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Methodological Challenges in Biomedical HIV Prevention Trials Summary ABSTRACT: This IOM committee was formed at the request of the Bill & Melinda Gates Foundation and charged with addressing methodological challenges in late-stage nonvaccine biomedical HIV prevention trials with a specific focus on microbicide and pre-exposure prophylaxis trials. A near-perfect biomedical intervention for preventing HIV infection is unlikely to be available in the near future. This underscores the need for late-stage clinical trials of biomedical interventions that can detect and quantify modest intervention effects on HIV infection, and adequately evaluate product safety. The committee’s key recommendations for pretrial research and planning include the following. Estimating HIV incidence is critical to determining the size and duration of a late-stage trial and should be based on direct longitudinal follow-up of individuals in the planned trial site(s), and corroborated by at least one other source. Investigators should also undertake pretrial assessments of a product’s potential effects on pregnant women and their fetuses to determine circumstances in which women who become pregnant during a trial might continue to use the study product. Investigators should place a high priority on developing effective strategies to achieve accrual targets, retain participants, and improve adherence to study products. The committee underscores the need for sponsors to adequately invest in trial site capacity (human, physical, and regulatory) and develop sustainability plans so that a trial site can continue to contribute to the community and other research studies after the trial is completed. Late-stage trials designed to evaluate biomedical interventions should incorporate randomized comparisons of behavioral interventions when pos-
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Methodological Challenges in Biomedical HIV Prevention Trials sible. Other important design recommendations include: using endpoint-driven trials; considering inclusion of both blinded and unblinded control arms in future trials; collecting information for evaluating the effects of biomedical interventions on women who become pregnant during a trial and their fetuses; and selecting methods for evaluating product adherence and risk-taking behavior. Key recommendations for conducting late-stage HIV prevention trials include monitoring the evolving results of a trial to ensure that it is maintaining the best interests of participants, adjusting the trial to improve adherence or other aspects of the study protocol, and using safety information that may become available from external sources. Recommendations for analyzing trial results include using participant adherence in evaluating the relationship between interventions and HIV risk; the practice of excluding results from participants judged to have been already infected at the time of enrollment, and accounting for product discontinuation due to pregnancy in the analysis of the risk of HIV infection. Finally, in order to enable more efficient evaluations of biomedical interventions, the committee recommends that researchers give priority to developing biomarkers of recent HIV infection which can be used in cross-sectional samples to estimate HIV incidence rates, identifying surrogate markers for HIV infection and product activity that investigators can reliably use as intermediate trial endpoints, and exploring alternative trial designs that might answer important research questions more efficiently than the traditional two-arm superiority design. In the more than 25 years of the human immunodeficiency (HIV) epidemic, significant strides have been made in identifying effective HIV prevention interventions. Early successes included biomedical interventions, most notably those that led to dramatic increases in safety of the blood supply (IOM, 1995) and the prevention of mother-to-child transmission (The International Perinatal HIV Group, 1999; Bulterys et al., 2004). Some behavioral interventions and voluntary testing and counseling interventions have also been shown to reduce reported sexual and injecting risk behaviors and non-HIV sexually transmitted infections (STIs), although none has been shown to reduce HIV infection (Auerbach et al., 2006). Treatment for injecting drug users and programs providing access to sterile injecting equipment can also decrease the risk of HIV infection in drug users (IOM, 2007). Condoms remain a vital prevention technology. When used correctly and consistently, condoms can reduce HIV infection risk by 80–90 percent (Weller and Davis, 2002; Kajubi et al., 2005), though in practice they are often not used to their potential. Most recently, three
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Methodological Challenges in Biomedical HIV Prevention Trials BOX S-1 Biomedical Approaches to HIV Prevention Tested in Late-Stage Efficacy Trials Male circumcision, or removal of the penile foreskin, has been shown to reduce the risk of HIV infection in men. Microbicides are topical substances applied to the vagina or rectum that can potentially prevent HIV. Pre-exposure prophylaxis (PrEP), employing antiretroviral drugs used for HIV treatment, may help prevent HIV infection. Cervical barriers were hypothesized to protect women from HIV by covering the cervix and blocking the upper genital tract, which is more vulnerable to HIV infection. Suppression of HSV-2, the primary cause of genital herpes, may help reduce sexual acquisition and transmission of HIV. Vaccines may enhance the body’s immune defenses to prevent HIV infection. SOURCE: Global HIV Prevention Working Group, 2006. randomized, controlled trials found that male circumcision reduced the risk of heterosexually acquired HIV infection among men (Auvert et al., 2005; Bailey et al., 2007; Gray et al., 2007). Yet the epidemic continues to take a terrible toll. With an estimated 2.5 million new HIV infections occurring globally each year (UNAIDS, 2007), efforts are urgently needed to better utilize existing effective HIV prevention strategies and to identify new ones. Because of the large number of women who become infected under circumstances not under their control, the need for additional women-controlled methods of prevention is vital. Researchers are currently testing or have recently evaluated a variety of biomedical HIV prevention interventions in late-stage clinical trials.1 These interventions include vaginal microbicides, pre-exposure prophylaxis (PrEP) using antiretroviral drugs, suppression of genital herpes (HSV-2) with acyclovir, cervical barriers, male circumcision, and vaccines2 (see Box S-1). These strategies primarily target sexual transmission of HIV, which accounts for the vast majority of new infections, although PrEP and vaccines may also help prevent HIV infection in populations at risk through other avenues, such as injecting drug use. Yet many recent trials have had disappointing results. Late-stage trials 1 Late stage trials of behavioral interventions are also underway but are not the focus of this report. 2 Vaccine trials are not covered in this report.
