Hostname: page-component-6bf8c574d5-h6jzd Total loading time: 0.001 Render date: 2025-02-14T22:57:43.089Z Has data issue: false hasContentIssue false
  • English
  • Français

Off-Label Prescribing: A Call for Heightened Professional and Government Oversight

Published online by Cambridge University Press:  01 January 2021

Rebecca Dresser  and
Joel Frader
Get access Rights & Permissions [Opens in a new window]

Extract

Off-label prescribing is an integral part of contemporary medicine. Many patients benefit when they receive drugs or devices under circumstances not specified on the label approved by the Food and Drug Administration (FDA). An off-label use may provide the best available intervention for a patient, as well as the standard of care for a particular health problem. In oncology, pediatrics, geriatrics, obstetrics, and other practice areas, patient care could not proceed without off-label prescribing. When scientific and medical evidence justify off-label uses, physicians promote patients’ interests by prescribing products off label.

Off-label prescribing can also harm patients, however. The potential for harm is greatest when an offlabel use lacks a solid evidentiary basis. A 2006 study examining prescribing practices for 169 commonly prescribed drugs found high rates of off-label use with little or no scientific support. Researchers examining off-label use in U.S. children’s hospitals concluded, “[W]e still have incomplete knowledge about the safety and efficacy of many medications commonly used to treat children across a range of drug classes and clinical diagnoses.”

Type
Independent
Information
Journal of Law, Medicine & Ethics , Volume 37 , Issue 3 , Fall 2009 , pp. 476 - 486
Copyright
Copyright © American Society of Law, Medicine and Ethics 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

See, e.g., Committee on Drugs, American Academy of Pediatrics, “Uses of Drugs Not Described in the Package Insert (Off-Label Uses)”, Pediatrics 110, no. 1 (2002): 181–183; National Cancer Institute, Understanding the Approval Process for New Cancer Treatments, available at <http://newscenter.cancer.gov/clinicaltrials/learning/approval-process-for-cancer-drugs/allpages/print>(last visited June 23, 2009); Rayburn, W. F. and Farmer, F. C., “Off-Label Prescribing During Pregnancy”, Obstetrics and Gynecology Clinics of North America 24, no. 3 (1997): 471-478; Siu, L. L., “Clinical Trials in the Elderly — A Concept Comes of Age”, New England Journal of Medicine 356, no. 15 (2007): 1575-1576.Google Scholar
Radley, D. C., Finkelstein, S. N. and Stafford, R. S., “Off-Label Prescribing among Office-Based Physicians”, Archives of Internal Medicine 166, no. 9 (2006): 1021–1026.CrossRefGoogle Scholar
Shah, S. S. et al., “Off-Label Drug Use in Hospitalized Children, Archives of Pediatric and Adolescent Medicine 161, no. 3 (2007): 282–290. See also Kumar, P. et al., “Medication Use in the Neonatal Intensive Care Unit: Current Patterns and Off-Label Use of Parenteral Medications”, Journal of Pediatrics 152, no. 3 (2008): 412-415.CrossRefGoogle ScholarPubMed
Asani, N. et al., “Innovative Off-Label Medication Use”, American Journal of Medical Quality 21, no. 4 (2006): 246–254.Google Scholar
Statement of Schultz, William B., FDA Deputy Commissioner for Policy, before the U.S. Senate Committee on Labor and Human Resources, February 22, 1996, available at <http://www.fda.gov/ola/1996/s1447.html> (last visited June 20, 2009).+(last+visited+June+20,+2009).>Google Scholar
Dresser, R., “The Curious Case of Off-Label Use”, Hastings Center Report 37, no. 3 (2007): 9–11.CrossRefGoogle Scholar
