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Appendix E
Mode! Federal Programs in
Pharmaceutical R&D
The federal government sponsors 13 pharmaceutical research and
development programs (OTA, 1993~. The programs cover a wide array of fields,
including drug addiction, cancer, malaria, and contraception. This appendix
describes several selected programs that have successfully brought medications
to market with the cooperation of commercial sponsors: the Antiepileptic Drug
Development Program of the National Institute of Neurological Disorders and
Stroke (NINDS) and the cancer-drug and AIDS-drug discovery and development
programs of the National Cancer Institute (NCI) and the National Institute of
Allergy and Infectious Diseases (NIAID) (Table E.11. Most of the information
obtained in this appendix was based on interviews with leaders of the programs
(see Appendix A). The goal of identifying the successful elements of the
programs is to help the Medications Development Division (MDD) of the
National Institute on Drug Abuse shape the future of its program.
ANTIEPILEPIIC DRUG DEVELOPMENT PROGRAM
Background
The Antiepileptic Drug Development Program (ADD) was created in 1975
to encourage the development of medications to treat epilepsy, which afflicts 2
million Americans. As early as 1968, when Congress asked the federal
government to make more drugs available, the National Institutes of Health
227
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228
DEVELOPMENT OF MEDICATIONS
(NIH) responded by launching an initiative that eventually resulted in the
formation of the ADD. The program is now situated within the Epilepsy Branch
of NINDS. Its current budget of about $4 million is spent on extramural
contracts administered by a staff of 21. The market for anti-epilepsy drugs is
estimated at $300 500 million.
When the program was created, drugs were available to treat epilepsy; but
despite optimal dosing, about 10 percent of patients still experienced seizures. In
addition, many patients suffered from side effects. There was no apparent
industry interest in developing more-effective and less-toxic medications. The
program was designed to stimulate the private sector by providing incentives to
develop and market a new generation of antiepilepsy drugs. The incentives
offered by the ADD were to share funding and to offer expertise, such as in the
design, monitoring, or analysis of a clinical trial (Kupferberg, 19901.
In the early years of the ADD, its resources were devoted almost entirely to
controlled clinical trials. The program pioneered new outcome measures designed
to evaluate a drug's efficacy in a clinical trial. These novel approaches to
establishing efficacy required fewer patients to be studied over a shorter period
and so were less expensive. Two drugs that were on the market in Europe,
carbamazepine and valproic acid, were the first tested by the ADD in clinical
trials and were found effective. By the middle 1 970s, the clinical data contributed
to the acquisition of Food and Drug Administration (FDA) marketing approval
for the ADD's industry partners.
The program began a preclinical screening component in 1974. Industry
provided the ADD with most of the chemicals, which are screened at no charge
and for which companies retain patent rights. Since the creation of the preclinical
screening program, 17,000 chemicals have been tested. Two of them have
reached or are about to reach the marketplace. The time between discovery and
marketing approval for those two successful chemicals was about 12 years.
The program's resources are divided almost equally between preclinical
research and clinical trials. The preclinical research primarily supports preclinical
screening and toxicity testing to determine target-organ toxicity. The clinical
trials are sponsored by contract at academic medical centers. Because of
innovations in clinical trial design, each trial normally requires fewer than 200
patients. The smaller trials (usually Phase I and II trials) are used to establish
safety and to gain enough efficacy information to attract an industry partner that
can sponsor larger trials. The larger trials, which build on the smaller ones, are
necessary for FDA regulatory requirements.
OCR for page 229
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230
DEVELOPMENT OF MEDICATIONS
Elements of Success
Over the course of almost 20 years, the program has succeeded, in
conjunction with drug companies, in bringing at least six drugs to market. The
varied medications now available to treat epilepsy are so effective for patients
that drug companies, perceiving the market to be saturated, have become less
interested in working with the ADD. Not resting on its laurels, the ADD is now
in the process of changing its direction to an entirely new and unexplored arena:
medications to prevent epilepsy symptoms.
Program administrators have attributed their success to the following factors:
· The existence of animal models. Animal models for epilepsy have
been indispensable in all fields of research, such as for screening tests to
search for potential treatments and for assessing drug efficacy, mechanism
of action, toxicity, and side effects.
