Burris S, Davis, Corey S. Assessing Social Risks Prior To Commencement Of A Clinical ..... Not Enough Graves: The War on Drugs, HIV/AIDS, and Violations.
ASSESSING SOCIAL RISKS PRIOR TO COMMENCEMENT OF A CLINICAL TRIAL: DUE DILIGENCE OR ETHICAL INFLATION
Scott Burris Corey s. Davis
Temple Law School Working Papers Published version can be found at: Burris S, Davis, Corey S. Assessing Social Risks Prior To Commencement Of A Clinical Trial: Due Diligence Or Ethical Inflation The American Journal of Bioethics, Vol. 9; No. 1, pp. 48-54, 2009
Electronic copy available at: http://ssrn.com/abstract=1517306
Assessing Social Risks Prior to Commencement of a Clinical Trial: Due Diligence or Ethical Inflation? Scott Burris, Corey Davis The American Journal of Bioethics, 9(11): 48–54, 2009
Federally funded research must be reviewed by an institutional review board (IRB) to determine, among other things, that research subjects are not exposed to undue risk. In many studies, the possible risks include negative socially mediated consequences, including exposure to embarrassment, discrimination, adverse legal action, stigma, or violence. Accurate assessment of such ’social risks’ has proven difficult for IRBs (Hirshon et al. 2002; Shah et al. 2004; McWilliams et al. 2003), complicated by lack of data, the complexity of social risks, and, particularly in the case of international research, limited IRB familiarity with the local social environment (Burris 1998; Dawson and Kass 2005; Hyder et al. 2004). Cognitive bias, including IRB risk aversion, may also contribute to misassessment of risks (Hyman 2006; Kahnemann et al. 1982). Both type I and type II errors are problematic, resulting either in unjustified interference with ethical research or the exposure of subjects to excess risk (Zywicki 2007). A number of commentators have suggested that the former problem is considerably more common than the later, particularly in non-clinical research (Gunsalus 2004; Burris 2008). We report here on a novel effort to empirically investigate social risks before beginning an HIV prevention trial among active drug users in Thailand and China. The study validated ex ante concerns that drug users were subject to serious social risks in the areas where research was planned, but also demonstrated that, if certain steps were taken prior to research initiation, participation in the research posed little or no marginal increase in risk and might even have a protective effect. Our experience shows that it is feasible to inform IRB deliberations with actual data on social risks, but also raises the question of whether and when such research is a necessary or productive use of scarce health research resources. Given growing concerns about IRB ’mission creep’, this project provides an occasion to reflect on the costs, benefits and limitations of expanding the scope of the IRB’s inquiry. THE HPTN 058 RAPID POLICY ASSESSMENT HIV Prevention Trials Network (HPTN) 058 is a phase III randomized controlled trial to evaluate the efficacy of a substitution treatment with Suboxone (Reckitt Benckiser, Slough, UK) plus drug and risk-reduction counseling compared with short-term detoxification plus drug and risk-reduction counseling for the prevention of HIV transmission among opiate dependent injectors. Funded by the National Institutes of Health through the HIV Prevention Trials Network, it recruits active drug users in Heng Chien, Guangxi Zhuang Autonomous Region, and Urumqi, Xinjiang Uighur Autonomous Region of China and in Chiang Mai, Thailand. The total duration of the trial will be approximately 4.5 years, with 1460 opiate dependent injection drug users (IDUs) enrolled. Ethical Concerns About Social Risk in the Trial During the pre-study planning process, members of the research team expressed concerns about the social risks for IDUs participating in the trial. Participants who were exposed as drug users
Electronic copy available at: http://ssrn.com/abstract=1517306
potentially faced multiple, intersecting stigmas—of drug addiction (Dean and Rud 1984), of HIV (Parker and Aggleton 2003), and of ethnicity (Wilson et al. 2007). Drug possession is illegal in both China and Thailand, and drug laws and law enforcement practices have well-documented negative health effects on IDUs (Burris et al. 2004; Kerr et al. 2005). The HPTN 058 team expected these risks to be present in both China and Thailand. Human Rights Watch recently reported in very negative terms about the Chinese government’s approach to drug control, particularly the long-term detention of drug users in detoxification and ’reeducation through labor’ facilities (Human Rights Watch 2003). The picture in Thailand looked even worse. There, in early 2003, Prime Minister Thaksin Shinawatra announced a ‘war on drugs’ aimed at producing a ’drug-free’ nation (Shinawatra 2003). The effort included intense pressure on drug users to enter ’treatment’ centers of varying quality, and an intense crackdown on users and dealers (Vongchak et al. 2005). It was accompanied by a wave of thousands of extrajudicial killings, false charges and blacklisting (Human Rights Watch 2004; Adams 2003; United States Department of State [2003] 2004). Concern that drug users were a vulnerable population was clearly justified, but the ethicality