PERSPECTIVE ACCESS TO PATIENT-LEVEL TRIAL DATA level playing field for all stake- From the European Medicines Agency, Mandel F, Kapur S More efficient drug dis- holders. What is sometimes la. London beled as"free riding"may ulti- This article was published on October 21, trials(RCTs)from the NEWMEDS repository. mately pay dividends for innovative companies and for public health. 1. Zarin DA. Participant-level data and the pean College of Nev tecnpSearch&content It is ironic that the organizations Med 2013:369-468-9 that most resist wider access to 2. European Medicines Agency Publication action-CiS2002&hoofdnaw data are the ones that stand to and access to clinicaltrial data: daft policy "abinswts whatpirlczeTEXTSsarction benefit so much from greater . eu/docs/en_GB/document._library/ other/ -ALL&abstrnbr-S 11.03) transparency. 2013/06/WC500144730.pdf) 5. Catalyzing the transformation of health- 3. Pharmaceutical Research and Manufa are innovation: a working paper from the those of the authors and do not necessarily Pharmaceutical Industries and Association reflect those of the European Medicines Principles for responsible cli taTechnologyJanuary2010(http://cbi.mit.edu/ Agency or any of its committees. haring(http://phrma.org/sites/default Disclosure forms provided by the authors pdf/Ph RMAPrinciples For ResponsibleClinical White-Paper-20100118pdf) are available with the full text of this article TrialData Sharing pdf 4. Rabinowitz ), Werbeloff N, Stauffer v, Copyright e 2013 Massachusetts Medical Society. The randomized registry trial The Next Disruptive Technology in Clinical Research? Michael S. Lauer, M D, and Ralph B. D'Agostino, Sr, Ph D Related article, p. 158 he randomized trial is one pants, as well as inadequate rep- such as hypertrophic cardiomyo- of the most powerful tools resentativeness. What good are athy and patients referred for sur- clinical researchers possess, a trials if the results aren,'t applica- gery, percutaneous invasive proce- tool that enables them to evaluate ble to real-world patients and if, dures, and device implantation the effectiveness of new(or estab- because of excessive expense, they Investigators and public health lished) therapies while account- can be used to answer only a tiny officials use registries to describe ing for the effects of unmeasured fraction of our important clinical practice patterns and trends, to confounders and selection bias by questions? identify outliers, and to detect indication. Randomized trials, One possible solution is to safety signals. They often use reg especially huge megatrials, have look to observational registries istries to assess comparative ef- transformed medical practice. for answers. Over the past 20 to fectiveness, too, but are forced to Thanks to randomized trials, we 30 years, a number of profession- admit that purely observational no longer, for example, treat acute al societies, government agencies, findings may not be internally myocardial infarction with lido- private corporations, and inde- valid owing to the absence of ran- caine and nitrates. Instead we use pendent researchers have estab- domization. rapid revascularization, anticoagu- lished high-quality registries that debates about comparative lants, and antiplatelet agents, and collect standardized data from effectiveness research have inten- during long-term follow-up we patients seen in a variety of set- sified over the past few years, we routinely prescribe statins, beta- tings In cardiovascular medicine, find ourselves in a kind of intel blockers, and angiotensin-convert- for example, registries in the lectual trap: yes, in theory we ing-enzyme inhibitors. But the United States and abroad have would like to conduct more ran- reputation of randomized trials collected vast amounts of data domized trials, but in practice las suffered of late, owing to from patients with acute coronary they are too complex and difficult reasonable concern about excess syndromes, stable coronary dis- to apply to many clinical ques- complexity,expense,and time re- ease, and heart failure, as well as tions. And, yes, in theorywe quired to recruit study partici- from patients with rare diseases could answer many questions at ENGLJMED 369: 17 NEJM. ORG OCTOBER 24, 2013
