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Clinical trial design


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Clinical trial design

  1. 1. Clinical Trials Design Dr Ritu Budania MBBS , MD
  2. 2. Overview •Introduction • Clinical Trial Designs •Challenges •Application in different phases of trial •Summary
  3. 3. Clinical Research All scientific approaches to evaluate medical disease in terms Prevention Diagnosis Treatment Humans
  4. 4. Clinical research design No intervention Intervention Observational Experimental Comparison group NoYes Analytical study (case control, cohort) Descriptive study Random allocation Yes No Randomized controlled trial Non-Randomised
  5. 5. Types of Clinical trials Treatment trials Prevention trials Quality of life trials Diagnostic trials
  6. 6. Drug development
  7. 7. Clinical Trial Designs
  8. 8. Designs  Parallel  Cross over  Factorial  Randomized withdrawal approach  Adaptive  Superiority  Non-inferiority
  9. 9. Parallel • Subjects are randomised to one of two or more arms • Each arm being allocated a different treatment • Most commonly used design
  10. 10. Eligibilty assessed Consent Control Test drug Randomised
  11. 11. Controls in Clinical Trials 1. Placebo 2.No-treatment 3.Active 4. Dose Response 5. External Controls 5 mg
  12. 12. 1. Placebo Control • Placebo- inert substance – looks exactly like test drug but contains no drug • In trials testing efficacy • Double blinded
  13. 13. Advantages of Placebo control • Minimizes bias • Ability to demonstrate efficacy
  14. 14. When to use placebo? 1.In disease in which no prior drug has been established as - standard therapy 2. Minimal risk, short term study 3.Add-on design
  15. 15. Disadvantages of Placebo Control: 1.Ethical Issues - Lack of treatment -Serious harm( such as death or irreversible morbidity) -Declaration of Helsinki – use of standard treatment as control -Used where minimal risk 2.Patient and physician concerns: -Patients may not enroll -Withdraw
  16. 16. 2. No treatment control • Subjects are randomly assigned to test treatment or to no treatment • Subjects, investigators are not blind to treatment • Bias
  17. 17. 3.Active control Standard treatment exists phase III study designs compare “new drug” to standard or compare standard to combination therapy that involves the standard + “new drug”
  18. 18. • 4.Dose response control • 5.External control Comparability ? Baseline characteristics? No randomization, blinding Bias
  19. 19. Uncontrolled trials • No controls • When- - Determine pharmacokinetic properties of a new drug (phase 1 trial) • Limitation- Bias , as no randomization, less validity than RCT
  20. 20. Run-In Design • Non-compliance
  21. 21. Run-In Design Screen & Consent Placebo Run-In Period R A N D O M I Z ECompliance Unsatisfactory Dropped B A compliance Satisfactory c
  22. 22. 2.Cross over • Each patient gets both drugs • the order in which the patient gets each drug is randomized • Each patient serves as his own control • Avoids between participant variation in estimating intervention effect • Requires a small sample size • Assumptions: –The effects of intervention during first period does not carry over into second period. –Internal and external factors are constant over time
  23. 23. A A B B A followed by B B followed by A ABA BAB ABAB BABA Cross over design with switch-back C.O. design with double switch-back Run in Wash out period
  24. 24. Prerequisites for crossover design • Disease – chronic (asthma, osteoarthritis) stable • Effects of drug should develop fully within treatment period (not for Hit and run type drugs) • Washout periods -sufficiently long for complete reversibility of drug effect • Wash out period- five half lives of drug
  25. 25. Crossover designs- problems 1.Carryover effect 2.Period effect- patients vary from 1 period to another 3.Not useful for acute disease 4.Difficulties in assigning adverse events which occur in later treatment periods to appropriate treatment 5.generally not used in vaccine trials because immune system is permanently affected (or at least affected for a long time)
