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Regulating Off-Label Drug Use — Rethinking the Role of the FDA Regulating Off-Label Drug Use —
Rethinking the Role of the FDA
Randall S. Stafford, M.D., Ph.D.
The Food and Drug Adminis- clinical indications (e.g., the an- off-label use is common (see tration (FDA) provides a bar- tipsychotic agent quetiapine [Se- graph) but often not supported by rier to market entry and use of roquel] prescribed for depression) strong evidence.2 A 2003 report unproven and unsafe products. or in unapproved subpopulations showed that for the 3 leading For prescription drugs, the FDA (e.g., paroxetine [Paxil] for depres- drugs in each of the 15 leading approval process requires sub- sion in children). Off-label use may drug classes, off-label use account- stantial evidence of efficacy and originate from a presumed drug ed for approximately 21% of pre- safety for specific clinical situa- class effect, extension to milder scriptions.3 The highest rates of tions. Although approval is indi- forms of an approved indication, off-label use were for anticonvul- cation-specific, the FDA has a extension to related conditions (the sants (74%), antipsychotics (60%), limited role once a drug is on the use of the antiasthmatic montelu- and antibiotics (41%). In an ex- market. Recent draft guidelines kast [Singulair] for chronic ob- amination of off-label prescribing covering manufacturers’ promo- structive pulmonary disease), ex- of 160 common drugs, off-label tion of drugs through the distri- pansion to distinct conditions use was also found to account for bution of journal articles suggest sharing a physiological link (the 21% of all prescriptions, and most that the FDA is moving toward an use of the antidiabetic drug met- off-label drug uses (73%) were formin to treat polycystic ovarian shown to have little or no scien- Although off-label prescribing syndrome), or extension to condi- tific support.2 Atypical antipsy- — the prescription of a medica- tions whose symptoms overlap chotics and antidepressants were tion in a manner different from with those of an approved indi- particularly likely to be used off- The spectrum of off-label use Off-label use is also common for done in the absence of adequate includes guideline-recommended many biologics (such as epoetin supporting data. Off-label uses practice (aspirin in diabetes for alfa [Procrit] and bevacizumab have not been formally evaluated, prophylaxis against cardiovascu- [Avastin]).
and evidence provided for one lar disease), last-resort therapy clinical situation may not apply to (tacrolimus [Prograf] for auto- drugs off-label carries important others. As an area of controversy, immune diseases, in addition to advantages. It permits innovation off-label use is subject to the con- transplantation), and first-line in clinical practice, particularly tradictory expectations of various therapy (gabapentin [Neurontin] when approved treatments have stakeholders, including health care for painful diabetic neuropathy, failed. It offers patients and phy- payers, the pharmaceutical in- in addition to its use in herpes sicians earlier access to potentially dustry, physicians, and consum- zoster). Though new indications valuable medications and allows ers. The FDA has a role in bal- may be added to a drug’s label physicians to adopt new practices ancing these expectations, but it through a supplemental new drug based on emerging evidence. And currently does so primarily through application, this occurs infrequent- it can provide the only available regulating corporate marketing. ly: generic drugs lack a corporate treatments for “orphan” conditions. Although there is a strong ra- sponsor to bear the required ex- At the same time, off-label use has tionale for greater FDA involve- penses, and for brand-name drugs potentially negative consequences. ment in off-label use, it is moving that are already widely used off- It undercuts expectations that drug toward relinquishing control in its label, conducting costly clinical safety and efficacy have been fully trials that could produce nonsup- evaluated. When newer, more ex- Off-label use arises through portive evidence is a potentially pensive drugs are used off-label, many pathways but usually entails risky business decision.
Evaluations have shown that undermines the incentives for n engl j med 358;14 www.nejm.org april 3, 2008 Downloaded from www.nejm.org at ANKARA UNIVERSITESI on April 2, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. Regulating Off-Label Drug Use — Rethinking the Role of the FDA No. of Uses (millions)
Therapie
Therapie
Psychiatric
Peptic Ulcer
Antiasthmatics
and Dyspepsia Anticonvulsants
Allergy Therapie Cardiac Therapie
Estimated Numbers of Prescriptions for On-Label and Off-Label Uses of Medications in Various
Functional Classes, 2001.
Numbers were estimated on the basis of the National Disease and Therapeutic Index, a survey conducted by IMS Health. Data are from Radley et al.2 SIZElieve that the agency is mak-
2x col mistake, particularly given tant questions about off-label drug AUTHOR, PLEASE NOTE:ch
the faith that physicians and con- prescribing, as in the examples of Figure has been redrawn and type has been reset. ers place in it.
Please check carefully.
The FDA influences the pre- pentin for chronic pain and olan- 04-03-08 of all available drugs in zapine (Zyprexa) for dementia.