Salbu, S. R., “Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy”, Florida Law Review 51, no. 2 (1999): 181–227.Google Scholar
See generally, Merrill, R. A., “The Architecture of Government Regulation of Medical Products”, Virginia Law Review 82, no. 8 (1996): 1753–1886.CrossRefGoogle Scholar
Kesselheim, A. S. and Avorn, J., “Pharmaceutical Promotion to Physicians and First Amendment Rights”, New England Journal of Medicine 358, no. 16 (2008): 1727–1732, at 1730.CrossRefGoogle Scholar
See generally Institute of Medicine, The Future of Drug Safety: Promoting and Protecting the Health of the Public (Washington, D.C.: National Academies Press, 2007).Google Scholar
21 U.S.C. § 396 (2000). See also 21 C.F.R. § 312.2(d) (2008); Buckman Co. v. Plaintiffs' Legal Comm., 531 U.S. 341, at 350 (2001); Landers, S. J., “New Law Expands FDA Monitoring, Funds”, American Medical News, October 22/29 (2008): at 22. In a rare departure from this approach, the FDCA imposes criminal penalties on physicians prescribing human growth hormone off label. See Perls, T. T., Reisman, N. R. and Olshansky, S. J., “Provision or Distribution of Growth Hormone for ‘Antiaging,’” JAMA 294, no. 17 (2005): 2086–2090.Google Scholar
See, e.g., Washington Legal Foundation v. Friedman, 13 F. Supp.2d 51 (D.D.C. 1998); Food and Drug Administration, “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,” January 2009, available at <http://www.fda.gov/oc/op/goodreprint.html> (last visited June 25, 2009); Gottlieb, S., “Opening Pandora's Pillbox: Using Modern Information Tools to Improve Drug Safety”, Health Affairs 24, no. 4 (2005): 938–948; American Medical Association House of Delegates, “Health and Ethics Policies: Patient Access to Treatments Prescribed by Their Physicians”, H-120.988, available at <http://www.ama-assn.org/ama/no-index/legislation-advocacy/8152.shtml> (last visited June 25, 2009).CrossRefGoogle Scholar
See Abernethy, A. et al., “Systematic Review: Reliability of Compendia Methods for Off-Label Oncology Indications”, Annals of Internal Medicine 150, no. 5 (2009): 336–343; Hampton, T., “Experts Weigh in on Promotion, Prescription of Off-Label Drugs”, JAMA 297, no. 7 (2007): 683-684; American Society of Clinical Oncology, “Reimbursement for Cancer Treatment: Coverage of Off-Label Indications”, Journal of Clinical Oncology 24, no. 19 (2006): 3206-3208.CrossRefGoogle Scholar
See Food and Drug Administration, supra note 12, at 3-4. See generally Government Accountability Office, FDA's Oversight of the Promotion of Drugs for Off-Label Uses, GAO-08-835 (July 2008); Blackwell, A. E. and Beck, J. M., “Drug Manufacturers' First Amendment Right to Advertise and Promote Their Products for Off-Label Use: Avoiding a Pyrrhic Victory”, Food and Drug Law Journal 58, no. 3 (2003): 439–462, at 441-444.Google Scholar
21 U.S.C. § 360aaa (2000).Google Scholar
Final Guidance on Industry-Supported Scientific and Educational Activities, 62 Federal Register 64,093-64,100 (Dec. 3, 1997).Google Scholar
Washington Legal Foundation v. Friedman, 13 F. Supp.2d 51 (D.D.C. 1998); Washington Legal Foundation v. Henney, 56 F. Supp.2d 81 (D.D.C. 1999).Google Scholar
Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000).Google Scholar
