Concepts for the Risk-Based Regulation of Clinical Research on Medicines and Medical Devices


Since 2010, discussions about more risk-proportionate trial authorization and supervision procedures gain momentum in the European Union and the United States. This article provides an overview of the current situation and analyses existing proposals for the risk-based assessment and categorization of clinical research. Experiences gained so far with the risk-based categorization and classification of trials and products in the pharmaceuticals and medical devices sector are described: they indicate that strict trial categorization systems would add burden to the whole process and could deliver benefit only within a very flexible regulatory framework. In contrast, partial exemptions from regulatory requirements for well-defined types of trials may respond better to the current expectations of stakeholders. For Europe, such exemptions could be adopted in a custom-made manner with the objective of facilitating the conduct of large, simple, evidence-building clinical trials as well as of patient-focused trials in situations of recognized unmet medical need.

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  1. 1.

    European Parliament and Council Directive 2001/20/EC of 4 Apr 2001. OJ; May 1, 2001: L121/34.

  2. 2.

    European Commission: Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC—Public Consultation Paper; October 2009. Accessed December 12, 2011.

  3. 3.

    European Commission. Assessment of the functioning of the “Clinical Trials Directive” 2001/20/EC—Summary of responses to the public health consultation paper; March 2010. Accessed December 12, 2011.

  4. 4.

    European Commission. Revision of the “Clinical Trials Directive” 2001/20/EC. Concept Paper for Public Consultation; February 2011. Accessed December 12, 2011.

  5. 5.

    European Commission. Revision of the “Clinical Trials Directive” 2001/20/EC. Summary of the Replies to the public consultation on the “Concept paper”; July 2011. Accessed December 12, 2011.

  6. 6.

    European Science Foundation. Forward Look: Investigator-Driven Clinical Trials. March 2009.

  7. 7.

    Frewer LJ, Coles D, Champion K, et al. Has the European Clinical Trials Directive been a success? BMJ. 2010;340:c1862.

    CAS  Article  Google Scholar 

  8. 8.

    Abouzeid C, Rappagliosi A. Clinical Trials Directive: better regulation required now. Lancet. 2010;376:332.

    Article  Google Scholar 

  9. 9.

    Califf RM. Clinical trials bureaucracy: unintended consequences of well-intentioned policy. Clin Trials. 2006;3:496–502.

    Article  Google Scholar 

  10. 10.

    Infectious Diseases Society of America. Grinding to a halt: the effects of the increasing regulatory burden on research and quality improvement efforts. Clin Infect Dis. 2009;49:328–335.

    Article  Google Scholar 

  11. 11.

    Grignolo A. The Clinical Trials Transformation Initiative (CTTI). Ann Ist Super Sanita. 2011;47:14–18.

    PubMed  Google Scholar 

  12. 12.

    Finlayson SR. The effect of the current regulatory environment on clinical research: an overview. Surg. 2009;145:626–630.

    Article  Google Scholar 

  13. 13.

    ICH. Guideline for good clinical practice E6(R1); March 1996. Accessed November 10, 2011.

  14. 14.

    European Commission. Guidance for the preparation of good clinical practice inspection reports; May 2008. Accessed November 10, 2011.

  15. 15.

    Streicher-Saied U, Gertzen H, Hecht A, Nusser B, Sanden PH, Schrag-Floß D. Investigator site audit performance. Appl Clin Trials. 2006;15:95–99.

    Google Scholar 

  16. 16.

    Road Map Initiative for Clinical Research in Europe. Multidisciplinary Workshop on Risk Based Approach in Clinical Trials; January 2010, Barcelona, Spain. Meeting report. Accessed November 10, 2011.

  17. 17.

    FDA. Pharmaceutical quality for the 21st century: a risk-based approach; May 2007. Accessed November 14, 2011.

  18. 18.

    ICH. Quality risk management Q9; November 2005. Accessed November 14, 2011.

  19. 19.

    ICH. Training programme for Q8/Q9/Q10: How ICH Q8, Q9, Q10 guidelines are working together throughout the product life cycle. Accessed November 15, 2011.

  20. 20.

    ISO/IEC guide 51:1999—safety aspects—guideline for their inclusion in standards.

  21. 21.

    ISO/IEC guide 73:2009—risk management—vocabulary—guidelines for use in standards.

  22. 22.

