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Comments on Draft Guidance for Industry on Off-Label Promotion of Drugs and Medical Devices

Re: Draft Guidance for Industry on Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses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 (Docket No. FDA-2008-D-0053)

Division of Dockets Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane
Room 1061
Rockville, MD 20852 

To whom it may concern:

Does any of this sound familiar?

FDA has serious concerns regarding the promotion of indications that have not been reviewed and approved by the Agency. Because promotional activities of drug companies and others are substantially motivated by profit and market expansion, the widespread promotion of prescription drugs and devices for uses that have not been determined to be safe and effective could be detrimental to the health and safety of the public …

We believe that the risks of allowing drug companies to distribute journal articles and other information about off label uses far outweigh any benefits.

It should. The excerpts are drawn from Food and Drug Administration (FDA) Senate testimony on off-label promotion on February 22, 1996.[1] What a difference a decade makes! The FDA now takes the position that the very forms of off-label prescribing that it so heavily criticized in 1996 may result in the public health being “advanced.”[2]

Of course it is possible that intervening events might have satisfied the FDA’s concerns, thus justifying the agency’s about-face. But the fact is that all the relevant developments of the past decade have made the case against off-label promotion still stronger.


Before examining some of these developments, it is worth briefly reviewing the history of off-label promotion regulation at the FDA.[3] The agency has always made clear that off-label use of a drug (the prescribing of a drug for a purpose not approved by the FDA) represents the “practice of medicine” and is consequently beyond its purview; physicians are thus free to prescribe a drug for any off-label purpose. It has, however, objected to certain promotional practices in which such off-label uses have been encouraged. Until 1997, pharmaceutical companies were precluded from any form of off-label promotion, including the provision of journal reprints, textbook chapters and the like to physicians if they primarily touted an off-label use. However, the 1997 Food and Drug Administration Modernization Act (FDAMA)[4] carved out an exception: scientific information on off-label uses could be provided to physicians provided a series of conditions were met. Two were most important: 1) the FDA had to review such information before it could be disseminated; and 2) the company had to submit a Supplemental New Drug Application seeking approval for the off-label use. Those provisions had a sunset date of September 30, 2006.

The new Draft Guidance presents itself as merely an attempt to fill in the gap left by the sunsetting of the FDAMA provisions. Its Background section refers only to “certain conditions” under which FDAMA permitted the dissemination of scientific information without mentioning any of them, let alone the two central ones enumerated above. Only closer examination of the Draft Guidance reveals that the two critical provisions have been removed, greatly weakening the already-weak protections that existed under FDAMA. 

Recent developments in the field of off-label promotion only magnify our concerns about the dangers of off-label promotion.

The Extent of Off-Label Prescribing is Now Better Quantified

Concern about the dangers of off-label prescribing has long existed. Until relatively recently, the last comprehensive estimate of the extent of the practice appeared in a 1985 study.[5] However, a 2003 Knight-Ridder report, using data on office-based physicians from the health information company Verispan, estimated 115 million off-label prescriptions for just the 15 highest-selling classes of drugs in the previous year.[6] An academic investigation using a similar database from IMS Health looked at 160 top-selling drugs and estimated 150 million off-label drug “mentions” (similar to prescriptions) among office-based physicians in 2001.[7] These represented 21% of all mentions for these medications; 73% of the off-label mentions had “little or no scientific support.”

Several Drug Disasters were in Part the Result of Off-Label Prescribing

Two examples from the last decade amply illustrate the dangers of off-label prescribing. The FDA medical officer reviewing Duract (bromfenac sodium), then the 20th nonsteroidal anti-inflammatory drug (NSAID) approved in the United States, unsuccessfully advocated a black box warning label as a condition of approval because, “The review of the ‘liver’ laboratory data from the submission shows that bromfenac sodium causes hepatocellular damage to a greater degree than other NSAIDs.”[8] Duract was approved for the treatment of acute pain, to be used for 10 days or less, but predictably it was prescribed by doctors, off-label, for more than 10 days. On June 22, 1998, the drug had to be withdrawn from the market in part because of off-label prescribing that resulted in cases of severe hepatitis and liver failure, with some patients requiring liver transplants.[9] 

In November 2001, the FDA granted approval to Pfizer for its COX-2 inhibitor Bextra (valdecoxib) for three uses (menstrual pain, rheumatoid arthritis, and osteoarthritis), but rejected its application for acute pain. Subsequently, an article by Pfizer-sponsored researchers appeared in the Journal of the American Dental Association[10] touting the drug for acute pain.  The conclusions of the article were reiterated in an accompanying press release. However, neither the article nor the press release mentioned the FDA’s rejection of the acute pain application. According to a New York Times investigation, the medical journal article “helped light a fire under Bextra,” which experienced a sixty percent increase in sales in the three months following the article’s publication.[11]  Bextra was subsequently removed from the market after it was associated with life-threatening cutaneous conditions, including Stevens-Johnson Syndrome.

