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Implementing post-trial access plans for HIV prevention research
  1. Amy Paul1,
  2. Maria W Merritt1,2,
  3. Jeremy Sugarman1,3
  1. 1 Berman Institute of Bioethics, Johns Hopkins University, Baltimore, Maryland, USA
  2. 2 Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
  3. 3 Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
  1. Correspondence to Dr Amy Paul, Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205, USA; apaul7{at}jhu.edu

Abstract

Ethics guidance increasingly recognises that researchers and sponsors have obligations to consider provisions for post-trial access (PTA) to interventions that are found to be beneficial in research. Yet, there is little information regarding whether and how such plans can actually be implemented. Understanding practical experiences of developing and implementing these plans is critical to both optimising their implementation and informing conceptual work related to PTA. This viewpoint is informed by experiences with developing and implementing PTA plans for six large-scale multicentre HIV prevention trials supported by the HIV Prevention Trials Network. These experiences suggest that planning and implementing PTA often involve challenges of planning under uncertainty and confronting practical barriers to accessing healthcare systems. Even in relatively favourable circumstances where a tested intervention medication is approved and available in the local healthcare system, system-level barriers can threaten the viability of PTA plans. The aggregate experience across these HIV prevention trials suggests that simply referring participants to local healthcare systems for PTA will not necessarily result in continued access to beneficial interventions for trial participants. Serious commitments to PTA will require additional efforts to learn from future approaches, measuring the success of PTA plans with dedicated follow-up and further developing normative guidance to help research stakeholders navigate the complex practical challenges of realising PTA.

  • research ethics
  • HIV infection and AIDS
  • clinical trials

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Introduction

Guidance regarding post-trial access (PTA) to interventions tested in clinical research has evolved over the last two decades.1 2 The current version of the Declaration of Helsinki affirms that ‘sponsors, researchers and host country governments should make provisions for post-trial access for all participants who still need an intervention identified as beneficial in the trial’.3 Recently, revised ethical guidelines from the Council for International Organizations of Medical Sciences (CIOMS) similarly state that, as part of an obligation to care for participants’ health needs, researchers and sponsors should make plans for participants’ continued access to study interventions that have demonstrated significant benefit and for transitioning participants who continue to need care and preventive measures after the research to appropriate health services.4 Thus, there is growing recognition that researchers and sponsors have obligations to consider provisions for PTA for interventions that are found to be beneficial in research and, to some extent, take steps to ensure access to them.

There is significant scholarly literature around PTA including both conceptual discussions and empirical reports.5–15 Normative literature regarding PTA responsibilities appeals to multiple principles, including a duty of care, relationship-based responsibilities and justice.5–7 However, there remains ambiguity about precisely which principles justify researchers’ PTA obligations. For example, if PTA obligations are grounded in a principle of reciprocity, one might say those benefiting from the research owe PTA to participants as a reciprocal benefit for the risk they assumed by participating. However, some have argued against reciprocity-based arguments, observing that even in cases where reciprocal benefits may be owed, PTA is not necessarily the appropriate way of fulfilling the grounding principle.8 9 When PTA obligations are grounded in a duty of care and interruption or discontinuation of the intervention would seriously and negatively impact the participant’s health, those primarily responsible for the participants care may be responsible for ensuring PTA to beneficial interventions, especially when there are no comparable alternatives. Yet, even when grounded in a duty of care, the obligation to provide PTA is limited. Both the HIV Prevention Trials Network’s (HPTN) ethics guidance and CIOMS guidelines, for example, acknowledge that practical barriers outside the researchers’ control will sometimes make it impossible to meet an obligation to provide PTA to interventions shown to be beneficial. Thus, how PTA is justified affects significantly who bears the responsibility of providing it and whether it is indeed required.6

