the Food and Drug Administration (FDA), the Drug Enforcement
Administration (DEA), and the pharmaceutical industry. In addition, over 20
persons knowledgeable about MDD were interviewed at length by an outside
consultant. (List of acknowledgements in Appendix A).
STRUCTURE AND FUNCTIONS OF THE
MEDICATIONS DEVELOPMENT DIVISION
Mission and History
In recognition of the need to stimulate the availability of medications to treat
drug addiction, the Anti-Drug Abuse Act of 1988 (Public Law 100-690)
authorized funds for a drug discovery and development program within 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 Develop-
ment Division in 1990. The ADAMHA Reorganization Act (Public Law 102-
321), enacted in July 1992, moved NIDA from the Alcohol, Drug Abuse, and
74
OCR for page 75
ASSESSMENT OF THE MDD
75
Mental Health Administration (ADAMHA) to the National Institutes of Health
(NIH). The act authorized a Medications Development Program at $85 million
in fiscal year (FY) 1993 and $95 million in FY 1994, although actual funding
has been only about one-third of the authorization.
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. A more complete description of MDD,
including the mission of each of its five branches, is in Appendix B.
The division, with a FY 1993 budget of about $36 million and a staff of 33,
appears to have the capacity to fund the development of at best only a small
number of drugs to the point of marketability for treating drug addiction
(Chapter 7 for costs of drug development). MDD does not operate inhouse
laboratories or clinical-development programs to fulfill its mission. Rather, it
manages this work through multiple external instruments, such as contracts,
grants, and interagency and collaborative agreements. For example, MDD has an
interagency agreement with the Department of Veterans Affairs (DVA) and pays
it to conduct large, multicenter clinical trials on promising treatment agents. In
this fashion, MDD could, in principle, develop a drug from the point of
discovery through FDA approval and then license it for marketing and
distribution (and perhaps manufacturing) by a commercial partner.
Although MDD might in theory develop a drug on its own in that fashion,
it is structured and funded instead to leverage its resources by seeking private
partners and offering them incentives to collaborate in the development of
medications for the treatment of drug addiction. The incentives offered by the
division include
.
The assumption of some-if not all of the costs of clinical
development by performing the clinical studies for the private partner.
.
The provision of technical assistance (e.g., screening chemicals for
utility as anti-addiction medications and designing and analyzing the results
of clinical trials).
The provision of assistance in working with FDA to secure
marketing approval.
.
MDD's role as a catalyst of a private sponsor's activity can be very versatile. It
might in one instance be limited to in vitro screening of a sponsor's drug or in
another might be as extensive as carrying out nearly all the development
activities, including the fulfillment of regulatory requirements of FDA and DEA.
OCR for page 76
76
DEVELOPMENT OF MEDICATIONS
Research Focus on Opiates and Cocaine
MDD's research is concerned almost exclusively with identifying and
developing treatment for opiate and cocaine addiction. The focus on opiate
research is an outgrowth of NIDA's historical strength in this research. MDD's
more recent focus on cocaine treatment, however, stemmed from criticism of
NIDA's alleged neglect of cocaine and crack addiction (GAO, 1990~. The
criticism prompted the division- at its very inception to concentrate its
resources on developing a portfolio of medications for both opiate and cocaine
addiction. Ironically, the almost exclusive focus on those two kinds of addiction
has engendered criticism from some quarters that MDD is neglecting other kinds,
such as alcoholism and nicotine addiction. However, the division maintains that
its focus on opiate and cocaine treatments is justified for three reasons (C.
Grudzinskas, NIDA, personal communication):
· Opiate- and cocaine-dependent individuals are disproportionately
responsible for violent crimes and for the transmission of the human
immunodeficiency virus (HIV).
.
The private sector has failed to provide an adequate number of
treatments for opiate addiction and has provided no treatments for cocaine
addiction, although it is actively pursuing treatments for nicotine addiction
and already has products on the market.
· Alcoholism research is the purview of another NIH institute, the
National Institute on Alcohol Abuse and Alcoholism (NIAAA).
For the purposes of this report, the Institute of Medicine (IOM) committee
accepts this justification and current emphasis of MDD on opiate and cocaine
addictions; although the committee recognizes that the two addictive drugs that
are most important with respect to morbidity, mortality, and economic costs are
alcohol and nicotine.
Program Objectives
MDD's mission statement describes its program objective: the development
of new medications to treat drug addiction. Furthermore, MDD has articulated
specific program objectives in its 1992 document Five Year Strategic Plan
(NIDA, 1992~. These can be simply stated:
OCR for page 77
ASSESSMENT OF THE MDD
.
value.
77
To screen at least 200 chemicals each year for possible therapeutic
To develop three new opiate medications in the next 5 years.
To develop one or two new cocaine medications in the next 5 years.
Organizational Structure
MDD is one of five research divisions of NIDA. It is organized like a small
pharmaceutical company with five branches (Chemistry/Pharmaceutics,
Pharmacology/Toxicology, Clinical Trials, Biometrics, and Regulatory Affairs)
that cover the usual drug-development activities from preclinical research to
regulation (see Appendix B for division and branch mission statements). As is
typical in the industry, the division's programs are carried out in a matrix
management style by teams drawn from the branches. There are four programs:
.
Opiate Treatment Discovery Program.
· Opiate Treatment Clinical Program.
