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10/3/2000

Stricter Controls Coming for Use of Teratogenic Acne Treatment

Cheryl A. Thompson

On the advice of a group of dermatologists and other nongovernmental experts, the Food and Drug Administration (FDA) will work with Roche Laboratories to develop a mandatory program for guaranteeing that no patient starts isotretinoin therapy while pregnant and no pregnancies occur in patients taking the acne treatment. The no-pregnancy guarantee will likely involve pharmacists checking a central database to verify that female patients with a prescription for the drug, known by the brand name Accutane, have recently had a negative pregnancy test.

The Sept. 18 move marks at least the second time in recent months that FDA met with a drug manufacturer to insist on a more aggressive approach to managing the risks associated with use of the company’s product. Similar to a June 27 meeting, at which the agency conferred with one of its advisory committees, FDA officials again asked advisers to decide which of various options proposed by the agency should be used to increase the strength of the risk management program for an already-marketed drug.

Pregnancies despite prevention efforts

Accutane, a teratogen that can cause severe brain abnormalities and leave newborns without external ears, was approved by FDA in 1982 for the treatment of severe cystic acne unresponsive to other therapies. The initial labeling included a warning against use by pregnant women. Typical therapy is supposed to last 15 to 20 weeks, or 105 to 140 days.

Over the years, the warnings have increased and Roche has instituted programs to prevent pregnancies and monitor the effectiveness of these efforts.

Yet, despite the warnings, pregnancy-prevention kits given to prescribers, educational videotapes for patients, and informed-consent forms, company-sponsored monitoring by the Slone Epidemiology Unit at Boston University School of Medicine shows that pregnancies do occur.

For every 1,000 U.S. women who take isotretinoin for 140 days, 2.8 pregnancies result, Sloan Director Allen A. Mitchell told FDA officials and the agency’s Dermatologic and Ophthalmic Drugs Advisory Committee.

John E. La Flore, chief medical officer at Roche, said the U.S. rate is similar to the worldwide rate and better than when the drug was in clinical tests. During a Phase III trial, 4.1 pregnancies occurred for every 1,000 140-day courses of Accutane therapy, he said, adding that this shows how effective the company’s efforts have been at preventing pregnancies among isotretinoin users.

But FDA believes that the pregnancy rate reported by the Sloan unit, which surveys women who volunteer to answer questionnaires while taking isotretinoin, underestimates the true rate.

FDA Epidemiologist Amarilys Vega pointed to the voluntary nature of Roche’s surveillance program and participation by less than half of female isotretinoin users as evidence that the real pregnancy rate must exceed 2.8 per 1,000 female users.

Further, said Vega, data gathered by the Sloan unit shows that "physicians do not use all of the elements in the [pregnancy-prevention] kit." Twenty-three percent of isotretinoin users surveyed by the Sloan Epidemiology Unit indicated they did not sign an informed-consent form and a similar percentage did not undergo pregnancy testing before starting therapy.

Increased prevention efforts

Vega said that, despite efforts by FDA and Roche, isotretinoin prescribers do not follow the pregnancy-prevention program.

While she described the company’s educational module as "outstanding," Vega said that the risk management program for isotretinoin must involve all female patients.

Vega presented five designs for a more effective pregnancy-prevention program, ranging from Roche’s proposal for an improved voluntary program to FDA’s proposal for a mandatory system that includes registered distribution by pharmacies (box).

Proposed Designs for Isotretinoin Risk Management Program

Program Component

Design 1
(Roche proposal)

Design 2

Design 3

Design 4

Design 5

Education and informed consent

x

x

x

x

x

Complete (not voluntary) participation by female patients

 

x

x

x

x

Tracking of pregnancy exposures

     

     Physician registry 

x

x

x

x

x

     Patient surveys 

x

x

x

x

x

     External data 

 

x

x

x

x

Optimal compliance via linkage

     

     Pregnancy testing 

  

x

x

x

     Other elements for
     pregnancy testing

   

x

x

Registered distribution to pharmacies

    

x

Source: Food and Drug Administration

Members of the advisory committee tended not to want to place an additional burden on pharmacies by requiring registration and certification, a program component of only design 5. Committee members also voiced concern about the inconvenience such a distribution system might pose for patients.

Vega countered that the special distribution program for thalidomide, a teratogen whose controlled distribution includes registration by pharmacies, places no burden on patients except perhaps for access.

Nonetheless, nearly all of the dozen or so committee members present at the meeting voted in favor of design 3 as the program most likely to achieve the no-pregnancy goals while balancing the associated burdens. In this design, pharmacists must verify that a negative pregnancy test result has been documented before they can dispense a supply of isotretinoin. A central database would be created specifically to track female patients and pregnancy exposures.

Although not bound by the advisory committee’s decision, FDA tends to follow the advice offered. The logistics of the improved risk management program will be worked out between FDA and Roche.