FDA Proposal on the Promotion of Off-Label - Drs. Fugh-Berman and Melnick respond

Docket #FDA-2008-D-0053

Comments re: The FDA’s Guidance for Industry on 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

Adriane Fugh-Berman MD, Department of Physiology and Biophysics, Georgetown University Medical Center

Douglas Melnick MD MPH, North Hollywood, CA

Loosening restrictions on the distribution of materials on off-label uses is an abdication of the FDA’s responsibility to protect the public. Off-label uses of pharmaceuticals have not been subject to the testing and review required for marketing approval. The scientific review of evidence of effectiveness and safety that drugs undergo prior to an approved, labeled indication for a drug protects patients. With off-label use, this protection does not exist.

While off-label use is sometimes necessary, it should be undertaken with the care and caution due the uncontrolled experiment to which a patient is being subjected. While some off-label uses are supported by randomized controlled trials, 73% of 150 million off-label prescriptions written in 2001 were for conditions that had little to no scientific support for efficacy[i].

Belief is an unreliable gauge of efficacy. In the 19th century, physicians believed that mercury, arsenic, and bloodletting were effective for common ailments. More recently, physicians believed that oxygen therapy benefited premature babies when instead it caused blindness[ii], and that menopausal hormone therapy benefited women’s health when the opposite was true[iii]. In these and many other cases, randomized controlled trials trumped prevailing medical opinion with truth. While “medically-recognized standards of care” may exist outside of a product’s approved product labeling, it is inappropriate for the manufacturers to create or promote these off-label uses without conducting the studies and applying for the new indication with the agency.

It is appalling that “FDA does, however, recognize the important public policy reasons for allowing manufacturers to disseminate truthful and non-misleading medical journal articles and medical or scientific reference publications on unapproved uses of approved drugs and approved or cleared medical devices to healthcare professionals and healthcare entities.”[iv] What public policy reasons could justify the promotion of untested uses by companies that are not confident enough in those uses to seek labeled indications?

Surely FDA is aware that the articles and other publications distributed by pharmaceutical companies always contain messages consistent with marketing goals and are often commissioned by the companies that distribute them. FDA’s proposed restrictions on what may be distributed are entirely inadequate. Subsets of biased publications are still biased publications.

Previously, although it was technically possible for pharmaceutical companies to distribute reprints regarding off-label uses, the FDA’s requirements were sufficiently stringent that companies generally avoided such distribution. FDA required an advance copy of any publications on off-label uses to be distributed, any information that the manufacturer had regarding effectiveness and safety of the new use, and a certification that the manufacturer was submitting a supplemental application for a new indication or reasons why a supplemental application was not being filed.

These safeguards have been jettisoned in the proposed guidance, part of which reads as if it were ghostwritten by industry. For example, under the guise of balance, the statement that “in cases where the conclusions of article or text to be disseminated have been specifically called into question by another article(s) or text(s), be disseminated with a representative publication that reaches contrary or different conclusions regarding the unapproved use.” This implies that it is not misleading to distribute a biased industry-funded article as long as it was paired with one of, say, 87 articles in the medical literature that unanimously reached a different conclusion.

Allowing industry to engage in off-label promotion via reprints enables pharmaceutical companies (and medical device companies) to maximize off-label sales while saving the substantial cost of efficacy trials. Clinical trials are a business risk; they could find a product ineffective, or reveal health risks.

In terms of public health, a risk-benefit ratio cannot be assessed without knowing whether benefits exist. If no benefits exist, no risk is acceptable. For industry, this guidance is a bonanza; there is no ceiling to industry profits when drugs may be promoted for untested, unproven benefits. The potential public health effects of this are horrifying to contemplate.

FDA appears to be giving industry carte blanche to distort the state of medical knowledge.

Under the FDA’s irresponsible and disastrous proposed guidance, pharmaceutical companies need only get a drug approved once, for any indication, and then can concentrate their efforts on seeding the medical literature with ghostwritten articles on off-label uses in order to arm sales reps with promotional materials disguised as scientific literature. By following this “publication route” (an alternative to filing a legitimate NDA or BLA with the FDA), drug manufacturers may increase sales in off-label indications and save millions by avoiding proper testing and filing.

Currently, health care professionals employed in the medical affairs offices of pharmaceutical companies are allowed to respond to unsolicited requests from prescribers about off-label uses. However, customer questions can be triggered by sales representatives. For example, prior to drug approval, sales reps may offer “disease-state presentations” designed to increase receptivity to a targeted drug. These presentations elicit off-label questions that are then answered by the medical affairs department. A pharmacist or another health care professionals may send material directly to a physician regarding off-label uses or may visit a physician. Medical affairs employees may be trained in the same marketing messages and may follow the same “playbooks” as the sales representatives.

The knowledge that off-label promotion is illegal, however, surely limits the scope of this practice. If FDA lifts the restriction on unsolicited information delivered directly by pharmaceutical sales representatives, off-label promotion will no longer be off-limits.
Pharmaceutical sales representatives, who are trained in psychological manipulation, will use reprints that promote off-label uses to badger physicians to prescribe drugs for non-approved conditions. Pharmaceutical reps are trained to answer questions about any materials they distribute in such a way that benefits perceptions about targeted drugs. FDA-mandated labeling will only serve to legitimize distributed reprints.

Physicians and researchers who discover useful off-label uses can discuss their findings in medical journals, and promising therapies should be tested in clinical trials. Truly useful off-label benefits of drugs do not remain a secret. Realistically, it is impossible for the FDA to figure out which publications have been ghostwritten or otherwise manipulated by the manufacturer (especially if a third-party company is involved) or unravel the various techniques of data manipulation that companies may employ in the generation of off-label publications using data sets not submitted to the FDA. Journal and book editors and publishers may be unaware that a manufacturer was involved in a publication. For example, a physician invited to contribute a book chapter could accept the invitation and the ask the manufacturer to write the chapter without notifying the editor.

The 1962 Kefauver Amendment to the Food, Drug, and Cosmetic Act required efficacy of a drug before marketing. Allowing promotion for untested uses after marketing makes no sense. Let’s not turn back the clock to the 19th century, when physicians prescribed drugs with no evidence of efficacy.

Industry has much to gain, and the public health much to lose, by the implementation of this guidance. Restrictions on off-label promotion of drugs should be strengthened, not gutted. The FDA should not jettison its responsibilities to protect consumers.

[i] Radley DC, Finkelstein SN, Stafford RS (2006) Off-label prescribing among office-based physicians. Arch Intern Med166(9):1021-6.

[ii] Jacobson RM, Feinstein AR.J Clin Epidemiol. 1992 Nov;45(11):1265-87.Oxygen as a cause of blindness in premature infants: "autopsy" of a decade of errors in clinical epidemiologic research.

[iii] Writing group for the Women's Health Initiative investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.

[iv] The FDA’s Guidance for Industry on 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. Accessed April 14, 2008.