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Medications development and the war on drugs: Victims of the gulf war?
BIOL i~YCHIATRY 1991 ~9:52L 523
521
EDITORIAL
Medications Development and the War on Drugs: Victims of the Gulf War? Medications development was being given a priority in the war on drugs by proposed congressional legislation supporting pharmacotherapies for substance abuse. This legislation c~led for $1 billion for an intensive collaboration of government, industry clinical investigators in a Manhattan Project-like effort to develop a "magic bullet" for cocaine dependence. Because this bill, initiated by Senator Biden, was not passed by the lOlth Congress, it is important that the psychiatric community lobby for its immediate passage. Its urgency is driven by the current epidemic of drug abuse, particularly cocaine, along with the massive spread of AIDS among drag abusers through needle sharing, tlwough "sex for crack," and through the transmission of HIV infection from pregnant addicts to the fetus. However, this legislation is at risk 3f being abandoned or greatly curtailed because the current budget crisis is acutely aggravated by the Persian Gulf war. Such a loss for our domestic war on drugs would be a sad commentary on our national priorities for the health of our citizens and for the needs of the addiction treatment community. This legislation clearly needs our lobbying efforts. The magnitude of this health care crisis has overwhelmed the ~atment resources of substance abuse providers as well as many parts of the general health care system. In 1988 there are estimated to be 7 million regular d-Jg abusers over the previous year, of whom 5.6 million would benefit from treatment, but the treatment capacity of the United States is currently limited to about 1.5 million. Thus, more efficient treatments are needed, and pharmacother~py has been very effective in other psychiatric disorders. A wide variety of treatment agents from detoxification to relapse prevention are needed. Neither blocking nor substitution agents have been developed for most abused drugs, and there is a clear need for benchmark agents as standards to screen for other effective pharmacotherapies. The discovery of these benchmark agents for depression and psychosis came first from open ended cimical investigation, and s ~ a r exploratory clinical investigation with a wide range of novel agents will probably be needed to develop benchmark agents for substance abuse treatment. The availability of new compounds for exploratory human testing is limited because strategic planning within the pharmaceutical industry, based on the marketing potential of a new compound, has dictated a very limited allocation of new compounds for clinical research. While strategic planning focuses research resources on problems with the largest potential for profits, creative medication discovery comes from the use of new -.-',mpounds for novel clinical problems for which the compound may not have been originally developed. Beyond simple cost containment in research, strategic planning has also attempted to minimize any potential damage to marketing potential of a new compound due to Food and Drug Administration's (FDA) regulatory behavior. The risk inherent in phase 2 exploratory testing is the~ side effects or toxicities may be uncovered in populations for which the medication was not originaiiy develo!~l. When a New Drug Application (NDA) is later filed with the FDA, this potentially damaging information about the © ',991 Society of Biological Psychiatry
0006-3223/91/$03.50
522
BIOL PSYCHIATRY 1991;29:521-523
Editorial
medication will also be reviewed by the FDA and might bold up approval of the compound for its developed indication. Thus, pharmaceu~cal companies are reluctant to allow wide exploration of the clinical potential of new compcuh~. This limited availability of compounds for clinical testing poses a particularly challenging and troublesome problem for those investigators interested in substance abuse, because virtually no compounds have been developed by the pharmaceutical companies specifically targeted for substance abuse treatment. In a recent survey by the Pharmaceutical Manufacturers Association (PMA) only one compound out of hundreds in human testing was specifically targeted for substance abuse treatment. Furthermore, most clinical studies s~cifically exclude substance abusers, making it very difficult to accumulate information about the utility of new compounds with these populations. Even after medications become approved for use for specific indications other than substance abuse such as anti-depressant or anti-psychotic medications, the use of these medications with specific substance abuse populations such as cocaine abusers may require approval through of an Investigational New Drug application (IND) from the FDA. Obtaining an IND requires participation of the pharmaceutical manufacturer to provide the Master File information on its manufacture and toxicity testing and may also require specific animal toxicity data for interactions between the potential treatment medication and drugs of abuse such as cocaine. Thus, clinical researchers in the field of substance abuse need help with these administrative problems. These are formidable obstacles to