Clinical studies must adhere to the seven ethical principles of conducting research in humans. They include value, validity, fair subject selection, favorable risk/benefit ratio, independent review, informed consent, and respect for enrolled participants (Grady 2004). Applying these principles to biologics to treat SUDs is of paramount relevance given the uncertainties of the risk and benefits of this approach, the potential of a large exposition to the biologic due to the high prevalence of drug use, and the vulnerabilities associated with having an SUD.

Participants in clinical studies of SUDs can be classified as “treatment seekers” or “nontreatment seekers.” The latter group can be “drug naïve” or “drug exposed,” depending on the exposure to the substance of abuse. Studies of the abuse liability of new chemical entities and those to evaluate the interaction of potentially therapeutic compounds with drugs of abuse are typically conducted in individuals who have used the target drug of abuse and are not seeking treatment. An ethical challenge is the potential appeal to individuals with SUDs of participating in these studies because they may receive the drug of abuse as part of the experiment. Given the relevance of this issue, practice guidelines for drug self-administration studies have been developed (Adler 1995; Almond 1992; Mendelson 1991; Kleber 1989).

A critical ethical issue in clinical studies is the validity of the data. One of the concerns in SUD studies is the surge of professional research subjects, which may be due to the increase of clinical trials and the access of protocol information in clinicaltrials.gov. These subjects may misrepresent themselves in order to meet the study inclusion/exclusion criteria and provide unreliable information during the study. To prevent the admission of these subjects, some clinical trials of SUDs require a positive urine sample for the drug of abuse, which can be perceived as coercion. Furthermore, when SUD individuals are under the effect of a psychoactive drug, the voluntary nature of the consent, understanding of the research methods and risks/benefits, and the validity of the collected information may also be questionable. Methods, including data repositories of study subjects, are being developed to detect and prevent the admission of professional subjects in clinical trials and, therefore avoid the need of requiring positive urine toxicology tests for study admission.

Clinical studies usually provide compensation to study subjects, especially when there is little or no direct benefit. Subjects are generally compensated for their time, effort, and discomfort associated with participating in the study. Compensation of subjects with active SUDs should be carefully designed. It should prevent the use of the money to buy drugs and the risk to overdose. Often, compensation is in the form of vouchers, paying to third parties on their behalf, or in small amounts.

Biologics have shown enormous public health benefit and they are making a significant impact in many areas of medicine such as oncology, rheumatology, dermatology, neurology, and psychiatry, including SUDs. However, there is some controversy about their use, even for those conditions such as measles for which their efficacy is widely established. The general public sometimes is concerned about the potential side effects of biologics and the perception of disturbing the natural order by modifying the natural defenses (i.e., vaccines and monoclonal antibodies) or the natural drug metabolism (i.e., enzymes). Moreover, the compulsory vaccination of children against some infectious diseases and the claim of adverse effects have created some resistance and a negative attitude toward the use of vaccines (Grady 2004). The reality is that all biologics have risks and benefits and there are important ethical considerations to keep in mind when they are administered to a few individuals for therapeutic purposes or to a large number of people for prophylaxis.

Biologics are complex and “large” molecules that do not cross the blood–brain barrier and thus have no CNS effects. Their main mechanism of action for SUDs is a pharmacokinetic antagonism in which the biologic precludes the access of drugs of abuse to the brain and thus prevents the reinforcing effects on this organ. Biologics target the molecule responsible for the SUD peripherally and change its metabolism, distribution, or clearance. Therefore, biologics are highly specific against a target drug of abuse and have limited side effects.

Biologics being investigated for SUDs include vaccines, monoclonal antibodies, and enzymes. Vaccines induce the production of antibodies by the immune system of the host. Monoclonal antibodies are produced by external methods. Both types of antibodies are expected to sequester the drug of abuse in serum. Enzymes are produced by multiple and complex methods with the goal of accelerating the degradation of the drug of abuse in serum, before it reaches the brain.

Biologics may be useful to treat SUDs because they prevent the effects of drugs of abuse on the brain reward systems. Studies have shown that biologics reduce the amount of drug that reaches the brain and the expected outcome is a reduction of the drug self-administration. The expectation is that biologics attenuate the rewarding effects of drugs of abuse and help to prevent drug use relapse. Biologics could also be used as antidotes for drug overdose and, eventually, to prevent the onset and progression of SUDs, and to prevent the access to the brain of the fetus when pregnant mothers use drugs.

One of the best methods to predict the risks and benefits of therapeutic products to humans is with a thorough evaluation in animals using preclinical models. Unfortunately, animal testing not always predicts the safety and efficacy in humans of the tested compound. This is particularly relevant in the study of biologics and especially for SUDs. Therefore, the clinical evaluation of biologics for SUDs inherently has a high degree of uncertainty, which poses special ethical issues (Kantak 2003; Katsnelson 2004).

