The NEW ENGLAND JOURNAL Of MEDICINE SOUNDING BOARD Randomized clinical trials Removing Unnecessary Obstacles Christina Reith, M.B., Ch B, Martin Landray, M.B., Ch B, P J. Devereaux, M.D., Ph D Jackie Bosch, M.Sc, Christopher B. Granger, M D, Colin Baigent, B.M., BCh Robert M. Califf, M.D., Rory Collins, M.B., B.S., and Salim Yusuf, M.D., D Phil. Since their widespread introduction in the mid- large increases in cost and effort caused by the dle of the 20th century, randomized trials of current regulatory system, many existing and new sufficiently large size have provided reliable as- interventions are not being evaluated, and the sessments of the safety and efficacy of treat- trials that are conducted are smaller and less ments that have produced substantial improve- formative than they might otherwise be 7,10 Trials ments in health. During the past decade, comparing widely accepted treatments are also however, increasingly onerous regulation and re- being inhibited because of the trend toward re- lated bureaucracy have made trials much more quiring excessively detailed informed consent difficult and costly to conduct, slowing further and related litigation (as in the case of recent improvements. 2,3 This adverse regulatory envi- neonatal intensive care trials 1, 12). The negative ronment hinders important research and urgent- effect these obstacles have on efforts to obtain ly needs to be changed for the benefit of patients reliable evidence regarding the safety and effi- cacy of treatments affects the care of people not As one example of the current problems just in developed countries but also in develop (Table 1), the requirement to obtain approval ing countries, where resources are more limited from many different bodies before starting a and the burden of disease is large. 13 Hence, there trial results in substantial delays and costs. 4 is an urgent need for major changes in proce Even where centralized regulatory and ethics re- dures for the initiation, conduct, monitoring, views have been adopted (e.g, in the United and safety reporting of clinical trials, such that Kingdom), hurdles remain when permission is they are more proportionate to the likely hazards required from each study site, resulting in dupli- of the trials. Otherwise, researchers may be in- cated effort and delays. For multicenter trials, hibited from conducting such trials at all, which this can involve hundreds of separate approvals, will ultimately place patients at much greater risk. take more than a year to complete, and cost Many regulators acknowledge the seriousness hundreds of thousands of dollars. 5 The situation of these problems, but their attempts to resolve is exacerbated when trials involve more than them have often further hampered research. For one country, each requiring separate approval instance, the European Union 2001 Clinical Trials from multiple organizations. For example, in Directive(Directive 2001/20/EC)4 was intended China, it typically takes up to a year to obtain to facilitate the performance of trials across Eu- regulatory approval. Such inefficiencies are in- rope and better protect the public. However, it is creasingly recognized as damaging to medical now widely accepted including by the Euro- progress, as noted in reports from the U.S. pean Commission itself -that this directive, President's Council of Advisors on Science and which was incorporated into legislation differ Technology and the Institute of Medicine. ently in different countries, failed to achieve Previous randomized trials have shown that either aim. ,10 As a consequence, trials that in number of widely used treatments are not ef- volve European Union sites, including those con- fective or safe; for example, treatment with anti- ducted by U.S. investigators, have been impeded, arrhythmic drugs after heart attacks causes car- and patient care has suffered. After public diac arrests, and routine glucocorticoid use for sultation, the European Commission isst head injury reduces survival. 8,9 Because of the proposal in July 2012 to replace the Clinical N ENGLJMED 369: 11 NEJMORC SEPTEMBER 12, 2013 1061n engl j med 369;11 nejm.org september 12, 2013 1061 s o u n d i n g b o a r d T h e n e w e ngl a nd j o u r na l o f m e dic i n e Randomized Clinical Trials — Removing Unnecessary Obstacles Christina Reith, M.B., Ch.B., Martin Landray, M.B., Ch.B., P.J. Devereaux, M.D., Ph.D., Jackie Bosch, M.Sc., Christopher B. Granger, M.D., Colin Baigent, B.M., B.Ch., Robert M. Califf, M.D., Rory Collins, M.B., B.S., and Salim Yusuf, M.D., D.Phil. Since their widespread introduction in the mid￾dle of the 20th century, randomized trials of sufficiently large size have provided reliable as￾sessments of the safety and efficacy of treat￾ments that have produced substantial improve￾ments in health.1 During the past decade, however, increasingly onerous regulation and re￾lated bureaucracy have made trials much more difficult and costly to conduct, slowing further improvements.2,3 This adverse regulatory envi￾ronment hinders important research and urgent￾ly needs to be changed for the benefit of patients and public health. As one example of the current problems (Table 1), the requirement to obtain approval from many different bodies before starting a trial results in substantial delays and costs.4 Even where centralized regulatory and ethics re￾views have been adopted (e.g., in the United Kingdom), hurdles remain when permission is required from each study site, resulting in dupli￾cated effort and delays. For multicenter trials, this can involve hundreds of separate approvals, take more than a year to complete, and cost hundreds of thousands of dollars.5 The situation is exacerbated when trials involve more than one country, each requiring separate approval from multiple organizations. For example, in China, it typically takes up to a year to obtain regulatory approval. Such inefficiencies are in￾creasingly recognized as damaging to medical progress, as noted in reports from the U.S. President’s Council of Advisors on Science and Technology6 and the Institute of Medicine.7 Previous randomized trials have shown that a number of widely used treatments are not ef￾fective or safe; for example, treatment with anti￾arrhythmic drugs after heart attacks causes car￾diac arrests, and routine glucocorticoid use for head injury reduces survival.8,9 Because of the large increases in cost and effort caused by the current regulatory system, many existing and new interventions are not being evaluated, and the trials that are conducted are smaller and less in￾formative than they might otherwise be.7,10 Trials comparing widely accepted treatments are also being inhibited because of the trend toward re￾quiring excessively detailed informed consent and related litigation (as in the case of recent neonatal intensive care trials11,12). The negative effect these obstacles have on efforts to obtain reliable evidence regarding the safety and effi￾cacy of treatments affects the care of people not just in developed countries but also in develop￾ing countries, where resources are more limited and the burden of disease is large.13 Hence, there is an urgent need for major changes in proce￾dures for the initiation, conduct, monitoring, and safety reporting of clinical trials, such that they are more proportionate to the likely hazards of the trials. Otherwise, researchers may be in￾hibited from conducting such trials at all, which will ultimately place patients at much greater risk. Many regulators acknowledge the seriousness of these problems, but their attempts to resolve them have often further hampered research. For instance, the European Union 2001 Clinical Trials Directive (Directive 2001/20/EC)14 was intended to facilitate the performance of trials across Eu￾rope and better protect the public. However, it is now widely accepted — including by the Euro￾pean Commission itself — that this directive, which was incorporated into legislation differ￾ently in different countries, failed to achieve either aim.2,10 As a consequence, trials that in￾volve European Union sites, including those con￾ducted by U.S. investigators, have been impeded, and patient care has suffered. After public con￾sultation, the European Commission issued a proposal in July 2012 to replace the Clinical Trials