I prescribe drugs off-label. Am I in violation of FDA regulations

You are a member of your local dermatologic society and attend monthly meetings in order to obtain CME credits. In order to finance the meeting and encourage attendance, the society has the monthly meetings financed by a prominent drug company.

The drug company provides journal articles documenting the off-label use of one of their prescription pharmaceutical agents. You obtain CME credits, read the journal article and begin prescribing the off-label medication. Is the drug company in violation of the U.S. Food and Drug Administration (FDA) rulings? Are your actions acceptable?

The FDA derives its authority to regulate various aspects of the pharmaceutical industry from the Federal Food, Drug and Cosmetic Act, United

States Code, Title 21 section 301. For a prescription drug to be distributed by a manufacturer in interstate commerce, the manufacturer is required to demonstrate that the drug is both safe and effective for its intended uses.

As part of the approval process, FDA also reviews the proposed labeling for the drug, which includes all proposed claims about the drug’s risks and benefits. Labeling encompasses all written, printed or graphic material upon any drug or any of its containers or wrappers; or, all written, printed or graphic material accompanying the drug.

The most obvious form of labeling is the package insert that accompanies the drug, but the term has also been construed to include nearly every form of drug company promotional activity, including booklets, mailing pieces, bulletins and literature that supplements, explains, or is textually related to the product.

FDA will only approve the company’s new drug application if the labeling conforms to FDA-approved uses. In 1962, Congress determined that a manufacturer seeking to market or promote a product for an unlabeled use must resubmit the drug for another series of clinical trials similar to those from the initial approval.

Off-label uses include treating a condition not indicated on the label, or treating the indicated condition but varying the dosage regimen or even the patient population. Manufacturer promotion of off-label uses constitutes misbranding and is in violation of the FDA statutes. Physicians are not held to the same standard as manufacturers. Once a drug has been approved by

FDA for marketing for any use, the prescription choices are left to the discretion of the physician. A dermatologist may prescribe an approved drug for any medical condition regardless of whether FDA has determined that the drug is safe and effective with respect to that illness.

Since off-label uses are presently an accepted aspect of a dermatologist’s prescribing regimen, the open dissemination of scientific and medical information regarding these treatments is of great-import. The FDA acknowledges that physicians need reliable and up-to-date information concerning of -label uses. FDA recognizes that sources for such information are varied, and include CME lectures and seminars. It specifically recognizes that the need for reliable information is particularly acute in the off–label treatment arena because the primary source of information usually available to physicians, such as the FDA approved label, is absent.

Off-label prescription practices can be problematic and have proven harmful. Therefore, the FDA, consistent with its mission to protect the public health, has been charged to develop guidelines.

In the late 1980s drug companies greatly increased their resources devoted to sponsoring CME seminars. Concerns about drug manufacturer promotional practices caught the attention of Congress. Among the issues was manufacturer promotion of unapproved claims for approved products.

Following Congressional hearings, FDA sought to distinguish between situations in which CME was “independent of the substantive influence of the supporting company,” and therefore not subject to regulation, as opposed to situations when the manufacturers are in a position to influence the presentation of information.

The FDA developed twelve factors to consider in evaluating programs and activities to determine “independence,” which include:

• Who controls the content and selects the presenters and the moderator;

• Whether there is meaningful disclosure as to the companies funding and whether unapproved uses will be discussed;

• The focus of the program, such as whether the central theme is on of -label product;

• The relationship between supporting companies and the CME provider;

• Audience selection;

• Opportunities for meaningful discussion and questioning; Dissemination of information;

• Ancillary promotional activities; and

• Complaints raised by the provider, presenters or attendees regarding attempts by the supporting company to influence content.

Additionally, while not required, a written agreement between the meeting provider and the supporting company can provide valuable evidence that the sponsoring company will not control the CME content, and that the meeting provider is solely responsible for conducting the activity.

In 1996, FDA issued a second set of guidelines concerning the distribution of “enduring” materials.

These include textbook excerpts and article reprints from medical and scientific journals.

These guidelines restrict manufacturer distribution of enduring materials when the publications address of -label uses for the company’s previously approved products. This would even include a publication from a peer-reviewed journal.

FDA allows manufacturers to disseminate reprints from journal articles but requires that the principal subject of the article should be the uses approved by FDA. This ruling, on its face, would prohibit manufacturer distribution of the aforementioned journal articles at the monthly dermatology meeting.

CASE GLANCE

In Washington Legal Foundation v. Michael A. Friedman, Commissioner, Food and Drug Administration and Donna Shalala, Secretary of U.S. Dep’t of Health and Human Services, the Washington Legal Foundation, a non-profit public interest law and policy center that defends the rights and individuals and businesses to go about their affairs without undue influence from government regulators, contended that journal articles - as scientific and academic speech - are entitled to the highest level of First Amendment free speech protection. There should be no FDA restrictions on the dissemination of such materials. FDA claimed that journal articles represent commercial speech that is not as strictly protected by the First Amendment, as is non-commercial speech.

The United States District Court for the District Court of Columbia, in analyzing the litigation, noted that the distribution of enduring materials and sponsorship of CME seminars does constitute speech and therefore is entitled to First Amendment protection.

The Court struggled with whether manufacturer distribution of peer reviewed articles promoting off-label uses at CME seminars was pure speech, demanding near absolute free speech protection, or commercial speech which could be somewhat restricted. In its decision in July of 1998, the Court noted that when considered outside the context of manufacturer product promotion, CME seminars, peer-reviewed articles and commercially available medical textbooks merit the highest degree of constitutional protection.

The question raised was whether speech that would be fully protected as scientific and/or educational speech can be transformed into commercial speech, with a lesser degree of free speech protection, simply because a commercial entity seeks to distribute materials that would lead to an increase in sales of the product addressed in the speech. Such restrictions might be appropriate when public health is an issue.

The court looked at the U.S. Supreme Court decision in Bolger v. Youngs Drug Products Corp.

The Supreme Court found it hard to fathom how dissemination of enduring materials or sponsorship of CME seminars could constitute a deceptive

or aggressive sales practice. After all, physicians may obtain the same information from other sources. However, the Court noted that for any given off-label treatment, there may be a wide variety of scientific research data available, some of which concludes that the off-label treatment is effective, some of which concludes it is not. The manufacturers will likely only seek to disseminate information that presents their product in a favorable light. Because of manufacturers significant financial resources, distribution of favorable articles is more likely than those showing unfavorable results. Thus, the Court decided that of -label articles, such as a peer-reviewed journal publication, represent commercial speech when distributed by a drug manufacturer at a monthly CME dermatology meeting.

The court then evaluated whether FDA’s ban of manufacturer’s distribution of of -label peer reviewed articles was appropriate and felt the absolute ban was more restrictive than necessary. All that should be required is “full, complete, and unambiguous disclosure by the manufacturer.” Such disclosure, advising physicians that FDA has not approved such use of the drug, avoids dissemination of potentially misleading information.

This requirement would still lead manufacturers to seek FDA labeling approval so as to allow broader distribution of the currently “of -label” drug. The court noted that in the balancing act between free speech and restriction of First Amendment rights, it is always better to allow free speech.

The court would have no difficulty with the distribution of off-label journal articles as long as the drug manufacturer provides full disclosure.

The First Amendment right of speech can be protected while at the same time the public at large is not placed in danger. Finally, dermatologists are not in violation of FDA statutes for prescribing the of -label use of prescription drugs.