During the past decade, there subsequent changes in drug la- draft guidelines address the dis- have been numerous conflicts beling, including black-box warn- tribution of journal articles by about off-label use. Payers increas- ings, can alert physicians that pharmaceutical sales representa- ingly question the need to pay for special caution is required. Spe- tives.1 Although the guidelines products that are not proven. Phy- cific restrictions on drug avail- nearly nullify themselves by em- sicians desire the autonomy to ability constrain use to specific phasizing their nonbinding nature, prescribe drugs that match indi- settings. Most important, the they also suggest a more permis- vidual patient needs regardless of FDA regulates the industry’s mar- sive attitude toward the promotion label, but they face difficulties keting practices. Current FDA of off-label uses of drugs. Though staying abreast of rapidly evolving policy on marketing for off-label they carry forward many provi- evidence. The pharmaceutical in- uses follows the FDA Modern- sions of the FDA Modernization dustry seeks to enlarge its mar- ization Act of 1997 (even though Act, there are two glaring omis- kets to ensure future profits and these regulations formally expired sions. First, manufacturers need sustain drug development. The in 2006). This legislation greatly no longer limit their promotion of public wants drugs that are safe, eased restrictions on drug pro- off-label uses to drugs and indi- evidence-based, and affordable; motions. FDA policy currently cations for which they are work- although consumers want the new- prohibits the direct promotion of ing toward FDA evaluation; and est therapies, they may also want products for unapproved uses.
The drug industry, however, for advance FDA review of the be disclosed. Recent indications may facilitate off-label use by ex- journal articles to be distributed. suggest that the FDA is unlikely ploiting areas of ambiguity where n engl j med 358;14 www.nejm.org april 3, 2008 Downloaded from www.nejm.org at ANKARA UNIVERSITESI on April 2, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. Regulating Off-Label Drug Use — Rethinking the Role of the FDA oversight may merely formalize its limited resources can be put to submitted through Regulations.
the FDA’s de facto policies, some better or more effective use in gov, under Docket No. FDA-2008- observers had been expecting confronting other ongoing chal- D-0053, using the “send a com- the agency to seek a greater role lenges. Nevertheless, I believe that ment” option.
in moderating off-label use. This the FDA must take an active role backward shift seems oddly in- in fostering evidence-based prac- fees from Bayer and grant support from congruous with current pressures tice, eliminating subversion of the Procter & Gamble and Toyo Shinyaku.
aimed at improving postmarket- approval process, and requiring ing drug evaluation. If there are a balanced and fair presentation Dr. Stafford is an associate professor of substantial safety concerns about of scientific evidence.
search Center, Program on Prevention Out- The FDA might consider under- comes and Practices, Stanford University, greater uncertainty with regard to taking a range of new activities in Stanford, CA.
off-label uses. The harms associ- regulating off-label use, includ- 1. Guidance for industry: good reprint prac-
ated with rofecoxib (Vioxx) that ing systematically collecting post- tices for the distribution of medical journal were recognized only after the marketing data to quantify the articles and medical or scientific reference publications on unapproved new uses of ap- drug’s widespread use among pa- harms and benefits of common proved drugs and approved or cleared medi- tients who were unlikely to receive off-label uses; synthesizing evi- cal devices (draft guidelines). Rockville, MD: incremental benefits4 represent but dence regarding off-label uses and Food and Drug Administration, February, 2008. (Accessed March 14, 2008, at http:// disseminating its reports; scru- www.fda.gov/OHRMS/DOCKETS/98fr/ There are several reasons why tinizing marketing efforts to re- FDA-2008-D-0053-gdl.pdf.) the FDA may be reluctant to take strict materials on off-label uses 2. Radley DC, Finkelstein SN, Stafford RS.
Off-label prescribing among office-based a more active role in diminishing that don’t have strong support; physicians. Arch Intern Med 2006;166: non–evidence-based off-label use. increasing the use of active drugs 1021-6.
Historically, restrictions on mar- as comparators in postmarketing 3. Adams C, Young A. Risky Rx: a Knight Rid-
der investigation. Newspaper article series, keting that is not misleading have clinical trials; and requiring in- November 2-4, 2003. (Accessed March 14, been successfully challenged as formation about anticipated off- 2008, at http://www.mcclatchydc.com/244/ infringements of commercial free label uses to be presented at the story/28122.html.) 4. Dai C, Stafford RS, Alexander GC. Nation-
speech. The FDA may be conced- time of a drug’s review for initial al trends in cyclooxygenase-2 inhibitor use ing to drug manufacturers the re- approval.
since market release: non-selective diffusion The FDA is accepting comments of a selectively cost-effective innovation. own off-label marketing practices. on its draft guidelines through Copyright 2008 Massachusetts Medical Society. The agency may also believe that April 21, 2008. Comments may be n engl j med 358;14 www.nejm.org april 3, 2008 Downloaded from www.nejm.org at ANKARA UNIVERSITESI on April 2, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

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