5
Review of Ethical Issues

Clinical research using human subjects—whether in the United States or in resource-limited settings—is replete with ethical complexity. Protecting the rights and welfare of those who volunteer to participate in research is a fundamental tenet of ethical research,1 and the research community has made a great deal of progress in recent decades in incorporating this ethical responsibility more fully into study design and implementation.2 Within

1  

The Nuremberg Code was the first international standard for conducting research with human subjects. The Nuremberg Tribunal, the court, through the Nuremberg Code, insisted that human rights in research be protected. The code gives to subjects the authority to protect themselves. The code contains a strict requirement that research subjects provide informed, voluntary, competent, and understanding consent (principle 1) and they retain the right to withdraw from research at any time (principle 9). Because the Nuremberg Code was linked to Nazi atrocities, murder, and torture, many physicians and medical organizations felt that the code was too absolute to be applied to modern research. In 1953, the World Medical Association (WMA), representing 80 countries including the United States, led a dialogue that resulted in the promulgation of the Declaration of Helsinki. Published in 1964, the declaration offered guidance for researchers in the conduct of research involving human subjects. Chief among its principles is the recognition of the validity of surrogate consent for subjects who lack the capacity or legal competence to render consent themselves, such as children (Murphy, 2004).

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. The Belmont report emphasized that research must respect the autonomy of



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study 5 Review of Ethical Issues Clinical research using human subjects—whether in the United States or in resource-limited settings—is replete with ethical complexity. Protecting the rights and welfare of those who volunteer to participate in research is a fundamental tenet of ethical research,1 and the research community has made a great deal of progress in recent decades in incorporating this ethical responsibility more fully into study design and implementation.2 Within 1   The Nuremberg Code was the first international standard for conducting research with human subjects. The Nuremberg Tribunal, the court, through the Nuremberg Code, insisted that human rights in research be protected. The code gives to subjects the authority to protect themselves. The code contains a strict requirement that research subjects provide informed, voluntary, competent, and understanding consent (principle 1) and they retain the right to withdraw from research at any time (principle 9). Because the Nuremberg Code was linked to Nazi atrocities, murder, and torture, many physicians and medical organizations felt that the code was too absolute to be applied to modern research. In 1953, the World Medical Association (WMA), representing 80 countries including the United States, led a dialogue that resulted in the promulgation of the Declaration of Helsinki. Published in 1964, the declaration offered guidance for researchers in the conduct of research involving human subjects. Chief among its principles is the recognition of the validity of surrogate consent for subjects who lack the capacity or legal competence to render consent themselves, such as children (Murphy, 2004). 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. The Belmont report emphasized that research must respect the autonomy of

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study the federal government, these efforts have included the formation in 1974 of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the activities in the early 1980s of the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The research community itself has largely supported two essential protections for human participants: independent review of research to assess its risks and potential benefits, and an opportunity for people to voluntarily and knowledgeably decide whether to participate in a particular study. Independent review is essential because it improves the likelihood that decisions are free from inappropriate influences that could distort the central task of evaluating risks and potential benefits. No one should participate in research unless independent review concludes that the risks are reasonable in relation to the potential benefits for both participants and society. 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. In U.S.-supported international research—that is, research by U.S. investigators working in another country—U.S. investigators subject to regulation either by the National Institutes of Health (NIH) or the U.S. Food and Drug Administration (FDA) may adopt the ethical standards and procedures of the host country, provided that such protections are substantially equivalent to those in the United States.3 In its own study of this     participants, must be fair in both conception and implementation, and must maximize potential benefits while minimizing possible harms. The report’s recommendations provided a coherent rationale for the federal policies and rules that underlie the current U.S. system of decentralized, independent research review, coupled with some degree of federal oversight (Office of Human Subjects Research and National Institutes of Health, 1979). 3   The procedures and standards for reviewing the study can be changed where the United States has recognized the host country as having a system of equivalent protections. 45 CFR Part 46.101(h) states: “When research covered by this policy takes place in foreign countries, procedures normally followed in the foreign countries to protect human subjects may differ from those set forth in this policy. [An example is a foreign institution which complies with guidelines consistent with the World Medical Association Declaration (Declaration of Helsinki amended 1989) issued either by sovereign states or by an organization whose function for the protection of human research subjects is internationally recognized.] In these circumstances, if a Department or Agency head determines that the procedures prescribed by the institution afford protections that are at least equivalent to those provided in this policy, the Department or Agency head may approve the substitution of the foreign procedures in lieu of the procedural requirements provided in this policy. Except when otherwise required by statute, Executive Order, or the Department or Agency head, notices of these actions as they occur will be published in the Federal Register or will be otherwise published as provided in Department or Agency procedures” (DHHS, 2004).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study topic, the National Bioethics Advisory Commission recommended that independent bodies in both the United States and the host country ensure that studies are consistent with ethical requirements in both countries. Where necessary, the commission recommended, resources should be given to the host country to perform this review. The Department of Health and Human Services (DHHS) is now soliciting comments on ways to improve international research by better identifying equivalent principles and practices for protecting human subjects in research conducted abroad (DHHS, 2005). Before HIVNET 012 began, two IRBs provided oversight of the study’s design and protocol. The U.S.