The NEW ENGLAND JOURNAL Of MEDICINE with the research community about the incorpora- and McMaster University- both in Hamilton, ON, Canada tion of risk-based approaches and other evidence-(- D. J-B SY ) and the Duke Clinical Research Institute,Duke University, Durham, NC based revisions. Certain entities have benefited quests to Dr. Reith at the Clinical Trial Service Unit and m the complexity of the current regulatory ological Studies Unit, Richard Doll Bldg,old Road Roosevelt Dr, Oxford OX3 7LF, United Kingdom, or at environment-not just contract research organi- reith@ctsu. x ac uk. zations and companies providing training in the ICH-GCP guidelines, but also regulatory groups 1. Collins R, MacMahon S Reliable assessment of the effects in pharmaceutical companies and other institu- of treatment on mortality and major morbidity, I: clinical trials tions, which have seen their revenue and influ- 2. McMahon AD, Conway Dl, Macdonald TM, McInnes GT. The ence increase substantially -and they too may unintended consequences of clinical trials regulations. PLoS Med ppose streamlining. Ultimately, rather than the 2009: 3011): e1000131. piecemeal changes that are currently being made 3. calit Mi, linical trials bureaucrac unintended conse- to the regulations and bureaucracy governing 4. Duley L, Antman K, Arena J, et al. Sp clinical trials, comprehensive reform of the whole conduct of randomized trials. Clin Trials 2008: 5:40- system is required. This should involve experts 3. Petersen LA, Simpson K, Sorelle R,Urech T, Chitwood low variability in the institutional review board review process in clinical trials developing authoritative "good affects minimal-risk multisite health services research. Ann In- clinical trial practice"guidelines founded on the tern Med 2012: 156: 72, Advisors on Science and Technology key principles that underpin the reliable assess-(PCAST). Report to the President on propelling innovation in ment of the safety and efficacy of treatments. At drug discovery, development, and evaluation. Washington, DC thesametimeprocessesthatareoflittleprovenPcAst,September2012(httpillwww.whitehouse-gowlsites/defaultl value should be strongly 7. Institute of Medicine. Envisaging a transformed clinical tr With support from all the relevant stakehold- terprise in the United States: establishing an agenda for rs-including regulators, academics, those in 2020: workshop summary. Washington, DC: National Acad industry, and patient representatives -and, 8. The Cardiac Arrhythmia Suppression Trial (CAST) Investiga crucially, a better understanding of these issues tors. Preliminary report: effect of encainide and flecainide on provide a more appropriate basis for the devel myocardi in a randomize trait of arhythmia suppressionafter at the governmental level, such guidelines could morta opment and interpretation of regulations for clin. 9. Roberts I, Yates D, Sandercock B, et al. Effect of inuravewith orticosteroids on death within 14 days in 10 008 adult ical trials. It is becoming increasingly clear that clinically significant head injury (MRC CRASH triaD): random- more extensive use of health records and infor- hd placebo- controled ran dancer matics platforms, 2 along with more refined the council on clinical trials on medicinal products for human ethical approaches characterized by the expecta- use oneill on tt ilec.europa. eu/health/files/clinicaltrials/ tion that participation in clinical trials is the 2012_07pr norm rather than the exception, 29 could support ll.Drazen JM, Solomon CG, Greene MEInformed consent and a dramatic increase in the emergence of defini- SUPPORT. N Engl J Med 2013: 368: 1929-31 tive evidence about treatments. Unless radical 12. Magnus D, Caplan AL Risk, consent, and SUPPORT. N Engl improvements are made to the regulatory envi- 13. Lang T, Cheah PY, White NJ. Clinical research: time for sen- ronment, the potential of clinical trials to assess sible global guidelines. Lancet 2011-377:1553-5 the safety and efficacy of new and existing treat- council of 4 April 2001 on the approximation of the laws, regula- ments and, thereby, to produce substantial im- tions and administrative provi f the Member States relat. provements in health care and public health will ing to the implementation of good clinical practice in the conduct not be fulfilled urnaloftheEuropeanCommunities(http://eur-lex.europa.eu All authors are members of the Sensible Guidelines Group, LexUriServ/LexUriServ do?uri=OJ: L: 2001: 121: 0034: 0044: en: PD Clip Hananized jointly by the Population Health Research1Bam, ouben P, Ihrig K,世Rm山改 ercial clinical trials inical Trial Service Unit and Epidemiological Studies Unit, Clin Trials 2009: 6: 585-96 Nuffield Department of Population Health, University of Oxford; 16. Guidance for Industry: oversight of clinical investigations and the Duke Clinical Research Institute, Duke University. a risk-based approach to monitoring. Rockville, MD: Food inclosureformsprovidedbytheauthorsareavailablewithandDrugAdministrationAugust2013(http://www.fda.govl the full text of this article at nEJM. org. downloads/ Drugs/ Guidance Compliance Regulatorylnformation/ From the Clinical Trial Service Unit and Epidemiologic ncil/Department of Health/Medicine ield Department of Population Health, care Products Regulatory of Oxford, Oxford, United Kingdom(CR, ML,CB adapted approaches to the manageme nical trials Population Health Research Institute, Hamilton Health vestigational medicinal products 011(http N ENGLJMED 369: 11 NEJM.ORG SEPTEMBER 12, 2013T h e n e w e ngl a nd j o u r na l o f m e dic i n e 1064 n engl j med 369;11 nejm.org september 12, 2013 with the research community about the incorpora￾tion of risk-based approaches and other evidence￾based revisions. Certain entities have