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1.2. Clinical Trial Protocol.pdf
- 1. Clinical Trial Protocol Kursusdan Pelatihan Metodologi Uji Klinik Jakarta, 3 Maret 2015 Arini Setiawati Clinical Study Unit Faculty of Medicine, University of Indonesia
- 2. Outline of aClinical Trial Protocol (1) ♦ ♦ ♦ ♦ Introduction - The disease - The drug to be studied - Study rationale - Study question / objective Ethical New 2 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - Study hypothesis (if applicable) ♦ ♦ ♦ ♦ Subjects / Patients - Study population - Inclusion criteria - Exclusion criteria New
- 3. Outline of aClinical Trial Protocol (2) ♦ ♦ ♦ ♦ Design - Type of design - Study drugs - Control groups - Patient allocation (randomization) dosage treatment period placebo standard drug 3 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - Patient allocation (randomization) - Intervention (open / blind) - Concomitant medications ♦ ♦ ♦ ♦ Efficacy assessment ♦ ♦ ♦ ♦ Efficacy endpoints prohibited permitted primary secondary
- 4. Outline of aClinical Trial Protocol (3) ♦ ♦ ♦ ♦ Sample size ♦ ♦ ♦ ♦ Dropouts & withdrawals ♦ ♦ ♦ ♦ Compliance ♦ ♦ ♦ ♦ Safety assessment ♦ ♦ ♦ ♦ Data management AEs SAEs 4 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ ♦ ♦ ♦ Data management ♦ ♦ ♦ ♦ Data analysis - Efficacy analysis - Safety analysis ♦ ♦ ♦ ♦ Title of CT ♦ ♦ ♦ ♦ References ITT PP
- 5. Ethical approval ♦ ♦ ♦ ♦ TheCT protocol with the informed consent form should be approved by the Ethics Committee before initiating the study 5 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ ♦ ♦ ♦ Informed consent approved by the EC should be obtained from each subject before screening the subject
- 6. Background of aClinical Trial explain the rationale for conducting the study Research question = Objective of the study 6 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 = the uncertainty that the investigator wants to resolve by conducting the study – for all studies (analytic & descriptive) • Primary research question / objective : only 1 • Secondary research questions / objectives
- 7. FINER Criteria fora Good Research Question Feasible : Adequate number of subjects Adequate technical expertise Affordable in time & money Manageable in scope Interesting : To the investigator Novel : Confirms or refutes previous findings Extends previous findings 7 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 Extends previous findings Provides new findings Ethical : Substantive Ethics : equipoise (< 2 : 1) Procedural Ethics : Ethics Committee, Informed Consent Relevant : To scientific knowledge To clinical & health policy To future research directions Cummings et al, 2001 Lilford, 1992
- 8. Research hypothesis = thetemporary answer to the research question that will be tested in the study – only for analytical studies (not for descriptive studies) ≠ ≠ ≠ ≠ statistical hypothesis • Research hypothesis : only 1 8 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 • Research hypothesis : only 1 - from primary objective - for sample size calculation • Several research hypotheses of similar importance - from primary & secondary objectives - calculate sample size for each hypothesis and take the largest sample size
- 9. Subjects / Patients Selectioncriteria = Eligibility criteria • Inclusion criteria : target population that are accessible - clinical characts : diagnostic criteria & prognostic factors - demographic characts : age, gender, etc. - geographic characts : study site 9 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - geographic characts : study site - temporal characts : study period • Exclusion criteria : - contraindications : hypersensitivity, pregnancy, etc. - precaution : liver dis, renal dis, elderly, etc. - ethical problem : children, etc. - compliance problem : alcoholics, drug abusers, etc
- 10. CT Design A. Noncomparative(open study) - no control group - before & after treatment comparison 10 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 B. Comparative - with control group - between treatment comparison
- 11. Comparative CTs (1) 1.Parallel groups - any drug & any disease → → → → mostly used - adequate run-in period, except infectious disease - large intersubject variation → → → → large number of 11 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - large intersubject variation → → → → large number of subjects required 2. Matched pairs - parallel groups matched in prognostic factors - rarely used – difficult to find the pair
- 12. Comparative CTs (2) 3.Cross-over design : 2-way, 3-way Group 1 Treatm. A A Group 2 Treatm. B B Period I Period II - very powerful design, because each subject becomes his/her own control 12 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 his/her own control - chronic relatively stable disease - order effect - symptomatic drug - period effect - run-in period - carry-over effect - wash-out period • intrasubject variation small • number of subject much smaller • longer follow-up time per subject → → → → more dropouts