of the research, as far as social risk was concerned, turned on a narrower issue: would participation in HPTN 058 expose IDUs to additional risks different or greater than the ones they already faced every day? Rather than base the social risk assessment on their raw perceptions of the risk (or those of the responsible IRBs), the HPTN 058 investigators decided to seek an independent empirical investigation of social and legal risks to research participants at the study sites. A rapid policy assessment (RPA) tool was developed based on a methodology called rapid policy assessment and response (RPAR). (More information about RPAR and RPA, and copies of the research and training tools are available at www.rpar.org).The RPA was intended to investigate the extent to which law, policies and enforcement strategies would place participants in the research at significantly elevated risk of arrest, incarceration, physical harm, unwanted disclosure of drug use, or loss of access to health care relative to injection drug users not participating in the research. The RPA protocol was reviewed and approved by the applicable IRBs at each study site, as well as at the sponsoring institutions. Implementation The assessment consisted of two components. The first reviewed the law relevant to injection drug use, HIV, and health care for IDUs in each study country, as well as existing scientific and gray literature relevant to drug policy and drug user risk behavior. This review was conducted by local lawyers in each country using standard legal research methods. National and local laws were collected in nine domains: drug use (including drug control laws, syringe laws, needle exchange programs and drug treatment); HIV-specific criminal exposure or transmission; criminal justice and procedure; right to health care and right to HIV treatment; reportability of HIV, AIDS, and STDs; HIV testing laws; privacy of medical information; anti-discrimination provisions, and any other laws that influence risk or stigma among drug users in a significant way. Both local and United States (US)-based researchers collected existing studies and epidemiological and criminal justice data. The qualitative research component assessed how these laws are put into practice and what influence practice has on the risks and benefits of IDU participation in the study. Data were collected via standardized interview forms by independent researchers at each site. Research teams were recruited in each country. Each local researcher received training on the RPA conducted by US researchers, including a thorough explanation of the law on the books and the existing data. The site researchers identified and recruited key informants in the legal and public
health fields as well as current and former injection drug users. The IDUs interviewed were selected using the criteria for enrollment in the HPTN 058 study. Specific questions addressed enforcement of drug and syringe laws, any criminalization of HIV exposure or transmission, operation of courts and prisons, drug policy politics, criminal justice data and known or suspected risks to study-enrolled IDUs. Emphasis within the interviews varied based on the knowledge and experience of the interviewee. The total cost of the project, including module development, all trainings and salaries was approximately US $135,000. The study protocol contemplates ongoing monitoring, including at a minimum maintaining adverse event reports encompassing social risks. Findings RPA results were described in reports provided to the responsible IRBs and made public on the Internet (Burris et al. 2007). The ‘Law on the Books’ and literature review components confirmed and detailed the prohibitionist character of the legal regimes governing drug users in both countries. In China, drug possession, distribution and production are subject to serious punishments, including the death penalty (National People’s Congress Standing Committee 1990; Human Rights Watch 2003). Drug users who are identified by the police are subject to registration, and may be entered into treatment or re-education through an administrative process. The ’treatment’, which can include ’cold-turkey’ detoxification, lasts between 3 months and 1 year. These treatment facilities typically include a forced labor component (National People’s Congress Standing Committee 1990). Drug users who repeatedly relapse graduate to another sort of administrative rehabilitation facility, the Education through Labor camp (Zou 2002). Several hundred thousand Chinese are confined in these facilities, about a third of whom are drug users (Biddulph 2003). Conditions in these facilities vary, but are rarely comfortable or sharply distinguishable from penal institutions. The system of administrative detention has been criticized by human rights advocates on many grounds, including the lack of due process or judicial oversight, poor conditions and unpaid labor (Human Rights Watch 2003). Methadone maintenance and needle exchange programs have only recently been implemented, and interference by police has been reported (Wu et al. 2007; Hammett et al. 2005; Gill and Okie 2007). The Thai research confirmed earlier published findings about Thai law and its potential impact on risk behavior. Thai law criminalizes