Cocaine Treatment Discovery Program.
Cocaine Treatment Clinical Program.
As an example, the Cocaine Treatment Discovery Program attempts to
acquire at least 200 chemicals each year from the pharmaceutical industry and
other sources. On acquisition, each chemical is subjected to a battery of in vitro
biochemical assays and in viva pharmacological and behavioral studies to
identify promising therapeutic agents to treat cocaine addiction. To carry out all
the steps necessary, the program draws staff from each of MDD's five branches
who have the appropriate expertise.
All of MDD's outside research and development is managed by three of the
five branches the Chemistry/Pharmaceutics Branch, the Pharmaco-
logy/Toxicology Branch, and the Clinical Trials Branch. The other two branches
provide technical support for those three. The Regulatory Affairs Branch seeks
industry partners, negotiates Cooperative Research and Development Agreements
(CRADAs), secures the regulatory approvals necessary to conduct research, and
serves as a critical link to many other private and public programs. The
Biometrics Branch, a staff of statisticians, provides assistance in protocol design,
data management, and statistical analysis.
OCR for page 78
78
DEVELOPMENT OF A,IEDICATIONS
Budget Process
In a departure from most NIH institutes, the overall budget for NIDA (in
addition to that for NIAAA and the National Institute of Mental Health) is
currently submitted to Congress by the President in what is called a "bypass
budget." This budget undergoes the same appropriations process once it is
delivered to Congress, but it is developed and presented to the Office of
Management and Budget without being reviewed by NIDA's parent agency, the
Department of Health and Human Services (DHHS). The submission of a bypass
budget was authorized only for 2 years (FY 1993 and FY 1994) by the
ADAMHA Reorganization Act of 1992 in an effort to ensure continuity of
funding for NIDA and to avoid competition with already-established NIH
institutes.
Neither the budget request nor the Congressional appropriation for NIDA is
specifically allocated down to the level of each NIDA division. Rather, the
budget is broken into major categories covering all the divisions, such as research
grants, centers, training, and contracts (Table 3.1~. Once funds are appropriated
to NIDA within these categories, the divisions must compete against each other
for funding. The competition must take into account that most of each division's
budget is already committed to continuing prior grants and contracts.
Resources and Funding Instruments
Despite MDD's authorization of $95 million in FY 1994, the actual
appropriations have been far less, although they have been increasing. MDD's
budget has grown steadily since 1988 (when it was known as the Medications
Development Program), climbing from $8 million in FY 1988 to $40 million in
FY 1994. Similarly, the number of full-time equivalent personnel (FTEs) has
increased from 10 in FY 1990 to 33 in FY 1994.
MDD has no internal laboratory or clinical research capabilities, so virtually
all its budget is spent on grants, contracts, and interagency agreements aimed at
drug development. In general, about half the MDD budget is devoted to grants
and the other half to contracts (which include interagency agreements). The
balance between grants and contracts has shifted because in the early years of the
division most of the funds were dispersed through contracts. The majority of the
budget (about 60 65 percent) was spent on contracts in FY 1990-1992. However,
in FY 1993, contracts consumed about half, or $18.5 million, of the total budget
of $35.6 million.
MDD is not the only division in NIDA that is involved in medication
development. Some activities in other NIDA divisions support medication
development, and these, with the MDD functions, are linked into an overall
OCR for page 79
ASSESSMENT OF THE MDD
79
program, the Medications Development Program. The other NIDA divisions that
contribute to the Medications Development Program are the Division of Basic
Research, the Division of Clinical Research, the Division of Epidemiology and
Prevention Research, and the Addiction Research Center (NIDA's intramural
research facility). In terms of funding, however, the MDD budget constitutes
approximately 80 percent of the Medications Development Program.
TABLE 3.1 NIDA FY 1995 Budget Appropriation
-
Number
Amount
Research Grants
Research projects 828 266,728,000
Research centers 33 46,146,000
Other research 118 18,853,000
. .
Training
Individual awards 77 1,640,000
Institutional awards 277 7,668,000
Research and development contracts
64
FTEs
41,330,000
Intramural research 107 24,747,000
Research management and support 279 30,580,000
Total 386 437,692,000
Clinical Trials (79,200,000)
SOURCE: U.S. DHHS, 1993.
Types of Grants and Contracts
There are many different types of NIH grants and contracts. The two types
of grants used most by MDD are RO1 (investigator-initiated grants) and R18
(research-demonstration grants). The R18 category is also called a treatment-
research unit (TRU). These units can be likened to a type of center grant, and
they range in size from $1.5 to $2 million each. Under a TRU, funds may be
spent on staff, facilities, and a variety of individual research projects for clinical
'TRUs are categorized formally as a type of demonstration project. In FY 1995, TRUs
will be discontinued and replaced by a formal center grant.
OCR for page 80
80
DEVELOPMENT OF MEDICATIONS
drug treatments. In FY 1993, four TRUs were funded by MDD at a total cost of
$9.5 million. TRUs are now being converted to center grants and apply
competitively for these grants as they come up for renewal.
Two general types of contracts are used by MDD: the N0 1 is a typical R&D
contract, and the other type is an interagency agreement. In FY 1993, about half
the total contract budget of $18.5 million was spent on R&D contracts and the
other half on interagency agreements.