- 13. Comparative CTs (3) 4.Factorial design - parallel groups - each combination of variable = 1 group eg. HOPE study : var. 1 = ramipril vs placebo var. 2 = vit. E vs placebo 13 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 Ramipril Pla Ram Vit E Ram + vit E Pla Ram + Vit E Pla E Ram + Pla E Pla Ram + Pla E - there may be interaction among variables
- 14. Comparative CTs (4) 5.Latin square design 6. Sequential design rarely used 14 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015
- 15. Control Groups (1) ♦ ♦ ♦ ♦to quantify the therapeutic & toxic effects of a new drug, there are 2 usual standards of reference : a) placebo 15 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 a) placebo b) standard drug (the best treatment available)
- 16. Control Groups (2) a)Placebo - in general : only in the absence of existing proven th/ - even if proven therapy is available, it may be ethically acceptable in case of : * the treatment response is only subjective (for mild dis.) (to control subjective response in efficacy & safety of the drug) * self-limiting disease * spontaneous remission period to distinguish between 16 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 * spontaneous remission period a true therapeutic effect or spontaneous changes in the course of the disease / symptoms * minor condition and no additional risk of serious or irreversible harm (eg. mild to mod. hypertension / T2DM for 3 months) * escape drug is provided - add-on therapy (on standard drug or best supportive care) to distinguish between
- 17. Control Groups (3) b)standard drug : the best current treatment - dangerous, severe or life-threatening disease - status of the new drug / for marketing approval by 17 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - status of the new drug / for marketing approval by BPOM - long-term studies to assess the effect of drug on mortality & morbidity
- 18. Patient allocation Random allocationis a must for all comparative clinical trials → → → → to obtain comparable groups in baseline characteristics, esp. in prognostic factors → → → → to avoid selection bias in treatment assignment 18 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 → → → → to avoid selection bias in treatment assignment → → → → to permit use of statistical tests a) simple randomization b) block randomization c) stratified randomization
- 19. Intervention ♦ ♦ ♦ ♦ Drug dosageof test drug & reference drug should be equipotent ! ♦ ♦ ♦ ♦ Drug administration a) double blind → → → → unbiased response & unbiased measurement of response * double dummy b) single blind – patient blind (usually) or 19 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 b) single blind – patient blind (usually) or investigator blind c) unblind – only if ethically not feasible for blindness d) unblind, with PROBE design ♦ ♦ ♦ ♦ Duration of treatment / observation long enough to show sustained efficacy
- 20. Concomitant medications ♦ ♦ ♦ ♦ shouldnot affect assessment of response ♦ ♦ ♦ ♦ if any effect → → → → become baseline therapy for both groups 20 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ ♦ ♦ ♦ escape / rescue medication – becomes an objective parameter for drug efficacy
- 21. Response variables (1) ♦ ♦ ♦ ♦Study endpoints : response variables chosen to assess drug effects ♦ ♦ ♦ ♦ Primary endpoint : - preferably only 1 - should be clinically relevant - based on the primary objective of the study ♦ Secondary endpoints : other drug effects that may / 21 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ Secondary endpoints : other drug effects that may / may not related to the primary endpoint (1 or more) ♦ Surrogate endpoint : replace clinical endpoint because can be measured at much shorter time, but must be predictive of clinical endpoint
- 22. Response variables (2) Measurementof endpoints : - objective methods should be used where possible and when appropriate - both subjective and objective methods should be 22 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - both subjective and objective methods should be validated and meet appropriate standards for accuracy, precision, reproducibility, reliability, and responsiveness (sensitivity to change over time)
- 23. Sample size calculation(1) ♦ ♦ ♦ ♦ Aim : able to answer the research question : ↓ ↓ ↓ ↓ - in case of superiority trial : able to make the minimal clinically significant difference determined by the investigator reach statistical significance 23 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 reach statistical significance - in case of equivalence trial : able to confirm statistically the small clinically nonsignificant difference
