FDA's proposed new benchmark for incorporating a Medication Guide in a Risk Evaluation and Mitigation Strategy would reduce the regulatory burden on sponsors whose products do not warrant restricted distribution measures.

In a draft guidance released on Feb. 25, the agency says that "in most cases" a MedGuide will be included as part of a REMS only when elements to assure safe use are needed. However, a MedGuide could be part of a REMS that lacks elements to assure safe use if the agency determines that having a MedGuide without a REMS will be insufficient to ensure a drug's benefits outweigh its risks.

Elements to assure safe use (ETASU) are generally reserved for those drugs posing the most significant risks. ETASU include healthcare provider training or certification, restricted dispensing, documenting safe use conditions, and mandatory patient monitoring or registry enrolment.

If FDA adopts this policy in a final guidance, sponsors and the agency could see a vast reduction in the number of products approved with REMS. This would result in less regulatory burden for sponsors, who much conduct REMS assessments at given intervals, and on FDA, which must evaluate the assessments.

The guidance also explains how sponsors can seek removal of those REMS that contain only a MedGuide and a timetable for assessment.

MedGuide-Only REMS Predominate

The FDA Amendments Act of 2007 gave FDA authority to require a MedGuide as part of a REMS. Since the law's drug safety provisions took effect in March 2008, the agency has considered any new MedGuide, or safety-related changes to an existing MedGuide, to be part of a REMS, the draft guidance says.

As a result, two-thirds of the REMS approved to date have been of the MedGuide-only variety.

Counting various dosage forms separately, FDA approved 175 REMS, according to figures on the agency's website updated as of Feb. 25. Of these, 116 were MedGuide-only REMS, 37 carried only MedGuides and communication plans, and 22 had ETASU.

Only one sponsor has been released from its REMS requirements, according to the website.

FDA approved a REMS for QOL Medical's enzyme replacement therapy Sucraid (sacrosidase) in November 2008. The REMS, which included a communication plan, ETASU and an implementation system, was aimed at communicating information about a manufacturing change and to ascertain whether the change resulted in an increase in allergy-related adverse events. In December 2010 FDA said the company's REMS assessment showed there were no reports of adverse events and it concluded the REMS was no longer required.

Looking For A Way Around REMS

To reduce the burden on sponsors, FDA and the health care system, the agency has been searching for a way to allow development of MedGuides outside of the REMS framework.

At the Drug Information Association's annual meeting in June, Office of New Drugs Director John Jenkins said the agency was looking for a "creative way" around the FDAAA provision on MedGuides in REMS. At that time, however, Jenkins said MedGuides were still considered to be a component of REMS ('FDA Seeks To Write MedGuides Outside REMS Process,' 'The Pink Sheet,' June 21, 2010).

However, FDA now appears to have subscribed to the views of the Pharmaceutical Research and Manufacturers of America, which last year called for the agency to revert to its original, pre-FDAAA authority to implement MedGuides (Also see "PhRMA Wants MedGuides Developed The Pre-FDAAA Way, Not Through REMS" - Pink Sheet, 26 July, 2010.).

The original authority stems from a 1998 final rule on patient-directed labeling (Also see ""MedGuides" Required Only In Classes Where Patient Info Already Requested" - Pink Sheet, 7 December, 1998.). The rule is known as Section 208.

FDA has the authority to determine, based on a drug's risks and public health concerns, whether a MedGuide should be required as part of a REMS when the 1998 rule's standards are met, the draft guidance states. The agency may decide the MedGuide should be required as labeling but not part of a REMS if the latter is not necessary to ensure the benefits of the drug outweigh its risk.

"While all Medication Guides must meet the standard and requirements in part 208, not every newly required Medication Guide will be an element of a REMS," the guidance states. "Depending on the risks involved, FDA may approve a Medication Guide under part 208 without requiring a REMS when that is adequate to address the serious and significant public health concern and meets the standard in 208.1."

Getting Out Of REMS

The guidance provides a pathway for sponsors to escape the burden of an existing MedGuide-only REMS.

Applicants may submit a prior approval supplement for a REMS modification that proposes to eliminate the program. Applicants with a REMS that includes both a MedGuide and a communication plan may submit a prior approval supplement that seeks removal of the MedGuide component.

All REMS programs include a timetable for assessment, and any proposed REMS modification must be accompanied by an assessment. If the REMS was assessed in the past 18 months, the assessment may consist of a statement to that effect. If the REMS was not assessed during that time period, the assessment may include an update on the status of any post-approval studies undertaken to investigate a safety issue.

Exercising Enforcement Discretion

The guidance also explains when FDA will use its enforcement discretion on MedGuide distribution requirements in certain settings.

A MedGuide need not be distributed when a drug is dispensed to a health care professional for administration to a patient in an in-patient setting or an out-patient setting, such as a dialysis or infusion center, the guidance says. However, there are four exceptions to this rule.

A MedGuide must be distributed: when the patient requests it; when the drug is dispensed in an outpatient setting and used by the patient without a professional's direct supervision; the first time the drug is dispensed for a patient in an outpatient setting; and the first time a drug is dispensed after a MedGuide is materially changed.

-Sue Sutter (s.sutter@elsevier.com)

MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy

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