Skip to main content

Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels

Abstract

Boxed warnings—also known as “black box” warnings—can be a powerful tool in communicating drug risks to physicians and patients. The overall number of boxed warnings has grown in recent years as the US Food and Drug Administration (FDA) has approved more drugs on the basis of limited pre-marketing information and as new safety issues for marketed drugs have been identified. Two recent manufacturers’ petitions to remove boxed warnings on the drugs rosiglitazone (Avandia) and varenicline (Chantix) have led to divergent FDA decisions and revealed different considerations involved in boxed warning imposition and removal. For ethical and practical reasons, the FDA is justified in applying a higher standard for boxed warning removal than for imposition, as removal of a boxed warning may have unintended effects on physician and patient behavior. However, no guidelines on boxed warning removal currently exist. To promote safe use of approved prescription drugs, the FDA should adopt a uniform and transparent process governing decisions to impose or remove boxed warnings.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Ricci JR, Coulen C, Berger JE, Moore MC, McQueen A, Jan SA. Prescriber compliance with black box warnings in older adult patients. Am J Manag Care. 2009;15(11):e103–8.

    PubMed  Google Scholar 

  2. 2.

    Cheung A, Sacks D, Dewa CS, Pong J, Levitt A. Pediatric prescribing practices and the FDA black-box warning on antidepressants. J Dev Behav Pediatr. 2008;29(3):213–5.

    Article  PubMed  Google Scholar 

  3. 3.

    Center for Biologics Evaluation and Research. Safety labeling changes—implementation of section 505(o)(4) of the FD&C Act. Rockville: Center for Biologics Evaluation and Research; 2013. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm250783.pdf. Accessed 14 Jan 2016.

  4. 4.

    Marks NS, Weiss K. Boxed warnings and other FDA communication tools. Am Fam Physician. 2010;81(3):259.

    PubMed  Google Scholar 

  5. 5.

    Cheng CM, Guglielmo BJ, Maselli J, Auerbach AD. Coverage of FDA medication boxed warnings in commonly used drug information resources. Arch Intern Med. 2010;170(9):831–3.

    Article  PubMed  Google Scholar 

  6. 6.

    Dorsey ER, Rabbani A, Gallagher SA, Conti RM, Alexander GC. Impact of FDA black box advisory on antipsychotic medication use. Arch Intern Med. 2010;170(1):96–103.

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Lu CY, Zhang F, Lakoma MD, Madden JM, Rusinak D, Penfold RB, et al. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study. BMJ. 2014;348:g3596.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Friedman RA. Antidepressants’ black-box warning—10 years later. N Engl J Med. 2014;371(18):1666–8.

    Article  PubMed  Google Scholar 

  9. 9.

    US Department of Health and Human Services. The health consequences of smoking—50 years of progress. A report of the Surgeon General: executive summary. Atlanta: US Department of Health and Human Services; 2014. http://www.surgeongeneral.gov/library/reports/50-years-of-progress/exec-summary.pdf. Accessed 7 Mar 2016.

  10. 10.

    US Food and Drug Administration. Chantix and Zyban to get boxed warning on serious mental health events. Silver Spring: US Food and Drug Administration; 2009. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm170356.htm. Accessed 5 Feb 2014.

  11. 11.

    Gunnell D, Irvine D, Wise L, Davies C, Martin RM. Varenicline and suicidal behaviour: a cohort study based on data from the General Practice Research Database. BMJ. 2009;339:b3805.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Meyer TE, Taylor LG, Xie S, Graham DJ, Mosholder AD, Williams JR, et al. Neuropsychiatric events in varenicline and nicotine replacement patch users in the Military Health System. Addiction. 2013;108(1):203–10.

    Article  PubMed  Google Scholar 

  13. 13.

    Pasternak B, Svanstrom H, Hviid A. Use of varenicline versus bupropion and risk of psychiatric adverse events. Addiction. 2013;108(7):1336–43.

    Article  PubMed  Google Scholar 

  14. 14.

    Thomas KH, Martin RM, Davies NM, Metcalfe C, Windmeijer F, Gunnell D. Smoking cessation treatment and risk of depression, suicide, and self harm in the Clinical Practice Research Datalink: prospective cohort study. BMJ. 2013;347:f5704.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    US Food and Drug Administration. October 16, 2014: Joint Meeting of the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Meeting Announcement. Silver Spring: US Food and Drug Administration; 2014. http://www.fda.gov/AdvisoryCommittees/ucm394876.htm. Accessed 14 Jan 2016.

