Brisk progress in HIV therapeutics has been facilitated by well-organized, randomized, controlled clinical trial (RCT) networks developed to test the safety and efficacy of candidate antiretroviral drugs and regimens. The Adult AIDS Clinical Trial Group (ACTG) and the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) networks, both funded by the National Institute for Allergy and Infectious Diseases (NIAID), are the largest HIV clinical trial groups in the United States. However, compared with the high rates of virologic response to highly active antiretroviral therapies (HAART) seen in these HIV RCTs, up to 50% of patients in clinic-based and prospective cohort studies fail to achieve initial or sustained responses to HAART [1–3], with survival reductions in those without durable viral suppression . Differences between trial findings and clinical experience have raised concerns regarding the comparability or generalizability of HIV RCTs to actual patient care (‘real-world') settings.
Selective eligibility criteria for RCTs may limit the ability to extrapolate findings to all groups of patients . In the HIV clinical trial setting, under-representation of women, ethnic minorities and intravenous drug users (IDUs) has been recognized as a persistent problem [5–9]. Although difficulties in recruitment and retention of such groups are often cited for their under-representation, RCT enrollment criteria may set up structural obstacles to equal participation. Complete information on the eligibility criteria and study enrollment procedures for clinical trials will allow HIV clinicians to assess the extent to which trial findings pertain to their patients.
Concerns regarding the generalizability of RCT findings in other chronic disease states, secondary to strict inclusion and exclusion criteria, frequent the literature [10–16]. Moreover, RCT publications may not report the complete methodologic information required to assess the selectivity of trial enrolment [17,18]; less than one-third (28%) of clinical trials report the proportion of participants screened who were trial-eligible per the enrollment criteria . Even fewer provide a comparison of characteristics between excluded and included participants [20–23]. Failure to catalog the full list of eligibility criteria used for trial enrollment in subsequent publications is a topic that is generally not addressed for RCTs. Both barriers to and rates of participation in HIV clinical trials have been reported , but a systematic evaluation of the impact of both published and actual eligibility methods on the generalizability of HIV RCT findings has yet to be performed.
The first major aim of this study was to apply the exclusion criteria of the major ACTG and CPCRA treatment trials to a large observational cohort study of HIV-infected women in order to assess the representativeness of this population in the literature. The second major aim was to look at gaps in exclusion criteria reporting between the original protocols and subsequent journal publications of these trials.
We obtained access to full and updated protocols for ACTG and CPCRA trials through direct contact with study leaders. We examined a total of 32 phase II (efficacy only) and phase III RCTs on HIV management published between 1994 and 2004 (20 ACTG trials [24–43] and 12 CPCRA trials [44–55]), for which both the original trial protocols and journal publications were available (ACTG and CPCRA protocol titles, numbers, and dates included after each cited publication in Reference section). Every major HIV trial from these networks during this 10-year period was included. We then calculated the overall proportion of participants in the largest US-based longitudinal cohort of HIV-positive women who would have been excluded from each RCT based on eligibility criteria in the trial protocol versus criteria in the corresponding publication. We used the Women's Interagency HIV Study (WIHS) cohort for these calculations because it is sociodemographically and racially representative of HIV-infected women in the US [56,57] and because its only exclusion criterion for original enrollment was age less than 13 years.
When applying the eligibility criteria for each trial, we only considered general exclusion and inclusion criteria, such as clinical criteria (patient demographics, concurrent or past illnesses, including opportunistic infections and malignancies, life expectancy, active symptomatology, including malabsorption, and substance use), general laboratory parameters, concurrent medications, and pregnancy/lactation status. We did not include eligibility criteria inherent to a trial's study question or involving history or type of antiretroviral exposure, CD4 cell counts, or HIV viral loads. To further allow the most conservative estimate of excluded women possible, we did not include the risk of pregnancy as an exclusion criterion in trials studying agents not known to be teratogens. Instead, we assumed, along with the authors of most of the HIV RCTs, that two forms of adequate birth control methods could be verified for trial participants. Enrollment criteria for the 32 RCTs were summarized in the manner exemplified for ACTG trial 388  and CPCRA trial 064  in Table 1.