· Strorlg support from constituency groups. The Epilepsy Foundation
of America, whose membership exceeds 20,000, has been very supportive
of the AD[). It has been instrumental in ensuring stable financial support
from Congress.
· Strong support from industry. Industry has provided the ADD with
about 1,000 chemicals per year for preclinical screening. It has also been
interested in working with the ADD in clinical trials and in seeking guidance
on drug development.
Realistic expectations. The program's leadership has worked
constructively with Congress to ensure that the ADD's goals remain realistic
in light of its resources. The pressure to produce results on an unreasonable
schedule is less than that in the case of medications for drug addiction
because the social burdens created by epilepsy are not as severe as those
created by drug addiction.
· Large market size. The market for an antiepilepsy drug is estimated
at $300-500 million, which is sufficient to attract pharmaceutical companies
to work with the ADD. The reimbursement climate has also been
advantageous.
· Favorable regulatory climate. FDA has been receptive to the need to
increase availability of antiepilepsy medications. The ADD enjoys good
working relationships with FDA staff.
· Medically defned outcome measures. Clinical trials are aided by
readily identifiable, medically acceptable outcome measures of drug efficacy.
This has led to new clinical-trial designs that can establish efficacy with
fewer patients at lower cost.
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APPENDIX E
231
NATIONAL CANCER INSTITUTE CANCER-DRUG
DISCOVERY AND DEVELOPMENT PROGRAMS
Background
NCI sponsors the largest and oldest drug discovery and development
program in the federal government. The NCI program was established in 1955
as the Cancer Chemotherapy National Service Center to fill a need that was not
being addressed by either universities or industry. As the program grew, it was
divided into several programs in NCI's Division of Cancer Treatment, where
they are now. The programs in the division support an increasingly broad
spectrum of preclinical and clinical research. In collaboration with industry, the
programs strive to make new cancer treatments available. The preclinical
screening programs have evaluated over 450,000 chemicals in almost 40 years
of testing. NCI's systematic commitment to all aspects of drug development has
resulted in the approval of 48 drugs- the majority of commercially available
cancer treatments including methotrexate, doxorubicin, and vincristine (Zubrod
et al., 1977; Grever et al., 1992~.
Today's commercial market for anticancer drugs depends on the incidence
of the cancer in question and many other factors. The market for a given drug
is estimated at anywhere from $1 million to $500 million. NCI's investment will
depend on a drug's therapeutic promise, the size of the potential market, and the
resources of its commercial partner.
All 5 programs in the NCI Division of Cancer Treatment play a role, but
three of them are most germane to drug discovery and development. Most of the
preclinical research is in the Developmental Therapeutics Program, which had a
FY 1993 budget of about $58 million and staff of 212. Most of the clinical
research is supported under the Cancer Therapy Evaluation Program and the
Clinical Oncology Program, which had a combined FY 1993 budget of about
$233 million. These three programs are described below.
Preclinical Research
The Developmental Therapeutics Program performs a broad spectrum of
preclinical research to identify promising cancer medications. This research is
undertaken by nine extramural branches and five intramural laboratories. Its
contract screening program alone evaluates the potential therapeutic value of
about 10,000 new chemicals each year. A revised screening battery, modified in
1985, subjects each chemical to tests against 60 human-tumor cell lines derived
from seven cancer types (lung, colon, melanoma, renal, ovarian, brain, and
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232
DEVELOPMENT OF MEDICATIONS
leukemia). After reviewing the results from these in vitro tests, a special
committee determines what secondary in vitro and in vivo studies are warranted.
About 4 percent of chemicals screened by the program have been referred for
further testing (Grever et al., 1992~. The program also screens antiviral drugs that
may show promise in combating HIV infection and AIDS.
The screening program acquires chemicals from industry and academe in
almost equal proportions. The testing is performed at no cost to the sponsor. In
the standard screening agreement, NCI stipulates that its testing does not
constitute "invention" under the patent laws and thereby cedes intellectual
property rights to the sponsor. Results are kept confidential unless the chemical
is pursued in clinical trials. When the decision is made to proceed to clinical
trials, the sponsor is given 1 year to file a patent before the screening results are
released (M. Grever, NCI, personal communication).