Interagency Agreements
Through interagency agreements with the DVA Cooperative Studies
Program, MDD has gained the capacity to undertake large-scale Phase III clinical
trials. Indeed, an overall capacity to carry out two large-scale clinical trials at the
same time is now available and operationally tested. As part of the recent
development of levo-alpha-acetylmethadol (LAAM), DVA (supported by MDD)
conducted a 25-site trial involving 625 participants. Simultaneously, a 12-site,
735-patient trial of buprenorphine was also undertaken.
Under this interagency agreement, MDD has spent about $6 million to
purchase access to DVA resources, such as physicians, statisticians, clinical
coordinators, computer operators, and all other types of professionals and
facilities needed for clinical trials and the analysis of their results. DVA has the
ability to coordinate and analyze data from both DVA and non-DVA sites. This
coordinating function is performed by DVA's Cooperative Studies Program in
Perry Point, Maryland. Trials at DVA sites are usually far less expensive than
those at other hospitals or clinics because overhead and physicians' salaries are
covered by DVA and the administrative costs are lower than those of a study
organized and monitored by a contract research organization. The clinical trial
for LAAM cost $6,000 per patient per year-a cost estimated by MDD to be
about half that for a trial performed by a commercial contractor (F. Vocci,
NIDA, personal communication).
Other interagency agreements with DVA cover Phase I-II clinical studies in
individual DVA hospitals in Los Angeles, Philadelphia, and Washington, D.C.
To address preclinical and toxicological research and development needs,
MDD has several other interagency agreements with other NIH institutes, the
Environmental Protection Agency, and the Anned Forces Institute of Pathology.
CRADAs
MDD's preferred means of collaborating with industry in the development
of drugs is through CRADAs, contracts governing collaborative research and
OCR for page 81
ASSESSMENT OF THE MDD
81
development. A CRADA is not a funding instrument for academic investigators
or private companies, but an agreement between government and industry to
work collaboratively to spur commercialization of a product. It contains a
research plan, including a protocol, and describes what each party contributes.
The government is permitted to provide access to researchers, facilities, and in-
kind services but is not permitted to contribute funds (although it may receive
them from the industry partner). A CRADA also defines in advance who will
receive intellectual property rights, and it gives the industry partner the right to
negotiate for exclusive licensing of any patent that the government obtains during
the course of the CRADA, including licensing for a new use of the sponsor's
product. For example, the commercial sponsor might obtain exclusive marketing
of a new psychoactive compound for the treatment of depression, as well as for
drug addiction.
Thus far, MDD has succeeded in negotiating two CRADAs with industry
partners, both for potential treatments for cocaine addiction: one for Phase II
clinical research on gepirone with Bristol Myers Squibb, and the other for Phase
II research for bupropion with Burroughs Wellcome. MDD is in the process of
developing other CRADAs, including one with Reckitt & Colman Pharmaceutic-
als, Inc., for preclinical and clinical research on buprenorphine alone or in
combination with naloxone for the treatment of opiate addiction (NIH, 1993~.
In addition to defining intellectual property rights clearly in advance, the
reason that a CRADA is useful to both MDD and a private partner is that it is
much more flexible than a contract. Contracts take a long time to award and are
difficult to alter once they are in place. But a CRADA can be started relatively
quickly (under a letter of intent) and is resilient enough to accommodate changes,
such as those often requested by FDA in the course of its evaluation of human
trials.
MDD officials reported to the committee that, although they are quite
willing to use CRADAs as a mechanism for collaborating with pharmaceutical
companies in conducting clinical studies, many potential partners are uninterested
in CRADAs because of a controversial provision that goes well beyond
MDD- the reasonable-pricing clause. This clause is a relatively recent policy
requirement in all CRADAs negotiated by DHHS, and is currently being re-
examined by NIH. The manner in which the reasonable-pricing clause acts as a
disincentive to the private sector is presented in Chapter 9 with a committee
recommendation.
Screening Agreements
A screening agreement is the vehicle that MDD uses to obtain chemicals for
testing from industry, academe, etc. These agreements are similar to the more
OCR for page 82
82
DEVELOPMENT OF MEDICATIONS
commonly known material-transfer agreements. Screening agreements spell out
the terms of MDD's acquisition of chemicals to carry out in vitro assays and in
viva pharmacological testing. The purpose of the assays is to evaluate which of
the many compounds already synthesized by drug firms hold potential for further
development for human use. All the testing performed by MDD under screening
agreements is carried out through contracts, and there is no charge to the
sponsors. Under a screening agreement, a commercial sponsor provides
confidential information about the chemical structure, physical properties, and
biological activity of its compound. The results of MDD's screening tests are
given to the sponsor and are entered into NIDA's structure-activity database.
Prior to 1994 the information from NIDA's screening tests remained confidential
for only 3 years. That agreement had 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.
The company benefits from the screening agreement by retaining all pre-existing
rights to its chemicals because the standard screening agreement stipulates that
the testing does not constitute "invention" under the patent laws.
Training
Increasing support for the training of researchers and clinician investigators
in drug-abuse research and treatment has been recognized by NIDA officials as
a particularly important goal. The General Accounting Office has also cited
research training as a field in which it thinks that NIDA should expand its efforts
(GAO, 1 9901.
