1. مسائل اخلاقي در كارآزمايي باليني دكتر اكبر فتوحي استاديار اپيدميولوژي دانشكده بهداشت و انستيتو تحقيقات بهداشتي

2. منابع

3. فهرست مطالب چرا كارآزمايي باليني؟ سود و زيان مراحل كارآزمايي باليني طرحهاي (design) كارآزمايي باليني مسائل اخلاقي در اجراي كارآزمايي باليني (GCP) دارونما رضايت نامه كارآزمايي باليني در گروه هاي خاص تضاد منافع (Conflict of interest) پرداخت غرامت در كارآزمايي باليني كميته هاي اخلاق و كارآزمايي باليني انتشار نتايج كارآزمايي باليني

4. چرا كارآزمايي باليني؟ Randomized clinical trials are the “ gold standard ” of the treatments evaluation. When is drug development worth pursuing? When is a clinical trial appropriate? An example: Hormone Replacement Therapy (HRT) Four core ethical principals in clinical trials: Authonomy Beneficence Non-maleficence Justice

5. بحث سود و زيان در كارآزمايي باليني عدالت در سود و زيان

6. مراحل كارآزمايي باليني Stage I (preclinical studies) Stage II (clinical studies) Phase 1 Phase 2 Phase 3 Phase 4

7. فازهاي كارآزمايي باليني PhaseParticipantsResearch questions NumberCharacteristics I20-80Usually young, healthy, male volunteers Tolerability Pharmacokinetics Pharmacodynamics II100-300Patients rather than volunteers Effectiveness Dosage, Safety III1,000-3,000Approximate real-life patient population Compare to placebo, current treatments Effects of compound on targets, side-effects

8. فازهاي كارآزمايي باليني ( ادامه ) PhaseResearch questions IIIbMarketing – cost/value Compares with market leader Further data on safety and efficacy IVNew formulations Identify best patients Safety assessment

9. طرحهاي (design) كارآزمايي باليني طرح هايي كه براي كم كردن بار اخلاقي كارآزمايي باليني پيشنهاد شده اند : Zelen design Adaptive design Sequential design طرح هايي كه داراي جنبه هاي اخلاقي خاص هستند : Community trials Crossover design

10. Zelen design

11. Adaptive design

12. Sequential design

13. Community trials

14. Crossover design

15. مسائل اخلاقي در اجراي كارآزمايي باليني ( Good Clinical Practice ) پروتكل پايش بيماران گروه كنترل رندميزاسيون كورسازي قطع زود هنگام كارآزمايي باليني بيماريابي و دعوت افراد به شركت در كارآزمايي باليني

16. دارونما آيا استفاده از دارونما اخلاقي است؟ آيا هميشه به گروه شاهد با دارونما نياز است؟ چه مواقعي مي توان از دارونما استفاده كرد؟ دارونما در ناخوشي هاي جزئي و شديد. دارونماي تهاجمي. قوانين مربوط به كاربرد دارونما.

17. دارونما ( ادامه ) When Placebo Controls May be Used: There is no standard treatment Standard treatment has been shown to be no better than placebo Evidence causes doubt about therapeutic advantage of standard therapy

18. دارونما ( ادامه ) When Placebo Controls May be Used: In a population of patients who are refractory to standard treatment and for whom there is no standard second- line treatment Testing add-on treatment to standard therapy when all subjects in the trial receive all treatments that would normally be prescribed

19. دارونما ( ادامه ) When Placebo Controls May be Used: (Controversial Conditions) Many argue that persons with conditions with a low risk of harm (understand as low probability or low magnitude of harm) may be entered into a placebo arm Many argue that placebo controls are ethical when resources are limited and standard treatment is not available

20. دارونما ( ادامه ) Declaration of Helsinki (prior to 2000) In any medical study, every patient-- including those of the control group, if any--should be assured of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in studies where no proven diagnostic or therapeutic method exists (emphasis added).

21. دارونما ( ادامه ) Declaration of Helsinki (2000) The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic, and therapeutic method exists (emphasis added).

22. دارونما ( ادامه ) Declaration of Helsinki (October 2002 statement)... a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:- Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method, or - Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.

