Isotretinoin REMS Still Needed, but Its Burden Could Be Reduced, FDA Staff Says

— Report suggests ways to lighten documentation rules for prescribing the severe acne treatment

by Joyce Frieden, Washington Editor, ľ��ֱ�� March 27, 2023

FDA ADCOMM isotretinoin REMS (iPledge) over a close up photo of a woman with severe acne on her face.

A risk evaluation and mitigation strategy (REMS) for the use of isotretinoin to treat severe acne is still very much needed, but there are ways to lighten its burden on patients and providers, according to FDA staff.

For example, because of the drug's risk of causing birth defects if taken while patients are pregnant, prescribing clinicians are required to access the clinician portal for the REMS to document monthly counseling for each patient. "Lack of this documentation is responsible for the majority of prescription authorization denials for patients who cannot become pregnant," the staff wrote.

"The review team recommends that the requirement for prescribers to access the iPLEDGE REMS system to document monthly counseling for patients who cannot become pregnant be extended to every 120 days or be removed. If this requirement is eliminated, there will be no need for either the patient or the prescriber to interact with the REMS system monthly, therefore alleviating significant administrative burden and treatment delays while continuing to ensure safe use."

The was issued in advance of a -- beginning on Tuesday -- to discuss the iPLEDGE program. The members of the Drug Safety and Risk Management Advisory Committee and the Dermatologic and Ophthalmic Drugs Advisory Committee will be asked to discuss and vote on a number of questions related to administration of iPLEDGE.

In addition to the monthly counseling question, another issue for the advisors centers around pregnancy testing. Currently, after initial pregnancy testing, all required pregnancy tests must use a laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). But during the COVID-19 public health emergency (PHE), patients were allowed to use home pregnancy testing.

"The number of pregnancies reported from 2020 through 2022 (i.e., during the PHE) remained stable compared to previous years. However, there are reports in the literature of patients falsifying the results of home pregnancy tests," agency staff noted. "The review team does not recommend the continued use of home pregnancy tests in the iPLEDGE REMS. The review team recommends pregnancy testing, with a sensitivity detection limit of at least 25 mIU/mL, be administered in a provider's office as an alternative to a CLIA-certified laboratory."

Also, if patients fail to pick up their isotretinoin within 7 days of the initial prescription, they're required under iPLEDGE to take two pregnancy tests at least 19 days apart before they can start treatment, in addition to taking pregnancy tests monthly during treatment, after the last dose, and 1 month after treatment concludes. "This 19-day lockout period has resulted in delays in therapy in patients who can become pregnant," the report said.

"Over the last five assessment reporting periods, approximately 15-20% of patients who can become pregnant missed obtaining their medication within the 7-day prescription window and were required to wait 19 days before their next pregnancy test," the authors wrote. Since year 12 of the program (2017-2018), "the iPLEDGE REMS reports 12 pregnancies that were detected during the 19-day lockout period, thus preventing fetal exposure to isotretinoin."

The staff added that published literature documents higher costs for patients because of this requirement as well as more visits to prescribers and repeat pregnancy tests; they also noted the requirement's benefits in terms of detecting pregnancies. The report didn't take a position on this requirement but instead asked for "input from the committee on the benefits and burden associated with this requirement, including whether alternative time frames could be considered."

FDA staff members also are seeking input on the requirement for participation in a pregnancy registry among patients taking isotretinoin. The registry is designed to document how much exposure the fetus had to the drug, what the outcome of the pregnancy was, and to provide information to analyze what caused the exposure. The authors suggest that although continuing to document the degree of exposure and determine the root cause of it is useful, "data on pregnancy and fetal outcomes are often incomplete or absent and at least one third of pregnancies are lost to follow-up. Given the extensive knowledge of teratogenic effects of isotretinoin, the review team questions the continued value of collecting this information."

The staff said it wants the committee's opinion on ways to streamline the registry so that it yields increased participation and high-quality data, and also whether it's worth continuing to collect pregnancy outcome data "for a product with a well-established safety profile."

At the end of the meeting, the advisory committee members will be on whether the 19-day lockout period should be maintained and under what circumstances prescribers should have to document counseling of patients who cannot become pregnant. They also will be asked to discuss whether pregnancy tests need to be performed at an office or lab rather than at home, and any additional steps that could be taken to reduce the burden of the REMS. The FDA doesn't have to follow the advice of its advisory committees, though it often does.

Joyce Frieden oversees ľ��ֱ��’s Washington coverage, including stories about Congress, the White House, the Supreme Court, healthcare trade associations, and federal agencies. She has 35 years of experience covering health policy.