Documentation of a negative pregnancy test would be required before Accutane prescriptions could be filled under a risk management program recommended by FDA's Dermatologic and Ophthalmic Drugs Advisory Committee Sept. 18.

The committee agreed 13-1 (with two abstentions) with FDA's proposal that a pregnancy prevention program for isotretinoin create a linkage between a negative pregnancy test and the dispensing of Accutane.

"To optimize compliance, we introduce the concept of a real-time linkage between pregnancy test results and dispensing," FDA Office of Postmarketing Drug Risk Assessment Epidemiologist Amarilys Vega, MD, explained - "a no test, no drug policy."

Under the design, a prescribing physician would have to document a negative test, which a dispensing pharmacist would have to verify prior to filling a script.

Requiring a pregnancy test may catch patients who are pregnant prior to starting therapy, National Institute of Child Health & Human Development researcher James Mills, MD, said.

He pointed to Roche data, collected by the Slone Epidemiology Unit at Boston University School of Public Health, indicating that 14% of women who became pregnant while on Accutane reported they were pregnant at their initial doctor visit. Between 1982 and March 31, 2000, 1,995 pregnancies in U.S. patients taking Accutane were reported to the company.

In addition, for 12% of pregnancy exposures, the patient did not wait until the second or third day of her menstrual cycle to begin therapy.

To ensure full patient participation in the pregnancy prevention program, the recommended design also calls for mandatory registration of all physicians and program participants, allowing for more accurate tracking of pregnancy exposures and outcomes, FDA's Vega explained.

Roche Chief Medical Officer & VP-Medical Affairs Russell Ellison, MD, said the company opposed "a program that tries to obtain compliance through conditional access" to the drug.

While Roche's new targeted pregnancy prevention program calls for two negative pregnancy tests prior to the initiation of Accutane therapy, compliance with the plan is voluntary.

Ellison maintained that mandatory risk management tools "could produce an indiscriminate barrier to access - people who otherwise qualify for the drug...would not be able to take it."

Although the committee commended Roche's efforts, a more restrictive risk management program was recommended.

"Drug use of Accutane among women of childbearing potential is escalating," Vega said. "In spite of all the sponsor's efforts to communicate Accutane's teratogenic potential, there is still limited compliance" with pregnancy testing before and during treatment and with appropriate use of contraception.

"Participation in [the] Slone survey is incomplete," at 40%, Vega added. Many committee members called for better tracking mechanisms.

The advisory committee unanimously supported FDA's goals for the pregnancy prevention program: that no one should begin Accutane if pregnant and that no pregnancies should occur while on Accutane. The committee also urged that there should be a program to assess progress towards these goals.

The committee-endorsed program would ensure that no one starts Accutane therapy if pregnant, and partially satisfies the second goal, as "pregnancies occur[ring] between office visits will be addressed as soon as possible," Vega said.

Of the five program designs presented to the committee, ranked by degree of restrictiveness, the committee chose the one in the middle.

Other risk management options considered by the committee included mandatory documentation of a conversation between prescriber and patient about contraceptive options prior to the dispensing of a script. FDA also presented a program that would require pharmacies to be registered with FDA in order to be authorized to dispense Accutane.

The committee expressed concern about the burden that the various proposals would place upon patients, physicians and pharmacists.

Celgene, which requires pharmacies to register in order to dispense Thalomid (thalidomide) through the STEPS program, agreed. "The biggest problem we've experienced with the program is the level of work that the pharmacies have to do," Celgene Executive Director-Sales and Commercial Operations Jay Kaminski said.

Comparisons between the teratogenic effects of thalidomide and Accutane were frequently made during the meeting.

In the Slone survey, less than half of the subjects actually used two forms of contraception. Only 67% postponed taking Accutane until a pregnancy test, and only 57% waited until the completion of their next menstrual cycle, as instructed.

Slone data also shows that 11% of the women who became pregnant had intended to remain abstinent, while 34% of women who became pregnant had planned to use contraceptives but failed to use contraception on the date of conception. These data indicate that 45% of the pregnancy exposures were unexpected events, Mills pointed out.

Because 45% of pregnancies were due to a lapse in abstinence or a failure to use contraception, Mills suggested that women "might benefit by post-coital contraception."

FDA said emergency contraceptives, which are part of the STEPS program, are "on our radar screen," and "definitely should be a feature of any of these designs." Information on emergency contraception is featured in Roche's plan, the company noted.

Voting consultant Arthur Levin, Center for Medical Consumers, argued that "it would be much more helpful to include resources that people could be directly referred to," such as a hotline.

Several committee members expressed concern about the extent of Accutane prescribing.

Committee Guest Edward Lammer, MD, noted that while there were about 70,000 annual Accutane scripts prescribed to female patients in the late eighties, "there are now over 200,000 new prescriptions per year in reproductive age women. I don't see how this can be justified."

"I think there's clearly a problem of overprescribing," Lammer added.

Voting consultant Roselyn Epps, MD, asked if Roche had any data regarding an increase in acne cases, "to support the increase in prescriptions given."

Ellison commented that the only relevant survey dates back to 1974, before Accutane was developed.

However, Ellison claimed that "there's not...a large number or an ever-increasing number of uses in milder acne." He estimated that between 10%-15% of Accutane use is for less severe forms of acne.

Accutane was introduced in 1982 with a pregnancy Category X and was contraindicated for treatment of female patients who are pregnant or might become pregnant.

The most recent labeling changes, requiring discussion of the need for using two forms of contraception simultaneously, two negative pregnancy tests, instructions to join the Slone Accutane survey and to view a video about contraception, were made in May. However, FDA is uncertain about how effective the changes to the label, which already has a two and a half page black box, will be (¹ Also see "Accutane Link To Depression Needs Further Study, FDA Committee Says" - Pink Sheet, 25 September, 2000.).

Roche maintained that, "for the vast majority of Accutane-exposed pregnancies, the female patients were specifically warned to avoid pregnancy during Accutane therapy."

After analyzing the existing risk management measures, Roche identified patterns among women who reported pregnancy exposures. Roche said it has designed its new pregnancy prevention program to target these behaviors.

Roche began implementing the targeted program in June. Elements of the risk management effort include a pamphlet for doctors, a video for patients, a new patient folder detailing a ten-step program, continuing medical education, education for office staff and pharmacists, as well as modifications to the Slone survey. Roche expects to increase enrollment in the Slone survey to 60% by March 2001.

Pregnancy Test Should Be Required For Accutane Rx, FDA Cmte. Urges

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