The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs

Document Type : Original Article


1 Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

2 The National Health Care Institute, Diemen, The Netherlands

3 Dutch Medicines Evaluation Board, Utrecht, The Netherlands

4 Department of Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, Utrecht, The Netherlands

5 Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark


The European Medicines Agency (EMA) aims to resolve uncertainties associated with conditionally approved drugs by imposing post-approval studies. Results from these studies may be relevant for health technology assessment (HTA) organizations. This study investigated the role of regulator-imposed post-approval studies within HTA.
For all conditionally approved drugs up to December 2018, regulator-imposed post-approval studies were identified from EMA’s public assessment reports. The availability for and inclusion of study results in relative effectiveness (re)assessments were analyzed for 4 European HTA organizations: NICE (National Institute for Health and Care Excellence, England/Wales), HAS (Haute Autorité de Santé, France), ZIN (Zorginstituut Nederland, the Netherlands) and the European Network for Health Technology Assessment (EUnetHTA, Europe). When study results became available between an HTA organization’s initial assessment and reassessment, it was evaluated whether and how they affected the assessment and its outcome.
For 36 conditionally approved drugs, 98 post-approval studies were imposed. In total, 81 initial relative effectiveness assessments (REAs) and 13 reassessments were available, with numbers of drugs (re)assessed varying greatly between jurisdictions. Study results were available for 16 initial REAs (20%) and included in 14 (88%), and available for 10 reassessments (77%) and included in all (100%). Five reassessments had an outcome different from the initial REA, with 4 (2 positive and 2 negative changes) relating directly to the new study results. Reassessments often cited the inability of post-approval studies to resolve the concerns reported in the initial REA.
Results from regulator-imposed post-approval studies for conditionally approved drugs were not often used in REAs by HTA organizations, because they were often not yet available at the time of initial assessment and because reassessments were scarce. When available, results from post-approval studies were almost always used within HTA, and they have led to changes in conclusions about drugs’ relative effectiveness. Post-approval studies can be relevant within HTA but the current lack of alignment between regulators and HTA organizations limits their potential.


