iPLEDGE update: Changes ahead

By Emily Margosian, Assistant Editor, August 1, 2024

Since 2005, isotretinoin has only been available through an FDA-mandated Risk Evaluation and Mitigation Strategies (REMS) program implemented to monitor medications with high potential for serious adverse effects. In the case of isotretinoin, the program was developed to prevent fetal exposure to the drug given the severe birth defects it can cause. The specific program for isotretinoin, iPLEDGE, was originally implemented in 2005 and subsequently approved as the iPLEDGE REMS in 2010.

For nearly 15 years, tireless physician advocates have worked with regulators to improve the program for physicians and patients alike. “Dermatologists in organized medicine have been working for years to achieve greater transparency in the complex structure of iPLEDGE and to improve its function both from the perspective of patient access to care as well as minimization of burdens on dermatologists and their practices,” said Klint Peebles, MD, FAAD, former member of the Academy’s iPLEDGE Workgroup. “As a result of strategic, coordinated efforts both at the grassroots and organizational levels in the Academy, the FDA was ultimately convinced to require modifications to the iPLEDGE program that would minimize many of these burdens on patients and their dermatologists while maintaining the safe, evidence-based use of isotretinoin.”

This month, dermatologist advocates and policy experts discuss significant recent changes to the program, and what they mean for physicians and their patients.

Past changes to the program

In December 2021, several key changes were made to the iPLEDGE program.

In a win for dermatologists and their patients, patient risk categories were reduced from three options to two: patients who can get pregnant, and patients who cannot get pregnant.

“As dermatologists, our goal is to provide high-quality and inclusive care. The previous patient risk categories unduly conflated gender identity with pregnancy potential, which was discriminatory and stigmatizing to many people,” explained Dr. Peebles. “Non-binary individuals, transgender men, and all other individuals who do not identify as ‘female’ but possess the anatomy capable of producing a pregnancy were inherently excluded in the prior iPLEDGE categorization model. Not only did this create difficult and challenging conversations in clinic, but it also resulted in many patients choosing to defer care altogether because of their understandable refusal to compromise their identity. The new categorization is simply based upon pregnancy potential alone, which is a huge step forward for inclusivity.”

“The new categorization is simply based upon pregnancy potential alone, which is a huge step forward for inclusivity.”

“From the standpoint of pregnancy prevention, the most relevant aspect is whether a person can or cannot become pregnant,” affirmed John Barbieri, MD, MBA, FAAD, co-chair of the AAD Acne Practice Guideline Workgroup and chair of the Academy’s iPLEDGE Workgroup. “The prior iPLEDGE categories could result in some individuals being required to register as a gender with which they did not identify. Simplifying the risk categories into persons who can become pregnant and persons who cannot become pregnant is a step in the right direction toward providing more effective care to all individuals with acne.”

Despite this win, there have been other changes to the program, unrelated to AADA advocacy, which have presented significant access challenges for patients. In late 2021, the iPLEDGE program administrator, Syneos Health, along with sponsors announced a new, all-digital platform.

“Unrelated to changes in patient categorization, in December 2021, the isotretinoin products manufacturing group (IPMG), which is responsible for implementing the iPLEDGE program, selected a new vendor to run the website and call center. Although the Academy’s iPLEDGE Workgroup had repeatedly warned the IPMG and FDA about the importance of beta-testing this new platform before widely rolling it out, such testing was never done,” recalled Dr. Barbieri. “Unfortunately, due to issues with this transition, nearly all patients and prescribers lost access to their accounts. Combined with the inadequately staffed support center, many patients and prescribers were unable to access the iPLEDGE program for weeks to months, leading to negative effects on patient care and access to isotretinoin.”

“The transition was a disaster,” agreed Andrea Zaenglein, MD, FAAD, member of the Academy’s iPLEDGE Workgroup. “While pharmacy groups worked with the IPMG on the process for a year, dermatologists were given a month’s notice that changes were coming. The IPMG did not consult with the iPLEDGE Workgroup, or as far as I know, any dermatologists in the acne world prior to the rollout.”

AADA takes action

During the fraught launch of the new platform, the AADA and iPLEDGE Workgroup immediately sprang into action.

“Historically, there’s been no meaningful way to reach the IPMG. The members of the group are not made public. Their only contact information is an email address,” explained Dr. Zaenglein. “Up until the website debacle of 2021, we were never able to make any meaningful contact with them. However, there were enough complaints about the rollout that the FDA instructed the IPMG to work with us to help solve the problems. We appreciate being able to do that. Even so, we would have meetings and there would be one person on video who was named and everybody else was just phone numbers. There’s not a lot of transparency with the organization, which is frustrating.”

“During this disastrous rollout, the AADA and iPLEDGE Workgroup put continuous pressure on the FDA and IPMG to resolve these issues. For instance, the IPMG had originally planned to eliminate the option to enroll patients using a paper consent. Through advocacy efforts by the AADA and iPLEDGE Workgroup, we were able to ensure continued use of paper consent to enroll patients in iPLEDGE,” said Dr. Barbieri.

New iPLEDGE wins

As a direct result of the AADA’s persistent advocacy efforts to fix the iPLEDGE program, in early 2023, the FDA announced it would host a two-day joint advisory committee meeting. Academy iPLEDGE Workgroup leaders presented oral testimony outlining Academy members’ concerns about and recommendations for the program, and the AADA submitted written comments. Additionally, nearly 300 member dermatologists submitted comments to the FDA through the AADA’s member action alert center.

In December 2023, in response to AADA member advocacy, the FDA required the IPMG to make key changes to the iPLEDGE program:

1. Remove the waiting period requirement (also referred to as the “19-day lockout”) for patients if they do not obtain isotretinoin within the first seven-day prescription window. Before initiating isotretinoin treatment, a confirmatory repeat pregnancy test must be completed in a medical setting without any required waiting period.