-based IRB, at Johns Hopkins University, was the Joint Committee on Clinical Investigation (JCCI). The Ugandan-based IRB, of the Uganda National Council for Science and Technology, was the AIDS Research Committee (ARC). Both IRBs approved the protocols and consent forms for the study, and continued their oversight during its implementation. 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. Studies should not enroll people who are not fully capable of resisting the request to become participants—such as prisoners and other institutionalized or otherwise vulnerable persons—merely because they are accessible. The historical emphasis on protecting people from exploitation, however, has failed to anticipate a time when, at least for some areas of medical research, people would demand the right to join certain studies because they might provide access to an innovative therapy, or provide the only chance for medical care for life-threatening diseases. In international research, some commentators have suggested that the general absence of adequate health care in resource-limited-settings can make the offer of enrollment in a research trial nearly impossible to resist. Studies in resource-limited countries, therefore, demand a high level of justification. Studies that exploit a population’s vulnerability—such as those that recruit people in poorer countries solely to benefit people in wealthier countries—should not be done. If, on the other hand, studies in resource-limited countries are designed to address important health problems in those same countries and could not be performed elsewhere, then the research is justified, and the consent process is used to help ensure that subjects are genuinely informed before volunteering (National Bioethics Advisory Commission, 2001a,b). This chapter focuses on four ethical issues related to HIVNET 012:

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study Compliance with requirements for independent IRB oversight. The use of placebo control arms. The circumstances that made the placebo control no longer appropriate. The informed-consent process. This chapter begins with a discussion of the decision to proceed with the HIVNET 012 study under an investigational new drug application (IND). THE INVESTIGATIONAL NEW DRUG APPLICATION When the FDA approves drugs for sale in the United States, that approval is based on studies that examine the drug with respect to a particular use. Once approved, the drug is labeled for that indication, and the manufacturer may advertise it for that indication only. But it is perfectly legal and commonplace for physicians to prescribe—and investigators to study—approved drugs for indications that go beyond their labels. Indeed, in the United States, estimates show that almost 80% of the medications prescribed for some conditions are off-label, and that off-label use is particularly frequent in pediatric patients (GAO, 1996; Radley et al., 2004; ‘t Jong et al., 2000). Physicians are expected to exercise good judgment when prescribing approved drugs for off-label use, basing their decisions on both anecdotal reports and the results of studies that specifically examine such off-label uses. In general, only when a manufacturer wishes to file a Supplemental New Drug Application (sNDA) to obtain the right to advertise an already approved drug for another indication will it have any incentive or need to approach FDA for permission to proceed with a study, or to abide by FDA requirements regarding conduct of the study. Although not required by FDA, HIVNET 012 was conducted under an IND held by the Division of AIDS (DAIDS). There is no requirement for non-U.S. studies or non-U.S. sites of multinational studies to operate under an IND; this is determined by the sponsor. However, where the sponsor decides to conduct a study under an IND, FDA’s IND regulations must be followed for the study and at all such sites.4 4   The need for sponsors of non-U.S. studies/sites to operate under an IND has changed over the years, most notably since the passage of the FDA Modernization Act (FDAMA) in 1997. Prior to FDAMA, one of the mechanisms for the export of a U.S. manufactured investigational product (for use in a clinical trial outside of the U.S.) was to agree to conduct the study under an IND at its non-U.S. sites. FDAMA created options for exporting a U.S.-manufactured investigational product outside of the IND process (e-mail communication, D. Lepay, March 31, 2005).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study INDs permit sponsors to begin testing investigational drugs in preparation for a New Drug Application (NDA) or to formalize the testing of new indications for an already approved drug in preparation for submission of an sNDA. FDA did not require an IND for HIVNET 012 because both zidovudine (ZDV) and nevirapine (NVP) were already approved for marketing in the United States and the manufacturer was not intending to submit an sNDA based on the trial’s data to change the labeling or advertising for either ZDV or NVP. Furthermore, HIVNET 012 would take place in a foreign country, outside FDA’s jurisdiction.5 DAIDS nevertheless decided to conduct the study under an IND because, in 1997, the agency pursued the vast majority of trials under such an application. DAIDS’ reasons to submit the study to an existing IND (application made to FDA in 1996) included: In 1997, the vast majority of DAIDS trials occurred under IND. The safety mechanism for reporting “off-label use” adverse events in a non-IND trial would have been MEDWATCH, a voluntary as opposed to a mandatory system. The initial trial included a placebo arm and was using two different drug regimens, both of which were off-label under both FDA and Ugandan regulations. When DAIDS is the sponsor of a study that used a product off-label in a protocol, that is, it has not been specifically reviewed and approved by any regulatory entity for this particular indication, DAIDS generally submits it under an IND. The trial was conducted in two “vulnerable” populations: pregnant women and newborns. The IND extends reporting requirements and oversight beyond the sponsor, IRB, and the Data Safey Monitoring Board (DSMB). It adds 5   While 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. Thus trials conducted abroad need not follow FDA regulations, even if the data from those trials might later be used in a submission to FDA for approval of a new drug or indication. Instead, FDA sets requirements for minimal ethical standards for such trials. FDA regulations permit the acceptance of foreign clinical studies in support of an application for marketing approval of a human drug, biological product, or device if certain conditions are met. Foreign studies performed under an IND or investigational device exemption (IDE) must meet the same requirements of 21 CFR Part 312 or 21 CFR Part 812, respectively, that apply to U.S. studies conducted under an IND or IDE (FDA and DHHS, 1996; Lin and Meschino, 1993). Under 21 CFR 312.120(c)(1), FDA will accept a foreign clinical study not conducted under an IND only if the study conforms to the ethical principles contained in the Declaration of Helsinki (Declaration), as set out in 21 CFR 312.120(c)(4), incorporating the 1989 version of the Declaration, or with the laws and regulations of the country in which the research was conducted, whichever provides greater protection of the human subjects.