In sum, permitting the promotion of off-label uses of drugs risks shifting patients from drugs with known efficacy for their conditions toward drugs for which safety and efficacy have not been demonstrated. Such promotions are most likely to take place for more expensive, recently approved (and thus on-patent) drugs, for which the safety record will be only limited.

Let the FDA’s 1996 testimony be the final word on this topic: “[W]e also know that allowing the promotion of these kinds of uses can have negative public health consequences – including exposing patients to unnecessary risks.”[1]

Drug Companies have been Prosecuted for Off-Label Prescribing

Ironically, the FDA’s proposal to relax its off-label promotion guidelines occurs in the wake of a series of False Claims Act settlements related to off-label promotion by leading pharmaceutical companies. The most well-known case involves Neurontin (gabapentin), for which nearly 90% of prescriptions were off label.[12] This case confirms the prescience of the FDA’s 1996 testimony:

In a world where off label uses can be widely promoted, manufacturers would have an incentive to do the minimal amount of studies necessary to obtain approval for the first, narrowest/easiest indication and then heavily promote the product for other broader (and possibly more speculative) uses.[1]

Documents obtained during the Neurontin litigation detailed a “publication strategy” in which marketing firms created studies and identified physicians to take authorship credit. [13] The manufacturer eventually paid $430 million to settle various civil and criminal claims. 

Other major False Claims Act settlements for drugs with significant off-label promotion were Lupron (leuprolide; $875 million), Serostim (human growth hormone; $704 million) and Abilify (aripiprazole; $515 million). Thus, even as the Justice Department is becoming more zealous about prosecuting off-label promotion, the FDA proposes relaxing its standards regarding this practice.

The Deficiencies of the Peer-Reviewed Medical Literature Have Become Clearer

While the Draft Guidance embraces the virtues of the peer-reviewed medical literature, growing evidence documents that it has become corrupted by corporate interests. The list of such distortions grows steadily, so we will mention just three of the better-known improprieties.

The antidepressant selective serotonin reuptake inhibitors (SSRIs) have long been used off-label in the pediatric population without adequate supporting clinical trials. Despite objective evidence demonstrating that SSRIs are, at best, moderately effective in children,[14] published studies generally exaggerated the benefits of these drugs, while certain negative studies provided to the FDA were never published.  Industry-funded academic scientists withheld from publication some studies that failed to demonstrate drug efficacy,[15] the inclusion of which would have altered the risk-benefit profile of the drugs.[16] 

In 2001, the Journal of the American Medical Association published a report claiming that, after six months of therapy, the COX-2 inhibitor Celebrex (celecoxib) was associated with a reduced incidence of gastrointestinal ulcers compared to two other pain medications.[17] If true, this outcome would have represented a significant advantage over other approved pain medications.  However, the authors of the study failed to disclose that at the time of publication they had already received data for the full twelve-month period for which the study was originally designed.[18] The twelve-month data showed no advantage for Celebrex over the other drugs.  Although the FDA, armed with the twelve-month data, never allowed the company to claim reduced ulcer incidence, the published study helped drive the massive Celebrex market.

For further confirmation of this regrettable trend, one need look no further than two articles in the most recent issue of the Journal of the American Medical Association. In one article, the authors document how the manufacturer of Vioxx (rofecoxib) arranged for articles, some ultimately published in peer-reviewed journals, to be ghostwritten by employees of medical publishing companies.[19] In the second article, the authors demonstrate that the company employed less-than-optimal statistical techniques that systematically downplayed mortality associated with Vioxx in published medical journal articles.[20]

In its 1996 Senate testimony, the FDA made plain the deficiencies of the peer-reviewed medical literature and raised still greater concerns about textbook chapters:

[P]eer reviewers almost never receive the study protocol, … cannot tell what the initial hypothesis was, … do not have access to the underlying data, … [and] must rely on the data and facts presented by the author …

The data and information supporting off label uses that appear in reference textbook chapters, … CME materials, and materials related to third party coverage and reimbursement are even less likely to be validated than that in peer-reviewed journals. In fact, we have no reason to believe that such data have been reviewed or validated at all. [1]

There is a Modern Trend Toward Evidence-Based Medicine

The modern trend in pharmaceutical prescribing and clinical medicine generally is away from the previous practice of prescribing based on anecdote and toward the dispassionate assessment of rigorously collected data, a movement called evidence-based medicine. Indeed, it is this very movement that was endorsed when the requirement that drugs demonstrate efficacy prior to marketing was first put into place in 1962. The FDA’s proposal, while precluding the use of anecdotes, is an important step away from the more stringent standards of evidence-based medicine and thus runs counter to contemporary developments in medical science.

