Review of the HIVNET 012 Perinatal HIV Prevention Study (2005) / Chapter Skim
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5 Review of Ethical Issues
5 Review of Ethical Issues
Pages 73-97
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From page 73... ...
. 2 The principles underlying the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research have served as a leading source of guidance on the ethical standards that should govern research with human participants in the United States for over 20 years.
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From page 74... ...
This is a precondition to offering people the opportunity to volunteer, as informed consent alone cannot justify enrollment. In the United States, the institutional review board, or IRB, has been the principal structure responsible for conducting such reviews.
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The decision to participate in research must be voluntary as well as informed. Even when risks are reasonable and investigators obtain informed consent, soliciting certain people as participants may nonetheless be unacceptable.
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· The circumstances that made the placebo control no longer appropriate. · The informed-consent process.
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. It adds 5While the National Bioethics Advisory Commission recommended that FDA not accept data from foreign-based studies that fail to meet FDA standards, the agency has not enacted such regulations.
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later decided to use the trial data to support a supplemental new drug application in order to obtain that labeling change and its associated advertising rights, that decision triggered a higher level of scrutiny of specific aspects of the trial, particularly record keeping. As noted elsewhere in this report, BI conducted a preliminary site visit, followed by a pre-FDA audit site visit by Westat Corporation, a DAIDS contractor.
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From page 79... ...
guidelines.6 DAIDS' remonitoring report also raised concerns about procedural lapses, such as undated and unsigned observations on case report files, missing documentation, multiple dosing errors, lack of source documentation to confirm serious adverse events, and improper correction of errors. [DHHS' Office for Human Research Protections (OHRP)
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From page 80... ...
Overall, then, in research subject to an IND or related to a new drug application, the Guidelines inform but do not define the FDA's own requirements pertaining to informed consent; IRB review; and the responsibilities of sponsors, contract research organizations, and investigators. FDA also requires adherence to other requirements, including IRB-imposed requirements not already covered in FDA regulations.
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From page 81... ...
REVIEW OF ETHICAL ISSUES 81 Thus, the HIVNET 012 investigators were not obligated to be trained in or to follow the ICH GCP Guideline, but rather were obligated to comply with the more stringent requirements laid out by FDA for IND studies and by the respective IRBs as a condition for approving the protocol. Their obligations with respect to administrative and procedural tasks -- such as dating and signing specific forms or providing certain kinds of documentation -- were defined by FDA regulation or by their IRBs, and not by the GCP Guideline.
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From page 82... ...
10 The DHHS Office of Human Research Protections requires federal-wide assurances for institutions conducting human subjects research with funding from DHHS agencies, such as NIH (FDA and DHHS, 2001)
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(As discussed in Chapter 4, the committee believes that the investigators' interpretation of the serious adverse events definition was appropriate.) DHHS regulations require that IRBs review and approve such changes, except when they are necessary to eliminate immediate hazards to participants (National Bioethics Advisory Commission, 2001a)
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. The language used to define serious adverse events was not changed after the protocol had been approved by the IRBs.
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From page 85... ...
The committee finds no evidence that the failures identified by OHRP with respect to ARC's continuing review procedures resulted in a loss of information that would, had it been obtained at the time, have altered the risk-benefit balance in a way that would have triggered either a change in the protocol or a change in the information given to human subjects. THE USE OF A PLACEBO ARM The use of placebo arms in controlled trials presents a special challenge (Djulbegovic et al., 2000; Edwards et al., 1998; Ellenberg and Temple, 2000; Lilford and Djulbegovic, 2001; Temple and Ellenberg, 2000)
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From page 86... ...
. The National Bioethics Advisory Commission agreed that it is ethically unacceptable to perform placebo-controlled clinical trials when effective, established treatments exist.
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The burden of justification lies with the investigators, however, and such study designs should be the exception, not the rule (National Bioethics Advisory Commission, 2001a)
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From page 88... ...
In its own review of the study protocol, ARC asked investigators to revise the consent form to share this justification with study participants. The revised consent form included the following statement: "Uganda, like many other developing countries, does not currently have the resources or capabilities to offer this complicated treatment [referring to long-term therapies used in the United States]
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From page 89... ...
The committee also finds that the HIVNET 012 trial was promptly and properly reevaluated and the placebo arms discontinued when new data emerged from other studies. COMPLIANCE WITH INFORMED CONSENT Even when risks are reasonable and a study design is acceptable, no one should participate in research without giving voluntary informed consent.15 Investigators must make appropriate disclosures and ensure that participants understand the information and their choices -- not only at the time of enrollment but throughout the research.
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From page 90... ...
Where study participants refused or were unable to involve the fathers, citing an array of concerns, the research team deemed those fathers "unavailable." Because the DHHS Office of Human Research Protections offers little guidance for interpreting "unavailability," it is impossible to evaluate the investigators' interpretation of the term. There is evidence that study staff encouraged pregnant women to involve the fathers, but since staff did not have independent access to the fathers, they could not involve them without cooperation from the pregnant women.
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From page 91... ...
Here, because some medical benefits arguably did accrue to the pregnant women, the requirement of paternal consent would seem to be premised primarily on DAIDS policy rather than federal research regulations. Because requiring the fathers' consent appears to be supererogatory -- that is, it exceeds DHHS requirements and is an additional requirement imposed by DAIDS and the IRBs -- any failure to comply would not violate U.S.
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From page 92... ...
Findings: The committee finds that the initial study design incorporated all rel evant protections relating to the need for voluntary informed consent, the acceptability of placebo control, the discontinuation of placebo control, and overall compliance with IRB reviews.
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From page 93... ...
In the case of HIVNET 012, the Westat site visit team and the DAIDS remonitoring team pointed to a number of deficiencies regarding the process and documentation of informed consent. These deficiencies include, for example, a lack of a date-stamp or version number on informed-consent forms to verify the timing of IRB approvals (DAIDS, NIAID, 2003)
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, concerns regarding continuing review by the host country (although with no evidence of injury to subjects as a result) , and concerns regarding full and precise documentation of compliance with all aspects of review and informed consent (again, without evidence of injury to subjects)
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From page 95... ...
Findings: Despite some lapses in documentation, the committee finds no evidence that study subjects failed to give voluntary informed consent. The committee finds that HIVNET 012 met the substantive standards for ethical conduct of research and was implemented in substantial compliance with regulations governing protection of human subjects, especially independent review of risks and benefits to them.
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From page 96... ...
A Phase III Placebo-Controlled Trial Too Determine the Efficacy of Oral AZT and the Efficacy of Oral Nevirapine for the Prevention of Vertical Transmission of HIV-1 Infection in Pregnant Ugandan Women and Their Neonates. HIVNET 012 Investigators.
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From page 97... ...
1997. HIVNET 012 Study-Specific Procedure: Phase III Efficacy Trial of Oral AZT vs Oral Nevirapine in Pregnant Ugandan Women and Their Neonates for the Prevention of Vertical Transmis sion of HIV-1 Infection.
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