    Agencia Italiana del farmaco. Linee guide per la clssficazione e conduzione degli studi osservazionali sui farmaci. Determinazione 20 marzo 2008 [AIFA provision of 20 March 2008: Guideline on classification and conduct of observational clinical studies]. Accessed December 16, 2011.

  23. 23.

    Orden SAS/3470/2009, de 16 de diciembre, por la que se publican las directrices sobre estudios posautorización de tipo observacional para medicamentos de uso humano [Order SAS/3470/2009: publication of the guideline on observational postauthorization studies on medicinal products for human use, 16 December 2009]. Accessed December 16, 2011.

  24. 24.

    GHTF. Implementation of risk management principles and activities within a quality management system, GHTF/SG3/N15R8: May 2005. Accessed December 16, 2011.

  25. 25.

    GHTF. Principles of medical devices classification GHTF/SG1/N15: June 2006. Accessed December 16, 2011.

  26. 26.

    Maisel WH. Medical device regulation: an introduction for the practising physician. Ann Intern Med. 2004;140:296–302.

    Article  Google Scholar 

  27. 27.

    Rosecrans HS. Why 510(k)? DIA Global Forum. 2011;3:20–22.

    Google Scholar 

  28. 28.

    Jeffreys DB. The regulation of medical devices and the role of the medical device agency. Br J Clin Pharmacol. 2001;52:229–235.

    Article  Google Scholar 

  29. 29.

    European Commission. Classification of Medical Devices, MEDDEV 2. 4/1 Rev. 9. June 2010. Accessed November 26, 2011.

  30. 30.

    Rid A, Emanuel EJ, Wendler D. Evaluating the risks of clinical research. JAMA 2010;304:1472–1479.

    CAS  Article  Google Scholar 

  31. 31.

    MRC/DH/MHRA Joint Project. Risk-adapted approaches to the management of clinical trials of investigational medicinal products. Version October 10, 2011. Accessed November 26, 2011.

  32. 32.

    Brosteanu O, Houben P, Ihrig K, et al. Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials. Clin Trials. 2009;6:585–596.

    Article  Google Scholar 

  33. 33.

    Journot V, Pignon JP, Gaultier C. Validation of a risk-assessment scale and a risk-adapted monitoring plan for academic clinical research studies-the Pre-Optimon study. Contemp Clin Trials. 2011;32:16–24.

    Article  Google Scholar 

  34. 34.

    OPTimisation du MONitorage Project. Optimon page. Accessed December 16, 2011.

  35. 35.

    FDA draft guidance for industry. oversight of clinical investigations—a risk-based approach to monitoring; August 2011. Accessed December 16, 2011.

  36. 36.

    Tantsyura V, Grimes I, Mitchel J, et al. Risk-based source data verification approaches: pro and cons. Drug Inf J. 2010;44:745–756.

    Article  Google Scholar 

  37. 37.

    Morrison BW, Cochran CJ, White JG, et al. Monitoring the quality of conduct of clinical trials: a survey of current practices. Clin Trials. 2011;8(3):342–349.

    Article  Google Scholar 

  38. 38.

    EFGCP and EORTC Consensus Workshop. Final report. Report of the Multi-Stakeholder Workshop on Consensus and Strategy Development; July 4, 2011. Accessed December 6, 2011.

  39. 39.

    Tsuji K, Tsutani K. Approval of new drugs 1999-2007: comparison of the US, the EU and Japan situations. J Clin Pharm Ther. 2010;35:289–301.

    CAS  Article  Google Scholar 

  40. 40.

    EMA. Draft reflection paper on risk based quality management in clinical trials (EMA/INS/GCP/394194/2011); August 2011. Accessed December 6, 2011.

  41. 41.

    European Commission. EU guidelines to good manufacturing practice—annex 20: quality risk management. Accessed December 6, 2011.

  42. 42.

    GHTF. Clinical evidence—key definitions and concepts, SG5/N1R8; May 2007. Accessed January 23, 2012.

  43. 43.

    McMahon AD, Conway DI, Macdonald TM, McInnes GT. The unintended consequences of clinical trials regulations. PLoS Med. 2009;3(11):e1000131.

    Article  Google Scholar 

  44. 44.

    Duley L, Antman K, Arena J, et al. Specific barriers to the conduct of clinical trials. Clin Trials. 2008;5:40–48.