See Washington Legal Foundation v. Henney, 128 F. Supp.2d 11 (D.D.C. 2000); Hutt, P. B., Merrill, R. and Grossman, L. A., Food and Drug Law: Cases and Materials, 3rd ed. (New York: Foundation Press, 2007): at 554. The False Claims Act, another federal statute, has been the basis of several high-profile legal actions against manufacturers for off-label promotional activities that allegedly induced physicians and others to claim reimbursement for uses that Medicare and Medicaid fail to cover. These lawsuits are designed to protect the government's financial interests in avoiding payment for ineffective treatments. For a detailed analysis of these cases, see Johnson, S. H., “Polluting Medical Judgment? False Assumptions in the Pursuit of False Claims Regarding Off-Label Prescribing”, Minnesota Journal of Law, Science & Technology 9, no. 1 (2008): 61-123.Google Scholar
See Food and Drug Administration, supra note 12.Google Scholar
See 21 C.F. R. § 314.70 (2008).CrossRefGoogle Scholar
See Fugh-Berman, A. and Melnick, D., “Off-Label Promotion, On-Target Sales”, PLoS Medicine 5, no. 10 (2008): 1432–1435; Psaty, B. M. and Ray, W., “FDA Guidance on Off-Label Promotion and the State of the Literature from Sponsors”, JAMA 299, no. 16 (2008): 1949-1951; Boos, J., “Off-Label Use — Label Off Use?” Annals of Oncology 14, no. 1 (2003): 1-5.CrossRefGoogle Scholar
See Noah, L., Law, Medicine and Medical Technology, 2nd ed. (New York: Foundation Press, 2007): 242.Google Scholar
Benjamin, D. K. et al., “Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity”, JAMA 296, no. 10 (2006): 1266–1273.CrossRefGoogle Scholar
Haffner, M. E., “Adopting Orphan Drugs — Two Dozen Years of Treating Rare Diseases”, New England Journal of Medicine 354, no. 5 (2006): 445–447.CrossRefGoogle Scholar
Falit, B., “The Path to Cheaper and Safer Drugs: Revamping the Pharmaceutical Industry in Light of GlaxoSmithKline's Settlement”, Journal of Law, Medicine & Ethics 33, no. 1 (2005): 174–179.Google Scholar
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (Bethesda, Maryland: National Institutes of Health, 1979), available at <http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
See American Medical Association, supra note 12.Google Scholar
See Committee on Drugs, supra note 1, at 181.Google Scholar
Id., at 182.Google Scholar
Harbour, R. and Miller, J., “A New System for Grading Recommendations in Evidence Based Guidelines”, BMJ 323, no. 7308 (2001): 334–336; Hadorn, D. C. et al. “Rating the Quality of Evidence for Clinical Practice Guidelines”, Journal of Clinical Epidemiology 49, no. 7 (1996): 749-754.CrossRefGoogle Scholar
See Hampton, , supra note 13; Radley, et al., supra note 2.Google Scholar
Stafford, R. S., “Regulating Off-Label Drug Use – Rethinking the Role of the FDA”, New England Journal of Medicine 358, no. 14 (2008): 1427–1429; Carrozza, J. P., “Drug-Eluting Stents – Pushing the Envelope Beyond the Labels?” New England Journal of Medicine 358, no. 4 (2008): 405-407; Kesselheim, A. S., Fischer, M. A. and Avorn, J., “The Rise and Fall of Natrecor for Congestive Heart Failure: Implications for Drug Policy”, Health Affairs 25, no. 4 (2006): 1095-1102.CrossRefGoogle Scholar
DeMonaco, H. J., Ali, A. and von Hippel, E., “The Major Role of Clinicians in the Discovery of Off-Label Therapies”, Pharmacotherapy 26, no. 3 (2006): 323–332.CrossRefGoogle Scholar
American Society of Health-System Pharmacists, American Hospital Formulary Service Drug Information, available at <http://www.ashp.org/ahfs> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
Thompson Micromedex, available at <http://www.micromedex.com/products/drugdex/index.html> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
Agency for Healthcare Research and Quality, Summary Guides, available at <http://effectivehealthcare.ahrq.gov/healthinfo.cfm?infotype=sg> (last visited May 19, 2009).+(last+visited+May+19,+2009).>Google Scholar