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Methodological Challenges in Biomedical HIV Prevention Trials have failed to demonstrate a benefit in reducing HIV infection risk, including a phase 3 trial of the diaphragm and Replens gel (Padian, 2007) and two phase 3 trials of HSV-2 suppression with acyclovir (Watson-Jones et al., 2007; Celum et al., 2008). Two vaginal microbicide trials (of N-9 and cellulose sulfate [CS]) were halted because of evidence that they may have a harmful effect (Van Damme et al., 2002; Van Damme, 2007), and a separate trial of CS was stopped as a precautionary measure based on evidence from the other CS trial (Cates, 2007). Several PrEP trials were prematurely closed or canceled because of ethical concerns raised by advocates, governments, and community members. One PrEP trial and two microbicide trials in (Savvy in Ghana and Nigeria) did not have sufficient power to determine efficacy of the intervention (Peterson et al., 2007a,b). In addition, two trials of an HIV vaccine were recently stopped based on a lack of evidence of benefit and concerns that the vaccine might also increase HIV infection risk.3 It was in this context that the Bill & Melinda Gates Foundation asked the Institute of Medicine (IOM) in November 2006 to convene a committee to examine the methodological challenges facing late-stage biomedical HIV prevention trials (see Box S-2 for the Statement of Task). The sponsor clarified that the committee’s review should cover late-stage nonvaccine biomedical HIV prevention trials, with a focus on microbicide and PrEP trials. The committee did not review vaccine or mother-to-child transmission trials. However, the committee did consider the role of risk reduction counseling in biomedical prevention trials (see Chapter 3). This report recommends a number of ways to improve the design, monitoring, and analysis of late-stage randomized clinical trials that evaluate nonvaccine biomedical interventions to prevent HIV infection. The goals are to increase the chances that these trials will detect a beneficial intervention effect and better quantify the effect size, to more fully assess the effects of using an intervention on behavior and how this and product adherence might influence effectiveness in preventing HIV infection, and to reduce biases that can lead to false positive trial results. Another goal is to allow early termination of these trials, if warranted by their interim results or external information. Below the committee highlights its key recommendations (see Box S-3 at the end of the chapter for a complete list). Where possible, the committee recommends investigators consider alternative trial designs which 3 The STEP study was discontinued based on recommendations made by a Data and Safety Monitoring Board, which concluded that the vaccine neither prevented HIV infection nor reduced the amount of virus in those who became infected with HIV (http://www.avac.org/pdf/STEP_data_release.7Nov.pdf), and possibly might have increased the risk of HIV infection. Based on review of the STEP data, the Phambili study in South Africa was also stopped (http://www.hvtn.org/media/pr/PhambiliSAAVIstatement.pdf).
