ClinicalTrials.gov Reporting: Strategies for Success at an Academic Health Center Erin K. O’Reilly, Ph.D., R.A.C.1,2, Nancy J. Hassell, C.C.R.P.3, Denise C. Snyder, M.S., R.D.2,4, Susan Natoli, M.S.W., C.C.R.P.2,4, Irwin Liu, Ph.D.2,5,6, Jackie Rimmler, M.S.2,5, Valerie Amspacher, B.S.1,2, Bruce K. Burnett, Ph.D., R.A.C.1,2, Amanda B. Parrish, Ph.D. R.A.C.1,2, Jelena P. Berglund, Ph.D., R.A.C.1,2, and Mark Stacy, M.D.2,7
Abstract The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials. Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training, and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation. Clin Trans Sci 2015; Volume 8: 48–51.
Keywords: trials registration, trials reporting, FDAAA 2007, ClinicalTrials.gov, applicable clinical trial Introduction
Examples of selective publication bias historically made the case for clinical trials registries,1 and led to the posting of the Clinical Trials Data Bank (http://clinicaltrials.gov) in February 2000 in response to the Food and Drug Administration Modernization Act of 1997 (FDAMA). Section 113 of FDAMA required the establishment of a registry for clinical trials of experimental treatments (drug and biological) for patients with serious or life-threatening diseases or conditions. Since then, the registry has been widely expanded to accommodate the requirements of FDAAA 2007. Specifically, section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 2007) broadened the type of trials that required registration to all “applicable clinical trials” (ACTs) and identified the “Responsible Party” as the entity that must register the trial.2 In addition, FDAAA 2007 required the entry of results for certain ACTs. The timelines established by FDAAA 2007 required ongoing ACTs to be registered by the end of 2007 and basic results reporting capability was available beginning 2008.* Built into the law are financial incentives for compliance in the form of fines, civil penalties and funding guarantees. For trials out of compliance, there can be an initial $10,000 fine followed by another $10,000 per day if the violation is not corrected within 30 days. Although these fines have yet to be imposed, they could add up to substantial amounts. In addition, National Institutes of Health (NIH) grantees must submit a “certification of compliance” in all grant applications and progress reports.3 The release of NIH funding is dependent upon grantees being current with registration and reporting requirements. Penalties for noncompliance may include the withholding or recovery of grant funds. Besides the legal and funding requirements described above, there are also requirements to be considered for publication. In 2004, the International Committee of Medical Journal Editors *
(ICMJE) incorporated the requirement for registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication.4,5 While only 14 journals are official members of the ICMJE, over 1,600 other medical journals have purportedly committed to follow ICMJE recommendations.6 Finally, in addition to legal, funding, and publication considerations, mandatory inclusion of the NCT number on Medicare claims for routine costs of qualifying clinical trials became effective as of January 2014. Thus, studies that would not require registration per FDAAA may require registration for Centers for Medicare and Medicaid Services (CMS) billing purposes.7 Despite these laws and the potential for penalties, meeting these requirements has proven to be a challenge for the research community, especially for results reporting. As of January 2011, only 22% of registered ACTs met requirements with industry funded trials (40%) more likely to report results than nonindustry funded trials (8%).8 Duke University Medical Center has created an institutional policy and developed systems to assist the research community with meeting trials disclosure obligations. The timeline and high-level steps taken are depicted in Figure 1. This manuscript will review the policies and operational plan that improved investigator compliance with these federal requirements. We hope that sharing our plan may assist other Academic Health Centers with implementing similar measures. Duke Task Force Leads Compliance Initiative
As a member of the Clinical and Translational Science Award (CTSA) program, Duke Medicine was included in a “Results Database Train the Trainer” workshop at the National Library
Results for ACTs results must be entered within 1 year of the primary completion date of the study.
Duke Translational Medicine Institute, Regulatory Affairs Office, Durham, North Carolina, USA ; 2Duke University School of Medicine, Durham, North Carolina, USA ; 3Duke University School of Nursing , Durham, North Carolina, USA ; 4Duke Office of Clinical Research, Durham, North Carolina, USA ; 5Duke Cancer Institute, Durham, North Carolina, USA ; 6Seattle Cancer Care Alliance (current) , Seattle, Washington, USA ; 7Duke Department of Neurology, Durham, North Carolina, USA .
