Under new guidelines released by the FDA on Jan. 13, sales reps for pharmaceutical drug and device manufacturers may distribute medical literature for educational purposes that describes “new” or off-label uses of approved products, and that information need not be reviewed by the agency prior to dissemination to neurologists and other providers.
Previously, when the companies submitted educational materials on off-label use, the law required manufacturers to certify that they were going to file an application — now or in the future — to seek FDA approval for the therapeutic indications mentioned in articles. This is no longer required.
The 1997 Food and Drug Administration Modernization Act, which governed off-label materials, expired in September 2006, and no new law was passed to replace it. This left the FDA, the drug industry, and physicians without a law providing rules or recommendations on how companies can disseminate medical articles containing off-label information for educational purposes.
“The FDA policy under the Bush Administration and under the Obama Administration has been, and almost certainly will continue, to take enforcement against off-label promotion, as contrasted with legitimate efforts by drug and device companies to educate physicians about new research,” Wayne Pines, formerly the FDA associate commissioner for public affairs, told Neurology Today. “That's the fine line that regulators seek to draw” in releasing the guidance.
Among recommendations, the FDA document suggests that articles should be published by an organization that uses an editorial board and peer-reviews articles, as well as that it has a full disclosure policy for all authors, editors, and others associated with the organization. (For other guidelines, see “FDA Guidance: Distribution of Materials on Off-Label Indications.”)
Pines said it remains to be seen how the guidance works in clinical practices, but some dos-and-don'ts are clear. “A drug rep can hand out the paper, but not in conjunction with an effort to promote the product; that is, to try to encourage the physician to prescribe the product,” said Pines, now president of healthcare for Apco Worldwide, a consulting firm based in Washington, DC. “Most importantly, the guidance does not authorize the promotion of any off-label uses, under any circumstances.”
GUIDANCE UNTESTED IN PRACTICE
Jacqueline A. French, MD, professor of neurology at New York University and director of the clinical trials consortium at its Comprehensive Epilepsy Center, said she is worried about “how this is going to implemented and enforced.”
Even with the guidance in place, “I wouldn't rely on a drug rep to provide information,” Dr. French told Neurology Today. “I would go to PubMed and look it up myself. But I am not sure everybody does that.”
“When the rep comes into the office, should they be allowed to hand you whatever literature they want?” Dr. French asked. “It's one thing if the busy clinician says, ‘I am treating all these children with epilepsy and your drug is only approved for adults, do you have any literature on kids?’ There might be a justification for giving the physician that literature. That's different from saying, ‘Here's three articles on treating kids.’”
Dr. French, who chairs the AAN Quality Standards Subcommittee, said physicians don't always understand what good research is. “We are always quite surprised when we do our guidelines that people are not aware of the issues that would make the paper biased or unbiased,” she said.
“The guidance provides a clarity that was lacking,” with the expiration of the law, said Coleen Klasmeier, a partner in the Washington, DC, office of the law firm Sidley Austin, LLP, where she is the head of the FDA regulatory practice. But she said there are some areas that might require further FDA guidance, such as defining what a “new use” of an approved drug or device might be.
She stressed that it is important for physicians to remember that the guidance is not law. “It is an important and instructive set of recommendations.”
Pines said the growing consensus that neurologists and others should practice evidence-based medicine is not at odds with consideration of reprints about off-label products.
“My own definition is that medicine should be practiced based on the latest and best scientific information, as well as the experience and medical judgment of the physician and the specific needs of the individual patient,” he said. “I don't see how the intent of this guidance is in conflict with that objective. The more information that physicians — and patients — have, the better the outcomes should be.”
LAWSUITS SHOW CONTINUING ENFORCEMENT
Pines noted that the guidance is consistent with the rules that apply when physicians serve as spokespeople for drug or device companies. “Physicians may discuss unapproved uses of products when speaking solely for themselves,” he said. “When paid by a drug or device company, however, they come under the same rules as the company…they may not promote off-label uses.”
Physicians should also be aware of ongoing investigations by the Department of Justice for drug companies' illegal off-label promotional activities, Pines added.
Just two days after the guidance was released, Eli Lilly & Co. pleaded guilty to promoting the off-label use of its antipsychotic drug, olanzapine (Zyprexa), for use in dementia, and had to pay the largest fine of a single defendant in Department of Justice history — $1.4 billion in fines and damages. In 2004, Warner-Lambert also agreed to pay $430 million related to off-label promotion of gabapentin (Neurontin), approved for partial complex seizures but marketed for many other uses.
The activities that the drug makers are alleged to have conducted did not fall under the guidance, and crossed the line into promotion and marketing of off-label uses, which are not permitted. Fines were in part due to violations of the False Claims Act, which targets payments improperly received from illegally marketed and promoted drugs.
Daniel Meron, the former general counsel of the Department of Health and Human Services, who is now a partner with the law firm of Latham & Watkins, LLP, noted that such investigations and prosecutions remain ongoing, even in the face of the guidance.
Meron noted that the guidance is limited in that it “recognizes the public policy and First Amendment considerations that underlie the dissemination of information on off-label uses by manufacturers, but it addresses only one form in which such dissemination takes place.” It does not, for example, address information sharing “among physicians and manufacturers about off-label uses that occurs in educational settings, trade shows and one-on-one interactions.”
The document also allows that any drug maker may face enforcement action, he said, if it “engages in other conduct that unlawfully promotes an unapproved use of a medical product — whether or not the manufacturer also engages in conduct in conformance with the recommendations in this guidance.”
FDA GUIDANCE: DISTRIBUTION OF MATERIALS ON OFF-LABEL INDICATIONS
Following are some of the criteria covered in the FDA document, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical Scientific Reference Publications on Unapproved New Uses of Approved Drugs or Cleared Medical Devices”:
- Literature on off-label indications should be available in bookstores or other independent distribution channels (for example, by subscription, Internet) where medical textbooks or periodicals are sold; and should not be written, edited, excerpted, or published specifically for, or at the request of, a drug or device manufacturer; or edited or significantly influenced by a drug or device manufacturer or any individuals having a financial relationship with the manufacturer.
- Articles should be published by an organization that uses an editorial board and peer-reviews articles, as well as has a full disclosure policy for all authors, editors, and others associated with the organization.
- The information “should address adequate and well-controlled clinical investigations that are considered scientifically sound by experts with scientific training and experience to evaluate the safety or effectiveness of the drug or device.”
- Letters to the editor; abstracts of publications, phase 1 (safety only) trials in healthy subjects; or reference publications that contain little or no substantive discussion of the relevant investigation or data should not be distributed.
For the full guidance, see www.fda.gov/oc/op/goodreprint.html.