Depo-Provera Black Box Warning Challenged In Physician Petition
This article was originally published in The Pink Sheet Daily
Executive Summary
Two obstetrician/gynecologists argue there is no published clinical evidence that extended use of the injectable contraceptive is harmful; they cite a Pfizer-funded study that found Depo-Provera users already had a higher risk of bone fracture than nonusers and the risk did not increase with use of the drug.
Two obstetrician/gynecologists are asking FDA to drop the black box warning on Depo-Provera (depot medroxyprogesterone acetate) that states women using the injectable contraceptive may lose significant bone mineral density and should not take it longer than two years unless other birth control methods are inadequate.
Andrew Kaunitz, a professor at the University of Florida College of Medicine-Jacksonville, and David Grimes, a clinical professor at the University of North Carolina School of Medicine, submitted a citizen petition to FDA in March asserting that there is no published clinical evidence showing harm with extended use of the drug. They say the black box warning was based on an invalid surrogate endpoint – bone mineral density – which is known not to predict bone fracture.
“The published evidence indicates that these severe restrictions are medically inappropriate,” the petition states. “By depriving women of long-term use of this safe, effective product, this black box warning paradoxically has harmed public health in the United States and around the world.”
FDA approved Pfizer Inc.’s Depo-Provera as a three-month injectable contraceptive in 1992 after many years of debate over the safety of the drug. At that time there were concerns that it might increase breast cancer risk based on beagle studies. In 2004 FDA required the addition of the black box warning based on the results of two five-year post-marketing studies (Also see "Depo-Provera "Black Box" Urges Limited Long-Term Use" - Pink Sheet, 17 Nov, 2004.). The drug is off patent and available as a generic.
Kaunitz said in an interview that he and Grimes decided to petition FDA to remove the black box warning following the publication of a retrospective cohort study of fractures in depot medroxyprogesterone acetate (DMPA) users. Kaunitz is one of the co-authors of the study, which was led by Lee Lanza, of RTI Health Solutions, under contract to Pfizer.
Pfizer funded the study to assess the risk of fractures using a United Kingdom database of general practices. A German case control study using the U.K. database suggested women who used DMPA experienced more fractures than those who did not. But the Lanza study, published in the March issue of the American College of Obstetricians and Gynecologists’ journal Obstetrics & Gynecology, found that before contraceptive use started, DMPA users had higher fracture risk than nonusers and the risk did not increase after they started DMPA.
Warning Is Not Evidence-Based, Profs Argue
Kaunitz testified before the FDA advisory committee before it voted to recommend approval of Depo-Provera. He said the injectable contraceptive is a major contributor to the prevention of unwanted pregnancy, especially in younger women, and that the black box warning has reduced its use.
The citizen petition includes statistics on contraception use in the U.S. from 1982 to 2008 published by the Centers for Disease Control and Prevention in August 2010. The CDC found that the percent distribution of Depo-Provera declined from 3.3% in 2002 to 2% in 2006-2008.
The petition states that FDA’s black box warning is inconsistent with other major medical and public health organizations around the world, including the World Health Organization and the American College of Obstetricians and Gynecologists.
Kaunitz and Grimes further argue that the warning is not evidence-based.
“The FDA is appropriately concerned when pharmaceutical companies mislabel their products in ways that are not based on sound science,” the petition states. “A dual standard cannot exist. The same evidence-based scientific standards must apply to the FDA itself.”
The petition notes that Kaunitz is a consultant for Teva Pharmaceutical Industries Ltd., which markets generic Depo-Provera, regarding oral and intrauterine contraception. He said he has not discussed Depo-Provera with Teva.
In 1984 Public Citizen urged FDA not to approve Depo-Provera, saying it had been shown to cause breast cancer in dogs and uterine cancer in monkeys. Asked about the citizen petition, Sidney Wolfe, director of Public Citizen’s Health Research Group, said he is opposed to eliminating the black box warning.
The effort to remove it “is kind of foolish,” Wolfe stated. “One could argue that the black box warnings should be increased to say there are some studies that suggest risk of fracture in some sub-groups.”