中醫藥臨床試驗設計[1]

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  • * Increase in New Drugs. * Generic decreasing or stabilized.

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  • 1. 中醫藥臨床試驗設計與執行 ~ 常見問題與分析 魏正宗 醫師 James Cheng-Chung WEI, MD, PhD 中山醫學大學附設醫院 過敏免疫風濕科主任 、 中藥臨床試驗中心主任 人體試驗委員會前主任委員
  • 2. Integrative Medicine
    • a combination of
    • mainstream medical therapies
    • and
    • Complementary and alternative medicine (CAM)
    • for which there is high-quality scientific evidence of safety and effectiveness
  • 3. The Evidence Pyramid
  • 4. 新藥開發流程 Scale-up 臨床前研究 臨床試驗 新藥審核 12-24 months 1-4 month 9-12 months 12-24 months 6-18 months Phase II Phase IV Pharmacology and Pharmacokinetics Animal Safety Testing Submit IND Submit NDA NDA Approval Formulation Chemistry and Physical Characterization Phase III 新藥監視 Botanicals with historical documentation of safe human use
  • 5. Ask a good (exciting) question before designing a clinical trial
    • Unmet medical needs
      • In view of holistic medicine
      • Complimentary to mainstream medicine
    • Unanswered questions
      • Critical appraisal of current evidence
    • Answerable
      • Practical methodology
  • 6. How to ask a goog question? ~From good daily patients care
    • Delicate care of individual patient
    • Detail records
    • Collect patients
    • Setup database
    • Thinking…
  • 7. Clinical Trials Design
    • Case series, Open exploratory study
    • Phase II Randomized controlled trial
      • Dose range study is necessary
      • Two stage design is a trend
      • DBPC trial is preferred
    • Phase III Randomized controlled trial
  • 8. Uncontrolled studies
    • Case series, Open study
    • Needs
      • Scientific records
      • Simple and well accepted endpoints
      • Clear documentation
  • 9.  
  • 10.  
  • 11. Defects of Uncontrolled studies
    • Disease natural course
    • Placebo effect
    • Horthorn effect
    • Regression to the mean
  • 12. 臨床試驗設計的 Gold standard ~ 隨機對照試驗 ( randomized controlled trials )
  • 13. Structure of Randomized Control Trials Randomized Endpoints Trial subjects Treatment Control
  • 14. Indications selection
    • Unmet needs
      • Important diseases
      • unsatisfactory efficacy or safety
      • TCM better than western medicine
    • For examples:
      • Cancer
      • Cardiovascular disease
      • Degenerative diseases: OA, dementia…
      • Immunological diseases: allergy, autoimmune disease…
      • Functional diseases: neurosis, aging…
  • 15. 選病 Trial subjects selection
    • Western diagnosis
      • May plus objective operable Chinese syndrome (pattern)
      • Diagnostic criteria
    • Inclusive criteria
    • Exclusive criteria
  • 16. Botanical Applications in FDA (as of December 31, 2007)
  • 17. 選方 Trial intervention
    • Traditional TCM formula
      • Licensed drug indication
      • Off-label use
    • New TCM drugs
      • New TCM formula
      • Crude extract of single herb or mixture
      • Pure compound
    • Functional foods
  • 18. How to find a good TCM intervention for clinical trial?
    • Literatures review
    • Modern research
    • Expert’s opinions
    • Pilot clinical trials
  • 19. 中草藥新藥臨床試驗 (IND) 申請須知
    • 下列情況下, 可暫不提供標準的藥理毒理試驗:
      • 傳統方
      • 已上市之非傳統方
      • 未超過傳統經驗範圍之新複方
      • 適當萃取或部份純化之傳統方 : 純化後之劑量不超過傳統經驗者,若能依學理推測其為安全者,在密切監測的臨床試驗條件下,可暫不提供藥理毒理試驗,但須視個案而定。
  • 20. Basic Principles in the FDA Botanical Guidance
    • Further purification not required
    • Identification of active constituents not essential
    • But Chemistry/Manufacturing controls will be extended to raw materials
    • Non-clinical evaluations may be reduced or delayed
    • Same level of clinical efficacy/safety requirements as non-botanical drugs
  • 21. Evidence of prior/current uses
    • Documentation of marketing history (volume of sales).