The Medical Letter, available at <http://medlet-best.securesites.com/html/who.htm> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
See American Society of Clinical Oncology, supra note 13.Google Scholar
Gazarian, M. et al., “Off-Label Use of Medicines: Consensus Recommendations for Evaluating Appropriateness”, Medical Journal of Australia 185, no. 10 (2006): 544–548.CrossRefGoogle Scholar
See Psaty, and Ray, , supra note 22; Kesselheim, and Avorn, , supra note 9; Schultz, , supra note 5.Google Scholar
Abernethy, et al., supra note 13; Tillman, K., Burton, B., Jacques, L. and Phurrough, S., “Compendia and Anticancer Therapy Under Medicare”, Annals of Internal Medicine 150, no. 3 (2009): 348–350.Google Scholar
Steinbrook, R., “Financial Support of Continuing Medical Education”, JAMA 299, no. 9 (2008): 1060–1062.CrossRefGoogle Scholar
Steinman, M. A. et al., “The Promotion of Gabapentin: An Analysis of Internal Industry Documents”, Annals of Internal Medicine 145, no. 4 (2006): 284–293.CrossRefGoogle Scholar
See Psaty, and Ray, , supra note 22.Google Scholar
Id. See also Falit, supra note 26.Google Scholar
See generally Elkins-Daukes, S. et al., “Off-Label Prescribing to Children: Attitudes and Experience of General Practitioners”, British Journal of Clinical Pharmacology 60, no. 2 (2005): 145–149; Noah, L., “Informed Consent and the Elusive Dichotomy Between Standard and Experimental Therapy”, American Journal of Law & Medicine 28, no. 4 (2002): 361-408, at 400-03; Noah, L., “Medicine's Epistemology: Mapping the Haphazard Diffusion of Knowledge in the Biomedical Community”, Arizona Law Review 44, no. 2 (2002): 373-466.CrossRefGoogle Scholar
See Johnson, , supra note 19, at 73–81.CrossRefGoogle Scholar
See Hampton, , supra note 13; Stafford, supra note 33.Google Scholar
See American Society of Clinical Oncology, supra note 13; Glendinning, D., “Suit Opposes Medicare Denials of Off-Label, Non-Compendia Drugs”, American Medical News, January 21, 2008, at 5.Google Scholar
See Schultz, , supra note 5.Google Scholar
Eaton, M. L. and Kennedy, D., Innovation in Medical Technology: Ethical Issues and Challenges (Baltimore, MD: Johns Hopkins University Press, 2007): 49; Committee on Drugs, supra note 1.Google Scholar
See Committee on Drugs, supra note 1.Google Scholar
See DeMonaco, et al., supra note 34.Google Scholar
Asani, N. et al., “Designing a Strategy to Promote Safe, Innovative Off-Label Uses of Medications”, American Journal of Medical Quality 21, no. 4 (2006): 255–261; see Asani, et al., supra note 4.CrossRefGoogle Scholar
See Monaco, De, supra note 34.Google Scholar
See Committee on Drugs, supra note 1, at 182.Google Scholar
Bickerstaffe, R. et al., “Ethics and Pharmaceutical Medicine The Full Report of the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK”, International Journal of Clinical Practice 60, no. 2 (2006): 242–252; Kessler, L. et al., “Clinical Use of Medical Devices in the ‘Bermuda Triangle,’” Health Affairs 23, no. 1 (2004): 200-207; Committee on Drugs, supra note 1.CrossRefGoogle Scholar
Cheng, A. C., Robinson, P. M. and Harvey, K., “Off-Label Use of Medicines: Consensus Recommendation for Evaluating Appropriateness”, Medical Journal of Australia 186, no. 7 (2006): 379–380; Kessler, et al., supra note 58.CrossRefGoogle Scholar
Harris Interactive, “U.S. Adults Ambivalent about the Risks and Benefits of Off-label Prescription Drug Use”, December 7, 2006, available at <http://www.harrisinteractive.com/news/printerfriend/index.asp?NewsID=1126> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