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study additional measures of oversight, including IND safety reporting, annual IND reports, and oversight by the FDA (e-mail communication, C. Hudgings, February 7, 2005). Conducting research under an IND places specific obligations on both the sponsor and the investigators. Many of these obligations merely echo good research practices pursued in non-IND trials, but others require more stringent record keeping, drug management, and quality-control checks than would be employed in a typical study. According to the IND regulations in effect in 1997, the sponsor had to select qualified investigators, provide them with the information they needed to conduct their work, and ensure proper monitoring. The sponsor also had to ensure that the investigation followed the general plan and protocols in the IND, and that FDA and all participating investigators were promptly informed of significant new adverse effects or risks (FDA and DHHS, 1997). The IND subjected the investigators to the following requirements: Conduct the investigation according to the signed investigator statement, the investigational plan, and applicable regulations. Protect the rights, safety, and welfare of research subjects. Control the drugs under investigation. Keep and retain specific records. Provide progress, safety, and final reports to the sponsor. (Investigators had to promptly report adverse effects reasonably regarded as caused by, or probably caused by the drug, and to immediately report an alarming adverse effect.) Assure that an IRB would be responsible for initial and continuing reviews and approvals; report to the IRB all changes in research activities and unanticipated problems, and make no changes in research without IRB approval (FDA and DHHS, 1997). FDA Form 1572, which all investigators must sign, lists these requirements. Although HIVNET 012 was conducted under an IND, documentation of its compliance with FDA regulations did not proceed entirely like that of a typical IND trial, as its purpose was neither to obtain a first approval of an investigational drug nor to obtain approval for a labeling change concerning a new indication of an approved drug. When Boehringer Ingelheim (BI) 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.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study Applying this higher level of scrutiny concerning documentation of applicable procedures, the Westat site visit resulted in a report that includes assertions of several procedural lapses. The Westat team attributed some of the lapses to a general lack of awareness of and training in so-called good clinical practice (GCP) 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) investigated claims of misdosing and faulty error reporting but failed to confirm these problems;7 see below for a discussion of the procedural lapses it did identify with respect to the Ugandan IRB.] The phrase “good clinical practice” can be used in two different ways. First, it may refer to the substantive and procedural practices with a long history and that are generally understood as the essential attributes of good research and appropriate medical care in the context of clinical trials. The phrase can also be used more narrowly to refer to the Good Clinical Practice (GCP) Guideline, a published set of guidelines that constitute one standard for conducting scientifically sound and ethical research (ICH, 1996). GCP Guideline have been developed over the last 20 years by the International Conference on Harmonisation (ICH) in order to facilitate the mutual acceptance of clinical data by the regulatory authorities in Europe, the United States, and Japan, and thus speed the process for approval of new pharmaceuticals and increase patient access to new treatments (DHHS and FDA, 1997). The ICH GCP Guideline describes the responsibilities of investigators, monitors, sponsors, and IRBs, and also covers aspects of monitoring, reporting, and archiving of clinical trials and their data. When FDA moved to adopt much of the harmonized guideline, it stated that: This guideline represents the agency’s current thinking on good clinical practices. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statutes, regulations, or both (DHHS and FDA, 1997). 6   It is worth noting that—despite the name—investigators can engage in excellent clinical practice without following the precise contours of the Good Clinical Practice Guidelines (ICH, 1996). 7   See March 15, 2002, and July 16, 2002, letters from Patrick McNeilly, Compliance Oversight Coordinator, Division of Compliance Oversight, OHRP to Zerababel M. Nyiira, Secretary, Ugandan National Council of Science and Technology (McNeilly, 2002a; McNeilly, 2002b).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study For a study (whether in or outside the United States) that is designated as being conducted under an IND, FDA IND regulations (including those in 21 CFR [Code of Federal Regulations] Parts 312, 50, 54, and 56) must be met. The ICH GCP Guideline has no bearing on IND requirements (which must be met for any IND study), and that has been the case since before 1997, the year enrollment in HIVNET 012 began (e-mail communication, D. Lepay, March 31, 2005). Thus, the FDA does not require adherence to the ICH GCP Guideline, although FDA has incorporated some elements of the Guideline into its own regulations governing research trials.8 FDA regulations are more detailed in certain requirements, particularly those for Ethics Committees and their operation, although the ICH GCP Guideline provides more detail about sponsor monitoring and auditing of studies, which FDA views as good guidance if not already an FDA regulatory requirement. Since FDA regulations do not currently impose ICH GCP Guidelines as a regulatory requirement, there is no obligation for investigators (either in or outside the United States) to be educated or trained in the ICH GCP Guideline and procedures. The FDA regulations simply require that investigators (and site staff) be qualified by education, training, and experience to perform their designated or assigned tasks. 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. In other words, investigators are responsible for fulfilling every requirement imposed by an IRB. FDA regulations do allow for waivers of specific IND requirements if these are requested by the sponsor and agreed to by FDA. This has allowed some sponsors to conduct non-U.S. studies under an IND when they know that specific IND requirements can not be met (e.g., some of the specific requirements of Ethics Committees, for example). Sponsors have, for example, requested a waiver of one or more IND requirements by indicating that they will follow the corresponding provisions in ICH GCP Guideline (which tend to be less detailed for the operation of Ethics Committees), and FDA has generally granted such waivers. But again, the waiver must be formally requested by the sponsor under the IND—and formally granted by FDA. In HIVNET 012, no such waiver was requested, and thus the trial proceeded under the more stringent FDA regulations rather than under the more relaxed ICH GCP Guideline. 8   See FDA regulations relating to good clinical practice and clinical trials at http://www.fda.gov/oc/gcp/regulations.html (FDA, March 9, 2005).