We applied the enrollment criteria listed in the 32 original RCT protocols and subsequent publications to 1717 WIHS participants for which data was available as of April 2003, using historical data when required. To allow a conservative estimate of excluded WIHS participants, if a data point relevant to a particular exclusion criterion was missing or not captured in the cohort database, the assumption was made that the participant would be included in the RCT. To compare the impact of the eligibility criteria listed in the trial publication to the enrollment criteria in the actual protocol, we calculated an ‘exclusion ratio’ for each trial. The exclusion ratio is defined as the number of WIHS women excluded from a trial based on publication criteria divided by the number excluded by protocol criteria. The average of these ratios was then determined for the ACTG trials, the CPCRA trials, and all trials combined.
Description of enrollment criteria
The background eligibility criteria from the protocols and publications were categorized and listed as in Table 1, which illustrates how the enrollment criteria in protocols and publications were compared for one ACTG trial and one CPCRA trial. As appropriate, inclusion criteria were reversed in order to list all the eligibility criteria as exclusion criteria for our analyses. Clinical criteria listed in the original protocols included subjective assessments by the clinical investigator of the candidate's general health or his/her ability to comply with the study protocol. Examples of subjective criteria from various RCT protocols are listed in Table 2 and include statements granting investigators the authority to dismiss trial candidates for presumed non-compliance, medical contraindications or substance abuse. These subjective criteria were listed in the actual protocols for eight ACTG and 10 CPCRA trials, but not one of these criteria was described in the published reports from these trials.
First aim: percentage of WIHS excluded from HIV treatment RCTs
Based on the protocols of the 20 ACTG trials, 28.4 to 67.6% (median 50.6%) of the WIHS cohort would have been excluded from participation per the eligibility criteria (Fig. 1): 20.7 to 62.3% (median 39.5%) excluded based on clinical criteria; 2.0 to 14.9% (median 9.0%) based on laboratory criteria; 0 to 24.8% (median 7.3%) based on medication criteria; and 0 to 2.6% (median 2.6%) based on pregnancy or lactation status. Based on the publications of these ACTG trials, 0 to 62% (median 21.2%) of WIHS would have been excluded from participation based on the listed eligibility criteria: 0 to 55% (median 16.8%) based on clinical criteria; 0 to 14.9% (median 3.7%) based on laboratory criteria; 0 to 20.2% (median 0%) based on medication criteria; and 0 to 2.6% (median 2.6%) based on pregnancy/lactation.
The enrollment criteria for CPCRA protocols were generally less stringent and excluded a lower percentage of WIHS participants than the ACTG protocols. Based on the eligibility criteria listed in the 12 CPCRA trial protocols, 0 to 41.8% (median 16.1%) of the WIHS cohort would have been excluded from participation (Fig. 2): 0 to 36.7% (median 12.9%) based on clinical criteria; 0 to 9.4% (median 4.1%) based on laboratory criteria; 0% based on medication criteria; and 0 to 2.6% (median 2.6%) based on pregnancy/lactation. Based on the criteria listed in the CPCRA publications, 0 to 38.9% (median 13.7%) of the WIHS cohort would have been excluded from participating: 0 to 34.3% (median 10.1%) based on clinical criteria; 0 to 9.4% based on laboratory criteria (median 1.5%); none for medication criteria; and 0 to 2.6% (median 2.6%) based on pregnancy/lactation.
Table 3 illustrates the effects on cohort exclusion for specific clinical, laboratory and medication eligibility criteria frequently employed for HIV trial enrollment. For instance, excluding patients with an ongoing or past history of grade 2 or above peripheral neuropathy (41% of trials) would eliminate 25.7% of WIHS participants and excluding patients with elevated total bilirubin (47% of trials) would eliminate 5.6%. Stratification of the cohort into self-identified race/ethnicities (African-American, Latina, Caucasian and other) revealed no significant race-based differences in the percentage excluded (data not shown).
