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An FDA advisory committee on Wednesday voted 17-4 (with one abstention) to recommend removing a "lockout period" from a risk evaluation and mitigation strategy (REMS) for isotretinoin prescribing that requires patients to wait an extra 19 days -- and take an additional pregnancy test -- if they miss a 7-day window for picking up their first prescription of the severe acne medication.

"I think this places an unduly high burden, physically and psychologically, on our patients," said committee member Ken Katz, MD, a dermatologist at Kaiser Permanente in San Francisco. "There's likely some, but very marginal, benefit to this additional period, and a lack of clear medical and scientific rationale for it ... It seems arbitrary. Likely we will miss some pregnancies, and we are missing some already, but the burden is not matched by the benefit."

"Missing the 7-day prescription window as a trigger for the 19-day lockout period is not very effective for identifying a subpopulation with a higher risk of pregnancy," said Tao Liu, PhD, of the Brown University School of Public Health in Providence, Rhode Island. "Actually, patients can miss the 7-day prescription window for many reasons not related to the pregnancy. And during these periods, the data suggests that the pregnancy rate is very low," so the lockout period doesn't have much effect.

Fertile Period Questioned

The vote came at the end of a to discuss the REMS program, known as iPLEDGE. The members of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee were asked to discuss and vote on a number of questions related to the administration of iPLEDGE.

Committee chair Vincent Lo Re III, MD, of the University of Pennsylvania's Perelman School of Medicine in Philadelphia, was one of those voting for keeping the lockout. "The 19-day lockout period ensures that patients who can become pregnant do not receive and start taking isotretinoin during their most fertile period," he said, adding that one study cited in the FDA briefing document found that testing for pregnancy 19 days after conception can detect up to 66% of pregnancies. "Since treatment with isotretinoin is elective, I felt it was valuable to avoid potential exposure to isotretinoin exposure as much as possible to avoid fetal malformations, spontaneous abortion, and premature birth."

The "fertile period" was one of the elements of contention during the meeting. "The rationale for the 19-day wait is to ensure the next confirmatory pregnancy test is completed after the most fertile period of the menstrual cycle is passed," said Gregory Wedin, PharmD, of Upsher-Smith Laboratories in Minnesota, who spoke on behalf of the Isotretinoin Products Manufacturers Group (IPMG). "This ensures the patient does not receive and start taking [the] drug during the most fertile period," which he identified as days 12-16 of a 28-day menstrual cycle.

But not everyone agreed with that assessment. "While we understand the concept of the mid-cycle fertile period that applies to patients on abstinence, the IPMG and FDA fail to take into account that these patients are at the same risk of failed abstinence each month," said Emmy Graber, MD, director of the American Acne and Rosacea Society, who spoke during the public hearing portion of the meeting. "In the 19-day lockout period, patients were not at greater risk of pregnancy, and therefore you're not capturing a fertile period of pregnancy, but rather the inherent contraceptive failure rate that applies to all patients at all months. With the fertile period reasoning, you could extend the 19-day lockout to 20 days, 30 days, or more."

Counseling Frequency

The FDA also asked the committee to vote on how frequently a provider should be required to document that patients on isotretinoin are counseled on the drug's risks; currently, providers must certify that they counsel patients monthly. A total of 10 committee members voted to require documentation that patients are counseled only once, when they first enroll in iPLEDGE and get their first prescription; one voted to keep the monthly requirement; six voted for every 120 days; and five voted for "some other frequency."

Member Abbey Berenson, MD, PhD, of the University of Texas Medical Branch in Galveston, said she voted for documenting counseling only once because there were only two reasons to counsel monthly: to remind patients that they shouldn't donate blood while they're on the drug, and to tell them not to share their medication. "There are many reasons people are eligible to not give blood, and at blood centers they're screened for that. And since they're only getting a 30-day supply [of the drug each time], to share it they would have to give up their own medication," which is unlikely given the severity of their acne.

Members also expressed concern about the lack of provider input in the iPLEDGE program, something that was stressed by John Barbieri, MD, of Harvard Medical School in Boston, who testified during the public hearing as deputy chair of the American Academy of Dermatology Association's (AADA) iPLEDGE Working Group. He noted that providers' difficulty in communicating with the IPMG -- for example, they were only given a generic IPMG email address to voice any concerns to -- might explain some of the problems that the IPMG encountered with the program. "Their lack of transparency and accountability has been a major hurdle in improving iPLEDGE," he said.

"I have serious concerns that the method of communication with IPMG is not an open forum," said committee member Maria Woodward, MD, of the University of Michigan in Ann Arbor. "Specifically I would recommend what the roles of those people would be ... That really worried me when I heard that that is not an open line of communication."

Usefulness of Pregnancy Registry

The iPLEDGE program's pregnancy registry also came up for discussion. The registry currently collects data on fetal exposure, pregnancy outcome, fetal outcome, and root cause analysis, and FDA staff sought committee members' views on whether the program should continue collecting all of that information and how the registry might be streamlined. Members generally agreed with the staff's recommendation that it stop collecting data on pregnancy outcomes -- especially since isotretinoin's teratogenicity is well-known -- and instead focus on the root cause analysis for how the pregnancies occurred in spite of iPLEDGE.

"Getting information on root cause analysis is really essential -- where has the rest of [iPLEDGE] failed that the person ended up being pregnant?" said committee member Sonja Rasmussen, MD, of Johns Hopkins University School of Medicine in Baltimore. "It would really help us know how to change the program in the future."

The FDA does not have to follow the advice of its advisory committees, but it often does.

Disclosure: Pediatric dermatologist Ilona Frieden, MD, a cousin of the writer, testified with Barbieri during the public hearing portion of the meeting. Ilona Frieden was not consulted about the reporting or writing of the story.

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