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study 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. Thus, it would be an error to conclude that the HIVNET 012 study was either flawed or unethical simply because the investigators did not precisely follow the GCP Guideline that was different from the requirements imposed upon them by the FDA and their IRBs. A more accurate interpretation of auditors’ criticisms is that they considered the staff’s performance uneven in some aspects (such as the precise format for recording changes on a document).9 Many of the procedural areas subject to assertions of uneven staff performance involved technical requirements that did not affect the rights or welfare of the research subjects. Instead, many of these supposed requirements reflected the precise documentation usually associated with formal submissions to the FDA for approval of a new drug or indication. Thus, it would not be fair to conclude that the trial was characterized by a lack of good clinical practice, or that the staff did not implement good medical care across all aspects of the program. Findings: The committee finds that HIVNET 012 was conducted under an IND as a matter of DAIDS policy, and that the study was not originally intended to provide data for later submission to FDA to support a 9   With regard to non-IND studies, there may soon be a more significant role for ICH GCP Guidelines. FDA regulations provide a mechanism to submit non-U.S., non-IND studies to the agency in support of marketing applications. These regulations are currently undergoing revision. Until the revision finalizes, these regulations require that certain broad requirements be met for non-U.S., non-IND studies: including certification of conformance with the Declaration of Helsinki (Declaration) or with local laws (when these provide greater protection for subjects than Declaration), conduct of studies by qualified investigators, applicability of the study to the U.S. population, and the ability for FDA to inspect the study. The revision to FDA regulations (currently published as a proposed rule for public comment) will link FDA’s acceptance of non-U.S., non-IND studies to internationally accepted GCP standards (e.g., ICH) and will require submission of certain documentation to establish that GCP standards were followed. But in 1997 and still today, unless and until the FDA revised rule finalizes, FDA regulations do not specifically cite or suggest ICH GCP as a requirement for acceptability of non-U.S., non-IND studies. Rather, ICH GCP is guidance; if followed, this should ensure that the current regulatory expectations for non-U.S., non-IND studies will be met.  

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study labeling change for NVP, an already approved drug. The decision by Boehringer Ingelheim to use the findings to support such a submission led to evaluating the documentation of regulatory compliance by the trial in light of a standard that did not apply when the trial began. The committee finds that the HIVNET 012 investigators met their ethical obligation to design and conduct the study in accordance with international standards for the ethical conduct of research and ethical management of patient care. The HIVNET 012 investigators also complied with their legal obligation to design and conduct the study in accordance with FDA regulations and under the oversight of IRBs in both Uganda and the United States. The HIVNET 012 trial was not required to comply with specific procedural rules outlined in the voluntary Good Clinical Practice Guidelines published by the International Conference on Harmonisation, and an ethical evaluation of HIVNET 012 should not rest directly or indirectly on the degree to which it conformed to GCP Guidelines, but rather on the degree to which it conformed to the FDA, IRB, and general medical ethics standards to which it was subject. The validity of the study’s findings is sustained by the fact that the trial was conducted in accordance with FDA requirements and met international standards for the ethical management of clinical trials. COMPLIANCE WITH REQUIREMENTS FOR INSTITUTIONAL REVIEW BOARDS As noted, HIVNET 012 was overseen by JCCI, the IRB at Johns Hopkins University; and by ARC, the IRB of the Uganda National Council for Science and Technology (UNCST). UNCST operates under a federal-wide assurance (FWA)10 and has agreed to follow guidelines from the Council for International Organizations of Medical Sciences (CIOMS) for review of protocols by its IRB. It is worth noting that U.S. rules and regulations are not the only ones that investigators may choose to follow in order to satisfy ethical requirements. The CIOMS rules represent an alternative to the U.S. regulations found in 45 CFR (for DHHS except FDA) and 21 CFR (for FDA). A failure to follow DHHS rules does not necessarily mean that researchers failed to conduct a study ethically, but only that they did not follow the particular method chosen by DHHS. 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).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study Before October 5, 2001, and at the time of HIVNET 012, the DHHS-supported research conducted by UNCST fell under single project assurances and cooperative project assurances, which required Makerere University to follow DHHS regulations for protecting human subjects. Pursuant to these regulations, the Ugandan IRB (ARC) approved HIVNET 012 protocol version 1.0 in July 1997, reviewed it again in March 1998 when the placebo arms were dropped (Amendment I), then again when the efficacy data was reported in July 1999 (Guay et al., 1999), and finally when Amendment II was submitted in April 2000 (PPD, 2003). In 2002, in response to allegations of noncompliance with DHHS regulations, the DHHS Office of Human Research Protections (OHRP) undertook a review of ARC. In correspondence with UNCST, OHRP identified what it perceived as a change in the protocol [a change in the interpretation of serious adverse events (SAEs)] that ARC and JCCI had approved. (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).11 Specifically, OHRP found what it identified as discrepancies between the definition of adverse events in the protocol and the definition that UNCST said was actually used at the site. The discrepancies, according to OHRP, consisted of using modified severity scales for rash and hemoglobin in order to address high background rates of rash and anemia, and use of hospitalization as the primary criterion for identifying a condition as a serious adverse event. (See Chapter 4 for a full discussion of the definition and interpretation of serious adverse events used by HIVNET 012 investigators as well as the findings of the committee with respect to the allegations described above.) OHRP reported that it did not find documentation that the definitions and interpretations used in the field were ever approved by the IRBs and that the change in reporting adverse events might have represented a failure to minimize risk to participants. Nonetheless, OHRP never found that those risks were, in fact, higher than necessary. 11   Concerns that the study did not implement the standard definition of adverse events, and did not follow the updated 1998 U.S. Code of Federal Regulations definition for SAE, also surfaced during the Westat site visit and the DAIDS remonitoring process. It should be noted, however, that the updated 1998 definitions (which differed slightly from the earlier regulations that governed HIVNET 012) did not apply to HIVNET 012, which was already underway subject to the regulations in place at the time HIVNET 012 was approved. When new versions of regulations are enacted, they apply prospectively to new trials, and only in exceptional circumstances do they apply retroactively to ongoing trials (FDA and DHHS, 1998).