Empirical reports on PTA describe varying approaches to and perspectives on PTA planning and disclosure in consent documents, trial protocols and other documents such as correspondence with funders describing PTA plans.10–12 Reports of PTA plan implementation are primarily focused on access to interventions not available in the healthcare system, in which case participants are transitioned into follow-on research studies or commitments are made by pharmaceutical manufacturers to supply the medications to participants until they are available through the health system.13–16 These experiences identified multiple challenges including delays between trial completion and regulatory approval of the investigational product, challenges with participant reimbursement and adherence and difficulty importing or providing drugs not approved in the country where the trial took place.13–16

Clinical trials involving HIV prevention interventions introduce additional facets of complexity regarding PTA. In some cases, it may be unclear whether the discontinuation of a prevention intervention constitutes a risk urgent enough to trigger PTA obligations, particularly when there are available alternatives (eg, condoms). Several HIV prevention trials have had the option of addressing PTA responsibilities by referring participants to the healthcare system for continued access to preventive therapy. For example, the HPTN has conducted trials where a medication being investigated for prevention was approved for use as treatment (but not prevention) and therefore available in the local healthcare system. For instance, HPTN 067 investigated two different regimens of Truvada (emtricitabine/tenofovir) for effectiveness as pre-exposure prophylaxis (PrEP) while the medication was available and approved for treatment (but not prevention) in the participants’ local healthcare system. Similarly, HPTN 069 investigated four different oral PrEP regimens, some of which were approved medications for HIV treatment and available in the local healthcare system. In such cases, participants could theoretically have access to these investigational medications through off-label use, although with potentially prohibitive out-of-pocket costs.

As meeting PTA responsibilities becomes a more established expectation in the research process and the mechanisms for fulfilling PTA become more diverse, it is essential to understand whether PTA plans achieve their goals. The following discussion was informed by the experience of the HPTN with PTA plans and their implementation. As background, the HPTN has had guidance regarding PTA since 2009, stating that ‘HPTN research seeking to establish the efficacy of an intervention must have a preliminary plan regarding the provision of successful interventions to research participants and communities’.17 The present discussion incorporates information obtained from HPTN research stakeholders (investigators and study staff) directly involved in the development and implementation of PTA plans of six multicentre trials (table 1). This includes descriptions of these plans that were discussed at a large meeting of research stakeholders from many HPTN trials, which was focused on the topic of PTA within the HPTN; it also includes selected follow-up interviews conducted under a protocol approved by the Johns Hopkins Bloomberg School of Public Health Institutional Review Board. Interviews sought to clarify the PTA approach for each of the trials described at the meeting yet were not sampled for theoretical saturation as in a formal qualitative study. Nevertheless, these experiences should be valuable to those concerned with PTA and are shared in this viewpoint along with our own commentary. In particular, examining PTA experiences in the HPTN helped to identify several potential strategies for overcoming practical challenges of developing and implementing PTA plans (table 2). In addition, the experiences described here are well positioned to inform approaches for improving the implementation of PTA plans in the future and identify needs for further normative guidance about PTA.

Table 1

Trials, sites and PTA approach

Table 2

Summary of practical PTA challenges and potential strategies to overcome them

Planning under uncertainty

Planning for PTA necessarily involves uncertainty regarding the effectiveness of the experimental intervention and its likely availability post-trial. This uncertainty is an important influence on whether and when PTA plans are made. Given the high level of uncertainty at the beginning of a trial, some sponsors and research teams refrain from making specific provisions for PTA at that time. For example, in a trial investigating a new antiretroviral medication, cabotegravir, as injectable PrEP, the uncertainty about the safety and efficacy of the product precluded getting even a conditional commitment for PTA from the sponsor during trial planning. As one research stakeholder explained, because relatively few people had received the medication as of the time when the research team was planning the trial, there were reservations about committing to PTA before having the more robust data that would be available after the trial. Furthermore, in this double-blind, double-dummy trial, all participants received an active agent (either the experimental injectable cabotegravir or the already proven oral Truvada) as well as a placebo for the other mode of administration for which they were not receiving an active agent (injection or oral). In addition, for safety reasons due to the long half-life of the injectable agent, participants are expected to continue taking oral PrEP for a long follow-up period to provide protection while the injectable agent is metabolised. Therefore, at the end of the study, participants would be using only established oral PrEP, regardless of whether the injectable is found to be safe and effective. It seems reasonable to assume that participants desiring to secure continued access to oral PrEP could do so. Given these complexities, especially uncertainty regarding whether the study product could ever be offered at all after the end of the trial, the study team did not discuss PTA to cabotegravir with participant communities before the trial.

