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Methodological Challenges in Biomedical HIV Prevention Trials 7 Site Preparedness Once the decision has been made to undertake a late-stage trial to evaluate a biomedical HIV intervention, the next step is to begin developing the study design and protocol. Key components of this effort include selecting appropriate populations and sites for the study, preparing these sites to participate in the study, and involving the community in developing the protocol and facilitating recruitment and interaction with study participants. In considering potential study sites, investigators must address a number of issues, including (1) whether the community could eventually benefit from the planned intervention if it proves to be effective; (2) whether the goals of the trial are consistent with the long-range needs and priorities of the community and the local and national government; (3) whether there is sufficient community support for hosting a study; and (4) whether the site, with adequate preparation, can identify an appropriate number of participants matching the study’s target population, and is likely to meet other criteria, such as a high enrollment-to-screening ratio and a high rate of product adherence and retention. Once a specific site is selected, it must be readied for participation in the trial. This work includes developing the needed human capacity, physical infrastructure, and regulatory processes, and performing pretrial research—sometimes simultaneously. The costs and resources needed to complete these steps can be substantial. However, sponsors, investigators, and the community must make the necessary investment to prepare sites for a successful trial. Because the resources required to do so are often enormous, donors,
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Methodological Challenges in Biomedical HIV Prevention Trials investigators, and communities should discuss long-term plans for the site once a trial is completed. Specifically, they need to consider to what extent the physical infrastructure and human capacity developed at a site can contribute to other research or activities that can bolster the health of the community, and who will help ensure that such long-term plans are realized. This chapter addresses the issues that arise in preparing a site for a late-stage biomedical HIV prevention trial. The published literature on site preparedness focuses largely on HIV vaccine studies and participants’ willingness to participate in them (see, for example, Dhalla et al., 2007). Fewer studies address site preparedness methods for nonvaccine biomedical HIV prevention studies. The committee therefore draws on its collective experiences, information gathered during visits to clinical trial sites in Africa (see Box 7-1), and those of other researchers to outline problems encountered in preparing a site for an HIV prevention trial, solutions devised to address them, and lessons learned to assist sponsors and investigators of new trials (see for example, Francis et al., 2003; Maziak et al., 2004; Cutts et al., 2006; Rerks-Ngarm et al., 2006; Skoler et al., 2006; NIMH Collaborative HIV/STD Prevention Trial Group, 2007a,b,c; Ramjee et al., 2007a,b; UNAIDS and AVAC, 2007; Van den Broeck et al., 2007). (See Chapter 8 for a critical aspect of site preparedness: estimating HIV incidence in a site’s catchment area.) The committee’s charge specifically excluded other challenges in site preparedness. These include best practices for engaging community members in preparing for a trial, treatment for participants who become HIV-infected during a trial, compensation for participants who experience trial-related adverse events, and informed-consent procedures. Although this report does not address these complicated and sensitive issues, additional work is needed to reach consensus on how to address them when planning a late-stage HIV prevention trial. DEVELOPING CAPACITY AND INFRASTRUCTURE The HIV prevention research agenda requires access to large study populations in settings with the capacity to conduct a wide range of clinical trials. Late-stage HIV prevention trials typically occur in areas with a high incidence of HIV, yet these areas often have the fewest resources and the most limited medical and research infrastructure (Ramjee et al., 2007a). The lack of infrastructure, expertise, and capacity to conduct clinical trials in resource-poor settings has been a significant constraint across many arenas, including testing vaccines for malaria and other diseases, preventing and treating cardiovascular disease, and improving maternal-child health, (Developing country trialists, 2006; Rojas et al., 2007; Stough, 2007).
