6
Response to the Charge to the Committee

This IOM committee was given a specific charge related to various aspects of the design and implementation of HIVNET 012. The preceding chapters of this report describe the planning and initiation of HIVNET 012, discuss the published findings, and assess issues and concerns regarding the study. In this chapter, the committee draws on the findings presented in Chapters 3 through 5 of this report to answer the nine questions posed to the committee.

The statement of task transmitted from NIH to IOM is as follows:

At the request of the National Institutes of Health (NIH), the Institutes of Medicine will conduct an independent review of the HIVNET 012 clinical trial conducted in Uganda…. The IOM committee will address methodological and data interpretation questions related to protocol design, data collection, recordkeeping, quality control, and analysis. The committee will assess the impact of these issues on the validity of the overall findings and conclusions of the trial.

The charge to the committee included nine questions. They are listed here in the order the chapters discuss them:


Study Design

  1. Was the protocol design appropriate?



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Review of the HIVNET 012 Perinatal HIV Prevention Study 6 Response to the Charge to the Committee This IOM committee was given a specific charge related to various aspects of the design and implementation of HIVNET 012. The preceding chapters of this report describe the planning and initiation of HIVNET 012, discuss the published findings, and assess issues and concerns regarding the study. In this chapter, the committee draws on the findings presented in Chapters 3 through 5 of this report to answer the nine questions posed to the committee. The statement of task transmitted from NIH to IOM is as follows: At the request of the National Institutes of Health (NIH), the Institutes of Medicine will conduct an independent review of the HIVNET 012 clinical trial conducted in Uganda…. The IOM committee will address methodological and data interpretation questions related to protocol design, data collection, recordkeeping, quality control, and analysis. The committee will assess the impact of these issues on the validity of the overall findings and conclusions of the trial. The charge to the committee included nine questions. They are listed here in the order the chapters discuss them: Study Design Was the protocol design appropriate?

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Review of the HIVNET 012 Perinatal HIV Prevention Study Implementation of the Study Does the fact that, in many cases, there were no informed consent forms from the fathers cause enough significant concern to invalidate the conclusions? Are there results available (published or unpublished) of assays of drug levels and should consideration be given to what, if any, impact they might have on the conclusions? Was the protocol followed sufficiently to conclude that the data are sustainable? Quality Control Procedures and Quality of the Data Was the quality control sufficient to uphold the conclusions? A certain number of documents were destroyed by a natural disaster. Is this a significant deterrent to drawing conclusions? Can the integrity of the data be sustained in view of the deficiencies of the data collection, and the consistency of its recording? Conclusions Are the conclusions supportable by the data? Is there any reason to suggest the need to retract the publications or to revise the conclusions? FINDINGS REGARDING THE STUDY DESIGN 1. Was the protocol design appropriate? Chapters 3 and 4 provide a detailed discussion of both the initial and modified design of HIVNET 012. In view of the enormous burden of mother-to-child transmission of HIV-1 in sub-Saharan Africa—which remains a critical public health problem—and the need to identify regimens that can be delivered widely to HIV-infected pregnant women with limited access to health care, the effort of HIVNET 012 investigators to study new regimens suitable for widespread use in a resource-poor setting was appropriate. The partnership between investigators at Johns Hopkins University and Makerere University, along with the resources of Mulago Hospital, brought together the medical knowledge, research expertise, and antenatal and postpartum care services needed to conduct the study. The treatment regimens chosen for evaluation in preventing mother-to-child transmission were appropriate. As no short-course oral regimen of

