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Appendix D Survey of Pharmaceutical Companies To aid the committee in assessing the incentives and disincentives to the pharmaceutical industry's investment in research and development in the field of anti-addiction medications, a questionnaire was sent by the Pharmaceutical Manufacturers Association, the Generic Pharmaceutical Industry Association, and the Biotechnology Industry Organization to their members currently involved with central nervous system medications. The questionnaire was developed by the committee and IOM staff in conjunction with the industry organizations. Responses were blinded and the committee did not have information on the company or the job title of the survey respondent. A total of 19 responses were received, and the responses were viewed by the committee as indicative but not definitive. Figure D.1 indicates how respondents rated the uncertainty or risk involved in R&D issues in the field of drug addiction as compared with the fields of cancer, AIDS, and cardiovascular disease. Clearly, these results are not a quantitative assessment of the industry, but the drug-addiction field is perceived to be high risk in all areas except for likelihood of competitive advantage over other treatments and likelihood of fast track FDA review. The committee used the survey solely as a point of reference and a starting point for committee and individual discussions with representatives of the pharmaceutical industry. 215
216 DEVELOPMENT OF MEDICATIONS Questionnaire on Factors Influencing Pharmaceutical Companies' Investment in R&D in Medications for Treating Illicit Drug Abuse The names of individual respondents or their f rms will not be given to the IOM Committee or be included in the Committee's report. (Responses are tabulated or are in bold type) 1. Has your company ever had a drug discovery pro gram in any of the following areas? a. cocaine/crack addiction Yes 3 No 16 b. heroin dependence Yes 4 No 15 c. alcoholism Yes 5 No 13 d. nicotine addiction Yes 3 No 14 2. Has your company ever had a drug development or in-licensina effort in any of the following areas? a. cocaine/crack addiction Yes 3 No 14 b. heroin dependence Yes 3 No 13 c. alcoholism Yes 6 No 11 d. nicotine addiction Yes 6 No 11 3. If your company has never had a drug discovery or drug development/in-licensing program in one or more of these areas, please indicate the area and the major reasoners) for this decision. a. role of the potential market 6 b. federal regulations 2 c. state, local or community barriers 1 d. difficulty in conducting clinical trials 4 other reasons (please state/explain) · Beyond current focus on neurological disorders · Drug discovery (and development) is not defined in the current mission of our business Other project opportunities/priorities and resources Not in area of expertise/experience Lack of preclinical leads
APPENDIX D 217 · Concern that use of a drug for "abuse" treatment might tarnish its image for other uses · Outside our area of expertise · Indicationts) lay outside our areas of strategic interest. 4(a). If your company once had a drug discovery or drug development/in-licensing program in one or more of these areas but no longer does, please indicate the area and state the major reasoners) for dropping the program. . Alcoholism program dropped due to market potential High recidivism Community concept that drugs shouldn't be used to cure an addiction · Nicotine addiction-loss of commercial interest due to unfavorable marketing experience with other products (nicotine transdermal patches) . No further leads at this time, would review alcohol or nicotine programs for any leads. (b). What incentives (including legislative proposals) would be necessary for your company to renew its effort in those areas (please state area)? R&D tax credits · Guaranteed market exclusivity for ten years or more · Availability of government sponsored patents on an exclusive basis · Guaranteed pricing freedom to achieve high margins to enable re-investment in R&D, educational programs, and broad marketing None, no commercial interest Sponsor preclinical support Reclassification of many schedule I drugs to schedule II Indemnification for usage in subject populations 5. If your company has a drug discovery or drug development/in-licensing program for medications to treat drug abuse please state the positive incentives that attracted you to this field. (NOTE: We are referring primarily to medications to treat cocaine and opiate addictions). . Drug being evaluated has potential for analgesia. This is our primary commercial interest
218 DEVELOPMENT OF MEDICATIONS . Urgency of medical need rapid approvability and demand for effective therapy · Our drug discovery program, re: cocaine abuse, involves interaction with MDD-NIDA, and NIH to search our existing compound file for potentially useful compounds. Incentive was statement by Senator Biden to Mr. George Sella (then PMA chairman). Our only current incentive is scientific interest, and good relations. · We decided to invest $10M or so in alcohol and nicotine due to good lead and its public health importance-program does work for both. · Large patient population, public good. · Large unmet medical need. · Significant experience in treating nicotine addiction shows that programs can be commercially viable. 6. Are you aware of NIDA's Medications Development Division (MDD)? yesl4 no5 7. Are you aware of NIDA's preclinical screening program? yes 12 no 4 vaguely 1 8. What is your perspective on the role of NIDA's MDD? · MDD has expressed considerable interest, is in position to provide considerable support for our project. · No major accomplishments to date · Could be very useful. It is viewed as a major deterrent to discovery/development efforts by companies like ours, because of 1) likelihood of government involvement in pricing, 2) concerns re: government being involved in the "go/no go" development decision-making and 3) involvement of taxpayer dollars. . Excellent approach to this problem. Highly productive. To evaluate potential drugs, particularly those well along in development, for use in the treatment of cocaine addiction (antagonists to cocaine, or drugs as adjuncts to psychotherapy). · NIDA's investment is helpful to industry to explore uses of drugs already in development as well as assist in exploration of early leads from related research programs in industry. · Very useful, underutilized.