medication development for substance abusers. Several solutions might make new and existing medications more readily available for investigational use by qualified clinical investigators. First, the use of currently marketed medications should not require the use of INDs in order to be used for primary substance abuse treatment. If hNDs are i~,_,i ~d, then Master Files from the pharmaceutical companies must be accessible to clhl:cal investigators and the government must support the necessary animal toxicity testing for interactions between these medications and drugs of abuse. Second, currently unmarketed investigational compounds still in phase 1 or 2 clinical testing should be available to qualified clinical investigators in order to exa_mine their utility in substance abuse populations. Two important considerations for this availability of inve~t;gational compounds would be the indemnification of the investigating institutions by the federal government and the assurance of tempered review of the new compound, if it is later brought to the FDA as a new drug appfication (NDA) for a nonsubstance abuse indication. By a tempered review I mean that information about potentially toxic interactions between drugs of abuse and the new compound or the lack of therapeutic efficacy in substance abusers should not limit its availability or "packaging information" for other indications such as depression. Unless the pharmaceutical industry obtains assurance from the FDA on this tempering of their review process, the potential for these exploratory investigations in substance abusing populations to damage a well-orchestrated strategic drug development based on marketing potential will strongly discourage full industry collaboration. In summary, four issues are important to clinical researchers in biological psychiatry. First, lobbying efforts are needed to get the Biden bill for medication development passed with adequate funding. Second, we need the pharmaceutical industry to make new medications available for exploratory testing in substance abusers. Third, we need researchers to educate themselves about the complexities and risks of exploratory medication studies in order to minimize the hazards to both patients and pharmaceutical manufacturers when conducting trials of new medications for substance abusers. Fourth, we need the IDA
Editorial
n~L ~ Y ~ Y
523
1991 ~9:521-523
to temper their regulatory behavior for new medications that may have greater risk for substance abusers than for other psychiatric populations. With these efforts we can hopefully get the domestic war on drugs into figh~ng ~hape ~ d nv: h_.~.~:eK s proposed ~4anhattan Project become another casumty of the Persian Gulf war. Thomas R. Kosten
521
EDITORIAL
Medications Development and the War on Drugs: Victims of the Gulf War? Medications development was being given a priority in the war on drugs by proposed congressional legislation supporting pharmacotherapies for substance abuse. This legislation c~led for $1 billion for an intensive collaboration of government, industry clinical investigators in a Manhattan Project-like effort to develop a "magic bullet" for cocaine dependence. Because this bill, initiated by Senator Biden, was not passed by the lOlth Congress, it is important that the psychiatric community lobby for its immediate passage. Its urgency is driven by the current epidemic of drug abuse, particularly cocaine, along with the massive spread of AIDS among drag abusers through needle sharing, tlwough "sex for crack," and through the transmission of HIV infection from pregnant addicts to the fetus. However, this legislation is at risk 3f being abandoned or greatly curtailed because the current budget crisis is acutely aggravated by the Persian Gulf war. Such a loss for our domestic war on drugs would be a sad commentary on our national priorities for the health of our citizens and for the needs of the addiction treatment community. This legislation clearly needs our lobbying efforts. The magnitude of this health care crisis has overwhelmed the ~atment resources of substance abuse providers as well as many parts of the general health care system. In 1988 there are estimated to be 7 million regular d-Jg abusers over the previous year, of whom 5.6 million would benefit from treatment, but the treatment capacity of the United States is currently limited to about 1.5 million. Thus, more efficient treatments are needed, and pharmacother~py has been very effective in other psychiatric disorders. A wide variety of treatment agents from detoxification to relapse prevention are needed. Neither blocking nor substitution agents have been developed for most abused drugs, and there is a clear need for benchmark agents as standards to screen for other effective pharmacotherapies. The discovery of these benchmark agents for depression and psychosis came first from open ended cimical investigation, and s ~ a r exploratory clinical investigation with a wide range of novel agents will probably be needed to develop benchmark agents for substance abuse treatment. The availability of new compounds for exploratory human testing is limited because strategic planning within the pharmaceutical industry, based on the marketing potential of a new compound, has dictated a very limited allocation of new compounds for clinical research. While strategic planning focuses research resources on problems with the largest potential for profits, creative medication discovery comes from the use of new -.