Evolution of Translational Omics Lessons Learned and the Path Forward (2012) / Chapter Skim
Currently Skimming:
5 Responsible Parties
5 Responsible Parties
Pages 105-162
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From page 105... ...
; all new drugs must demonstrate clinical utility in well-designed clinical trials to gain FDA approval. Thus, those responsible for the integrity of omics research -- investigators, institutions, funders, FDA, and journals -- should rethink the processes and protections designed to ensure that omics research is scientifically rigorous, transparent, and conducted ethically, with proper institutional and regulatory oversight.
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The committee recognized that the recommendations presented in this chapter may increase the oversight requirements for omics research in some cases, but decided that these potential costs were offset by the added safeguards to the integrity of this research. If an institution does not have the infrastructure or capability to follow the recommended Test Development and Evaluation Process defined in this report, then the committee believes that the institution should consider not engaging in the translation of omics-based discoveries into validated tests for use in clinical trials and potentially clinical practice.
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Institutions and the institutional leadership, on the other hand, have the primary responsibility for the policies and procedures, reward systems, and values that contribute to the overarching institutional culture as well as for the infrastructure of oversight and support for research. Institutions and their leaders also have the greatest responsibility for in-depth investigation of potential lapses in scientific integrity because they employ, promote, and supervise the investigators who conduct these studies.
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. This situation is problematic because the underlying science must be sound if patients are going to participate in clinical trials and, eventually, in consultation with their physicians, use research results for medical care decisions.
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Dr. Joseph Nevins, senior mentor of the investigators whose genomic predictors were used in the three clinical trials named in the IOM committee's statement of task, stated during discussions with the committee that "a critical flaw in the research effort was one of data corruption" (Nevins, 2011)
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The authoring committee directed individual investigators to accept formal responsibility for ensuring the integrity of the research process and creating an environment, a reward system, and a training system that encourage responsible research practices. A more recent National Academies report, On Being a Scientist: A Guide to Responsible Conduct in Research (NAS, 2009)
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All members of the research team, including biostatisticians and bioinformatics scientists, should have access to mentors with the appropriate expertise and credentials. Senior investigators' conduct can reinforce or weaken the importance of complying with these scientific norms and values.
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They are responsible for reading the complete manuscript, suggesting edits, and for being alert to misinterpretation, such as misrepresentation of findings and limitations, and discussing such observations with appropriate members of the team or oversight groups. Data and Code Availability and Transparency The scientific community widely agrees that investigators should make the research data and code supporting a manuscript, as well as the statistical analysis plan that had been finalized before data were unblinded and available for analysis, publicly available at the time of publication (NAS, 1992, 2009; NRC, 1985, 2003)
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The National Academies has issued numerous reports emphasizing the importance of data sharing. Sharing Research Data recommended that sharing research data at the time of publication should be a regular practice in science (NRC, 1985)
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. Vickers also referenced a survey conducted by John Kirwan of the University of Bristol on investigators' attitudes toward sharing data from clinical trials.
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. Institutions and Institutional Leaders This section describes the roles and responsibilities for institutions that conduct biomedical omics research aimed at improving patient care, including: fostering a culture of scientific integrity, overseeing research, increasing awareness of reporting systems for lapses in research integrity, investigating credible concerns about scientific integrity, monitoring and managing financial and non-financial conflicts of interest, and supporting and protecting the intellectual independence of biostatisticians, bioinformatics scientists, pathologists, and other collaborators in omics research.
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, the trials were initiated using omics-based tests that were not "locked down" or properly validated and turned out to be unreliable. Three years later, the Duke IRB initiated an investigation of the three clinical trials based on the concerns of the National Cancer Institute and external statisticians.