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Review of the HIVNET 012 Perinatal HIV Prevention Study ZDV or NVP had been shown to be effective at the time the study began,1 the inclusion of a placebo group in the initial design was ethically justified. Once results from a study in Thailand indicated that a short course of ZDV was effective in reducing the rate of mother-to-child transmission of HIV (Shaffer et al., 1999), the investigators promptly discontinued the placebo arms and continued the study as a Phase IIB study comparing two short-course regimens, ZDV versus NVP. The modified design was also appropriate and highly relevant to settings with substantial rates of mother-to-child transmission and limited resources. As described in Chapter 3, the committee found that the eligibility criteria for participation in the study were appropriate. In addition, the randomization procedures were properly designed and implemented, resulting in two treatment groups that were comparable at enrollment with respect to measured characteristics. Moreover, the initial and revised sample sizes in the original Phase III placebo-controlled design and the subsequent Phase IIB trial were sufficient to meet the scientific objectives of the initial and modified studies. The statistical methods employed in the HIVNET 012 publications were appropriate. As discussed in Chapter 4, the efficacy endpoints and timing of assessments were appropriate, and the plans for interim monitoring of safety and efficacy by the Data Safety Monitoring Board, as described in the study protocol, were scientifically appropriate and met ethical and regulatory requirements. As discussed in Chapter 5, the committee found that the initial study design, which included a separate placebo arm for each of ZDV and NVP, was properly reviewed by the relevant institutional review boards (IRBs) in the United States and Uganda. Moreover, the initial study design incorporated all relevant human subject protections and an appropriate follow-up period to identify both the risks and benefits of the treatment regimens. The study design also incorporated all relevant human subject protections relating to the need for voluntary informed consent. Moreover, although paternal informed consent may not have been necessary based on the nature of the study, the decision to seek paternal informed consent, if feasible, was consistent with federal regulations. Finally, the plan for oversight by the relevant IRBs and the DAIDS Data and Safety Monitoring Board (DSMB) met the requirement for monitoring of ongoing research. Thus the design of 1   At the time of the HIVNET 012 study, the only regimen available for preventing mother-to-child transmission was from the Pediatric AIDS Clinical Trials Group (PACTG) 076 trial. That trial demonstrated that an intensive three-part regimen of ZDV—given to the mother during pregnancy, labor, and delivery, and to newborns in the first 6weeks of life—could reduce mother-to-child transmission by two-thirds (Connor et al., 1994). The complexity and expense of this regimen made it prohibitive for use in most developing countries.

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Review of the HIVNET 012 Perinatal HIV Prevention Study HIVNET 012—both before and after the discontinuation of the placebo arms—met all relevant ethical requirements. In summary, the committee found that the protocol designs for HIVNET 012—both before and after the discontinuation of the placebo arms—were appropriate. FINDINGS REGARDING THE IMPLEMENTATION OF THE STUDY 2. Does the fact that, in many cases, there were no informed-consent forms from the fathers cause enough significant concern to invalidate the conclusions? The Department of Health and Human Services (DHHS) has adopted additional regulations that specifically address research with pregnant women. These regulations distinguish between research of possible benefit to the woman, to which she can consent without consulting the father, and research of no possible benefit to her but of possible benefit (or risk) only to the fetus, in which case paternal consent is required. Even here, however, paternal consent may be foregone if one of several exceptions are met, including the unavailability of the father. Because the protocol approved by the IRBs asked for paternal consent if the fathers were reasonably available, study staff regularly counseled potential participants regarding the need to involve the fathers in the consent process. For various reasons, however, including physical distance of the fathers or the fear of intense stigmatization, social and economic repercussions, and even violence against the women if their HIV status became known (Fitzgerald et al., 2004), the women were rarely able or willing to produce the fathers so that their consent could be sought. Federal regulations provide little or no guidance on how to interpret the phrase “reasonably available,” and the investigators understood it to mean that if, after counseling a woman, the father was unavailable to the investigators, then one of the criteria for an exception had been met. The practices followed by the investigators with respect to paternal consent therefore would not violate U.S. regulations but rather would, if deficient, violate the terms under which the IRBs approved the study. Given the seeming permissibility of the interpretation of “unavailable,” the investigators did not fail to comply with the protocol, but rather did not provide written documentation of their efforts to comply (PPD, 2003)—that is, to document each discussion and whether it yielded an agreement to produce the father. The remedy for such deviations from protocol (but not from federal regulations) would lie not with DHHS but with the IRBs. However, the committee considered the absence of paternal consent as reflecting an appropriate effort to balance ethical concerns—one that weighed the obli-