Specifically with respect to medication development, two major factors
appear to be limiting the training of scientists and clinical investigators in this
field. The first is the scarcity of training funds. In the FY 1994 bypass-budget
request, NIDA asked to raise the number of trainees from 297 to 440 full-time
training positions. However, only modest increases were funded.
The second factor is a lack of interest of young physicians in drug-abuse
research and treatment. This is a general professional problem related to the
relative isolation of treatment of drug abuse from the mainstream of academic
medicine and medical practice, the personal health risks of working with patients
who often have such other serious illnesses as HIV infection or tuberculosis, the
difficulties of conducting high-quality clinical research in the social environment
in which the bulk of addiction occurs, the perceived low respectability of the
field, and the involvement of many patients with crime or the criminal justice
OCR for page 83
ASSESSMENT OF THE MDD
83
system. Those are difficult obstacles to overcome, but the committee believes
that the designation of several major national drug abuse research centers
(Chapter 2 and 6) will help to attract scientists and physicians.
MDD has proposed a different approach to help to rectify the scarcity of
physicians who have training in drug-addiction research: creating a
$500,000-1,000,000 training program in FY 1994 (C. Grudzinskas, NIDA,
personal communication). This program would be administered through FDA's
Staff College and would provide stipends for 9-12 clinicians to receive 3 years
of training through rotations at three federal programs: MDD, the FDA Pilot
Drug Evaluation staff, and the NIDA Addiction Research Center.
Another incentive to attract clinicians to the drug-addiction field that NIDA
would like to be able to offer is a loan-repayment program. There is a precedent
for this type of incentive: under new legislative authority, the National Institute
of Allergy and Infectious Diseases is able to help its employees to repay
educational loans in exchange for service in acquired immune deficiency
syndrome (AIDS) research. The desired authority for clinicians in drug treatment
and research would be along the lines of this model.
The lack of trained clinicians in the field of drug addiction is viewed as an
obstacle to progress, not only by MDD in realizing its goals of medication
development, but also in treatment and clinical research. Chapter 6 discusses
training issues in greater depth.
RELATIONSHIPS WITH OTHER FEDERAL AGENCIES
AND THE PRIVATE SECTOR
Food and Drug Adm
ministration
M DD and FDA are parts of the same agency, the Public Health Service
(PHS), and are also linked through FDA's drug review process. NIDA may also
sponsor investigational new drug (IND)applications.2To receive an IND,NIDA
or any other sponsor has to submit an extensive application to FDA containing
the results of laboratory and animal testing, details of manufacturing processes,
and clinical-research plans. The granting of an IND gives the authority to begin
testing in humans. NIDA or its industry partner is also responsible for meeting
all FDA requirements to conduct clinical trials and obtain evidence necessary to
win marketing approval. Chapter 7 further examines the role of FDA and its
influence on the private sector in developing anti-addiction medications.
As part of the process of developing LAAM, MDD has reached an excellent
working relationship with the FDA Pilot Drug Evaluation group. This relation
2NIDA holds INDs for LOAM, buprenorphine, and depot naltrexone.
OCR for page 84
84
DEVELOPMENT OF MEDICATIONS
ship includes continuing communication, discussion of problems as they arise,
and trust between the staffs of the two organizations. FDA has also developed
special software to allow sponsors to submit clinical data on-line electronically
as they are entered into the sponsor's database; this approach played a crucial
role in the rapid approval of LAAM.
FDA and NIDA also participate in the process for scheduling drugs of abuse
arid in the promulgation of regulations on treatment standards for the use of
narcotics in treating drug addiction. Under the Comprehensive Drug Abuse
Prevention and Control Act of 1970, the secretary of DHHS must issue
regulations that describe how any new narcotic medication can be administered
and used in narcotic treatment programs. Regulations under this law related to
the use of methadone in treating opiate addiction have been in place since 1972
and were amended to accommodate the recent approval of LAAM (FDA, 1993~.
Those regulations are further discussed in Chapter 8 and are considered in detail
in a forthcoming IOM report on methadone regulations (IOM, 1995~.
Drug Enforcement Administration
Under the Controlled Substances Act, DEA and NIDA have defined roles in
the scheduling of drugs of abuse.3 Scheduling is a means of restricting the
availability of drugs to ensure that they are accessible for medical purposes but
not for illicit trafficking. The law requires that NIDA's parent agency, DHHS,
evaluate the medical utility and the abuse potential of a narcotic drug and
recommend in which of five schedules or categories a drug should be placed.
DHHS relies heavily on NIDA and FDA for preparing this evaluation. Once
DHHS submits its evaluation and recommendation to DEA, DEA is legally
bound by the Controlled Substances Act to place a drug in a schedule that is not
more restrictive than that recommended by DHHS (Chapter 7~.
In addition to their roles with respect to drug scheduling, NIDA and DEA
are brought together under additional requirements of the Controlled Substances
Act. If NIDA (or a private sponsor) holds an IND to test a Schedule I drug (i.e.,
a drug with no accepted medical use and a high potential for abuse), the sponsor
is required to have its research sites registered with DEA. DEA must inspect
each research site and grant a permit before a Schedule I substance may be
shipped to that site. This requirement for individual inspections led to lengthy
delays in NIDA's Phase III study of LAAM and is a disincentive to industry in
3By statute, the formal relationship is between DEA and the secretary of DHHS. The
secretary has delegated this authority to the assistant secretary for health as the director
of PHS. In practice, most of the negotiations between DEA and PHS are conducted by
representatives of DEA and the two PHS agencies, EDA and NIDA.
