Determining whether a risk evaluation and mitigation strategy (REMS) with elements to assure safe use (ETASU) is doing the job is proving to be quite a challenge in the absence of definitive, comparative patient-outcome data.

That point was driven home repeatedly Thursday during a joint meeting of the FDA's Drug Safety and Risk Management and Dermatologic and Ophthalmic Drug advisory committees.

The lack of patient-outcome data came up during a review of the iPLEDGE REMS for severe acne drug isotretinoin, first marketed as Accutane (Roche AG) in 1982. The goal of iPLEDGE is to eliminate fetal exposure to the teratogenic drug while minimizing the burden of the plan on the health care system and patients. (See BioWorld Today, Nov. 30, 2011.)

Eric Davis, director of medical services at Mylan Inc., which makes a generic version of isotretinoin, presented data that showed the total number of pregnancies in patients taking isotretinoin have dropped over the years since iPLEDGE has been implemented. In the third year of the program, 183 pregnancies were reported. In year five, the pregnancy rate was 0.12 percent, or 150 pregnancies, in isotretinoin patients.

To provide some perspective, Davis pointed out that the unintended pregnancy rate in the U.S. for women age 15 to 44 is 5.1 percent.

What Davis, or the FDA, couldn't provide were comparative baseline figures that would show whether iPLEDGE has had an impact on the pregnancy rates among women taking the acne medication. The problem is that, before iPLEDGE was implemented, there was no systematic collection of those data, the FDA's Kathryn O'Connell said.

The agency also has difficulty determining whether the REMS unduly affected appropriate access to the drug. When iPLEDGE was implemented, use of isotretinoin by males dropped 29 percent and use by females dropped 55 percent. Utilization picked up and then leveled off, Marta Wosinska, director for the analysis staff at the Center for Drug Evaluation and Research's Office for Planning and Analysis, told the committee members.

The data problem is not restricted to isotretinoin, as steep limitations exist for most REMS with ETASU. The FDA has no baseline data for most of the 31 drugs with those REMS. Sixteen drugs were approved along with the REMS, and 10 are for older drugs that were 'deemed' approved.

'We do not have a clean baseline for access on 80 percent of these cases,' Wosinska said.

Data also are limited because the REMS tend to be for specialty drugs with limited utilization and the drugs may be distributed through specialty pharmas that don't share prescription data. In addition, patients are often lost to follow-up when they discontinue the drug.

'For a very high share of REMS, we will not be able to quantify what impact the REMS has on patient access,' Wosinska said. However, the severity of the condition and the availability of other treatment options are likely to affect patients' and providers' willingness to embrace the burden of a REMS, she added.

Several members of the advisory committees expressed frustration at the lack of data and encouraged the FDA to do more to develop that information.

If a lot of resources are being put into a program, the FDA and industry need to know the impact the program is having, said Michael Bigby, associate professor of dermatology at Harvard Medical School and Beth Israel Deaconess Medical Center.

Since the one-year anniversary of the REMS for erythropoiesis-stimulating agents (ESAs) is approaching, Mark Woods, clinical coordinator and residency program director of the pharmacy department at Saint Luke's Hospital in Kansas City, Mo., suggested that the FDA use the ESA REMS as a case study to determine burden.

In his practice, he said, the REMS has had a chilling effect on the use of ESAs, which are among the 20 percent of drugs with REMS that would have baseline information available.

Looking Ahead

Despite the data problems, the FDA is forging ahead with ways to improve REMS and make them less burdensome for all involved. In minimizing the burden, the agency recognizes the diversity of the REMS processes, Wosinska said. The agency realizes that the lessons learned from a REMS in one setting can't necessarily be extrapolated to another.

Nevertheless, the agency is exploring ways to bring more standardization to the process. It's looking at REMS that cover both the innovator and generic versions of a drug as a paradigm for classwide REMS, such as those that cover opioids, said Reema Jain, risk management analyst in CDER's Office of Surveillance and Epidemiology. (See BioWorld Today, April 21, 2011.)

The agency also is developing standardized recertification/training elements. And it is developing ways to introduce engineering controls into the dispensing of drugs with REMS by integrating the plans into pharmacy management systems.

Other approaches the agency is considering include:

• developing a single web portal for user log-in to enroll and manage REMS programs;

• establishing standards based on intervention or risk;

• standardizing forms;

• allowing hospitals to get emergency supplies of drugs with REMS for admitted patients;

• expanding access beyond specialty pharmas.