Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The risks of risk aversion in drug regulation

Subjects

Abstract

Drugs are approved by regulatory agencies on the basis of their assessment of whether the available evidence indicates that the benefits of the drug outweigh its risks. In recent years, regulatory agencies have been criticized both for being overly tolerant of risks or being excessively risk-averse, which reflects the challenge in determining an appropriate balance between benefit and risk with the limited data that is typically available before drug approval. The negative consequences of regulatory tolerance in allowing drugs onto the market that turn out to be unsafe are obvious, but the potential for adverse effects on public health owing to the absence of new drugs because of regulatory risk-aversion is less apparent. Here, we discuss the consequences of regulatory risk-aversion for public health and suggest what might be done to best align acceptance of risk and uncertainty by regulators with the interests of public health.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Public health benefits versus risk aversion in drug regulation.

References

  1. 1

    European Medicines Agency (EMA). Benefit–risk methodology project. Work package 1 report: description of the current practice of benefit-risk assessment for centralised procedure products in the EU regulatory network. EMA website[online], (2011).

  2. 2

    Beckman, R. A., Clark, J. & Chen, C. Integrating predictive biomarkers and classifiers into oncology clinical development programmes. Nature Rev. Drug Discov. 10, 735–748 (2011).

    CAS  Article  Google Scholar 

  3. 3

    Manski, C. Adaptive partial drug approval: a health policy proposal. Economists' Voice 6, 1–5 (2009).

    Article  Google Scholar 

  4. 4

    Commission of the European Communities. Communication from the commission on the precautionary principle. EC website[online], (2000).

  5. 5

    Wiener, J. B. Whose precaution after all? A comment on the comparison and evolution of risk regulatory systems. Duke Journal Comparative International Law 13, 207 (2003).

    Google Scholar 

  6. 6

    The European Risk Forum (ERF). The ERF study. The precautionary principle application and way forward. ERF website[online], (2011).

  7. 7

    Gezondheidsraad (Health Council of the Netherlands). Advice: Prudent precaution. Gezondheidsraad website[online], (2008).

  8. 8

    Lenert, L. A., Markowitz, D. R. & Blaschke, T. F. Primum non nocere? Valuing of the risk of drug toxicity in therapeutic decision making. Clin. Pharmacol. Ther. 53, 285–291 (1993).

    CAS  Article  Google Scholar 

  9. 9

    Lofstedt, R. E. Risk versus hazard — how to regulate in the 21st century. Eur. J. Risk Regulation 2, 149–168 (2011).

    Article  Google Scholar 

  10. 10

    Graham, J. D. & Wiener, J. B. Risk vs. Risk: Tradeoffs in Protecting Health and the Environment 1–352 (Harvard Univ. Press, 1995).

    Google Scholar 

  11. 11

    McNeil, B. J., Pauker, S. G., Sox, H. C. Jr & Tversky, A. On the elicitation of preferences for alternative therapies. N. Engl. J. Med. 306, 1259–1262 (1982).

    CAS  Article  Google Scholar 

  12. 12

    Johnson, F. R. et al. Are gastroenterologists less tolerant of treatment risks than patients? Benefit–risk preferences in Crohn's disease management. J. Manag. Care Pharm. 16, 616–628 (2010).

    PubMed  Google Scholar 

  13. 13

    Poland, G. A. & Jacobson, R. M. The age-old struggle against the antivaccinationists. N. Engl. J. Med. 364, 97–99 (2011).

    CAS  Article  Google Scholar 

  14. 14

    European Medicines Agency (EMA). Benefit–risk methodology project. Report on risk perception study module. EMA website[online], (2012).

  15. 15

    Bouvy, J. C. The Evaluation of Drug Regulation. Economic Approaches into the Valuation and Evaluation of the Drug Regulatory Framework. Thesis, Utrecht Univ. and Erasmus Univ. Rotterdam (2013).

    Google Scholar 

  16. 16

    Arnardottir, H. Regulatory Benefit–Risk Assessment. Different Perspectives. Thesis, Univ. Medical Center Groningen (2013).

    Google Scholar 

  17. 17

    Arnott, J. et al. Enhancing communication about paediatric medicines: lessons from a qualitative study of parents' experiences of their child's suspected adverse drug reaction. PLoS ONE 7, e46022 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Carpenter, D. Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA. 1–824 (Princeton Univ. Press, 2010).

    Google Scholar 

  19. 19

    Thun-Hohenstein, E. Who's afraid of a cure for cancer? Ukraine Drug Net website[online], (2004).

  20. 20

    Moore, T. J. & Furberg, C. D. The safety risks of innovation. The FDA's Expedited Drug Development pathway. JAMA 308, 869–870 (2012).