  16. 16.

    GlaxoSmithKline. Annual report 2006. GlaxoSmithKline; 2006. http://www.gsk.com/media/279918/annual-report-2006.pdf.

  17. 17.

    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457–71.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373(9681):2125–35.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(2):240–9 e1.

  20. 20.

    Nissen SE. The hidden agenda behind the FDA’s new Avandia hearings. Jersey City: Forbes.com LLC; 2013. http://www.forbes.com/sites/matthewherper/2013/05/23/steven-nissen-the-hidden-agenda-behind-the-fdas-avandia-hearings. Accessed 30 Apr 2015.

  21. 21.

    Hamburg MA, Sharfstein JM. The FDA as a public health agency. N Engl J Med. 2009;360(24):2493–5.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Beyer-Westendorf J, Buller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different? J Thromb Haemost. 2011;9(11):2153–8.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Manja V, Lakshminrusimha S. Epidemiology and clinical research design, part 1: study types. NeoReviews. 2014;15(12):e558–69.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Behrman RE, Benner JS, Brown JS, McClellan M, Woodcock J, Platt R. Developing the Sentinel system—a national resource for evidence development. N Engl J Med. 2011;364(6):498–9.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Psaty BM, Breckenridge AM. Mini-Sentinel and regulatory science—big data rendered fit and functional. N Engl J Med. 2014;370(23):2165–7.

    Article  PubMed  Google Scholar 

  26. 26.

    Burton TM. FDA removes marketing limits on diabetes drug Avandia. New York: Wall Street Journal; 2013. http://www.wsj.com/articles/SB10001424052702304465604579220271002055140. Accessed 14 Jan 2016.

  27. 27.

    Lasser KE, Seger DL, Yu DT, Karson AS, Fiskio JM, Seger AC, et al. Adherence to black box warnings for prescription medications in outpatients. Arch Intern Med. 2006;166(3):338–44.

    Article  PubMed  Google Scholar 

  28. 28.

    Darrow JJ, Avorn J, Kesselheim AS. New FDA breakthrough-drug category—implications for patients. N Engl J Med. 2014;370(13):1252–8.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Frank C, Himmelstein DU, Woolhandler S, Bor DH, Wolfe SM, Heymann O, et al. Era of faster FDA drug approval has also seen increased black-box warnings and market withdrawals. Health Aff. 2014;33(8):1453–9.

    Article  Google Scholar 

  30. 30.

    Wolfe SM. Does $760m a year of industry funding affect the FDA’s drug approval process? BMJ. 2014;349:g5012.

    Article  PubMed  Google Scholar 

  31. 31.

    Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004;27(7):1791–3.

    Article  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to James S. Yeh.

Ethics declarations

Funding

Aaron Kesselheim’s work is funded by a Greenwall Faculty Scholar program grant, the Harvard Program in Therapeutic Science, and the Laura and John Arnold Foundation.

Conflict of interest

James Yeh, Ameet Sarpatwari, and Aaron Kesselheim have no conflicts of interest that are directly relevant to the content of this study.

Box 1. US Food and Drug Administration (FDA) requirement for inclusion of a boxed warning and adverse events of prescription drugs [21 CFR 201.57(c)(1)]

Box 1. US Food and Drug Administration (FDA) requirement for inclusion of a boxed warning and adverse events of prescription drugs [21 CFR 201.57(c)(1)]

Boxed warning. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required by the FDA to be presented in a box. The boxed warning ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. The box must contain, in uppercase letters, a heading inside the box that includes the word “WARNING” and conveys the general focus of the information in the box. The box must briefly explain the risk and refer to more detailed information in the “Contraindications” or “Warnings and Precautions” section, accompanied by the identifying number for the section or subsection containing the detailed information.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yeh, J.S., Sarpatwari, A. & Kesselheim, A.S. Ethical and Practical Considerations in Removing Black Box Warnings from Drug Labels. Drug Saf 39, 709–714 (2016). https://doi.org/10.1007/s40264-016-0419-8

Download citation

Keywords

  • Rosiglitazone
  • Varenicline
  • Boxed Warning
  • Neuropsychiatric Adverse Event
  • Avandia