-',mpounds for novel clinical problems for which the compound may not have been originally developed. Beyond simple cost containment in research, strategic planning has also attempted to minimize any potential damage to marketing potential of a new compound due to Food and Drug Administration's (FDA) regulatory behavior. The risk inherent in phase 2 exploratory testing is the~ side effects or toxicities may be uncovered in populations for which the medication was not originaiiy develo!~l. When a New Drug Application (NDA) is later filed with the FDA, this potentially damaging information about the © ',991 Society of Biological Psychiatry
0006-3223/91/$03.50
522
BIOL PSYCHIATRY 1991;29:521-523
Editorial
medication will also be reviewed by the FDA and might bold up approval of the compound for its developed indication. Thus, pharmaceu~cal companies are reluctant to allow wide exploration of the clinical potential of new compcuh~. This limited availability of compounds for clinical testing poses a particularly challenging and troublesome problem for those investigators interested in substance abuse, because virtually no compounds have been developed by the pharmaceutical companies specifically targeted for substance abuse treatment. In a recent survey by the Pharmaceutical Manufacturers Association (PMA) only one compound out of hundreds in human testing was specifically targeted for substance abuse treatment. Furthermore, most clinical studies s~cifically exclude substance abusers, making it very difficult to accumulate information about the utility of new compounds with these populations. Even after medications become approved for use for specific indications other than substance abuse such as anti-depressant or anti-psychotic medications, the use of these medications with specific substance abuse populations such as cocaine abusers may require approval through of an Investigational New Drug application (IND) from the FDA. Obtaining an IND requires participation of the pharmaceutical manufacturer to provide the Master File information on its manufacture and toxicity testing and may also require specific animal toxicity data for interactions between the potential treatment medication and drugs of abuse such as cocaine. Thus, clinical researchers in the field of substance abuse need help with these administrative problems. These are formidable obstacles to medication development for substance abusers. Several solutions might make new and existing medications more readily available for investigational use by qualified clinical investigators. First, the use of currently marketed medications should not require the use of INDs in order to be used for primary substance abuse treatment. If hNDs are i~,_,i ~d, then Master Files from the pharmaceutical companies must be accessible to clhl:cal investigators and the government must support the necessary animal toxicity testing for interactions between these medications and drugs of abuse. Second, currently unmarketed investigational compounds still in phase 1 or 2 clinical testing should be available to qualified clinical investigators in order to exa_mine their utility in substance abuse populations. Two important considerations for this availability of inve~t;gational compounds would be the indemnification of the investigating institutions by the federal government and the assurance of tempered review of the new compound, if it is later brought to the FDA as a new drug appfication (NDA) for a nonsubstance abuse indication. By a tempered review I mean that information about potentially toxic interactions between drugs of abuse and the new compound or the lack of therapeutic efficacy in substance abusers should not limit its availability or "packaging information" for other indications such as depression. Unless the pharmaceutical industry obtains assurance from the FDA on this tempering of their review process, the potential for these exploratory investigations in substance abusing populations to damage a well-orchestrated strategic drug development based on marketing potential will strongly discourage full industry collaboration. In summary, four issues are important to clinical researchers in biological psychiatry. First, lobbying efforts are needed to get the Biden bill for medication development passed with adequate funding. Second, we need the pharmaceutical industry to make new medications available for exploratory testing in substance abusers. Third, we need researchers to educate themselves about the complexities and risks of exploratory medication studies in order to minimize the hazards to both patients and pharmaceutical manufacturers when conducting trials of new medications for substance abusers. Fourth, we need the IDA
Editorial
n~L ~ Y ~ Y
523
1991 ~9:521-523
to temper their regulatory behavior for new medications that may have greater risk for substance abusers than for other psychiatric populations. With these efforts we can hopefully get the domestic war on drugs into figh~ng ~hape ~ d nv: h_.~.~:eK s proposed ~4anhattan Project become another casumty of the Persian Gulf war. Thomas R. Kosten