n engl j med 369;17 nejm.org october 24, 2013 PERSPECTIVE 1579 level playing field for all stakeholders. What is sometimes labeled as “free riding” may ultimately pay dividends for innovative companies and for public health. It is ironic that the organizations that most resist wider access to data are the ones that stand to benefit so much from greater transparency. The views expressed in this article are those of the authors and do not necessarily reflect those of the European Medicines Agency or any of its committees. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the European Medicines Agency, London. This article was published on October 21, 2013, at NEJM.org. 1. Zarin DA. Participant-level data and the new frontier in trial transparency. N Engl J Med 2013;369:468-9. 2. European Medicines Agency. Publication and access to clinical-trial data: draft policy 0070. June 24, 2013 (http://www.ema.europa .eu/docs/en_GB/document_library/Other/ 2013/06/WC500144730.pdf). 3. Pharmaceutical Research and Manufacturers of America, European Federation of Pharmaceutical Industries and Associations. Principles for responsible clinical trial data sharing (http://phrma.org/sites/default/files/ pdf/PhRMAPrinciplesForResponsibleClinical TrialDataSharing.pdf). 4. Rabinowitz J, Werbeloff N, Stauffer V, Mandel F, Kapur S. More efficient drug discovery trials in schizophrenia: insights from 29 placebo-controlled randomised controlled trials (RCTs) from the NEWMEDS repository. Presented at the 24th Congress of the European College of Neuropsychopharmacology, Paris, September 3–7, 2011 (http://conference services.elsevier.nl/11ecnp/index.cfm?fuse action=CIS2002&hoofdnav=Search&content =zk.results_all&topicselected=*&searchtext =rabinowitz&what=FREE%20TEXT&selection =ALL&abstrnbr=S.11.03). 5. Catalyzing the transformation of healthcare innovation: a working paper from the MIT Center for Biomedical Innovation. Cambridge: Massachusetts Institute of Technology, January 2010 (http://cbi.mit.edu/ wp-content/uploads/2011/04/MIT-NewDigs -White-Paper-20100118.pdf). DOI: 10.1056/NEJMp1310771 Copyright © 2013 Massachusetts Medical Society. Access to Patient-Level Trial Data The Randomized Registry Trial — The Next Disruptive Technology in Clinical Research? Michael S. Lauer, M.D., and Ralph B. D’Agostino, Sr., Ph.D. Related article, p. 1587 The randomized trial is one of the most powerful tools clinical researchers possess, a tool that enables them to evaluate the effectiveness of new (or established) therapies while accounting for the effects of unmeasured confounders and selection bias by indication. Randomized trials, especially huge megatrials, have transformed medical practice. Thanks to randomized trials, we no longer, for example, treat acute myocardial infarction with lidocaine and nitrates. Instead we use rapid revascularization, anticoagulants, and antiplatelet agents, and during long-term follow-up we routinely prescribe statins, betablockers, and angiotensin-converting–enzyme inhibitors. But the reputation of randomized trials has suffered of late,1 owing to reasonable concern about excess complexity, expense, and time required to recruit study participants, as well as inadequate representativeness. What good are trials if the results aren’t applicable to real-world patients and if, because of excessive expense, they can be used to answer only a tiny fraction of our important clinical questions? One possible solution is to look to observational registries for answers. Over the past 20 to 30 years, a number of professional societies, government agencies, private corporations, and independent researchers have established high-quality registries that collect standardized data from patients seen in a variety of settings. In cardiovascular medicine, for example, registries in the United States and abroad have collected vast amounts of data from patients with acute coronary syndromes, stable coronary disease, and heart failure, as well as from patients with rare diseases such as hypertrophic cardiomyopathy and patients referred for surgery, percutaneous invasive procedures, and device implantation. Investigators and public health officials use registries to describe practice patterns and trends, to identify outliers, and to detect safety signals. They often use registries to assess comparative effectiveness, too, but are forced to admit that purely observational findings may not be internally valid owing to the absence of randomization. As debates about comparativeeffectiveness research have intensified over the past few years, we find ourselves in a kind of intellectual trap: yes, in theory we would like to conduct more randomized trials, but in practice they are too complex and difficult to apply to many clinical questions. And, yes, in theory we could answer many questions at
PERSPECTIVE THE RANDOMIZED REGISTRY TRIAL 0,000 Patients receiving primary PCI Patients who underwent 6000 ndomization 5,000- 2400 1.000 Rapid Randomization in the TASTE Trial, with Enrollment of Most Patients Receiving Primary Percutaneous Coronary Intervention(PCI) daptedfromtheInstituteofMedicine(www.iom.edu/-/media/files/activity/%20files/quality/vsrt/i Granger.pdf). The incremental cost of the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia(TASTE)trial was $300,000, or $50 for each participant who underwent randomization. low cost with large-scale observa- this clever design, which lever- trial complements the strengths tional registries, but despite sta- aged clinical information that and addresses the weaknesses tistical advances, comparative ob- was already