Growth of REMS Challenges FDA, Stakeholders

[August 1, 2010, AJHP News]

Kate Traynor

WASHINGTON, DC 19 July 2010—About a third of the new molecular entities and biological products approved by FDA during the first half of 2010 have required a risk evaluation and mitigation strategy, or REMS, to satisfy the agency's requirements for marketing the product.

Through June, FDA approved a total of 51 new or revised REMS, most of which consisted of a printed medication guide—known popularly as a MedGuide—either alone or with other REMS components, according to data on the agency's website.

Of those 51 REMS, 7 were for new molecular entities approved since the start of this year. In all, FDA has approved REMS for nearly 130 products since the provisions for the risk-management programs went into effect in 2008 as required by the Food and Drug Administration Amendments Act of 2007.

What's in a REMS? About 60% of REMS have a MedGuide as the sole component, said Claudia Karwowski of FDA's Office of Surveillance and Epidemiology, speaking in June at the Drug Information Association's (DIA's) annual meeting in Washington, D.C.

FDA requires medication guides for prescription products when the agency believes that a MedGuide is necessary to prevent serious adverse events; that it informs patients about known serious adverse events associated with the product; or the instructions in the document are necessary to ensure the effective use of the product.

Karwowski said that during REMS assessments for not-yet-approved drugs, FDA considers the likely postmarketing use of the products as well as their proposed indications and experience from clinical trials.

Nearly every REMS requires the creation and distribution of a MedGuide. FDA normally requires that the MedGuide be distributed to patients each time the medication is dispensed—even in the inpatient setting.

Mwango Kashoki, associate director of safety at FDA's Office of New Drugs, told DIA attendees that the continued need for inpatient distribution of MedGuides is "under discussion" at the agency.

A REMS may include a risk communication plan for health care providers. The communication plan may consist of "Dear Healthcare Provider" or "Dear Pharmacist" letters along with other outreach mechanisms.

For example, Genentech Inc.'s tocilizumab product, Actemra, was licensed in January with a REMS that requires the company to send letters to pharmacists, potential prescribers, and specialists who may treat patients who take the medication.

In addition, the REMS requires Genentech to display safety information about tocilizumab at professional rheumatology meetings where the company has a booth. Genentech must also have information about the medication printed quarterly in eight specified journals for three years and in one specified cancer journal for five years.

Karwowski said a communication plan is the "primary element" of about 25% of FDA-approved REMS programs, and "Dear Healthcare Professional" and "Dear Pharmacist" letters are the most common components of such plans.

Fifteen REMS include specific elements to assure safe use, or ETASU, which can require health care professionals, including pharmacists, to complete special training before obtaining, prescribing, or dispensing the drug. Some of these REMS also involve a restricted-distribution network.

FDA has statutory authority to require a so-called implementation system for ETASU to ensure that pharmacists and other health care providers are complying with those elements.

For example, the implementation system for darbepoetin alfa or epoetin alfa, when used in patients with cancer, requires prescribers and purchasers to submit to audits by the manufacturer. Auditing may include an examination of records documenting that physicians are properly trained and that patients have received REMS-mandated counseling. Failure to comply could result in the loss of the ability to purchase these medications (see April 1, 2010, AJHP news).

Kashoki said ETASU are implemented only when other REMS elements are insufficient to ensure the safe use of a product. Absent the ETASU, she said, the drug would be withdrawn from the market or never approved in the first place.

"We generally think that the most serious and preventable risks would more likely lead to the more restrictive programs," Karwowski noted. She also said FDA has "heard a lot" from health care providers about the lack of compensation for the time and effort spent complying with ETASU and other REMS requirements.

Drugs currently required to have ETASU are alglucosidase alfa, alvimopan, ambrisentan, bosentan, darbepoetin alfa, eculizumab, eltrombopag, epoetin alfa, fentanyl, hydromorphone hydrochloride, olanzapine, oxycodone hydrochloride, romiplostim, sacrisidase, and vigabatrin.

Strain on the system. Kashoki said FDA was required by statute to implement REMS at the same time the agency was developing policies and procedures for the programs—a situation she described as "difficult" for the agency to manage.

"We are learning as we go," she said.

In addition to approving new REMS, FDA evaluates the full documentation for existing REMS programs when modifications are needed, including minor technical or editorial changes to a MedGuide or other REMS documents, Karwowski said. She acknowledged that the time needed to work with REMS is "an administrative burden on FDA."

Representatives from Amgen and Eli Lilly and Company who spoke at the DIA meeting confirmed that working with FDA to incorporate minor changes to a REMS is burdensome for the industry, as well. The representatives called on FDA to be more transparent in its REMS approval process, communicate with companies early in the REMS review process, and ensure that different divisions at FDA use similar procedures when evaluating the programs.

Nayan Acharya, senior director of risk management and pharmacoepidemiology for Lilly, said the industry would benefit from clear guidance about assessing the effectiveness of MedGuides, a requirement of each REMS that involves a MedGuide.

He said that because manufacturers do not directly interact with patients, simply getting a MedGuide to a patient is a complex process that involves wholesalers, pharmacies, and other entities. Much of that process, he said, is "beyond the industry's control."

Karwowski said FDA is working on a draft guidance document for REMS assessments.