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study A number of researchers also consider placebo controls to be ethically acceptable when a standard effective therapy exists but is not locally available, whether due to cost, logistical difficulties, or cultural barriers to use. That may occur, for example, in a resource-limited country where health care resources are scanty and study participants do not have access to established, effective treatments. Access may be limited solely by financial constraints or by logistical problems as well, such as a lack of climate-controlled drug storage facilities or equipment for screening patients. Another kind of logistical barrier is created when one health imperative—breastfeeding in a country without a safe water supply for infant formula—renders an otherwise effective intervention futile, such as avoidance of breastfeeding in conjunction with other therapies. In such situations, researchers can regard the population as not having, for all practical purposes, an effective standard treatment, thereby making a placebo control acceptable. In these cases, some would argue, measuring the absolute efficacy of a new and potentially more affordable and available intervention is more relevant than comparing it to an established treatment that is unlikely to be available in the host country (Levine, 1999). Other researchers, when considering placebo controls in settings where effective therapy exists but is not locally available, will acknowledge the greater usefulness of the resulting data if a study includes a placebo control. However, they will nonetheless argue that when poverty makes people eligible to enroll in a trial that would be unacceptable in wealthier settings, it is a form of exploitation. This debate remains unresolved among ethicists, policy makers, and the research community (Cohen, 1997). Overall, then, placebo or other controls using less than an effective, established treatment are disfavored in the case of serious illness, but may nonetheless be justified under special circumstances, such as where effective, established treatments are difficult to provide or maintain. 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). HIVNET 012 initially adopted placebo controls as part of a four-arm study. The protocol chair described the need for the placebo arms in a June 6, 1997, request to JCCI, the Johns Hopkins University IRB. In response to a JCCI request for more information on the need for the placebo arms, the protocol chair indicated that the standard of care in Uganda was to provide no antiretroviral therapy to prevent mother-to-child transmission or to treat mother or infant. This was due in part to the expense of delivering such antiretroviral interventions, estimated at $100 for interventions initiated at 38 weeks of pregnancy, $200 for interventions initiated at 36 weeks of pregnancy, and $1,000 for the oral and intravenous three-part ZDV regime used in the AIDS Clinical Trials Group (ACTG) 076 study. By

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study contrast, the protocol chair stated, per capita annual health care expenditures in Uganda are about $3.50 (Jackson, 1997). Investigators presented the placebo arms as necessary because they would allow the study to compare the effectiveness of both ZDV and NVP not only to each other, but also to the prevailing situation in Uganda, where no antiretroviral therapy was available. Thus the placebo arms would efficiently allow the trial to determine whether either ZDV or NVP reduced transmission rates in this setting, while also assessing which of these two antiretroviral drugs was more effective. As an alternative to placebo, investigators could have compared their findings to historical rates of mother-to-child transmission in Uganda. But the HIVNET 012 protocol chair wrote that such an approach would have been unreliable, owing to the great variability of those rates. Such variability reflected differences in the factors influencing mother-to-child transmission, such as the stage of mothers’ HIV-1 disease and CD4+ lymphocyte counts, as well as variations in follow-up. The protocol chair also noted that the NIH DSMB would review the study on an ongoing basis and evaluate the results, taking rules for halting the study developed by the protocol team into account.14 The chair indicated that the DSMB would include a Ugandan representative. In light of these justifications, JCCI approved the study with placebo. 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] to pregnant women. There is a need to find simpler treatments that work which could be used in Uganda. Therefore the purpose of this trial is to compare a placebo with NVP or AZT [ZDV].” JCCI approved this revision on September 29, 1997 (Hendrix, 1997). As noted, in February 1998, shortly after enrollment into the original four-arm trial began, the results of the Thai trial on prevention of mother-to-child transmission were announced. In light of the demonstrated effectiveness of an intervention that could be feasible in a setting such as Uganda, HIVNET 012 investigators concluded that placebo controls were no longer justifiable. They discontinued the placebo arms, modified the protocol, and assigned new participants to the two active arms only (Jackson et al., 2003). The process of submitting justification for a placebo arm to indepen- 14   Data Safety Monitoring Boards (DSMBs) evaluate research data on an ongoing basis to ensure participant safety and/or study integrity.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study dent review, and then reevaluating the acceptability of a placebo arm after new relevant information appeared, is consistent with accepted practices for both investigators and IRBs, as they seek to maximize scientific benefit without violating their duties to study participants. Finding: The committee finds that the initial design of the HIVNET 012 trial, which incorporated two placebo arms, was properly reviewed and approved by the Johns Hopkins University and Ugandan IRBs, and that justifications for the use of placebo arms were adequately presented. 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. By engaging in this process, researchers demonstrate their concern and respect for those they aim to enroll in a study. The process also allows those who do not wish to participate to protect themselves. Investigators must tailor both the information and the way they convey it to the needs of participants in the particular research context while meeting full disclosure requirements. Researchers must also adapt requirements for documenting such disclosure to the research setting. This requires a consent process that is culturally appropriate, forms of documentation that are sensitive to local concerns (e.g., in some settings, a fear of signing documents), and information delivery geared to the educational levels and cultural understandings of the local population (Benatar, 2002; Gostin, 1995; Lindegger and Richter, 2000; Marshall, 2001; Molyneux et al., 2004). In HIVNET 012, not only were consent forms translated into local languages, but the Ugandan IRB reviewed the entire consent process and the information given to participants, including language pertaining to placebos and randomization. 