Second aim: calculating gap in eligibility criteria reporting between protocols and publications
Figure 1 illustrates the gaps in eligibility criteria reporting between protocols versus publications for each ACTG trial. For the ACTG trials, the mean of the exclusion ratios (publication/protocol) was 0.51, indicating that, on average, only half of the women actually excluded by protocol criteria seemed to be excluded based on publication criteria. Based on exclusion ratios, only four (243, 306, 347 and 343) of the 20 ACTG trials listed the full set of enrollment criteria in their subsequent publications. Half of the ACTG trials listed fewer than 50% of the eligibility criteria for the RCT in their publications; 30% (six of 20) disclosed less than a quarter of the actual enrollment criteria in their publications. Of note, eight out of 20 of the ACTG protocols contained subjective, investigator-dependent eligibility criteria (not revealed in publications), for which we could not quantify the percentage of WIHS with potential for exclusion.
Figure 2 shows the same data for the CPCRA trials. A greater proportion of CPCRA trials (seven of 12) listed the full set of evaluable enrollment criteria in the publications, although 10 out of 12 of these trials contained subjective exclusion criteria in protocols that were not disclosed in publications. For the CPCRA trials, the mean of the exclusion ratios (publication/protocol) was 0.75, which means that, on average, one-quarter of the women excluded by actual protocol criteria would have been deemed eligible by publication criteria.
For all the treatment trials combined, the average of the exclusion ratios was 0.60. Therefore, the number of women in the WIHS cohort ineligible for trial participation per publication criteria averaged only 60% of those actually excluded based on the protocols.
Our report examines the background eligibility criteria of 32 seminal HIV treatment RCTs in the ACTG and CPCRA networks to assess disclosure rates of enrollment criteria reporting. Our first major aim, to examine the impact of clinical trial eligibility criteria on the generalizability of trial findings, has been studied for other disease states. Our second major aim was unique in that this study is the first systematic evaluation of gaps in reporting between clinical trial protocols and publications for any clinical condition. To assess the impact of incomplete reporting in major HIV RCTS, we analyzed the percentage of a representative cohort of HIV-infected women who would have been excluded from trial participation based on criteria listed in protocols and publications. We determined that a range of 0 to 67.6% (median 42%) of participants in the WIHS observational cohort would have been excluded from participating in these influential HIV RCTs per the original protocols. However significant disparities in eligibility criteria reporting between protocols and publications were found. A reader referring to methods in HIV trial publications would have underestimated the percentage of WIHS participants actually excluded from these trials (based on protocol criteria) by 40%. Furthermore, 83% of CPCRA trials and 40% of the ACTG trials listed subjective, investigator-dependent, eligibility criteria in the original protocols (Table 2) that were not mentioned in the publications.
Impact of the percentage of WIHS excluded from HIV treatment RCTs (first aim)
Although our work is one of largest such studies in the HIV treatment literature, concerns regarding the generalizability of RCT findings due to restrictive eligibility criteria have been raised for multiple other chronic medical conditions [13,20,58–60], including cancer treatment , lipid-lowering therapy , cardiovascular trials , and depression . One group recently examined the enrollment criteria of the 20 controlled trials that determine the current guidelines for the management of hypertension . When the eligibility criteria for these trials were applied to the general US hypertensive population, it was found that 42.5% of the general population would have been excluded from participation in these trials. These analyses have prompted re-evaluation of the necessity [61,62], and even the ethical implications , of over-rigorous enrollment criteria for RCTs.
As patients are excluded from a clinical trial setting, a progressively smaller subset of the reference population is captured, compromising trial generalizability. Our analysis did not examine the impact of HIV RCT eligibility criteria on the exclusion of HIV-infected men, so we cannot comment on whether enrollment criteria in these HIV clinical trials would have differentially excluded women. Lower participation of women in HIV RCTs has been recognized as a persistent problem in the HIV literature, however; a meta-analysis of 49 RCTs of antiretroviral efficacy in HIV-infected adults performed between 1990 and 2000 found that the proportional mean of women in these trials was merely 12.25%, with just two of the trials able to support any analysis of results by sex . Given that our analysis establishes that over half (median 50.6%) of the largest cohort of HIV-infected women in the US would have been excluded from participating in 20 key ACTG trials based on protocol enrollment criteria, re-examination of these criteria may lead to increased participation of women in HIV RCTs.