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Review of the HIVNET 012 Perinatal HIV Prevention Study gation to involve both parents in decisions about research that might affect their fetus and the desire for confidentiality on the part of the mother. Therefore, the absence of paternal informed consent is not a basis for disregarding the conclusions of the study. 3. Are there results available (published or unpublished) of assays of drug levels and should consideration be given to what, if any, impact, they might have on the conclusions? As described in Chapter 3, tests on stored cord blood specimens indicate that there was a high level of adherence to the study regimens (Jackson et al., 2003; Jackson et al., 2005). Cord blood was obtained from the infants in both treatment arms and frozen for later analysis. In the ZDV arm, specimens were available for 278 of 308 infants. Among these infants, NVP was detected in cord blood in only one sample. In the NVP arm, specimens were available for 275 of the 311 infants. Of these, 3 infants did not receive NVP and no NVP was detected in cord blood. Among the remaining 272, 256 (94%) had a detectable concentration of NVP in cord blood. These observations indicate a high degree of adherence in the NVP arm. Because ZDV has a short half-life of 1.1 hours in non-pregnant women and possibly a shorter half-life in pregnant women, obtaining direct evidence of blood levels of ZDV in those assigned to ZDV therapy was not feasible. In addition to information based on NVP cord blood levels, other data support adherence to study regimens. Only 37 women enrolled in HIVNET 012 did not deliver at Mulago Hospital. In the two treatment groups combined, 308 women reported taking their study-assigned treatment before arriving at the hospital, 212 women received their assigned treatment after arriving at the hospital, and no data on dosing were available for 2 women. Aside from 9 babies who died or were lost to follow-up, 13 infants did not start study treatment (6 in the zidovudine group and 7 in the nevirapine group). The median number of zidovudine doses received by neonates was 14, the number specified in the protocol (SCHARP, 2004). Two other measures of adherence were available to the committee. In the group of mothers assigned to NVP, HIV RNA concentration fell by approximately one log 1 week after they received the dose and returned to baseline by the 6-week sample. This is consistent with the expected prompt and substantial effect of NVP on HIV replication. No similar change in HIV RNA concentration was noted in mothers assigned to ZDV treatment, as expected given the short half-life of this drug. Finally, HIV resistance to NVP was found only in mothers assigned to NVP treatment, consistent with prior exposure to this medication.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Based on a review of this evidence, including the fact that the drugs were identifiable during the unblinded phase and study staff performed a substantial fraction of drug administrations, the committee concluded that participants achieved a high level of adherence to the study regimens, as reported by the HIVNET 012 investigators in their Lancet publications (Guay et al., 1999; Jackson et al., 2003). 4. Was the protocol followed sufficiently to conclude that the data are sustainable? In almost every respect, the HIVNET 012 investigators followed the study protocol closely. The committee did find that the investigators interpreted the protocol definition of serious adverse effects (SAEs) to be predominantly, but not solely, hospitalizations, severe laboratory toxicities, life-threatening illness, and death, which was a reasonable interpretation based on the background rates of illness in Uganda. As a result, conditions that might have been judged to be serious by other investigators in resource-rich countries but did not result in hospitalization in Uganda may not have been recorded as serious adverse events by the HIVNET 012 investigators. The committee did, however, review the source documents, case report forms, and entries in the study data base for a sample of 49 infants, and found that all deaths and hospitalizations experienced by these infants were consistently and accurately recorded in the case report forms and study data base. Thus, the data on survival and hospitalization are accurate and provide a reliable basis for assessment of the safety of the study regimens. FINDINGS REGARDING DATA COLLECTION AND QUALITY CONTROL 5. Can the integrity of the data be sustained in view of the deficiencies of the data collection, and the consistency of its recording? As discussed in Chapter 4, the methods used to collect and record HIVNET 012 data were, in most respects, sound. Study staff maintained source files that consisted of a binder of medical information for each mother/infant pair. Because of difficulties in obtaining records of hospitalizations at Mulago Hospital beyond those from regular antenatal, delivery/birth, and follow-up study visits, the investigators supplemented study source documents with “hospital admission forms” designed to record abstractions of relevant information about study participants’ hospitalizations (Guay, 2004). In addition, the investigators used appropriately designed case report forms, stored in participant-ID-labeled binders for each

