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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).
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