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A Decade of Safety-Related Regulatory Action in the Netherlands

A Retrospective Analysis of Direct Healthcare Professional Communications from 1999 to 2009

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Abstract

Background: As pre-approval trials are inherently limited in assessing the complete benefit-risk profile of a new drug, serious safety issues may emerge once a drug gains widespread use after approval. Regulators face the dilemma of balancing timely market access with the need for complete data on risks. This challenge has led to a life-cycle approach but, so far, few data are available on post-approval safety issues requiring regulatory action.

Objective: The aim of this study is to determine the frequency, timing and nature of safety issues that necessitated safety-related regulatory action in the form of a Direct Healthcare Professional Communication (DHPC) issued by pharmaceutical companies in collaboration with the Dutch Medicines Evaluation Board during the past decade.

Methods: All DHPCs issued in the Netherlands from 1 January 1999 to 1 January 2009 were retrospectively collected from the national regulatory authorities. Elapsed time between the approval date and the issue of the DHPC was determined. Characteristics of the action including the nature of the safety issue (according to Medical Dictionary for Regulatory Activities [MedDRA®] terminology), type of drug and procedural aspects of the regulatory action taken were reviewed. DHPC characteristics were tabulated and explorative non-parametric tests were performed to study the effect of safety issue, drug class, drug type, orphan drug and first-in-class status on elapsed time from approval to the DHPC.

Results: 157 DHPCs were issued concerning 112 different active substances, approximately 9% (112/1200) of active substances available in the Netherlands in 2007. The number of DHPCs issued increased by 2.1 (95% CI 1.2, 3.1; p< 0.001) DHPCs per year over the past decade, reaching a total of 25 in 2008. The median time between approval and DHPC was 5.3 years (range 0.13-48 years). No significant trend in elapsed time to DHPC was observed in relation to the studied years (p = 0.06). One-third of all DHPCs were issued in the first 3 years after approval, but 27% (n=43/157) of the DHPCs were issued 10 or more years after approval. Timing of DHPCs differed depending on safety issue, drug class, drug type and orphan drug status. DHPCs mostly concerned adverse events in the system organ class of ‘cardiac disorders’ (15%), ‘injury, poisoning and procedural complications’ (13%) and ‘general disorders and administration site conditions’ (10%). In ten cases the drug was eventually withdrawn. Withdrawal occurred a median duration of 2.4 years after registration (range of 1.5–48 years) and was most frequently due to cardiac disorders (including QT interval prolongation; four occasions) and hepatobiliary disorders (two occasions).

Conclusions: In the past decade, the number of DHPCs has increased over time. This is likely caused by a multitude of factors: increased risk awareness by the public, media, regulators and other stakeholders; the type of drugs approved, such as orphan drugs and biologicals; and the regulatory process, including conditional approvals. The number of DHPCs may in the future increase further with the possibility of screening large epidemiological databases proactively for adverse drug events. Nine percent of all marketed drugs required a safety-related action. Regulatory action is taken shortly (<3 years) after market approval nearly as often as after intermediate (3–10 years) and long-term (>10 years) market exposure. These findings underline the need for risk management during the whole life cycle of a drug.

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Table I

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Notes

  1. 1The DHPCs from the Netherlands Health Care Inspectorate are not available online. The DHPCs retrieved during this study are available from the authors upon request

References

  1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998; 279: 1200–5

    Article  PubMed  CAS  Google Scholar 

  2. Leendertse AJ, Egberts ACG, Stoker LJ, et al., for the HARM Study Group. Frequency of and risk factors for preventable medication-related hospital admissions in the Netherlands. Arch Intern Med 2008; 168: 1890–6

    Article  PubMed  Google Scholar 

  3. Califf RM. Benefit assessment of therapeutic products: the Centers for Education and Research on Therapeutics. Pharmacoepidemiol Drug Saf 2007; 16: 5–16

    Article  PubMed  Google Scholar 

  4. Wieringa NF, Peschar JL, Denig P, et al. Connecting pre-marketing clinical research and medical practice: opinion-based study of core issues and possible changes in drug regulation. Int J Technol Assess Health Care 2003; 19: 202–19

    Article  PubMed  Google Scholar 

  5. European Medicines Agency. Committee for medicinal products for human use (CHMP). Guideline on risk management systems for medicinal products for human use (CHMP/ 96268/2005) [online]. Available from URL: http://www.ema.europa.eu/pdfs/human/euleg/9626805en.pdf [Accessed 2009 Nov 12]

  6. Eichler HG, Pignatti F, Flamion B, et al. Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nat Rev Drug Discov 2008; 7: 818–26