  26. 26. Use of cross over design: • Bioequivalence studies • Phase I
  27. 27. Parallel Crossover Groups assigned different treatments Each patient receives both treatments Shorter duration Longer Sample size- large Smaller No carryover effect Carryover effect Acute cases Not in acute, Chronic,stable
  28. 28. Latin Square Design A  B  C B  C  A C  A  B I II III 1 2 3 Subjects Period
  29. 29. Greco-Latin Squares Effect of treatment & effect of another factor (eg. ancillary Treatment, diet etc) A  B  C B  C  A C  A  B I II III 1 2 3 Subjects
  30. 30. Intensive Design: Comparing 2 Tts.(A & B) each subject receives same Tt. several times. Period I II III IV V VI Treatment A B B A A B - For short period of Rx/single dose - For testing efficacy of new compound
  31. 31. 3.Factorial design - two or more interventions - Allows study of interactive effects
  32. 32. 2×2 factorial design B only Neither A nor B A onlyBoth A and B Advantages -Two drugs studied at same time -Discover interactions -Test FDC Disadvantages 1.Complexity of trial design 2. Complexity of statistical analysis
  33. 33. 33 Incomplete Factorial Design Eg. depression; if unethical to do nothing • A – Desipramine • B – Congnitive therapy • C – Combination of A & B 3 n eligible A no, B yes A yes, B no A yes, B yes
  34. 34. 4.Randomized withdrawal approach Third, the design is particularly useful in determining how long a therapy should be continued (e.g., post-infarction treatments with a beta-blocker
  35. 35. Group 1 Group II Pt Sex Age IQ Pt Sex Age IQ 1. m 25 95 4 m 25 95 2. f 35 100 5 f 35 100 3. m 45 105 6 m 45 105 5. Matched pairs - Pts. With same characteristics - Expected to respond similarly Group characteristics 2 males 1 female 2 males 1 female Average age 35 yrs. 35 yrs. Average IQ 100 100 Pt 1. matches with Pt 4 2. ‫״‬ ‫״‬ ‫״‬ 5 3. ‫״‬ ‫״‬ ‫״‬ 6 Advantage- Less Variability Group -I Group-II
  36. 36. Clinical trial design innovations • Adaptive Design - allows adaptations or modifications to trial design after its initiation without undermining validity and integrity of trial
  37. 37. 1.Maximum Information Design • interim analyses until the target or maximum information level reached. • Whenever the pre-specified target information level is reached, the patient recruitment is stopped. 2.N-Adjustable Design
  38. 38. 3. Group sequential design prematurely terminating trial based on the results of interim analyses • Early-efficacy stopping • Early futility stopping
  39. 39. (4) Drop-Losers Design - allows dropping of treatment arm(s) during study based on interim analysis results -trial starts with several treatment groups; at each stage, interim analyses are performed - losers (inferior groups) are dropped based on prespecified criteria. -best arm(s) will be retained. -used in a phase-II/III combined trial
  40. 40. 5.Adaptive Randomization Design • Response-adaptive randomization (RAR) - allocation probability is based on response of previous patients. • The purpose is to provide the patients with a better chance of being assigned to the better/best treatment
  41. 41. 42 Superiority Trials Show that new treatment is better than control or standard (maybe a placebo) • Examples: Placebo-controlled efficacy trials Active controlled
  42. 42. Non-Inferiority Trials -Show that new treatment Is not worse that the standard by more than some margin -Active control equivalence trial -Placebo not used -Better tolerated, less dosing
  43. 43. X is non inferior Placebo Active Control DELTA
  44. 44. Multicentric trials 1. Large sample size needed- in less time 2. Availability of eligible patients is a constraint 3. Role of Racial/ Ethnic factors to be studied • Strict protocol compliance by Investigators at all centres • Central monitoring committee • Phase III trials
  45. 45. Challenges in Design: Control of bias (Randomization, Blinding )
  46. 46. Bias  Prejudice  Deviation from truth  Selection/Allocation bias  Observer bias Good study design - minimizing all possible sources of bias
  47. 47. Randomization -Assigns patients to treatment arms by chance -Eliminates selection bias Pseudo randomization