1
Correspondence: Erin O’Reilly ([email protected]) DOI: 10.1111/cts.12235
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Figure 1. Timeline for improving trials disclosure compliance.
of Medicine (NLM) in Bethesda, MD, in 2012. Topics included results entry and strategies for compliance. When workshop participants returned to campus and shared the knowledge gained, the need to support clinical researchers to achieve compliance with the regulatory requirements of FDAMA and FDAAA, as well as the publishing requirements of ICMJE was recognized. To kick-start the process, the Duke Clinical Trials Disclosure Task Force was formed. The Task Force was composed of representatives from the School of Medicine, Office of Clinical Research, Office of Regulatory Affairs, and the Cancer Institute. Their mandate was to assess the current state of compliance, formulate a plan to address any noncompliance, and develop standardized policies and processes to ensure ongoing compliance. The Task Force determined the following steps were critical to successful, institution-wide compliance: assessment of the current state of compliance; policy development, implementation and enforcement; training; auditing; annual reassessment; and creation of a centralized resource for implementation. Each step will be further described below within the context of resources required and lessons learned. Assessment of current compliance began with pulling error reports for registrations associated with the Duke Medicine account from the ClinicalTrials.gov protocol registration system (PRS). Additionally, the Duke research informatics group accessed data from the Duke electronic Institutional Review Board (eIRB) data repository to query a list of principal investigator (PI)initiated studies requiring review for compliance. Initial error reports highlighting registration problems and records with late results were presented to the Task Force. The error reports were divided and submitted to Clinical Research Units (CRUs)** for action. The CRUs were provided target dates for cleaning
up assigned records. These early error reports contained the following minimal information: NCT Number, ClinicalTrials.gov problem term, IRB number, IRB status, brief title of study, record owner name, current status, date of latest record verification, date of latest record update, and CRU name. Initially, the CRUs were updated on a weekly basis, to better monitor progress. Assistance was offered to teams by members of the Task Force as well as newly hired staff. Any problems with staff not responding to the error reports were escalated to the Associate and Vice Deans for Clinical Research, both active members of the Task Force. In the meantime, the Duke Office of Clinical Research (DOCR), a central administrative office within the School of Medicine, authored a clinical trials disclosure policy that would apply to all of Duke Medicine. The initial policy draft was circulated among Task Force members and forwarded to the School of Medicine compliance office for additional review and finalization. The policy, adopted by the School of Medicine, outlines requirements, provides a framework for compliance and support, and addresses consequences of noncompliance, including registration on ClinicalTrials.gov as a requirement prior to institutional study approval for ACTs. Training and awareness began with the hiring of additional staff, enabling an initial base of subject matter experts devoted solely to clinical trials disclosure and ClinicalTrials.gov. This centralized resource, consisting of three full time staff members, focused on informing the research community of laws and guidelines related to clinical trials disclosure. Initial training and reinforcement awareness occurred through a variety of venues to ensure optimal understanding and adoption. These included oneon-one meetings with PIs and research staff, educational outreach presentations to the research community and each CRU, newsletter
**CRUs are the organizational and functional structures that provide oversight for clinical research at Duke Medicine. Each CRU is composed of one or more Departments or Institutes. The CRU is the operating business unit responsible for the integrity, financial accountability, regulatory compliance, quality, and academic productivity of clinical research studies. Examples of CRUs at Duke include medicine, oncology, psychiatry, surgery, and pediatrics.
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articles, and development of hands on workshops for university and core groups. These “hands on” workshops allow Duke Staff to practice results entry skills and are offered quarterly to the Duke research community. This centralized resource is now responsible for auditing and annual reassessment steps. Currently, these roles include: assisting with daily monitoring of ClinicalTrials.gov regarding new study registration; registration and results reporting review; maintaining a training and education program; handling questions from research teams; reviewing problem reports and communications; maintaining escalation procedures for noncompliance; as well as writing policies and procedures for integrating reviews and notifications upon eIRB submission. Currently, monthly problem reports are sent to each CRU. Each problem record is reviewed by the centralized staff, and specific instructions are provided concerning outstanding compliance needs. In total, these reports contain the following information: priority status (length of time on report), a detailed description of action required, ClinicalTrials.gov problem term, study identification number (this is the same as the IRB number at Duke), record owner name, principal investigator name, study coordinator name, department, division and CRU name. In addition, a REDCap database is now used to combine record status and primary completion dates to generate proactive reports which identify upcoming results reporting and record verification due dates. While DOCR is responsible for establishing the policy, ongoing monitoring, and tools/training for the ClinicalTrials.gov process, the CRUs at Duke are responsible for overseeing research portfolio activity and are the vehicle for dissemination to their research teams. Reports combining