The percentage of WIHS participants excluded from the HIV RCTs examined was not secondary to the risk of pregnancy, an oft-cited reason for differential exclusion of women from major treatment trials. Except for studies of known teratogens , these HIV RCTS did not exclude women based on the risk of pregnancy, but rather stressed the requirement for adequate contraception during participation of the trial. We therefore chose not to exclude any women of childbearing potential in the WIHS cohort from the HIV RCTs and found that only 2.6% of WIHS women were either pregnant or lactating at the time of this analysis. Therefore, pregnancy or the risk of pregnancy could not account for the high percentages of WIHS women excluded from ACTG clinical trials based on criteria in the original protocols.
Impact of incomplete eligibility criteria reporting (second aim)
Direct comparison of the effects of applying published versus protocol enrollment criteria for HIV RCTs demonstrated significant differences in the percentage of WIHS participants eligible for trial participation. Incomplete reporting of eligibility criteria may reflect restrictions imposed by the journal format, such as word-count limitations, for the publication of RCT findings. We examined the HIV trial descriptions posted on the NIH clinical trials website (www.clinicaltrials.gov) and found the listing of eligibility criteria to be generally more complete than in publications, but less complete than in protocols (data not shown). Therefore, no publicly available listing of complete selection criteria for HIV RCTs exists. Since most of the HIV RCT publications understate the extent of selection criteria, the reader may believe that study results are more widely generalizable than they actually are. The Consolidated Standards of Reporting Trials (CONSORT) statement in 1996  identifies key information about entry criteria (including inclusion and exclusion criteria), randomization methods, patient follow-up, and outcome determination that should be reported for every RCT publication. Our analysis demonstrates that current reporting of eligibility criteria, at least for these HIV clinical trials, may not be meeting these standards.
Significantly, none of the reports that examine eligibility criteria in RCTs for other disease states [10,11,13–16,20,58–60] assess the disparity between enrollment criteria listed in protocols versus publications. One study did examine the reporting of eligibility criteria in trials that formed the basis of eight ‘Clinical Alerts’ issued by the NIH between January 1988 and September 1994 (including two HIV treatment trials) and found that only 63% of the protocol eligibility criteria were reported in the accompanying journal articles , similar to our proportion of 60%. However, this report did not examine the impact such gaps in disclosure would mean for eligibility of a representative population to participate in the clinical trials, nor did it examine the systematic gap in reporting for a single disease state.
Limitations of our analysis
One limitation of our analysis is that only protocols for NIH-funded HIV RCTs for which publications were available (up to April 2004) could be examined. Newer protocols may have adopted less restrictive exclusion criteria, and full disclosure of protocol eligibility in the future will allow assessment of any such changes. This paper comments on the impact of exclusion criteria on the possible participation of a representative cohort of US women. We are undertaking a comparison between the percentage of participants excluded from WIHS and the male Multicenter AIDS Cohort Study (MACS) to determine if exclusion criteria may eliminate participants differentially by sex. Finally, the self-reported nature of active diseases or symptoms in the WIHS cohort, such as active opportunistic or other infections, or the presence of peripheral neuropathy, may have over-estimated their prevalence, although self-report presumably plays a large role in clinical trial enrollment as well.