The biologic products investigated for SUDs include vaccines against nicotine, cocaine, methamphetamine, and opioids; monoclonal antibodies against nicotine, cocaine, methamphetamine, and phencyclidine; and enzymes against cocaine. Of these products, vaccines to treat nicotine and cocaine addiction, monoclonal antibodies to treat methamphetamine addiction, and enzymes to treat cocaine addiction and intoxication have been investigated in humans. The fact that these products have been clinically evaluated indicates that the research protocols have been reviewed and approved by Institutional Review Boards (IRBs) and/or ethics committees and reviewed and authorized by the FDA. Therefore, it is expected that the products tested in humans offer an acceptable risk/benefit to study participants and have the potential to be safe and effective approaches to facilitate abstinence, reduce drug use, or prevent drug use relapse.

Regulatory agencies treat biologics differently than regular medications because of their complex chemical structures and susceptibility to variation during manufacturing. In some cases, the FDA decides whether new products are biologic or nonbiologic on a case-by-case basis. To test a biologic in humans, the FDA requires an Investigational New Drug (IND) application in effect. The IND must contain adequate information about the product to determine if it is reasonably safe to be evaluated in humans. The IND should include the product’s chemistry, manufacturing methods, pharmacologic effects, and mechanism of action as well as its absorption, distribution, metabolism, and excretion. Additionally, for vaccines, the FDA requires an assessment of their immunogenicity. The IND application should also include the plan of future clinical studies and any new study should be submitted as an amendment to the FDA. At any time in the process, the FDA can place the study on hold when the risk is greater than the benefit of a biologic.

The IRBs play a key role in ensuring that a biologic is not only medically safe but also ethically acceptable to be evaluated in humans. IRBs are expected to review the IND application and should have all the safety information to make an informed decision about approving the administration of a biologic to humans. The IRB has the authority to disapprove a study even when the IND is in effect but not the other way around. Investigators are not allowed to run the protocol and administered the biologic subjects when the FDA has place the study on clinical hold.

Typically, the clinical development of biologics involves three phases. Phase I involves the administration of the biologic for the first time in humans. Usually, the investigators evaluate the safety, pharmacology, and, in the case of vaccines, immunogenicity. Depending on the aims, these studies may be conducted in healthy volunteers with or without SUDs. In general, there are few ethical concerns of conducting phase I studies of biologics in individuals with the respective SUD unless there is another contraindication. It is considered that healthy volunteers without SUD will not derive benefit from the biologic and the risk–benefit profile of the product is acceptable for ethical purposes (Kingham et al. 2014).

Phase II and III trials are controlled studies that evaluate the safety and efficacy of the biologic usually in a large sample of patients with the respective SUD. Phase II studies further the knowledge about the safety and efficacy (including immunogenicity for vaccines) of the product. Phase III are usually pivotal studies to determine the efficacy and are required for registration with the FDA. These studies generally include placebo controls. However, they may not be justified when an effective treatment is available and withholding treatment would expose patients to unnecessary risk. This may be the case of biologics to treat opioids and nicotine dependence, for which FDA-approved medications are available and the use of active controls receiving treatment as usual may be an alternative to the placebo control group.

It may be conceivable that the “animal rule” could apply to biologics. This rule addresses serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances and for which human efficacy studies are unethical and infeasible. In theory, a biologic such as a monoclonal antibody or an enzyme to treat a life-threatening illicit drug overdose could be approved by the FDA following this rule. Possibly, clinical studies may be conducted during the post-marketing phase to confirm the clinical benefit.

One of the most critical challenges in the development of biologics to treat SUDs is the selection of endpoints that are clinically meaningful and acceptable to the FDA for the approval of the product. Currently, the only acceptable endpoint by the FDA for clinical trials of pharmacotherapies for SUDs is drug use abstinence. However, this endpoint is practically unattainable. Therefore, there is a concern about the appropriateness of enrolling patients in clinical trials of SUDs when the studies are unlikely to provide the results that will support an FDA approval of the biologic. Efforts are being made by NIDA and multiple investigators to develop alternate endpoints that can be accepted by the FDA (Kiluk et al. 2014; Carroll et al. 2014).

The notion of a vaccine against drugs of abuse was first described in 1974 in a study in monkeys that showed that after morphine immunization, they showed a reduction in heroin self-administration (Bonese et al. 1974). Vaccines induce the production of antibodies by the immune system. The mechanism of vaccines for drug addiction is based on a pharmacokinetic antagonism in which the antigen–antibody complex is a large-size molecule that cannot cross the blood–brain barrier and prevent the access of the drug to the brain. Thus, vaccines do not have psychoactive effects and are expected to prevent the reinforcing effects of the drug and extinguish the cycle of addiction. In the case of SUDs, vaccines induce the production of antibodies specifically against the drug of abuse. Vaccines against nicotine, cocaine, methamphetamine, and opioids are being investigated. Of these, vaccines to treat nicotine and cocaine dependence have been tested in humans (Montoya 2008).

One of the main requirements for vaccines to be effective is that vaccinated individuals have an immune system that is capable of generating the respective antidrug antibodies. For this reason, immunosuppressed individuals, such as those with advanced AIDS or malnutrition, may not be good candidates for vaccination. This is relevant because these conditions are frequently observed among individuals with SUDs. Therefore, antidrug vaccines may have a limited applicability for SUD individuals with those conditions and it may be necessary to exclude them from participation in clinical trials.