eIRB data and ClinicalTrials. gov system have enabled a successful rollout to 16 CRUs. The CRUs hold the closest relationship with study teams and work in partnership with DOCR to achieve compliance with the law. The centralized DOCR group provides the “how to” subject matter expertise and assistance as needed. The CRUs provide the “connection” between DOCR and the research teams. This synergy encourages open dialogue, support, and communication when questions arise. Reports are issued to teams on a consistent schedule and DOCR is responsive to study team inquiries and requests for assistance. It is the culmination of these ongoing efforts that ensures the work is completed. In order to control institutional compliance risks, Duke Medicine acts as the Responsible Party for all records at Duke with the exception of individual IND/IDE holders. However, the principal investigator is held responsible for the content of their study records. Investigators are given access to records along with anyone they delegate from a study team, and are responsible for entering study-specific information and for maintaining the records. The centralized DOCR staff can review the records, make administrative changes, and assist the research team in many ways including direct assistance with results entry. Any institution will still have some compliance issues and the consequences at Duke for noncompliance are simple yet effective. Initially, IRB and institutional approval for ACTs is withheld until the study is registered. For ongoing noncompliance issues with existing records, such as overdue results or record verifications, all new research associated with that particular investigator can be halted during the institutional review process. Finally, the Vice Dean for Clinical Research and the Chief Compliance Officer can be consulted for a collaborative decision regarding whether an investigator should be administratively suspended from conducting clinical research. 50
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Category
Average monthly number
New studies submitted to the eIRB that require qualifying trial assessment
103
PI initiated studies submitted to the eIRB that require ACT assessment*
55
New Duke Medicine study records created at ClinicalTrials.gov
13
Newly entered records projected to require future results reporting
4
Changes to PRS records that require review and release†
105
*This average number (55) is a subset of the total monthly average of new studies submitted to the eIRB (103). † This number does not include records released by IND/IDE holders. In those cases, the individual investigator serving as the Responsible Party acts to review and release the records.
Table 1. Metrics of records handled by the centralized resource group.
Return on Investment
The creation of a centralized resource with three full time staff members represents a large commitment from an institutional perspective. Table 1 shows the workload handled by the DOCR centralized resource group. Since the formation of the group, the number of Duke Medicine records appearing on problem reports as well as those identified as being late for results reporting has decreased almost fivefold (specific data not shown). In addition to increasing record compliance, this centralized resource group has allowed Duke Medicine to quickly implement changes to accommodate the new CMS requirements enforced as of January 2014. Communication pathways were swiftly developed to link clinical trials billing and research teams. There is now a process whereby qualifying trial status is determined prior to granting institutional approval. For studies deemed qualifying trials, institutional approval is held until an NCT number is obtained. To ensure CMS reimbursement, NCT numbers are entered in the eIRB, which is accessible by the clinical trials billing office. Conclusion
Due to implementation of the institutional policy and creation of the centralized resource, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. This centralized approach proved essential for having the proper resources available to meet the ongoing requirements of FDAAA 2007 as well as the new CMS billing requirements. We believe a consistent centralized approach will ensure success in the face of changing agency rules and new legislation. Formal regulations for the implementation of Section 801 of FDAAA 2007 are still in development,9,10 and Duke Medicine can more easily adapt to any changes these regulations may bring because of the centralized approach. Feature: ClinicalTrials.gov—The Duke Cancer Institute (DCI) Experience
Academic cancer centers face considerable pressures to comply with numerous clinical trial disclosure requirements, including those described in ICMJE, FDAMA, and FDAAA. Consistent with this view, oncology trials constitute the largest clinical discipline across all ClinicalTrials.gov registrations.11 Likewise, oncology trials comprise the largest subset of ClinicalTrials. WWW.CTSJOURNAL.COM
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gov registrations within Duke Medicine. Given the volume and inherent complexity of oncology trials, academic cancer centers must commit significant resources to ensure compliance with trial disclosure requirements. The DCI receives National Cancer Institute (NCI) funding through the P30 Cancer Center Support Grant (CCSG) to build and support clinical research infrastructure. Using this infrastructure, the DCI had considered taking full responsibility for ClinicalTrials. gov oversight of cancer-specific studies. However, the DCI chose to partner with and follow the lead of the centralized resource group due to the high level of administrative oversight and operational coordination required by ClinicalTrials.gov compliance efforts. This partnership ensured more optimal, efficient, and uniform oversight of ClinicalTrials.gov requirements. To date, DCI investigators and study teams have utilized and benefited from the centralized resource group. Here, we highlight how the DCI’s CCSG-based infrastructure has been leveraged to provide additional awareness and support of ClinicalTrials.gov registrations and results reporting. Protocol review and monitoring system (PRMS) A required component of the CCSG, the PRMS assures adequate internal