APPENDIX D 219 · Generally involve CRADAs with "fair pricing" provisions and thus not usable. Already working with NIDA in a constructive collaboration. Waste of time. They are not effective. PMA companies could do a better job if there were an incentive. 9. Please add any additional comments that you feel would assist the Institute of Medicine's Committee on Medications Development and Research at the National Institute on Drug Abuse to better understand the incentives and disincentives for private sector R&D involvement in producing medications to treat illicit drug abuse (particularly cocaine and opiate addictions). · Development of medications to treat drug abuse is perceived to be of low commercial value. Therefore, direct financial support or co- development is essential to provide sufficient incentive. · Speaking as a member of a firm not involved in any programs, but strictly as an outside observer, disincentives are enormous when the proposed new compound becomes entrapped in DEA's scheduling system. These barriers should be changed. efforts. . Increase transparency. Offer consultative support to ongoing industrial research We have concerns about handing over control of the product development decision making to NIDA along with the official in- volvement of pricing, plus the likelihood of "unofficial" pressures to continue development even if the sponsor wished to discontinue. The involvement of tax dollars in "for-profit" drug development projects by pharmaceutical companies is also viewed as risky in today's political climate. · Adequate patent protection is essential. · Avoidance of accusations of collusion with a government agency. · Recognition of altruism in cooperative ventures. · Have FDA run DEA. · Change many Schedule I drugs to Schedule II. · Eliminate "fair pricing" clause from HHS CRADAs. · The primary disincentive is that your medication (the company's) is the only one with a traceable history. The subjects treated not only may have concomitant ethical pharmaceuticals, but also drugs of questionable origin and purity. Drug/drug interactions, unexpected adverse interactions due to prior history of usage leave only the company vulnerable to litigation. 10. Please fill out Attachments 1 and 2.
220 DEVELOPMENT OF MEDICATIONS Attachment 1 The intent of this exercise is to gain information on how pharmaceutical companies view the drug abuse area in relation to other project areas, with respect to certain factors commonly used to judge R&D priorities. (NOTE: By "drug abuse area" we mean illicit drug use, primarily in the form of opiate and cocaine addictions, we do not mean use of alcohol, nicotine, or abuse of prescription drugs.) Please put a number from 1 to 5 in each blank, based on the scale below. High uncertainty or risk Average uncertain or risk Cancer Drug Abuse AIDS Low uncertainty or risk Cardiovascular These four disease categories were repeated in the survey for each of the following 12 areas. The responses are displayed in Figure D.1. Sufficient scientific knowledge of disease to begin a drug discovery/drug development program Availability of screening techniques and animal models Clear efficacy endpoints for ethical studies Availability of qualified clinical investigators Likelihood of fast track review or special handling by FDA 6. Patentability of product 7. Product liability risk 8. Sufficient market size 9. Likelihood of competitive advantage over other treatments 10. Adequate price and reliable reimbursement
APPENDIX D 11 . Sufficient prod 221 ected return on investment 12. Good public image; intangible benefits to company or other company products. High 5 4 In - 3 lo ~ 2 Law High 5 4 3 1 o - ._ _ _ _ _ _1 1 1 - 8111 1 _1 1 LOW _ Liability At ~Competi6 - Reimh~t Invoke ~ht~ O _ C ~_ - _- 1 1 ~_ l ~_ l I~Im ~ ~1 _~1 4@~ - Scieno ~Screening Endpo nts Personnel FOA re~new P~entab~ 1 1 1~ 1 ~ _ _ (Ca~ ~ Den Ah - e O AIDS g' Cation i Figure D. 1 Survey results. Issues involved in R&D were ranked for four diseases: cancer, drug addiction, AIDS, and cardiovascular disease (see Attachment 1 of the survey).