    Article  PubMed  CAS  Google Scholar 

  7. Hirst C, Cook S, Dai W, et al. A call for international harmonization in therapeutic risk management. Pharmacoepidemiol Drug Saf 2006; 15: 839–49

    Article  PubMed  Google Scholar 

  8. European Medicines Agency. Committee for medicinal products for human use (CHMP). ICH Topic E 2 E Pharmacovigilance Planning (Pvp). Note for guidance on planning pharmacovigilance activities (CPMP/ICH/5716/03) [online]. Available from URL: http://www.ema.europa.eu/pdfs/human/ich/571603en.pdf [Accessed 2009 Nov 12]

  9. US Department of Health and Human Services, Food and Drug Administration Task Force on Risk Management. Report to the FDA Commissioner. Managing the risks from medical product use: creating a risk management framework, 1999 [online]. Available from URL: http://www.fda.gov/downloads/Safety/SafetyofSpecificProducts/UCM180520.pdf [Accessed 2009 Nov 12]

  10. Tsintis P, La Mache E. CIOMS and ICH initiatives in pharmacovigilance and risk management: overview and implications. Drug Saf 2004; 27(8): 509–17

    Article  PubMed  Google Scholar 

  11. Waller PC, Evans SJ. A model for the future conduct of pharmacovigilance. Pharmacoepidemiol Drug Saf 2003 Jan–Feb; 12(1): 17–29

    Article  PubMed  Google Scholar 

  12. Murphy S, Roberts R. “Black box” 101: how the Food and Drug Administration evaluates, communicates, and manages drug benefit/risk. J Allergy Clin Immunol 2006; 117: 34–9

    Article  PubMed  Google Scholar 

  13. Lasser K, Allen P, Woolhandler S, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002; 287: 2215–20

    Article  PubMed  Google Scholar 

  14. FDA drug review: postapproval risks 1975–1985. Washington, DC: US General Accounting Office, 1990. Publication GAO/PEMD-90-15

  15. Giezen TJ, Mantel-Teeuwisse AK, Straus SMJM, et al. Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA 2008; 300: 1887–96

    Article  PubMed  CAS  Google Scholar 

  16. DeAngelis CD, Fontanarosa PB. Prescription drugs, products liability, and preemption of tort litigation. JAMA 2008; 300: 1939–41

    Article  PubMed  CAS  Google Scholar 

  17. Bouder F. A case study of long QT regulation: a regulatory tennis game across the Atlantic. J Risk Res 2007; 10: 385–412

    Article  Google Scholar 

  18. Dutch Medicines Evaluation Board (CBG-MEB). Strategic business plan 2009–2013. Broadening the scope of regulation: beyond gatekeeping [online]. Available from URL: http://www.cbg-meb.nl/NR/rdonlyres/6772072F-890D-4E07-BE43-D57809696D0F/0/CBG_Business_Plan_0913.pdf [Accessed 2009 Nov 12]

  19. Dutch Medicines Evaluation Board (CBG-MEB). Pharmacovigilance news [online]. Available from URL: http://www.cbg-meb.nl/CBG/en/human-medicines/actueel/default.htm [Accessed 2009 Nov 12]

  20. European Medicines Agency [online]. Available from URL: http://www.ema.europa.eu/ [Accessed 2009 Nov 12]

  21. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2010 [online]. Available from URL: http://www.whocc.no/atcddd/ [Accessed 2009 Nov 12]

  22. Furberg CD, Levin AA, Gross PA, et al. The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med 2006; 166: 1938–42

    Article  PubMed  Google Scholar 

  23. Lofstedt RE. The impact of the cox-2 inhibitor issue on perceptions of the pharmaceutical industry: content analysis and communication implications. J Health Commun 2007; 12:471–91

    Article  PubMed  Google Scholar 

  24. Avorn J. Evaluating drug effects in the post-Vioxx world: there must be a better way. Circulation 2006; 113: 2173–6

    Article  PubMed  Google Scholar 

  25. Karha J, Topol EJ. The sad story of Vioxx, and what we should learn from it. Cleve Clin J Med 2004; 71: 933–4

    Article  PubMed  Google Scholar 

  26. Kesselheim AS, Avorn J. The role of litigation in defining drug risks. JAMA 2007; 297: 308–11

    Article  PubMed  CAS  Google Scholar 

  27. Abraham J. Transnational industrial power, the medical profession and the regulatory state: adverse drug reactions and the crisis over the safety of Halcion in the Netherlands and the UK. Soc Sci Med 2002; 55: 1671–90