oversight of the scientific aspects of all oncology clinical trials. During scientific review of ACTs, the PRMS evaluates the necessity of protocol primary and secondary objectives. FDAAA requires results reporting on all primary and secondary objectives for ACTs in which the study product is approved, or within 30 days of product approval. Since this is a highly labor-intensive effort, the PRMS may advise the investigator to weigh the benefits and drawbacks of certain primary or secondary objectives. Also, staff within the PRMS help broaden the educational outreach efforts of the DOCR centralized resource group. PRMS staff host various educational and communication forums to generate more awareness about ClinicalTrials.gov requirements within the oncology clinical research community. Biostatistics shared resource The DCI is organized into 11 disease-based groups, each with biostatistical support that is subsidized by the DCI and CCSG. Given the intensive data and analytic effort required during ClinicalTrials.gov results reporting, these biostatisticians have been essential to accurate reporting of required data. Additionally, as biostatisticians have become more aware of the implications of ClinicalTrials.gov requirements, they have become more proactive about discussing ClinicalTrials.gov considerations during clinical trial design and database creation. Some have even created Microsoft Excel–based tools to simplify the transfer of data for all required elements of ClinicalTrials.gov reporting. Clinical protocol and data management (CPDM) The CPDM system, another required component of the CCSG, provides central management and oversight functions for coordinating, facilitating, and reporting on oncology clinical trials. The DCI employs a Clinical Research Analyst (CRA) who helps maintain the CPDM system, provides ClinicalTrials.gov support, and performs day-to-day functions for the NCI’s Clinical Trials Reporting Program (CTRP), which requires collection of trial data that are similar but not identical to ClinicalTrials.gov trial data. The CRA is positioned to serve four key functions. First, the CRA functions as the primary liaison to the centralized resource group. The CRA understands the unique organizational
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structure of the DCI and facilitates the workflow of the centralized resource group. Second, the CRA is familiar with characteristics of the DCI trial portfolio databases and is positioned to update these databases in order to track ClinicalTrials.gov registrations. Third, the CRA facilitates interactions between the PI, study team, and biostatisticians to help define “best practice” in efforts devoted to ClinicalTrials.gov compliance. Fourth, the CRA has created tools and templates to aid study teams in creation of ClinicalTrials.gov registrations and results reports. In summary, the Duke experience suggests that ClinicalTrials. gov compliance is a priority requiring institution-wide oversight and collaboration. The DCI has benefited from additional ClinicalTrials.gov support due to CCSG-based infrastructure. Other NCI-designated academic cancer centers may consider whether such infrastructure can support their ClinicalTrials.gov compliance needs within unique organizational contexts. Acknowledgments
This paper was supported by the National Center for Advancing Translational Science of the NIH through Grant No. UL1TR001117. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors acknowledge the contributions of Leigh A. Burgess, M.H.A., M.Ed., M.A., Vijaya Chadaram, R.N., M.S.N., C.C.R.P., Lorna N. Dula, Jessica Houlihan, and Bonnie Vernarelli R.N., M.S.N., M.B.A., who participated as active members of the Task Force. Conflict of Interest
B. K. Burnett declares that his spouse has equity of more than $10,000 in Biogen Idec, a pharmaceutical company. Also his spouse has an income of more than $10,000 from Biogen Idec, a pharmaceutical company. J. P. Berglund declares that her spouse has equity of more than $10,000 in both Liquidia Technologies and Immune Design. Also her spouse has a income of more than $10,000 from Immune Design. References 1. Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol. 1986; 4(10): 1529–1541. 2. National Institutes of Health. Elaboration of Definitions of Responsible Party and Applicable Clinical Trial. Available at: http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf. Published Mar 9, 2009. Accessed September 10, 2014. 3. National Institutes of Health Implementation of FDAAA – FDAAA Requirements for NIH Grantees At-A-Glance. National Institutes of Health Office of Extramural Research Web site. Available at: http:// grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm. Updated 2011. Accessed September 10, 2014. 4. International Committee of Medical Journal Editors. News and Editorials. Available at: http:// www.icmje.org/news-and-editorials/clin_trial_sep2004.pdf. Accessed September 10, 2014. 5. International Committee of Medical Journal Editors. Clinical Trials Registration. Available at: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinicaltrial-registration.html. Accessed September 10, 2014. 6. International Committee of Medical Journal. Journals Following the ICMJE Recommendations. Available at: http://www.icmje.org/journals-following-the-icmje-recommendations. Accessed August 29, 2014. 7. Medicare learning network matters. Centers for Medicare and Medicaid Services Web site. Available at: http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/MM8401.pdf. Revised June 9, 2014. Accessed September 10, 2014. 8. Prayle AP, Hurley MN, Smyth AR. Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. BMJ. 2012; 344:d7373. 9. Public meeting on expansion of the clinical trial registry and results data bank. Available at: http://www.regulations.gov/#!docketDetail;D=NIH-2009-0002. Accessed September 10, 2014. 10. National Institutes of Health. Development of regulations to implement FDAAA 801. Available at: http://clinicaltrials.gov/ct2/manage-recs/fdaaa#DevelopmentOfRegulations. Accessed September 10, 2014. 11. Hirsch BR, Califf RM, Cheng SK, Tasneem A, Horton J, Chiswell K, Schulman KA, Dilts DM, Abernethy AP. Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov. JAMA Intern Med. 2013; 173(11): 972–979.