OCR for page 85
ASSESSMENT OF THE MDD
85
the development of anti-addiction medications. Additionally, there are state
controlled substances acts that have an effect on pharmaceutical R&D (Chapter
8~.
Office of Protection from Research Risks
NIH's Office of Protection from Research Risks (OPRR) reviews and
archives all consent and approval forms for NIH-sponsored research. For any
U.S. human trials, participants must give informed consent, and the protocol and
consent form must be approved by an institutional review board (IRB), a special
review body set up by each institution that sponsors research. These are basic
requirements of ethical clinical research and of the federal regulations for the
protection of human subjects. In arranging for the recent LAAM study, obtaining
IRB approval of individual study sites became unusually complex, primarily
because LAAM was, until it was approved by FDA, a Schedule I substance
under the Controlled Substances Act. It is useful to note these complexities in
some detail because they illustrate the procedural problems that make clinical
research on anti-addiction compounds difficult; they will complicate future
clinical trials involving narcotics unless new policy solutions can be found.
In the LAAM study, the numerous sites conducting the trials were not
traditional research institutions; rather, they were methadone clinics, many of
which did not have pre-existing IRBs to evaluate protocols and consent forms.
Furthermore, these clinics did not have on file with OPRR an assurances that
they would comply with all human-subjects regulations or the required
registration. To solve that problem, MDD helped each methadone clinic either
to establish its own IRB or to use an existing IRB in another institution that had
the competence to evaluate drug-addiction research. MDD, through DVA, also
helped each methadone clinic to file with OPRR a single-project assurance
containing a statement that all human-subjects protections would be complied
with during the study, a list of IRB members, and a proposed informed-consent
form. If NIDA supports future studies at the same clinics, a new single project
assurance will need to be filed for each clinic.
Tile history of consent forms and protocol reviews in the LAAM study
illustrates the kinds of issues that bring procedural complexity to multicenter
trials (Vocci, 1993, presentation to IOM committee). The consent form became
the mechanism in this trial for informing study participants that, in spite of a
general policy in clinical trials that personal information is confidential, this
policy would be broken in the LAAM study if a patient were found to have a
reportable transmissible disease (e.g., tuberculosis) or made voluntary disclosures
4Most institutions file a multiproject assurance with OPRR to cover many projects at
once for a period of 5 years.
OCR for page 86
86
DEVELOPMENT OF MEDICATIONS
about committing child abuse. To develop a consensus on these points, MDD
developed additional language for the consent form to provide greater detail
about the limits of confidentiality. The consent form had to be agreed on by the
appropriate IRBs, the DVA Human Subjects Protection Committee (because
some of the sites were located in the DVA medical system), FDA, and OPRR.
MDD also helped research sites to obtain confidentiality certificates to protect
patients' privacy (in the event of a court challenge) and to protect research
confidentiality.
All those activities, although time-consuming and labor-intensive, would
have been conducted by the sponsor of any large, multicenter clinical trial,
regardless of the type of compound being tested, as part of compliance with FDA
and DHHS regulations. Because LAAM was a Schedule I substance, however,
an additional set of procedural requirements driven by the Controlled Substances
Act came into play: multiple reviews of the protocol to ensure that it met the
scientific requirements of FDA; the DEA regulations related to recordkeeping,
security, and diversion; the methadone regulation of DHHS; and the counterpart
narcotic regulations of each state that contained a participating clinic. The MDD
staff estimates that about 15 drafts of the protocol, with iterative consultation and
agreement, were necessary. Nevertheless, one state (California) could never
agree, because one point in its drug regulations is more stringent than the federal
methadone regulations, so no clinic in California participated in the study (F.
Vocci, NIDA, personal communication). The committee realizes that individual
state regulations may negatively impact the ability to conduct clinical trials. See
Chapter 8 for further discussion of state regulations.
Pharmaceutical Industry
The pharmaceutical industry plays an integral role in the drug-development
strategy adopted by MDD. As stated earlier, MDD offers drug firms both
resources and technical assistance to bring a medication to market. MDD prefers
a very active industry role, but at the very least a partner is needed to market and
distribute any medication that is jointly developed.
Another key role for industry is to provide MDD with chemicals to screen
for potential therapeutic value. MDD or the industry partner may proceed with
development if a compound shows therapeutic promise after a battery of
screening tests. The role of screening in drug discovery is discussed in Chapter
2.
In addition to working with individual companies, MDD has received input
from the Pharmaceutical Manufacturers Association (PMA, now the Pharmaceu-
tical Research and Manufacturers of America, PhRMA), a trade association
whose members are some of the largest U.S. drug manufacturers. In 1990, PMA
OCR for page 87
ASSESSMENT OF THE MDD
87
created the PMA Commission on Medicines for Treatment of Drug Dependence
and Abuse (CDDA), and this commission has, through a subcommittee, presented
to MDD its perspective on a strategy for screening potential treatments for
cocaine addiction. A technical subcommittee of CDDA has provided information
about methods for clinical and statistical design that are often used in medica
tion-development clinical trials.
ASSESSMENT OF THE MEDICATIONS DEVELOPMENT DIVISION
MDD has made considerable progress in the 4 years since its inception. The
committee's impressions of the specific accomplishments of the division are
noted here.