Suggestions for improvement
One possible modification to HIV trial enrollment procedures would be to minimize broad and/or arbitrary eligibility criteria. A broad definition of one exclusion criterion alone had a pronounced impact on the potential generalizability of RCT results: mild neuropathy (greater than grade I neuropathy) excluded more than one-quarter of women in WIHS in 41% of the HIV RCTs (Table 3). A narrowing of this exclusion criterion to grade III neuropathy would have eliminated only 8.3% of the cohort, resulting in an RCT participant pool that would have been more representative of WIHS subjects. Likewise, arbitrary cutoffs for laboratory criteria should be examined carefully (Table 3). The requirement of an absolute neutrophil count (ANC) of > 1000 × 106 cells/l for participation in 11 of 32 trials would exclude 6.2% of WIHS women, whereas the use of a more clinically-meaningful cutoff of > 500 × 106 cells/l would exclude < 1%. Since mild neutropenia is common among African Americans , careful reconsideration of this exclusion criterion may result in trial diversification.
Another revision to trial enrollment procedures would be the minimization of the broadest selection criteria, namely those employing ‘investigator judgment’, to determine eligibility. A survey of cancer investigators examined enrollment decisions based on subjective eligibility criteria, such as estimation of substance abuse, and determined that these criteria predictably lead to more variable enrollment decisions than objective criteria . Investigator judgement as to whether a patient can adhere to the study protocol based on social or psychological factors may introduce social biases into HIV RCTs. Provider assessment of adherence to antiretroviral therapy, for example, can be inaccurate , especially when assumptions about patient compliance in light of certain social conditions, such as homelessness or poverty, are made . Social challenges, such as lack of insurance, substance abuse, depression, trading sex for money or drugs, housing, debt or child care issues, and violence, are proportionally higher in HIV-infected women than men , which may result in selective exclusion of women from RCTs based on these subjective criteria.
One of the objectives of the NIAID in funding the CPCRA was to recruit previously under-represented HIV-infected patients into the clinical trial setting . Since minorities are over-represented among HIV-infected women in comparison with men , greater recruitment of women may simultaneously improve racial disparities in RCTs. Although objective exclusion criteria do not exclude WIHS participants in CPCRA trials (Fig. 2) to the same extent as ACTG trials (Fig. 1), the CPCRA trial protocols include more subjective criteria (Table 2), for which it is fair to conjecture that the exclusions may be sizable. It is likely that the elimination of investigator discretionary criteria would result in more diverse study population for RCTs. In the setting of HIV research, where women and ethnic minorities are increasingly represented in the afflicted population, the call for diversity is especially pressing.
Finally, full disclosure of the enrollment criteria of RCTs for HIV and other disease states should be mandated in publications. Space limitations to publishing the full list of eligibility criteria can be managed through weblinks from the electronic publication (and URL listings in the paper article) to the original RCT protocols.
We found that significant under-reporting of the full list of HIV trial enrollment criteria in publications may have a significant impact on the generalizability of a trial's findings to a representative HIV-infected population. Furthermore, structural barriers to participation in HIV clinical trials through restrictive eligibility criteria may lead to under-representation of certain HIV-infected groups. A critical appraisal of the necessity and effects of each enrollment criterion should be performed. Subjective, investigator-dependent, eligibility criteria should be minimized. In the few circumstances when it is not feasible to eliminate these or otherwise broaden eligibility, and representative participants cannot be enrolled in RCTs, alternative research methods, such as observational cohort studies, may be required to supplement knowledge on treatment effectiveness in the ‘real world' setting. Standardization and openness of clinical trial reporting will allow clinicians to more fully assess the applicability of a trial finding to an individual patient and allow researchers and policymakers to expand scientific investigation for all representative populations with HIV.
We wish to thank staff of NIAID, CPCRA, (especially David Cohn MD and Eric Daniels) and ACTG for their notable co-operation with this study; and Virginia Ernster PhD (Department of Epidemiology, University of California, San Francisco) for her helpful comments on this paper.
Sponsorship: Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group. The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute, the National Institute on Drug Abuse (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590). Funding was also provided by the National Institute of Child Health and Human Development (UO1-CH-32632) and the National Center for Research Resources (MO1-RR-00071, MO1-RR-00079, MO1-RR-00083). M.G. was supported in part for preparation of the manuscript by a Mentored Clinical Scientist Development Program Award (K12 AR47659) from the National Institutes of Health.
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