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Abstract The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials. Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training, and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation. Clin Trans Sci 2015; Volume 8: 48–51.
Keywords: trials registration, trials reporting, FDAAA 2007, ClinicalTrials.gov, applicable clinical trial Introduction
Examples of selective publication bias historically made the case for clinical trials registries,1 and led to the posting of the Clinical Trials Data Bank (http://clinicaltrials.gov) in February 2000 in response to the Food and Drug Administration Modernization Act of 1997 (FDAMA). Section 113 of FDAMA required the establishment of a registry for clinical trials of experimental treatments (drug and biological) for patients with serious or life-threatening diseases or conditions. Since then, the registry has been widely expanded to accommodate the requirements of FDAAA 2007. Specifically, section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA 2007) broadened the type of trials that required registration to all “applicable clinical trials” (ACTs) and identified the “Responsible Party” as the entity that must register the trial.2 In addition, FDAAA 2007 required the entry of results for certain ACTs. The timelines established by FDAAA 2007 required ongoing ACTs to be registered by the end of 2007 and basic results reporting capability was available beginning 2008.* Built into the law are financial incentives for compliance in the form of fines, civil penalties and funding guarantees. For trials out of compliance, there can be an initial $10,000 fine followed by another $10,000 per day if the violation is not corrected within 30 days. Although these fines have yet to be imposed, they could add up to substantial amounts. In addition, National Institutes of Health (NIH) grantees must submit a “certification of compliance” in all grant applications and progress reports.3 The release of NIH funding is dependent upon grantees being current with registration and reporting requirements. Penalties for noncompliance may include the withholding or recovery of grant funds. Besides the legal and funding requirements described above, there are also requirements to be considered for publication. In 2004, the International Committee of Medical Journal Editors *
(ICMJE) incorporated the requirement for registration of clinical trials in a public trials registry at or before the time of first patient enrollment as a condition of consideration for publication.4,5 While only 14 journals are official members of the ICMJE, over 1,600 other medical journals have purportedly committed to follow ICMJE recommendations.6 Finally, in addition to legal, funding, and publication considerations, mandatory inclusion of the NCT number on Medicare claims for routine costs of qualifying clinical trials became effective as of January 2014. Thus, studies that would not require registration per FDAAA may require registration for Centers for Medicare and Medicaid Services (CMS) billing purposes.7 Despite these laws and the potential for penalties, meeting these requirements has proven to be a challenge for the research community, especially for results reporting. As of January 2011, only 22% of registered ACTs met requirements with industry funded trials (40%) more likely to report results than nonindustry funded trials (8%).8 Duke University Medical Center has created an institutional policy and developed systems to assist the research community with meeting trials disclosure obligations. The timeline and high-level steps taken are depicted in Figure 1. This manuscript will review the policies and operational plan that improved investigator compliance with these federal requirements. We hope that sharing our plan may assist other Academic Health Centers with implementing similar measures. Duke Task Force Leads Compliance Initiative
As a member of the Clinical and Translational Science Award (CTSA) program, Duke Medicine was included in a “Results Database Train the Trainer” workshop at the National Library
Results for ACTs results must be entered within 1 year of the primary completion date of the study.
Duke Translational Medicine Institute, Regulatory Affairs Office, Durham, North Carolina, USA ; 2Duke University School of Medicine, Durham, North Carolina, USA ; 3Duke University School of Nursing , Durham, North Carolina, USA ; 4Duke Office of Clinical Research, Durham, North Carolina, USA ; 5Duke Cancer Institute, Durham, North Carolina, USA ; 6Seattle Cancer Care Alliance (current) , Seattle, Washington, USA ; 7Duke Department of Neurology, Durham, North Carolina, USA .
1
Correspondence: Erin O’Reilly ([email protected]) DOI: 10.1111/cts.12235
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Figure 1. Timeline for improving trials disclosure compliance.