15   Some exceptions can be made for research that poses minimal risk. Investigators can obtain consent from incompetent subjects, such as children or those with neurological impairment, from an appropriate surrogate.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study Studies funded by DHHS involving children or pregnant women are subject to additional consent requirements. These include consent from appropriate guardians (in the case of children) and fathers (in some research involving pregnant women), and—if the research is of no possible direct medical benefit to the fetus or child—limits on the risks a study can impose upon the fetus or child. As HIVNET 012 did offer the prospect of direct medical benefit to the children, once born, it was not subject to special limits on the risks it could impose. Nonetheless, special consent requirements apply even to this research. When research with a pregnant woman holds out the prospect of benefit to herself as well as the fetus, DHHS regulations (45 CFR Part 46.203) state that investigators must minimize risks to the extent possible, and that they must obtain the consent of the woman but not that of the father. In other words, women do not need the consent of a second party to enroll in research that might be of some benefit to themselves. By contrast, where the research is solely of possible benefit (and risk) to the fetus, consent of the father is also required, unless “he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.” Per DAIDS policy, the HIVNET 012 consent forms included a line that the father of the fetus or infant could sign if he was available (HIVNET 012 Investigators, 1998). In-country researchers regularly counseled participants to involve the fathers in the consent process. 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. The research team was also severely constrained by concerns about violating confidentiality by revealing the women’s HIV status to the fathers, especially given the stigmatization of HIV-positive individuals. The team felt that such disclosure would have been a breach of medical ethics and would have put the women at risk—social, economic, and physical—if confidentiality were breached. Thus, after counseling women to involve the fathers, if the women failed to help investigators locate the fathers, then these men were deemed to be unavailable. Where fathers were available, their consent was required prior to enrollment, as per the approved protocol. In an example given by the investigators, one woman’s partner came with her when she was considering participating in the study. The father did not consent, and the woman was

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study not permitted to participate in the study, despite her own interest in doing so. Federal regulations requiring paternal consent apply only when research is of “no possible medical benefit” to the pregnant women themselves. 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. regulations, but rather would fail to meet the terms under which the IRBs approved the study. The remedy for such a deviation from protocol, therefore, would not lie with DHHS but rather with DAIDS and the IRBs. HIVNET 012 does not appear to have failed to comply with the DAIDS requirement for paternal consent, where available. Given that the investigators’ interpretation of paternal unavailability is consistent with the federal regulations and the IRB requirement, the deviation from protocol would be the failure to document attempts to obtain paternal consent, rather than a failure to obtain it. The rules governing research on children—relevant here because they received ZDV or NVP and remained in the study for follow-up weeks and months after birth—stipulate that investigators should ideally obtain consent from both parents. Again, however, exception is made when one of the parents is unavailable. Because consent is an ongoing process and participants have the right to withdraw from a study at any time, investigators must provide for situations where the consenting parent dies or becomes unavailable. In such cases, a new decision maker—whether father or guardian—must be sought and assurances received that the child is still authorized to participate. In HIVNET 012, infant follow-up proceeded even in cases of maternal demise. If a participating mother died during the first 18 months of the study, no additional consent for follow-up of the child was obtained since the mother had already given consent for 18 months of follow-up. No study products were being administered, only follow-up was being performed (e-mail communication, L. Guay, March 22 and 23, 2005). Despite having obtained consent for the 18-month follow-up prior to the mother’s demise, a guardian should have been identified to take over for the absent mother. As all seminal research ethics documents note, research subjects are entitled to withdraw from research at any time, and in the case of children, a guardian is needed at all times so that withdrawal remains an option.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study Although they were not receiving treatment, children were exposed to some limited risks during the follow-up period. Physical risks were limited to the blood draws needed to confirm HIV status, and blood draws, at least in U.S.-based studies, are considered to entail minimal risk. But social risks remained as well; if a child’s HIV-positive status became widely known, it might trigger social stigma or other harmful reactions by members of the community. Even if these risks were minimal, opportunity ought to have been provided at all times during the follow-up for a responsible adult to terminate a child’s participation. An exception could have been made if the relevant IRBs had concluded that the criteria for waiving consent had been met, but no such request appears to have been made to the IRBs. Investigators explained that they were constrained by respect for confidentiality of the information that the deceased woman had shared with the research team, including her HIV status (Guay, 2004). Reaching out to other family members for consent for continued follow-up of the infant would have required disclosing the mother’s and the infant’s status. Nonetheless, absent a waiver from the relevant IRBs, research practices dictate making some arrangement for an appropriate, competent adult to oversee a child’s participation in a study at all times. With respect to obtaining consent for extended follow-up to