    Article  PubMed  Google Scholar 

  28. Platt R, Wilson M, Chan KA, et al. The new Sentinel network: improving the evidence of medical-product safety. N Engl J Med 2009; 361: 645–7

    Article  PubMed  CAS  Google Scholar 

  29. Avorn J, Schneeweiss S. Managing drug-risk information: what to do with all those new numbers. N Engl J Med 2009; 361: 647–9

    Article  PubMed  CAS  Google Scholar 

  30. Augoustides JG. Perioperative safety of aprotinin in coronary artery bypass graft surgery. Drug Saf 2008; 31: 557–60

    Article  PubMed  CAS  Google Scholar 

  31. Ray WA, Stein CM. The aprotinin story: is BART the final chapter? N Engl J Med 2008; 358: 2398–400

    Article  PubMed  CAS  Google Scholar 

  32. Giezen TJ, Mantel-Teeuwisse AK, Leufkens HG. Pharmacovigilance of biopharmaceuticals: challenges remain. Drug Saf 2009; 32: 811–7

    Article  PubMed  Google Scholar 

  33. European Medicines Agency. Human medicines: orphan medicinal products [online]. Available from URL: http://www.ema.europa.eu/htms/human/orphans/intro.htm [Accessed 2009 Nov 12]

  34. European Medicines Agency. European public assessment report for Acomplia [online]. Available from URL: http://www.ema.europa.eu/humandocs/Humans/EPAR/acomplia/acomplia.htm [Accessed 2009 Nov 12]

  35. Spitzer WO, Lewis MA, Heinemann LAJ, et al. Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. BMJ 1996; 312: 83–8

    Article  PubMed  CAS  Google Scholar 

  36. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative Randomized Controlled Trial. JAMA 2002; 288: 321–33

    Article  Google Scholar 

  37. Beral V, Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003; 362: 419–27

    Article  PubMed  CAS  Google Scholar 

  38. Lexchin J. Drug withdrawals from the Canadian market for safety reasons, 1963–2004. CMAJ 2005; 172: 765–7

    Article  PubMed  Google Scholar 

  39. Bakke OM, Manocchia M, de Abajo F, et al. Drug safety discontinuations in the United Kingdom, the United States, and Spain from 1974 through 1993: a regulatory perspective. Clin Pharmacol Ther 1995; 58: 108–17

    Article  PubMed  CAS  Google Scholar 

  40. Layton D, Souverein PC, Heerdink ER, et al. Evaluation of risk profiles for gastrointestinal and cardiovascular adverse effects in nonselective NSAID and COX-2 inhibitor users: a cohort study using pharmacy dispensing data in the Netherlands. Drug Saf 2008; 31: 143–58

    Article  PubMed  CAS  Google Scholar 

  41. De Bruin ML, van Puijenbroek EP, Egberts ACG, et al. Nonsedating antihistamine drugs and cardiac arrhythmias-biased risk estimates from spontaneous reporting systems? Br J Clin Pharmacol 2001; 53: 370–4

    Article  Google Scholar 

  42. Pariente A, Daveluy A, Laribière-Salame G, et al. Effect of date of drug marketing on disproportionality measures in pharmacovigilance: the example of suicide with SSRIs using data from the UK MHRA. Drug Saf 2009; 32: 441–7

    Article  PubMed  Google Scholar 

  43. Psaty BM, Burke SP. Protecting the health of the public: Institute of Medicine recommendations on drug safety. N Engl J Med 2006; 355: 1753–5

    Article  PubMed  CAS  Google Scholar 

  44. Olson MK. Are novel drugs more risky for patients than less novel drugs? J Health Econ 2004; 23: 1135–58

    Article  PubMed  Google Scholar 

  45. European Medicines Agency. Working with patients and consumers: centrally authorised medicines [online]. Available from URL: http://www.ema.europa.eu/Patients/authorised.htm [Accessed 2009 Nov 12]

  46. Wilkinson JJ, Force RW, Cady PS. Impact of safety warnings on drug utilization: marketplace life span of cisapride and troglitazone. Pharmacotherapy 2004; 24: 978–86

    Article  PubMed  CAS  Google Scholar 

  47. Cluxton RJJ, Li Z, Heaton PC, et al. Impact of regulatory labeling for troglitazone and rosiglitazone on hepatic enzyme monitoring compliance: findings from the state of Ohio medicaid program. Pharmacoepidemiol Drug Saf 2005; 14: 1–9

