Clinical trial design


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  • Placebo : test treatment or an identical-appearing treatment that does not contain the test drug
    No treatment : subjects are assigned to the test treatment or to no study treatment
    Dose-response: subjects are randomized to one of several fixed dose groups
    Active: subjects are assigned to the test treatment or to an active control treatment
    External(including historical): compares a group of subjects receiving the test treatment with a group of patients external to the study. Can be historical, i.e, group of patients treated at an earlier time

  • 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