Methodological Challenges in Biomedical HIV Prevention Trials (2008) / Chapter Skim
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4 Design Considerations: Pregnancy
4 Design Considerations: Pregnancy
Pages 104-118
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From page 104... ...
High pregnancy rates and the product use implications for women who become pregnant have important implications for the design, conduct, and generalizability of biomedical HIV prevention trials, including loss in trial power when the occurrence of pregnancies has not been adequately accounted for when planning the size and duration of the trial, and potential interpretational problems when women who become pregnant are taken off product. Beyond the loss of study power and generalizability of results that the occurrence and handling of pregnancies can produce, removal of product in trial participants that become pregnant raises questions about the real-world use of approved products during pregnancy, because safety and efficacy data for pregnant women will not be available.
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From page 105... ...
Biomedical HIV prevention trials involving sexually active women of childbearing age also usually make other forms of contraception available, such as hormonal patches or injections, oral contraceptives, and to a lesser extent, intrauterine devices, through onsite provision of contraception or referrals to local family planning clinics. However, women are often unable to negotiate condom use with their sexual partners, and adherence to other contraceptive methods is less than universal (Raymond et al., 2007)
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From page 106... ...
can also monitor actual pregnancy rates during a trial, and adjust its sample size and duration if these exceed expectations. Of course, this strategy may come at a significant cost in time (for events-driven trials)
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From page 107... ...
This raises important questions about the best ways to collect safety information, and whether there are circumstances under which it would be ethical to allow women who become pregnant to continue receiving the study product. Historical Context In evaluating whether there are circumstances when women who become pregnant during a trial should have the option of remaining on product, it is important to understand the historical context, legal transformations, and ethical considerations that have shaped current policy and practice.
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From page 108... ...
These standards reflected a move toward greater protection for vulnerable populations in response to research abuses, and, most notably, the fetal injuries that occurred during the thalidomide disaster. Moreover, until the 1990s, developers of biomedical products rarely relied on animal studies to identify potential reproductive risks to women and the effects on their offspring until phase 3 clinical trials revealed a product's efficacy.
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From page 109... ...
The guidelines also recommended that investigators complete reproductive toxicity studies before phase 2 or phase 3 trials, and the informed-consent process was to include all available information about potential reproductive toxicities. In contrast to the IOM committee's position, however, FDA guidelines said that the potential risk to the fetus took precedence over the choice of the woman who had become pregnant in trials before efficacy had been established.
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From page 110... ...
A recent report by UNAIDS and the World Health Organization, Ethical Considerations in Biomedical HIV Prevention Trials, recommends a more inclu sionary approach (2007, p.
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From page 111... ...
Several sources can provide information on the potential benefits and risks of an HIV prevention product or device. These include preclinical studies in animals, experience with a product in other clinical trials or applications, follow-up of women who are exposed to the product and become pregnant during the trial, and research and monitoring during the posttrial phase.
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From page 112... ...
. The guidelines also recommend that all female reproductive toxicity studies and the standard battery of genotoxicity studies be completed prior to inclusion in any clinical trial for women of childbearing potential who are not using highly effec tive birth control or whose pregnancy status is unknown and for women who are pregnant.
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From page 113... ...
The guidelines on timing of reproductive toxicity studies vary by region, particularly with respect to trial populations of women of childbearing potential on highly effective birth control (ICH, 2000)
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From page 114... ...
. No data have yet been published to demonstrate the efficacy of this approach. Information Collected During a Trial Given high pregnancy rates during clinical trials of HIV interventions, some late-stage efficacy trials will accrue significant experience with product exposure early in the first trimester, one of the most vulnerable times for teratogenicity, even when the trial is designed to discontinue product upon detection of pregnancy.
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From page 115... ...
For example, drug companies that produce antiretrovirals support a pregnancy registry that is intended to provide early signals of birth defects associated with prenatal exposure. Health care professionals may register pregnant women who have used the drugs, so information on pregnancy outcomes can be recorded.
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From page 116... ...
Recommendation 4-2: Although the current policy of excluding preg nant women from biomedical HIV prevention and other trials stems from an historically protectionist orientation adopted by regulators, the principles of research ethics neither mandate nor preclude use of the product by pregnant women. Because any approved product subse quently would likely be used by many woman who become pregnant, sponsors and investigators of a biomedical intervention should specify in advance of any late-stage trial how they will establish its safety and efficacy for pregnant women and their fetuses, based on information collected both during and after clinical trials.
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From page 117... ...
When interim analyses provide evidence of fetal safety and potential benefit to women, regulators and IRBs should consider allowing women to stay on product while pregnant. REFERENCES Barreiro, P., J
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From page 118... ...
2007. Ethical considerations in biomedical HIV prevention trials.
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