age 5, the investigators did recognize the need to identify a responsible adult in cases where the mother had died. The investigators report that, in most cases, a child was then under the care of a relative who was not the father of the child. As a result, the investigators sought guidance from the DAIDS regulatory affairs branch and ARC about who was allowed to consent on behalf of the child. ARC indicated that a parent or legal guardian could consent. Investigators then grappled with local rules governing who constitutes a “legal guardian” after the death of the mother for the purpose of consenting on behalf of the child. The Uganda IRB referred the investigators to the Uganda courts, and after a lengthy process of review, the Ugandan courts determined that, under the Ugandan Child Welfare Act, the individual (parent, relative, guardian) who assumes primary care and support of the child in terms of providing for the welfare of the child (i.e., assumes “parental responsibility”) has the right to sign consent on behalf of the child. Investigators used this guidance to determine who could consent to a child’s participation in the extended follow-up. Findings: The committee finds that the initial study design incorporated all relevant 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.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study The committee finds that the investigators correctly identified appropriate guardians to consent to extended 5-year follow-up in situations where the original consenting parent had died, but that the investigators failed to do this in situations where the consenting parent died while the child was still enrolled in the original, 18-month follow-up. The committee finds that requesting additional consent from the fathers before enrolling the pregnant women or their infants in the study was not necessarily required by U.S. federal regulations but was required per DAIDS policy and was therefore incorporated into the IRB-approved protocol. Finally, the committee finds that the failure to obtain such additional paternal consent was based on the practical unavailability of the fathers and the ethical constraints that prevented the research staff from contacting fathers in the absence of the mother’s support and consent. 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). The investigators acknowledged procedural deficiencies and implemented procedures to correct them (HIVNET 012 Investigators, 2003). However, the Westat and the DAIDS remonitoring reports did not find that subjects failed to give informed consent. A key element in determining whether a study violated subjects’ rights is the evaluation of the risks and benefits of participating. If the study had shown that the rate of adverse events—serious or not, by any definition—was significantly different than that described at the time of enrollment, researchers would have had to alert both new and existing subjects, and apply updated information to new enrollments. As noted by OHRP and Westat, the Ugandan IRB did not provide effective continuing review. On the other hand, the change from a four-arm placebo-controlled study to a two-arm study with active arms represented exactly the kind of change in risk-benefit analysis that triggers a reevaluation of both the study design and the consent process. This information was promptly shared with the relevant IRBs, and the change in the study design was approved. Once the two-arm portion of the study began, however, enrollment proceeded rapidly, and no apparent finding from the interim data collected in the months between commencing and concluding the study enrollment would have changed the risk-benefit balance. While OHRP did criticize the Ugandan IRB for its inadequate continu-

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study ing review, the primary purpose of such review is to determine whether an alteration in the study protocol or the informed-consent process is in order, as mandated by both DHHS regulations and DAIDS special guidance for HIV research (Lin and Meschino, 1993). Per the protocol design, the NIH Data Safety and Monitoring Board or an independent body or group of experts provides the analysis of adverse events and interim data on which the IRB bases its decision. In this case, even assuming the absence of effective local review, the study did not produce evidence of differential risk of adverse effects that should have led to modifications in study design. Nor does it appear that the emerging evidence of efficacy could have led to an early decision to terminate randomization, given the need to document the HIV-1 status of infants and the fast pace of enrollment. Finding: The committee finds that while auditors reported procedural lapses by the Ugandan IRB, there was evidence of rapid and appropriate response by the IRB in approving modification of the design of HIVNET 012 and discontinuation of placebo arms. There was also no evidence that participants signed the wrong version of the consent form. In sum, most of the criticisms concerning the ethics of HIVNET 012 are either based on a misunderstanding of procedural standards (as with compliance with GCP Guidelines), disputes over the interpretation of serious adverse events (where the committee finds that the interpretation used was appropriate), 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). The one exception concerns the absence, in some circumstances, of a responsible adult to take over for a deceased parent who had originally gave consent to enroll a child in the 18-month follow-up period. While there is no evidence that this lapse harmed any children, neither is the absence of such a substitute guardian consistent with proper research practices. Ethical management of a research trial does not consist solely of following procedures. It entails ensuring that subjects are protected, by requiring a reasonable balance of risks and benefits before commencing the study, and by insisting that subjects give free and informed consent before enrolling. Specific procedures exist to reduce the likelihood that ethical lapses will occur. As such, it may be appropriate for agencies such as the FDA to refuse to accept data from trials that do not meet all these procedural requirements. Such an approach may promote adherence to these procedures by those planning and implementing various studies. But for the scientific and