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Methodological Challenges in Biomedical HIV Prevention Trials BOX 7-1 Themes from Committee Site Visits Committee and staff members conducted informational visits to nine HIV prevention trials in Uganda and South Africa, including those studying microbicides, male circumcision, and HSV-2 suppression. Besides talking with study staff and trial participants at those sites, the committee also consulted other stakeholders, such as community representatives and staff from health ministries. Study staff noted that they had significantly underestimated the length and cost of the process needed to develop a study protocol and gain approval from an IRB. Investigators also reported that they had underestimated the time required for site preparation and staff training. Several other recurring themes and observations arose during these discussions (all sites did not raise all issues): The involvement of local investigators and staff in developing the research protocol varied by site, and tended to be greater in pre-phase 3 studies, such as feasibility studies. Staff members requested more equal partnerships at all stages of protocol development and trial conduct. Staff at several sites discussed the importance of engaging trial participants in social and informational events, such as “town meetings” and peer support groups. Such events provide a forum for airing common concerns, disseminating information, and providing feedback to study staff on trial conduct, and to participants on trial progress. Such events also help empower participants and foster ownership of trial conduct and outcomes. Participants’ reasons for joining trials include reimbursement, access to better medical care, access to microbicide gel as lubrication and thus better sex, and Human Capacity To be successful, late-stage HIV prevention trials require a well-trained and coordinated study team that includes laboratory managers and technicians, pharmacists, data and information technology staff, regulatory personnel, research nurses, HIV counselors, home visitors, social scientists, physicians, and others. The lack of personnel in developing countries who are trained or experienced in conducting clinical trials is repeatedly cited as a major limitation (Initiative on Public-Private Partnerships for Health, 2002; Vardas et al., 2005; Excler, 2006). Research units often must invest significant resources in developing specially trained personnel to conduct HIV prevention trials (Nchinda, 2002; Lehner et al., 2005). Senior investigators with the expertise to complete a trial successfully are particularly critical. However, few experienced senior-level investigators
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Methodological Challenges in Biomedical HIV Prevention Trials the desire to help prevent HIV. Staff and community representatives expressed concern that participants may overlook potential risks given these benefits. Trials must devote significant resources and effort to retain participants. Key factors include developing a trusting relationship with participants and supporting their other nontrial concerns. Providing services such as medical care, counseling, and social support also improves retention. Study staff recommend relying on peer leaders to provide support to trial participants, as well as to collect information on their sexual behavior and adherence, as participants may be more likely to give truthful responses to peers than to health professionals. Providing family-planning services onsite reduces pregnancy rates. Shorter follow-up of participants would enable trials to decrease pregnancy rates, as it is difficult for young women to delay getting pregnant for several years. Staff members expressed concern that providing hormonal contraception might encourage participants to stop using condoms. Many couples use condoms primarily as a mechanism for family planning, and not to protect themselves from HIV infection. Community members and staff at some sites also expressed concern about excluding women who become pregnant. Given the large number of clinical trials under way in close proximity, study staff expressed concern that participants will enroll in multiple studies. Some potential participants lack enough information to distinguish different HIV prevention trials. Media play an important role in disseminating both correct and incorrect information. Trials need to appoint a community liaison to educate people about the trial and correct misinformation. Community members, media, and government officials alike need more research literacy. Health ministries need research and assistance in translating effective trial results into larger-scale programs. may be available in an area, and they may be overburdened with other responsibilities. Successful trials therefore require the full-time commitment of junior investigators, who may have more time to dedicate to a trial even if they lack some experience (Initiative on Public-Private Partnerships for Health, 2002). A training and mentoring system that enables junior investigators to learn from more senior investigators—onsite and internationally—will help expand the local capacity for independent investigation (Nchinda, 2002; Maziak et al., 2004). Several successful programs have targeted medical and postgraduate students for training to build research capacity. These programs mentor such students by involving them in small studies, allowing them to learn basic research skills and potentially motivating them to perform research during their careers (Maziak et al., 2004; Wallis et al., 2007). Developing and supporting a culture of research at local universities and medical and nursing schools can provide the basis for further training.