Staff and Resources
The committee recognizes that MDD appears to be hampered by lack of
personnel, and it is the understanding of the committee that any large increase
of funds could not benefit the program unless accompanied by additional staff.
The committee, however, did not evaluate in detail the staff and resources
devoted to various activities of MDD. Although the current budget of $40
million and the 33-FTE staff 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 (Chapter
2~.
Furthermore, given the fills panoply of responsibilities needed to accomplish
the mission of MDD (see mission statements in Appendix B), the staff appears
overextended. For example, MDD has only one physician on staff, but a clinical
trial can be best designed and monitored by a physician working with the support
of other research professionals. Thus, the clinical trials must be designed and
monitored by current staff in addition to their numerous other responsibilities.
Similarly, the requirements of the screening program appear to need additional
qualified staff, especially if NIDA and MDD decide to implement the com-
mittee's recommendations for improving the cocaine screening program (Chapter
2~. The committee is aware, however, of the budgetary and hiring constraints and
suggests ways to overcome them in Chapter 2.
OCR for page 88
88
DEVELOPMENT OF MEDICATIONS
Drug-Discovery Programs
The committee commends MDD for its interest in establishing screening
programs for new compounds that might have anti-opiate or anti-cocaine activity
and for its screening efforts. As noted in Chapter 2, however, the anti-opiate field
is relatively mature with respect to the availability of scientific methods for the
discovery of anti-opiate compounds, whereas the anti-cocaine field is in its
infancy. Because of the lack of established in vitro screening methods and
validated animal models that are predictive in humans for anti-cocaine medica-
tions, the committee feels that there is a need for basic research to develop
laboratory models of critical behavioral characteristics of the addictive process.
In addition, improvement of such methods and models should be given high
priority for grant and contract support by MDD (see elaboration and recommen-
dations in Chapter 2~.
The committee also supports the limited screening of compounds with the
methods already identified by MDD with the advice of the PMA CDDA to gain
experience and build effective working relationships with industry partners.
However, the committee does not see such screening as the primary route to
identifying new treatments for cocaine addiction, nor as essential to progress, at
least in the near term. The committee recommends that emphasis be given to the
early clinical evaluation of known psychoactive compounds in moderate-sized,
controlled clinical trials for the early determination of efficacy. Those compounds
might be drugs approved for other uses, drugs under development by pharmaceu-
tical companies, or compounds related to such drugs.
Clinical Trials
The committee commends MDD for completing the development of LAAM
and recognizes that MDD analyzed a file of accumulated data on some 6,300
patients and negotiated with FDA a final Phase III clinical trial necessary for
LAAM's approval. The committee is impressed that MDD has gained invaluable
experience and built an effective clinical-investigator network and administrative
base that can be used for the conduct of Phase III studies on other anti-addiction
drugs. Inasmuch as the pharmaceutical industry considers the difficulty of
organizing and conducting clinical studies to be an obstacle to its interest in this
field (Chapter 9), MDD's building of a major, continuing clinical-trial capability
represents a resource of permanent value to both MDD and the private sector.
The committee encourages MDD to maintain this resource and build on it further
in its partnership arrangements with individual drug firms.
With respect to the conduct of clinical research in patients with drug
addiction, the committee is impressed that such research is greatly complicated
OCR for page 89
ASSESSMENT OF THE MDD
89
from an administrative point of view and that costs are increased by the presence
of multiple independent regulations, including the IND regulations of FDA, the
narcotic-treatment regulations of DHHS, the DEA regulations related to
recordkeeping, security, and scheduling, and state scheduling and treatment
regulations. Those regulations are major disincentives to the private sector in the
development of anti-addiction compounds; they are discussed extensively in
Chapters 7 and 8, where several recommendations are proposed for overcoming
those barriers.
Clinical-Research Training
Patients with drug-abuse problems often require diagnostic assessment and
treatment for such sequelae as liver disease, HIV, other infection,
large number of patients with primary psychiatric disease also require treatment
for drug abuse (Beeder and Millman, 1992~. But the number of physicians
~neciallv trained to care for this large patient population is small, as are the
numbers of sites and clinical investigators for studying drug abuse (Chapter 6~.
As discussed earlier, the appeal of this field is limited by the stigma of drug
addiction, the noncompliance of drug-dependent individuals as subjects in clinical
trials, the risk of infectious diseases that afflict these patients, and the general
lack of insurance coverage for drug-abuse treatment. The lack of clinical research
and treatment centers has and will continue to have an impact on MDD's ability
to carry out sophisticated clinical studies of pharmacological and other treatments
~. . .
and trauma. A
in those patients.
The committee noted in Chapter 2 that the designation of national drug
abuse research centers will attract qualified young physicians into the field of
drug abuse. The committee believes that such centers should provide training and
drug-abuse education to clinicians as a mechanism of encouraging the develop-
ment of medical expertise (Chapter 6~.
Other incentives that might attract physicians early in their training to pursue
.
careers in the field of drug-abuse research and treatment are awarding of
_
certificates of "added qual~cat~on on completion of at least a year of full-time
formal training in this subspecialty, educational-loan forgiveness programs, and
reasonably paid fellowship programs that are competitive with private-sector
salaries.
