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

Autoři: Catherine Schuster Bruce aff001;  Petra Brhlikova aff002;  Joseph Heath aff003;  Patricia McGettigan aff001
Působiště autorů: William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London, United Kingdom aff001;  The Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom aff002;  Greater Manchester Mental Health NHS Foundation Trust, Prestwich, Manchester, United Kingdom aff003
Vyšlo v časopise: 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 16(9): e32767. doi:10.1371/journal.pmed.1002873
Kategorie: Research Article



In situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.

Methods and findings

We used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as ‘validated’. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being ‘reasonably likely’ (n = 30; 61%) or of having ‘biological plausibility’ (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.


The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Klíčová slova:

Medicine and health sciences – Oncology – Cancer treatment – Cancers and neoplasms – Hematologic cancers and related disorders – Myelomas and lymphoproliferative diseases – Myelomas – Clinical medicine – Clinical trials – Phase III clinical investigation – Phase II clinical investigation – Pharmacology – Drug research and development – Hematology – Plasma cell disorders – Gastroenterology and hepatology – Liver diseases – Chronic liver disease – Chronic hepatitis – Social sciences – Sociology – Communications – Marketing – Research and analysis methods – People and places – Geographical locations – Europe


1. European Medicines Agency. About Us page. Available from: [cited 2019 Aug 19].

2. European Medicines Agency. Support for early access. Available from: [cited 2019 Aug 19].

3. European Medicines Agency. Conditional Marketing Authorisation. Available from: [cited 2019 Aug 19].

4. The Commission of the European Communities. 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. Available from: [cited 2019 Aug 19].

5. European Medicines Agency. Accelerated Assessment. Available from: [cited 2019 Aug 19].

6. Banzi R, Gerardi C, Bertele V, Garattini G. Approvals of drugs with uncertain benefit–risk profiles in Europe. Eur J Intern Med 2015;26(8):572–84. doi: 10.1016/j.ejim.2015.08.008 26342723

7. Fleming TR, Powers JH. Biomarkers and surrogate endpoints in clinical trials. Stat Med 2012;31(25):2973–84. doi: 10.1002/sim.5403 22711298

8. Ciani O, Buyse M, Drummond M, Rasi G, Saad ED, Taylor RD. Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward. Value Health 2017;20(3):487–495. doi: 10.1016/j.jval.2016.10.011 28292495

9. Ciani O., Davis S., Tappenden P., Garside R., Stein K., Cantrell A et al. Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers. International Journal of Technology Assessment in Health Care 2014; 30(3):312–324. doi: 10.1017/S0266462314000300 25308694

10. Haslam A, Hey S, Gill J, Prasad V. A systematic review of trial-level meta-analyses measuring the strength of association between surrogate end-points and overall survival in oncology. Eur J Cancer 2019;106:196–211. doi: 10.1016/j.ejca.2018.11.012 30528804

11. Kemp R, Prasad V. Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Medicine 2017;15:134. doi: 10.1186/s12916-017-0902-9 28728605

12. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med 2015;175(8):1389–98. doi: 10.1001/jamainternmed.2015.2829 26098871

13. Hernandez-Villafuerte K, Fischer A, Latimer N. Challenges and methodologies in using progression free survival as a surrogate for overall survival in oncology. Int J Technol Assess Health Care. 2018:34(3):300–316. doi: 10.1017/S0266462318000338 29987997

14. Yudkin J, Kasia LJ, Wood Johnson R. The idolatry of the surrogate. BMJ 2011;343:d7995. doi: 10.1136/bmj.d7995 22205706

15. European Medicines Agency. Conditional Marketing Authorisation: Report on ten years of experience at the European Medicines Agency. Available from: [cited 2019 Aug 19].

16. Chen EY, Joshi SK, Tran A, Prasad V. Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials. JAMA Intern Med. 2019;179(5):642–647. doi: 10.1001/jamainternmed.2018.8351 30933235

17. Kesselheim AS, Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987–2014: cohort study. BMJ 2015;351:h4633. doi: 10.1136/bmj.h4633 26400751

18. US FDA. Center for drug evaluation and research: Advancing health through innovation: 2017 new drug therapy approvals. January 2018. Available from: [cited 2019 Aug 19].

19. European Medicines Agency: Medicines. Available from: [cited 2019 Aug 19].

20. European Medicines Agency. Annual Report 2018. Available from: [cited 2019 Aug 19].

21. European Medicines Agency. Exceptional circumstances. Available from: [cited 2019 Aug 19].

22. European Medicines Agency. Qualification of novel methodologies for medicine development. Available from: [cited 2019 Aug 19].

23. Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Affairs 2005; 24:67–78. doi: 10.1377/hlthaff.24.1.67 15647217

24. Gyawali B, Hey SP, Kesselheim AS. Assessment of clinical benefit of cancer drugs receiving accelerated approval. JAMA Intern Med 2019. doi: 10.1001/jamainternmed.2019.0462 31135808

25. Chen EY, Raghunathan V, Prasad V. An overview of cancer drugs approved by the US Food and Drug Administration based on surrogate endpoint of response rate. JAMA Intern Med 2019. doi: 10.1001/jamainternmed.2019.0583 31135822

26. Naci H, Smalley KR, Kesselheim AS. Characteristics of pre-approval and post-approval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318(7):626–636. doi: 10.1001/jama.2017.9415 28810023

27. Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KT et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: A review. JAMA Oncol. 2018;4(6):849–856. doi: 10.1001/jamaoncol.2017.5618 29494733

28. Davis C, Naci H, Gurpinar E, Poplovska 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 28978555

29. Anon. Lilly reports results of Phase 3 soft tissue sarcoma study of Lartruvo. Available from: [cited 2019 Jan 18].

30. EMA recommends withdrawal of marketing authorisation for cancer medicine Lartruvo [press release 2019 April 26]. European Medicines Agency c1995-2018. Available from: [cited 2019 Aug 19].

31. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Guideline on the clinical evaluation of direct acting antivirals for the treatment of chronic hepatitis. EMEA/CHMP/EWP/30039/2008 Rev 1. Available from: [cited 2019 Aug 19].

32. Jakobsen JC, Nielsen EE, Feinberg J, Kalakam KK, Fobian K, Hauser G et al. Direct‐acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev 2017;9. Article.No.CD012143.

33. Jakobson JC, Nielsen EE, Koretz RL, Gluud C. Do direct acting antivirals cure chronic hepatitis C? BMJ 2018;361. (and Responses)

34. Backus LI, Belperio PS, Shahoumain TA, Mole LA. Direct-acting antiviral sustained virologic response: Impact on mortality in patients without advanced liver disease. Hepatology 2018;68:827–38. doi: 10.1002/hep.29811 29377196

35. Backus LI, Belperio PS, Shahoumain TA, Mole LA. Direct-acting antiviral sustained virologic response: Impact on mortality in patients with advanced liver disease. Hepatology 2018;69:487–97. doi: 10.1002/hep.29408

36. Szczesniak R, Heltshe SL, Stanojevic S, Mayer-Hamblett N. Use of FEV1 in Cystic Fibrosis Epidemiologic Studies and Clinical Trials: A statistical perspective for the clinical researcher. J Cyst Fibros. 2017;16(3):318–326. doi: 10.1016/j.jcf.2017.01.002 28117136

37. European Medicines Agency. Report of the workshop on endpoints for cystic fibrosis clinical trials. (2012) EMA/769571/2012].

38. Wallis RS, Peppard T, Hermann D. Month 2 culture status and treatment duration as predictors of recurrence in pulmonary tuberculosis: Model validation and update. PLoS ONE 2015;10(4):e0125403. doi: 10.1371/journal.pone.0125403 25923700

39. Ley B, Bradford WZ, Vittinghoff E, Weycker D, du Bois RM, Collard HR. Predictors of mortality poorly predict common measures of disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016;194:711–718. doi: 10.1164/rccm.201508-1546OC 26938706

40. du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis test properties and minimal clinically important difference. Am J Respir Crit Care Med 2011;184:1382–1389. doi: 10.1164/rccm.201105-0840OC 21940789

41. Vinik EJ, Vinik AI, Paulson JF, Merkies ISJ, Packman J, Grogan DR, Coelho T. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. J Peripheral NS. 2014;19:104–114.

42. Dyck PJ, Kincaid JC, Dyck JB, Chaudhry V, Goyal NA, Alves C et al. Assessing mNIS+7Ionis and international neurologists’ profiency in a FAP trial. Muscle Nerve 2017;56(5):901–11. doi: 10.1002/mus.25563 28063170

43. Kim C, Prasad V. Strength of validation for surrogate end points used in the us food and drug administration’s approval of oncology drugs. Mayo Clin Proc 2017;S0025-6196(16)00125-7.