222 DEVELOPMENT OF MEDICATIONS Attachment 2 POLICY SUGGESTIONS For each box in Attachment 1 in which you put a 1 or 2 for Drug Abuse, i.e., for each factor for which you think the Drug Abuse area is handicapped by higher-tharl-average uncertainty or risk, please state briefly what you would recommend to improve the situation. Suggestions should be one-liners (e.g., "amend the Orphan Drug Act to include all drugs intended for drug abuse", "increase the basic science budget at NIDA by $50 million per year," "change regulations requiring . . .", etc.~. The intent is not to get fully evaluated policy recommendations that are fonnally approved by your company but rather to get your personal ideas for further consideration. Please treat this as a "brainstorming by mail" or a "public policy suggestion box". No individual attributions will be seven to the IOM Committee on Medications Development and Research at NIDA. 1. Basic scientific knowledge · More emphasis on underlying biochemical mechanisms needed. · Not a high profile research area, nor widely viewed as attractive. · Improve quality and focus of ongoing research, especially in molecular biology of addictive process. · What is molecular basis of addiction. · Why will addicts relapse on drug therapy. · Fund special NIDA extramural research efforts via executive branch edict or legislation. · Need further mechanistic work, availability of modern day screens, etc. Inter-company interaction should be encouraged. Increase NIDA budget. Increase NIH support of this domain of research. Increase NIDA budget. Fund biotech startups. 2. Screening techniques and animal models · Technically demanding and applicability to humans not certain. · Do not over-rely on these; expedite pathway to clinic with good hypotheses. Good models are lacking. Fund special NIDA extramural research efforts. Increase NIDA budget.
APPENDIX D 3. Efficacy endpoints 223 More money to MDD-NIDA, the process is now painfully slow. Primates too expensive-develop in vitro screens? Start search for susceptibility genes. Develop transgenic animals with increased "abuse liability." · Since there are both psychological as well as physiological dependencies at work, a clear endpoint especially on the psychological aspects would- be difficult. · Clear FDA guidelines would help. · Do not ask drug to do everything- acute drug effects in many cases will be combined with long term counselling to keep patient clean. · Develop NIDA/FDA/industry consensus guidelines for study requirements and officially-recognized endpoints. Movement to clinical trials should be accelerated. Very difficult to improve. No clear standards except very expensive followup surrogates. Need more validation of surrogate endpoints. 4. Availability of qualified clinical investigators · The field is not one to attract the best medical school faculty. · A general problem in psychotherapeutics-particularly acute drug dependence. Need more physicians; scientists. · Consider an investigative network similar to the ACTG mechanism for anti-HIV treatments. . 5. FDA review . Training and research support need improvement. Not certain of FDA's view of this area. · An FDA fast track is based on disease slate vs. availability of existing treatments. This in my opinion, would not warrant FDA's highest attention (over drugs in categories of AIDS or cancer treatment). · Expedite. · Declare substance-abuse drugs and biologicals "AA" priority, like AIDS drugs. · Safety should be the major criterion, with efficacy being a clinical finding; e.g. more flexibility in evaluating animal pharmacology should be allowed. · Automatic priority ranking for any drug with significant lower abuse of target agents.
