The following press release was issued on December 1, 2006 by Public Citizen:
Drug-Company Sponsored Research Trial Needlessly Put Indigent Pregnant Women and Their Infants at Risk
Placebos Administered to Pregnant Women With Genital Herpes Simplex Virus Resulted in Unnecessary Cesarean Deliveries
WASHINGTON, D.C. – Dozens of primarily indigent pregnant women enrolled in a drug-company sponsored research trial were needlessly put at risk by being treated with a placebo rather than a generic drug proven to help them, according to a letter authored by Public Citizen and two medical school professors and obstetricians published in the December edition of the journal Obstetrics & Gynecology.
The trial, funded by Glaxo-Wellcome (now GlaxoSmithKline), measured the efficacy of valacyclovir administered to pregnant women with a history of genital herpes simplex virus (HSV) in reducing outbreaks of genital HSV lesions at the time of labor. Women with HSV outbreaks during pregnancy, especially those who experience a first episode, are more likely to have another outbreak while in labor. When this occurs, a Cesarean delivery is routinely performed to prevent HSV transmission to the baby, which can result in sometimes-fatal neonatal HSV infection.
The clinical trial ran from April 1998 to November 2004 at Parkland Hospital in Dallas, which serves a predominantly low-income population. The results were published in the July 2006 edition of Obstetrics & Gynecology, the official journal of the American College of Obstetricians and Gynecologists (ACOG).
Valacyclovir is a drug that is converted in the body into acyclovir. Since 1999, acyclovir has been recommended by ACOG to be considered at 36 weeks of gestation for pregnant women with their first episode of HSV during that pregnancy to prevent another outbreak at the time of labor and the need for a Cesarean delivery. The authors of the study ignored this guideline by including in the trial 62 women who had a first episode of genital HSV during the pregnancy, most presumably recruited after the ACOG guidelines were published.
In addition, four of the researchers who wrote the 2006 article published a review article in 2003 that concluded that acyclovir significantly reduced Cesarean rates for women with both first and recurrent episodes of HSV compared to a placebo. Nonetheless, for more than a year after submitting their findings, the researchers continued to enroll women with both first and recurrent episodes, half of whom received placebos.
“At the very same time these researchers were publishing their conclusion that acyclovir could reduce Cesareans, they weren’t offering this drug to these indigent patients,” said Dr. Adam Urato, an obstetrician at the University of South Florida and one of the letter’s authors. “They were knowingly placing their patients at higher risk. Did the patients understand that the researchers themselves had concluded that acyclovir reduced the risk of Cesarean?”
As a result of this conduct by both the drug company and the researchers, a significant number of the women assigned to receive the placebo had an HSV outbreak that led to a Cesarean section – an outbreak that likely could have been prevented if they had been appropriately treated with acyclovir. The Declaration of Helsinki, developed by the World Medical Association as a statement of ethical principles in medical research involving human subjects, states that any “new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”
The authors of the letter called upon the University of Texas Southwestern Medical Center at Dallas, which authorized the study, to issue a formal apology to the pregnant women enrolled and to perform a full investigation as to what went wrong to allow such a trial to take place. They also called for compensation for the women involved in the trial who were not properly treated and underwent Cesarean sections.
In addition, they urged ACOG and the editors at Obstetrics & Gynecology to initiate an inquiry as to how this study was handled by the journal. The Declaration of Helsinki also implores journals that “reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.”
“Indigent pregnant women represent a particularly vulnerable population,” said Dr. Aaron Caughey, an obstetrician at the University of California, San Francisco, and the lead author of the letter. “That a research trial could be performed that put pregnant women at risk when an effective medication was available flies in the face of responsible medical research.”
Public Citizen has a long history of involvement in the debate over the appropriate use of placebos in clinical trials, particularly in developing countries. “We have long contended that if researchers and drug companies could get away with administering placebos under questionable conditions in developing countries, they would do the same to poor people in the United States,” said Dr. Peter Lurie, deputy director of Public Citizen’s Health Research Group. “Now they have.”
Here is the letter to the editor in Obstetrics & Gynecology by Dr.s Caughey, Lurie and Urato:
Trials of Prophylaxis to Prevent Recurrent Herpes Should not Utilize a Placebo Arm (HRG Publication #1794)
Caughey AB, Urato AC, Lurie P. Valacyclovir Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial. Obstet Gynecol 2006;108:1550.
Valacyclovir Prophylaxis to Prevent Recurrent Herpes at Delivery: A Randomized Clinical Trial
To the Editor:
We were not surprised to read that valacyclovir administered to pregnant women with a history of genital herpes simplex virus (HSV) led to fewer recurrent lesions than placebo. After all, valacyclovir is a prodrug of acyclovir, which has been demonstrated repeatedly to reduce recurrent lesions in pregnant women., We were surprised that 168 women were randomly assigned to placebo instead of acyclovir. According to the Declaration of Helsinki, any “new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.”
The study began recruiting in 1998; in 1999, the American College of Obstetricians and Gynecologists (ACOG) concluded that “For women at or beyond 36 weeks of gestation with a first episode of HSV occurring during the current pregnancy, antiviral therapy should be considered.” Nonetheless, 62 women with first episode HSV were enrolled in the study. In 2003, the same authors published a meta-analysis that reviewed five studies that included mostly recurrent HSV patients. Their review concluded that acyclovir reduces recurrent lesions and decreases cesarean rates. If the authors understood that acyclovir reduced recurrent lesions, why did they continue to assign such patients to placebo until November 2004?
We understand that a pharmaceutical company might prefer to compare its product to placebo rather than to a known effective therapy, but we are at a loss as to why researchers would place their patients at higher risk. What were the patients told as the new evidence accumulated?
Finally, we question why Obstetrics & Gynecology would publish such a study without at least an editorial when the Declaration of Helsinki implores journals that “Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.”
Aaron B. Caughey, MD PhD
University of California, San Francisco
Department of Obstetrics, Gynecology, and Reproductive Sciences
San Francisco, California
Adam C. Urato, MD
University of South Florida
Department of Obstetrics and Gynecology
Peter Lurie, MD, MPH
Public Citizen’s Health Research Group