44. Gyawali B, Hey SP, Kesselheim AS. A comparison of response patterns for progression-free survival and overall survival following treatment for cancer with PD-1 Inhibitors: A meta-analysis of correlation and differences in effect sizes JAMA Netw Open. 2018;1(2):e180416. doi: 10.1001/jamanetworkopen.2018.0416 30646078

45. Grössmann N, Del Paggio JC, Wolf S, Sullivan R, Booth CM, Rosian K et al. Five years of EMA-approved systemic cancer therapies for solid tumours—a comparison of two thresholds for meaningful clinical benefit. EurJCan 2017;82:66–71.

46. RECIST Committee. RECIST 1.1: Update and clarification. Eur J Cancer. 2016;62:132–137. doi: 10.1016/j.ejca.2016.03.081 27189322

47. EMA. Guideline on the evaluation of anticancer medicinal products in man (with Appendix 1) 22 September 2017; EMA/CHMP/205/95/Rev.5. Available from: [cited ].

48. National Institute for Health and Care Excellence. Guide to the methods of technology appraisal 2013. Available from: [cited 2019 Aug 19].

49. EUnetHTA. Endpoints used in relative effectiveness assessment of pharmaceuticals: Surrogate endpoints. 2013. Available from: [cited 2019 Aug 19].

50. Institute for Quality and Efficiency in Healthcare (IQWiG). Validity of surrogate endpoints in oncology. Rapid Report A10-05. 2011. Available from: [cited 2019 Aug 19].

51. Weisler B, McGauran N, Kaiser T. New drugs: Where did we go wrong and what can we do better? BMJ 2019;366:l4340. doi: 10.1136/bmj.l4340 31292109

52. Chalmers JD, Thorat T, Wilkinson CL, Neumann PJ. Drugs cleared through the FDA’s expedited review offer greater gains than drugs approved by conventional process. Health Affairs 2017;36(8):1408–15. doi: 10.1377/hlthaff.2016.1541 28784733

53. Arnardottir AH, Haaijer-Ruskamp FM, Straus SM, Eichler HG, de Graeff PA, Mol PG. Additional safety risk to exceptionally approved drugs in Europe? Br J Clin Pharmacol 2011;72(3):490–9. doi: 10.1111/j.1365-2125.2011.03995.x 21501215

54. Banzi R, Gerardi C, Bertele V, Garattini S. Conditional approval of medicines by the EMA. BMJ 2017;357:j2062. doi: 10.1136/bmj.j2062 28465401

55. Lexchin J. Quality of evidence considered by Health Canada in granting full market authorisation to new drugs with a conditional approval: a retrospective cohort study. BMJ Open 2018;8:e020377. doi: 10.1136/bmjopen-2017-020377 29705760

56. Hoekman J, Klamer T, Mantel-Teeuwisse A, Leufkens H, DeBruin M. Characteristics and follow‐up of postmarketing studies of conditionally authorized medicines in the EU. BrJClinPharmacol. 2016;82:213–226.