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Methodological Challenges in Biomedical HIV Prevention Trials BOX S-2 Statement of Task The Institute of Medicine (IOM) will convene a committee to examine methodological challenges in HIV prevention trials. The committee will prepare a report to improve the methodology, design, and conduct of HIV prevention trials, focusing on microbicide and pre-exposure prophylaxis (PrEP) trials, in order to increase their likelihood of success and to enable donors to optimally invest resources. The committee will undertake a study with the following tasks: The committee will review select phase 2 and 3 HIV prevention trials in order to provide an assessment of best practices for site preparedness and estimation of incidence. The committee will make recommendations regarding methodological best practices for microbicide and PrEP efficacy trials. Issues to be addressed include but are not limited to: loss of study power through lower-than-expected incidence and high pregnancy rates; other design considerations such as choice of endpoints and control groups; methods for monitoring the interim results of trials (including adjustments to trial size/duration); pooling of data from trials testing the same product; methods for improving adherence to study regimens and the quality of self-reported behavioral data; and optimizing retention of trial participants. The committee will also consider the ethical issues directly related to methodological issues under study, such as those that might arise during interim monitoring of trials. This study will not address broader ethical issues such as adequacy of informed consent, compensation for trial-related adverse events, access to HIV treatment for seroconverters, and best practices for engaging community members. could offer potential advantages over the traditional two-arm superiority design. EFFICACY VERSUS EFFECTIVENESS TRIALS AND LACK OF A RELIABLE SURROGATE MARKER An initial consideration when designing a clinical trial is whether the goal is to assess efficacy—whether a product works in a tightly controlled setting—or effectiveness: whether a product works in the real world. For HIV prevention trials, in which investigators can only partially control participants’ adherence to the product regimen and risk-taking behavior, this distinction between efficacy and effectiveness can be substantial (Chapter 2).
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Methodological Challenges in Biomedical HIV Prevention Trials Effectiveness trials have historically measured disease outcomes, such as clinical improvement or survival. In contrast, efficacy trials often use intermediate, or “surrogate,” endpoints rather than clinical outcomes—if those surrogates are sufficiently predictive of the clinical endpoint, and if the effect of the interventions on the surrogate predicts its effect on the clinical response (see, for example, Prentice, 1989). This allows investigators to assess interventions in much less time and/or with fewer subjects. For example, HIV treatment trials use viral suppression as a surrogate marker for clinical progression. Both efficacy and effectiveness trials for biomedical prevention interventions must use HIV infection as the primary endpoint, as no reliable marker is available to serve as a surrogate endpoint. This slows research considerably. Moreover, because HIV infection is a relatively uncommon event (compared with other disease outcomes), even in areas with high HIV incidence rates, short-term HIV prevention efficacy trials often need to enroll large numbers of subjects, just as longer-term effectiveness trials do. Late-stage effectiveness trials that evaluate HIV infection offer the opportunity to evaluate potential surrogate markers for HIV infection, and the committee believes that this is a worthwhile secondary goal for these studies. The choice of candidate surrogates must be securely anchored in the knowledge of the pathophysiology of infection, and how the surrogate marker relates biologically to HIV infection. In addition to increasing the time and resources needed to evaluate a new nonvaccine HIV intervention, the lack of a surrogate marker raises another complication. If an efficacy trial demonstrates a reduction in the short-term risk of becoming HIV infected, it may be difficult to ethically justify conducting a subsequent longer-term effectiveness trial that uses a placebo group, even if there remain uncertainties about the ability of the intervention to confer a longer-term protective effect. Similar ethical concerns may affect Phase 2B trials, which follow subjects for similar durations as phase 3 effectiveness trials, but aim to save funds by enrolling fewer subjects, and then conducting a longer trial only if the Phase 2B trial results are sufficiently promising. This situation has led the committee to recommend the following: Although such research is challenging, priority should be given to identifying and validating surrogate endpoints for HIV infection for use in late-stage trials of nonvaccine biomedical interventions. Until a surrogate endpoint is identified, modified trial designs should be used to provide information on both the short- and longer-term benefits of an intervention. In particular, investigators should consider greater use
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Methodological Challenges in Biomedical HIV Prevention Trials of two modified designs—an efficacy study with extended follow-up and a phase 3 trial with stopping rules for futility. The first modified trial design can allow investigators to obtain some information on longer-term effectiveness in an efficacy trial whose main goal is to assess short-term efficacy. The second modified trial design can allow investigators to terminate a longer-term effectiveness trial if an interim analysis shows insufficient evidence of short-term efficacy. The rationale behind these designs is that an HIV prevention product that has efficacy might not be effective in a real-world setting, and that a product that does not have efficacy would likely not be effective in a real-world setting (Chapter 2). ESTIMATING POWER AND SAMPLE SIZE Several factors can adversely affect a trial’s power if investigators do not adequately account for them when calculating a trial’s sample size and duration before the study starts. These include HIV incidence, participant attrition, and the number of participants who discontinue using the study product because of pregnancy or other reasons. Although the committee emphasizes