News & Analysis Medical News & Perspectives .......p881
Lab Reports....................................p885
News From the CDC.......................p886
Clinical Trial Data: Share and Share Alike?
Cooler Temps Diminish Immune Response Against Rhinovirus in Mice
Rebuilding Haiti’s Health System
The JAMA Forum ...........................p883 Leading by Example—Health Systems Improving the Care of Employees
Alcohol Poisoning Deaths Hit Middle-Aged Men Hardest
Soil Screening Research Uncovers Promising New Antibiotic Oxytocin Restores Sociability in a Mouse Model of Autism Analysis Provides Map of Protein Expression in Human Tissues
Medical News & Perspectives
Clinical Trial Data: Share and Share Alike? Mike Mitka, MSJ
National Academies Press
A
key question for investigators conducting clinical trials has changed direction. Instead of asking why they should share data with other researchers or drug and medical device manufacturers, they’re more likely to ask how to disseminate the information. Reluctance to share data has been the norm rather than the exception, leading to fewer published clinical trial results and a dearth of independent reanalyses that could confirm original results. For example, a study of clinical trials that were completed in 2009 found only 22% complied with a mandate to report summary results on ClinicalTrials .gov within 1 year of completion (Prayle AP et al. BMJ. 2012;344:d7373). And another study looking at 37 reanalyses of data from randomized clinical trials found only 5 were performed entirely by independent authors (Ebrahim S et al. JAMA. 2014;312[10]: 1024-1032). In recent years, a number of proposals have attempted to establish rules and frameworks for data sharing. The latest set of recommendations comes from the Institute of Medicine (IOM), which earlier this year issued a preliminary report proposing standards for sharing clinical trial data (http://bit .ly/1K80N82). The IOM report comes on the heels of 2 proposals published by the Department of Health and Human Services (HHS) and the National Institutes of Health (NIH) seeking to increase transparency of clinical trials through information submitted to ClinicalTrials.gov, the publicly accessible database run by the National Library of Medicine.
The first HHS/NIH proposal would regulate registering and submitting summary results from certain clinical trials in compliance with Title VII of the Food and Drug Administration (FDA) Amendments Act of 2007. The proposed regulation would apply to legally defined clinical trials, which would include controlled, interventional studies of drugs, biological products, and devices regulated by the FDA but exclude, generally, phase 1 studies of drugs and biological products and feasibility studies of devices. The second proposal would require investigators conducting all NIH-funded clinical trials to submit summary result information to ClinicalTrials.gov regardless of the study phase, type of intervention, or
jama.com
whether they are subject to FDA registration and results submission requirements. In addition, the European Federation of Pharmaceutical Industries and Associations and the Pharmaceutical Research and Manufacturers of America implemented their own principles for responsible clinical trial data sharing in January 2014. During the same month, Johnson & Johnson agreed to partner with the Yale University Open Data Access Project (YODA). The medical equipment and supplies giant will release its pharmaceutical trial data, with subsequent availability of data from medical device and consumer product trials, to members of YODA, who have all decision-making authority over releasing the data for appropriate investigations by other researchers. Meanwhile, the European Medicines Agency is establishing standards for transparency of clinical data for trials carried out in the European Union. These new standards are tentatively to be applied to new clinical trials beginning on or after May 26, 2016.
Goals and Recommendations The IOM report is intended to establish guidelines for all interested parties who want to share clinical trial data, said Bernard Lo, MD, chair of the IOM writing committee and president of the Greenwall Foundation, which funds bioe thic s research. “There’s been a lot of movement toward the sharing of clinical trial data,” Lo said from his New York City office. Those developments created a need for some common standards, he added. “The
(Reprinted) JAMA March 3, 2015 Volume 313, Number 9
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a J H Quillen College User on 05/31/2015
881
News & Analysis
toughest part for us was deciding what specific data should be shared and at what time and with what safeguards to put in place to protect the original investigators.” The IOM report, sponsored by the NIH, the FDA, and key stakeholders, including drug and device manufacturers and research funding organizations, offers 4 recommendations: • Stakeholders in clinical trials should foster a culture of data sharing as the norm and should commit to maximizing benefits, minimizing risk, and overcoming the challenges of data sharing for all parties. • Sponsors and investigators should share the analytic data set supporting clinical trial results no later than 6 months after publication and the full analyzable data set with metadata no later than 18 months after study completion. • Holders of clinical trial data should implement operational strategies to mitigate risk and optimize benefits of sharing sensitive trial information, which would involve data use agreements, independent review panels with members of the lay public in governance, and transparent data access. • The IOM report sponsors, together with trusted impartial organizations, should convene a multistakeholder body with global reach and broad representation to address technological, sustainability, infrastructure, and workforce challenges associated with data sharing. The recommendations acknowledge that data sharing can pose risks and burdens. They include protecting trial participants’ privacy and honoring their consent, safeguarding study sponsors’ legitimate economic interests, guarding against poor secondary analyses that could diminish trust in clinical trials, providing researchers who conduct the original trials adequate time to analyze their data, and addressing research institutions’ fears that sharing data will become an unfunded requirement. “Right now sponsors bear all the cost of data sharing, and it is not sustainable or fair,” Lo said. “Those doing secondary analyses also benefit from that data and should bear some fair share of its costs.”