The Draft Guidance would permit the industry to substitute marketing for science. Once the drug has been approved for a single indication and thus has its proverbial foot in the door, the industry could turn to its marketing arm to exploit the drug’s full financial potential by promoting unproven, off-label uses without having to engage in a sometimes lengthy, expensive and unpredictable effort to secure formal FDA approval.

Once again, the FDA had it right in its 1996 testimony:

Permitting the promotion of off label uses based on studies reported in journal articles or other texts that are clearly an inadequate basis for approval by FDA would undercut the efficacy standard … One of the most serious consequences of allowing companies to freely promote off label uses is that companies would have no incentive to conduct or fund the necessary scientific research and to present data to FDA to verify the safety and efficacy of those off label uses … Because the incentive to conduct research on uses of drugs and devices will decrease, the end result will be that dissemination of off label information pursuant to this bill will actually reduce the amount of information that health care providers receive about drugs and devices. [1]

The Dangers of the Absence of an Efficacy Standard Have Been Reinforced

Recent ill-considered forays into deregulation of products other than prescription drugs underscore the dangers of the lack of an efficacy standard. For instance, the Dietary Supplement Health and Education Act of 1994 provided that dietary supplements should be regulated as foods, rather than drugs.  Producers of these products need not, therefore, demonstrate that their products are either effective or safe. Recent estimates peg the sales of these unproven nostrums at $18 billion annually.[21] Such uses can exact a significant toll. For example, the widely used supplement ephedra was never demonstrated to be an effective weight-loss agent using FDA’s standards for prescription drugs. It ultimately had to be removed from the market after it had been associated with over 155 deaths, most due to heart attacks and strokes.[22]

The practice of pharmacy compounding was similarly rescued from obscurity (at least for a time) by FDAMA provisions exempting compounded drugs from having to demonstrate safety or efficacy.  Predictably, entrepreneurs rapidly filled the safety and efficacy void with unsustainable claims and hazardous products. For example, compounded betamethasone, contaminated with the bacteria serratia, was responsible for three deaths and 10 hospitalizations when it was injected into patients’ spinal columns.[23] The pharmacy compounding provisions of FDAMA were ultimately struck down by the Supreme Court.[24]

Perhaps the most profound challenge to the FDA’s efficacy standard came from the Abigail Alliance, which sought to provide access for patients with terminal illnesses to prescription drugs that had merely completed the first of the three phases of clinical drug development. In other words, the Alliance desired expanded access to drugs for which efficacy had not been proved. Had it been successful, the efficacy standard would have been completely undermined, with unpredictable, but certainly negative, effects upon U.S. drug regulation. However, the full U.S. Court of Appeals for the District of Columbia ruled against the Alliance, stating:

Thus, we must conclude that, prior to distribution of a drug outside of controlled studies, the Government has a rational basis for ensuring that there is a scientifically and medically acceptable level of knowledge about the risks and benefits of such a drug.[25]

In sum, recent experience shows that in areas where the efficacy standard is absent, unsupported and even dangerous claims and promotional activities inevitably proliferate. Moreover, in a case where the FDA rose in defense of the efficacy standard, its claims were upheld.

Specific Elements of the Draft Guidance

We urge the FDA to strengthen the Guidance. First, the agency should require sponsors wishing to disseminate journal articles and textbook materials touting off-label indications to provide the materials to the agency 60 days before dissemination. This time period will allow the FDA to raise concerns prior to dissemination, while at the same time not impeding sponsors’ ability to disseminate such material fairly promptly. Second, the FDA should require a sponsor wishing to disseminate these materials either to submit a Supplemental New Drug Application seeking approval for the off-label use or a certification that it intends to do so within six months. In the absence of such a requirement, the agency should develop incentives to encourage submission of NDA supplements.

If the approach outlined in the Draft Guidance is maintained, we strongly support the conditions the agency has proposed. In particular, the requirements that the reprint be labeled as relating to an off-label use, that any conflicts of interest be clearly identified and that journals have true independence are minimum standards for off-label promotion.

We feel strongly that the only studies acceptable for distribution would be those that, consistent with the standards FDA requires for on-label uses, are “adequate and well-controlled.” With the FDA proposing, in effect, to dilute its efficacy standard by permitting off-label promotions, it makes little sense to permit the evidence behind the off-label claims to be inherently of a nature weaker than those required to secure formal FDA approval. Epidemiologic studies, historically controlled studies and open-label studies have little place in the evaluation of drug efficacy, particularly when they are distributed in the context of an off-label promotion.