of Medicine (NLM) in Bethesda, MD, in 2012. Topics included results entry and strategies for compliance. When workshop participants returned to campus and shared the knowledge gained, the need to support clinical researchers to achieve compliance with the regulatory requirements of FDAMA and FDAAA, as well as the publishing requirements of ICMJE was recognized. To kick-start the process, the Duke Clinical Trials Disclosure Task Force was formed. The Task Force was composed of representatives from the School of Medicine, Office of Clinical Research, Office of Regulatory Affairs, and the Cancer Institute. Their mandate was to assess the current state of compliance, formulate a plan to address any noncompliance, and develop standardized policies and processes to ensure ongoing compliance. The Task Force determined the following steps were critical to successful, institution-wide compliance: assessment of the current state of compliance; policy development, implementation and enforcement; training; auditing; annual reassessment; and creation of a centralized resource for implementation. Each step will be further described below within the context of resources required and lessons learned. Assessment of current compliance began with pulling error reports for registrations associated with the Duke Medicine account from the ClinicalTrials.gov protocol registration system (PRS). Additionally, the Duke research informatics group accessed data from the Duke electronic Institutional Review Board (eIRB) data repository to query a list of principal investigator (PI)initiated studies requiring review for compliance. Initial error reports highlighting registration problems and records with late results were presented to the Task Force. The error reports were divided and submitted to Clinical Research Units (CRUs)** for action. The CRUs were provided target dates for cleaning
up assigned records. These early error reports contained the following minimal information: NCT Number, ClinicalTrials.gov problem term, IRB number, IRB status, brief title of study, record owner name, current status, date of latest record verification, date of latest record update, and CRU name. Initially, the CRUs were updated on a weekly basis, to better monitor progress. Assistance was offered to teams by members of the Task Force as well as newly hired staff. Any problems with staff not responding to the error reports were escalated to the Associate and Vice Deans for Clinical Research, both active members of the Task Force. In the meantime, the Duke Office of Clinical Research (DOCR), a central administrative office within the School of Medicine, authored a clinical trials disclosure policy that would apply to all of Duke Medicine. The initial policy draft was circulated among Task Force members and forwarded to the School of Medicine compliance office for additional review and finalization. The policy, adopted by the School of Medicine, outlines requirements, provides a framework for compliance and support, and addresses consequences of noncompliance, including registration on ClinicalTrials.gov as a requirement prior to institutional study approval for ACTs. Training and awareness began with the hiring of additional staff, enabling an initial base of subject matter experts devoted solely to clinical trials disclosure and ClinicalTrials.gov. This centralized resource, consisting of three full time staff members, focused on informing the research community of laws and guidelines related to clinical trials disclosure. Initial training and reinforcement awareness occurred through a variety of venues to ensure optimal understanding and adoption. These included oneon-one meetings with PIs and research staff, educational outreach presentations to the research community and each CRU, newsletter
**CRUs are the organizational and functional structures that provide oversight for clinical research at Duke Medicine. Each CRU is composed of one or more Departments or Institutes. The CRU is the operating business unit responsible for the integrity, financial accountability, regulatory compliance, quality, and academic productivity of clinical research studies. Examples of CRUs at Duke include medicine, oncology, psychiatry, surgery, and pediatrics.
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articles, and development of hands on workshops for university and core groups. These “hands on” workshops allow Duke Staff to practice results entry skills and are offered quarterly to the Duke research community. This centralized resource is now responsible for auditing and annual reassessment steps. Currently, these roles include: assisting with daily monitoring of ClinicalTrials.gov regarding new study registration; registration and results reporting review; maintaining a training and education program; handling questions from research teams; reviewing problem reports and communications; maintaining escalation procedures for noncompliance; as well as writing policies and procedures for integrating reviews and notifications upon eIRB submission. Currently, monthly problem reports are sent to each CRU. Each problem record is reviewed by the centralized staff, and specific instructions are provided concerning outstanding compliance needs. In total, these reports contain the following information: priority status (length of time on report), a detailed description of action required, ClinicalTrials.gov problem term, study identification number (this is the same as the IRB number at Duke), record owner name, principal investigator name, study coordinator name, department, division and CRU name. In addition, a REDCap database is now used to combine record status and primary completion dates to generate proactive reports which identify upcoming results reporting and record verification due dates. While DOCR is responsible for establishing the policy, ongoing monitoring, and tools/training for the ClinicalTrials.gov process, the CRUs at Duke are responsible for overseeing research portfolio activity and are the vehicle for dissemination to their research teams. Reports combining eIRB data and ClinicalTrials. gov system have enabled a successful rollout to 16 CRUs. The CRUs hold the closest relationship with study teams and work in partnership with DOCR to achieve compliance with the law. The centralized DOCR group provides the “how to” subject matter expertise and assistance as needed. The CRUs provide the “connection” between DOCR and the research teams. This synergy encourages open dialogue, support, and communication when questions arise. Reports are issued to teams on a consistent schedule and DOCR is responsive to study team inquiries and requests for assistance. It is the culmination of these ongoing efforts that ensures the work is completed. In order to control institutional compliance risks, Duke Medicine acts as the Responsible Party for all records at Duke with the exception of individual IND/IDE holders. However, the principal investigator is held responsible for the content of their study records. Investigators are given access to records along with anyone they delegate from a study team, and are responsible for entering study-specific information and for maintaining the records. The centralized DOCR staff can review the records, make administrative changes, and assist the research team in many ways including direct assistance with results entry. Any institution will still have some compliance issues and the consequences at Duke for noncompliance are simple yet effective. Initially, IRB and institutional approval for ACTs is withheld until the study is registered. For ongoing noncompliance issues with existing records, such as overdue results or record verifications, all new research associated with that particular investigator can be halted during the institutional review process. Finally, the Vice Dean for Clinical Research and the Chief Compliance Officer can be consulted for a collaborative decision regarding whether an investigator should be administratively suspended from conducting clinical research. 50
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Category
Average monthly number
New studies submitted to the eIRB that require qualifying trial assessment
103
PI initiated studies submitted to the eIRB that require ACT assessment*
55
New Duke Medicine study records created at ClinicalTrials.gov
13
Newly entered records projected to require future results reporting
4
Changes to PRS records that require review and release†
105
*This average number (55) is a subset of the total monthly average of new studies submitted to the eIRB (103). † This number does not include records released by IND/IDE holders. In those cases, the individual investigator serving as the Responsible Party acts to review and release the records.