Why Data Sharing Matters Harlan M. Krumholz, MD, a professor of medicine at the Yale School of Medicine in New Haven, Connecticut, and director of 882
the YODA project, said he welcomes the endorsement from a mainstream organization like the IOM supporting openness and timely publication principles once ignored by researchers. But he thought the IOM could have done more. “The report failed to break new ground; it was timid toward sharing legacy data …seemingly not to offend any of the stakeholders,” Krumholz said. “A lot of what they wrote about is being done already and not in academia. The report should be considered the floor for minimum standards and not the ceiling.” Although it appears that pharmaceutical and device manufacturers would be hesitant to share data for fear of undermining their economic interests, Krumholz believes incidents with data, such as those used by Medtronic for its bone morphogenetic protein 2 (BMP-2) for spine fusion that led to marketing excesses, forced the industry to become more open. “People were losing faith in the veracity of their work, and even though they may have been doing overall excellent work, those few problems were affecting perception,” Krumholz said. “There was also the sense that it was becoming hard to attract quality researchers when those industries were being disparaged.” Academia, however, has a different story. “In academia we lack enlightened leadership, and there is no pressure to either report or publish trial results,” Krumholz said. “Obviously people want to publish, but that almost a third of trials are not published is telling you that there are some forces conspiring against transparency of results.” Krumholz was referring to a 2014 study, which found that of 400 randomly selected studies listed as “completed,” 118 (29.5%) failed to have their primary outcomes published in a journal or posted to ClinicalTrials.gov. Timeliness also is a concern. It took a median of 602 days from study completion to publication or website posting (Saito JH and Gill CJ. PLoS One. 2014; 9[7]:e101826). Christopher J. Gill, MD, MS, a coauthor of the PLoS One study and director of Boston University School of Public Health’s pharmaceuticals program, said transparency in science is essential. “There is an undeniable inconvenience for providing your data sets online, but the academic community has been burned by a slew of retracted papers,”
Gill said. “That kind of problem would be addressed by having the data sets online because having all information transparent enforces openness and vigor in the academic community.” The article by Saito and Gill highlights another important reason for clinical trial data sharing and transparency in research— the people being studied. Lo noted that participants give their time and undergo some medical risk to contribute to scientific knowledge. “A substantial number of clinical trials don’t publish their results in a reasonable period of time, and so those contributions are wasted,” he said.
Data Sharing’s Future Feasibility Although the IOM report provides a highlevel blueprint of how to approach trial data sharing, it isn’t clear how these recommendations will be put into practice. For example, open questions surround feasibility and implementation, particularly as the IOM committee concluded that existing datasharing platforms are too inefficient and expensive to meet the anticipated storage and management demands of clinical trial data should all parties comply with the recommendations. The report also raises the question of data usability, pointing out that the data must be accessible in a form that will allow investigators to easily search and computationally analyze the data sets—a need that is currently unmet, the IOM report concluded. It’s also unclear how sharing clinical trial data will benefit patients if the data languish in shared repositories. Ensuring compliance with the recommendations for clinical trial sharing presents another hurdle. The IOM report only goes so far as to outline key stakeholders’ responsibilities in fostering an expectation of data sharing that would encourage compliance. However, the recent HHS/NIH proposal could serve to provide additional incentives, because applicable clinical trials that fail to abide by FDA Amendments Act requirements could face civil penalties as high as $10 000 per day (http://1.usa.gov /1DGs0Lj). Even though clinical trial data sharing is openly acknowledged as a substantial undertaking, many agree that maximizing the benefits of shared data, while minimizing the risks, is a worthy goal. “It’s a new way of thinking of how you conduct clinical trials,” Lo said.