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Review of the HIVNET 012 Perinatal HIV Prevention Study mother/infant pair, to transmit data accurately and in a timely fashion to the data-coordinating center for the study. Rates of retention and adherence to the schedule for study visits were high and a high percentage of blood samples required by the study protocol were obtained, leading to accurate assessment of rates of transmission of HIV-1 and HIV-1-free survival in both treatment groups. According to the remonitoring study and the investigators, detailed information on the chain of custody of study drugs was sometimes not available. However, notations in the source files, participant reports, the substantial fraction of dosing that occurred in the hospital, and the findings regarding blood levels of NVP and viral load all support the published report by the HIVNET 012 investigators that a high level of adherence to study regimens was accomplished among study participants. Evidence of oral informed consent before the initial blood draw was not consistently documented. However, the committee finds that these reported lapses in documentation are of minor significance and do not threaten the findings from this study. The committee also focused on the collection of data about adverse events. As discussed in Chapter 4, the investigators classified clinical events as serious adverse events primarily but not exclusively if they were associated with hospitalization. That was done taking into account the prevalence of co-morbid conditions in Uganda such as tuberculosis and malaria and clinician judgment in terms of assessment of severity of events. The grading system for hemoglobin and rash were modified prior to study start to reflect local conditions and these modifications were written in the Study Specific Procedures. The acceptable, but narrow, interpretation of “serious” may have led to reporting of fewer serious adverse events than would have been reported with a broader interpretation. To gain a greater understanding of study practices, the committee reviewed a sample of source documents and case report forms for 49 infants. In this review, the committee found some evidence of underreporting of concomitant serious adverse events present when an SAE was reported. However, if a participant’s source documents showed one or more serious adverse events had occurred simultaneously, at least one of those events on that occasion was noted in the case report form and documented in the study database. In addition, the committee found that all deaths and all hospitalizations occurring in the subset of infants whose records were reviewed by the committee had been recorded in the study database. Thus, the committee concluded that information on the number of hospitalizations and deaths among participants is complete and accurate. Although the methods employed by the investigators apparently led to some underreporting of adverse events, the committee found no evidence to suggest that this possible underreporting occurred differentially in the two treatment arms. In summary, with the few qualifications noted above and

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Review of the HIVNET 012 Perinatal HIV Prevention Study based on the body of information it reviewed, the committee concludes that the integrity of the study data can be supported. 6. Was the quality control sufficient to uphold the conclusions? Quality control was reported in previous audits (Chamberlin et al., 2002; DAIDS, NIAID, 2003) as deficient in some procedural areas, including a lack of written standard operating procedures, inconsistent signing or initialing and dating of forms, corrections not made according to generally accepted standards, and a lack of systematic review of case report forms by investigators before transmittal to the statistical center. The investigators disagreed with audit findings in some areas, and they took steps to improve procedures in the remaining areas. However, quality control procedures in the laboratory were satisfactory, and the Statistical Center for HIV/AIDS Research and Prevention (SCHARP) employed internal quality-control mechanisms to regularly review and “clean” data in a timely fashion—identifying inaccuracies, inconsistencies, and missing information across various forms in the database, correcting some problems, and checking with the study site to address the remainder. The committee established that data on study participants were gathered, recorded in source documents, recorded on case report forms, and transmitted to the statistical center in a timely manner. The committee has also documented a high degree of concordance between the data recorded on the source documents and in the study database. Because the source documents—along with hospital admission forms and later actual hospital records obtained by study staff—were intended to serve as a readily available and substantially complete medical record, this consistency leads the committee to conclude that the data were accurately ascertained and recorded. Moreover, this approach to collection of the information ordinarily maintained in the patient medical record was an effective and realistic way to maintain the analogue of a primary medical record in a setting where health organizations did not maintain longitudinal medical records for patients. Thus, the approach to record keeping employed in this study was reasonable and sufficient to meet the research objectives of the study. In the judgment of this committee, the occasional gaps in these source documents arising from circumstances such as provision of care by individuals not associated with the study does not cast doubt on the accuracy of the research database. 7. A certain number of documents were destroyed by a natural disaster. Is this a significant deterrent to drawing conclusions? Based on a review of secondary sources (Westat Site Visit Report and

