When To End A REMS? Soliris Review Stirs Debate On How To Scale Back

Risk management program for Alexion’s orphan drug eculizumab appears to be succeeding, but what does FDA need to see to make it less burdensome?

More than seven years after FDA was empowered to require Risk Evaluation and Mitigation Strategies to ensure that drugs’ benefits outweigh their risks, the agency is still struggling to figure out how much evidence is needed to scale back a REMS.

The apparent success of the REMS for Alexion Pharmaceuticals Inc.’s Soliris (eculizumab) shows the challenges FDA faces in determining when REMS elements to assure safe use (ETASU) should be eased for a product.

At a Drug Safety and Risk Management Advisory Committee review of the Soliris REMS Nov. 18, committee members, FDA and Alexon all seemed to agree the risk management strategy is functioning well.

“We really don’t know exactly what would happen if we pull it back,” FDA’s Manzo said of the Soliris REMS.

The Soliris REMS is directed at reducing the occurrence and morbidity of meningococcal infections, and educating prescribers and patients about this infection risk and the need for vaccination.

Data gathered through the REMS program show that vaccination rates are high, with at least 97% of all U.S. patients vaccinated, according to Alexion. The rate of meningococcal infections is lower than would have been expected from the clinical trial experience, and most of the infections that have occurred were not associated with mortality or serious morbidity. Of 16 post-marketing reports of meningococcal infection in the U.S., only one was fatal.

However, some committee members questioned whether these findings resulted from the REMS program itself or the fact that the highly specialized doctors treating patients who take Soliris are well acquainted with the orphan drug and have become better at managing its risks and making sure their patients are just as aware.

Cleveland Clinic hematologist Mikkael Sekeres questioned whether the Soliris post-marketing assessments are good “because we’ve gotten better at using the drug and monitoring it? Or is it because the REMS is working and we don’t want to mess around with that?”

That answer generally is challenging to ascertain, FDA officials suggested.

“I think that’s where we run into a lot of difficulties, when to pull back, what level of information we need to be able to pull back and types of information that we would need,” Office of Medication Error Prevention and Risk Management Acting Director Claudia Manzo said.

“In particular in this case, we don’t have comparator group – a … group of patients that are being managed outside the REMS in the U.S. And so we really don’t know exactly what would happen if we pull it back,” Manzo said.

Although no formal vote was taken, a majority of advisory committee members favored revising the current REMS requirements rather than keeping the risk management program as is or removing it entirely. Most panelists supported streamlining the program’s educational materials and assessment process but did not call for eliminating the ETASU requirement that physicians who prescribe Soliris be enrolled in the REMS (Also see "Soliris REMS Should Be Modified, Not Eliminated, FDA Panel Says" - Pink Sheet, 18 Nov, 2014.).

To Release Or Not To Release?

FDA’s website lists more than 140 products that have been released from their REMS. In most cases, those releases resulted from FDA’s determination that MedGuides could exist outside of the risk management programs.

There are a few notable cases where REMS with either ETASU or communication plans have been released. For example, the agency recently eliminated the REMS for Genzyme Corp.’s Lumizyme (alglucosidase alfa) in conjunction with approval of an expanded indication for the Pompe disease treatment. FDA determined that the communication plan and ETASU restricting the enzyme replacement therapy to a specific age group no longer was necessary (Also see "Genzyme’s Lumizyme REMS Eliminated Due To Expanded Indication" - Pink Sheet, 5 Aug, 2014.).

At the Soliris meeting, Cynthia LaCivita, acting director of the Division of Risk Management, said that in deciding whether a REMS is still necessary, the agency takes into consideration whether there are new data or additional information that change the product’s risk/benefit profile.

When asked for recent examples of a REMS pullback, Manzo cited the experience with GlaxoSmithKline PLC’s Avandia (rosiglitazone). FDA replaced prescribing and distribution restrictions with a requirement for prescriber training after the readjudicated results from the RECORD trial showed no increased cardiovascular risk compared to other diabetes drugs (Also see "FDA Replaces Avandia REMS Distribution Restrictions With Prescriber Training" - Pink Sheet, 25 Nov, 2013.).