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a J H Quillen College User on 05/31/2015
jama.com
Lab Reports....................................p885
News From the CDC.......................p886
Clinical Trial Data: Share and Share Alike?
Cooler Temps Diminish Immune Response Against Rhinovirus in Mice
Rebuilding Haiti’s Health System
The JAMA Forum ...........................p883 Leading by Example—Health Systems Improving the Care of Employees
Alcohol Poisoning Deaths Hit Middle-Aged Men Hardest
Soil Screening Research Uncovers Promising New Antibiotic Oxytocin Restores Sociability in a Mouse Model of Autism Analysis Provides Map of Protein Expression in Human Tissues
Medical News & Perspectives
Clinical Trial Data: Share and Share Alike? Mike Mitka, MSJ
National Academies Press
A
key question for investigators conducting clinical trials has changed direction. Instead of asking why they should share data with other researchers or drug and medical device manufacturers, they’re more likely to ask how to disseminate the information. Reluctance to share data has been the norm rather than the exception, leading to fewer published clinical trial results and a dearth of independent reanalyses that could confirm original results. For example, a study of clinical trials that were completed in 2009 found only 22% complied with a mandate to report summary results on ClinicalTrials .gov within 1 year of completion (Prayle AP et al. BMJ. 2012;344:d7373). And another study looking at 37 reanalyses of data from randomized clinical trials found only 5 were performed entirely by independent authors (Ebrahim S et al. JAMA. 2014;312[10]: 1024-1032). In recent years, a number of proposals have attempted to establish rules and frameworks for data sharing. The latest set of recommendations comes from the Institute of Medicine (IOM), which earlier this year issued a preliminary report proposing standards for sharing clinical trial data (http://bit .ly/1K80N82). The IOM report comes on the heels of 2 proposals published by the Department of Health and Human Services (HHS) and the National Institutes of Health (NIH) seeking to increase transparency of clinical trials through information submitted to ClinicalTrials.gov, the publicly accessible database run by the National Library of Medicine.
The first HHS/NIH proposal would regulate registering and submitting summary results from certain clinical trials in compliance with Title VII of the Food and Drug Administration (FDA) Amendments Act of 2007. The proposed regulation would apply to legally defined clinical trials, which would include controlled, interventional studies of drugs, biological products, and devices regulated by the FDA but exclude, generally, phase 1 studies of drugs and biological products and feasibility studies of devices. The second proposal would require investigators conducting all NIH-funded clinical trials to submit summary result information to ClinicalTrials.gov regardless of the study phase, type of intervention, or
jama.com
whether they are subject to FDA registration and results submission requirements. In addition, the European Federation of Pharmaceutical Industries and Associations and the Pharmaceutical Research and Manufacturers of America implemented their own principles for responsible clinical trial data sharing in January 2014. During the same month, Johnson & Johnson agreed to partner with the Yale University Open Data Access Project (YODA). The medical equipment and supplies giant will release its pharmaceutical trial data, with subsequent availability of data from medical device and consumer product trials, to members of YODA, who have all decision-making authority over releasing the data for appropriate investigations by other researchers. Meanwhile, the European Medicines Agency is establishing standards for transparency of clinical data for trials carried out in the European Union. These new standards are tentatively to be applied to new clinical trials beginning on or after May 26, 2016.
Goals and Recommendations The IOM report is intended to establish guidelines for all interested parties who want to share clinical trial data, said Bernard Lo, MD, chair of the IOM writing committee and president of the Greenwall Foundation, which funds bioe thic s research. “There’s been a lot of movement toward the sharing of clinical trial data,” Lo said from his New York City office. Those developments created a need for some common standards, he added. “The
(Reprinted) JAMA March 3, 2015 Volume 313, Number 9
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a J H Quillen College User on 05/31/2015
881
News & Analysis
toughest part for us was deciding what specific data should be shared and at what time and with what safeguards to put in place to protect the original investigators.” The IOM report, sponsored by the NIH, the FDA, and key stakeholders, including drug and device manufacturers and research funding organizations, offers 4 recommendations: • Stakeholders in clinical trials should foster a culture of data sharing as the norm and should commit to maximizing benefits, minimizing risk, and overcoming the challenges of data sharing for all parties. • Sponsors and investigators should share the analytic data set supporting clinical trial results no later than 6 months after publication and the full analyzable data set with metadata no later than 18 months after study completion. • Holders of clinical trial data should implement operational strategies to mitigate risk and optimize benefits of sharing sensitive trial information, which would involve data use agreements, independent review panels with members of the lay public in governance, and transparent data access. • The IOM report sponsors, together with trusted impartial organizations, should convene a multistakeholder body with global reach and broad representation to address technological, sustainability, infrastructure, and workforce challenges associated with data sharing. The recommendations acknowledge that data sharing can pose risks and burdens. They include protecting trial participants’ privacy and honoring their consent, safeguarding study sponsors’ legitimate economic interests, guarding against poor secondary analyses that could diminish trust in clinical trials, providing researchers who conduct the original trials adequate time to analyze their data, and addressing research institutions’ fears that sharing data will become an unfunded requirement. “Right now sponsors bear all the cost of data sharing, and it is not sustainable or fair,” Lo said. “Those doing secondary analyses also benefit from that data and should bear some fair share of its costs.”