  1. European Medicines Agency. Guideline on the Scientific Application and the Practical Arrangements Necessary to Implement Regulation (EC) No 507/2006 on the Conditional Marketing Authorisation for Medicinal Products for Human use Falling within the Scope of Regulation (EC) No 726/2004. Updated 07/03/2016.  Accessed May 6, 2019.
  2. Commission Regulation (EC) No 507/2006 of 29 March 2006 on the Conditional Marketing Authorisation for Medicinal Products for Human use Falling within the Scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council. Official Journal of the European Union; 2006.
  3. Davis C, Naci H, Gurpinar E, Poplavska E, Pinto A, Aggarwal A. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ. 2017;359:j4530. doi:10.1136/bmj.j4530
  4. Grössmann N, Wild C. Between January 2009 and April 2016, 134 novel anticancer therapies were approved: what is the level of knowledge concerning the clinical benefit at the time of approval? ESMO Open. 2016;1(6):e000125. doi:10.1136/esmoopen-2016-000125
  5. Hoekman J, Boon WP, Bouvy JC, Ebbers HC, de Jong JP, De Bruin ML. Use of the conditional marketing authorization pathway for oncology medicines in Europe. Clin Pharmacol Ther. 2015;98(5):534-541. doi:10.1002/cpt.174
  6. Drummond MF, Schwartz JS, Jönsson B, et al. Key principles for the improved conduct of health technology assessments for resource allocation decisions. Int J Technol Assess Health Care. 2008;24(3):244-258. doi:10.1017/s0266462308080343
  7. European Network for Health Technology Assessment. Endpoints used for Relative Effectiveness Assessment: Health-Related Quality of Life and Utility Measures.   Updated 2015. Accessed May 6, 2019.
  8. European Network for Health Technology Assessment. Endpoints used for Relative Effectiveness Assessment: Clinical Endpoints. Updated 2015.  Accessed May 6, 2019.
  9. European Network for Health Technology Assessment. Endpoints used in Relative Effectiveness Assessment: Surrogate Endpoints.  Updated 2015.   Accessed May 6, 2019.
  10. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. E9, Statistical Principles for Clinical Trials.  Updated 1998. Accessed May 6, 2019.
  11. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. E8, General Considerations for Clinical Trials.  Updated 1997. Accessed May 6, 2019.
  12. European Medicines Agency. Guideline on the Evaluation of Anticancer Medicinal Products in Man.  Updated 2016. Accessed May 10, 2019.
  13. Bognar K, Romley JA, Bae JP, Murray J, Chou JW, Lakdawalla DN. The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions. J Health Econ. 2017;51:1-12. doi:10.1016/j.jhealeco.2016.12.001
  14. Vreman RA, Bouvy JC, Bloem LT, et al. Weighing of evidence by health technology assessment bodies: retrospective study of reimbursement recommendations for conditionally approved drugs. Clin Pharmacol Ther. 2019;105(3):684-691. doi:10.1002/cpt.1251
  15. European Medicines Agency. EMA-EUnetHTA Three-Year Work Plan: 2017–2020.  Accessed May 4, 2018. Published November 13, 2017.
  16. Hoekman J, Klamer TT, Mantel-Teeuwisse AK, Leufkens HG, De Bruin ML. Characteristics and follow-up of postmarketing studies of conditionally authorized medicines in the EU. Br J Clin Pharmacol. 2016;82(1):213-226. doi:10.1111/bcp.12940
  17. Bloem LT, Mantel-Teeuwisse AK, Leufkens HGM, De Bruin ML, Klungel OH, Hoekman J. Postauthorization changes to specific obligations of conditionally authorized medicines in the European Union: a retrospective cohort study. Clin Pharmacol Ther. 2019;105(2):426-435. doi:10.1002/cpt.1169
  18. Schuster Bruce C, Brhlikova P, Heath J, McGettigan P. The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: a cross-sectional study of products authorised 2011-2018. PLoS Med. 2019;16(9):e1002873. doi:10.1371/journal.pmed.1002873
  19. Lipska I, Hoekman J, McAuslane N, Leufkens HG, Hövels AM. Does conditional approval for new oncology drugs in Europe lead to differences in health technology assessment decisions? Clin Pharmacol Ther. 2015;98(5):489-491. doi:10.1002/cpt.198
  20. Vreman RA, Mantel-Teeuwisse AK, Hövels AM, Leufkens HGM, Goettsch WG. Differences in health technology assessment recommendations among European jurisdictions: the role of practice variations. Value Health. 2020;23(1):10-16. doi:10.1016/j.jval.2019.07.017
  21. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: Wiley; 2008.
  22. Vreman RA, Naci H, Goettsch WG, et al. Decision making under uncertainty: comparing regulatory and health technology assessment reviews of medicines in the United States and Europe. Clin Pharmacol Ther. 2020;108(2):350-357. doi:10.1002/cpt.1835
  23. Vreman RA, de Ruijter AS, Zawada A, et al. Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations. Drug Discov Today. 2020;25(7):1223-1231. doi:10.1016/j.drudis.2020.04.012
  24. European Medicines Agency. EMA Regulatory Science to 2025. European Medicines Agency; 2018.
  25. Ruof J, Staab T, Dintsios CM, Schröter J, Schwartz FW. Comparison of post-authorisation measures from regulatory authorities with additional evidence requirements from the HTA body in Germany - are additional data requirements by the Federal Joint Committee justified? Health Econ Rev. 2016;6(1):46. doi:10.1186/s13561-016-0124-4
  26. Cipriani A, Ioannidis JPA, Rothwell PM, et al. Generating comparative evidence on new drugs and devices after approval. Lancet. 2020;395(10228):998-1010. doi:10.1016/s0140-6736(19)33177-0
  27. Tafuri G, Pagnini M, Moseley J, et al. How aligned are the perspectives of EU regulators and HTA bodies? a comparative analysis of regulatory-HTA parallel scientific advice. Br J Clin Pharmacol. 2016;82(4):965-973. doi:10.1111/bcp.13023
  28. Tafuri G, Lucas I, Estevão S, et al. The impact of parallel regulatory-health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations. Br J Clin Pharmacol. 2018;84(5):1013-1019. doi:10.1111/bcp.13524
  29. Ermisch M, Bucsics A, Vella Bonanno P, et al. Payers' views of the changes arising through the possible adoption of adaptive pathways. Front Pharmacol. 2016;7:305. doi:10.3389/fphar.2016.00305
  30. Vella Bonanno P, Ermisch M, Godman B, et al. Adaptive pathways: possible next steps for payers in preparation for their potential implementation. Front Pharmacol. 2017;8:497. doi:10.3389/fphar.2017.00497
  31. Wenzl M, Chapman S. Performance-Based Managed Entry Agreements for New Medicines in OECD Countries and EU Member States: How They Work and Possible Improvements Going Forward. OECD Health Working Papers, No. 115. Paris: OECD Publishing; 2019. doi:10.1787/6e5e4c0f-en

Articles in Press, Accepted Manuscript
Available Online from 27 October 2020