224 DEVELOPMENT OF MEDICATIONS · Safety a real problem in the treated population. FDA will be all over drug interactions and serious adverse reactions. 6. Patent protection · No special issues use patents for psychotherapeutics discovered for other indications will be common. . Give (via legislation) substance-abuse drugs Waxman-Hatch type exclusivity/patent life extension. · The patent office must recognize the speculative nature of current research when evaluating relevance of animal testing data. 7. Product liability . Side effects of CNS drugs used long term. · High-unstable patient population leads to high potential for adverse events (which can easily be non-drug related). · Government indemnification, as for vaccines, should be provided. . Insurance pool similar to vaccines for products intended to treat drug liability. · Government should subsidize insurance costs for adverse drug effects during testing and clinical use. · Government assumption of risk. Tort reform. Use legislation to eliminate lawyers. Who do you sue the company or the guy on the end of the block with the gun? 8. Market size Hard to identify or characterize. Potentially large, but returns on investments may be poor if reimbursement not forthcoming in managed care most patients are financially distressed. · Supportive therapy is used to exclusion of drug therapy. Candidates can't afford intensive medical therapy. May not be a problem if government reimburses. Tied up in health care reform, pricing, etc. · Patient unreliability is the big problem, possibly address by creating a national network between drug treatment centers and programs. · Out-licensing partners should be sought; smaller returns become more meaningful (profitable) to smaller, lower overhead operations.
APPENDIX D 225 · If primary purchaser is government, insures no tax or rebate, free market pricing. · Increase percent of "war on drugs" billions that goes to treatment. Spend less on enforcement reduce the demand for illicit drugs by effective treatment programs. 9. Competitive advantage No effective therapies available for any addiction. Reduce the disincentive and sponsors may be willing to seek products with advantages. · Company that loses out because of competition by a selected drug should receive some compensation. . Free market. Try more experimental approaches. 10. Price and reimbursement . Not sure who is going to pay. · Ensure pricing that would allow sufficient return on investment. · Typically, it would be my opinion that these patients may not be under routine care of a PCP or have their own insurance/ability to pay. Expect unreasonable political pressure to have low prices because of government subsidy to research or reimbursement. · Very uncertain, due to Health Care Reform, but protection from direct and indirect price caps, e.g., by legislation exemption, substance-abuse treatments, is essential. · Government support for high prices. · Tax advantages would have to support the low prices necessitated by this class of drug. · Make drug treatment programs mandatory part of HMO and insurance industry payment programs. · Federal and state government primary customer. . 11. Retune on investment · Not well understood. R01 May be difficult to determine length of time of recovery for Government interference and negative image of drug therapy will not provide reasonable margins. · Will this be completely reimbursed? · Costs of development should be distributed among "partners" e.g. government, venture capital.
226 DEVELOPMENT OF MEDICATIONS 12. Public image and intangibles · Publish NIDA's work at a more high profile level. · A mixed area: charging the typical drug abuser for therapy will be seen negatively. · "Substitute addictions" will be invented by the press for successful therapies. · Remove the disincentives, so that the prospects of bad publicity, poor pricing, etc. no longer outweigh the goodwill that would accrue for sponsors of successful treatments or preventive measures. · Could work around this problem if had clear benefits. · Get the current administration to spend less time bashing the pharmaceutical industry. · Too visible an arena, much like AIDS. Too susceptible to government/Congress trying to make "political" points on pricing at the same time crying about lack of treatment. It's a no win situation. Other comments: · Drug efficacy must be assessed in the context of overall care for the addict; clinical studies isolating drug from other modalities may set unrealistically high hurdles. · I think the major problem is no science in this area. · The PMA seems to be focusing on the business aspect of this project, while interactions are mainly at the scientific level. What is absolutely essential at this time is a forum to share compounds and data, and to worry about "who will develop?" later. NIH-Addiction Research Center should also be involved with companies; that funnel compounds to MDD-NIDA at this time. An excellent forum is the College on Problems of Drug Dependence (CPDD). Their involvement in any such venture is extremely helpful. · Trials a special problem of compliance and longterm followup. Although NIH could help fund, their behavior on CRADAs makes this unattractive re #10 and #11 above. · Make NIDA/industry collaborations better and really allow industry to make a reasonable return on investment.