Among the many unique screening program resources supported by NCI is
the Natural Product Repository. In recognition that natural products have
contributed to many of the currently used anticancer agents, this repository
contains almost 70,000 extracts of natural products systematically collected
worldwide by NCI contractors. Taxol, one of NCI's most recent and important
contributions to cancer treatment, was collected under this program in the early
1 960s.
In addition to the screening program, the Developmental Therapeutics
Program supports many other preclinical tasks. In its preclinical pharmacology
research, it develops analytic methods to determine drug concentrations and
metabolites in animals. This provides critical data about drug and metabolite
excretion or clearance for use in later human testing. In its formulation research,
it strives to ensure that potential medications have bioavailability in humans,
especially at the target site. In some cases, this requires the modification of an
otherwise insoluble agent to an active species. Finally, in its preclinical
toxicology research, it examines acute and subacute toxicity of test chemicals in
. . ~
various anlma species.
Clinical Research
Clinical research is supported in two complementary programs: the Cancer
Therapy Evaluation Program, which supports extramural research, and the
Clinical Oncology Program, which supports intramural research. Together, these
programs were budgeted in FY 1993 at about $233 million.
The Cancer Therapy Evaluation Program supports a large national network
of clinical oncology cooperative groups at hospitals and other clinical sites. The
FY 1993 budget was about $179 million. The groups provide state-of-the-art care
for patients and participate in clinical trials designed to develop better cancer
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APPENDIX E
233
therapies. The program consists of more than 300 hospitals and community
clinics and nearly 2500 physicians. In FY 1993, about 800 protocols were used
to investigate the therapeutic potential of some 200 new therapies alone or in
combination with approved drugs. Of those 800 protocols, 150 involved Phase
III clinical trials. The cooperative agreements that fund the cooperative groups
support data management, investigational-drug costs (if any), and quality
assurance, but they do not provide funds for patient care. Almost 75 percent of
the new drugs being studied by the groups are provided by industry, 10 percent
are provided by university researchers, and about 10 percent come from the
Division of Cancer Treatment's preclinical research sponsored by the
Developmental Therapeutics Program. Statistical and regulatory support to aid
research design and approvals is in the program's Biometrics Research Branch
and Regulatory Affairs Branch, respectively.
The Clinical Oncology Program, funded in FY 1993 at $53 million, is based
at NIH's Clinical Center. Not only does this program conduct clinical trials of
cancer treatments, but it also conducts trials of treatments for cancers associated
with AIDS, such as Kaposi's sarcoma.
Elements of Success
Since the creation of the program, the NCI has contributed to the marketing
of 48 anticancer drugs. That figure constitutes more than half of all U.S. drugs
marketed to treat cancer.
Program administrators have attributed their success to the following factors:
· Clinical-trials capacity. Through the clinical oncology cooperative
groups and the NIH Clinical Center, NCI supports a vast network of over
300 hospitals and 2,500 physicians. Thousands of new patients each year can
take advantage of NCI-supported clinical trials.
.
Adequate resources. In almost 40 years of existence, NCI's drug
discovery and development programs have received sufficient resources
(funding and personnel) to develop a large infrastructure. The programs have
the capacity to perform every phase of drug development, from test tube to
clinic, except bulk manufacturing, marketing, and distribution.
Animal models. Many cancer treatments have been identified with
the aid of animal models for particular tumor types. An animal model can
be used in preclinical screening and in assessing drug efficacy, toxicity,
mechanism of action and side effects.
· Advances in basic research. For years, NCI has had a strong
commitment to understanding the molecular biology of malignant
.
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DEVELOPMENT OF MEDICATIONS
transformation. This basic-research investment is expected to yield numerous
innovations in drug development.
· Coral dentiality of screening results. Industry provides NCI with an
average of 5,000 chemicals per year for screening. NCI's standard screening
agreement used to acquire chemicals assures the sponsor complete
confidentiality except when a chemical shows clinical promise, in which case
the sponsor is given 1 year to file a patent application before the results are
made public.
