Placebo use in pregnant herpes patients critiqued
Active control vs. alternative drug not proven safe
The debate about the appropriateness of placebos in clinical trials recently spilled over into the pages of the journal Obstetrics and Gynecology, where two obstetricians and a representative of the national public-interest watchdog group Public Citizen wrote to complain about a published study of an antiviral drug used to prevent herpes outbreaks in pregnant women.
The original study, published in the July 2006 issue of the journal, measured the efficacy of an antiviral drug, valacyclovir, against a placebo in preventing herpes outbreaks that would have required the pregnant subjects to have a cesarean section at delivery.
The study by researchers at the University of Texas Southwestern in Dallas found that valacyclovir treatment, after 36 weeks of gestation, led to a significant reduction in recurrent herpes outbreaks requiring cesarean deliveries. Thirteen percent of the women in the placebo group had a herpes outbreak that required a cesarean, compared to 4% of the valacyclovir group.
Adam Urato, MD, an assistant professor of maternal-fetal medicine at the University of South Florida, Tampa, FL, was one of the authors of a letter published in the December 2006 issue of Obstetrics and Gynecology, criticizing the use of a placebo in the study. Urato says he was struck by the timing of the valacyclovir study, when compared to two events:
• The 1999 recommendation by the American College of Obstetricians and Gynecologists (ACOG) that another antiviral drug, acyclovir, be considered for women who suffer a first episode of herpes during their pregnancy. Women with first episodes during pregnancy are at increased risk for additional outbreaks, including those that might make a cesarean section necessary.
While the ACOG guidelines for those women recommend only that acyclovir be "considered," Urato says that advice was given a Level B recommendation, which carries great weight with obstetricians.
"Level B is almost [ACOG's] strongest recommendation," he says. "There are not a lot of things in our field that are supported to that extent. So that's a significant recommendation that they made back in 1999."
• A 2003 meta-analysis, by many of the same authors of the valacyclovir study, concluded that acyclovir reduced rates of cesarean section for women with recurrent herpes outbreaks.
Given those two findings, Urato says, the researchers were ethically bound not to give placebos to women in the study after those dates — 1999 for women with their first herpes episodes, 2003 for those with recurrent outbreaks.
"[The valacyclovir authors] say that in 2003, if a woman with herpes outbreaks is given acyclovir instead of placebo, it will decrease her rate of C-section, as well as decrease her rate of viral shedding," he says. "That's their conclusion, it's pretty unambiguous.
"They said that in 2003, but then they continued giving women placebo through 2004. So you have to ask the question, as we did, were these investigators knowingly placing their patients at increased risk?"
Authors defend study
The main authors of the study, along with the IRB at UT Southwestern, did not respond to requests for interviews regarding the study. Public relations officials at the university's medical center referred inquiries to the published response by the study's authors in the December 2006 issue of Obstetrics and Gynecology.
In that response, the authors argue that when their IRB approved the study in 1997, the effectiveness of acyclovir was unclear, and that clinical equipoise, or genuine uncertainty about the effectiveness of the two arms in their study, existed throughout the time that they enrolled subjects.
They write that previous studies of acyclovir didn't provide "sufficient power" to address whether the use of acyclovir reduced the risk of neonatal herpes, and that the safety of the drug to the fetus hadn't been established.
"Even in 2003, when there existed evidence of some maternal benefit, the risk of exposure to the fetus remained," the authors write. "In our opinion, the balance of risks and benefits to both the fetus and pregnant woman justified continuation of the placebo-controlled trial."
Urato calls that response disingenuous, pointing out that women and fetuses in the active arm of the study were being exposed to valacyclovir.
"I don't think their lengthy justification regarding fetal safety addresses the principal issue — they were placing their patients at known higher risk for cesarean," he says. "They knew it because they published it in 2003."
He says that at the very least, patients would have to be informed during the consent process that if they were randomized into the placebo arm of the study, they could be at increased risk for cesarean delivery.
Group monitors placebo use
Peter Lurie, MD, MPH, deputy director of Public Citizen's Health Research Group in Washington, DC, co-authored the letter with Urato and lead author Aaron Caughey, MD, PhD, an obstetrician at the University of California, San Francisco.
Lurie says Public Citizen has spoken out for years against what it sees as the inappropriate use of placebo controls in clinical trials. The group criticized clinical trials in Africa during the 1990s that used placebos with HIV-positive pregnant women instead of a drug known to be effective in preventing mother-to-child transmission of HIV.
He says inappropriate use of placebos is "widespread," in part because the FDA tends to favor them over active-control trials.
Lurie says his group doesn't entirely rule out the use of placebos in clinical research.
"We do think it's acceptable to give a placebo for let's say, a treatment [for a serious condition], which barely works and which has adverse effects," he says. "We think it's acceptable to give a placebo for seasonal allergy, for headache, we think that's fine, because it's less serious when assigned to a placebo group.
"But the moment that it involves life or death, a serious outcome, I don't think it's reasonable to randomize people anymore," Lurie says. "When more women will end up with cesarean sections, I think that's a serious outcome."
References:
Sheffield JS, et al. Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet Gynecol. 2006;108:141-147.
Caughey AB, et al. Valacyclovir prophylaxis to prevent recurrent herpes at delivery: a randomized clinical trial. Obstet Gynecol. 2006;108:1550; author reply 1550-1552.
The debate about the appropriateness of placebos in clinical trials recently spilled over into the pages of the journal Obstetrics and Gynecology, where two obstetricians and a representative of the national public-interest watchdog group Public Citizen wrote to complain about a published study of an antiviral drug used to prevent herpes outbreaks in pregnant women.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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