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Methodological Challenges in Biomedical HIV Prevention Trials Given the limited number of physicians available in many settings, greater use of research nurses to perform a wide variety of activities, including coordinating a study, may be an efficient and cost-effective approach. However, nursing programs in the developing world may not routinely train students to conduct research or address research ethics. Only a few trials and training programs now train nurses to coordinate research (Edwards and Roelofs, 2007). Developing countries often lack personnel with training and experience in data management and analysis and information technology (Acosta et al., 2007; Van den Broeck et al., 2007). This is particularly true for well-trained, experienced biostatisticians, who are critical to designing clinical trials, writing study protocols, and analyzing results. Given the growing complexity of electronic media and database management, training site personnel in setting up and maintaining computer hardware and software, database management, including designing instruments for collecting data, and quality control systems is also essential. Even if large, multicenter trials rely on offsite data management centers, investigators must develop the capacity of local personnel to track participant visits, identify missing participants for immediate tracing, track specimens, monitor lab test results, manage pharmacy systems, and manage an administrative database and financial accountability. These efforts must be compliant with Good Clinical Practices, include the requisite documentation, and require oversight by well-trained personnel. Establishing and maintaining a trial site also requires additional administrative and coordination expertise (Chandiwana and Ornbjerg, 2003; Maziak et al., 2004; Lehner et al., 2005). This expertise includes personnel trained in project administration, finance and grant management, human resources, and facilities management. The National Institute of Child Health and Development’s International Extramural Associates Program provides training and support in some of these areas. A comprehensive approach to training is required to build the long-term, sustainable, and independent research capacity to rapidly mount large-scale HIV prevention trials in developing countries. One example of such a training program is the National Institutes of Health’s Fogarty International Center, which builds the capacity of low- and middle-income countries to conduct research in a variety of health arenas (Kupfer et al., 2004). Links between Fogarty AIDS International Training and Research Programs and in-country HIV research units have allowed trainees to immediately use their skills to benefit research units at home (Orem et al., 2005). This one program, however, only meets a fraction of the need for training. Creating long-term research capacity in developing countries will require investing in master’s and doctoral training programs (Nchinda, 2002; Maziak et al., 2004). Regional programs—such as “summer insti-
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Methodological Challenges in Biomedical HIV Prevention Trials tutes” in epidemiology, training provided during clinical trials, and south-to-south training, wherein research units or institutions in developing countries train and mentor less experienced units—can also be effective in enhancing human capacity (Nchinda, 2002; Maziak et al., 2004). Public-private partnerships and research networks have also provided some local, regional, and international training in areas such as Good Laboratory Practices, Good Clinical Practices, ethics, managing investigational products, and laboratory procedures (Nchinda, 2002). Such efforts include the International AIDS Vaccine Initiative, European and Developing Countries Clinical Trials Partnership, and the clinical trial networks created by the Division of AIDS of the National Institute of Allergy and Infectious Diseases. Physical Infrastructure Physical infrastructure includes adequate facilities for recruiting, screening, and following study participants; providing pharmacy services for the trial interventions and concomitant care; ensuring reliable laboratory services; and managing data. New research sites usually require significant up-front investment in all of these areas. Sites also need the transportation capacity to travel to the homes of participants who miss visits to the study clinic (Nchinda, 2002; Cutts et al., 2006; Van den Broeck et al., 2007). Sites that enroll a large number of participants from a large catchment area may need to establish satellite clinics, in addition to the main clinic, to facilitate study visits for study participants from far away. Clinics should have enough private, comfortable space to allow participants to speak freely during HIV testing and counseling sessions, as well as during sensitive discussions of risk behavior. Inadequate attention to the space available will lead to overcrowded clinics with long waiting times, which may discourage participants from returning for scheduled visits. Research budgets often overlook or do not support the significant costs of providing basic services to a trial site, such as installing and maintaining a stable supply of electricity and water, phone services, plumbing facilities that can adhere to sanitation standards, a system for safely disposing of biohazard wastes, and security. For example, U.S. federal funding for studies abroad does not cover the costs of running a facility, although it does fund a site’s efforts to comply with public policies, such as those that ensure ethical treatment of human subjects. If local institutions cannot reliably provide these services, sponsors and investigators must include the substantial costs of providing them in their research budgets. Another critical component of physical infrastructure is a research pharmacy that can handle blinded study products according to Good Clini-
