Developing ethical research governance framework from institutional toward international levels: Challenges and opportunities 15th FERCAP (Forum for Ethical Review Committees in Asia& the Western Pacific) International Conference Improving Research Governance through Ethical Research Venue: Nagasaki University, Sakamoto Campus, Nagasaki, Japan November 23/ November 22-24, 2015 Chieko Kurihara, Atsuo Waki, Yuko Kato, Kazuko Suzuki, Shizuko Kawakami, Shin Tamoyama, Kinya Kubokawa, Shinji Yoshinaga Research Governance and Human Research Protection Office, Dept. of Planning and Management, National Institute of Radiological Sciences

Developing ethical research governance framework from institutional toward international levels: Challenges and opportunities 15th FERCAP (Forum for Ethical Review Committees in Asia& the Western Pacific) International Conference Improving Research Governance through Ethical Research Venue: Nagasaki University, Sakamoto Campus, Nagasaki, Japan November 23/ November 22-24, 2015 Chieko Kurihara, Atsuo Waki, Yuko Kato, Kazuko Suzuki, Shizuko Kawakami, Shin Tamoyama, Kinya Kubokawa, Shinji Yoshinaga Research Governance and Human Research Protection Office, Dept. of Planning and Management, National Institute of Radiological Sciences

No conflicts of interests to influence upon this presentation

Background - In Japan, GCP (good clinical practice) regulations under the Pharmaceutical and Medical Device Act covers only clinical trials aiming at new drug/device approval (NDA). - Other clinical trial/research is regulated by governmental guidelines, which was revised at the end of 2014 and enforced since April of This newly implemented guidelines require invasive and interventional clinical research (clinical trial) to include monitoring and if necessary audit program since this October.

Objective of this presentation: To introduce our activities to develop new institutional research governance framework responding such regulatory reformation and discuss key factors to facilitate ethical and sound scientific research, not only institutional level; but also national and international level. Method: Narrative, non-systematic review of our experience since December of 2014.

Clinical trials aiming at NDA Clinical trial of drugs/devices Biomedical research involving human subjects US-FDA CFR; EU Directives/Regulations; Asian/African law Scientific research involving human subjects (Behavioral, social science) Declaration of Helsinki, Japanese guideline - living human - Individual identifiable human data, sample Comparison of research regulations in the world GCP Ordinance under Japanese Pharmaceutical & Medical Device Act US human subject protection Reg.; several Some of European and Asian countries e.g., Korea, Taiwan

Clinical trials aiming at NDA Clinical trial of drugs/devices Biomedical research involving human subjects US-FDA CFR; EU Directives/Regulations; Asian/African law Scientific research involving human subjects (Behavioral, social science) Declaration of Helsinki, Japanese guideline - living human - Individual identifiable human data, sample Flexible GL, Good for experimental study but not useful for clinical development DISCREPANCY GCP Ordinance under Japanese Pharmaceutical & Medical Device Act Too much strict for IIT -strict performance of monitoring and audit US human subject protection Reg.; several Some of European and Asian countries e.g., Korea, Taiwan Comparison of research regulations in the world

Clinical trials aiming at NDA Clinical trial of drugs/devices Biomedical research involving human subjects US-FDA CFR; EU Directives/Regulations; Asian/African law Scientific research involving human subjects (Behavioral, social science) Declaration of Helsinki, Japanese guideline - living human - Individual identifiable human data, sample Flexible GL, Good for experimental study but not useful for clinical development DISCREPANCY More flexible More strengthen GCP Ordinance under Japanese Pharmaceutical & Medical Device Act Too much strict for IIT -strict performance of monitoring and audit US human subject protection Reg.; several Some of European and Asian countries e.g., Korea, Taiwan Comparison of research regulations in the world

Members of Research Governance and Human Research Protection Office (authors) Previously this unit (EC/IRB office) was managed by 1 director and 1 staff; Then expanded to at a maximum 8 and now 7 members for reformation of EC/IRB management system, as well as research governance system. We discussed many issues to reform research governance system at 10 times of meeting (photos were deleted from presentation slide)

Statistics of review performance Month/ Total NewIIS3* * IIT (2) (1) (0)(1)(3)(1)(2)(0)(1) (15) SIT Cont.IIS-full IIS-ex SIT SIT-ex IIS: investigator-initiated study; IIT: investigator-initiated trial (which may need monitoring/audit, among IIS; SIT: sponsor-initiated trial; ex-: expedited review; cont.: continuing review, including reporting *: Only 1 protocol did not authorized Fiscal Year # of authorized protocols **20 As of Oct 2015 **: # of fiscal year from April 2014 to March 2015, which is not identical with total # of 2014 in above table

Findings: Most important points of reformation of our institute: (1) Develop monitoring & audit scheme for IIT; (2) Develop SOPs to follow new regulations; (3) Adjust research governance system to be compatible with other institutional regulations; (4) Provide educational seminars and consultations; (5) Reform ethical review system.

(1) Develop the scheme of monitoring and audit for investigator-initiated clinical research Basic principle Whether or not to be covered by regulatory requirement (invasive+interventional) it is welcomed that investigator use institutional resource to conduct monitoring and/or audit, according to their own decision considering risk level of each research project.

Seven tools and example documents and formats to be used for monitoring and audit Example format of monitoring SOP Example format of monitoring report Example format of detailed check-sheet

Important findings of monitoring (at this moment no serious deviation, but…) - Even if a research protocol passed EC/IRB review, it doesn’t mean that researcher follow all the detailed description in approved protocol; - Monitoring is the best educational tool of research ethics through intensive and friendly conversation among ethics experts and research scientists.

(2) Develop several number of SOPs to follow new guidelines as; - Revise the SOP of clinical research overall procedures (in process) (Now, not separated SOPs but included one main SOP) Especially focusing checklist for research submission; SAE reporting; DSMB; COI management - Reminding letters to researcher not to forget clinical trial registration; information disclosure - Develop new SOP/manual of EC/IRB management in detail (some are shared only among the staff) Not to forget important tasks of management office

(3) Adjust research governance system to be compatible with other institutional rules, e.g.,: -conflict of interest management; -privacy protection and information security; -record retention rules. This became necessary to avoid that monitors find deviation of not only research regulations but also deviation of other institutional regulations, under the national regulations.

(4) Provide educational seminars to implement new research governance framework, as well as consultations; General guidelines and proceduresMonitoring and audit program

(5) Reform ethical review system toward more efficient way. -Revised application form so that investigator and reviewer can find the categories of research: For example: - Needs monitoring and/or audit? - Expedited review is possible? -To inform review results to applicants as early as possible.

Discussion We regard all of these findings is not only meaningful at institutional level, but also it deserves information sharing among national and international communities, for more ethical, sound scientific conduct of research involving human subjects.

Feb, 2012Aug 23, 2015/Nov 8, 2015 China3163 South Korea2629 Taiwan23 Thailand1217 Philippines519 India48 Indonesia48 Sri Lanka23 Bhutan11 Malaysia02 Japan00 Feb Recognized ECs/IRBs How is it today?

Feb, 2012Aug 23, 2015/Nov 8, 2015 China3163 South Korea2629 Taiwan23 Thailand1217 Philippines519 India48 Indonesia48 Sri Lanka23 Bhutan11 Malaysia02 Japan00 Feb Recognized ECs/IRBs How is it today? × １ Today Conglaturation, Nagasaki Univ.

Sept, 2013Aug 23, 2015Nov 8, 2015 USA South Korea566 Taiwan166 India365 China134 Singapore111 Thailand011 Japan000 Canada222 Mexico122 Saudi Arabia011 Find an accredited organization accredited-organization

Imaginable organization chart of research governance in Japan Clinical Research Center President of Institution or Hospital Institutional Review Board (GCP trial) R&D-related Office R&D Steering Committee Ethics Committee (research under GL) Committee Office QA office Project Management Biostatistics Bioinformatics Data management Medical writing Pharmaceutical Affairs CRC QC staff Pipeline management Industry relationship Intellectual property COI committee GMP facility GLP facility Cell Processing Center Phase 1 Unit Ethics support From University Faculty OR Ethic-related Unit Ethics is a part of R&D-driven quality assurance system

Imaginable organization chart of research governance in Japan Clinical Research Center President of Institution or Hospital Institutional Review Board (GCP trial) R&D-related Office R&D Steering Committee Ethics Committee (research under GL) Committee Office QA office Project Management Biostatistics Bioinformatics Data management Medical writing Pharmaceutical Affairs CRC QC staff Pipeline management Industry relationship Intellectual property COI committee GMP facility GLP facility Cell Processing Center Phase 1 Unit Ethics support From University Faculty OR Ethic-related Unit HRPP HRPC QA is a part of HRPP

FERCAP SIDCER recognition seems to be compatible with AAHRPP accreditation; Asian institutes seem to be aiming for AAHRPP after getting FERCAP; AAHRPP accreditation is not limited to EC/IRB, but cover whole the issue of human subject protection and quality assurance. Ethics and Quality Assurance

Conclusion: Take Home Message (1) Through experience of monitoring we found that EC/IRB system is not enough for ethical and sound scientific research conduct (not only plan; reports). (2) EC/IRB accreditation is first step, which leads to establishment of quality assurance and human research subject protection program (HRPP). HRPP would be primary goal, for the true purpose of human subject protection.