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Review of the HIVNET 012 Perinatal HIV Prevention Study DAIDS remonitoring report and materials) and the investigators’ presentation before the committee, the committee concludes that no primary study data appear to have been destroyed. First, when study staff obtained records from Mulago Hospital on participants and began to reorganize those records, they found that a small number had been slightly damaged by rodents or insects, but not to an extent that rendered them unusable (Guay, 2004). Second, a broken pipe caused some flooding or water damage that affected one or more of the health visitors’ log books, containing notes about their visits to participants’ homes (Chamberlin et al., 2002). These were secondary materials not used as source documents for the study, and much of the information contained in the damaged notebook(s) was legible and copied into a new notebook or notebooks (Guay, 2004). None of the participants’ clinical charts or other primary source documents was affected by this event. Thus, the extent and significance of missing documents was quite limited and has no bearing on the integrity of the study. FINDINGS REGARDING THE STUDY CONCLUSIONS 8. Are the conclusions supportable by the data? Based on the information summarized in this report, the committee concludes that the findings from HIVNET 012 regarding efficacy of NVP—including the reduction in rate of mother-to-child transmission of HIV-1 and HIV-1 infection-free survival at 4–6 weeks, 14–16 weeks, and 18 months in the NVP arm—are sound and fully supportable by the data. The reported high levels of adherence to treatment regimens can also be supported. Taken together, these two sets of results published in the two Lancet articles show a substantial reduction in the rate of transmission of HIV-1 infection in the NVP arm compared to the ZDV arm at 6–8 weeks, 14–16 weeks, and 18 months (Guay et al., 1999; Jackson et al., 2003). Similarly the probability of HIV-1-free survival at these three time points was significantly increased in the NVP treatment group. The committee concludes that these findings on the efficacy of the NVP treatment regimen relative to the ZDV regimen studied in HIVNET 012 are well supported by the study’s design and conduct and the quality of the data and are therefore appropriate for use in policy making. The modified HIVNET 012 study was an actively controlled trial with no placebo group, so the trial was not able to demonstrate the safety of the two active regimens relative to untreated controls. However, there was no evidence that the rates of unreported adverse events varied by treatment group, suggesting that the comparative safety analyses reported by the HIVNET 012 investigators are not biased. From our review of the full data-