The Draft Guidance represents a complete about-face from the well-reasoned position the agency staked out in its 1996 Senate testimony. By permitting promotional claims based on data it would itself find unacceptable for the granting of approval, the agency is almost literally shooting itself in the foot. The greater tragedy is that, assuming an FDA-approved medication for their condition already exists, patients will bear the brunt of this gift to industry by being shunted to medications that are generally more expensive, sometimes less safe and always unproven according to FDA standards.

Yours sincerely,

Peter Lurie, M.D., M.P.H.
Deputy Director 

Sidney M. Wolfe, M.D.
Health Research Group at Public Citizen


[1] Schultz WB, Deputy Commissioner for Policy, Food and Drug Administration. Testimony before Senate Labor and Human Resources Committee, February 22, 1996.

[2] Food and Drug Administration. 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. Draft Guidance. February 2008. Available at http://www.fda.gov/oc/op/goodreprint.html. Accessed April 20, 2008.

[3] In these comments, we refer only to drugs, but our comments apply equally to biologics and medical devices.

[4] 21 USC 360aaa.

[5] Strom BL, Melmon KL, Miettinen OS. Post-marketing studies of drug efficacy: why? American Journal of Medicine 1985;78:475-80.

[6] Young A, Adams C. Prescribing drugs “off-label” routine but can harm patients. McClatchy Newspapers, November 2, 2003. Available at: http://www.mcclatchydc.com/244/v-print/story/28122.html. Accessed April 17, 2008.

[7] Radley DC, Finkelstein SM, Stafford RS. Off-label prescribing among office-based physicians. Archives of Internal Medicine 2006;166:1021-6.

[8] Widmark RM (unpublished data). FDA medical officer review memo, bromfenac sodium, December 22, 1995.

[9] Food and Drug Administration. Questions and answers for withdrawal of Duract. June 22, 1998. http://www.fda.gov/cder/news/duract/qa.htm. Accessed April 20, 2008. Now available at: http://web.archive.org/web/20080504232324/http://www.fda.gov/cder/news/duract/qa.htm.

[10] Daniels SE, Desjardins PJ, Talwalker S, Recker DP, Verburg KM. The analgesic efficacy of valdecoxib vs. oxycodone/acetaminophen after oral surgery. Journal of the American Dental Association 2002;133:611-21.

[11] Petersen M. Madison Ave. has growing role in the business of drug research. New York Times, November 22, 2002, p. A1.

[12] Harris G. Pfizer to pay $430 million over promoting drug to doctors. New York Times, May 14, 2004.

[13] Steinman MA, Bero LA, Chren MM, Landefeld CS. Narrative review: the promotion of gabapentin: an analysis of internal industry documents. Annals of Internal Medicine. 2006;145:284-93.

[14] Jureidini JN, Doecke CJ, Mansfield PR, Haby MM, Menkes DB, Tonkin AL. Efficacy and safety of antidepressants for children and adolescents. British Medical Journal 2004;328:879-83.

[15] Meier B. Contracts keep drug research out of reach. New York Times, November 29, 2004, p. A1.

[16] Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363:1341-5. 

[17] Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Journal of the American Medical Association 2000;284:1247-55.

[18] Okie S. Missing data on Celebrex; full study altered picture of drug. Washington Post, August 5, 2001, p. A11.

[19] Ross JS, Hill KP, Egilman DS, Krumholz HM. Guest authorship and ghostwriting in publications related to rofecoxib: a case study of industry documents from rofecoxib litigation. Journal of the American Medical Association 2008;299:1800-12.

[20] Psaty BM, Kronmal RA. Reporting mortality findings in trials of rofecoxib for Alzheimer Disease or cognitive impairment: a case study based on documents from rofecoxib litigation. Journal of the American Medical Association 2008;299:1813-7.

[21] Institute of Medicine and National Research Council. Dietary Supplements: A Framework for Evaluating Safety. National Academy Press. April 1, 2004.

[22] Wolfe SM. Ephedra Ban Comes Too Late; FDA Should Have Acted Much Sooner. Public Citizen’s Health Research Group, Dec 30, 2003. Available at: https://www.citizen.org/pressroom/pressroomredirect.cfm?ID=1617. Accessed April 21, 2008.

[23] Hallissy E, Russell S. Bad medicine: Pharmacy mix-ups a recipe for misery. San Francisco Chronicle, June 23, 2002.

[24] Thompson v. Western States Medical Center, 535 U.S. 357 (2002).