being gathered for of the two most prominent types servational registry studies are the registry and for other preexist- of comparative-effectiveness re- suspect because they lack the rig- ing databases, the investigators search. The trial is still a trial, a or of randomization 2 were able to quickly identify po- rigorous randomized experiment Enter the registry-based ran- tential participants, to enroll thou- that isolates a causal link (or the domized trial. With the Thrombus sands of patients in little time absence of one) between a treat Aspiration in ST-Elevation Myo- (see figure), to avoid filling out ment and an outcome. Because cardial Infarction in Scandinavia long case-report forms, to obtain the trial is inexpensive, investiga (TASTE)trial, the results of which accurate follow-up with minimal tors can enroll large numbers of are now reported in the Journal effort, and to report their find- patients, thus offering clinicians (pages 1587-1597), a new para- ings, all for less than the amount insights that are potentially based digm has emerged that can poten- of a typical modular R01 grant on a representative sample, a real tially release us from the circular (i.e, a grant for research initiated world population created from (and expensive) trap of the ran- by an individual investigator) from consecutively enrolled registry pa domized-versus-registry debate. the National Institutes of Health. tients The TASTE investigators designed Their findings may well be broadly Despite this appeal, a number a large-scale trial to answer an generalizable, since they included of fundamental questions must important clinical question and in the randomization process the be addressed if we are to trans- carried it out at remarkably low majority of all patients treated for form our clinical-research enter cost by building on the platform ST-segment-elevation myocardial prise to give registry-based ran of an already-existing high-qual- infarction in the study area. domized trials, or other trials ity observational registry. With The registry-based randomized with highly efficient designs, a N ENGLJ MED 369: 17 NEJM.ORG OCTOBER 24, 2013
PERSPECTIVE 1580 n engl j med 369;17 nejm.org october 24, 2013 low cost with large-scale observational registries, but despite statistical advances, comparative observational registry studies are suspect because they lack the rigor of randomization.2 Enter the registry-based randomized trial. With the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial, the results of which are now reported in the Journal (pages 1587–1597), a new paradigm has emerged that can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate.3 The TASTE investigators designed a large-scale trial to answer an important clinical question and carried it out at remarkably low cost by building on the platform of an already-existing high-quality observational registry. With this clever design, which leveraged clinical information that was already being gathered for the registry and for other preexisting databases, the investigators were able to quickly identify potential participants, to enroll thousands of patients in little time (see figure), to avoid filling out long case-report forms, to obtain accurate follow-up with minimal effort, and to report their findings, all for less than the amount of a typical modular R01 grant (i.e., a grant for research initiated by an individual investigator) from the National Institutes of Health. Their findings may well be broadly generalizable, since they included in the randomization process the majority of all patients treated for ST-segment–elevation myocardial infarction in the study area. The registry-based randomized trial complements the strengths and addresses the weaknesses of the two most prominent types of comparative-effectiveness research. The trial is still a trial, a rigorous randomized experiment that isolates a causal link (or the absence of one) between a treatment and an outcome. Because the trial is inexpensive, investigators can enroll large numbers of patients, thus offering clinicians insights that are potentially based on a representative sample, a realworld population created from consecutively enrolled registry patients. Despite this appeal, a number of fundamental questions must be addressed if we are to transform our clinical-research enterprise to give registry-based randomized trials, or other trials with highly efficient designs, a The Randomized Registry Trial No. of Patients 10,000 4,000 5,000 1,000 6,000 2,000 3,000 0 7,000 8,000 9,000 Patients receiving primary PCI Patients who underwent randomization June 2010 July 2010 Aug. 2010 Sept. 2010 Oct. 2010 Nov. 2010 Dec. 2010 June 2012 July 2012 Aug. 2012 Sept. 2012 Jan. 2011 Feb. 2011 March 2011 April 2011 May 2011 June 2011 July 2011 Aug. 2011 Sept. 2011 Oct. 2011 Nov. 2011 Dec. 2011 Jan. 2012 Feb. 2012 March 2012 April 2012 May 2012 Rapid Randomization in the TASTE Trial, with Enrollment of Most Patients Receiving Primary Percutaneous Coronary Intervention (PCI). Adapted from the Institute of Medicine (www.iom.edu/~/media/Files/Activity%20Files/Quality/VSRT/LST%20Workshop/Presentations/ Granger.pdf). The incremental cost of the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial was $300,000, or $50 for each participant who underwent randomization