    Article  PubMed  Google Scholar 

  48. Graham D, Drinkard C, Shatin D, et al. Liver enzyme monitoring in patients treated with troglitazone. JAMA 2001; 286: 831–3

    Article  PubMed  CAS  Google Scholar 

  49. Guo JJ, Curkendall S, Jones JK, et al. Impact of cisapride label changes on codispensing of contraindicated medications. Pharmacoepidemiol Drug Saf 2003; 12: 295–301

    Article  PubMed  Google Scholar 

  50. Weatherby LB, Walker AM, Fife D, et al. Contraindicated medications dispensed with cisapride: temporal trends in relation to the sending of ‘Dear Doctor’ letters. Pharmaco-epidemiol Drug Saf 2001; 10: 211–8

    Article  CAS  Google Scholar 

  51. Smalley W, Shatin D, Wysowski D, et al. contraindicated use of cisapride: impact of Food and Drug Administration regulatory action. JAMA 2000; 284: 3036–9

    Article  PubMed  CAS  Google Scholar 

  52. Staniscia T, Romano F, Festi D, et al. Co-dispensing of contraindicated medications in patients using cisapride in Italy. Pharmacoepidemiol Drug Saf 2006; 15: 469–76

    Article  PubMed  Google Scholar 

  53. Weatherby LB, Nordstrom BL, Fife D, et al. The impact of wording in “Dear doctor” letters and in black box labels. Clin Pharmacol Ther 2002; 72: 735–42

    Article  PubMed  Google Scholar 

  54. De Bruin ML, Panneman MJ, Leufkens HG, et al. Use of cisapride with contraindicated drugs in the Netherlands. Ann Pharmacother 2002; 36: 338–43

    Article  PubMed  Google Scholar 

  55. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). ICH E 14. The clinical evaluation of QT/QTs interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs (CPMP/ ICH/2/04) [online]. Available from URL: http://www.ema.europa.eu/pdfs/human/ich/000204en.pdf [Accessed 2009 Nov 12]

  56. Darpo B, Nebout T, Sager PT. Clinical evaluation of QT/QTc prolongation and proarrhythmic potential for nonantiarrhythmic drugs: The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 Guideline. J Clin Pharmacol 2006; 46: 498–507

    Article  PubMed  CAS  Google Scholar 

  57. Woosley RL. Drug labeling revisions: guaranteed to fail? JAMA 2000; 284: 3047–9

    Article  PubMed  CAS  Google Scholar 

  58. Goldman SA. Communication of medical product risk: how effective is effective enough? Drug Saf 2004; 27: 519–34

    Article  PubMed  Google Scholar 

  59. Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006; 97: S44–51

    Article  Google Scholar 

  60. Psaty BM, Furberg CD, Ray WA, et al. Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA 2004; 292: 2622–31

    Article  PubMed  CAS  Google Scholar 

  61. Garcia-Pando A, Garcia del Pozo J, Sanchez Sanchez A, et al. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 2002; 63: 135–8

    Article  CAS  Google Scholar 

  62. Tavassoli N, Montastruc J. Is there any relationship between actual benefit and added value of drugs and pharmacovigilance alerts? Br J Clin Pharmacol 2009; 68: 124–5

    Article  PubMed  Google Scholar 

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Acknowledgements

This study is published in the framework of a larger project on the effectiveness of regulatory risk communication. This research project is supported by an unconditional grant from the Dutch Medicines Evaluation Board (MEB). The authors who are also (part-time) employees of the MEB (Peter Mol, Sabine Straus and Pieter de Graeff) express that the opinions presented in this paper are their personal opinion and do not necessarily reflect those of the MEB. All authors report that they do not have any conflicts of interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, FB 20, Graduate School of Medicine, University Medical Center Groningen, University of Groningen, P.O. Box 197, 9700 AD, Groningen, the Netherlands

    Peter G.M. Mol, Sigrid Piening, Jonie T. N. de Vries, Pieter A. de Graeff & Flora M. Haaijer-Ruskamp

  2. Dutch Medicines Evaluation Board, The Hague, the Netherlands

    Peter G.M. Mol, Sabine M. J. M. Straus & Pieter A. de Graeff

  3. Department of Medical Informatics, Erasmus Medical Center, Rotterdam, the Netherlands

    Sabine M. J. M. Straus

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  1. Peter G.M. Mol
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Correspondence to Peter G.M. Mol.

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Mol, P.G., Straus, S.M.J.M., Piening, S. et al. A Decade of Safety-Related Regulatory Action in the Netherlands. Drug-Safety 33, 463–474 (2010). https://doi.org/10.2165/11532840-000000000-00000

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