    CAS  Article  Google Scholar 

  21. 21

    Eichler, H. G. et al. Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response. Nature Rev. Drug Discov. 10, 495–506 (2011).

    CAS  Article  Google Scholar 

  22. 22

    European Medicines Agency (EMA). Assessment report. Forxiga (dapagliflozin). Procedure No.: EMEA/H/C/002322. EMA webite[online], (2012).

  23. 23

    Dodd, C. N. et al. International collaboration to assess the risk of Guillain Barré syndrome following influenza A (H1N1) 2009 monovalent vaccines. Vaccine 31, 4448–4458 (2013).

    Article  Google Scholar 

  24. 24

    Warren, J. B., Day, S. & Feldschreiber, P. Symmetrical analysis of risk–benefit. Br. J. Clin. Pharmacol. 74, 757–761 (2012).

    Article  Google Scholar 

  25. 25

    Bouvy, J. C., Koopmanschap, M. A., Shah, R. R. & Schellekens, H. The cost-effectiveness of drug regulation: the example of thorough QT/QTc studies. Clin. Pharmacol. Ther. 91, 281–288 (2012).

    CAS  Article  Google Scholar 

  26. 26

    Bouvy, J. C., Ebbers, H. C., Schellekens, H. & Koopmanschap, M. A. The cost-effectiveness of periodic safety update reports for biologicals in Europe. Clin. Pharmacol. Ther. 93, 433–442 (2013).

    CAS  Article  Google Scholar 

  27. 27

    The Academy of Medical Sciences (UK). A new pathway for the regulation and governance of health research, 2011. The Academy of Sciences website[online], (2011).

  28. 28

    Duley, L. et al. Specific barriers to the conduct of randomized trials. Clin. Trials 5, 40–48 (2008).

    Article  Google Scholar 

  29. 29

    Kramer, J. M., Smith, P. B. & Califf, R. M. Impediments to clinical research in the United States. Clin. Pharmacol. Ther. 91, 535–541 (2012).

    CAS  Article  Google Scholar 

  30. 30

    Arrowsmith, J. Trial watch: Phase II failures: 2008–2010. Nature Rev. Drug Discov. 10, 328–329 (2011).

    CAS  Article  Google Scholar 

  31. 31

    Fernandez, J. M., Stein, R. M. & Lo, A. W. Commercializing biomedical research through securitization techniques. Nature Biotech. 30, 964–975 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Roy, A. S. A. Stifling new cures: The true cost of lengthy clinical drug trials. Manhattan Institute website[online], (2012).

  33. 33

    The Infectious Diseases Society of America (IDSA). Limited population antibacterial drug (lPAD) legislation would expedite development of much-needed antibiotics. IDSA website[online], (2012).

  34. 34

    Karres, J. & Tomasi, P. New medicines for type II diabetes in adolescents: many products, few patients. Expert Rev. Clin. Pharmacol. 6, 227–229 (2013).

    CAS  Article  Google Scholar 

  35. 35

    Klein, R. M. FDA's latest efforts in patient-focused drug development ... now in full swing! US FDA website[online], (2013).

  36. 36

    European Medicines Agency (EMA). The role of patients as members of the EMA Human Scientific Committees. EMA website[online], (2011).

  37. 37

    European Medicines Agency (EMA). Outcome report on pilot phase for participation of patient representatives in Scientific Advisory Group (SAG) meetings. EMA website[online], (2011).

  38. 38

    Johnson, F. R. et al. Multiple sclerosis patients' benefit–risk preferences: serious adverse event risks versus treatment efficacy. J. Neurol. 256, 554–562 (2009).

    Article  Google Scholar 

  39. 39

    Eichler, H. G., Abadie, E., Baker, M. & Rasi, G. Fifty years after thalidomide; what role for regulators? Br. J. Clin. Pharmacol. 74, 731–733 (2012).

    Article  Google Scholar 

  40. 40

    Slovic, P. Trust, emotion, sex, politics, and science: surveying the risk-assessment battlefield. Risk Anal. 19, 689–701 (1999).

    CAS  Google Scholar 

  41. 41

    Kahneman, D. Thinking, Fast and Slow 1–512 (Penguin, 2011).

    Google Scholar 

  42. 42

    Zineh, I. & Woodcock, J. Clinical pharmacology and the catalysis of regulatory science: opportunities for the advancement of drug development and evaluation. Clin. Pharmacol. Ther. 93, 515–525 (2013).

    CAS  Article  Google Scholar 

  43. 43

    Guo, J. J. et al. A review of quantitative risk–benefit methodologies for assessing drug safety and efficacy-report of the ISPOR risk–benefit management working group. Value Health 13, 657–666 (2010).