Relationships with Regulatory Agencies
MDD has established an excellent working relationship with the Pilot Drug
Evaluation staff of FDA, particularly in the last few years as a result of the
OCR for page 90
Do
DEVELOPMENT OF MEDICATIONS
effective collaboration that brought the development of LAAM to completion.
This relationship includes a spirit of trust, reciprocal access (to nonproprietary
information), the establishment of a data linkage that permits data from NIDA
clinical trials to be transmitted to FDA for early scrutiny and analysis as they are
entered into the clinical-trials database, and a common commitment to conducting
good clinical studies and reviewing the results rapidly. The relationship is an
important long-term asset to both agencies. It can serve as the basis for
continuing communication and productive effort in the development of future
anti-addiction medications and maintaining the scientific independence of NIDA
and the regulatory role of FDA. The committee believes that this relationship
should be strongly encouraged to continue. To that end, the committee urges a
formalization of the relationship between NIDA and FDA (Chapter 9 for
discussion and recommendation).
Unfortunately, DEA's role in regulating research and treatment sites has
been an obstacle for MDD. The LAAM clinical trial was delayed by 3 - months
because of the time DEA required to inspect each of the 24 separate research
sites before this Schedule I narcotic could be dispensed in a clinical protocol.
Another major obstacle to drug development is the extraordinary degree of
regulation surrounding a treatment after it is approved for marketing. The
separate regulatory system resulted from the passage of the Narcotic Addict
Treatment Act in 1974. This act, which amended the Controlled Substances Act
(21 USC 823), placed drug treatment out of the mainstream of medicine through
elaborate requirements for practitioners who dispense narcotics for maintenance
or detoxification treatment. The federal requirements, which are enforced by
FDA and DEA, include annual registration covering the practitioner's qualif~ca-
tions, security arrangements, recordkeeping, and compliance with treatment
standards. Additionally, many states have enacted more stringent treatment
regulations (Chapters 81.
Interaction with the Private Sector
The committee commends MDD for its initiatives involving the private
sector, although MDD has had difficulties in gaining industry partners and
industry chemicals for screening. MDD provides incentives to gain industry
partners (e.g., technical assistance, working with FDA for drug approval, and
absorbing some of the costs of drug development), but they are not considered
strong enough to overcome the numerous obstacles to private-sector investment
in the field of anti-addiction medications.
The committee believes that there are two possible explanations for
industry's apparent lack of interest in volunteering chemicals from its chemical
libraries. The first is that industry and MDD have different expectations about
OCR for page 91
ASSESSMENT OF THE MDD
91
the potential value of these libraries as a resource. To some companies, the
libraries represent an investment in the future that must be closely protected.
Even though the chemicals might have been archived because of seemingly less
immediate commercial potential, the companies recognize that this potential
could change overnight if new discoveries are made. Furthermore, rather than
turning over a chemical to MDD, a company might prefer to license the chemical
to another, usually smaller company for further testing.
The second explanation has been industry discontent with the screening
agreement developed by MDD to obtain chemicals for testing. Although the
screening agreement assures commercial sponsors the intellectual property rights,
the unresolved legal issues between NIH and Burroughs Wellcome over patenting
of the AIDS treatment zidovudine (AZT) has created a climate of uncertainty and
distrust (Felsenthal, 1993~. Prior to 1994 some pharmaceutical companies were
also uncomfortable with the provision of the screening agreement that gave MDD
the right to disclose the results of its screening of an industry chemical within
3 years. However the screening agreement was changed in 1994 to stipulate that
there will unlimited confidentially of screening test data. This change has made
NIDA's policy consistent with other federal drug-development programs
(Appendix E).
SUMMARY
MDD has made substantial progress since its inception in 1990. Among its
accomplishments are the following:
.
· It has completed the evaluation of LAAM' a long-acting substitute
for methadone for the treatment of opiate addiction, and obtained approval
for marketing from FDA.
· It has evaluated several other drugs in major clinical studies,
including buprenorphine for opiate addiction, and has sponsored smaller
exploratory studies on a variety of compounds.
· It has established through its contractors, especially DVA, a
network of experienced clinical investigators.
It has established an excellent working relationship with FDA.
To promote drug discovery, it has established a screening program
with the goal of identifying new compounds with potential activity against
cocaine addiction.
· It has conducted a program of outreach to pharmaceutical
companies and worked with the PMA Commission on Medicines for the
Treatment of Drug Dependence and Abuse to interest companies in
OCR for page 92
92
DEVELOPMENT OF MEDICATIONS
supplying drugs for screening and in collaborating in the clinical evaluation
of their drugs.
Those are major accomplishments for a young organization and provide an
excellent base for continuing productivity. However, MDD has had difficulty in
stimulating private-sector interest, in acquiring industry partners, and in obtaining
a suitable number of compounds for screening. Those difficulties may result from
government policy issues that go beyond the power of MDD or NIDA to resolve
alone. Nevertheless, it is the opinion of the committee that NIDA can address
some of those issues in the context of its current operations: it can increase
emphasis on leadership of a public-private cooperative effort, increase emphasis
on the early evaluation of promising compounds in clinical pharmacology and
early Phase II studies, and create an investigator network that is available to the
private sector for Phase III studies. All those moves are aimed at improving
NIDA's and MDD's leadership role, management, and strategies for screening.