    • Referenced in CAM literatures, textbook, compendia
    • Contemporary scientific reports
    • All types of old data will be considered .
  • 22. Structure of Randomized Control Trials Randomized Endpoints Trial subjects Treatment Control
  • 23. Methods of control
    • Placebo control
      • 目的在於克服對照組病人由於心理因素所造成的偏倚 (bias)
      • 常用無藥理作用的乳糖、澱粉等 , 安慰劑要求在外觀、顔色、形狀與試驗藥物完全一致
      • 要特別注意醫療道德上的可行性。
    • Standard control (active control)
      • 研究藥物的療效時,可以公認的常規有效療法作爲對照。
  • 24. “Bad” controls
    • Self control (before-and-after study)
      • 如用藥前後的自身對比觀察;
      • 對照與實驗在同一物件身上進行,例如身體對稱部位的比較觀察
    • Historical control
      • 已先前研究之結果為對照
      • 只適用於”不隨時空環境不同而改變結果”之疾病
    • Blank control
      • 在對照組不加任何處理的 “ 空白 ” 條件下進行觀察。
  • 25. Add-on therapy design
    • Standard therapy as background for all arms
    • Add-on TCM or placebo to see the addictive effect
    • Ethic consideration
    • Better compliance
    • As complimentary therapies
  • 26. Controlled trial: Drug A and B in the treatment of obesity
    • Sample size: 30 in each arm
    • Trial subjects: obesity
    • Intervention: Drug “A” or “B”
    • Duration: 14 days
    • Endpoint: body weight
    • Result: in arm A: 100 kg to 50kg, in arm B: 80 kg to 40 kg.
    • Conclusion: Drug A is better than B in reducing body weight?
  • 27. Double blind +/- double dummy Randomization Endpoints Trial subjects “ A” "Placebo” or “B”
  • 28. 隨機化 Randomization
    • 每一個研究物件或觀察單位都有完全均等的機會被抽取或分配到某一組
    • 不受研究者或研究物件主觀意願所左右。
    • 隨機 才能有”可比較性” ( Baseline comparability)
  • 29. Randomization
    • 簡單隨機化 :可通過抛擲硬幣、抽籤、摸球、 亂數表 來完成。
    • 區組隨機化 :根據受試者進入研究的時間先後順序,將其分成內含相等例數 ( eg. 4, 6, 8 ) 的若干區組,而後,區組內的受試者被隨機分配至不同組別。
    • 分層隨機化 : 依研究需要的某些變項( eg. BMI, gender )劃分為互斥的若干層,然後確認各層在母群體中的比例,接著按此比例分別自每一層利用隨機抽取樣本 。
  • 30. Endpoints
    • Scientific: well accepted, clear and operable outcome measurements
    • Survival> QOL>Symptomatic>Laboratory
    • Surrogate endpoints
    • TCM endpoints if operable
    • Primary and secondary endpoints
    • Safety and efficacy
  • 31. 盲法( Blind Method )
    • 受試者或研究人員,可能導致對效果判斷的偏倚,可通過盲法來控制.
    • 可行性及倫理考量
    • Single blind
      • 只有研究者知道,而受試者不知道。
    • Double blind
      • 研究者(包括資料分析者)和受試者雙方都不知道。
  • 32. 雙虛擬設計 (double-blind, double-dummy)
    • 不同治療組別藥物劑型不同時,可採取雙盲、雙虛擬 (double-blind, double-dummy) 設計,分別有試驗用藥及對照藥的安慰劑,亦可以解決雙盲作業執行上的困難。
  • 33. Study design: RCT Active group,36 week -4 0 4 8 12 screening randomization end of trial Inactive group, 24 中藥方劑治療僵直性脊椎炎之先導性臨床試驗 A ( NSAID ) B ( Sulfasalazine ) C (小活絡丹) D (龜鹿二仙膠) E (左歸丸)
  • 34. 中藥方劑治療僵直性脊椎炎之先導性臨床試驗 Results
    • In active AS patients , 33.33% of NSAID arm, 41.67% of sulfasalazine arm, and 16.67% of TCM formula 1( 小活絡丹 ) arm fit the ASAS response criteria.