the need for accurate a priori estimates of these factors in calculating the required sample size for a late-stage trial, the committee also realizes that such estimates can be imprecise for a variety of reasons, including both random sampling error and systematic sources of bias. As a guard against inaccurate estimates, the committee recommends the use of “events-driven” trial designs, which follow participants until a prespecified number of subjects become HIV infected, rather than for a prespecified period of time (Chapter 2). CHOICE OF CONTROL GROUP In most randomized trials that test whether a new intervention is superior to the current standard, a double-blind design is highly desirable to help ensure an unbiased evaluation of the relative effect of the intervention. However, the use of a blinded control group in late-stage HIV prevention trials of a biomedical intervention can be disadvantageous if a participant’s knowledge of his/her intervention would affect that person’s risk-taking behavior. In that case, the relative effectiveness observed in the trial might not reflect that seen when the intervention is introduced into the community. Trials that include unblinded arms that more closely mimic the real world could potentially provide more useful results. The committee believes that both blinded and unblinded control arms can provide useful information on the effects of an intervention on risk-taking behavior and the risk of
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Methodological Challenges in Biomedical HIV Prevention Trials HIV infection. Investigators and donors should consider conducting trials that include both control groups (Chapter 2). In some instances, there can be value in identifying alternative interventions that are believed to have similar effectiveness to more standard interventions (such as risk reduction counseling and condom use), but which have other advantages. These advantages could include reduced cost, fewer side effects, or the personal preference of the user. For example, women who find negotiating condom use difficult might prefer microbicides or PrEP. For these settings, noninferiority (or “equivalence”) designs, which aim to identify interventions of similar efficacy rather than aiming to show that one is superior, could be useful (Chapter 10). EVALUATING AND INTEGRATING BEHAVIORAL RISK-REDUCTION STRATEGIES INTO BIOMEDICAL PREVENTION TRIALS In discussions over the past decade about the ethics of vaccine trials, researchers, community representatives, human rights advocates, and ethicists reached broad agreement—based on several ethical principles, including beneficence, autonomy, and justice—that participants in clinical trials of HIV prevention interventions should receive risk-reduction counseling, and access to condoms and other means to reduce their risk of becoming infected with HIV (UNAIDS, 2000). Despite this widespread agreement, considerable uncertainty remains about what the nature and intensity of such interventions should be. Uncertainty about the appropriate prevention standard in biomedical HIV prevention trials stems in part from ethical considerations. For example, should the standard risk-reduction intervention be the one shown to be most effective, regardless of cost or sustainability? The ethical uncertainties are compounded by the lack of definitive findings on the effectiveness of behavioral risk-reduction interventions in many of the resource-poor settings where biomedical HIV prevention trials are conducted. That knowledge gap reflects the fact that studies of behavioral risk-reduction interventions have largely been conducted in the United States, and from the difficulty of extrapolating behavioral risk-reduction interventions shown to be efficacious in one setting and population to settings with different populations, risk behaviors, and sociocultural norms. Finally, although some behavioral risk-reduction interventions have been shown to decrease self-reported risk behaviors, and a few have shown decreases in STIs, none to date have been shown to significantly reduce HIV infection rates. Effective behavioral interventions increase the effectiveness of biomedical interventions and are valuable in their own right. Thus, in light of the uncertainties about the effectiveness of behavioral risk reduction
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Methodological Challenges in Biomedical HIV Prevention Trials interventions in settings where many biomedical trials are being planned, the committee believes that investigators designing biomedical intervention trials should also incorporate randomized comparisons of behavioral interventions into the trials whenever possible (Chapter 3). While doing so would increase the logistical complexity of a site’s responsibilities, finding improved behavioral interventions for reducing HIV risk would provide lasting benefits to the community. One methodological approach to achieving this is to use a partially blinded factorial design (see Chapter 10). Such a design can assess both the relative efficacy of a new biomedical intervention and the comparative effectiveness of different behavioral interventions without an increase in sample size. Other types of trial designs can also make an important impact on the HIV epidemic by attempting to identify ways of using a variety of partially effective interventions more efficiently. These include noninferiority trials, trials utilizing HIV discordant couples, and dynamic designs (which aim to evaluate strategies for using and modifying different combinations of behavioral and biomedical interventions over time) (see Chapter 10). In addition, investigators should involve behavioral and social scientists, the community, and other stakeholders, in the early planning stages of a trial, to identify the most appropriate and sustainable behavioral risk-reduction interventions for use in that community, and to most efficiently plan their implementation. If a trial will adapt specific interventions shown to be effective in other settings, investigators should field-test the strategies during the planning of the trial, to ensure that they can be implemented as envisioned. PREGNANCY Many late-stage biomedical HIV prevention trials are conducted among sexually active women of reproductive age in areas with high fertility rates. Despite intensive counseling on family planning, and provision of or access to contraceptives, a large percentage of women enrolled in biomedical HIV prevention trials become pregnant. Trials testing new products and devices (or new indications of existing drugs) typically restrict pregnant women from enrolling and take women who become pregnant during the trial off the product, either permanently or for the duration of their pregnancy, based on concerns about its potential effect on the pregnant woman and the fetus. If a study discontinues product use among participants who become pregnant and no longer follows them for HIV infection, it can lose statistical power. That is, it will be less able to detect any effect of the biomedical intervention, because of the reduced number of women-years of observation. Failing to follow a woman who becomes pregnant for HIV infection can also bias the analyses of a trial’s results. Thus the committee emphasizes