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Methodological Challenges in Biomedical HIV Prevention Trials cal Practices (GCP), with enough space to store and maintain the products in a temperature-controlled setting. In areas of unstable power, this includes access to continuous power backup and stabilization, and a system of alarms that will alert study staff to a temperature problem 24 hours a day (Cutts et al., 2006). Most HIV prevention trials require laboratory tests to evaluate primary endpoints such as HIV status, and to monitor the toxicity of the study product. Yet adequate labs that use Good Laboratory Practices, and have the ability to provide testing that meets those standards, are commonly limited or unavailable at potential sites (Lehner et al., 2005). Deficiencies in laboratory performance can lead to unreliable results, an inability to analyze or use data, or even suspension of the trial or site (Shetty et al., 2003; Peterson et al., 2007). Investigators therefore need to consider the proximity of a capable laboratory to the research clinic, and its ability to rapidly process tests of participants’ HIV status and overall health. Trials also need capacity to store laboratory reagents and large numbers of study specimens (Lehner et al., 2005), a computerized system for identifying and tracking specimens (Van den Broeck et al., 2007), and a reliable system for specimen shipping according to International Air Transport Association guidelines, as well as appropriate material transfer agreements. Bringing local laboratories up to the standards required for clinical trials often requires significant initial and continued technical assistance and oversight. The ideal approach is to develop high-quality laboratories that are self-sustaining through income from tests, and that are capable of supporting a wide range of research and care, both locally and regionally (Chandiwana and Ornbjerg, 2003). Modern information technology and data management capabilities, including computer resources and Internet links, are also essential for late-stage HIV prevention trials, to ensure effective communication and the ability to rapidly and accurately enter, analyze, and transmit data and report adverse events (Nchinda, 2002; Lehner et al., 2005; Van den Broeck et al., 2007). In many developing countries, Internet services may be limited, unreliable, or, if present, costly to establish and maintain. Research budgets need to reflect the resources required to set up and sustain these services. Efforts to fulfill these demanding requirements are usually costly and time and labor intensive, regardless of whether investigators rely on infrastructure at a separate research facility or upgrade local public health facilities to take on these activities (van de Wijgert and Jones, 2006). For a study to succeed, any infrastructure investments must occur up front, as part of site preparation.
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Methodological Challenges in Biomedical HIV Prevention Trials Regulatory Infrastructure Trials also need infrastructure beyond the specific study site. For example, investigators must assess the capacity and regulations of local organizations such as institutional review boards (IRBs), ethics committees (ECs), national drug authorities, ministries of health, universities, and other scientific and research advisory bodies. Studies funded by the U.S. government must ensure that a local IRB registers with the Office of Human Research Protections of the U.S. Department of Health and Human Services, and that the IRB adheres to international standards of study review. IRBs and ECs must have formal systems for conducting an initial comprehensive review of the research protocol, annual reviews, and real-time reviews of serious adverse events, and for documenting those reviews. The local IRB/EC must also have the proper membership, training in research ethics, regulations, and methodology, and adequate support to conduct these activities in a timely fashion. Trials may further require an institutional biosafety committee (IBC), depending on the product being investigated and the funding agency. Few developing countries have an existing IBC with the capacity to oversee human trials. Both IRBs/ECs and IBCs must include members who are familiar with the local setting and represent the communities from which the trials are recruiting. The lack of a knowledgeable and suitable IRB/EC can significantly delay or even prevent HIV prevention research, as has occurred at several research sites in developing countries (Vardas et al., 2005; Kass et al., 2007). If a potential site lacks this regulatory infrastructure, investigators may consider several options. An approach that usually provides the greatest long-term benefit to the community and country is to provide training and resources to enable an existing IRB to meet international review standards. If that is not possible, investigators should explore alternatives, such as creating or using a central IRB with representatives from countries involved in the trial, or inviting members of the local lay and scientific communities to join an existing IRB or IBC of the sponsoring institution or country. Other agencies may also regulate the conduct of clinical trials, including the U.S. Food and Drug Administration (FDA) or European and in-country drug authorities (e.g., the Medicines Control Council in South Africa). Assessment of the site infrastructure must therefore include an evaluation of a site’s ability to meet all the requirements of these agencies. This often presents a challenge and can cause significant delays for multicenter trials with multiple layers of review in each participating country (NIMH Collaborative HIV/STD Prevention Trial Group, 2007a).