Favorable regulatory climate. NCI has experienced long-standing
collegial relations with FDA. In addition, many anticancer drugs have
benefited from special expedited review by FDA because they qualify under
recent FDA regulations as treatments for serious or life-threatening diseases.
· Support of constituency groups. Constituency groups have for years
worked with Congress and the executive branch to play a vigorous role in
support of NCI research. NCI enjoys the largest budget of all NIH institutes
and submits its annual budget directly to the President in what is called a
bypass budget to avoid competition with other health programs.
· Staff commitment. The Division of Cancer Treatment has benefited
from a vigilant commitment of its staff to bring drugs for cancer treatment
to market.
.
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS
DISEASES DRUG DISCOVERY AND
DEVELOPMENT PROGRAMS
Background
Antiviral and anti-infection drugs to treat AIDS are the focus of research and
development programs of the NIAID. Created in 1987, these programs were
designed to work with university and private researchers to bring drugs quickly
to market to treat both HIV infection and the opportunistic infections afflicting
AIDS patients.
The commercial market for antiviral and anti-infection drugs for HIV and
AIDS-related disease depends on the indication. There has been robust
commercial response, to judge the fact that 74 companies now have 103
medications in clinical trials or awaiting regulatory approval at FDA (PMA,
19931. The 1992 domestic sales of AZT (zidovudine) resulted in $195 million
in revenues to the manufacturer (P. Arno, Albert Einstein College of Medicine,
personal communication). NIAID's Division of AIDS sponsors three programs
that are collectively committed to the discovery and development of AIDS drugs.
The budget for the three programs in FY 1993 totaled about $185 million, $60
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APPENDIX E
235
million for preclinical research and $125 million for clinical research. About 90
full-time equivalent staff administer this total budget.
Preclinical Research
The division's Basic Research and Development Program is responsible for
preclinical research on AIDS antiviral and anti-infection treatments. Through
extramural grants, contracts, and cooperative agreements, this program has an
innovative goal: to facilitate the development of drugs, immunity modulators,
gene therapies, and other novel treatments through the support of high-risk basic
and applied research that is unlikely to be supported by the private sector. Basic
research is not usually supported in most other federal research and development
programs, but the novelty of this program is that it links basic research with drug
development and clinical research. The program does not support screening tests,
because all preclinical screening of AIDS antiviral drugs is perfonned separately
by NCI.
The cooperative agreements supported by the Basic Research and
Development Program are the vehicles used to bring university and industry
researchers together to work on multidisciplinary preclinical research, both basic
and applied. The cooperative agreements fund national cooperative drug
discovery groups (NCDDGs) that strive to identify treatments for HIV infection
and the opportunistic infections associated with AIDS. The cooperative
agreements constitute about 20 percent of the program's $60 million budget.
The Basic Research and Development Program, though relatively young,
already has witnessed some success: it has sponsored the preclinical research
leading to clinical trials for six new medications. One of these innovative
medications is a non-nucleoside inhibitor of HIV reverse transcriptase,
bisheteroarylpiperazine (BHAP), which is being developed with Upjohn.
Clinical Research
All AIDS-related clinical research is supported by two programs in the
Division of AIDS: the Clinical Research Program and the Treatment Research
Operations Program. Together, these programs support the largest network
capable of performing all types of clinical trials for AIDS therapies. Budgeted
at approximately $125 million, the research is supported mostly extramurally at
universities, medical centers, and community programs and intramurally at NIH's
Clinical Center.
The bulk of the funds is devoted to AIDS clinical trial groups (ACTGs).
ACTGs are extramural clinical-research sites that evaluate therapies for all
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DEVELOPMENT OF MEDICATIONS
aspects of HIV disease in adults and children, ranging from early safety studies
(Phase I) to multicenter efficacy studies (Phase III). Since the creation of the
network at over 50 locations, more than 23,000 patients have participated in 192
clinical studies. These studies have contributed to the approval by FDA of the
three leading AIDS medications that inhibit replication of the virus: AZT, ddI
(didanosine), and ddc (dideoxycytidine).