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In response to this situation, the university formed the Translational Medicine Quality Framework Committee to make recommendations to university leadership on appropriate oversight policies for omics research being tested in clinical trials (TMQF Committee, 2011)
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Moreover, omics-based test development sweeps across basic research, translational research, clinical research, and regulatory requirements for clinical applications. Although there is no guidebook detailing exactly what steps and actions institutions should implement to encourage good behavior, a recent NRC (2002)
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• cientific Review Boards: Evaluate the science underlying an intervention or S test proposed for assessment in a clinical trial • ata and Safety Monitoring Boards (also called Data Monitoring Commit D tees) : Independently monitor clinical trials to ensure the continuing safety of human subjects and the validity and integrity of the data • onflict of Interest Committees: Review individuals' and institutions' possible C conflicts of interest
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. Given the complexity of omics research and omics-based tests, the multidisciplinary nature of omics and research, and the potential for conflicts of interest in developing and evaluating tests for clinical use, institutional leaders should pay heightened attention to providing appropriate oversight and promoting a culture of scientific integrity and transparency (Recommendation 4b)
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Rather, various data management strategies are often developed locally by basic omics research groups where quality control and data integrity and security are not optimal. However, there are commercial software systems that can provide such data management security requirements, and institutions can readily purchase a system that is used by a central data management office for any omics research that is intended to lead to a product for clinical use, and, thus, should go through a rigorous clinical evaluation such as a randomized clinical trial.
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. Thus, the committee recommends that institutional leaders designate an institutional official who is responsible for comprehensive and timely documentation, disclosure, and management of financial and non-financial conflicts of interest, both individual and institutional (Recommendation 4[b]
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conducting an investigation into credible concerns about scientific integrity. The National Academies has stated that whistleblowing can be valuable in preserving the integrity of the research process and should be supported by the entire research community (NAS, 1992)
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Thus, the committee recommends that institutional leaders designate an institutional official who is responsible for establishing and managing a
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. Ultimately, these decisions depend on the circumstances of each case and require careful attention and judgment by the institutional leadership.
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This section emphasizes the important role that biostatisticians, bioinformatics scientists, and pathologists play in omics research. However, many of the issues discussed below apply more broadly to the various collaborators who are involved in omics research and test development, including experts in omics technology and clinical trials.
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Thus, the committee recommends that institutions that conduct biomedical omics research, including test development and clinical trials, should train, recognize, and support the faculty-level careers of individuals from the multiple collaborating disciplines, including biostatistics, bioinformatics, pathology, omics technologies, and clinical trialists (Recommendation 4c)
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The committee also recommends that institutions ensure that biostatisticians, bioinformatics scientists, pathologists, and individuals from the other multiple disciplines that collaborate in omics research are represented on all relevant review and oversight bodies within the institutions (Recommendation 4[c]
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The committee recommends that institutions ensure that individuals from the multiple disciplines that collaborate on omics research and test development are intellectually independent, preferably reporting to an independent mentor and/or department chair as well as to the project leader (Recommendation 4[c]
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. In omics research, whether funded by a federal or non-federal entity, it is important that the peer review process involve biostatisticians and bioinformatics scientists who can assess the research methods, including the quality of complex biomarker trial designs if necessary, and the proposed data collection and analysis plans (see discussion on biostatistics/ bioinformatics in the institutions section above)
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It is unclear whether the other funders of the clinical trials had similar policies in place, but it is clear that, where such policies exist, funders face a challenge in overseeing compliance with them. In 2009, NCI contacted Duke regarding its concerns about the validity of the omics-based tests being used in the three clinical trials named in the IOM statement of task.
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. Thus, privately funded omics studies that are not clinical trials are not included in either of these repositories.
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. The committee recommends that funders require investigators to make all data, metadata, prespecified analysis plans, computer code, and fully specified computational procedures publicly available and readily interpretable either at the time of publication or, if not published, at the end of funding, and funders should financially support this requirement (Recommendation 5[a]
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All data, metadata, prespecified analysis plans, code, and fully specified computational models of the independent study should again be made publicly available either at the time of publication or at the end of funding, and funders should financially support this requirement (Recommendation 5a above)
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Funding institutions may need to set aside a small fund to support investigations of serious allegations. In the case of the Duke clinical trials evaluating omics-based tests, funding came from multiple sources including NCI and the Department of Defense (DOD)
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Laboratories that provide LDT services are regulated by CMS under the Clinical Laboratory Improvement Amendments6 (CLIA) to ensure the quality of the laboratory testing services.
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. However, in retrospect, the Duke IRB recog nized that an IDE should have been obtained for the omics-based tests because the tests were used to direct patient management in the clinical trials (FDA, 2011b)
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ePersonal communication, Lisa McShane, National Cancer Institute, February 9, 2012. developed tests (Recommendation 6a)
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Communication of IDE Requirements The committee recommends that FDA communicate the IDE requirements for use of omics-based tests in clinical trials to the Office of Human Research Protections (OHRP) , IRBs, and other relevant institutional leadership (Recommendation 6b)
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. Specific policies may include requiring registration of clinical trials involving omics-based tests in www.clinicaltrials.gov; ensuring data and code availability; protecting the scientific integrity of published research; and developing a process to respond to significant scientific concerns.