Research trials can span many years, often operating in a dynamic drug development and regulatory environment. As trials progress, a medication may be approved for a new use, making it more likely to be offered through regular clinical practice. This was true for a trial investigating the HIV treatment drug Truvada as PrEP. At the beginning of the trial, Truvada was not approved for use as prevention, and no PTA provisions were made initially. While the trial was underway, the medication was approved for prevention and the study team then made efforts to refer participants to the healthcare system as they neared the end of the trial.

Challenges also arose in planning for PTA before a product had gained regulatory approval for any purpose. In a trial investigating whether Suboxone as opioid substitution therapy along with counselling would reduce HIV incidence in people who inject drugs at sites in China and Thailand, Suboxone was not approved for any use in either country. The pharmaceutical manufacturer, however, had given some assurance that it would be willing to provide the drug to participants post-trial, if it were shown effective. Although the trial was stopped early for futility with respect to the primary outcome of HIV incidence, the trial team committed to allowing participants who had started opioid substitution therapy to finish it and the manufacturer was willing to provide the medication. Regulatory authorities, however, did not allow sites to import the medication for PTA in China. Moreover, trial sites had been established specifically for the trial and did not have the capacity to continue to administer Suboxone without the trial funding. As a result, participants were not able to continue Suboxone and were instead transitioned to methadone treatment centres for opioid substitution therapy.

This experience raises a question of how uncertainty ought to influence the PTA planning process. Considering PTA at the very beginning of a trial may create opportunities for PTA that would not be possible if all planning is put off until the availability of the product is more certain. For example, designing a trial to be conducted within existing care infrastructures may eliminate the need to transition participants elsewhere for PTA. For trials that cannot be conducted within existing care infrastructures, developing PTA plans early on might allow the research team to devote more time and resources to supporting participants’ possible eventual transition than if planning is delayed until near the end. Discussions held early and under conditions of high uncertainty, however, would need to avoid encouraging the therapeutic or preventive misconception or otherwise unduly raising participants’ hopes about the effectiveness of the investigational intervention.

Furthermore, because the regulatory environment and other contextual factors relevant to PTA for a given trial can change over time, requiring a specific PTA plan to be in place at the beginning of a study may not suffice. Rather, PTA considerations may need to be revisited throughout the trial and revised as the health system evolves and the likelihood of availability of particular interventions outside the research setting changes. Among the HPTN trials, there were different approaches taken under conditions of uncertainty: some trials made a commitment knowing that specific implementation mechanisms would have to be worked out later, while others opted not to make commitments with high uncertainty about the effectiveness and likely availability of the investigational product in the health system. Thus,further guidance may be needed to clarify when and to what extent uncertainty ought to limit PTA commitments.

The influence of healthcare professionals

PTA can also be influenced by healthcare professionals. When seeking Truvada PrEP from a healthcare professional for PTA following HPTN trials, some participants reported feeling stigmatised. Particularly when research trials are investigating HIV prevention interventions for marginalised populations, ensuring that healthcare professionals to whom participants are referred for PTA are welcoming and willing to prescribe a newly approved medication may be important for successful PTA implementation. While stigma will not exist in all areas for all interventions, research participants referred to the healthcare system for a newly approved intervention may be among the first to seek it as part of regular clinical care. Given the potential lag time between a medication’s regulatory approval and its adoption in clinical practice, providing PTA through transition to the local healthcare system may be facilitated by investments in clinician education and efforts to update clinical practice. Yet, it is unclear to what extent, if any, this ought to be a responsibility of the research team. While adopting new approaches in clinical practice will always take time, to what extent should researchers bear the burdens of changing clinical practice? To what extent should research participants bear them? A few of the HPTN stakeholders suggested that research teams could at least enhance their PTA referrals by identifying clinics where participants have reported good experiences. Recent guidance from the Multi-Regional Clinical Trials (MRCT) Research Center clarifies investigators’ post-trial responsibilities, specifying that among investigators’ responsibilities at the final trial visit is, if needed, contacting a treating physician and arranging transition to follow-up care.18