Another prominent clinical-trial network supported by the Division of AIDS
is the Community Programs for Clinical Research on AIDS (CPCRA). More than
10,000 patients have been enrolled in CPCRA studies, which are conducted in
such community settings as hospitals, health centers, private practices, clinics,
and drug-treatment facilities. The purpose of these programs is to learn how
available treatments can be used more effectively and to learn the long-term
effects of treatments. For example, one CPCRA trial has found that patients
intolerant to AZT can receive similar benefits from ddi and ddc. The CPCRA
network is also being used to study tuberculosis treatments for people infected
with both HIV and tuberculosis bacteria.
The Division also supports another kind of program, the Division of AIDS
Treatment Research Initiative (DATRI). The hallmark of the DATRI is the rapid
conduct of early clinical trials to propel new drugs to market.
Elements of Success
NIAID's preclinical and clinical research programs have played a pivotal
role in the development of three approved AIDS antiviral drugs and most of the
49 commercially sponsored medications undergoing clinical trials for the
treatment of AIDS-related opportunistic infections.
Program administrators have attributed their success to the following factors:
· Large clinical-trial network. The clinical research for AIDS
treatments is conducted at over 200 sites nationwide. Since 1987, over
32,000 patients have participated in clinical studies. The clinical-trial
network is the largest in the United States that conducts human trials of
experimental AIDS therapies.
.
Linking of basic research to drug development. A unique feature
of the Division of AIDS is that it weaves together basic and applied
research. The basic research is targeted to drug development through the
issuance of program announcements that solicit the submission of
investigator-initiated grant proposals.
· Accepted medical treatment. The landmark approval of AZT not
only has slowed disease progression but has also proved to be an important
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APPENDIX E
237
benchmark against which to test the efficacy of promising experimental
treatments.
Staff commitment. NIAID staff are staunchly committed to AIDS-
drug discovery and development, as evidenced by their track record of
success, which is even more impressive considering that this $185 million
program is administered by only 90 full-time-equivalent staff.
.
Collaboration with industry. NIAID has experienced excellent
collaborative relationships with industry. With over 1 million people infected
with HIV in the United Sates and far more infected outside the United
States, there has been a substantial industry interest in collaborating with
NIAID in the development of antiviral and anti-infection treatments.
· Collaboration with constituency groups. Constituency groups have
emerged as a major force in drug discovery. They have pushed NIAID to be
more aggressive in the pursuit of new therapies, and they have worked with
Congress to ensure that NIAID's budget expands accordingly. The
relationship sometimes can be turbulent, but it is guided by mutual respect
and common goals.
· Supportive relationship win FDA. NIAID has experienced strong
support from FDA in expediting the approval of medications. FDA is invited
to attend meetings between NIAID and industry informally to provide advice
and technical assistance. In addition, many AIDS drugs have benefited from
special expedited review by FDA because they qualify under recent FDA
regulations as treatments for serious or life-threatening diseases.
· *ponsorship of small, frequent conferences. Innovative research
ideas emerge from the division's sponsorship of eight to 12 meetings per
year that bring together 70-100 researchers from universities, industry, and
government.
REFERENCES
Grever MR, Schepartz SA, Chabner BA. 1992. The National Cancer Institute: cancer drug
discovery and development program. Seminars in Oncology 19:622~38.
Kupferberg HI. 1990. Preclinical drug development in the Antiepileptic Drug Develop-
ment Program: a cooperative effort of government and industry. In: Meldrum BS,
Williams M, eds. Current and Future Trends in Anticonvulsant, Anxiety, and Stroke
Therapy. New York: Wiley-Liss. 1 13-130.
OTA (Office of Technology Assessment). 1993. Pharmaceutical R & D: Costs, Risks and
Rewards. Washington, DC: Government Printing Office. OTA-H-522.
PMA (Pharmaceutical Manufacturers Association). 1993. AIDS Medicines: Drugs and
Vaccines In Development. Washington, DC: PMA.
Zubrod CG, Schepartz SA, Carter SK. 1977. Historical background of the National
Cancer Institute's drug development thrust. National Cancer Institute Monographs
45:7-11.
Representative terms from entire chapter:
drug development
