Drug Safety

, Volume 32, Issue 2, pp 91–98 | Cite as

A Strategy for Regulatory Action When New Adverse Effects of a Licensed Product Emerge

  • Jeffrey K. Aronson
  • Deirdre Price
  • Robin E. Ferner
Special Article


Regulatory agencies grant product licences (marketing authorizations) for medicinal products in the light of evidence that the balance between benefit and harm in the population is favourable. Here we consider a framework for allowing regulatory agencies to make rational decisions when reviewing product licences in the light of new information about harms that change that balance. The regulator can revoke the product licence, restrict the product’s availability or change the ‘label’ in different ways. We examine the features of the adverse effect that may be relevant in making the decision: namely, individual differences in susceptibility; the possibility of monitoring; and the availability of protective strategies. The balance of benefit and harm, and the time-course and dose relation of the adverse effect play important roles in the decision-making process. We set out how these factors can help determine the logical response to new information on the balance between benefit and harm, and provide a series of relevant examples. We believe that when regulatory agencies have to decide how to amend the product licence of a drug when new serious adverse effects cause concern, they would find it useful to adopt a framework of this kind, using different strategies for different cases. Our proposed framework could also be useful in risk management planning during drug development.


  1. 1.
    Commission on Human Medicines [online]. Available from URL: http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE&nodeId=863 [Accessed 2008 Jun 10]
  2. 2.
    US Food and Drug Administration. FDA’s Mission Statement [online]. Available from URL: http://www.fda.gov/opacom/morechoices/mission.html [Accessed 2008 Jun 10]
  3. 3.
    O’Brien BJ, Elswood J, Calin A. Willingness to accept risk in the treatment of rheumatic disease. J Epidemiol Commun Health 1990; 44: 249–52CrossRefGoogle Scholar
  4. 4.
    Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003; 327: 1222–5PubMedCrossRefGoogle Scholar
  5. 5.
    Glasziou P, Irwig L, Mant D. Monitoring in chronic disease: a rational approach. BMJ 2005; 330: 644–8PubMedCrossRefGoogle Scholar
  6. 6.
    Coleman JJ, Ferner RE, Aronson JK. Monitoring for the adverse effects of drugs. In: Glasziou P, Irwig L, Aronson JK, editors. Evidence-based medical monitoring: from principles to practice. Oxford: Wiley-Blackwell, 2008: 194–210CrossRefGoogle Scholar
  7. 7.
    Coleman JJ, Ferner RE, Evans SJW. Monitoring for adverse drug reactions. Br J Clin Pharmacol 2006; 61: 371–8PubMedCrossRefGoogle Scholar
  8. 8.
    Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2005; 28: 851–70PubMedCrossRefGoogle Scholar
  9. 9.
    Aronson JK. Monitoring for harms of therapy. Br J Clin Pharmacol 2006; 61(4): 365–6PubMedCrossRefGoogle Scholar
  10. 10.
    Alvir JM, Lieberman JA, Safferman AZ, et al. Clozapine-induced agranulocytosis: incidence and risk factors in the United States. N Engl J Med 1993; 329: 162–7PubMedCrossRefGoogle Scholar
  11. 11.
    Pearce SH. Spontaneous reporting of adverse reactions to carbimazole and propylthiouracil in the UK. Clin Endocrinol 2004; 61: 589–94CrossRefGoogle Scholar
  12. 12.
    Sudarshan MK, Kodandaram NS, Venkatesh GM, et al. Evaluation of a new premedication protocol for administration of equine rabies immunoglobulin in patients with hypersensitivity. Indian J Public Health 2007; 51: 91–6PubMedGoogle Scholar
  13. 13.
    Loke YK. Assessing the benefit-harm balance at the bedside. BMJ 2004; 329(7456): 7–8PubMedCrossRefGoogle Scholar
  14. 14.
    Greenhalgh T, Kostopoulou O, Harries C. Making decisions about benefits and harms of medicines. BMJ 2004; 329(7456): 47–50PubMedCrossRefGoogle Scholar
  15. 15.
    Mann RD. Multi-criteria decision analysis: a new approach to an old problem. Pharmacoepidemiol Drug Saf 2007; 16 Suppl. 1: S1PubMedCrossRefGoogle Scholar
  16. 16.
    European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Reflection paper on benefit-risk assessment methods in the context of the evaluation of marketing authorisation applications of medicinal products for human use. March 2008 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/brmethods/1540407enfin.pdf [Accessed 2008 Jun 10]
  17. 17.
    Aronson JK. Risk perception in drug therapy. Br J Clin Pharmacol 2006; 62(2): 135–7PubMedCrossRefGoogle Scholar
  18. 18.
    International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Final concept paper. E2E: pharmacovigilance planning. Dated and endorsed by the Steering Committee on 11 September 2002 [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA3564.pdf [Accessed 2008 Jun 10]
  19. 19.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER). Guidance for industry. Development and use of risk minimization action plans. March 2005 [online]. Available from URL: http://www.fda.gov/cder/Guidance/6358fnl.htm [Accessed 2008 Jun 10]
  20. 20.
    European Medicines Agency. Volume 9A of the rules governing medicinal products in the European Union. Guidelines on pharmacovigilance for medicinal products for human use [online]. Available from URL: http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-9/pdf/vol9_2007-07_upd07.pdf [Accessed 2008 Jun 10]
  21. 21.
    US Department of Health and Human Services, Food and Drug Administration. Prescription Drug User Fee Act (PDUFA) IV. Drug safety five-year plan. March 2008 [online]. Available from URL: http://www.fda.gov/cder/pdufa/PDUFA_IV_5yr_plan_draft.pdf [Accessed 2008 Jun 10]
  22. 22.
    Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications. Drug Saf 2004; 27(8): 509–17PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Jeffrey K. Aronson
    • 1
  • Deirdre Price
    • 2
  • Robin E. Ferner
    • 3
  1. 1.Reader in Clinical PharmacologyUniversity Department of Primary Health CareHeadingtonUK
  2. 2.University Department of Clinical PharmacologyHeadingtonUK
  3. 3.West Midlands Centre for Adverse Drug ReactionsCity HospitalBirminghamUK

Personalised recommendations