Beck, J. M. and Azari, E. D., “FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions”, Food and Drug Law Journal 53, no. 1 (1998): 71–104.Google Scholar
See Femrite v. Abbott Northwestern Hospital, 568 N.W.2d 535 (Minn. App.1997); Johns, M. Z., “Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest”, Hastings Law Journal 58, no. 5 (2007): 967–1024.Google Scholar
See Committee on Drugs, supra note 1.Google Scholar
Eichler, H., Abadie, E., Raine, J. M. and Salmonson, T., “Safe Drugs and the Cost of Good Intentions”, New England Journal of Medicine 360, no. 14 (2009): 1378–1380.CrossRefGoogle Scholar
Working Group, New South Wales Therapeutic Advisory Group, “Off-Label Use of Registered Medicines and Use of Medicines under the Personal Importation Scheme in NSW Public Hospitals,” September 2003, available at <http://www.ciap.health.nsw.gov.au/nswtag/publications/otherdocs/off_label_use_registered_medicines.pdf> (last visited June 25, 2009).+(last+visited+June+25,+2009).>Google Scholar
See Johns, , supra note 62; Mehlman, M., “Off-Label Prescribing”, May 2005, available at <http://www.thedoctorwillseey-ounow.com/articles/bioethics/> (last visited June 25, 2009); Salbu, supra note 7, at 222-24; Shapiro, S. A., “Limiting Physician Freedom to Prescribe a Drug for Any Purpose”, Northwestern Law Review 73, no. 5 (1979): 801–872, at 870-872.Google Scholar
See Stafford, , supra note 33, at 1428 (“although consumers want the newest therapies, they may also want the level of supporting evidence disclosed.”)Google Scholar
Levine, R., Ethics and Regulation of Clinical Research, 2nd ed. (New Haven, Conn: Yale University Press, 1986): at 4–5; see Belmont Report, supra note 27.Google Scholar
Institute of Medicine, supra note 10; Anderson, G. M. et al., “Newly Approved Does Not Always Mean New and Improved”, JAMA 299, no. 13 (2008): 1598–1600.CrossRefGoogle Scholar
See Hampton, , supra note 13; Anderson, , supra note 69.Google Scholar
Ethics and Human Rights Committee, American College of Physicians, “Ethics Manual”, Annals of Internal Medicine 142, no. 7 (2005): 560–582.Google Scholar
Kumar, S., Witzig, T. E. and Rajkumar, S. V., “Thalidomide as an Anti-Cancer Agent”, Journal of Cellular and Molecular Medicine 6, no. 2 (2002): 867–874; Office of Oncology Drug Products, Food and Drug Administration, “FDA Approves Thalomid (Thalidomide) to Treat Multiple Myeloma”, available at <http://www.fda.gov/cder/Offices/OODP/whatsnew/thalidomide.htm> (last visited June 25, 2009).CrossRefGoogle Scholar
See Gazarian, et al., supra note 40.Google Scholar
See Kessler, et al., supra note 58 at 201.Google Scholar
Roberts, R. et al., “Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies”, JAMA 290, no. 7 (2003): 905–911.CrossRefGoogle Scholar
See Stafford, , supra note 33.Google Scholar
See Cheng, et al., supra note 59.Google Scholar
See Gazarian, , supra note 40.Google Scholar
Colman, E., “Anorectics on Trial: A Half Century of Federal Regulation of Prescription Appetite Suppressants”, Annals of Internal Medicine 143, no. 5 (2005): 380–385.CrossRefGoogle Scholar
See Kesselheim, et al., supra note 33.Google Scholar
See Haffner, , supra note 25.Google Scholar
Id.Google Scholar
See Hampton, , supra note 13.Google Scholar
See Haffner, , supra note 25.Google Scholar
See Benjamin, et al., supra note 24; McCullough, L. B., Coverdale, J. H. and Chervenak, F. A., “A Comprehensive Ethical Framework for Responsibly Designing and Conducting Pharmacologic Research that Involves Pregnant Women”, American Journal of Obstetrics and Gynecology 193, no. 3 (2005): 901–907; Siu, supra note 1.Google Scholar
