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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

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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.

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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:

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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.

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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

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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.

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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

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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

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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

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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.

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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.

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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.

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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

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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.

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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

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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

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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

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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

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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.

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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~.

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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.