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

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.

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.

Shah S. S. , “Off-Label Drug Use in Hospitalized Children, Archives of Pediatric and Adolescent Medicine 161, no. 3 (2007): 282–290. See also Kumar P. , “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.

Asani N. , “Innovative Off-Label Medication Use”, American Journal of Medical Quality 21, no. 4 (2006): 246–254.

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).

Dresser R. , “The Curious Case of Off-Label Use”, Hastings Center Report 37, no. 3 (2007): 9–11.

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.

See generally, Merrill R. A. , “The Architecture of Government Regulation of Medical Products”, Virginia Law Review 82, no. 8 (1996): 1753–1886.

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, at1730.

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).

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.

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).

See Abernethy A. , “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.

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.

21 U.S.C. § 360aaa (2000).

Final Guidance on Industry-Supported Scientific and Educational Activities, 62 Federal Register 64,093–164,100 (Dec. 3, 1997).

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).

Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000).

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.

See Food and Drug Administration, supra note 12.

See 21 C.F. R. § 314.70 (2008).

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.

See Noah L. , Law, Medicine and Medical Technology, 2nd ed. (New York: Foundation Press, 2007): 242.

Benjamin D. K. , “Peer-Reviewed Publication of Clinical Trials Completed for Pediatric Exclusivity”, JAMA 296, no. 10 (2006): 1266–1273.

Haffner M. E. , “Adopting Orphan Drugs — Two Dozen Years of Treating Rare Diseases”, New England Journal of Medicine 354, no. 5 (2006): 445–447.

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.

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).

See American Medical Association, supra note 12.

See Committee on Drugs, supra note 1, at 181.

Id., at 182.

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. “Rating the Quality of Evidence for Clinical Practice Guidelines”, Journal of Clinical Epidemiology 49, no. 7 (1996): 749–754.

See Hampton , supra note 13; Radley , supra note 2.

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.

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.

American Society of Health-System Pharmacists, American Hospital Formulary Service Drug Information, available at <http://www.ashp.org/ahfs> (last visited June 25, 2009).

Thompson Micromedex, available at <http://www.micromedex.com/products/drugdex/index.html> (last visited June 25, 2009).

Agency for Healthcare Research and Quality, Summary Guides, available at <http://effectivehealthcare.ahrq.gov/healthinfo.cfm?infotype=sg> (last visited May 19, 2009).

The Medical Letter, available at <http://medlet-best.securesites.com/html/who.htm> (last visited June 25, 2009).

See American Society of Clinical Oncology, supra note 13.

Gazarian M. , “Off-Label Use of Medicines: Consensus Recommendations for Evaluating Appropriateness”, Medical Journal of Australia 185, no. 10 (2006): 544–548.

See Psaty and Ray , supra note 22; Kesselheim and Avorn , supra note 9; Schultz , supra note 5.

Abernethy , 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.

Steinbrook R. , “Financial Support of Continuing Medical Education”, JAMA 299, no. 9 (2008): 1060–1062.

Steinman M. A. , “The Promotion of Gabapentin: An Analysis of Internal Industry Documents”, Annals of Internal Medicine 145, no. 4 (2006): 284–293.

See Psaty and Ray , supra note 22.

Id. See also Falit, supra note 26.

See generally Elkins-Daukes S. , “Off-Label Prescribing to Children: Attitudes and Experience of General Practitioners”, British Journal of Clinical Pharmacology 60, no. 2 (2005): 145–149; L. Noah, “Informed Consent and the Elusive Dichotomy Between Standard and Experimental Therapy”, American Journal of Law & Medicine 28, no. 4 (2002): 361–408, at400–403; Noah L. , “Medicine's Epistemology: Mapping the Haphazard Diffusion of Knowledge in the Biomedical Community”, Arizona Law Review 44, no. 2 (2002): 373–446.

See Johnson , supra note 19, at 73–81.

See Hampton , supra note 13; Stafford, supra note 33.

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.

See Schultz , supra note 5.

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.

See Committee on Drugs, supra note 1.

See DeMonaco , supra note 34.

Asani N. , “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 , supra note 4.

See Monaco De , supra note 34.

See Committee on Drugs, supra note 1, at 182.

Bickerstaffe R. , “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. , “Clinical Use of Medical Devices in the ‘Bermuda Triangle,’” Health Affairs 23, no. 1 (2004): 200–207; Committee on Drugs, supra note 1.

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 , supra note 58.

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).

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.

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.

See Committee on Drugs, supra note 1.

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.

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).

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 222–224; 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.

See Stafford , supra note 33, at 1428 (“although consumers want the newest therapies, they may also want the level of supporting evidence disclosed.”)

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.

Institute of Medicine, supra note 10; Anderson G. M. , “Newly Approved Does Not Always Mean New and Improved”, JAMA 299, no. 13 (2008): 1598–1600.

See Hampton , supra note 13; Anderson , supra note 69.

Ethics and Human Rights Committee, American College of Physicians, “Ethics Manual”, Annals of Internal Medicine 142, no. 7 (2005): 560–582.

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).

See Gazarian , supra note 40.

See Kessler , supra note 58 at 201.

Roberts R. , “Pediatric Drug Labeling: Improving the Safety and Efficacy of Pediatric Therapies”, JAMA 290, no. 7 (2003): 905–911.

See Stafford , supra note 33.

See Cheng , supra note 59.

See Gazarian , supra note 40.

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.

See Kesselheim , supra note 33.

See Haffner , supra note 25.

Id.

See Hampton , supra note 13.

See Haffner , supra note 25.

See Benjamin , 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.

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.

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. S. R. Daniels, F. R. Greer, and the American Academy of Pediatrics Committee on Nutrition, “Lipid Screening and Cardiovascular Health in Childhood”, Pediatrics 122, no. 1 (2007): 198–208.

See Gottlieb , supra note 12, at 947

Pub. L. No. 110-85, 121 Stat. 823 (2007).

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.

See Kuehn B. , “FDA Turns to Electronic ‘Sentinel’ to Flag Prescription Drug Safety Problems”, JAMA 300, no. 2 (2008): 156–157.

See Psaty and Ray , supra note 22; Falit, supra note 26.

This action was based on a recommendation by the Institute of Medicine. See Institute of Medicine, supra note 10, at 169–170.

Food and Drug Administration, supra note 12.

Id., at 2.

Id., at 2–4.

Harris G. , “F.D.A. Seeks to Broaden Range of Use for Drugs”, New York Times, February 16, 2008.

See, e.g., Psaty and Ray , supra note 22; Kesselheim and Avorn , supra note 9; Stafford, supra note 33.

Dresser R. , “Off-Label Indications for Medication Use and the Published Literature, ”JAMA 300, no. 12 (2008): 1411.

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.

See Gottlieb , supra note 12; Boos, supra note 22.

See Stafford , supra note 33, at 1429.

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.

See Eichler , 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).

See, e.g., Committee on Drugs, supra note 1; Bickerstaffe , 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.