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Methodological Challenges in Biomedical HIV Prevention Trials the importance of continuing to follow pregnant women for HIV infection regardless of whether they discontinue use of the product, and using this information in the analysis of trial results. This will minimize bias, yet such discontinuations will reduce study power. Thus, the committee also recommends ways of calculating the required sample size and duration of a trial to adjust for the anticipated loss of power when an intervention will be discontinued upon pregnancy. An even greater concern is that trials that discontinue product use in women who become pregnant typically do not provide any information about the safety and efficacy of the product for pregnant women and their fetuses. This is important because if the intervention were introduced into the community, many women would continue to use it after becoming pregnant, despite any cautions about its unknown effects on pregnancy. Assessing safety and efficacy in pregnant women after completing a trial is challenging. Because pregnancy is a common occurrence among women who would use a biomedical HIV intervention, it is critical that an overall product evaluation plan include specific and realistic plans for assessing the intervention’s impact on pregnant women and their fetuses. Because of the difficulty of obtaining such information after a successful trial, the committee finds that the current “one size fits all” policy of discontinuing product use upon pregnancy is unnecessary and potentially counterproductive. The committee suggests specific circumstances in which it might be ethical to allow trial participants who become pregnant to continue to use the study product. The committee also recommends that trials collect and analyze information on pregnancy outcomes on all women who become pregnant during a trial, regardless of their study arm or whether they discontinue product use, as this will provide preliminary information on the possible effects of the product on the fetus. The committee further recommends that investigators specify in advance of a late-stage clinical trial how they will establish product safety and efficacy for pregnant women and their fetuses, based on information collected before, during, and after the trial. Investigators should complete reproductive toxicity and pharmacokinetic studies in animals—ideally before the start of phase 2 clinical trials, but no later than the start of phase 2B/3 trials. The study protocol should specify how investigators will collect and monitor information on pregnancy outcomes during the trial, and indicate activities that they will undertake if the trial demonstrates that the product is effective in preventing HIV infection (Chapter 4).
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Methodological Challenges in Biomedical HIV Prevention Trials PRODUCT ADHERENCE AND RISK-TAKING BEHAVIOR The ultimate effectiveness of a biomedical intervention is mediated by how well participants adhere to the regimen for using it, and by their risk-taking behavior during the trial. For example, if a trial shows that a product provides an overall benefit, being able to relate the level of protection to the level of adherence could be very useful in interpreting the results. Similarly, if a trial fails to show a protective effect, it would be valuable to distinguish the extent to which the product was not biologically efficacious, participants did not use it as directed, or they engaged in more risky behavior because they thought the product was protecting them. Although researchers agree on the importance of product adherence in both research and real-world settings, there is less agreement on how to define, measure, improve, and analyze it. Clinical trials often report adherence by a single number, such as the percentage of coital acts in which participants use a gel, or the percentage of pills they take over a given time period (Chesney, 2006). While simple, use of such measures to define adherence may mask crucial insights into adherence problems, product acceptability, and potential areas for intervention (Kerr et al., 2005; Berg and Arnsten, 2006). Because understanding these patterns can be critical to identifying and ameliorating problems with product use, investigators should develop, evaluate, and use adherence measures that can capture different adherence patterns over time. Investigators can gather information on product adherence and risk behavior through a variety of measures. Indirect measures include self-reports, pill counts, electronic product monitoring, pharmacy refills, and biomarkers of product exposure and risk behavior. Direct measures of product adherence include pharmacokinetic studies (which measure drug levels or metabolites in subjects’ blood or bodily fluids), and directly observed therapy. These measures vary substantially in expense, the effort required of participants and their partners, their perceived invasiveness, and their accuracy and reliability (Berg and Arnsten, 2006). Several studies have found that using multiple measures to “triangulate” adherence levels and risk behaviors is helpful in reducing the error introduced by any particular method (Liu et al., 2001; Pool, 2006). The committee endorses this approach. Rather than collecting detailed information on all participants, investigators could collect such information on a well-chosen random sample, and collect less detailed information on other participants. While directly observed therapy (DOT) or modified DOT could be very useful for proof-of-concept trials, investigators should not use these approaches in effectiveness trials if that approach will not work in real-world practice because the trial results may be poor predictors of the effectiveness of an intervention.