the possession of extremely minor amounts of drugs. The penal regime prescribes severe punishments, makes all offences under it cognizable and non-bailable, and also gives wide powers of search, seizure and arrest to the police (Pandey 2006). There is a presumption of guilt against the possessor of drugs or apparatus for their manufacture. Although syringes are available without prescription at pharmacies, syringe exchange is officially opposed by the Thai government. The existing syringe exchange programs were reportedly small and under-funded (Gray 1995; 1998; Reid 2002). Since much of this information was already known to the protocol team, the qualitative research component was of great importance in shedding light on how these laws and policies work in practice, particularly as to IDUs involved in research. According to the key informants interviewed, there is at least some disconnect between the ’law on the streets’ and the ’law on the books.’ For example, key informant interviewees reported that Chinese police in the research sites do not regularly focus their efforts on arresting individual drug users for drug possession. On a day-to-day basis, IDUs tend to have trouble with police mainly when they are suspected of another crime, such as theft. Periodically, however, police conduct ’crack-downs’ in which they
do target individual users. In spite of China’s prohibitionist drug control regime, NGO staff, health researchers, and local health officials at both Heng Chien and Urumqi had been able to successfully implement and operate research projects and public health interventions involving IDUs. Before beginning any intervention focusing on drug users, the researchers would typically explain the work to and develop an understanding with the local police. Interviewees stressed that regular negotiation and communication with the police are also very important during the operation of such programs. For example, interviewees reported that in Heng Chien, a peer educator working at the syringe exchange program was detained after the police received information that there were drug dealers at the program site. Health officials negotiated with the police, which resulted in the release of the peer educator and an understanding that police would not arrest IDUs at the site in the future. Similar information was gathered in Thailand. Interviewees reported that the police were often willing to accept bribes and that policing was often uneven, with favored persons or groups receiving special treatment. Widespread stigma against drug users was also reported. Interrogation procedures were often described as ‘harsh’, and prison conditions as ‘extremely poor’. However, researchers reported that much of police practice was decentralized and that good results had been achieved when local police were notified of the existence and purpose of research and health programs, although there were reports of police questioning or detaining research subjects on occasion. One official at a drug treatment center reported that police had previously arrested IDUs near the center. Consequently, the center staff were afraid that their patients would not come to the center to receive medical care and treatment. Officials at the drug treatment center wrote a letter to the police describing the purpose of the center and explaining that police activity made patients afraid to attend. The police then stopped arresting IDUs utilizing the center. Overall, the local researchers concluded that while drug users in China and Thailand, as elsewhere, are subject to a variety of socioeconomic, dignitary, and legal harms due to stigma and criminalization, these harms are not more likely to occur because of participation in HPTN 058 as long as researchers ensure that local police are involved in and accept the research project. In fact, enrollment may even have a protective effect if researchers successfully interface with local police. Some IDU respondents in China reported not being detained, or being released, upon showing that they were involved in research projects. Based on this, the RPA research team advised the HPTN that the research team should work with local law enforcement, drug treatment and public health officials to promote their understanding of and cooperation with the research project. The RPA report also recommended that the research team develop internal operating procedures for communicating with authorities to maximize benefits and autonomy and minimize risks to participants. The research team was advised to be mindful that stigmatization from community members may also be a risk factor for IDUs and that systems should therefore be designed to minimize the chance that a person will be inadvertently identified to the community as a study member (and, therefore, an IDU). In addition to informing the IRB and study investigators, the project had positive ancillary effects. The ’law on the books’ analysis in Thailand was adopted by the Thai Drug User’s Network as a useful instrument for training and advocacy, and was translated and published in Thai. Conducting the research demonstrated the investigators’ concern for the welfare of subjects, and using researchers from Thailand and China entailed some capacity building in policy research.