23. رضايت نامه Consent - legally effective agreement of the subject or the subject's legally authorized representative based on information that is given to the subject or the representative in language that is understandable Assent - child’s affirmative agreement to participate in research Permission - agreement of parent(s) or guardian to the participation of their child or ward in research

24. رضايت نامه ( ادامه ) Objectives of Informed Consent To Ensure: Voluntariness Comprehension Information To Demonstrate That: Person freely gave consent to participate Consent given by a competent person Person has been given all information Person knows this is research – not treatment

25. رضايت نامه ( ادامه ) Components of Informed Consent Must Include the Following Information: Why research being done? What researchers want to accomplish? What will be done and for how long? Risks & benefits of trial Other treatments available Can withdraw from trial whenever desire Compensation for unexpected injuries

26. كارآزمايي باليني در گروه هاي خاص داوطلبين سالم ( فاز 1 كارآزمايي باليني ) افراد با دانش و آگاهي محدود ( كودكان، افراد با اختلالات رواني يا اختلالات يادگيري ) افراد با اختيار محدود ( زنداني ها، دانشجويان، كارمندان ) افراد با توانايي و منابع محدود ( بيماران با بيماريهاي شديد، فقرا، كشورهاي فقير، اقليت ها )

27. كارآزمايي باليني با داوطلبين سالم در کارآزمايي واکسن و فاز 1 کارآزمايي دارويي غربالگري سلامتي حداکثر ميزان نمونه گيري خون

28. كارآزمايي باليني در افراد با دانش و آگاهي محدود محدود به مواردی که اين افراد بيشترين فايده را از بهبود شيوه درماني ميبرند قبلاً حداقل خطر در مطالعات ثابت شده باشد رضايت نامه از فرد

29. كارآزمايي باليني در افراد با اختيار محدود جذب داوطلب از کارمندان و دانشجويان زندانيان

30. كارآزمايي باليني در كودكان موارد خاصی که تنها کودکان را گرفتار ميکند تعيين اثر بخشی و دوز مناسب در اطفال قبلاً در بالغين اثر بخشی و عوارض قابل قبول ثابت شده باشد. رضايت والدين + رضايت کودک رازداری

31. كارآزمايي باليني در افراد با توانايي و منابع محدود

32. تضاد منافع ( Conflict of interest ) محققين مراكز تحقيقاتي شركتهاي دارويي

33. تضاد منافع ( محققين و مراكز تحقيقاتي )

34. تضاد منافع ( شركتهاي دارويي ) Does the for-profit motivation of industry create un-ethical research? Cost of developing one drug from discovery to market: $250-500 million Average development time- 10 years 3000 drugs in clinical testing each year 60-75 new drugs filed in NDA each year 6-12 new drugs approved each year

35. تضاد منافع ( شركتهاي دارويي ) Do companies design studies likely to favor their products?

36. Protections for Financial Conflicts of Interest Disclosure To institution/IRB/COI committee To patients In journals Management Data safety and monitoring boards (DSMBs) Independent consent monitors Prohibitions Against types/amounts of financial interests By removing researchers from study

37. پرداخت غرامت در كارآزمايي باليني

38. كميته هاي اخلاق و كارآزمايي باليني IRB responsible for such tasks: Review research to ensure that potential benefits outweigh risks Develop and issue written procedures Review research for risk/benefit analysis & proper protection of subjects Issue written notice of approval/disapproval to the Investigator Review and respond to proposed protocol changes submitted by the Investigator Review reports of deaths, and serious and unexpected adverse events received from the Investigator Conduct periodic continuing review of the study, study risks, selection of subjects, privacy of subjects, confidentiality of data, and the consent process

39. انتشار نتايج كارآزمايي باليني International Committee of Medical Journal Editors نويسندگان سپاسگذاري نامه روی مقاله ويراستار, مرورکننده و ناشر مالکيت نتايج

40. Authorship conception and design, or analysis and interpretation of data, or both drafting the article or revising it for critically important intellectual content final approval of the version to be published.

41. Acknowledgements contributions that need acknowledging but do not justify authorship (advice, critical review of study proposal, data collection, participation in clinical trial) acknowledgements of technical help acknowledgements of financial and material support financial relationships that may constitute a conflict of interest.

42. covering letter information on prior duplicate publication or submission elsewhere of any part of the work statement of financial or other relationships that might lead to a conflict of interests statement that the manuscript has been read and approved by all authors the name, address, and telephone number of the corresponding author

43. Editors, peer reviewers and publishers Acceptance or rejection of articles should be on scientific grounds only Peer reviewers must respect and maintain the confidentiality of the unpublished information to which they have privileged access

44. Ownership of results original data must be held by the sponsoring institution Copies of all data may be taken by the researcher