In addition, NIDA can be influential by contributing to the resolution of several
current policy issues, including the reasonable-pricing clause in CRADAs, and
the difficulty of conducting clinical research under multiple, independent FDA,
DEA, DHHS, and state regulations. Those issues are discussed in detail in
Chapters 7, 8, and 9 which propose recommendations and options.
CONCLUSIONS AND RECOMMENDATIONS
The committee has noted the need for strong leadership in promoting
pharmacotherapy as an important component of our national strategy for
combating drug addiction. Leadership must come from many sources, especially
the highest levels of the federal bureaucracy (Chapter 9~. An important leadership
role belongs uniquely to NIDA and especially to MDD for its implementation.
MDD must view itself as the leader in stimulating and accelerating development
of anti-addiction medications in the United States. That requires a cooperative
national endeavor that includes NIDA, academic scientists, and the private sector
to integrate the R&D efforts of identifying and developing new drugs for the
treatment of addiction. It is not an easy task, given the lack of scientific progress,
the limited resources, and the many disincentives to private involvement in this
field. Nevertheless, without such leadership, further progress is likely to be
haphazard at best.
The committee views this national leadership role in anti-addiction
medication development, as one of the key functions of NIDA. MDD should be
viewed as the leader of a goal-oriented program that is part of the culture and
mission of NIDA and NIH. Consequently, it should be empowered to lead, as
well as to fulfill, a scientific and technical mission.
OCR for page 93
ASSESSMENT OF THE MDD
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 (NCDDG-AIDS) of the National Institute of
Allergy and Infectious Disease, and the Anticonvulsant Drug
Development Program of the National Institute of Neurological
Disorders and Stroke.
93
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. The intent has been to stimulate success of the
enterprise from a national point of view by promoting scientific and technical
collaboration and then licensing successful drugs to the private sector for
marketing.
With the establishment of MDD, the nation now has a focal point for
leadership in the development of therapeutic agents for addiction. In the
committee's view, the primary policy responsibility of MDD should be to
provide such leadership as a complement to its scientific responsibilities.
Yet, NIDA has been prevented from forming effective partnerships with
industry because of the many obstacles and disincentives faced by pharmaceutical
companies in the development of anti-addiction medications. Unfortunately, there
is little formal literature on drug development specifically as it applies to anti-
addiction medications, so the documentation for the information presented, is, in
part, testimony from senior executives of the pharmaceutical industry, the
committee's expertise, results of a survey of the pharmaceutical, generic-drug,
and biotechnology companies (Appendix D); and the June 13, 1994 IOM
Workshop (Appendix F). Three major issues were identified as obstacles and
disincentives to private sector investment in this field, they include:
· an inadequate science base on addiction and the prevention of
relapse, especially for cocaine (Chapter 2~;
.
an uncertain market environment, including the treatment setting
(Chapter 4~; treatment financing (Chapter 5~; lack of trained specialists for
drug addiction treatment and research (Chapter 6~; federal and state laws and
regulations (Chapters 7 and 8~; and market size; pricing issues, societal
stigma, liability issues, and difficulties in conducting clinical research
(Chapter 9~; and
· a lack of sustained federal leadership (Chapter 9~.
OCR for page 94
94
DEVELOPMENT OF MEDICATIONS
The committee believes that innovative pha~macotherapies are most likely to be
developed through an effective public-private sector partnership with NIDA and
a limited number of committed pharmaceutical or biotechnology companies. The
remainder of this report identifies the obstacles and disincentives to private sector
R&D of anti-addiction medications and offers policy and legislative solutions to
overcome the obstacles arid stimulate private sector involvement.
REFERENCES
Beeder AB, Millman RB. 1992. Treatment of patients with psychopathology and
substance abuse. In: Lowinson JH, Ruiz P. Millman RB, eds. Substance Abuse: A
Comprehensive Textbook. 2nd ed. Baltimore: Williams ~ Wilkins. 675090.
Felsenthal E. 1993. Who invented AZT? Big bucks are riding on what sleuths find. Wall
Street Journal October 21, 1993.
FDA (Food and Drug Administration). 1993. Levo-alpha-acetyl-methadol (LAAM) in
maintenance: revision of conditions for use in the treatment of narcotic addiction.
July 20, 1993. Federal Register 58~137~:38704-3871 1.
GAO (General Accounting Office). 1990. Drug Abuse: Research on Treatment May Not
Address Current Needs. Washington, DC: GAO. GAO HRD-90-1 14.
IOM (Institute of Medicine). 1995. Federal Regulation of Methadone Treatment. Rettig
R. Yarmolinsky A, eds. Washington, DC: National Academy Press.
NIDA (National Institute on Drug Abuse). 1992. National Institute on Drug Abuse
Medications Development Program 5 Year Strategic Plan.
NIH (National Institutes of Health). 1993. National Institute on Drug Abuse: announce-
ment of intent to enter a Cooperative Research and Development Agreement
(CRADA). May 12, 1993. Federal Register 58~90~.
U.S. DHHS (U.S. Department of Health and Human Services). 1993. Justification of
Estimates for Appropriations Committees. Fiscal Year 1994. Volume VI, National
Institutes of Health.
Vocci FJ. Sorer H. 1992. Pharmacotherapies for treatment of opioid dependence. Journal
of Health Care for the Poor and Underserved 3:109-124.
Representative terms from entire chapter:
drug addiction