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However, the committee did not explore the roles and responsibilities of journals in these case studies because of the lack of publicly available information and limited resources. NOTE: See Appendixes A and B on the case studies for more information.
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. Trial Registration The FDA Modernization Act of 1997 created www.clinicaltrials.gov to increase the transparency of clinical trials.
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Thus, the committee recommends that journal editors require authors who submit manuscripts describing clinical evaluations of omics-based tests to register all clinical trials at www.clinicaltrials.gov or another clinical trial registry acceptable to the journal (Recommendation 7[a]
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written descriptions of any nonscriptable analysis steps, and (5) the prespecified analysis plans (Baggerly and Coombes, 2011)
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The committee recommends that journal editors require authors who submit manuscripts describing clinical evaluations of omics-based tests to BOX 5-8 Lessons from the Banking Industry on Data and Code Sharing The Journal of Money, Credit, and Banking instituted a policy in 1982-1984 requiring authors to submit the data and code supporting their manuscripts to the journal. Despite this policy, investigators showed that the majority of the published studies could not be replicated with the data and code provided.
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However, at a minimum, these documents should specify the research questions being addressed, primary outcomes of interest, and the data analysis strategy. Previous statements made by organizations about the benefits of journal editors requiring authors to submit their research protocols for clinical trials with their manuscripts have had little impact on journals' practices (Korn and Ehringhaus, 2006)
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. Journal editors also can institute policies that enforce the authors' responsibility for the scientific integrity of the manuscript.
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. In addition, the committee recommends that journal editors should require authors who submit manuscripts describing clinical evaluations of omics-based tests to use appropriate reporting guidelines (e.g., the Consolidated Standards of Reporting Trials [CONSORT]
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Journal editors also could invite peer-reviewed commentaries or editorials that are linked to the key primary articles in PubMed. The committee also recommends that journals alert the institutional leadership and all authors when a serious question of accuracy or integrity has been raised (Recommendation 7c)
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While this may reduce the number of clinically oriented studies and publications in omics research, if the end result is higher-quality publications, this would be a positive change, given the limited resources for research. RECOMMENDATION 4: Institutions 4a: Institutions are responsible for establishing, supporting, and over seeing the infrastructure and research processes for omics-based test development and evaluation as well as best practices for clini cal trials and observational research, including those incorporating omics technologies, and should assure that the evaluation process outlined in this report is followed for omics-based test development and evaluation at their institution.
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FDA should take steps to improve understanding of regulatory requirements for omics-based tests, by directly communicating with investigators and academic institutions and by developing a guidance or regulation that spells out the relevant requirements in this dynamic field. Finally, the responsibilities of journal editors with respect to the adoption and adherence to the omics-based test development and evaluation process are complicated by the wide spectrum of policies adopted and resources available to individual journals.
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6b: FDA should communicate the IDE requirements for use of omics based tests in clinical trials to the OHRP, IRBs, and other relevant institutional leadership. RECOMMENDATION 7: Journals 7: Journal editors should: 7a: Require authors who submit manuscripts describing clinical evalu ations of omics-based tests to: i.
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7c: Alert the institutional leadership and all authors when a serious question of accuracy or integrity has been raised. REFERENCES ACS (American Cancer Society)
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Presented at the Workshop of the IOM Com mittee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC, March 30-31. Baggerly, K
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2011a. Discussion at the Workshop of the IOM Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC, March 30-31.
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A statement from the International Committee of Medical Journal Editors. Journal of the American Medical Association 293(23)
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2010. Clinical trials: Discerning hype from substance.
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2010a. NCI Address to the Institute of Medicine Committee on the Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials.
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NCI Address to Institute of Medicine Committee Con vened to Review Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials. Meeting 1: Review of Omics-Based Tests for Predicting Patient Outcomes in Clinical Trials, Washington, DC.
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2003. CRC clinical trials management system (CTMS)
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Controlled Clinical Trials 21(5)
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2008. Moving toward transparency of clinical trials.
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