New Treatments for Addiction Behavioral, Ethical, Legal, and Social Questions (2004) / Chapter Skim
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Appendix B: What Will We Learn from the FDA Clinical Trials Process and What Will We Still Want to Know About Immunotherapies and Depot Medications to Treat Drug Dependence?
Appendix B: What Will We Learn from the FDA Clinical Trials Process and What Will We Still Want to Know About Immunotherapies and Depot Medications to Treat Drug Dependence?
Pages 98-124
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From page 98... ...
The medications currently available for human use include vaccines for active immunizations against cocaine and nicotine and long- acting depot formulations of naltrexone, an opiate antagonist for alcoholism and opiate dependence. Monoclonal antibodies for passive immunotherapy are still in animal testing, but one for phencyclidine should be ready for human use within 2 years.
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From page 99... ...
Also reviewed are the three types of treatment protocols: overdose, relapse prevention, and protection. Overall, the purpose here is to consider what might be learned during the FDA clinical trials process to inform later applications of these therapies and postmarketing experience.
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From page 100... ...
Consequently, inhibiting this pharmacological reinforcement will have little effect on such motivations to use the substance and be much less cost effective than alternative protection strategies. Overdose Protocols A typical overdose protocol might use monoclonal antibodies to reverse an acute overdose of a drug such as PCP (Owens and Mayershohn, 1986; Valentine et al., 1996)
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From page 101... ...
after starting monoclonal treatment or after an intensive care unit stay should be the same, although the patient will be able to enter this aftercare much more quickly following reversal of the acute overdose by the monoclonal. Relapse Prevention Protocols A typical relapse prevention protocol might use any of the three types of agents to enhance compliance with treatment.
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From page 102... ...
Relapse prevention using monoclonal antibodies (passive immuniza
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From page 103... ...
. Relapse prevention using active immunization has several additional complications that are not present with monoclonal antibodies or depot medications.
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From page 104... ...
. Thus, if a protection protocol is to be developed, it is unlikely to occur, even for those at high risk of drug abuse, until well after overdose or relapse prevention protocols are well established.
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From page 105... ...
, creating the possibility of adverse effects in an otherwise healthy population. THE FDA CLINICAL TRIALS PROCESS Phase I The FDA clinical trials process, which is designed to assess safety and efficacy (but not cost efficiency)
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From page 106... ...
In established drug users, testing of active immunization may need to occur in an inpatient setting for up to 3 months, to prevent the use of drugs that might interact with active immunization. Monoclonal antibodies or depot medications can be tested with single doses in healthy nonusers or drug users who are currently abstinent, perhaps in a residential setting.
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From page 107... ...
. Because of the potential FDA requirement that depot naltrexone be demonstrated to have efficacy against placebo for opioid dependence, alcohol dependence has been the initial indication for developing depot naltrexone.
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From page 108... ...
However, it involves a patient population that is likely to be very difficult to follow closely using urine toxicology testing and that may be at high risk of using large doses of the abused drug to override the blockade provided by the immunotherapy. Therefore, in these drug abusers it may not be feasible to assess the potential efficacy of the antibodies for relapse prevention; instead, a follow-up of the overdose episode would focus on safety considerations.
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From page 109... ...
Among the populations not likely to be studied in the initial three phases of FDA clinical trials process are adolescents, pregnant women, medically ill people, and prisoners. These populations may be considered for later controlled trials before off-label use becomes widespread.
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From page 110... ...
Off-Label Uses Before additional postmarketing clinical trials are completed, some physicians may decide to use these depot medications or immunotherapies for different diagnoses or in different types of intervention protocols than their approved indications. This off-label use extends beyond simply using the medication in an additional population that may not have been included in the Phase III clinical trials.
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From page 111... ...
Furthermore, FDA clinical trials are likely to be conducted in adults, not children, so there will be limited or no prior experience with the use of these agents in adolescents. While the development process and the postmarketing experiences differ across various therapies, when the FDA clinical trials process is completed and there is a successful new immunotherapy or depot medication, there may still be a number of unanswered questions relevant to the common practice of off-label medication use (Cohen, 1997b; McIntyre et al., 2000; American Academy of Pediatrics, 2002)
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From page 112... ...
Fourth is the testing and clinical use of these treatments in settings other than specialty clinics, including primary care settings. Nicotine The FDA testing of immunotherapies or depot medications is likely to be more informative about the treatment of nicotine dependence than the treatment of any other abused substance.
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From page 113... ...
Thus, immunotherapies would have to be tested first in adolescent smokers with demonstrated nicotine dependence in order to assess safety. Passive immunization with monoclonal antibodies could be examined in relatively large groups of adolescents after initial approval of an immunotherapy for adults.
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From page 114... ...
Second, active immunotherapies are not useful for overdose reversal, but both active and passive or monoclonal immunotherapies are likely to be useful for relapse prevention. Because the lower cost of active immunotherapies makes them attractive in settings with limited resources, it may be critical to examine both approaches.
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From page 115... ...
But even with monoclonal antibodies, the scientific information that might be obtained during the FDA clinical trials process will be inadequate to formulate guidelines for off-label uses in adolescents or pregnant women. Since animal models are the best available approximation of use in pregnant women, safety studies of immunotherapies and depot medications in pregnant animals should be a required part of any successful NDA.
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From page 116... ...
Consequently, the design of placebocontrolled clinical trials of depot formulations of naltrexone for opioid dependence is likely to break new ground, because unmasking the blind will be relatively easy and is likely to occur. Other Drugs of Abuse -- Phencyclidine While immunotherapies are theoretically possible for hallucinogens, cannabis, and "club drugs," such as MDMA (methylenedioxy-n-methylamphetamine)
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From page 117... ...
Alcohol Immunotherapies are not possible for alcohol, but Phase III clinical trials of depot naltrexone are under way, and trials of depot formulations of other opioid antagonists such as nalmefene are being planned. Depot medications are not likely to have application in the treatment of either alcohol overdose (for which supportive measures and, at the extreme, hemodialysis, are the treatments of choice)
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From page 118... ...
Consequently, once approved for the treatment of alcohol dependence, these medications are likely to be used off label for the treatment of opioid dependence. Consequently, FDA approval for alcohol dependence may necessitate evidence of the safety of these formulations for use in opioid addicts.
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From page 119... ...
Nevertheless, these relapse prevention trials will be more relevant to the widespread application of these treatments than trials focusing on the reversal of overdose. At best only some of the important questions will be answered during the FDA clinical trials process required for the approval of an NDA for immunotherapies and depot medications.
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From page 120... ...
Use of depot medications such as naltrexone for alcoholism are likely to be well informed by the FDA process, but other uses of depot naltrexone such as for heroin dependence may be less thoroughly studied before the formulation is available for commercial use. In summary, the FDA clinical trials process will provide a wealth of information about the safety and efficacy of these new medications.
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From page 121... ...
. The use of calcium carbamide in relapse prevention counseling: Results of a randomized controlled trial.
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From page 122... ...
. Naltrexone maintenance treatment for opioid dependence.
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From page 123... ...
. Naltrexone and coping skills therapy for alcohol dependence: A controlled study.
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From page 124... ...
. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: A meta-analysis of randomized controlled trials.
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