Preparing participants to transition to the healthcare system

The most frequently described challenges in PTA following HPTN trials involved participants’ abilities to navigate a complex healthcare system. While these challenges may have been particularly acute given that participants at risk of HIV infection may also face many social and economic barriers to accessing care, transitioning from a research setting to clinical practice is not necessarily straightforward. Many participants may not have a primary care provider or easy access to a care facility. They may not have the means to pay for services. Even when a medication can be made available at reduced or no cost to participants, there are often ancillary costs, such as those associated with office visits, laboratory testing or transportation to health facilities, that may become prohibitive for low-income populations. Significant time and energy has been spent by HPTN research stakeholders helping participants obtain insurance or enrol in programmes sponsored by pharmaceutical manufacturers to make the intervention available free of charge. Seemingly simple steps such as transmitting application forms and producing pay stubs can be significant barriers; without dedicated resources, study staff may have limited ability to assist participants with these administrative aspects of transitioning to the healthcare system for PTA.

Based on their experiences related to PTA, several HPTN research stakeholders suggested that dedicating staff time and resources to help participants transition into the healthcare system would facilitate their continued access. Other suggestions included integrating preparation for PTA into trial operations, for example, seeking feedback from participants midway through the trial to inform the PTA plan, dedicating time to discuss PTA plans with participants during trial visits or adding a transition period to trial protocols to include specific visits for PTA counselling. While potentially helpful, these suggestions rely on dedicated resources to facilitate the implementation of PTA plans. Again, this raises a normative question for PTA commitments: is it the responsibility of researchers and sponsors only to ensure that all participants have access to effective preventive therapies, or does that responsibility extend further, to ensuring that participants actually receive them?

Current ethical guidelines leave the scope of researchers’ PTA responsibilities unclear. For example, consider the CIOMS guidance claiming that PTA obligations are grounded in a duty to care, supported by the principles of beneficence and reciprocity. One could argue that researchers’ duty to care for participants is met simply by providing any avenue of access. Indeed, the guidance states that at minimum researchers should link participants to an appropriate health service. After referral, ensuring access arguably becomes the responsibility of healthcare professionals rather than researchers, and participants may be said to have no greater or lesser claim on the system than non-research participants.

However, CIOMS guidance also notes that ‘gaps in prevention can have significant impact on the welfare of participants’.19 If it is known that referral alone often does not result in continued access to preventive interventions, then referral is arguably not enough to fulfil an obligation for researchers to safeguard the health of participants, nor does it effectively provide a reciprocal benefit owed to participants for bearing the burdens of research. In such cases, researcher’s responsibilities may extend to the point of ensuring continued access in practice, and greater support for transition planning and implementation may be needed to fulfil PTA obligations.

How far should researchers’ responsibilities extend?

If the scope of researcher’s responsibilities for PTA were to encompass, to some extent, efforts to ensure that participants who wish to continue are actually able to do so in practice, there are significant questions as to the strength of those responsibilities.

The HPTN sometimes encountered challenges related to managing patient preferences about where they received continued access—some preferred the convenience of the closest clinic to their home, while others would trade convenience for anonymity in a clinic far from home. Yet without support for transportation, which many research participants may be accustomed to receiving as part of a research trial, it may not be feasible for all participants to have access to their preferred clinic. Supporting individual preferences may often require resources outside the scope of the trial.

Similarly, transitioning to the healthcare system for PTA can change participants’ experiences of care. In research settings, participants often receive dedicated attention from study staff, have preplanned appointments with little wait time and receive reimbursement of transportation expenses. In clinical settings, participants must cope with the ‘hassle’ of healthcare systems that may be less individually oriented than research settings. This difference in at least perceived quality of care has also been noted in the context of referrals that occur during research trials,20 suggesting that the challenge is not isolated to PTA.