Table 1. Metrics of records handled by the centralized resource group.
Return on Investment
The creation of a centralized resource with three full time staff members represents a large commitment from an institutional perspective. Table 1 shows the workload handled by the DOCR centralized resource group. Since the formation of the group, the number of Duke Medicine records appearing on problem reports as well as those identified as being late for results reporting has decreased almost fivefold (specific data not shown). In addition to increasing record compliance, this centralized resource group has allowed Duke Medicine to quickly implement changes to accommodate the new CMS requirements enforced as of January 2014. Communication pathways were swiftly developed to link clinical trials billing and research teams. There is now a process whereby qualifying trial status is determined prior to granting institutional approval. For studies deemed qualifying trials, institutional approval is held until an NCT number is obtained. To ensure CMS reimbursement, NCT numbers are entered in the eIRB, which is accessible by the clinical trials billing office. Conclusion
Due to implementation of the institutional policy and creation of the centralized resource, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. This centralized approach proved essential for having the proper resources available to meet the ongoing requirements of FDAAA 2007 as well as the new CMS billing requirements. We believe a consistent centralized approach will ensure success in the face of changing agency rules and new legislation. Formal regulations for the implementation of Section 801 of FDAAA 2007 are still in development,9,10 and Duke Medicine can more easily adapt to any changes these regulations may bring because of the centralized approach. Feature: ClinicalTrials.gov—The Duke Cancer Institute (DCI) Experience
Academic cancer centers face considerable pressures to comply with numerous clinical trial disclosure requirements, including those described in ICMJE, FDAMA, and FDAAA. Consistent with this view, oncology trials constitute the largest clinical discipline across all ClinicalTrials.gov registrations.11 Likewise, oncology trials comprise the largest subset of ClinicalTrials. WWW.CTSJOURNAL.COM
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gov registrations within Duke Medicine. Given the volume and inherent complexity of oncology trials, academic cancer centers must commit significant resources to ensure compliance with trial disclosure requirements. The DCI receives National Cancer Institute (NCI) funding through the P30 Cancer Center Support Grant (CCSG) to build and support clinical research infrastructure. Using this infrastructure, the DCI had considered taking full responsibility for ClinicalTrials. gov oversight of cancer-specific studies. However, the DCI chose to partner with and follow the lead of the centralized resource group due to the high level of administrative oversight and operational coordination required by ClinicalTrials.gov compliance efforts. This partnership ensured more optimal, efficient, and uniform oversight of ClinicalTrials.gov requirements. To date, DCI investigators and study teams have utilized and benefited from the centralized resource group. Here, we highlight how the DCI’s CCSG-based infrastructure has been leveraged to provide additional awareness and support of ClinicalTrials.gov registrations and results reporting. Protocol review and monitoring system (PRMS) A required component of the CCSG, the PRMS assures adequate internal oversight of the scientific aspects of all oncology clinical trials. During scientific review of ACTs, the PRMS evaluates the necessity of protocol primary and secondary objectives. FDAAA requires results reporting on all primary and secondary objectives for ACTs in which the study product is approved, or within 30 days of product approval. Since this is a highly labor-intensive effort, the PRMS may advise the investigator to weigh the benefits and drawbacks of certain primary or secondary objectives. Also, staff within the PRMS help broaden the educational outreach efforts of the DOCR centralized resource group. PRMS staff host various educational and communication forums to generate more awareness about ClinicalTrials.gov requirements within the oncology clinical research community. Biostatistics shared resource The DCI is organized into 11 disease-based groups, each with biostatistical support that is subsidized by the DCI and CCSG. Given the intensive data and analytic effort required during ClinicalTrials.gov results reporting, these biostatisticians have been essential to accurate reporting of required data. Additionally, as biostatisticians have become more aware of the implications of ClinicalTrials.gov requirements, they have become more proactive about discussing ClinicalTrials.gov considerations during clinical trial design and database creation. Some have even created Microsoft Excel–based tools to