Pediatric Research Equity Act of 2003, Pub Law No 108-155, 117 Stat 1936 (codified at 21 USC § 355c); Center for Drug Evaluation and Research, Food and Drug Administration, “Guideline for the Study of Drugs Likely to be Used in the Elderly,” Rockville, Maryland, 1989; Haffner, , supra note 25.Google Scholar
Food and Drug Administration, “Antidepressant Use in Children, Adolescents, and Adults,” available at <http://www.fda.gov/cder/drugs/antidepressants/default.htm> (last visited May 19, 2009). Another example concerns the use of cholesterol and lipid-lowering drugs in children. Although pediatricians worry about long-term cardiovascular damage in children with high cholesterol and lipids, experts lack evidence on whether cholesterol and lipid-lowering drugs are safe and effective in children. Daniels, S. R., Greer, F. R., and the American Academy of Pediatrics Committee on Nutrition, “Lipid Screening and Cardiovascular Health in Childhood”, Pediatrics 122, no. 1 (2007): 198–208.CrossRefGoogle Scholar
See Gottlieb, , supra note 12, at 947Google Scholar
Pub. L. No. 110-85, 121 Stat. 823 (2007).Google Scholar
See generally Schultz, W. B., “Broadening the FDA's Drug-Safety Authority”, New England Journal of Medicine 357, no. 22 (2007): 2217–2219; Gilhooley, M., “Addressing Potential Drug Risks: The Limits of Testing, Risk Signal, Preemption, and the Drug Reform Legislation”, South Carolina Law Review 59, no. 2 (2008): 347-390.CrossRefGoogle Scholar
See Kuehn, B., “FDA Turns to Electronic ‘Sentinel’ to Flag Prescription Drug Safety Problems”, JAMA 300, no. 2 (2008): 156–157.CrossRefGoogle Scholar
See Psaty, and Ray, , supra note 22; Falit, supra note 26.Google Scholar
This action was based on a recommendation by the Institute of Medicine. See Institute of Medicine, supra note 10, at 169–170.Google Scholar
Food and Drug Administration, supra note 12.Google Scholar
Id., at 2.Google Scholar
Id., at 2–4.Google Scholar
Harris, G., “F.D.A. Seeks to Broaden Range of Use for Drugs”, New York Times, February 16, 2008.Google Scholar
See, e.g., Psaty, and Ray, , supra note 22; Kesselheim, and Avorn, , supra note 9; Stafford, supra note 33.Google Scholar
Dresser, R., “Off-Label Indications for Medication Use and the Published Literature, ”JAMA 300, no. 12 (2008): 1411.Google ScholarPubMed
See Hall, R. F. and Sobotka, E. S., “Inconsistent Government Policies: Why FDA Off-Label Regulation Cannot Survive First Amendment Review under Greater New Orleans”, Food and Drug Law Journal 62, no. 1 (2007): 1–48; Blackwell, and Beck, , supra note 14; Psaty, and Ray, , supra note 22; Mehlman, , supra note 66.Google Scholar
See Gottlieb, , supra note 12; Boos, supra note 22.Google Scholar
See Stafford, , supra note 33, at 1429.Google Scholar
Oates, M., “Facilitating Informed Medical Treatment Through Production and Disclosure of Research into Off-Label Uses of Pharmaceuticals”, New York University Law Review 80, no. 4 (2005): 1272–1308.Google Scholar
See Eichler, et al., supra note 64; Hall, and Sobotka, , supra note 100. See also Gillick, M. R., “Controlling Off-Label Medication Use”, Annals of Internal Medicine 150, no. 5 (2009): 344–347 (recommending that the Center for Medicare Services make a National Coverage Determination for off-label uses of drugs that are both risky and expensive).Google Scholar
See, e.g., Committee on Drugs, supra note 1; Bickerstaffe, et al., supra note 58; Reitsma, A. M. and Moreno, J. D., “Recommendations”, in Reitsma, A. M. and Moreno, J. M., eds., Ethical Guidelines for Innovative Surgery (Hagerstown, Maryland: University Publishing Group, 2006): at 199–212.Google Scholar