کارگاه آموزشی اصول طراحی و اجرای كارآزمايي باليني

1. کارگاه آموزشی اصول طراحی و اجرایكارآزمايي باليني Workshop on Designing and Conducting Clinical Trials A.A. Keshtkar MD, MPH, PhD

2. تعاریف، تاریخچه و کلیات A.A. Keshtkar MD, MPH, PhD

3. تعريف: نوعي از مطالعات مداخله‌اي است كه: • مداخله معمولا يك دارو يا يك روش درماني (جراحي) يا پيشگيري است. • نمونه هاي مورد مداخله بيماران هستند. A.A. Keshtkar MD, MPH, PhD

4. خصوصيات كارآزماييهاي باليني در شرايط اپتیمم: • گروه كنترل همزمان وجود دارد • مداخله بطور تصادفي تخصيص داده ميشود Randomized controlled trial (RCT) A.A. Keshtkar MD, MPH, PhD

5. خصوصيات كارآزماييهاي باليني در شرايط ايده‌ال: • گروه كنترل همزمان وجود دارد • مداخله بطور تصادفي تخصيص داده ميشود • حداقل در دو گروه (بيماران و ارزيابي كنندگان باليني) كورسازي (Blindness) انجام ميشود Randomized double-blind controlled trial A.A. Keshtkar MD, MPH, PhD

6. تاريخچه كارآزماييهاي باليني : • قبل از 1950 • عمدتا كارآزماييهاي بدون گروه كنترل • در 1948 اولين كارازمايي كنترل دار: اثر استرپتومايسين در درمان سل • بعد از 1950 • كارآزمايي فيلد field trial واكسن پوليو salk • كارآزماييهاي كموتراپي كانسرها • كارآزماييهاي MI • كارازماييهاي صنايع دارويي A.A. Keshtkar MD, MPH, PhD

7. تاريخچه كارآزماييهاي باليني : A.A. Keshtkar MD, MPH, PhD

8. تقسيم بندي‌هاي كارآزماييهاي باليني : • تقسيم بندي از نظر نوع مداخله • تقسيم بندي از نظر شواهد مورد نياز براي يك مداخله • تقسيم بندي از نظر طرح مطالعه A.A. Keshtkar MD, MPH, PhD

9. تقسيم بندي‌ كارآزماييهاي باليني از نظر نوع مداخله: • كارآزمايي باليني: مداخله يك روش درماني است. • كارآزمايي فيلد: مداخله يك روش پيشگيري است. A.A. Keshtkar MD, MPH, PhD

10. تقسيم بندي‌ كارآزماييهاي باليني از نظر نوع شواهد: • كارآزمايي باليني فاز يك: • هدف: تعيين safety دارو، مطالعه بر روي داوطلبان سالم • كارآزمايي باليني فاز دو: • هدف: تعیین اثرات درمانی در مقیاس کوچک تعيين شاخصهاي فارماكولوژيك داروها، مطالعه بر روي بيماران • كارآزمايي باليني فاز سه: • هدف: تعيين اثرات باليني و پاسخ درماني دارو در مقياس بزرگتر • كارازمايي باليني فاز چهار: • هدف: تعيين عوارض پس از عرضه در بازار دارويي و عوارض دراز مدت داروها A.A. Keshtkar MD, MPH, PhD

11. تقسيم بندي‌ كارآزماييهاي باليني از نظر نوع شواهد: Circulation 2007;115;1164-1169 A.A. Keshtkar MD, MPH, PhD

12. تقسيم بندي‌ كارآزماييهاي باليني از نظر طرح مطالعه: • كارآزمايي باليني بدون گروه كنترل: • اثر ممكن است ناشي از شانس باشد • متغيرهاي مداخله گر يا مخدوش كننده قابل كنترل نيست • كارآزمايي باليني با كنترل تاريخي before-after trial: • تفاوت در دو گروه ممكن است عامل ايجاد كننده سوگرايي bias باشد • معيارهاي انتخاب بيماران، تعيين پاسخ درماني و ... ممكن است در دو مقطع زماني متفاوت باشد. • RCT با طرح موازي (دو بازوي درماني يا بيشتر) : • گروه كنترل دارد، درمان تصادفي تخصيص داده ميشود • افراد هر گروه درماني تا انتهاي مطالعه از يك درمان خاص استفاده ميكنند • Cross-over RCT: • گروه كنترل دارد، درمان تصادفي تخصيص داده ميشود • نوع درمان هر گروه در مقطعي از مطالعه جابجا ميگردد A.A. Keshtkar MD, MPH, PhD

13. A Outcome assessment patients B Outcome assessment Outcome assessment A patients Wash-out period Outcome assessment B كارآزمايي باليني طرح موازي: كارآزمايي باليني طرح cross-over: A.A. Keshtkar MD, MPH, PhD