DISCUSSION The HPTN investigators were concerned about the social risks to drug users of participating in an HIV prevention trial, and anticipated that the responsible IRBs and ethics consultants would be as well. A substantial amount of money was spent to do a qualitative assessment of this risk. The findings were, at least to students of drug policy and health, not particularly surprising: IDUs face the daily risk of police intervention leading to arrest, incarceration and/or involuntary treatment. Both in the patterns of police arrest behavior and in the extent to which police exercise discretion in applying drug laws, the findings of the RPA conform to what an informed observer might have suggested, and what was found through review of available literature. The finding that police do not regard participation in research negatively, and are readily persuaded not to use a research site as a convenient place to arrest drug users could also have been predicted, although it was by no means certain and had not been specifically addressed in previous studies. Based in part on the RPA findings, the HPTN 058 study was funded and is proceeding. We turn now to the question of whether this experience has, or should have, any implications for how investigators and IRBs assess the social risks facing vulnerable research populations. IRBs have been criticized for exaggerating social risks (Carpenter 2007), but actual data on their performance are quite limited. There are a few studies showing overly assiduous protection of subjects with psychiatric illness—for example, a study using vignettes reported that IRB members inflated the coercion vulnerability and legal risk of mentally ill research subjects (Luebbert et al. 2008). An interesting experiment more than 30 years ago found that IRBs brought social or political biases to the assessment of social risks (Ceci et al. 1985), which remains a plausible concern. There are also empirical reports of inconsistency in risk assessment (Rogers et al. 1999). In fairness, however, risks depending upon the interaction of research practices, the social position of subjects, and the attitudes and behavior of a variety of social actors are inherently difficult to predict, yet must be addressed. How one judges the RPA as a way of improving IRB risk assessment may well depend upon how comfortable one feels about the implementation of the Common Rule overall. For critics, two of the main problems with the IRB system are mission creep—the gradual increase in the number and stringency of requirements placed on researchers (Burris 2008; Gunsalus 2004; Gunsalus et al. 2006; Burris and Welsh 2006)—and an excessive concern for minor risks. From this point of view, requiring researchers to spend a significant amount of time and money to do research on social risks could, if it became the norm, be a substantial burden that would not provide benefits if the baseline social risk in most cases were, in fact, low. Researchers and commentators have also complained of an increasing tendency towards bureaucratic self-protection in the review process, which translates into an excessive focus on and aversion to the risk that the IRB or its host institution might be criticized for research they have sanctioned (Hyman 2006; Burris and Moss 2006). Investigators themselves seem to be very concerned about getting into ethical trouble, in a sense that is distinct from an unwillingness to behave unethically (Burris and Moss 2006). For an IRB or university counsel in the grip of such a culture, requiring preliminary research on social risks would be another way to demonstrate due diligence in subject protection, and another layer of insulation from regulatory or public criticism. In matters of research outside the United States, IRBs have been criticized for failing to comprehend differing cultures, legal environments and resource levels. International researchers have reported being asked to do things they regard as in conflict with local mores and, in some cases, local laws (Burris and Moss 2006). While these concerns have a general validity, their applicability in this instance is limited.
This was not a case of an IRB making up or exaggerating a risk based on poor information. The risks to potential study enrollees were, based on existing research, certainly non-trivial, even if there were reasons to doubt their likelihood, and it was the researchers, rather than the IRB, that proposed the assessment. Far from judging an international research protocol in substantial ignorance of local laws and customs, the IRB was presented with detailed information about both the applicable policies and the manner of their local implementation. As a general matter, it is at least a discipline on IRBs and researchers to investigate social risk, and if over time a series of similar studies consistently has negative results, it may allow us to worry less about them. Doing the assessment also had some collateral benefit for the subject population. Whatever the intentions of the HPTN investigators, the RPA could also be seen as serving a self-protective purpose. There had recently been extensive criticism of a previous drug trial conducted with the target population in Thailand, where key community groups including the Thai Drug User’s Network and the Thai AIDS Treatment Advocacy Group claimed that serious ethical concerns had been ignored by the trial investigators (Chua et al. 2005). TDN cited numerous possible ethical concerns in that trial, including lack of community involvement in the design of the protocol, lack of a community advisory board, potential for coercion of methadone clinic clients into the trial by methadone clinic staff who doubled as trial recruiters, and substandard post-trial provisions of treatment and care (Curtis 2006). Protests by activists were successful in shutting down similar trials in Cameroon and Cambodia, and there had been calls in the medical literature for trial investigators to engage in pre-trial ’preventative diplomacy’ and make genuine attempts to address community concerns else such protests shut down other