Why Data Sharing Matters Harlan M. Krumholz, MD, a professor of medicine at the Yale School of Medicine in New Haven, Connecticut, and director of 882
the YODA project, said he welcomes the endorsement from a mainstream organization like the IOM supporting openness and timely publication principles once ignored by researchers. But he thought the IOM could have done more. “The report failed to break new ground; it was timid toward sharing legacy data …seemingly not to offend any of the stakeholders,” Krumholz said. “A lot of what they wrote about is being done already and not in academia. The report should be considered the floor for minimum standards and not the ceiling.” Although it appears that pharmaceutical and device manufacturers would be hesitant to share data for fear of undermining their economic interests, Krumholz believes incidents with data, such as those used by Medtronic for its bone morphogenetic protein 2 (BMP-2) for spine fusion that led to marketing excesses, forced the industry to become more open. “People were losing faith in the veracity of their work, and even though they may have been doing overall excellent work, those few problems were affecting perception,” Krumholz said. “There was also the sense that it was becoming hard to attract quality researchers when those industries were being disparaged.” Academia, however, has a different story. “In academia we lack enlightened leadership, and there is no pressure to either report or publish trial results,” Krumholz said. “Obviously people want to publish, but that almost a third of trials are not published is telling you that there are some forces conspiring against transparency of results.” Krumholz was referring to a 2014 study, which found that of 400 randomly selected studies listed as “completed,” 118 (29.5%) failed to have their primary outcomes published in a journal or posted to ClinicalTrials.gov. Timeliness also is a concern. It took a median of 602 days from study completion to publication or website posting (Saito JH and Gill CJ. PLoS One. 2014; 9[7]:e101826). Christopher J. Gill, MD, MS, a coauthor of the PLoS One study and director of Boston University School of Public Health’s pharmaceuticals program, said transparency in science is essential. “There is an undeniable inconvenience for providing your data sets online, but the academic community has been burned by a slew of retracted papers,”
Gill said. “That kind of problem would be addressed by having the data sets online because having all information transparent enforces openness and vigor in the academic community.” The article by Saito and Gill highlights another important reason for clinical trial data sharing and transparency in research— the people being studied. Lo noted that participants give their time and undergo some medical risk to contribute to scientific knowledge. “A substantial number of clinical trials don’t publish their results in a reasonable period of time, and so those contributions are wasted,” he said.
Data Sharing’s Future Feasibility Although the IOM report provides a highlevel blueprint of how to approach trial data sharing, it isn’t clear how these recommendations will be put into practice. For example, open questions surround feasibility and implementation, particularly as the IOM committee concluded that existing datasharing platforms are too inefficient and expensive to meet the anticipated storage and management demands of clinical trial data should all parties comply with the recommendations. The report also raises the question of data usability, pointing out that the data must be accessible in a form that will allow investigators to easily search and computationally analyze the data sets—a need that is currently unmet, the IOM report concluded. It’s also unclear how sharing clinical trial data will benefit patients if the data languish in shared repositories. Ensuring compliance with the recommendations for clinical trial sharing presents another hurdle. The IOM report only goes so far as to outline key stakeholders’ responsibilities in fostering an expectation of data sharing that would encourage compliance. However, the recent HHS/NIH proposal could serve to provide additional incentives, because applicable clinical trials that fail to abide by FDA Amendments Act requirements could face civil penalties as high as $10 000 per day (http://1.usa.gov /1DGs0Lj). Even though clinical trial data sharing is openly acknowledged as a substantial undertaking, many agree that maximizing the benefits of shared data, while minimizing the risks, is a worthy goal. “It’s a new way of thinking of how you conduct clinical trials,” Lo said.
JAMA March 3, 2015 Volume 313, Number 9 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a J H Quillen College User on 05/31/2015
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