14. مراحل اصلي‌ كارآزماييهاي باليني : • مشخص نمودن اهداف/ فرضيه (فرضیات) مطالعه • تعريف eligible criteria (معيارهاي ورود و خروج از مطالعه) • انتخاب بيماران (در صورت نياز انتخاب تصادفي) • تخصيص تصادفي درمان/ دارونما يا درمانها به گروهها • تصميم گيري در مورد كورسازي blindness • پيگيري بيماران • ارزيابي پاسخ درماني و جمع آوري داده ها • تجزيه و تحليل نتايج A.A. Keshtkar MD, MPH, PhD

15. Goals and objectives of Clinical Trials A.A. Keshtkar MD, MPH, PhD

16. The ultimate goal of Clinical Trials • Obtaining an unbiased inference with possibly best precision in order to scientifically address the clinical questions regarding the study drug / intervention under investigation with respect to a target patient population A.A. Keshtkar MD, MPH, PhD

17. Most common mistake in the goal setting: The investigator(s) often attempts to answer all possible questions with respect to a certain therapeutic area in a single trial regardless the size of the trial. A.A. Keshtkar MD, MPH, PhD

18. Example: effect of test drug on postmenopausal osteoporosis Primary Objectives: 1. This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the efficacy based on bone mineral density (BMD) of the test drug under investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis. 2. This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to evaluate the safety of the test drug under investigation at dose y, frequency z, compared to a placebo, in the treatment of postmenopausal women with osteoporosis. A.A. Keshtkar MD, MPH, PhD

19. Example: effect of test drug on postmenopausal osteoporosis Secondary Objectives: 1. To evaluate the effectiveness of the test drug under investigation on the incidence of vertebral fractures. 2. To evaluate the effectiveness of the test drug under investigation on biochemical markers of bone turnover. A.A. Keshtkar MD, MPH, PhD

20. Example: 1 year survival following non small cell lung cancer treatment Primary Objectives: This is a randomized, parallel-group trial to demonstrate that the one-year survival of the patients with pretreated advanced (Stage IIIB/IV) non-small-cell lung cancer (NSCLC) receiving the oral investigational drug is not inferior to those receiving intravenous (IV) docetaxel. A.A. Keshtkar MD, MPH, PhD

21. Example: 1 year survival following non small cell lung cancer treatment Secondary Objectives: evaluate overall survival, time to progression, response rate, time to response, improvement in quality of life, and qualitative and quantitative toxicities. A.A. Keshtkar MD, MPH, PhD

22. Target population and Patients selection A.A. Keshtkar MD, MPH, PhD

23. Eligibility criteria: Inclusion & Exclusion criteria • patients must meet allthe inclusion criteria and patients meeting anyof the exclusion criteria will be excluded from the study. • The strict criteria increases relaibility and decreases generalizability of study results. • The inclusive criteria increases generalizability and confounds study results. A.A. Keshtkar MD, MPH, PhD

24. Example: RCT of clinical and microbiologic efficacy and safety of an antibiotic agent in the treatment of febrile episodes in neutropenic cancer patients A.A. Keshtkar MD, MPH, PhD

25. Single study site vs Multicenter study sites • To recruit enough number of patients and to complete the study within the time frame, as an alternative, a multicenter trial is usually considered • How many study sites should be used? • As a rule of thumb, the number of sites should not be greater than the number of patients within each selected study site A.A. Keshtkar MD, MPH, PhD

26. Selection of Control Group in Clinical Trials A.A. Keshtkar MD, MPH, PhD

27. Two main options for selecting control group: • concurrent control groupas one chosen from the same population as the test group • external or historical control is chosen separated from the target patient population treated in the same trial A.A. Keshtkar MD, MPH, PhD

28. 4 types of treatment that a patient can receive in the control group: (1) placebo (2) no treatment (3) different dose or regimen of the test drug, (4) different active treatments A.A. Keshtkar MD, MPH, PhD

29. Different Designs of Clinical Trials A.A. Keshtkar MD, MPH, PhD

30. Parallel Group Design Definition: a parallel group design is a complete randomized design in which each patient receives one and only one treatment in a random fashion • two types of parallel group design: • group comparison (or parallel-group) designs • matched pairs parallel designs A.A. Keshtkar MD, MPH, PhD

31. Parallel Group Design Example: three-group parallel design with a test treatment and two controls Run-in Periods: Before patients enter a clinical trial, a run-in (or lead-in) period of placebo, no active treatment, dietary control, or active maintenance therapy (e.g., diuretic and/or digoxin in heart failure studies) is usually employed prior to randomization A.A. Keshtkar MD, MPH, PhD