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Review of the HIVNET 012 Perinatal HIV Prevention Study base, laboratory data and data on deaths were largely complete. In addition, in a review of 49 infants, we found that all hospitalizations and deaths were in the database as well as at least one SAE on each occasion on which one or more SAEs occurred. Thus, the committee concludes that the investigators’ findings regarding similarity of the rates of infant serious adverse events in the two treatment groups are supportable. 9. Is there any reason to suggest the need to retract the publications or to revise the conclusions? Based on its review, the committee finds no reason to retract the publications or alter the conclusions of the HIVNET 012 study. The committee concludes that data and findings presented in Guay et al. (1999) and Jackson et al. (2003) are sound and presented in a balanced manner and can be relied upon for scientific and policy-making purposes. The reasons for the committee’s confidence in data and findings reported in these publications are several-fold. First, the randomization procedures were properly designed and implemented, meeting the goal of creating two comparable treatment groups, which serves as the basis for valid conclusions about safety and efficacy. Second, based on information from drug assay tests and other data, participants received the appropriate drug, and there was a high level of adherence to the study regimens. Furthermore, the investigators achieved high rates of retention and follow-up among participants. The committee’s analyses indicate that the efficacy data are well-supported. Despite the narrow interpretation of the definition of SAE employed in the field and the failure to capture some AEs recorded in the source documents in the study database, all infant hospitalizations, severe laboratory abnormalities, laboratory toxicities, and mortality data reviewed by the committee were captured in the database. The committee also found that some (non-serious) adverse events noted in the source documents were not reported on the case report forms. The underreporting of some (non-serious) AEs and some concomitant SAEs that accompanied a reported SAE may limit the generalizability of absolute adverse event rates and counts to other settings. However, the committee has found no reason to believe that the rates of unreported adverse events varied by treatment group, suggesting that the comparative safety analyses reported by the HIVNET 012 investigators are valid. REFERENCES Chamberlin J, Gustavson SA, Hensley M, Lander S. 2002. Site Visit Report, Kampala Uganda, February 18-28, 2002. Westat Corporation, MD.

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Review of the HIVNET 012 Perinatal HIV Prevention Study Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O’Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, Jimenez E, O’Neill E, Bazin B, Delfraissy J, Culnane M, Coombs R, Elkins M, Moye J, Stratton P, Balsley J, for The Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. 1994. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. New England Journal of Medicine 331(18): 1173-1180. DAIDS, NIAID (Division of AIDS, National Institutes of Allergy and Infectious Diseases). 2003. HIVNET 012 Monitoring Report. Fitzgerald DW, Maxi A, Marcelin A, Johnson WD, Pape JW. 2004. Notification of positive HIV test results in Haiti: Can we better intervene at this critical crossroads in the life of HIV-infected patients in a resource-poor country? AIDS Patient Care and STDs 18(11):658-664. Guay L. 2004. Presentation to IOM’s Committee on Reviewing the HIVNET 012 Perinatal HIV Prevention Study. Transcript of September 30, 2004, Data-Gathering Meeting. Guay LA, Musoke P, Fleming T, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Ducar C, Deseyve M, Emel L, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Dransfield K, Bray D, Mmiro F, Jackson JB. 1999. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 354(9181):795-802. Jackson B, Parsons T, Musoke P, Nakabiito C, Donnell D, Fleming T, Mirochnick M, Mofenson L, Fowler M, Mmiro F, Guay L, and HIVNET 012. 2005. Association of Cord Blood Nevirapine with Self-Reported Timing of Dose and HIV-1 Transmission in the HIVNET 012 Study, Abstract #71. [Online] Available at http://www.retroconference.org/org/2005/cd/Abstracts/25816.htm. Accessed March 7, 2005. Jackson JB, Musoke P, Fleming T, Guay LA, Bagenda D, Allen M, Nakabiito C, Sherman J, Bakaki P, Owor M, Ducar C, Deseyve M, Mwatha A, Emel L, Duefield C, Mirochnick M, Fowler MG, Mofenson L, Miotti P, Gigliotti M, Bray D, Mmiro F. 2003. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial. Lancet 362(9387):859-868. PPD. 2003. Kampala Issues List–HIVNET 012 Re-Monitoring and Ongoing Monitoring Visits. SCHARP (Statistical Center for HIV/AIDS Research and Prevention). 2004. File: t_m_delivery.pdf. Document sent as part of an e-mail from Deborah Donnell to A. Gable, October 25. Re: Data information requests for IOM study. Shaffer N, Chuachoowong R, Mock PA, Bhadrakom C, Siriwasin W, Young NL, Chotpitayasunondh T, Chearskul S, Roongpisuthipong A, Chinayon P, Karon J, Mastro TD, Simonds RJ. 1999. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: A randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet 353(9155):773-780.