Research stakeholders also reported that trial participants often develop a rapport with study staff and potentially other participants; research trials can create a social dynamic that participants enjoy, and while no stakeholders suggested that PTA responsibilities include maintaining this dynamic, the absence of such a rapport may be a deterrent for participants transitioning to the healthcare systems for PTA.

Conclusion

As PTA becomes more engrained in clinical research, it is important to develop ethical guidance that is responsive to the practical realities of implementing PTA. Experiences with PTA in the HPTN offer valuable insight into the practical demands of developing and implementing PTA plans, as well as suggestions for improving continued access to beneficial trial interventions. While some sponsors, such as the National Institutes of Health, may be prohibited by their institutional mandate from funding activities after a research study is complete, some post-trial preparation activities could be done during a trial. With relatively few additional resources, study teams could dedicate time during study protocol visits to discussing PTA options with participants and identifying potential barriers to access. With greater investment of resources, study sponsors might fund additional staff to support participants in navigating the healthcare system to facilitate PTA. Sponsors might alternatively consider building a transition phase into the research study, so that it becomes part of a research trial and has dedicated resources behind it.

These potential strategies point to an apparent shortcoming of existing guidance: through focusing primarily on the formulation of PTA plans, there is inadequate attention paid to the institutional and structural factors needed to implement PTA plans successfully. In the experiences of the HPTN, lack of resources for transition support and health system disparities that preclude participants from accessing affordable care have hindered the implementation of PTA plans that were in other ways consistent with PTA guidelines. Future guidance should focus more specifically on the roles of research sponsors and governments in transitioning participants to local health system providers, as these actors are better placed than researchers to accomplish such tasks.

Furthermore, open questions remain that call for additional normative guidance on the content and distribution of PTA responsibilities. Under what conditions, if any, is it appropriate to make provisional PTA commitments without knowing precisely how they might be realised? Is referral sufficient to fulfil researchers’ obligations, or ought they to go further and ensure that all those who want to continue can and do—and for how long? Do research stakeholders have any responsibility to counteract prevailing health system inequities where these make PTA less feasible for people who are already disadvantaged? How ought responsibility be distributed among researchers, sponsors, healthcare providers and product manufacturers for the additional support needed to overcome barriers to access? While multiple ethics guidance documents acknowledge that PTA responsibilities are shared by sponsors and researchers, few provide guidance on how those responsibilities should be distributed. The MRCT Center goes farthest in specifying distinct responsibilities for researchers, sponsors and local government health systems, yet there remains a need to specify how research stakeholders should account for structural and institutional barriers that can hinder responsible transition. Though it is likely neither feasible nor within the scope of researchers’ post-trial responsibilities to ‘fix’ the healthcare system, the persistence of structural barriers to access nevertheless undermines the goal of PTA plans. If we are serious about realising PTA commitments, we need to invest in efforts to learn from PTA experiences, measure the success of PTA plans with dedicated follow-up with participants and develop guidance that helps all research stakeholders navigate their post-trial responsibilities through the practical complexities of health systems.

References

Footnotes

  • Contributors AP contributed to conceptualisation of the paper, drafted the follow-up interview guide, conducted follow-up interviews with key stakeholders and drafted and revised the paper. JS conceptualised the paper, participated in the initial large group discusssion on PTA, reviewed and revised the follow-up interview guide and critically reviewed and revised the paper. MWM contributed to conceptualisation of the study, reviewed and revised the follow-up interview guide and critically reviewed and revised the paper.

  • Funding This work was supported by the Hecht-Levi Fellowship Program in Bioethics at the Johns Hopkins Berman Institute of Bioethics; the Johns Hopkins University Center for AIDS Research (P30AI094189); and the HIV Prevention Trials Network (HPTN). Overall support for the HPTN is provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 (HPTN Statistical and Data Management Center), and UM1AI068613 (HPTN Laboratory Center).

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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