    • In inactive AS patients , 9.1% of TCM formula 2 ( 龜鹿二仙膠 ) and 25% of TCM formula 3 ( 左歸丸 ) got response.
    • TCM formula 2 ( 龜鹿二仙膠 ) & TCM formula 3 ( 左歸丸 ) gave significant improvement in functional index and QOL score .
    • No significant adverse events were found.
  • 35. Dose ranging Phase II/III trial design Meet all criteria Randomization (~ 588 patients) 20% 40% 40% ~ 196 patients ~ 392 patients
  • 36. Crossover Clinical Trial Drug B Drug A W A S H O U T Phase 1 Period Eligible Patients /subjects Drug A Drug B Informed consent Drug B Drug A Phase 2
  • 37. 平行設計與交叉設計
    • 平行設計 (parallel design) :每位受試者僅能接受一種治療,也就是說各治療組間彼此互為獨立。由於統計模式的應用上無需做許多的假設即可成立,許多傳統方法皆能適用,因而被較廣泛地使用。
    • 交叉設計 (crossover design) :交叉設計則每位受試者可以在不同的時段 (period) 接受不同的治療,惟兩個治療時段間必須有沖洗期 (wash-out period) ,以避免繼續效應 (carryover effect) 。
  • 38. Adaptive designs
    • Stopping trial early due to safety, futility, or efficacy
    • Dose finding at stage 1
    • Interim analysis
    • Sample size re-estimation
    • Adaptive randomization
  • 39.  
  • 40. 臨床研究的執行
    • 研究計畫書 protocol
    • 優良臨床試驗準則 Good clinical practice
    • 個案報告表 Case Report Form
    • 安全性 Adverse events
    • 試驗藥品之管理
    • 資料處理與分析
    • 品質保證及品質管制
  • 41. Chinese Medicine Clinical Trial Center GCRC (General Clinical Research Center)
    • SMO (site-management organization) model granted by the DOH, Taiwan
    SMO (site-management organization) GCRC (General Clinical Research Center) CMCTC Chinese Medicine Clinical Trial Center Administrative 2 assistants Clinical affairs 1 CRA/manager 4 CRC Data management 1 Statistic PhD 2 Statistic MS 2 MD 1 Pharmacist 20 Consultants
  • 42. 臨床試驗管理中心
    • 協助全院醫師臨床試驗之
      • 設計與規劃
      • 合約簽署
      • IRB 之送件審查
      • 提供研究護士
      • 提供專責藥師
      • 場地設備
      • 研究物品文件管理及儲存
      • 統計分析
    • 教育訓練
    • 院內對外相關研究單位聯繫的窗口
  • 43. 中山醫學大學附設醫院 中藥臨床試驗中心 研究重點
    • 整合醫學與另類醫學
    • 中草藥臨床研究
    • 保健食品及營養補充品
    • 過敏 , 免疫及風濕病之治療
      • 關節炎、痛風、僵直性脊椎炎
      • 過敏、乾癬
      • 免疫調節
    • 臨床試驗服務平台
    • 中草藥暨機能性食品臨床研究中心
    • 生物科技之產學合作窗口
  • 44.  
  • 45. 中醫藥臨床研究發展方向
    • 注意中藥的 GAP 、 GMP 、 CMC
    • 以國際公認之療效評估指標、現代方法學,建立中醫特色的研究設計
    • 臨床試驗要符合 ICH-GCP 精神,採國際高規格要求
    • 整合研究資源
    • 創造產業價值
  • 46. Contact us: CSMUH Chinese Medicine Clinical Trial Center http://www.csh.org.tw/into/herb James Cheng-Chung Wei, MD, PhD ( 魏正宗 ) [email_address]