However, Sekeres distinguished Avandia – a case where an initial safety signal did not pan out with further post-marketing scrutiny – from that of Soliris, where the risk still exists due to the nature of how the drug works.

“This isn’t really the same thing. This is an infection that we know [patients] are at much higher risk for because of the mechanism of action of the drug,” he said.

“I think if any of the current REMS programs are a candidate for release, it would be this one,” Dana-Farber hematologist Steensma said.

Sekeres described REMS as a government-proscribed safety net that may not be necessary in the case of very rare diseases that are primarily treated in specialty centers.

Eculizumab, a complement inhibitor, is approved for two orphan indications: treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis; and treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy.

“In these specialty centers, I think that people are keyed in to doing this education and reiterating this education with patients. I don’t think we necessarily need the safety net of a government-proscribed program for that to happen,” Sekeres said.

Sekeres’ comments resonated with another hematologist on the panel, David Steensma, Dana-Farber Cancer Institute.

“You’re dealing with prescribers who are a very highly trained professional group in a rare disorder that’s treated in a limited number of centers with yet another burdensome [REMS] program on top of dozens of others in some practices,” Steensma said. “I think if any of the current REMS programs are a candidate for release, it would be this one.”

However, Sekeres and Steensma were in the minority in advocating for elimination of the REMS, as most advisory committee members favored keeping the program with some modifications. Some panelists said more needed to be known about Soliris prescribers and patients, particularly those who did not respond to the knowledge surveys conducted as part of the REMS assessments.

“Overall, I think the REMS is a success and we should keep it in place largely the same as it currently is,” said Lewis Nelson, an emergency medicine physician at New York University. “I’d be afraid to let this go without having a better understanding of who is involved at the prescriber level, who these patients are and what they really understand.”

“I think it’s still too early to release the REMS at this point,” said Charles Lee, president and founder of Polyglot Systems. “I don’t think we’re at a level to feel comfortable that everybody knows all the risk involved with this medicine.”

RiskMAP Evolves Into A REMS

The FDA Amendments Act of 2007 not only created the REMS paradigm, it required the agency to annually bring a drug subject to REMS with ETASU before the advisory committee for an evaluation.

FDA asked the committee to consider whether the Soliris REMS assures safe use, is not unduly burdensome to patient access to the drug, and to the extent practicable minimizes the burden to the health care delivery system.

Labeling includes a boxed warning about the occurrence of life-threatening and fatal meningococcal infections and the need to recognize and treat such infections early.

Soliris was first approved in March 2007 with a Risk Minimization Action Plan. When FDAAA’s drug safety provisions took effect in March 2008, Soliris was among the products deemed to have a REMS in effect (Also see "FDA Gives Firms With RiskMAP Drugs 6 Months To Submit Strategy Proposals" - Pink Sheet, 26 Mar, 2008.).

The REMS was formally approved in June 2010. The program comprises a medication guide, ETASU in the form of prescriber certification, and a timetable for submission of assessments (Also see "Alexion's Soliris Adds Prescriber Certification In Move From RiskMAP To REMS" - Pink Sheet, 2 Jul, 2010.).

To become certified, prescribers agree to counsel patients and provide the educational materials to each patient, and to provide the MedGuide to patients prior to each infusion. Prescribers also agree to review educational materials and product labeling and to comply with the directions for safe use, including ensuring that patients are vaccinated. They also must report any cases of meningococcal infection.

The REMS includes a wallet card, also known as the patient safety card, which reminds the patient about the symptoms of meningococcal infection. The card also can be used to alert a health care provider who has not prescribed Soliris, such as an emergency room physician, about the risk of meningococcal infection.

In their briefing documents for the meeting, both FDA and Alexion said the program was achieving its goals, although Alexion said changes in the REMS assessment process may be warranted because it appears that prescriber surveys are creating a burden (Also see "Alexion’s Soliris REMS Working Well But Might Benefit From Small Changes" - Pink Sheet, 14 Nov, 2014.).

Alexion’s support for continuing the REMS spurred Sekeres to question whether the program was conferring marketing benefits (see sidebar).