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March 3 --The Food and Drug Administration, responding to requests for more clarity, announced a draft guidance that would revise previously issued guidance on what printed materials about off-label uses for approved products are acceptable for distribution.
The draft guidance, which was the subject of a notice in the March 3 Federal Register (79 Fed. Reg. 11,793), would revise a 2009 guidance, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.” That guidance allowed drug and device companies in some cases to provide information such as journal articles to doctors about unapproved uses for approved products .
In July 2011 and September 2013, the FDA said, it received citizen petitions on behalf of drug and device manufacturers asking for greater clarity about the requirements of off-label uses as well as a review of the regulations .
“This draft guidance describes recommended practices for drug or medical device manufacturers or their representatives to follow when distributing to health care professionals or health care entities scientific and medical publications that discuss unapproved new uses of approved drugs or approved or cleared medical devices,” the FDA said in an advance copy of its Federal Register notice. “FDA continues to consider the specific requests made in the citizen petitions, which include requests for issuance or revision of regulations, and has not yet reached a final determination on those petitions.”
The agency estimated that about 400 companies distribute scientific and medical publications that discuss unapproved new uses.
The latest draft guidance, “Distributing Scientific and Medical Publications on Unapproved New Uses--Recommended Practices,” would provide recommendations on the characteristics of scientific and medical publications that companies may opt to distribute, the FDA said.
“Elaborated in more detail in the draft guidance, these characteristics in general include that these publications be from journals, scientific or medical reference texts, and CPGs [clinical practice guidelines] that are produced by independent sources and meet criteria for professional/peer review; be based on specified types of scientific evidence; and be complete, unabridged, and without highlighting or characterization by the manufacturer. In addition, the draft guidance provides recommendations for additional information to be supplied with the publications,” the FDA said.
The draft guidance includes separate but related recommendations for the three types of publications: scientific or medical journal articles, scientific or medical texts and CPGs.
In general, the draft guidance recommends that the information have a “prominently displayed and permanently affixed statement that some of the uses for the drugs and/or devices being distributed might not have FDA approval or clearance.”
The statement also must include any financial interest disclosures, whether they stem from the authors who wrote the information being distributed, or from the drug or device manufacturer. For the front page of the CPG or the textbook, the FDA said this statement should be on a stamp, sticker “or other similar means.”
The FDA draft guidance also recommends that for all three information sources, the manufacturer disclose all significant risks or safety concerns associated with the unapproved use.
For science or medical journals, the agency said, the information should be distributed with:
• approved labeling;
• a bibliography, when such information exists, of publications discussing adequate and well-controlled clinical studies published in scientific journals, medical journals or scientific texts about the use of the drug or medical device covered by the information; and
• a representative publication, when such information exists, that reaches contrary or different conclusions regarding the unapproved use--especially when the conclusions of articles to be distributed have been specifically called into question in another publication.
For medical or scientific texts, the agency broke down its recommendations based on whether the manufacturer was distributing the reference text in its entirety or pulling only specific chapters.
“In situations where a reference text is distributed in its entirety but one or more individual chapters of that reference text devote primary substantive discussion to an individual product or products of the manufacturer distributing it,” the FDA said, this information should be “disseminated with the approved product labeling for each such product or, in the case of a medical device reviewed under section 510(k) of the FD&C [Federal Food, Drug, and Cosmetic] Act, labeling for the indications in the product's cleared indications for use statement.”
When a manufacturer distributes an individual chapter or chapters, the FDA said that when necessary, context should be provided “with other unaltered/unabridged chapters extracted directly from the same scientific or medical reference text, such as chapters which provide related or supportive information.”
For clinical practice guidelines, the agency said, “In situations where a CPG is distributed in its entirety but one or more individual sections of that CPG devotes primary substantive discussion to an individual product or products of the manufacturer distributing it,” the information should “be disseminated with the approved product labeling for each such product or, in the case of a medical device reviewed under section 510(k) of the FD&C Act, labeling for the indications in the product's cleared indications for use statement.”
If a manufacturer distributes an individual section or sections of the CPG that includes information on unapproved/uncleared uses of the manufacturer's product(s), the FDA said the section or sections should, “When necessary to provide context, be disseminated with other unaltered/unabridged sections extracted directly from the same CPG, such as sections which provide related or supportive information.”
Arnold I. Friede, a senior food and drug law attorney with Sandler, Travis & Rosenberg PA, in Miami, told Bloomberg BNA on March 3 that while the FDA attempted to offer clarity, he questioned whether the burden from the draft guidance would make off-label use even worth the risk of noncompliance.
He said, “You've got to provide so much information that the question is: First of all will you do that; and second of all what is the utility of the off-label information if the doctor has to wade through all of this other evidence to get the message?”
These proposed requirements would be layered on top of what Friede described as the “pre-existing enforcement environment,” in which most big drug and device manufacturers have corporate integrity agreements that govern their off-label promotions.
“They have to ask themselves, 'Are they really going to take substantial advantage of this?'” Friede said. “Or have we gotten to the point where even though the industry has asked for clarity that it's just not going to be all that meaningful?”
Comments are due May 2, and can be submitted at http://www.regulations.gov using the docket number FDA-2008-D-0053. Written comments may be sent using the docket number to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Md. 20852.
To contact the reporter on this story: Jeannie Baumann in Washington at firstname.lastname@example.org
To contact the editor responsible for this story: Randy Kubetin at email@example.com
The March 3 Federal Register notice is available at http://www.gpo.gov/fdsys/pkg/FR-2014-03-03/html/2014-04560.htm.
The FDA's 2009 guidance is available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm.
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