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study medical community at large, the failure to follow some or even all of the procedures does not render a particular trial unethical, absent evidence that subjects were exploited or harmed. Using valid data from such trials to pursue further research and improve patients’ lives is entirely appropriate. 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. The committee finds that there is no reason based in ethical concerns about the design or implementation of the study that would justify excluding its findings from use in scientific and policy deliberations. REFERENCES American Medical Association. 1999. Current Opinions of the Council on Ethical and Judicial Affairs. E-2.075 The Use of Placebo Controls in Clinical Trials. American Medical Association Code of Ethics. Benatar S. 2002. Some reflections and recommendations on research ethics in developing countries. Social Science & Medicine 54(7):1131-1141. Cohen J. 1997. Ethics of AZT studies in poorer countries attacked. Science 276:1022. DAIDS, NIAID (Division of AIDS, National Institute for Allergy and Infectious Diseases). 2003. HIVNET 012 Monitoring Report. DHHS (Department of Health and Human Services). 2005. Protection of Human Subjects, Proposed Criteria for Determinations of Equivalent Protection. Federal Register 70(57): 15322-15327. DHHS. 2004. Code of Federal Regulations: Public Welfare. 45 CFR § 46.101. DHHS and FDA (U.S. Food and Drug Administration). 1997. International Conference on Harmonization (ICH); Guideline on Stability Testing for New Dosage Forms; Availability. Federal Register 62(90):25691-25709. Djulbegovic B, Lacevic M, Cantor A, Fields KK, Bennett CL, Adams JR, Kuderer NM, Lyman GH. 2000. The uncertainty principle and industry-sponsored research. Lancet 356(9230):635-638. Edwards SJ, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J. 1998. Ethical issues in the design and conduct of randomised controlled trials. Health Technology Assessment 2(15):i-vi, 1-132. Ellenberg SS, Temple R. 2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: Practical issues and specific cases. Annals of Internal Medicine 133(6):464-470. FDA and DHHS. 2001. Code of Federal Regulations: FDA Investigational New Drug Application. 45 CFR § 46. FDA and DHHS. 1998. Code of Federal Regulations: FDA Investigational New Drug Application. 21 CFR § 312.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study FDA and DHHS. 1997. Code of Federal Regulations: FDA Investigational New Drug Application. 21 CFR § 312. Subpart D: Sections 312.50 and 312.60. FDA and DHHS. 1996. Code of Federal Regulations: FDA Investigational New Drug Application. 21 CFR § 312. FDA. FDA Regulations Relating to Good Clinical Practice and Clinical Trials. [Online] Available at: http://www.fda.gov/oc/gcp/regulations.html. Accessed March 9, 2005. GAO (General Accounting Office, now Government Accountability Office). 1996. Prescription Drugs: Implications of Drug Labeling and Off-label Use. Testimony of Sarah Jagger, Director of Health Services Quality and Public Health Issues of the Health, Education, and Human Services Division of the U.S. General Accounting Office, Before the Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government Reform and Oversight, U.S. House of Representatives, GAO/T-HEHS-96-212. Gostin L. 1995. Informed consent, cultural sensitivity, and respect for persons. Journal of the American Medical Association 274(10):844-845. 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 L, Jackson B. 2003. Makerere University–Johns Hopkins University Quality Management Plan. 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. Hendrix TR. September 22, 1997. Letter to Jackson B. HIVNET Group. Protocol Version 1.0, 2 June 1997. 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. 2003. MUJHU Quality Management Plan. HIVNET 012 Investigators. 1998. Sample Informed Consent Form. ICH (International Conference on Harmonisation). 1996. Guideline for Good Clinical Practice. Available at http://www.ich.org. Jackson B. July 9, 1997. Letter to Hendrix TR. 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. Levine RJ. 1999. The need to revise the Declaration of Helsinki. New England Journal of Medicine 341(7):531-534. Lilford RJ, Djulbegovic B. 2001. Declaration of Helsinki should be strengthened. Equipoise is essential principle of human experimentation. BMJ 322(7281):299-300. Lin MH, Meschino JA. September 13, 1993. Letter to colleague. Lindegger G, Richter L. 2000. HIV vaccine trials: Critical issues in informed consent. South African Journal of Science 96(313-317). Marshall P. 2001. The Relevance of Culture for Informed Consent in U.S.-funded International Health Research: Findings and Recommendations from the Case Study on Informed Consent for Genetic Epidemiological Studies of Hypertension, Breast Cancer, and Diabetes Mellitus in Nigeria. Commissioned Paper for National Bioethics Advisory Commission: Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries II:C1-C38.

OCR for page 73
Review of the HIVNET 012 Perinatal HIV Prevention Study McNeilly P (OHRP). March 24, 2003a. Letter to Nyiira ZM and Sewankambo NK. [Online] Available at http://www.hhsgov/ohrp/detrm_letrs/YR03/mar03e.pdf. Accessed February 15, 2005. McNeilly P (Office of Human Research Protections, OHRP). March 15, 2002a. Letter to Nyiira ZM and Sewankambo NK. McNeilly P (OHRP). July 16, 2002b. Letter to Nyiira ZM and Sewankambo NK. McNeilly P (OHRP). October 28, 2002c. Letter to Nyiira ZM and Sewankambo NK. [Online] Available at http://www.hhsgov/ohrp/detrm_letrs/YR02/oct02e.pdf. Accessed February 15, 2005. Molyneux C, Peshu N, Marsha K. 2004. Understanding of informed consent in a low-income setting: Three case studies from the Kenyan coast. Social Science & Medicine 59:2547-2559. Murphy T. 2004. Case Studies in Biomedical Research Ethics. Cambridge, MA: MIT Press. National Bioethics Advisory Commission. 2001a. Ethical and Policy Issues in Research Involving Human Participants. Available at http://www.bioethics.gov/reports/past_commissions/nbac_human_part.pdf. National Bioethics Advisory Commission. 2001b. Ethical and Policy Issuses in International Research: Clinical Trials in Developing Countries. Volume 1: Report and Recommendations of the National Bioethics Advisory Commision. Available at http://www.bioethics.gov/reports/past_commissions/nbac_international.pdf. Office of Human Subjects Research, National Institutes of Health. 1979. The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. PPD. 2003. Clinic Site Monitoring Group HPTN Interim Site Visit Report. 1Q03 Regulatory File Review, February 3-7, 2003. Radley D, Stafford R, Finkelstein S, Cockburn L. 2004. Powerpoint Presentation: Off-label Prescription among Outpatient Physicians. [Online] Available at http://www.academyhealth.org/2004/ppt/radley.ppt. Accessed March 14, 2005. SCHARP (Statistical Center for HIV/AIDS Research and Prevention). 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 Transmission of HIV-1 Infection. ‘t Jong GW, Vulto AG, de Hoog M, Schimmel KJ, Tibboel D, van den Anker JN. 2000. Unapproved and off-label use of drugs in a children’s hospital. New England Journal of Medicine 343(15):1125. Temple R, Ellenberg SS. 2000. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: Ethical and scientific issues. Annals of Internal Medicine 133(6):455-463.