    Article  Google Scholar 

  45. 45.

    Hartmann M, Hartmann-Vareilles F. The clinical trials directive: how is it affecting Europe’s noncommercial research? PLoS Clin Trials. 2006 Jun;1(2):e13.

    Article  Google Scholar 

  46. 46.

    Kelly M, Lazzaro M, Peteresen C. Canadian drug regulatory framework. Can J Neurol Sci. 2007;34 (suppl. 1):S3–S10.

    Article  Google Scholar 

  47. 47.

    Segeworth J, Derewlany L. Institution/investigator-initiated clinical trials in Canada. Can J Clin Pharmacol. 2006;13:e236–e239.

    Google Scholar 

  48. 48.

    Tsubouchi M, Matsui S, Banno Y, Kurokawa K, Kawakami K. Overview of the clinical application of regenerative medicine products in Japan. Health Policy. 2008;88:62–72.

    Article  Google Scholar 

  49. 49.

    Matsuba H, Kiuchi T, Tsutani K, Uchida E, Ohashi Y. The Japanese perspective on registries and a review of clinical trial process in Japan. In: Foote M, ed. Clinical Trial Registries: A Practical Guide for Sponsors and Researchers of Medicinal Products. Basel, Switzerland: Birkhäuser Verlag; 2006:83–106.

    Google Scholar 

  50. 50.

    HHS Guidance. Office for Human Research Protections (OHRP)—Categories of research that may be reviewed by the institutional review board (IRB) through an expedited review procedure (OHRP, November 1998). Accessed January, 20, 2012.

  51. 51.

    FDA Guidance for Industry. Investigational new drug applications (IND)—determining whether human research studies can be conducted without an IND (CDER/CBER, October 2010). Accessed January, 20, 2012.

  52. 52.

    FDA Guidance for Industry. IND exemptions for studies of lawfully marketed drug or biological products for the treatment of cancer (CDER/CBER, January 2004). Accessed January, 20, 2012.

  53. 53.

    FDA Final rule. Expanded access to investigational drugs for treatment use (docket no. FDA–2006–N–0238). FR August 13, 2009;74(155):40900–40945. Accessed January, 20, 2012.

    Google Scholar 

  54. 54.

    FDA Guidance on IDE policies and procedures (CDRH, January 1998). Accessed January, 20, 2012.

  55. 55.

    FDA Guidance for institutional review boards, clinical investigators, and sponsors: exception from informed consent requirements for emergency research (CDER/CBER/CDRH, March 2011). Accessed January, 20, 2012.

  56. 56.

    FDA information sheet guidance for sponsors, clinical investigators, and IRBs. Waiver of IRB requirements for drug and biological product studies (FDA, January 2006). Accessed January, 20, 2012.

  57. 57.

    Druml C. Informed consent of incapable (ICU) patients in Europe: existing laws and the EU directive. Curr Opin Crit Care. 2004;10(6):570–573.

    Article  Google Scholar 

  58. 58.

    Lemaire F, Bion J, Blanco J, et al. The European Union directive on clinical research: present status of implementation in EU member states’ legislations with regard to the incompetent patient. Intensive Care Med. 2005;31:476–479.

    CAS  Article  Google Scholar 

  59. 59.

    Meunier F, Dubois N, Negrouk A, et al. Throwing a wrench in the works? Lancet Oncol. 2003;4:717–719.

    Article  Google Scholar 

  60. 60.

    Hearn J, Sullivan R. The impact of the “clinical trials” directive on the cost and conduct of non-commercial cancer trials in the UK. Eur J Cancer. 2007;43:8–13.

    CAS  Article  Google Scholar 

  61. 61.

    Hilbrich L, Sleight P. Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials. Eur Heart J. 2006;27:2158–2164.

    Article  Google Scholar 

  62. 62.

    OECD Global Science Forum. Facilitating international cooperation in non-commercial clinical trials. October 2011. Accessed June 11, 2012.

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Correspondence to Markus Hartmann PhD, MDRA.

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Hartmann, M., Hartmann-Vareilles, F. Concepts for the Risk-Based Regulation of Clinical Research on Medicines and Medical Devices. Ther Innov Regul Sci 46, 545–554 (2012).

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  • clinical trial legislation
  • EU Clinical Trials Directive
  • risk-based approach
  • quality risk management
  • clinical investigation of medical devices