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Methodological Challenges in Biomedical HIV Prevention Trials to HIV infection upon product discontinuation owing to pregnancy or other reasons (Chapter 9). In sum, the committee concludes that alternative trial designs, more extensive site preparation, and careful monitoring and analysis of trial results are key to evaluating prevention interventions and determining which of them can exert the greatest possible long-term impact on the HIV epidemic.
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Methodological Challenges in Biomedical HIV Prevention Trials BOX S-3 Findings and Recommendations Chapter 2 Basic Design Features: Size, Duration, and Type of Trials, and Choice of Control Group Recommendation 2-1: Investigators should take steps to develop accurate a priori estimates of rates of participant accrual, HIV incidence, product discontinuation, and participant retention, and incorporate those into the sample size calculations. As a guard against inaccurate estimates, investigators should consider using an “events-driven” approach, by analyzing study results when the prespecified number of enrolled subjects has become HIV infected, rather than at prespecified calendar times. Recommendation 2-2: Until validated surrogate endpoint(s) for HIV infection or product activity is (are) identified, investigators should use modified trial designs that can provide information on both the short- and long-term benefits of an intervention. Recommendation 2-3: Sponsors, investigators, and regulatory agencies should consider using both blinded and unblinded control groups in future trials to more fully understand the effects of the intervention on HIV infection risk and behavior. Chapter 3 Design Considerations: Risk-Reduction Counseling Recommendation 3-1: Given the lack of evidence on the effectiveness of behavioral risk-reduction interventions in settings where many HIV biomedical trials are planned, investigators planning such trials should incorporate randomized comparisons of behavioral risk-reduction interventions into their designs whenever possible. Recommendation 3-2: Donors and investigators should involve behavioral and social scientists in the early planning stages of a trial, to identify the most appropriate behavioral risk reduction interventions, and to efficiently plan their implementation during the trial. Recommendation 3-3: Investigators planning to test behavioral risk-reduction interventions as part of a late-stage biomedical HIV prevention trial should consult with the community, governments, donors, and other stakeholders about the cost and sustainability of those interventions in the community. Recommendation 3-4: If a trial will adapt specific behavioral interventions shown to be effective in other settings, investigators should field-test the strategies during the planning of the trial, to ensure that they can be implemented as envisioned.
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Methodological Challenges in Biomedical HIV Prevention Trials Chapter 4 Design Considerations: Pregnancy Recommendation 4-1: Investigators should take several steps to minimize the loss of study power and potential biases in results that can occur when women become pregnant during a trial: Before the start of the trial, investigators should attempt to accurately estimate the rate of pregnancy that will occur during participant follow-up, and use these estimates in calculating sample size and trial duration. Data monitoring committees should monitor actual pregnancy rates during the trial, and recommend appropriate adjustments to sample size and trial duration if these rates exceed expectations. Investigators should continue to follow all women who become pregnant for HIV infection, regardless of whether they discontinue the study product. Recommendation 4-2: Although the current policy of excluding pregnant women from biomedical HIV prevention and other trials stems from an historically protectionist orientation adopted by regulators, the principles of research ethics neither mandate nor preclude use of the product by pregnant women. Because any approved product subsequently would likely be used by many women who become pregnant, sponsors and investigators of a biomedical intervention should specify in advance of any late-stage trial how they will establish its safety and efficacy for pregnant women and their fetuses, based on information collected both during and after clinical trials. At a minimum, investigators should take the following steps to collect such information. Investigators should conduct appropriate preclinical tests in animals, including reproductive toxicity and pharmacokinetic studies, to allow a more informed decision on whether to continue product use in pregnant women participating in late-stage trials. These tests would ideally be completed before the product or device enters phase 2 testing, but should be completed no later than phase 3 testing. Investigators should routinely collect and analyze information about birth outcomes from women who become pregnant during a trial, regardless of whether a product is discontinued upon detection of pregnancy. In trials that discontinue the use of a product by women who become pregnant, investigators should allow women who are no longer pregnant to have the choice of resuming the study medication. Investigators should conduct observational or randomized studies in pregnant women in the postapproval, premarketing, and posttrial periods, to provide additional information on the safety and efficacy of biomedical HIV prevention interventions for pregnant women. Recommendation 4-3: Regulators, sponsors, and investigators should evaluate the strength of the evidence on the beneficial and harmful effects to both a preg-