32. Parallel Group DesignExamples of Parallel Group Design in Clinical Trials of Metformin A.A. Keshtkar MD, MPH, PhD

33. Cluster Randomized Design Definition: in cluster randomized designs, randomization is performed at the cluster level rather than at the subject level. Thus, the unit of analysis may and may not be the same as the unit of randomization. A.A. Keshtkar MD, MPH, PhD

34. Cluster Randomized Design Two commonly encountered mistakes in most cluster randomized trials: 1. Although the trials adopt a cluster randomization, the analysis of data completely ignores this fact and uses subject as the unit of analysis. 2. Sample size estimation fails to take into consideration the variance inflation factor A.A. Keshtkar MD, MPH, PhD

35. Cluster Randomized DesignExample: Hutchinson Smoking Prevention Project (HSPP) A.A. Keshtkar MD, MPH, PhD

36. Crossover Design • Definition: a modified randomized block design in which each block receives more than one treatment at different dosing periods. A block can be a patient or a group of patients. Patients in each block receive different sequences of treatments • A crossover design is called a complete crossover design if each sequence contains all treatments under investigation. A.A. Keshtkar MD, MPH, PhD

37. Crossover DesignExample: Standard two-sequence, two-period crossover design p: sequences, q: periodsp * q crossover design (2 * 2 crossover design) A.A. Keshtkar MD, MPH, PhD

38. Crossover DesignAdvantages: (1) It allows a within-patient comparison between treatments, since each patient serves as his or her own control (2) It removes the interpatient variability from the comparison between treatments (3) With a proper randomization of patients to the treatment sequences, it provides the best unbiased estimates for the differences between treatments. A.A. Keshtkar MD, MPH, PhD

39. Crossover Designis implemented under situations: (1) objective measures and interpretable data for both efficacy and safety are obtained (2) chronic (relatively stable) disease are under study (3) prophylactic drugs with relatively short half-life are being investigated (4) relatively short treatment periods are considered (5) baseline and washout periods are feasible A.A. Keshtkar MD, MPH, PhD

40. Crossover DesignExamples of Crossover Design in Clinical Trials of Metformin A.A. Keshtkar MD, MPH, PhD

41. RandomizationandBlinding A.A. Keshtkar MD, MPH, PhD

42. RandomizationConcept: • In nonrandomized controlled trial bias often occurs due to preconceived ideas or perceptions acquired during the study by: • the investigator and supporting staff who might influence reporting response to therapy or adverse events • the patient who might influence compliance, cooperation, or provision of information. A.A. Keshtkar MD, MPH, PhD

43. Randomization MethodsThe old or unacceptable methods (early 1970s): the investigators or patients may be aware of which treatment the patients receive, subjective bias can consciously or unconsciously occur in both the assignment of patients to treatments and the evaluation of clinical outcomes for the treatment under investigation A.A. Keshtkar MD, MPH, PhD

44. Randomization Methods:1. Complete Randomization: • Using Simple Randomization • Properties: • The chance that a patient receives either the test drug or the placebo is 50%. • Randomization of assignments is performed independently for each of the N patients A.A. Keshtkar MD, MPH, PhD

45. Randomization Methods:1. Complete Randomization: • Generated by: • Random numbers table • Statistical softwares • Disadvantage: • Treatment impalance • Decreasing statistical power A.A. Keshtkar MD, MPH, PhD

46. Randomization Methods:2. Permuted-Block Randomization: • مشخص نمودن حجم هر بلوك (مثال: بلوك چهارتايي) • تهيه ليست بلوكها و اختصاص عدد به آنها • AABB(1), ABAB(2), ABBA(3), BBAA(4), BABA(5), BAAB(6), • انتخاب اعداد تصادفي بين 1 تا 6 • ... 5 2 4 1 • مشخص نمودن ليست تخصيص درمان treatment assignment • A-A-B-B-B-B-A-A-A-B-A-B-B-A-B-A….. A.A. Keshtkar MD, MPH, PhD

47. Randomization Methods:2. Permuted-Block Randomization: • As block size increases, the potential selection bias decreases • Although the use of random block size can reduce the selection bias, it cannot completely eliminate the bias. • The only way to eliminate the selection bias is to enforce a double-blinded procedure during the entire course of study for which both investigators and patients are blinded to block size and treatment assignments. A.A. Keshtkar MD, MPH, PhD

48. Blinding (Masking): • Randomization + Blinding = No bias in RCT • Types of blindness: • Open-label • Single blind • Double blind • Triple blind A.A. Keshtkar MD, MPH, PhD

49. Follow-upandOutcome Assessment A.A. Keshtkar MD, MPH, PhD

50. Follow-up DurationDeterminants: • Treatment duration • The trial outcomes (early vs late outcomes) • Biologic concepts A.A. Keshtkar MD, MPH, PhD