trials as well (Singh and Mills 2005). The HPTN investigators may have seen the RPA as a way to forestall any institutional risk aversion on the part of any of the responsible IRBs, universities or funders and a means to placate groups such as TDN. Certainly investigators were frank with the RPA team about their desire to demonstrate the sincerity of their concerns to key stakeholders that had been unhappy with earlier trials among drug users. It is not problematic, at least to us, that a course of ethical behavior might also serve instrumental purposes; in fact, the RPA can be seen as a means of integrating community members and their knowledge and concerns into the planning and operation of the study. The concern, for students of the Common Rule system, would be that empirical risk assessment might come into common use for instrumental purposes, even when it is not really needed to properly assess a study protocol. Although it was relatively expensive, the 058 assessment has the benefits of being empirically informed and easily adapted for similar studies or follow-up in this study. Nearly half of the budget for the social risk assessment went into compensation for US-based researchers and training-related travel. Many of these costs can be reduced or eliminated if instead local researchers adapt the RPA tools and conduct trainings to fit their local situation. For example, sample sizes can be reduced, the legal component can be eliminated if similar analyses exist, and so on. To this end, we have made those tools freely available on the RPAR website. There are of course several alternatives to such an assessment, should an IRB decide that an analysis of social risks is warranted. Perhaps the least expensive and cumbersome is a review of the existing literature. Such a review in this instance would have shown that being a drug user is risky, but there would have been no evidence to suggest that participating in research added meaningfully to this risk. That doesn’t mean there would not be a significant risk in this instance, but only that there was no positive evidence. Had the investigators simply reviewed the literature on IDUs, police and research participation, it would have been reasonable to allow the research
to go forward with periodic review of adverse event reports involving social risks and harms, or to require further inquiry only in Thailand, given contemporary reports of the violent government crackdown. However, we note that, although it makes sense in retrospect, there is little precedent in the reported literature for our finding that pre-emptive cooperation and involvement of local police in research projects involving IDUs has a protective effect on study participants. Alternatively or in addition, the investigators could have systematically reviewed their own prior experiences with research among IDUs at the several sites, and performed an explicit assessment of risks based on that knowledge. In this study all of the site research teams had done research with similar IDU populations in the past, and were familiar with the need at these sites to work out an understanding with law enforcement officials. Either of these steps would have been less expensive and time consuming than the independent review, although this may only be possible where researchers have previous experience with the population targeted by the proposed research. Review by an independent, outside evaluator also deflects any complaints of conflict of interest that might be claimed to exist, particularly where the target population is traditionally stigmatized and a great deal of energy and money is dependent on the study going forward. Looking ahead, the HPTN 058 assessment may be most problematic as an instance of the moral hazard facing IRBs as regulatory bodies with considerable power and few constraints. Regulatory critics have noted several important features of the IRB as a regulatory device. The IRB lacks a mechanism to fully recognize, let alone internalize, the costs of the demands it places upon researchers (Zywicki 2007). IRBs, abetted by ethicists and federal regulators, continue to develop new ethical requirements, a process that has been described as ethical inflation (Burris and Welsh 2006) These new standards may be difficult, inefficient or counterproductive to enforce, and may express themselves in demands for actions such as the HPTN 058 assessment. As IRBs and their institutions become more and more risk averse, more intensive oversight and more demands on researchers may be on the horizon (Burris and Moss 2006). Even if the assessment was a sensible requirement in the context of 058, does it risk growing into a standard requirement, a new threshold beneath which other IRBs are unwilling to go? In the absence of significant changes to the system (Burris 2008), the appropriate use of empirical assessment of risk will require IRBs to exercise conscious self-restraint in calling for its use. Having carried out the RPA, we are proud of the results and happy with the scholarly exchanges that went into it; we were glad to be asked to participate in a project that took seriously the needs of a population we seek to serve in our work. We remain unsure that the example we set should be widely or routinely followed, and look forward to further discussion in the bioethics literature. CONCLUSION IRBs harm the research enterprise when they demand protocol changes to reduce trivial or imaginary risks. Conversely, they may sometimes fail in their duty to protect subjects if they allow research to go forward without properly evaluating and considering possible risk to research subjects. Empirical evidence gathered by an RPA-type assessment can inform IRB decision-making, but entails significant cost in money and time. The HPTN 058 RPA largely confirmed what informed researchers would have predicted was the risk environment for IDUs participating in the study. The study provided some political cover to both the researchers and the IRB, at a cost that represented a relatively small part
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