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Methodological Challenges in Biomedical HIV Prevention Trials nant woman and her fetus on a product-by-product basis, and evaluate whether there are circumstances in which women who become pregnant can continue to receive the study product, based on what is known about its benefits and risks. Recommendation 4-4: Trials using products with favorable risk-benefit profiles, but which are nonetheless discontinued upon pregnancy, should monitor pregnancy outcomes during the interim analysis of trial results, as this information might alter the risk-benefit profile to allow continuation of the product during pregnancy. Such trials might be modified to thereafter allow women who become pregnant to remain on product or offer them the opportunity to be randomized to remain on product versus to discontinue product. Recommendation 4-5: Regulatory agencies and institutional review boards (IRBs) should receive periodic safety updates during a trial that include experience with the product during pregnancy. When interim analyses provide evidence of fetal safety and potential benefit to women, regulators and IRBs should consider allowing women to stay on product while pregnant. Chapter 5 Design Considerations: Adherence Recommendation 5-1: Because simple measures of adherence can mask substantially different underlying adherence problems, investigators should develop and use adherence measures that can capture different adherence patterns over time. Recommendation 5-2: In light of the uncertainty about the accuracy of various methods for collecting data on adherence and risk behavior, investigators of biomedical HIV prevention trials should strive to use multiple types of measures to triangulate adherence estimates. Rather than collecting detailed information on all participants, investigators could collect more detailed information on a well-chosen random sample, and collect less detailed information on all participants. Recommendation 5-3: Although directly observed therapy (DOT) or modified DOT could be very useful in proof-of-concept trials, investigators should not use these methods in effectiveness trials if that approach will not be used in real-world practice, because the trial results may then be poor predictors of the effectiveness of the interventions. Recommendation 5-4: Donors should fund and investigators should undertake empirical evaluations of strategies to increase adherence to biomedical HIV prevention products during and after a clinical trial. These evaluations should be adequately powered, methodologically rigorous, socially and culturally relevant, grounded in behavioral and social science theories, and conducted in the regions where the strategies will be utilized.
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Methodological Challenges in Biomedical HIV Prevention Trials Recommendation 5-5: Investigators should specify in the study protocol detailed plans for monitoring, measuring, and analyzing adherence data, and steps they will take to improve adherence if it is poorer than anticipated. Recommendation 5-6: Investigators should provide data on product adherence and risk behavior results to the data monitoring committee, as this information may influence the committee’s views of the relative efficacy and safety of the study arms, and the feasibility of the study. Recommendation 5-7: Investigators should analyze adherence and behavior as both outcomes in an HIV prevention trial and modifiers of the effect of the biomedical intervention on HIV infection risk. Recommendation 5-8: Investigators should analyze the potential impact of adherence by doing the following: Perform a stratified analysis when adherence appears similar between study arms. Such analyses aim to provide unbiased comparisons of subpopulations across study arms. Postulate causal models and performing randomization-based analyses. Perform matched case-control adherence analyses involving subjects who become HIV infected. Chapter 6 Design Considerations: Recruitment and Retention Recommendation 6-1: Investigators should conduct pretrial research to assess the community and individuals’ interest in the trial, to pilot test recruitment and retention strategies, and to set a realistic timeline and resource needs for the enrollment period and for retention. Recommendation 6-2: Because of the loss in study power that can result from inadequate accrual and because the potential biases resulting from losses to follow-up cannot be avoided simply by increasing sample size, investigators should place a high priority on developing effective strategies to achieve accrual rate goals and to minimize losses to follow-up. Specifically, investigators should do the following: Develop a detailed and multifaceted plan for retaining enrolled participants before beginning a study for systematically and frequently monitoring the results, and for modifying the plan if strategies are not working. Collect as much detailed tracking information as possible on participants. Develop systems to engage, train, and reward staff for building trust and accountability with participants and within the community, and for meeting recruitment and retention targets. Recommendation 6-3: Funders and investigators should include evaluations of the effectiveness of recruitment and retention strategies in future research plans.