The 19-day lockout was of particular frustration for many physicians and their patients, according to Dr. Zaenglein. “Patients are not at any greater risk of pregnancy during those 19 days than they are in subsequent months. Administrators failed to recognize that the patient already agreed to their form of contraception for 30 days. It also made no biologic sense. If you are on a birth control pill, you don’t ovulate, so those timing windows are irrelevant. For the abstinence patients, they’re abstinent so their risk is the same each month,” she explained. “It’s an administrative nightmare for physicians and exceedingly punitive for patients. The program would say it’s the fault of the patient somehow, but almost always it was due to insurance issues or clerical errors that they had no control over. Imagine telling a 15-year-old with severe acne, ‘I’m sorry; you have to wait nearly another month to start this medicine.’ It was heart-wrenching and unnecessary.”

2. Revise the requirement for prescribers to document patient counseling in patients who cannot become pregnant from monthly to only at enrollment.

According to Dr. Barbieri, this recommendation is one of the biggest proposed changes to the program. “Depending on how it is implemented, this could eliminate the need for monthly visits for persons of non-childbearing potential, which could improve flexibility and access to care.”

“This was a big win for us,” agreed Dr. Zaenglein. “When it went to the voting group, they recognized that the REMS program is designed to mitigate pregnancy, and that patients who cannot become pregnant…cannot become pregnant. Therefore, keeping them in this closed loop — making them come in monthly to adhere to that requirement — was excessively burdensome for both patients and dermatologists.”

3. Remove the requirement that pregnancy tests must be performed at a CLIA-certified laboratory. Due to this change, prescribers are now allowed the option of using home pregnancy testing for their patients (as they were during the COVID public health emergency) during and after isotretinoin treatment. However, all pregnancy testing before isotretinoin treatment initiation must be completed in a medical setting (such as a prescriber’s office, clinic, laboratory, etc.) as of November 2023.

“Now patients can get their initial tests done in a private practice office setting, for example, which may not have had access to a CLIA-certified lab,” explained Dr. Zaenglein. “While the pre-treatment pregnancy test must still be in a medical setting, subsequent labs can be done with at-home pregnancy tests.”

“Another positive aspect of this is the fact that some gender-diverse patients may experience dysphoria in association with pregnancy testing,” said Dr. Peebles. “Allowing such testing to occur in the safety and privacy of the home can be reassuring and helpful to these individuals as they seek to navigate these requirements in the most affirming and validating manner possible.”

Overall, all of the changes recommended by the FDA will significantly reduce the numerous pain points that dermatologists and their staff experience when complying with iPLEDGE requirements. “These will make a huge practical, day-to-day difference in dermatology practices across the country,” said Dr. Peebles.

Grassroots advocacy at work

Long-term iPLEDGE reform advocates agree: the new recommendations were the result of tireless grassroots efforts. “We’re excited for these changes to come, and we worked very hard to get them,” said Dr. Zaenglein. “We were relentless in our advocacy. We regularly corresponded with the FDA to keep it at the forefront. We reached out to the IPMG; we reached out to the Assistant Secretary for Health. We’ve done so many things to try to make this program better. If our group hadn’t been so persistent in requesting for the FDA to have that meeting, I’m not sure it would have happened.”

“We’re excited for these changes to come, and we worked very hard to get them. We were relentless in our advocacy.”

“These changes are the result of years of advocacy work culminating in the FDA Advisory Panel meeting in March 2023 in which the workgroup successfully presented our case for making reforms to the iPLEDGE program,” agreed Dr. Barbieri. “I cannot thank patients and AAD members enough for their support, both in pressuring the FDA to address the IPMG’s disastrous 2021 rollout of the new website and in supporting our ongoing advocacy efforts to improve the iPLEDGE program. This support has been critical to encourage the FDA to act and engage with the iPLEDGE Workgroup.”

When will the changes take effect?

While these changes are exciting, they may take a year or more to be implemented fully. The AADA has already requested to participate in the next phase of this process.

“The IPMG was given six months to submit a proposal for how they will implement these changes. Despite repeated requests from the AADA and iPLEDGE workgroup to be involved in this process, the IPMG continues to refuse to transparently engage with key stakeholders such as patients, dermatologists, and pharmacists,” said Dr. Barbieri. “There is currently no timeline for when these changes will take effect or how exactly they will be implemented, but we hope to hear more from the FDA soon once they have had a chance to review the IPMG’s proposal that was due at the end of May 2024.”

What’s next?

Despite these wins, more work remains as the AADA continues to advocate for more transparency and inclusiveness of key stakeholders in the iPLEDGE program.

“Arguably one of the most important objectives is for dermatologists and organized medicine to be explicitly and intentionally included in all conversations surrounding the regulatory oversight and operation of iPLEDGE,” said Dr. Peebles. “As a result of the problematic roll-out of the revised iPLEDGE program in 2021, we learned very quickly about the complex structure of the program, and the general lack of coordination and communication among stakeholders. We are advocating for greater transparency at all levels of the process and insist that dermatologists have a presence and a role at the table.”

In addition to greater transparency, the iPLEDGE Workgroup is also advocating for ongoing improvements to the iPLEDGE website to improve accessibility and functionality. Other reform efforts include allowing home pregnancy testing as an option for the confirmatory pregnancy tests, recognizing highly effective forms of contraception, and shortening the 30-day waiting period. “Continued support from members of grassroots efforts and advocacy with congressional representatives will be important to obtain the needed attention from the FDA regarding these long-overdue reforms to the iPLEDGE program,” said Dr. Barbieri.

Additional DermWorld Resources