PERSPECTIVE HE RANDOMIZED REGISTRY TRIAL prominent role Will registry data Scandinavia, in places where be possible to design and conduct (or data coming from other digi- health care and clinical data are megatrials with what we have al sources, such as electronic fragmented and of lower quality? bigger data and smaller budgets health records) be of high enough Some American investigators are Yet we must also recognize and quality? Will too many data fields already using the approach (e. g, acknowledge the daunting chal- be missing? How will we balance the Study of Access Site for En- lenges that diverse groups of re- we transition single registries nary Intervention for Women; overcome to get there ders must efficacy versus effectiveness? Can hancement of Percutaneous Coro- searchers and stakehe from efficacy to effectiveness, NCTo1406236) But even if we can The view ssed in this article are making it possible to assess ex- perform many more randomized those of the authors and do not necessarily ternal validity much more expedi- registry trials in the United States, tional Heart, Lung, and Blood Institute. Dr tiously than we do now? What are we must recognize that the ap- Lauer is the National Institutes of Health lations to study? How will we ap- lems we have with trials. For tee ot the tate pcortered ne of ome iwe roach concerns about privacy certain kinds of trials, such as expressed here represent those of PCORI or and informed consent (particu- metabolic efficacy studies that its Methodology Committee larly in the context of trials that focus on complex physiologic and closure forms provided by the authors are available with the full text of this article compare acceptable standards of metabolic pathways hypothesized at NEJM.org care and use cluster-randomiza- to respond to changes in diet or ble?Will researchers be able to agents, current organizational Cardiovascular Sciences, the Natons o tion methods)? Is blinding possi- to experimental pharmacologic From the Office of the Director, Division of Heart, Lung, and Blood Institute, Bethesda obtain long-term follow-up or structures would probably work MD(MSL); and the Mathematics and Sta- measure composite outcomes? much better with only minor tistics Department, Boston University, and How will we standardize and ad- modifications judicate certain outcomes? Can The randomized registry trial that even within a registry there a technology that transforms ex- 2013, at NE/M.org. hed on September I we assure representativeness, given represents a disruptive technology, This article was published on September may be systematic differences be- isting standards, procedures, and tween patients who are and are cost structures. Will it be given 1. Antman EM, Harrington RA Transform not eligible for randomization or serious consideration as a way to mission critical for health and economic between those who do or do not resolve the recognized limitations well-being. JAMA 2012:308: 1743.4 2. Pocock S), Elbourne DR Randomized tri- consent of current clinical-trial design? als or observational tribulations? N Engl J These are only some of the Theodore Roosevelt once said, Med 2000:342: 1907-9 problems we will have to address. "Do what you can, with what you 3. Frobert o, Lagergvist B, Gudnason The TASTe trial was performed have, where you are. " Today we myocardial infarction in Scandinavia(TASTE Scand afford care and information technology randomized effectiveness trials ized, controlled clinical registry trial based environments are markedly dif. that cost tens or hundreds of mil- ty Registry(SCAAR)platform: study design ferent from those elsewhere in lions of dollars. But today we alse the world. Can randomized regis- have registries and other power- Dol: 10.1056/NEJMp1310102 try trials be undertaken outside ful digital platforms. Today it may Copyright o 2013 Massachusetts Medical. Smoothing the Way to High Quality, Safety, and Economy Eugene Litvak, Ph. D, and Harvey V. Fineberg, M. D, Ph D n recent years, health care in- aid Services is implementing fections associated with ventila- have awakened to multiple incentives and penalties tors or central venous catheters the need to provide safe, high- intended to help realize this have had demonstrated success quality care at lower cost. The goal. For example, innovations We believe that greater attention Centers for Medicare and Medic- designed to reduce the rate of in- to a frequently overlooked param- N ENGLJ MED 369: 17 NEJM.ORG OCTOBER 24, 2013