    Article  Google Scholar 

  44. 44

    European Medicines Agency (EMA). Benefit–risk methodology project. Work package 3 report: field tests. EMA website[online], (2011).

  45. 45

    Protect Consortium. Review of methodologies for benefit and risk assessment of medication. PROTECT website[online], (2013).

  46. 46

    Bouder, F., Slavin, D. & Löfstedt, R. The Tolerability of Risk. A New Framework for Risk Management 1–160 (Earthscan, 2007).

    Google Scholar 

  47. 47

    Bandle, T. in The Tolerability of Risk. A New Framework for Risk Management Ch.5 (eds Bouder, F., Slavin, D. & Löfstedt, R.) 93–104 (Earthscan, 2007).

    Google Scholar 

  48. 48

    European Commission. Improvement of risk assessment in view of the needs of risk managers and policy makers. EC website[online], (2011).

  49. 49

    US Food and Drug Administration (FDA). Guidance for industry. Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. FDA website[online], (2008).

  50. 50

    Vesikari, T. et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N. Engl. J. Med. 354, 23–33 (2006).

    CAS  Article  Google Scholar 

  51. 51

    The Women's Health Initiative Study Group. Design of the Women's Health Initiative Clinical Trial and Observational Study. Control. Clin. Trials 19, 61–109 (1998).

  52. 52

    European Medicines Agency (EMA). ICH guideline E2C (R2) on periodic benefit–risk evaluation report (PBRER). EMA website[online], (2013).

  53. 53

    Institute of Medicine of the National Academies. Report: Ethical And Scientific Issues In Studying The Safety Of Approved Drugs. 1–292 (National Academies, 2012).

  54. 54

    Chowdhury, B. A. & Dal Pan, G. The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N. Engl. J. Med. 362, 1169–1171 (2010).

    CAS  Article  Google Scholar 

  55. 55

    Woodcock, J., Khan, M. & Yu, L. X. Withdrawal of generic budeprion for nonbioequivalence. N. Engl. J. Med. 367, 2463–2465 (2012).

    CAS  Article  Google Scholar 

  56. 56

    Southworth, M. R., Reichman, M. E. & Unger, E. F. Dabigatran and postmarketing reports of bleeding. N. Engl. J. Med. 368, 1272–1274 (2013).

    CAS  Article  Google Scholar 

  57. 57

    European Medicines Agency (EMA). Concept paper on extrapolation of efficacy and safety in medicine development. Draft. EMA website[online], (2012).

  58. 58

    Rawlins, M. D. Cutting the cost of drug development? Nature Rev. Drug Discov. 3, 360–364 (2004).

    CAS  Article  Google Scholar 

  59. 59

    BBC. GlaxoSmithKline to pay $3bn in US drug fraud scandal. BBC website[online], (2012).

  60. 60

    Thomas, K. Health groups criticize allergy drug promotion. NY Times website[online], (2012).

  61. 61

    Applbaum, K. Is marketing the enemy of pharmaceutical innovation? Hastings Center Report 39, 13–17 (2009).

    Article  Google Scholar 

  62. 62

    Adams, B. EMA under fire from European Parliament. Pharmafile website[online], (2011).

  63. 63

    Mullard, A. Mediator scandal rocks French medical community. Lancet 377, 890–892 (2011).

    Article  Google Scholar 

  64. 64

    Thepharmaletter. US public confidence in the FDA plunges, new drug oversight a priority, survey finds. Thepharmaletter website[online], (2008).

  65. 65

    Health Canada. The regulatory roadmap for health products and food. Health Canada website[online], (2012).

  66. 66

    US Food and Drug Administration (FDA). FDA transparency initiative. FDA website[online], (2012).

  67. 67

    European Medicines Agency (EMA). Special topics. Transparency. EMA website[online], (2013).

  68. 68

    European Medicines Agency (EMA). European Medicines Agency releases for public consultation its draft policy on the publication and access to clinical-trial data. EMA website[online], (2013).

  69. 69

    Kang, P. The Tysabri game plan. Forbes website[online], (2006).

  70. 70

    Calfee, J. A Representative Survey of M. S. Patients on Attitudes Towards the Benefits and Risks of Drug Therapy. 1–29 (AEI-Brookings Joint Center for Regulatory Studies, 2006).

    Google Scholar 

  71. 71

    Miller, C. E., Karpinski, M. & Jezewski, M. A. Relapsing–remitting multiple sclerosis patients' experience with natalizumab. Int. J. MS Care 14, 39–44 (2012).

    Article  Google Scholar 

  72. 72

    Vinhas de Souza, M. et al. Drug-induced PML: a global agenda for a global challenge. Clin. Pharmacol. Ther. 91, 747–750 (2012).

    CAS  Article  Google Scholar 

  73. 73

    European Medicines Agency (EMA). Tysabri: EPAR — product information. EMA website[online], (2013).

  74. 74

    US Food and Drug Administration (FDA). Lotronex (alosetron hydrochloride) information. FDA website[online], (2012).

  75. 75

    US Food and Drug Administration (FDA). Questions and answers about lotronex (6/7/2002). FDA website[online], (2013).

  76. 76

    Chang, L. et al. Incidence of ischemic colitis and serious complications of constipation among patients using alosetron: systematic review of clinical trials and post-marketing surveillance data. Am. J. Gastroenterol. 101, 1069–1079 (2006).

    Article  Google Scholar 

  77. 77

    Chang, L., Tong, K. & Ameen, V. Ischemic colitis and complications of constipation associated with the use of alosetron under a risk management plan: clinical characteristics, outcomes, and incidences. Am. J. Gastroenterol. 105, 866–875 (2010).

    Article  Google Scholar 

  78. 78

    US Food and Drug Administration (FDA). Proposal to withdraw approval for the breast cancer indication for bevacizumab (avastin). June 28, 2011. A matter of record (301) 890–4188. FDA website[online], (2011).

  79. 79

    US Food and Drug Administration (FDA). Proposal to withdraw approval for the breast cancer indication for avastin (bevacizumab). Decision of the Commissioner. FDA website[online], (2011).

  80. 80

    Manganiello, M. & Anderson, M. Back to Basics. HIV/AIDS advocacy as a model for catalyzing change. HCM Strategists website[online], (2011).

  81. 81

    Weber, B. Spencer Cox, AIDS activist, dies at 44. NYTimes website[online], (2012).

  82. 82

    European Organisation for Rare Diseases (EURORDIS). Activity report 2012 & workplan 2013. EURORDIS website[online], (2012).

  83. 83

    European Organisation for Rare Diseases (EURORDIS). “Medicines for children: better, more and faster”. EURORDIS position paper on the proposal for a regulation on medicinal products for paediatric use. EURORDIS website[online], (2005).

  84. 84

    Contact Group Myeloma and Waldenstrom Patients (CMWP). European Symposium Myeloma Waldenström 2008. Final report. CMWP website[online], (2008).

  85. 85

    Wicks, P., Vaughan, T. E., Massagli, M. P. & Heywood, J. Accelerated clinical discovery using self-reported patient data collected online and a patient-matching algorithm. Nature Biotech. 29, 411–414 (2011).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank H. Parkinson for her invaluable technical assistance in the production of this article.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Brigitte Bloechl-Daum.

Ethics declarations

Competing interests

Sir Alasdair Breckenridge is a partner with NDA Partners, a US consulting firm specializing in expert product development and providing regulatory advice to medical products industries.

Related links

PowerPoint slides

Glossary

Disability-adjusted life year

(DALY). One DALY can be thought of as one lost year of 'healthy' life.

Discrete choice experiment

A quantitative technique for eliciting preferences that involves asking individuals to state their preferences for hypothetical alternative scenarios, goods or services. Each alternative is described by several attributes and the responses are used to assess whether preferences are influenced by the attributes and also the relative importance of the attributes.

Framing effects

A concept that describes how different ways of presenting the same information often evoke different emotions and decisions. For example, the statement that “the likelihood of survival 1 month after surgery is 90%” is typically considered more reassuring than the equivalent statement that “mortality within 1 month of surgery is 10%”.

Orphan drug

Drugs that are intended for the diagnosis, prevention or treatment of life-threatening or very serious diseases that are also rare. Definitions of 'rare' vary in different regions; for example in the European Union, the definition is diseases that affect not more than 5 in 10,000 persons.

Precautionary principle

A strategy to cope with possible risks in which scientific understanding is incomplete. In the literature and in international treaties and declarations, various definitions can be found. Some consider it to be “a need to err on the side of caution because of uncertainties about the safety of technologies or infrastructure” or “when human activities may lead to morally unacceptable harm that is scientifically plausible but uncertain, actions shall be taken to avoid or diminish that harm”, whereas others consider it to mean that “where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent [environmental] degradation.”

Priming effects

A concept that describes how the activation of one thought (for example, through exposure to an image) may trigger related thoughts that influence subsequent actions or decisions. For example, in experimental settings, people primed with thoughts of money were less willing to help others with a particular task.

Quality-adjusted life year

A measure of disease burden that includes both the quality and the quantity of life.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Eichler, HG., Bloechl-Daum, B., Brasseur, D. et al. The risks of risk aversion in drug regulation. Nat Rev Drug Discov 12, 907–916 (2013). https://doi.org/10.1038/nrd4129

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing