The medications that currently are available for human trials or 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 will be ready for human testing within the next few years. The clinical trials to test these medications may involve three kinds of testing: (1) for individuals who overdose, (2) for drug-dependent individuals who either volunteer for the medication or are encouraged/coerced to use the medication by another agent to prevent relapse, and (3) for nondependent individuals who either volunteer or are induced to receive the medication as a protection against initiating or increasing substance use (i.e., primary or secondary prevention, respectively) (Blaine et al., 1994; Klein, 1998). In all three kinds of tests, clinical trials subjects are likely to be adult males and nonpregnant adult females.
The FDA clinical trials process is designed to assess safety and efficacy of new medications through four phases of testing (Blaine et al., 1994). Phase I is designed to establish the safety of new medications, in escalating doses, typically in a population of healthy adults. With active immunization, subjects are likely to require a series of doses in order to produce an optimal level of circulating antibody. Since repeated booster immunization could increase the risk for unexpected side effects, this type of study
should be conducted in abstinent former users. In contrast, with both passive immunization and sustained-release formulations, initial safety can be tested with a single dose in healthy non-users or abstinent former users (Kosten and Kranzler, this volume).
Phase II testing seeks to determine the optimum dosage of a medication and may also include comparison of the effects of new medications with those of a placebo treatment. Potential indications for use become important with phase II testing. FDA requirements may be different for depot medications than they would be for other kinds of new drugs. Because, in most cases, efficacy of the oral medication will already be established for sustained-release formulations, placebo-controlled testing may not be required as part of phase III (or phase II) testing (Kirchmayer, Davoli, and Verster, 2002). However, the efficacy of depot formulations will need to be tested against placebos.
Phase III testing is designed to establish safety and efficacy with large-scale, placebo-controlled studies. The specific outcomes of the studies and their designs may differ on the basis of the indications that are being considered. These indications will also affect the population from which subjects are recruited. For instance, if relapse prevention is the outcome of interest, former drug users who are currently abstinent would be the population of interest. The committee believes that a diverse group of patients who need relapse prevention ought to be examined during the phase III testing process, before moving to protection protocols or special populations, such as pregnant women.
Phase IV testing is used to monitor the use of a medication once it has been approved and is available for clinical practice. Populations that were not originally studied might be assessed, and relatively rare side effects might be detected. This standard stage-wise strategy for completing clinical trials is very unlikely to provide any information about the use of these interventions for a variety of important clinical applications. In particular, the committee believes that significant ethical issues in phase IV testing will arise with immunotherapies and sustained-release formulations.
PHASE IV CONSIDERATIONS
The surveillance that is an intrinsic part of the postmarketing experience will be critical, particularly for monitoring off-label uses in which premature applications may place certain populations at unacceptable risk. There is likely to be pressure to use these therapies in populations for which insufficient safety or efficacy data are available from the clinical trials, such as adolescents, pregnant women, polydrug abusers, criminal justice populations, or even military personnel. In these untested populations, as well as in those initially included in the clinical trials to support
FDA approval, postmarketing surveillance may provide data on relapse rates, drug substitution, and increased sensitivity to the abused drug after sustained treatment, events that may increase the potential for accidental drug overdoses (Kosten and Kranzler, this volume). Overall, these surveillance activities, as well as NIDA-funded health services studies, may offer substantially better data than the traditional clinical trials on the use of these immunotherapy and sustained-release medications in real-world situations. These studies could be conducted in the NIDA Clinical Trials Network.
In view of the strengths and limitations of data from clinical trials to support approval by the FDA for a specific indication, several issues will be particularly important during testing and postmarketing surveillance: NIDA’s working collaboratively with the FDA to test and monitor the immunotherapy medications; NIDA’s role to ensure commercial development of these immunotherapies; uses with a variety of special populations; prevention studies; and potential off-label uses after FDA approval.
NIDA and FDA Cooperation
It will be important for NIDA and the FDA to work together to establish guidelines for testing and monitoring immunotherapy and depot medications in the general medical community, where off-label use is quite likely. Mechanisms for achieving this cooperation might include reconstituting the FDA Drug Abuse Advisory Committee and conducting joint workshops that involve consultants from outside NIDA and the FDA.
A second key issue involves NIDA support for clinical trials and commercial development through established mechanisms. This is particularly important in light of the barriers to the development of pharmacotherapies for drug abuse, as well articulated in a recent report on addictions medications development (Institute of Medicine, 1998). Established mechanisms to support these efforts include at lest four funding programs: Cooperative Research and Development Agreements, Small Business Innovation Research, Small Business Technology Transfer, and Strategic Program for Innovative Research on Cocaine (and Other Psychomotor Stimulants) Addiction Program. These grant programs have facilitated very productive partnerships among small businesses, such as biotechnology companies, academia, and the federal government. Products have included active vaccines, monoclonal antibodies, and depot medications.
A number of issues may arise with respect to special populations, a group that is likely to include pregnant women and adolescents, as well as people with particular indications, such as overdoses and for prevention of addiction in drug-naïve users. The committee does not believe that studies with these populations should run in parallel with the initial studies to establish safety and efficacy in competent adults. For example, testing in pregnant women is likely to raise a number of potential ethical issues in the absence of any preclinical data.
Vaccination raises a specific concern about the effect of these medications on fetal development, which undergirds the committee’s cautions with respect to pregnant women. Immunotherapies would allow for the transfer of drug-specific antibodies to a fetus, with unknown effects. It is not known if this could even lead to greater fetal exposure to a targeted drug, possibly by pregnant women attempting to override medications or by switching their drugs of choice. If there is increased fetal exposure, it is likely to have negative effects on fetal development, as many of the drugs of abuse for which immunotherapies are currently being developed have either suspected or established adverse effects on fetal development (Plessinger, 1998; Ernst, 1999; Addis et al., 2001).
Of course, there is the hope and expectation that vaccination would reduce the amount of drug to which a fetus is exposed, as it reduces the distribution of drugs to the mother’s brain and other organs. However, maternal antibodies are also transferred across the placenta (Simister and Story, 1997), and they could expose the fetus to the drug that is bound to antibodies. The antibodies might actually prolong the amount of time during which a fetus is exposed to a drug bound to antibodies because the antibody-bound drug is generally eliminated more slowly from the body (Keyler et al., 1999; Proksch et al., 2000). It is unknown how elimination by a fetus will be affected.
There are limited data to assess which of these outcomes is most likely. To date, only one preliminary study has sought to assess whether vaccination with immunotherapies would lead to greater or lesser amounts of drug exposure for a developing fetus (Shoeman, Keyler, and Pentel, 2002). Consequently, the committee believes that preclinical studies of these medications for use in pregnant women would provide the necessary safety data for use in all women, should the outcomes show acceptable safety profiles. This group may be especially important as most drug-dependent women are of childbearing age. Furthermore, long-term follow-up of children born to women who have received these medications during pregnancy is also likely to provide useful information on potential effects for a developing fetus.
Similarly, testing in adolescents should also await preclinical data. In addition, data might also be useful to address legal and social implications for the child and child-parent relationship. For example, what are the implications of having a parent decide on treatment for a minor who does not want to be treated or who may not feel free to decline treatment? Although adolescent populations are likely to be candidates for protection, rather than for relapse prevention, the committee believes that even testing for protection in adults would benefit from first having safety and efficacy data in relapse-prevention trials with competent adults.
The committee urges caution in testing these medications in children and adolescents for several reasons. First, these medications have yet to demonstrate efficacy in adults, and more toxicity testing would need to be done to ensure the level of safety required for administering these medications to adolescents or even young adults. Second, the biological focus of any blocking medication would not affect the some of the reasons that adolescents use drugs. The incentive to use licit and illicit drugs by children and adolescents is often not related to their pharmacological effects. Rather, peer pressure, demonstrating rebelliousness to parents, signaling membership in a clique or subculture, and asserting a social message are highly likely to be reasons for use of alcohol, tobacco, and other drugs by children and adolescents (von Sydow et al., 2002; Griesler et al., 2002; McCuller et al., 2001; Hofle et al., 1999; Farrelly et al., 1999; Sobeck et al., 2000; Flannery et al., 1999). A treatment that targets the pharmacological effects of licit and illicit drugs is unlikely to affect these motivations, and it may be substantially less cost effective than other prevention strategies.