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Methodological Challenges in Biomedical HIV Prevention Trials Chapter 7 Site Preparedness 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. 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. Recommendation 7-4: Donors should fund and investigators should undertake extensive pretrial 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. 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. 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 access to suitable study populations or existing research infrastructure, with cost sharing benefiting both partners. Chapter 8 Estimating HIV Incidence Recommendation 8-1: Investigators should base their estimate of HIV incidence on at least one source of data from the direct longitudinal follow-up of individuals in the trial setting. Given the importance of accurate estimates and the inherent uncertainties of any single approach, the direct estimate of HIV incidence should be corroborated by at least one other source. Recommendation 8-2: Donors and appropriate U.S. and international agencies should make development of a reliable, accurate biomarker-based test for recent
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Methodological Challenges in Biomedical HIV Prevention Trials HIV infection that can be run with blood from a single draw a high priority. They should provide the necessary funding and laboratory resources to conduct a substantial cross-sectional screening program. This will require recruiting subjects from countries with low-level, concentrated, and generalized epidemics during the preseroconversion period and following them for several years. Recommendation 8-3: Although further validation studies are being conducted to examine concerns that the STAHRS and BED tests may produce biased estimates of HIV incidence, investigators should not rely solely at this time on these or other biomarker assays of recent infection to estimate HIV incidence for the specific purpose of designing a prevention trial. Chapter 9 Performing Interim Monitoring and Analyzing Trial Results Recommendation 9-1: The data monitoring committees of trials with sponsors and scientific leaders from outside the host countries should include multiple representatives from those countries. These members—who should compose at least one-third of the committee—should include scientists, ethicists, and lay people familiar with the community and local norms. Recommendation 9-2: The data monitoring committees for HIV prevention trials should always have the option of unblinding interim results if they believe that doing so might lead them to recommend that the trial be modified or terminated, or lead to other actions that are in the best interests of the trial participants. In particular, when the efficacy data show nonsignificant trends favoring one of the blinded arms, a DMC should unblind itself as this might reflect an intervention that may be harming patients. Recommendation 9-3: Investigators should clearly describe in the study protocol the basis and criteria for any recommendation by the data monitoring committee to modify a trial’s size or duration. If such changes are implemented, the protocol should also specify how investigators should evaluate the trial results. Recommendation 9-4: For effectiveness trials, guidelines for stopping HIV prevention trials based on positive interim results should require evidence of a sustained impact on cumulative HIV incidence. Recommendation 9-5: Investigators, donors, and regulatory agencies should encourage research on how to combine safety information from concurrent trials of similar products, including the scientific advantages and disadvantages of sharing information, the timing and logistics of doing so, ethical concerns (such as how such information might affect the informed-consent process), and how to report the results from such trials.
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Methodological Challenges in Biomedical HIV Prevention Trials Recommendation 9-6: Investigators should base their primary analysis of the efficacy of an intervention on all randomized subjects. Secondary sensitivity analyses that exclude subjects believed to have been HIV infected when they were randomized can be useful. However, investigators should not substitute such analyses for the primary analysis, unless such exclusions (and nonexclusions) can confidently be made without error. Recommendation 9-7: Investigators of trials evaluating an intervention that is believed to have a delayed impact may find it efficient to exclude people found to be HIV infected after randomization but before a given follow-up time. If so, the trial protocol should specify and justify such an approach, and investigators should use it only if follow-up of subjects and assessment and confirmation of HIV infection during this period is identical in all study arms. Investigators should undertake secondary analyses based on all randomized subjects. Recommendation 9-8: In all trials, investigators should continue to follow women who become pregnant for HIV infection, regardless of whether they discontinue their study intervention. In addition, intention-to-treat analyses should be the primary basis for comparing intervention groups with respect to HIV infection and other efficacy endpoints. Investigators can include as-treated analyses as secondary analyses, but should interpret them cautiously, because of the possibility that such discontinuations represent a type of informative censoring. Chapter 10 Alternative Trial Designs Recommendation 10-1: Investigators planning late-stage randomized trials of biomedical interventions are encouraged to utilize partially blinded factorial designs in order to also evaluate the relative effectiveness of different behavioral intervention strategies. Factorial designs can provide valuable information about both types of interventions with the same sample size as a trial evaluating only the biomedical intervention. Recommendation 10-2: When feasible and consistent with the scientific goals of a late-stage HIV prevention trial, investigators are encouraged to consider discordant couple designs because of their advantages over designs in which the actual HIV exposures of participants are unknown. Recommendation 10-3: Investigators should consider the potential merits of using noninferiority, cluster randomization, and dynamic designs in future biomedical HIV prevention trials.
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