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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
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.
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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.
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
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
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 .
234 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
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
236 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
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.