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Methodological Challenges in Biomedical HIV Prevention Trials Recommendation 7-1: Donors and investigators should invest in the human capacity and physical infrastructure needed to ensure successful HIV prevention trials in resource-poor settings. These efforts should include a comprehensive and realistic assessment of how to prepare a site, a training plan for staff, and a mentoring plan for inexperienced investigators. Recommendation 7-2: If the regulatory infrastructure of a planned study site is insufficient, study sponsors, funding agencies, research organizations, and other stakeholders should assist local IRBs in developing the ability to provide comprehensive and timely oversight of clinical trials according to international standards. PROTOCOL DEVELOPMENT Developing a trial’s protocol requires an extensive process to address scientific, regulatory, and logistical issues. These include creating informed-consent documents, procedures for screening and enrolling subjects, counseling strategies, case report forms, study evaluations, and visit schedules. Because the sociocultural context influences participants’ behavior and willingness to participate in trials, it is vital that investigators and sponsors work collaboratively with local researchers and other members of the community in developing the protocol (McCoy et al., 2005; Rerks-Ngarm et al., 2006). Investigators should engage community members as early as possible in the protocol planning process. As the 2007 UNAIDS and AVAC report Good Participatory Practice Guidelines for Biomedical HIV Prevention Trials notes, “Best practices build in mechanisms for input from both local investigators and communities prior to trial protocol finalization and for participation of local investigators and community representatives on the protocol team” (UNAIDS and AVAC, 2007, p. 23). Protocol development is even more complex when prevention trials include multiple sites within one country, or sites in multiple countries (Excler, 2006). Because sociocultural beliefs, attitudes, and practices vary within and among regions and countries, investigators of multisite trials have the added challenge of recognizing and adapting to these differences across sites while maintaining the integrity of the study design. All these factors require obtaining substantial input from local investigators and community leaders in the regions where a trial will be conducted (McCoy et al., 2005; NIMH Collaborative HIV/STD Prevention Trial Group, 2007a,b). Another challenge for multicenter, multicountry trials is that local IRBs and ECs may require or request information on how investigators will conduct the trial at their site. This information may include details about the study team, the specific population to be studied, how and where
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Methodological Challenges in Biomedical HIV Prevention Trials populations will be recruited, what local laboratories the study will use, and what incentives participants will receive. For one protocol, sites may enroll different populations at different sites (e.g., discordant couples at one site and sexually active women at another), requiring different approaches to recruiting and protecting study participants. Local IRBs need this site-specific information to properly evaluate the protocol in their setting. However, protocols for multicenter HIV prevention trials often do not contain this level of detail on each study site. Some studies have addressed this gap by creating template protocols with common features but allowing each site to insert unique information into particular sections, thus allowing site-specific protocols. In other cases, a single common protocol contains site-specific addenda that provide more detailed information. When only one protocol for a study is allowed, such as for U.S. government-funded projects conducted under a U.S. FDA Investigational New Drug (IND) application, another option is to submit a separate site-specific implementation plan in addition to a common protocol for local IRB review. This can allow for more rapid and thorough local review of multicenter protocols. Particularly for multicenter trials involving multiple IRBs, investigators may revise a study protocol numerous times before obtaining final approval (Musil et al., 2004). This process requires accurate and culturally appropriate translation of informed-consent forms and other participant materials, with the assistance of a trial-specific community advisory board or with outreach to other community groups. In some countries, IRB and other regulatory reviews may take 6 to 9 months (Maggon, 2004). Recommendation 7-3: Sponsors and investigators from outside the trial region should solicit meaningful input from local investigators and community representatives as they develop the study protocol, and throughout the trial. The trial should itself promote equal partnerships between outside and local investigators. PRETRIAL RESEARCH Qualitative pretrial research is critical in developing culturally relevant adaptations of interventions, informed consent, and study procedures; facilitating site selection; and in working closely with a community (Corneli et al., 2007; NIMH Collaborative HIV/STD Prevention Trial Group, 2007b; Vallely et al., 2007). Qualitative research can provide key insights into participants’ behavior and the sociocultural context and other factors that shape it. Investigators have used numerous strategies to collect qualitative data before, during, and after clinical trials, including one-on-one interviews