simplify the transfer of data for all required elements of ClinicalTrials.gov reporting. Clinical protocol and data management (CPDM) The CPDM system, another required component of the CCSG, provides central management and oversight functions for coordinating, facilitating, and reporting on oncology clinical trials. The DCI employs a Clinical Research Analyst (CRA) who helps maintain the CPDM system, provides ClinicalTrials.gov support, and performs day-to-day functions for the NCI’s Clinical Trials Reporting Program (CTRP), which requires collection of trial data that are similar but not identical to ClinicalTrials.gov trial data. The CRA is positioned to serve four key functions. First, the CRA functions as the primary liaison to the centralized resource group. The CRA understands the unique organizational
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structure of the DCI and facilitates the workflow of the centralized resource group. Second, the CRA is familiar with characteristics of the DCI trial portfolio databases and is positioned to update these databases in order to track ClinicalTrials.gov registrations. Third, the CRA facilitates interactions between the PI, study team, and biostatisticians to help define “best practice” in efforts devoted to ClinicalTrials.gov compliance. Fourth, the CRA has created tools and templates to aid study teams in creation of ClinicalTrials.gov registrations and results reports. In summary, the Duke experience suggests that ClinicalTrials. gov compliance is a priority requiring institution-wide oversight and collaboration. The DCI has benefited from additional ClinicalTrials.gov support due to CCSG-based infrastructure. Other NCI-designated academic cancer centers may consider whether such infrastructure can support their ClinicalTrials.gov compliance needs within unique organizational contexts. Acknowledgments
This paper was supported by the National Center for Advancing Translational Science of the NIH through Grant No. UL1TR001117. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The authors acknowledge the contributions of Leigh A. Burgess, M.H.A., M.Ed., M.A., Vijaya Chadaram, R.N., M.S.N., C.C.R.P., Lorna N. Dula, Jessica Houlihan, and Bonnie Vernarelli R.N., M.S.N., M.B.A., who participated as active members of the Task Force. Conflict of Interest
B. K. Burnett declares that his spouse has equity of more than $10,000 in Biogen Idec, a pharmaceutical company. Also his spouse has an income of more than $10,000 from Biogen Idec, a pharmaceutical company. J. P. Berglund declares that her spouse has equity of more than $10,000 in both Liquidia Technologies and Immune Design. Also her spouse has a income of more than $10,000 from Immune Design. References 1. Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol. 1986; 4(10): 1529–1541. 2. National Institutes of Health. Elaboration of Definitions of Responsible Party and Applicable Clinical Trial. Available at: http://prsinfo.clinicaltrials.gov/ElaborationsOnDefinitions.pdf. Published Mar 9, 2009. Accessed September 10, 2014. 3. National Institutes of Health Implementation of FDAAA – FDAAA Requirements for NIH Grantees At-A-Glance. National Institutes of Health Office of Extramural Research Web site. Available at: http:// grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm. Updated 2011. Accessed September 10, 2014. 4. International Committee of Medical Journal Editors. News and Editorials. Available at: http:// www.icmje.org/news-and-editorials/clin_trial_sep2004.pdf. Accessed September 10, 2014. 5. International Committee of Medical Journal Editors. Clinical Trials Registration. Available at: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinicaltrial-registration.html. Accessed September 10, 2014. 6. International Committee of Medical Journal. Journals Following the ICMJE Recommendations. Available at: http://www.icmje.org/journals-following-the-icmje-recommendations. Accessed August 29, 2014. 7. Medicare learning network matters. Centers for Medicare and Medicaid Services Web site. Available at: http://www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNMattersArticles/Downloads/MM8401.pdf. Revised June 9, 2014. Accessed September 10, 2014. 8. Prayle AP, Hurley MN, Smyth AR. Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study. BMJ. 2012; 344:d7373. 9. Public meeting on expansion of the clinical trial registry and results data bank. Available at: http://www.regulations.gov/#!docketDetail;D=NIH-2009-0002. Accessed September 10, 2014. 10. National Institutes of Health. Development of regulations to implement FDAAA 801. Available at: http://clinicaltrials.gov/ct2/manage-recs/fdaaa#DevelopmentOfRegulations. Accessed September 10, 2014. 11. Hirsch BR, Califf RM, Cheng SK, Tasneem A, Horton J, Chiswell K, Schulman KA, Dilts DM, Abernethy AP. Characteristics of oncology clinical trials: insights from a systematic analysis of ClinicalTrials.gov. JAMA Intern Med. 2013; 173(11): 972–979.
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