- 24. Sample size calculation(2) ♦ ♦ ♦ ♦ calculate for the primary objective only or for each hypothesis → → → → take the largest sample ♦ ♦ ♦ ♦ calculate based on the primary efficacy variable : - numerical scale 24 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - numerical scale - nominal 2 categories → → → → 2 proportions - ordinal scale → → → → make 2 proportions ♦ ♦ ♦ ♦ too small → → → → false negative
- 25. Dropouts ∼ ∼ ∼ ∼ Withdrawals(1) ♦ ♦ ♦ ♦ ≠ ≠ ≠ ≠ ineligible patients ♦ ♦ ♦ ♦ Eligible pts - drop from the study before end of study, due to : * reasons unrelated to treatment : - move to another city / country 25 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - move to another city / country - loss of patient’s interest - too busy to continue participation - etc. * unknown reason, not come for visit & out of contact → → → → loss to follow-up ♦ ♦ ♦ ♦ These dropouts are calculated in sample size estimation → → → → withdraw
- 26. Dropouts ∼ ∼ ∼ ∼ Withdrawals(2) ♦ ♦ ♦ ♦ Eligible pts who drop from the study or withdrawn by the investigator due to reasons related to treatment : - adverse events before end of study 26 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - inefficacy of the study drug are not drop-outs, and should be included in the analysis ! ♦ ♦ ♦ ♦ These dropouts are not replaced
- 27. Compliance ♦ ♦ ♦ ♦ methods tominimize noncompliance - clear information of the CT → → → → clearly under- standing patients - simple dosage - patient diary card 27 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - patient diary card - adequate supervision ♦ ♦ ♦ ♦ Measures to check compliance - excess number of tablets → → → → count number of tablets returned - measure drug level in serum / urine
- 28. Adverse events (AEs) ♦ ♦ ♦ ♦all AEs are recorded, irrespective of their relationship to study drugs ♦ ♦ ♦ ♦ the relationship to study drugs, according to the investigator : - probably related, - possibly related, - unlikely 28 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 - unlikely ♦ ♦ ♦ ♦ serious AEs (SAEs) : reported to sponsor & CRO within 24 hrs, followed promptly by detailed, written reports ♦ serious & unexpected ADRs : reported to EC & NRA within 15 calender days (Indonesia) = SUSAR = susp. unexp. serious adv. reaction In Indonesia : all SAEs are reported
- 29. Efficacy analysis :ITT vs PP (1) 1) Intent-to-treat (ITT) analysis * include all randomized pts, regardless of compliance with protocol * without eligibility violation * take at least one dose of trial medication * have at least one data post randomization → → → → 29 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 * have at least one data post randomization Full Analysis Set (FAS) - last observation carried forward (LOCF) - pragmatic approach : more likely to mirror the actual clinical practice - bias is minimal - secure foundation for statistical tests
- 30. Efficacy analysis :ITT vs PP (2) 2) Per-protocol (PP) analysis * include only pts who comply with the protocol : have a certain pre-specified minimal exposure to treatment * bias (may be severe) because adherence to the 30 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 * bias (may be severe) because adherence to the study protocol may be related to treatment & outcome – explanatory approach In confirmatory trials : used both ITT & PP analyses - superiority trials : ITT – analysis set of choice - noninferiority trials : ITT & PP – equal importance & should lead to similar conclusions
- 31. Efficacy analysis :ITT vs PP (3) ♦ ♦ ♦ ♦ specify the statistical test used for every response variable to be analyzed ♦ ♦ ♦ ♦ planned analysis : to answer the study objective / hypothesis 31 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 hypothesis ♦ ♦ ♦ ♦ interim analysis - after min. 50% of the calculated sample size - ↓ ↓ ↓ ↓ level of significance α α α α
- 32. Safety analysis ♦ ♦ ♦ ♦ includepts who received at least one dose of study medication (although ineligible) and have at least one post-baseline data ♦ ♦ ♦ ♦ compare the incidence rates of (descriptively) 32 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ ♦ ♦ ♦ compare the incidence rates of (descriptively) - all adverse events - AEs considered possibly & probably related to the study medications (= ADRs) - abnormal laboratory values
- 33. Title of theCT ♦ ♦ ♦ ♦ consistent with the content ? ♦ ♦ ♦ ♦ concise but informative - not too short → → → → not specific - not too long → → → → discard words such as “study on”, “observation on” 33 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 “observation on” ♦ ♦ ♦ ♦ site & period : - included only if the results will be specific for the respective site & period - usually not included if the results will be not different anywhere & anytime
- 34. References ♦ ♦ ♦ ♦ support “Background”,“Sample size” and “Discussion” ♦ ♦ ♦ ♦ as up-to-date as possible 34 Kursus dan Pelatihan Metodologi Uji Klinik, 3 - 5 Maret 2015 ♦ ♦ ♦ ♦ as up-to-date as possible
- 35.