Of the potential unintended consequences of vaccines is the limited access to the brain of the drug of abuse, which may result in increasing drug use to compensate. Vaccinated individuals may try to overcome the pharmacokinetic antagonism and present the peripheral effects of drug overdose. Moreover, when the effect of the vaccine is decreasing and the antibody titers are lower, the vaccinated individual may also be at risk of overdose because the amount of antibodies is not enough to prevent the access of the drug to the brain. This is particularly relevant among individuals with opioid dependence who were able to reduce or stop their opioid use and developed lower tolerance to the brain effects of opioids. Therefore, it is critical to inform individuals with SUDs who participate in clinical trials about the risks of compensatory drug use, the development of tolerance, and the possibility of drug overdose.

A potential application of an antidrug vaccine is to treat individuals with SUDs who have been detoxified, are about to be released from prison, and are motivated to remain abstinent. A vaccine, in this case, could be used as a tool for relapse prevention. This approach is similar to the relapse prevention treatment with depot naltrexone for opioid-dependent individuals before they are released from prison, which has shown encouraging results (Lee et al. 2015). In these cases, patients should be instructed that they must refrain from using drugs when they are release from prison because of the risk of drug overdose, as it was mentioned before.

One of the risks of antidrug vaccines is the precipitation or exacerbation of drug use craving due to the blockade of the access of the drug to the brain. As a result, clinical studies with vaccines and concomitant anti-craving medications may be necessary. In this case, the anti-craving medications may carry additional risks. Therefore, clinical investigators need to consider the risks and benefits of the combined investigational treatments and carefully communicate them to patients. Human laboratory studies of craving, which provide SUD individuals the drug of abuse, may reduce cravings but undermine the individual’s ability to consider the risks of participation or become motivated to seek treatment. It is important to remind the study participant that if any time during the study he/she becomes interested in receiving drug abuse treatment, the participation in the study will need to be stopped and support/referral to a treatment program will be provided (Carter and Hall 2013). In general, the treatment with biologics should always include psychosocial support to help patients with the craving and other clinical manifestation of the SUD (Ashcroft and Franey 2004; Wolters et al. 2014a, b; Hall et al. 2004).

Given that the current biologics are specific for a single drug of abuse, it is possible that some treated individuals switch to use another type of drug. For example, patients treated with a heroin vaccine may switch to a different type of opioid such as oxycodone. It is also possible that a patient treated with a cocaine vaccine may switch to use another stimulant such as amphetamines. It is important, therefore, for research ethics committees and IRB to consider the risks that study subjects or patients may increase their drug of abuse or acquire a new form of drug addiction (Ashcroft and Franey 2004). Currently, investigators are evaluating polyvalent vaccines that may be effective for more than one drug of abuse (Pravetoni et al. 2012, 2013).

Treatment with antidrug vaccines can produce antidrug antibodies that can be detected in blood and may raise ethical concerns about privacy, social stigma, and discrimination. This unwanted disclosure may have social or occupational implications that need to be addressed with persons receiving this type of treatment (Ashcroft and Franey 2004). Another potential risk of vaccines is the induction of allergic reactions or anaphylaxis. In this case, the consent form should warn participants of this risk and research programs should have the necessary tools to treat an anaphylactic shock.

One of the potential applications of biologics, more specifically vaccines, is the prevention of the neurobehavioral effects of drugs of abuse. As such, vaccines could be prescribed to prevent the initiation of drug use or the progression from drug use to addiction. These potential indications have not yet been evaluated and it is unlikely that they will be because of the methodological complexity of this type of research. If these indications were demonstrated, there is a concern about their administration without consent to individuals who may be at risk of developing drug addiction or in whom a drug addiction has a significantly higher clinical risk (Ashcroft and Franey 2004; Hasman and Holm 2004). However, for now, this is more a hypothetical than a real concern that may be addressed if or when clinical studies are developed.

Drug abuse is frequently associated with HIV infection, and comorbid SUD and HIV infection are clinically complex. Some investigators are proposing vaccines to treat both HIV infection and SUD (more details at http://​projectreporter.​nih.​gov PI: Gary Matyas, Grant ID: 5DP1DA034787-03). Although an anti HIV–SUD vaccine appears interesting, clinical research on HIV infection involves additional ethical issues. They include first-in-human testing of potentially ineffective or harmful interventions, the presence of immunodeficiency, the medical and psychosocial consequences of each disorder, the expectations and access to potentially efficacious therapies in the early stages of clinical testing, and, sometimes, the involvement of communities and advocacy groups in the design and conduct of clinical trials. Moreover, there is controversy about how to move compounds from bench to bedside and whether the first trial participants should be the sickest-first (oncology) or the healthiest-first (pharmacology) model. It may be especially challenging to accurately communicate in the consent form all the risks and benefits of a biologic for HIV and SUD because of the uncertain and complex risk/benefit (Lo and Grady 2013; Henderson 2015; Garner et al. 2014; Sugarman et al. 2014; Bailey and Sugarman 2013). Currently, anti HIV–SUD vaccines are more a concept than a reality. If they become available, investigators will need to address the added ethical complexities of conducting SUD and HIV clinical research.