  48. 48. Randomization methods 1. Simple randomization 2. Block Randomization 3. Stratified Randomization ( age, gender, stage, severity) Tossing coin Dice Random number table Computer generated
  49. 49. Randomized controlled trials • Gold standard • Minimize bias • Costly, time consuming
  50. 50. Allocation Concealment • Preventing next assignment in clinical trial from being known • procedure for protecting randomization process so that treatment to be allocated is not known before the patient is entered into the study
  51. 51. Methods of Allocation concealement • Sequentially numbered, opaque, sealed envelopes, • Pharmacy-controlled allocations • Coded identical containers or kits • Central randomisation systems
  52. 52. Blinding • ensuring that neither patients, healthcare providers, nor researchers know to which group specific patients are assigned
  53. 53. Reasons for blinding -Patients on active treatment - adhere Placebo- do not adhere - Observer’s bias- Principal investigator-more vigorously examine active group
  54. 54. Blinding types • Open label • Single blind • Double blind • Triple blind • PROBE (Prospective Randomized Open with Blinded End point Assessment) No standard definition Should be specified who is blinded and how
  55. 55. Double dummy technique Randomise Placebo Placebo
  56. 56. Blinding not possible when • Surgery with non–surgical treatment • Types of dialysis [hemodialysis versus peritoneal dialysis]
  57. 57. Application of various designs in phases of clinical trial
  58. 58. Phase I (Human Pharmacology) Aims: – To find safe dose range – Pharmacokinetics of drug – Drug food interaction – First in man study Sample: • Healthy volunteers • Drug -too toxic (cancer, HIV): patients Sample size- 20-50
  59. 59. Phase I contd Design Open label Non-randomized Dose escalation Uncontrolled Randomized 2 way crossover study of one dose level of drug under fasting and fed conditions 6010/21/2016
  60. 60. Phase II (Therapeutic exploratory) IIa IIb II a- Proof of concept Sample – Patients Sample size- 40-100 subjects Placebo control preferred not- multi centered
  61. 61. Phase II b- Dose range finding • To find optimal dose response range • 300-400 patients • Placebo/ active control • Multicentric
  62. 62. Phase III Confirmatory trials- confirm drug is safe and effective • Sample- 1000-3000 patients • Active controlled • Randomized • Double blinded • Parallel • Non-inferiority • Multicentric
  63. 63. Phase IV Post- marketing surveillance • Detect long term ,rare side effects • Pharmacoeconomics • New indication Uncontrolled ObservationalNew drug status- 4 years
  64. 64. Bioequivalence studies • For generic drug submission • ANDA- Abbreviated new drug application • RLD- Reference listed drug • Parallel-Group Design •Even number of subjects in two groups •Each receive a different formulation
  65. 65. Single dose,two way crossover fasting Single dose,two way crossover fed Single dose parallel fasting Multiple dose, crossover fasting
  66. 66. Microdosing (Phase 0) • Candidate drugs fail- suboptimal human pharmacokinetics • FDA- 100 mcg drug or < 1/100 th of pharmacological dose determined from animal models • LCMS
  67. 67. Hierarchy of Evidence
  68. 68. Summary Success of clinical trial- appropriate clinical design, control group RCT – gold standard Blinding, randomization- minimize bias
  69. 69. References 1.ICH E8 ,9,10 Guidelines : General consideration for clinical trials, Current Step 4 version, 1997 2. Lawrence J. Appel. Primer on the Design, Conduct, and Interpretation of Clinical Trials. Clin J Am Soc Nephrol 1: 1360–1367, 2006 3.Shein-Chung Chow and Mark Chang. Adaptive design methods in clinical trials – a review .Orphanet Journal of Rare Diseases 2008, 3:11 4.Kenneth F Schulz, David A Grimes. Blinding in randomised trials: hiding who got what. THE LANCET 2002 ,359:2 5.New Movement in Drug Development Technology – Micro-dosing and its challenges, QUARTERL REVIEW No.40 / July 2011
  70. 70. 6.Thereasa A , Clinical pharmacology ; Goodman and Gilmans, Pharmacological basis of therapeutics; 12;1731-50; 2010. 7.HL Sharma and KK Sharma, Clinical pharmacology , Principles of Pharmacology;2;871-91;2010