57. Fampyra (First published: 04/08/2011; Last updated: 04/08/2011). [cited 2019 Jul 23].

58. Votubia (First published: 19/09/2011; Last updated: 19/09/2011). [cited 2019 Jul 23].

59. Caprelsa (First published: 02/03/2012; Last updated: 02/03/2012). [cited 2019 Jul 23].

60. Pixuvri (First published: 31/05/2012; Last updated: 31/05/2012). [cited 2019 Jul 23].

61. Xalkori (First published: 14/11/2012; Last updated: 14/11/2012). [cited 2019 Jul 23].

62. Adcetris (First published: 22/11/2012; Last updated: 22/11/2012). [cited 2019 Jul 23].

63. Bosulif (First published: 09/04/2013; Last updated: 09/04/2012). [cited 2019 Jul 23].

64. Erivedge (First published: 30/07/2013; Last updated: 30/07/2013) [cited 2019 Jul 23].

65. Sirturo (First published: 14/03/2014; Last updated: 14/03/2014) [cited 2019 Jul 23].

66. Cometriq (First published: 26/03/2014; Last updated: 26/03/2014) [cited 2019 Jul 23].

67. Deltyba (First published: 08/05/2014; Last updated: 08/05/2014) [cited 2019 Jul 23].

68. Translarna (First published: 04/09/2014; Last updated: 04/09/2014) [cited 2019 Jul 23].

69. Zykadia (First published: 04/06/2015; Last updated: 04/06/2015) [cited 2019 Jul 23].

70. Blincyto (First published: 07/12/2015; Last updated: 07/12/2015) [cited 2019 Jul 23].

71. Tagrisso (First published: 17/02/2016; Last updated: 17/02/2016) [cited 2019 Jul 23].

72. Darzalex (First published: 27/05/2016; Last updated: 27/05/2016) [cited 2019 Jul 23].

73. Zalmoxis (First published: 05/09/2016; Last updated: 05/09/2016) [cited 2019 Jul 23].

74. Lartruvo (First published: 23/11/2016; Last updated: 23/11/2016) [cited 2019 Jul 23].

75. Ninlaro (First published: 07/12/2016; Last updated: 07/12/2016) [cited 2019 Jul 23].

76. Venclyxto (First published: 21/12/2016; Last updated: 21/12/2016) [cited 2019 Jul 23].

77. Ocaliva (First published: 19/12/2016; Last updated: 19/12/2016) [cited 2019 Jul 23].

78. Alecensa (First published 11/04/2017; Last updated 11/04/2017) [cited 2019 Jul 23].

79. Natpar (First published: 26/04/2017; Last updated: 26/04/2017) [cited 2019 Jul 23].

80. Bavencio (First published: 13/10/2017; Last updated: 13/10/2017) [cited 2019 Jul 23].

81. Crysvita (First published: 12/03/2018; Last updated: 12/03/2018) [cited 2019 Jul 23].

82. Rubraca (First published: 31/05/2018; Last updated: 31/05/2018) [cited 2019 Jul 23].

83. Zytiga (First published: 23/09/2011; Last updated: 23/09/2011) [cited 2019 Jul 23].

84. Zelboraf (First published: 19/03/2012; Last updated: 19/03/2012) [cited 2019 Jul 23].

85. Kalydeco (First published: 06/08/2012; Last updated: 06/08/2012) [cited 2019 Jul 23].

86. Iclusiq (First published: 11/07/2013; Last updated: 11/07/2013) [cited 2019 Jul 23].

87. Sovaldi (First published: 05/02/2014; Last updated: 05/02/2014) [cited 2019 Jul 23].

88. Sylvant (First published: 19/06/2014; Last updated: 19/06/2014) [cited 2019 Jul 23].

89. Daklinza (First published: 15/09/2014; Last updated: 15/09/2014) [cited 2019 Jul 23].

90. Harvoni (First published: 04/12/2014; Last updated: 04/12/2014) [cited 2019 Jul 23].

91. Viekirax (First published: 09/03/2015; Last updated: 09/03/2015) [cited 2019 Jul 23].

92. Ofev (First published: 13/02/2015; Last updated: 13/02/2015) [cited 2019 Jul 23].

93. Exviera (First published: 12/02/2015; Last updated: 12/02/2015) [cited 2019 Jul 23].

94. Lenvima (First published: 25/06/2015; Last updated: 25/06/2015) [cited 2019 Jul 23].

95. Kanuma (First published: 01/09/2015; Last updated: 01/09/2015) [cited 2019 Jul 23].

96. Kyprolis (First published: 01/12/2015; Last updated: 01/12/2015) [cited 2019 Jul 23].

97. Empliciti (First published: 19/05/2016; Last updated: 19/05/2016) [cited 2019 Jul 23].

98. Epclusa (First published: 28/07/2016; Last updated: 28/07/2016) [cited 2019 Jul 23].

99. Kisplyx (First published: 16/11/2016; Last updated: 16/11/2016) [cited 2019 Jul 23].

100. Cabometyx (First published: 12/10/2016; Last updated: 12/10/2016) [cited 2019 Jul 23].

101. Spinraza (First published: 21/06/2017; Last updated: n/a) [cited 2019 Jul 23].

102. Maviret (First published: 17/08/2017; Last updated: 17/08/2017) [cited 2019 Jul 23].

103. Vosevi (First published: 22/09/2017; Last updated: 22/09/2017) [cited 2019 Jul 23].

104. Jorveza (First published: 18/01/2018; Last updated: 18/01/2018) [cited 2019 Jul 23].

105. Tegsedi (First published: 06/08/2018; Last updated: 06/08/2018) [cited 2019 Jul 23].

106. Onpattro (First published: 30/10/2018; Last updated: n/a) [cited 2019 Jul 23].

107. Takhzyro (First published: 17/12/2018; Last updated: n/a) [cited 2019 Jul 23].

Interní lékařství

Článek vyšel v časopise

PLOS Medicine

2019 Číslo 9
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se