The committee also believes that initial testing of these medications for overdose treatment would also be best with competent adults. Testing for treatment of overdose with patient-subjects who are not capable of providing informed consent would benefit from demonstration of safety and efficacy in trials with competent adults or, when this is not possible, trials for other uses (relapse-prevention or protection). If a trial involves the use of “emergency research” provisions in order to include patient-subjects who are not capable of providing informed consent, then advance approval by “community consultation” should include persons who are at risk of overdose and not simply community leaders who do not have any drug addiction problems.
The FDA has established procedures for gaining community consent through a consultative process for emergency research (see Center for Drug Evaluation and Research, 2003). Emergency research involves “subjects who are experiencing immediately life-threatening conditions for which available treatments are unproven or unsatisfactory.” Informed consent is not able to be obtained because of the person’s medical condi-
tion and a legally authorized representative or guardian is also not available to provide the informed consent. In this circumstance, FDA regulations allow for a community consultation process whereby researchers solicit opinions and input from representatives of the community in which the research will be done and from which subjects will be drawn. This consultative process can serve as a form of community consent for procedures being tested to treat emergency conditions when neither the subjects or their legally authorized representative is available to give individual, informed consent.
None of the phase III studies is likely to address issues relevant to the prophylaxis of addiction in nonabusers (primary prevention) because of the substantial cost and long duration of this type of clinical trial to establish safety and efficacy. Nevertheless, subjects with sustained abstinence, who are at high risk for relapse, might be approached for secondary prevention studies during phase IV monitoring. Four issues will be important for these prevention studies: the nature of the study population, the range of agents tested, the targeting of multiple therapeutic targets or integration with existing treatments, and the use of a variety of settings where testing and treatment are provided. The issue of where to conduct treatment may be a particular challenge, because many substance abuse treatment programs lack the medical infrastructure to deliver pharmacotherapies. In the past, coordination between substance abuse treatment programs and medical settings has not been very successful, as we describe in Chapter 3.
As noted above, many ethical issues will arise as off-label uses of these immunotherapies or depot medications proliferate in the postapproval period. New populations may be studied, including adolescents, prisoners, and pregnant women, and new treatment settings, such as primary-care medical clinics, may be examined. The FDA testing process will provide only limited help in generalizing to off-label uses, and the extent to which the process will help will vary across the specific abused substances.
Off-label uses in medical settings are likely to be provided most effectively for nicotine products but much more poorly for cocaine, amphetamines, and PCP. The difficulties with services for the latter drugs include limited information on their use from the pivotal trials (e.g., the reversal of overdose using monoclonal antibodies for PCP), need for close coordination with substance abuse treatment settings that have limited
medical backgrounds, and social pressure to make any effective treatment available. Use of depot medications, such as naltrexone, for treating alcoholism are likely to be well informed by the FDA approval process, but other uses of depot naltrexone, such as treatment of heroin dependence, may not have been carefully studied.
Recommendation 2 Recognizing that immunotherapy medications will be used in off-label situations that have not been specifically approved by the Federal Drug Administration, the National Institute of Drug Abuse should support preclinical studies addressing the potential safety and efficacy of these medications when given to vulnerable populations (e.g., pregnant women and their fetus, adolescents, etc.). Long-term studies should be done with laboratory animals of different ages, as well as their offspring, before trials with vulnerable human populations are undertaken.
Recommendation 3 The National Institute on Drug Abuse should support studies of the likely extent and nature of off-label drug use, including factors and incentives that would promote or retard such use, and the opportunities for policy makers to intervene should the patterns of off-label use depart from what is in the best interest of the society.