n engl j med 369;17 nejm.org october 24, 2013 PERSPECTIVE 1581 The Randomized Registry Trial prominent role. Will registry data (or data coming from other digital sources, such as electronic health records) be of high enough quality? Will too many data fields be missing? How will we balance efficacy versus effectiveness? Can we transition single registries from efficacy to effectiveness, making it possible to assess external validity much more expeditiously than we do now? What are the best populations or subpopulations to study? How will we approach concerns about privacy and informed consent (particularly in the context of trials that compare acceptable standards of care and use cluster-randomization methods)? Is blinding possible? Will researchers be able to obtain long-term follow-up or measure composite outcomes? How will we standardize and adjudicate certain outcomes? Can we assure representativeness, given that even within a registry there may be systematic differences between patients who are and are not eligible for randomization or between those who do or do not consent? These are only some of the problems we will have to address. The TASTE trial was performed in Scandinavia, where the health care and information technology environments are markedly different from those elsewhere in the world. Can randomized registry trials be undertaken outside Scandinavia, in places where health care and clinical data are fragmented and of lower quality? Some American investigators are already using the approach (e.g., the Study of Access Site for Enhancement of Percutaneous Coronary Intervention for Women; NCT01406236). But even if we can perform many more randomized registry trials in the United States, we must recognize that the approach cannot solve all the problems we have with trials. For certain kinds of trials, such as metabolic efficacy studies that focus on complex physiologic and metabolic pathways hypothesized to respond to changes in diet or to experimental pharmacologic agents, current organizational structures would probably work much better with only minor modifications. The randomized registry trial represents a disruptive technology, a technology that transforms existing standards, procedures, and cost structures. Will it be given serious consideration as a way to resolve the recognized limitations of current clinical-trial design? Theodore Roosevelt once said, “Do what you can, with what you have, where you are.” Today we can no longer afford to undertake randomized effectiveness trials that cost tens or hundreds of millions of dollars. But today we also have registries and other powerful digital platforms. Today it may be possible to design and conduct megatrials with what we have: bigger data and smaller budgets. Yet we must also recognize and acknowledge the daunting challenges that diverse groups of researchers and stakeholders must overcome to get there. The views expressed in this article are those of the authors and do not necessarily represent the official positions of the National Heart, Lung, and Blood Institute. Dr. Lauer is the National Institutes of Health representative on the Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI); none of the views expressed here represent those of PCORI or its Methodology Committee. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. From the Office of the Director, Division of Cardiovascular Sciences, the National Heart, Lung, and Blood Institute, Bethesda, MD (M.S.L.); and the Mathematics and Statistics Department, Boston University, and the Harvard Clinical Research Institute — both in Boston (R.B.D.). This article was published on September 1, 2013, at NEJM.org. 1. Antman EM, Harrington RA. Transforming clinical trials in cardiovascular disease: mission critical for health and economic well-being. JAMA 2012;308:1743-4. 2. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000;342:1907-9. 3. Fröbert O, Lagerqvist B, Gudnason T, et al. Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE trial): a multicenter, prospective, randomized, controlled clinical registry trial based on the Swedish Angiography and Angioplasty Registry (SCAAR) platform: study design and rationale. Am Heart J 2010;160:1042-8. DOI: 10.1056/NEJMp1310102 Copyright © 2013 Massachusetts Medical Society. Smoothing the Way to High Quality, Safety, and Economy Eugene Litvak, Ph.D., and Harvey V. Fineberg, M.D., Ph.D. I n recent years, health care institutions have awakened to the need to provide safe, highquality care at lower cost. The Centers for Medicare and Medicaid Services is implementing multiple incentives and penalties intended to help realize this goal. For example, innovations designed to reduce the rate of infections associated with ventilators or central venous catheters have had demonstrated success. We believe that greater attention to a frequently overlooked param-
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission