韓志平 中山醫學大學附設醫院 人體試驗委員會 資料與安全監測計畫 DSMP IRB/EC concerns 韓志平 中山醫學大學附設醫院 人體試驗委員會

基因時代的進展太快，以至於一般民眾無法深入了解，縱想了解，亦不得其門而入。對於許多人來說，生命科學純粹是學術領域的事情，只有專家才有發言權，這也造成研究者對於「告知」的困難，和「不告知」或敷衍了事的藉口。特別是告知什麼？告知到什麼程度？誰來告知？民眾真的明白嗎？ 學術機構扮演很重要的角色，因為學術機構的學術聲譽和學術良知就好像「王后的貞操」一樣，不容懷疑。但近年來，生技公司的介入卻大幅改變了這個現象，生物技術公司對大學研究的投資帶來什麼影響？ 採血研究未經同意，國外團體指侵犯人權，專利應屬原民 -----

參加人體試驗有危險嗎? FDA inspectors (>600人) : 1977-2000, 2308 案接受查核, 70 PI不正當行為受罰, 禁止在參加臨床試驗, 其中16人被起訴(罰金,公共服務,保釋), 但仍有6人判刑坐牢 1995 : NIH - Fialuridine Px 15 subjects with Chronic Hepatitis B --- 3人輕度肝毒性, 另7人嚴重肝毒性(2/7未換肝, 均死亡; 5/7 換肝, 2人存活, 3人死亡; 總共5人死亡) 。 2006/3/16 : 免疫標把治療之TGN1412 作用於非人靈長類動物身上T細胞未見毒性，但對人的免疫系統産生一種非預期的嚴重不良反應，導致臨床一期試驗的參與者(6人)出現多器官衰竭。 From中國時報 謝教授

XXXXXX領先，發現乳癌幹細胞有兩個關鍵的醣脂質，透過阻斷醣脂質合成，不但可製成乳癌疫苗，還能篩選現有藥物來抗癌，最快明年初可進入第二期人體試驗，讓乳癌不再可怕。 在行政院國科會經費支援下，中央研究院「老藥新用」，把用於增強癌症病人白血球的顆粒生長激素 (G-CSF)注射到實驗鼠身上，結果改善阿茲海默症實驗鼠症狀，已獲准進入二階段人體實驗。研究團隊說，這種老藥還可以改善受損心臟細胞，不排除可以治療脊椎神經受損而下肢癱瘓的患者。 Social impact, Community impact, Psychological impact? (risks)

人體臨床試驗之必要性與正當性 （一）    目的正當性。 （二）    可容許危險（刑責 ？ ）。 （三）    政府（&/or IRB only）核准 。 The final step in a long research process.

Background Introduction (Origin & Policy of PHRC & NIH) DSMP & DSMB DSMP Contents Key Elements Does every research protocol require a DSMP or a DSMB? (ex: behavioral intervention?) Summary Conclusion 96,98,99年醫策會IRB/EC人體試驗訪查基準 --- 6. 試驗風險評估與監測之充分性 (2) DSMP in CSMUH IRB & others 人體試驗檢體安全追蹤報告

Background (Ellen Roche & OHRP, 醫策會訪查基準6.2)

Ellen Roche 24 y/o，氣喘研究健康受試者，為Johns Hopkins雇員，吸入未核准藥物(IND？ ) ， 2001年7月2日死亡，肺部破壞。 2001年7月16-18日OHRP site visit --- 5 staffs，3 consultants, 1 FDA代表。 2001年7月19日起， 暫停所有政府資助計畫。

OHRP Findings (IRB缺失1) IRB not given published toxicity information on the product (毒性資料不足) The drug was not approved for human use, no IND (新藥) Quality of the drug uncertain (藥物品質不明) IRB inappropriately used expedited review (簡審) IRB did not approve protocol changes (自行變更)

OHRP Findings (IRB缺失-2) Informed consent (知情同意): procedures inadequately described (程序) failed to disclose drug status (告知藥物現況) inadequately disclose risks (揭露風險) Inadequate IRB information for continuing review (追蹤審查) Inappropriate IRB minutes and backlog(會議記錄) Some IRB members had conflicts of interest (利益迴避) IRB overloaded, lacking staff (IRB人員不足，工作量重) IRB members in need of education (委員需要再教育)

OHRP Actions Suspended all federally-sponsored research (暫停所有政府出資計畫) Required re-evaluation of protocols (委外重新審查所有計畫書) Requested a plan to restructure the system for protecting human subjects (擬定改措施) Required plan to educate IRB members, staff and researchers (IRB委員,工作人員, PI 再教育計畫)

“What experience and history teach is this -- that people and governments never have learned anything from history” (歷史一再重演) Georg W.F. Hegel (1770-1831)

96,98,99年度醫策會訪查基準

2. Introduction (Origin & Policy of PHRC & NIH)

Partners Human Research Committee (PHRC) POLICY The PHRC requires DSMP in all interventional clinical research protocols that involve more than minimal risk to subjects. (介入型研究、高於最低風險) The DSMP must be described in sufficient detail for the PHRC to determine whether the plan is appropriate for the research. All human research proposals submitted for review by the PHRC are subject to this policy. The PHRC (IRBs) are responsible for the review and approval of all human subject research conducted by staff of Massachusetts General Hospital (MGH), Brigham and Women’s Hospital (BWH), Faulkner Hospital (FH), & other Partners affiliated hospitals. http://healthcare.partners.org/phsirb/datasafe.htm (2008)

NIH Requirements Every clinical trial should have provision for data and safety monitoring. (每一件臨床研究皆有資料安全監測準備) NIH GUIDE, Vol 8, No, 8, June 5, 1979 It is the policy of the NIH that each Institute and Center should have a system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials. (要求研究機構內︰需有適當的查核監督機制，確保 ---) NIH POLICY FOR DSM , June 10, 1998

Applications Submitted to NIH Approximately 40,000 grant applications are submitted to NIH each year, of which 25-30 % are funded

NIH Policy Phase I Physiologic, PK, Toxicity, and Dose-finding Phase II Efficacy, Safety Phase III Pivotal Efficacy, Safety (Multicenter, Blind) NIH policy :　requires a general description of a DSMP for all clinical investigations - biomedical and behavioral intervention studies. (要求主持人計畫書內容︰須包含DSMP --- 1979,1998-2000) 國內現況 ????? grants.nih.gov/grants/guide/notice-files/not98-084.html grants.nih.gov/grants/guide/notice-files/not-OD-00-038.html www.cancer.gov/clinicaltrials/conducting/dsm-guidelines

3. DSMP & DSMB 資料安全監測計畫 & 資料安全監測委員會

Definition of DSM plan --- 計畫 A defined process --- . the timing, tools and/or method(s) for monitoring and evaluation. (自我監測評估) procedures for treatment or resolution (including circumstances which would result in halting or terminating research). (解決問題狀況) procedures for and timing of reports to oversight bodies, and description of oversight bodies involved with the study (e.g. study team, DOH, IRB, or DSMB). (與其它監督及稽/查核單位互動)

The Purpose of DSMP 風險管理機制︰預估各式風險，規劃解決對策 To protect the safety of research participants, minimize risks for subjects (受試者安全) To ensure the scientific integrity and validity of study results (資料完備正確) To institute changes in protocol for protection of subjects (必要應變措施) To terminate studies when significant risks have been uncovered (停損退場機制)

Characteristics of DSMP may be a stand-alone document --- an individualized plan for study’s objectives, design, and estimated risk level (獨立計畫) or the section of a protocol. (附屬原計畫書內) Be designed by PI/ sponsor Be reviewed by IRB/EC It depends --- the variety and type of monitoring plan may differ depending upon the nature, size, and complexity of the clinical trial being conducted. (DSMP設計規劃因案件個別特性而不同)

為何需要 DSMP ? GCP中已有「受試者安全」與「資料完備」通則規範。但請主持人於計畫書中整體規劃、落實執行，檢討改進；IRB及法規單位定期監督查核，使受試者權益與試驗品質，獲得最大保障︰ - 試驗前 -- 在設計及撰寫計畫書時，要求對DSM做適當規 劃與量身打造。 - 試驗中 -- PI在執行計劃時，有自我監控與反省機制， 帶給受試者更好的安全保障。 - 試驗後 -- 於結案報告中合併檢討。 系統性檢視「最小合理風險」是必要的，嚴謹的DSMP與計畫書設計，並不能保證免除人體試驗時發生受試者危害時，所衍生的法律責任。 ※ 建議 : IRB, DOH, NSC, NHRI, --- , 共同推動 DSMP

What is a DSM Board? ---委員會 “ An independent committee that may be established by the sponsor to assess at intervals ※※※ - the progress of a clinical trial, (試驗進展) - the safety data, and as (安全性資料) - the critical efficacy endpoints, and to (關鍵性療效指標) - recommend to the sponsor whether to 1. continue, (試驗繼續進行) 2. modify, or (修改計劃書後繼續進行) 3. stop a trial ” (終止或終止試驗) ICH GCP E6 (1.25)

By any other name... Data & Safety Monitoring Boards (DSMB). Independent Data Monitoring Committee (IDMC). Data Monitoring Committee (DMC). Data Review Board (DRB).

“Whom” does a DSMB need? DSMB chair and members (主席與委員) minimal number is 3 people (至少三人) experts including scientists, physician(s), statistician(s), bioethicist(s), and others (醫師，統計學專家，生物倫理專家，其他) Independent to related organization is better.(獨立)

When & Which kind of trials need a DSMB? 多中心隨機對照雙盲研究，其主要目的降低嚴重疾病的發病率或死亡率。 高風險的早期研究或創新性治療，其臨床安全性訊息非常有限，或先前的資料引起有潛在嚴重不良後果的關注。(Risky, High-impact, Early phases of novel intervention, Advanced experimental technologies, life-threatening illnesses ) 設計複雜，預期可能因缺乏療效導致發病率或死亡率增加，尤其是長期的研究。(interim analyses) 在緊急情況下實施的研究或涉及弱勢人群的研究。(見仁見智) 彰基, NIH DSM June 10, 1998 Policy, Further guidance issued June 5, 2000, Juntra teaching slide 2008

WHI: Women's Health Initiative （婦女健康關懷研究） 一個雙盲、前瞻性、大樣本(16608人)的研究，原預計八年時間研究，但在進行5.2年以後，發現服用雌激素加黃體素婦女組比控制組婦女，風險(罹患乳癌、心血管疾病、中風、血栓)比效益(減少骨折、大腸直腸癌)多。所以，在2002年7月9日宣佈終止雌激素加黃體素這組研究。

4. Data & Safety Monitoring Plan Contents: (Data Monitoring, Safety Monitoring, Expected Action / Plan)

Data monitoring plan --- Contents (1) 資料管理 What are the specific procedures for managing and protecting data? (資料保全) How data is collected and by whom? (誰收集) How records/data are maintained? (數據紀錄維護) Who will access the data? (誰有權檢視) How and where will the records/data be stored or maintained? (如何保存?保管於何處？) Will the PI decide or the IRB review this issue? (PI決定送IRB審查) (Validity, Integrity)

Data monitoring plan --- Contents (2) 資料管理 Security of records / data (資料與紀錄安全) Limited access-locked cabinets (檔案櫃上鎖) Protection of subject privacy / confidentiality (受試者隱密與隱私) Databases password protected (資料庫密碼之保全) Encryption of data sent over internet (如何網路資料傳輸) Restricted ability to alter data (誰有權更正資料) May have double entry to increase accuracy (雙重輸入以維護正確性) (Validity, Integrity)

Data monitoring plan --- Contents (3) 資料管理 How is confidentiality managed? (保密措施) Computer systems? (電腦) Identifiable mailings? (郵件) Procedures for monitoring and reporting confidentiality breeches? (如何監測有無洩密) Notification to subjects if confidentiality may be breeched? --- e.g., laws for reporting drug abuse, criminal behavior, suicide ideation. (一旦藥癮，犯罪行為，自殺議題等敏感議題研究資料外洩時，如何告知受試者?) (Validity, Integrity)

Safety monitoring plan --- Contents (1) 受試者安全維護 What procedures are in place for SAE evaluation & reporting? Who is responsible? (SAE如何評估?誰負責通報?向誰通報?) How will the study address an instance where the occurrence of an SUSAR could potentially place other participants at heightened risk? (發生嚴重非預期且相關之不良反應，會對其他高風險受試者採取什麼措施?) Will protocol be stopped? Will threshold be determined? (Subjects’ AEs that could “reasonably occur”)

Safety monitoring plan --- Contents (2) 受試者安全維護 Are there procedures / criteria in place for determining when personnel must break confidentiality (report) if an adverse event is likely or imminent with respect to a certain study participant? (保護受試者可能受到危害時，如何因應?) Need for special DSMB? (有無必要?) Multi-site, Phase III clinical trials involving interventions that entail potential risk to participants High risk PI-Initiated trial require a DSMB? ※※(機構?) (Subjects’ AEs that could “reasonably occur”)

Expected Action / Plan --- Contents 可能採取之行動與計畫 Withdraw Criteria? (受試者退出條件) Rescue Medication? (救援醫療) Termination Actions of a Study? (中止試驗條件) - significant benefits identified so should be provided to all. (療效太好) - significant risks have occurred, outweighing the benefits. (療效太差，受試者風險高於利益) - study cannot be concluded successfully. (難以下結論)

5. Key Elements of DSMP (要件︰Risk Level 略, Monitoring, Reporting, Conflict of interest 略, Interim analysis 略, ----) from: http://gcrc.med.miami.edu/x27.xml, 2008, GCRC, School of Medicine, Miami University

Key Elements (1) : Monitoring - 1 Who will be doing the monitoring (誰來監測?) --- based on level of risk --- - PI-self (PI自己) - study team safety monitor (研究團隊成員) - Sponsor/CRO medical monitor (出資委託者) - Independent DSMB

Key Elements (1) : Monitoring - 2 Frequency of monitoring (監測頻率?) - At certain time periods - After specific number of subjects enrolled - Unexpected or increased incidence of SAEs

Key Elements (1) : Monitoring - 3 Appropriate Items to be monitored include (監測什麼?): – Enrollment – AEs – Outcome measures – Drop-out rate – Compliance with data collection – Protocol deviations – Medication compliance – Stopping rules, individual and study-wide

Key Element (2) : Reporting Process for reporting AEs and unanticipated problems – Who will do the reporting (誰通報?) – To what entities will reporting be done(通報給誰?) ＊ Sponsor / Funding Agency ＊ IRB / DOH (SAE, change to SUSAR) – Frequency of reporting (多久通報一次?) – AE grading and attribution (如何判斷不良事件?) Common Terminology Criteria for Adverse Events http://ctep.cancer.gov/forms/CTCAEv3.pdf

6. Does every research protocol require a DSMP or a DSMB?

Example: A DSMP would formalize action items, such as: In general, the same requirements would be applied to behavioral intervention studies as would be applied to treatment intervention studies. (社會行為科學研究 / 依個案不同量身訂做) ex: methodology for notifying an attending physician / investigator of emergent events (突發事件因應措施) obtaining psychiatric consults for findings of suicidality (自殺意圖) procedures and education for staff regarding protection of private information (資料保全) procedures to follow when subjects experience significant social or emotional upset in response to the research interaction (e.g. a panic attack after an interview and questionnaire, stressful information transfer, --- ) (心靈傷害) IRBMED UNIVERSITY OF MICHIGAN MEDICAL SCHOOL, 2008

Which Studies Require DSMP or DSMB? Clinical Research? Yes No Phase III or Multicenter Yes No Blinded, high-risk intervention, Phase I, II, or vulnerable population? Yes No IRB + DSMP + DSMB IRB + DSMP Modified NIH policy & 2004 Vanderbilt University Medical Center

7. Summary

A DSMP does not equal to a DSMB. (DSMP不是DSMB) All clinical studies need a DSM plan/ or a section of description in protocol, some of them need a DSM board. (每一個試驗都需要有DSMP，有一部份還需要有DSMB) A DSM Plan is processes, how the study will be monitored to ensure participant safety, scientific integrity, data validity and compliance with regulatory requirements. A DSM Board is a group of experts, established to assess at intervals the progress of a clinical trial (the safety data and the critical efficacy endpoints), and to recommend to the sponsor whether to continue, modify or stop a trial.

Ensuring research participant safety is the highest priority of any clinical research project. (維護受試者最大權益) The Principal Investigator bears primary responsibility for insuring participant safety. (PI負最大責任) All safety plans and review bodies are empowered to assist the Principal Investigator in maintaining the reasonable safety during the process of conducting a research project. (受試者合理最小風險)

8. Conclusion

Data & Safety Monitoring Plans (風險管理機制) how monitoring will be done by whom (who reviews AEs) how frequently Reporting actions, stopping rules “the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects” (45 CFR 46.111)

建議『IRB/EC』參考與改善方式 IRB設計自評表，主持人填寫後送審 --- 研究對受試者以最小合理範圍風險設計? 主持人自我監測頻率？妥適照護方式? 風險等級較高，易受傷害族群等案件，應考慮設立DSMB或另外提出監控計劃來確保受試者安全與試驗資料可信？ IRB審查後，對風險認知與計畫主持人有落差時，應以受試者權益考量為主，做成決議 --- IRB可要求PI/sponsor嚴格控管風險，設置停損點，增加追蹤審查頻率， 後續照護方式，增設DSMB 等。 IRB要求計劃書內將如何自我「監測與接受稽核試驗進行之規劃」 ？列為每一案件必要說明段落︰主持人撰寫，IRB審核。 提供『監測與稽核試驗進行之規劃』撰寫說明與 DSMP範本。 舉証:有紀錄可查。 (中山附醫 --- 僅供參考)

10. DSMP in CSMU Hospital & others

(一) Integrated in protocol (提供instructions) 撰寫說明重點提示︰基本要件 (參考2001 NCI Guideline ) 如何監測 (monitoring) 研究進行時，受試者安全? 如何處理非預期不良事件與反應？通報機制？誰通報？通報對象？（包括IRB， 法規單位，委託機構等？） 如何確保資料正確及計畫順利執行？ 萬一計畫因故產生執行偏差、或中/終止時，將如何採取應變措施等？ 『監測與稽核試驗進行之規劃』項目︰主持人可依據研究計畫案件「個別」特性，針對「受試者安全」與「資料完備」議題，在執行計畫前，預先做系統性的考量規劃並具體說明，如何給予最適當人身維護方式與資料保全措施。

(二) A separated plan --- (提供templates) 內容包括下列六大項次︰ - Categories of submitted protocol (訂定適用範圍) - Risk assessment (風險等級) - Monitoring methods (自我監測方式) - Before/During/After trial implementation. (試驗執行 – 前/中/後 -- 具體規劃) - DSMB (non-essential非必要選項) - Other actions (其它可能行動) Focus on risky trial and registration trial, now!

Eight categories of submitted protocols 原則上顯著高於最小風險，仍須參考完整試驗內容決定 - 符合醫療法第八條規定之新藥、新醫療技術、新醫療器 材 - 已上市藥物超出核准之適應症使用(off-label use) - 上市後監視、學名藥 、生體相等性試驗、已上市藥物符合適應症使用 - 不超出典籍記載之中草藥方使用 - 符合衛生署規定之ㄧ般食品、補充品 - 單純剩餘／新採檢體收集 - 復健、醫學影像、問卷調查等非侵入性試驗 - 病歷、檢體、現有資料庫分析、觀察型研究 原則上略高於最小風險，仍須參考完整試驗內容決定 原則上屬於最小風險，仍須參考完整試驗內容 決定

Our DSMP template

DSMP Report template

NIH funded studies are required to submit a DSMP for clinical trials as part of the research application. IRB reserves the right to require DSMP for minimal risk studies that are not supported by the NIH. DSMP must be provided as part of application for review and approval by the IRB. A DSMP is unique to a trial.

Template

Template

11. 人體試驗檢體安全追蹤報告

中山合約及廠商切結書 主試驗計劃書（含同意書）及藥物基因體學計畫書（含同意書）不宜涉及受試者檢體使用於「非特定用途」、「非特定基因檢測」；前述相關之「非特定研究」或「檢體保管使用超過主試驗進行期間」應以「附加試驗」單獨送審。 「附加試驗」進行採集、使用、或送往國外處理與保管，但需據實填寫「人體試驗檢體安全追蹤報告」，並同意接受乙方人體試驗委員會進行追蹤列管。 若甲方有違反計畫書之檢體使用之情事，致受試者權益受損之虞，甲方無條件同意乙方可單獨進行海內外實地訪查權，海內外實地訪查之費用完全由甲方負擔。

結論 No short cut, but the right way. 明知對受試者不公平，或造成不合理的傷害，再偉大的試驗也不應該被通過。 「臨床試驗除罪化」 vs 「受試者權益不容忽視 」 No short cut, but the right way.

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