benefited from the complexity of the current regulatory environment — not just contract research organi￾zations and companies providing training in the ICH-GCP guidelines, but also regulatory groups in pharmaceutical companies and other institu￾tions, which have seen their revenue and influ￾ence increase substantially — and they too may oppose streamlining. Ultimately, rather than the piecemeal changes that are currently being made to the regulations and bureaucracy governing clinical trials, comprehensive reform of the whole system is required. This should involve experts in clinical trials developing authoritative “good clinical trial practice” guidelines founded on the key principles that underpin the reliable assess￾ment of the safety and efficacy of treatments. At the same time, processes that are of little proven value should be strongly discouraged. With support from all the relevant stakehold￾ers — including regulators, academics, those in industry, and patient representatives — and, crucially, a better understanding of these issues at the governmental level, such guidelines could provide a more appropriate basis for the devel￾opment and interpretation of regulations for clin￾ical trials. It is becoming increasingly clear that more extensive use of health records and infor￾matics platforms,28 along with more refined ethical approaches characterized by the expecta￾tion that participation in clinical trials is the norm rather than the exception,29 could support a dramatic increase in the emergence of defini￾tive evidence about treatments. Unless radical improvements are made to the regulatory envi￾ronment, the potential of clinical trials to assess the safety and efficacy of new and existing treat￾ments and, thereby, to produce substantial im￾provements in health care and public health will not be fulfilled. All authors are members of the Sensible Guidelines Group, which is organized jointly by the Population Health Research Institute, Hamilton Health Sciences and McMaster University; the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford; and the Duke Clinical Research Institute, Duke University. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Clinical Trial Service Unit and Epidemiological Stud￾ies Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom (C.R., M.L., C.B., R.C.); the Population Health Research Institute, Hamilton Health Sciences and McMaster University — both in Hamilton, ON, Canada (P.J.D., J.B., S.Y.); and the Duke Clinical Research Institute, Duke University, Durham, NC (C.B.G., R.M.C.). Address reprint re￾quests to Dr. Reith at the Clinical Trial Service Unit and Epidemi￾ological Studies Unit, Richard Doll Bldg., Old Road Campus, Roosevelt Dr., Oxford OX3 7LF, United Kingdom, or at christina .reith@ctsu.ox.ac.uk. 1. Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet 2001;357:373-80. 2. McMahon AD, Conway DI, Macdonald TM, McInnes GT. The unintended consequences of clinical trials regulations. PLoS Med 2009;3(11):e1000131. 3. Califf RM. Clinical trials bureaucracy: unintended conse￾quences of well-intentioned policy. Clin Trials 2006;3:496-502. 4. Duley L, Antman K, Arena J, et al. Specific barriers to the conduct of randomized trials. Clin Trials 2008;5:40-8. 5. Petersen LA, Simpson K, Sorelle R, Urech T, Chitwood SS. How variability in the institutional review board review process affects minimal-risk multisite health services research. Ann In￾tern Med 2012;156:728-35. 6. President’s Council of Advisors on Science and Technology (PCAST). Report to the President on propelling innovation in drug discovery, development, and evaluation. Washington, DC: PCAST, September 2012 (http://www.whitehouse.gov/sites/default/ files/microsites/ostp/pcast-fda-final.pdf). 7. Institute of Medicine. Envisaging a transformed clinical tri￾als enterprise in the United States: establishing an agenda for 2020: workshop summary. Washington, DC: National Acade￾mies Press, 2012. 8. The Cardiac Arrhythmia Suppression Trial (CAST) Investiga￾tors. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med 1989;321:406-12. 9. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH trial): random￾ised placebo-controlled trial. Lancet 2004;364:1321-8. 10. Proposal for a regulation of the European parliament and of the council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. Brussels: European Commission, 2012 (http://ec.europa.eu/health/files/clinicaltrials/ 2012_07/proposal/2012_07_proposal_en.pdf). 11. Drazen JM, Solomon CG, Greene MF. Informed consent and SUPPORT. N Engl J Med 2013;368:1929-31. 12. Magnus D, Caplan AL. Risk, consent, and SUPPORT. N Engl J Med 2013;368:1864-5. 13. Lang T, Cheah PY, White NJ. Clinical research: time for sen￾sible global guidelines. Lancet 2011;377:1553-5. 14. Directive 2001/20/EC of the European parliament and of the council of 4 April 2001 on the approximation of the laws, regula￾tions and administrative provisions of the Member States relat￾ing to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal of the European Communities (http://eur-lex.europa.eu/ LexUriServ/LexUriServ.do?uri=OJ:L:2001:121:0034:0044:en:PDF). 15. Brosteanu O, Houben P, Ihrig K, et al. Risk analysis and risk adapted on-site monitoring in noncommercial clinical trials. Clin Trials 2009;6:585-96. 16. Guidance for Industry: oversight of clinical investigations — a risk-based approach to monitoring. Rockville, MD: Food and Drug Administration, August 2013 (http://www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/UCM269919.pdf). 17. Medical Research Council/Department of Health/Medicines and Healthcare Products Regulatory Agency Joint Project. Risk￾adapted approaches to the management of clinical trials of in￾vestigational medicinal products. October 2011 (http://www