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Methodological Challenges in Biomedical HIV Prevention Trials with research participants, interviews with key informants outside the study, case studies, focus groups, exercises to map the location of potential participants, direct observation, and rapid ethnographic assessment methods (Corneli et al., 2007; NIMH Collaborative HIV/STD Prevention Trial Group, 2007b). Without such research, investigators would have overlooked important aspects of many trials and jeopardized their implementation (Corneli et al., 2007). Pretrial research can also be critical to more accurately determining key attributes of study participants, and thus the power and interpretability of the trial results. For example, pretrial studies can estimate HIV incidence in the study population (see Chapter 8), likely product adherence, pregnancy rates, and accrual and retention rates (see Chapter 2). Failure to accurately estimate these factors can lead to failed trials, or trials that yield equivocal results. Researchers have found pretrial research to gain more precise estimates of these factors critical in overcoming some of the challenges of conducting microbicide and other clinical trials in developing countries (Ramjee et al., 2000). Preparedness studies can also be useful in refining a number of processes important to a successful study. Such studies can be used to identify gaps in staffing or training, to develop procedures for running the research clinic smoothly, to improve the informed-consent process and materials, and to evaluate product acceptability. Investigators could use a similar approach to test their system for monitoring and reporting adverse events, and to gauge the capacity of the IRB to perform timely reviews. Recommendation 7-4: Donors should fund and investigators should undertake extensive pre-trial research to develop accurate estimates of HIV incidence, participant accrual, retention, and pregnancy rates, and to develop and evaluate logistical and regulatory processes to be used during the trial. ENSURING SUSTAINABILITY In light of the extensive efforts required to prepare a site for an HIV prevention trial, and the need for further HIV prevention trials in any given study area, funders and investigators need to consider sustaining site capacity beyond the needs of a given prevention trial. In most cases it is cost inefficient and not in the community’s best interest if investigators go to great lengths to prepare a site for a trial, only to shut down the site after completion of the trial. Creating a sustainable research infrastructure that can be used for other studies can provide long-term benefits to the community even if the current trial fails to show a protective benefit (Nchinda, 2002; Lehner et al., 2005;
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Methodological Challenges in Biomedical HIV Prevention Trials McCoy et al., 2005). Long-term research units may provide HIV testing and counseling services as they determine whether people are eligible to participate in a trial, expand the number of local health care personnel, and establish laboratory and radiological services accessible to the whole community. Unfortunately, some trial sites have been shut down after a single trial. The result is a substantial loss of knowledge and experience. More important, this can be very discouraging to investigators and staff who have invested considerable time and effort in conducting a trial, as well as to the participants and the community. This type of disappointment may jeopardize community support for other HIV prevention trials and types of research. Advance planning, and the flexibility to address other questions in the context of an HIV prevention trial, may decrease the need to shut down a new research unit in the face of negative results. Recommendation 7-5: When considering a new trial site that requires extensive preparation, investigators, sponsors, and community leaders should discuss and carefully consider how the site could be sustained after completion of the trial. If investigators or donors do not expect the human capacity and site infrastructure to continue beyond the planned trial, the committee questions the value to the community of the investment in preparing a new site. Sponsors have established many HIV-related research networks and local cohorts of potential trial participants over the last decade, with the goal of expanding the capacity to conduct HIV prevention and treatment trials in both the developed and developing world (Brown and Nitayaphan, 2004). The expected benefits of such “pluripotent” research sites include consolidation of resources and shared efficiencies across trials (Nchinda, 2002; Lehner et al., 2005). The creation of research centers of excellence—with the infrastructure and capacity to conduct studies across disciplines and diseases—is an ideal mechanism to leverage financial support from a variety of sources, take full advantage of an investment in site development, provide job security for investigators and staff (who can then commit to careers as “clinical trialists”), and maintain community support (Nchinda, 2002; Chandiwana and Ornbjerg, 2003; Lehner et al., 2005). Recommendation 7-6: Given limited funding and the extensive investment required to prepare research sites, donors and investigators should explore creative and flexible collaborations with HIV and non-HIV trial networks, health organizations, and local research units that have
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