FDA is demonstrating its intent to use discretion in enforcement with a draft guidance aimed at clarifying when Medication Guides must be distributed. However, as a practical matter, pharmaceutical manufacturers may still have to maintain their existing distribution systems for the guides.

The draft guidance, “Medication Guides – Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies,” states that MedGuides need not be distributed when a drug is dispensed to a health care professional for administration in an inpatient setting or an outpatient setting, although 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.

New MedGuide policy would relieve sponsors of having to perform some assessments required under FDAAA.

FDA plans to specify when a change is considered to be material in a letter approving a revised MedGuide, and sponsors must notify health care providers that such a change was made.

Reconciling FDAAA With Section 208

The FDA Amendments Act of 2007 gave the agency authority to require a MedGuide as part of a REMS. The agency immediately started considering all new MedGuides as falling under the REMS program, though it did not apply the policy for previously approved MedGuides. Treating MedGuides as a REMS gave FDA greater enforcement authority.

Questions have arisen concerning FDA’s policy on whether the MedGuide must be distributed every time the drug is dispensed because the agency’s 1998 final rule on MedGuides, known as Section 208, states that the regulations are intended to apply primarily in the outpatient setting, according to the guidance.

The guidance observes that in some cases, MedGuides have been approved as part of REMS for drugs that are frequently distributed in inpatient settings or in outpatient settings where the drug is administered by a health care professional.

Even though FDA says it will not require distribution in inpatient and certain outpatient settings, it may not be practical for manufacturers to adjust the distribution of MedGuides depending upon the ultimate end user, said Frank Gallo, executive director for REMS at the contract research organization PPD.

“What I think we’re going to see is really in practice the manufacturers are going to continue to make the MedGuides available just as they are today,” he said, suggesting the greater impact would be felt by health care providers, who would not be obligated to distribute the guide each time a drug is administered.

Marc Hoffman, vice president of scientific and medical affairs at Covance Periapproval Services, similarly noted that for some drugs and end users, it will be easier for a manufacturer to continue including a MedGuide rather than having to undertake two separate manufacturing runs.

Burdens And Penalties Of REMS

While the guidance’s distribution provisions may not dramatically alter manufacturer practices, it appears the document’s allowance for approval of MedGuides outside of the REMS framework could have a more significant impact by reducing regulatory obligations on sponsors (Also see "MedGuide-Only REMS Will Be The Exception, Not The Norm, As FDA Relaxes Policy" - Pink Sheet, 25 February, 2011.).

REMS

Approving a new MedGuide outside of a REMS, or removing a MedGuide from an existing REMS, would relieve sponsors of having to perform burdensome assessments required under FDAAA.

Assessments for MedGuide-only REMS generally gauge whether patients received, read and understood the document. Data from some early assessments suggest that although most patients received the MedGuides, only two-thirds understood the key risk messages (Also see "Early REMS Assessments Show Room For Improvement In MedGuides" - Pink Sheet, 29 November, 2010.).

Sponsors are not required to conduct similar assessments under Section 208.

Pulling MedGuides out of the REMS framework also would remove the threat of civil money penalties authorized under FDAAA. Such penalties may reach $250,000 per violation for failing to comply with the requirements of a REMS, up to a maximum of $1 million for all violations in a single proceeding.

Although FDA apparently has not yet levied civil money penalties under REMS, the threat of large fines for violations such as failing to distribute MedGuides has concerned companies.

MedGuide-Only REMS Lead The Pack

Since FDAAA’s drug safety provisions took effect in March 2008, the agency has largely considered any new MedGuide or safety-related changes to an existing MedGuide to be part of a REMS.

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 178 REMS, according to figures on the agency’s website updated as of March 3. Of these, 118 were MedGuide-only, 38 comprised both MedGuides and communication plans, and 22 had elements to assure safe use.

Only one product, QOL Medical’s Sucraid (sacrosidase) has been released from its REMS obligations (Also see "QOL Medical’s Sucraid Is First To Lose Its REMS" - Pink Sheet, 7 March, 2011.).

Both the pharmaceutical industry and FDA have been eager to find a way of allowing MedGuides to be approved 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 (Also see "FDA Seeks To Write MedGuides Outside REMS Process" - Pink Sheet, 21 June, 2010.).

Although it was thought the agency might seek a legislative fix to the situation through the PDUFA V reauthorization, 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 authority to implement MedGuides under Section 208 (Also see "PhRMA Wants MedGuides Developed The Pre-FDAAA Way, Not Through REMS" - Pink Sheet, 26 July, 2010.).

FDA has the authority to determine 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," FDA says.

“In most cases” a MedGuide will be included as part of a REMS only when elements to assure safe use are needed.

The guidance states that "in most cases" a MedGuide will be included as part of a REMS only when elements to assure safe use are needed.

The document also explains how sponsors can seek removal of those REMS that contain only a MedGuide and a timetable for assessment (Also see "FDA To Sponsors: Say Goodbye To MedGuide-Only REMS" - Pink Sheet, 7 March, 2011.).

Sponsors who have an existing MedGuide-only REMS may submit a prior approval supplement for a REMS modification that proposes to eliminate the risk management 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 from the REMS.

The guidance does not address the possibility of moving a MedGuide outside of a REMS that also contains ETASU.

Gallo said he does not foresee MedGuides and REMS becoming mutually exclusive. “I think there will remain cases where they want to track if the MedGuide was received and if the goals of the MedGuide and/or REMS are being met.”

By Sue Sutter

FDA MedGuide Distribution Guidance May Mean Little Change For Manufacturers

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