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Designs of clinical trials

This document discusses various types of clinical trial designs. It begins by defining clinical trials and describing key elements like the PICO framework. It then covers ways to reduce bias through randomization and blinding. The document categorizes clinical trials based on factors like number of centers, control groups, randomization, and blinding. It provides details on traditional study designs like parallel group designs and crossover designs. It also discusses special designs for small populations and miscellaneous designs. Overall, the document provides an overview of different clinical trial designs, methods to reduce bias, and ways to categorize trial types.

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Designs of Clinical Trials Dr. Prashant Shukla Junior Resident Dept of Pharmacology
Contents  Definition  Bias- ways to reduce it.  Classification of clinical trials  Individual designs: Traditional Study designs Study designs for small populations  Miscellaneous trials 2/18/2015 2
Clinical Trials  (As per the revised Schedule ‘Y’ of the Drugs & Cosmetic Act 2005). 122-DAA. Definition of Clinical trial It is a systematic study of new drug(s) in human subjects to generate data for discovering and/or verifying the clinical, pharmacological, and/or adverse effects with the objective of determining their safety and/or efficacy of the new drugs. 2/18/2015 3
Key elements of Clinical Trials The acronym PICO is used by health professionals to convey all elements of the clinical scenario in an orderly fashion:  P - Patient, Population of patients, Problem  I - Intervention (a therapy, test)  C - Comparison (another therapy, placebo)  O - Outcome (survival, response)2/18/2015 4
Bias  Bias is a systematic error contained in the study design, conduct or interpretation of a study. Whereas extensive lists of particular bias forms exist, there are two basic forms of bias: 1. Selection bias occurs if study populations are selected in an erroneous way that comparison groups are not comparable. 2. Information bias occurs if measurements are different between2/18/2015 5
Techniques to avoid bias The two most important techniques are: 1. Randomisation of subjects. 2. Blinding of subjects as well as investigator. 3. Monitoring of clinical trial. 4. Checking original source documents. 5. Source data verification. 6. Clinical data management. 7. Quality control (QC) and Quality assurance (QA) procedures. 2/18/2015 6
Randomisation  It aims to obviate systematic differences between groups due to factors other than intervention.  It gives each patient a known (or equal) chance of being assigned to any of the groups.  The most common methods of randomisation are: 1. Simple randomization 2. Blocked randomization 3. Stratified randomization 4. Cluster randomization2/18/2015 7
Blinding  Single- blind design:  Double- blind design:  Triple- blind design: 2/18/2015 8
TYPES OF CLINICAL TRIALS  Superiority Trials: compare a std treatment or intervention with a new or alternative approach anticipated to be more effective.  Inferiority Trials: An alternative therapy (perhaps one that is cheaper, less toxic or easier to administer) is suggested to replace the standard provided its efficacy is no worse than the std.  Equivalence: Test treatment is required to be neither less nor more efficacious than 2/18/2015 9
Did investigator assign exposure? Experimental study Observational study Analytical study Random allocation Comparison group? YES NO Descriptiv e study NO YES RCT Non- rando mize d YE S NO Cohort Study Case- control Cross- sectiona l2/18/2015 10
How to categorize clinical trials?  Number of participating centers: 1. Single center vs Multicenter 2. National vs International  Control group: 1. Non comparative 2. Historical controls 3. Concurrent controls 4. “Self” controls 2/18/2015 11
How to categorize clinical trials?  Randomization: 1. Non- randomized 2. Simple randomized 3. Balanced (stratified) randomized trials 4. Cluster randomized trials  Blinding (Masking): 1. Open label or non- blinded trial 2. Single blinded 3. Double blinded 4. Triple blinded 5. Double dummy 2/18/2015 12
How to categorize clinical trials?  Purpose: 1. Treatment trials 2. Prevention trials 3. Screening trials 4. Quality of life trials 5. Compassionate use trials 6. Genetics trials 2/18/2015 13
How to categorize clinical trials? Trial format: 1. Traditional designs for clinical trials A. Parallel group trials B. Cross over trials C. Factorial design D. Add on design E. Randomized withdrawal design F. Early escape design 2. Special Design issues for small clinical trials A. N- of- 1 design B. Sequential design C. Decision analysis- based design D. Adaptive design E. Risk based allocation design2/18/2015 14
How to categorize clinical trials?  Trial format (contd.): 3. Miscellaneous Designs A. Cluster randomized design B. Enrichment design C. Placebo Challenging design D. Blind Reader design E. Trial with Zelen’s design F. Trial with Wennberg’s design G. Trial with Comprehensive cohort design H. Design using historical controls I. Rolling design 2/18/2015 15
Factors to consider in selecting a clinical trial design 2/18/2015 16 Study population and indication Treatment duration Carry over effects Cost and logistics Patient convenience Statistical considerations
Role of Placebo in Clinical trials  No standard treatment exists.  Standard treatment is ineffective.  Standard treatment is inappropriate for the particular clinical trials.  The placebo is reportedly effective in treating the disease.  The disease is mild and lack of treatment is not considered to be medically important. 2/18/2015 17
Role of Placebo in Clinical trials...  The placebo is given as an add-on treatment to an already existing regimen that is not sufficient to treat patients.  The disease process is characterized by frequent spontaneous exacerbations and remission(e.g., peptic ulcer).  “Escape clauses” or points are 2/18/2015 18
Run in period Before randomization of patients a run-in (or lead-in) period of placebo, no active treatment, dietary control, or active maintenance therapy is usually employed. Advantages: 1. It acts as a washout period to remove effects of previous therapy. 2. It can be used to obtain baseline data and to evaluate if patient fulfills study entry criteria. 3. It can be used as a training period for patients, investigators, and their staff. 4. It helps in identifying placebo responders. 5. It provides useful information regarding patient compliance. 6. It can be used to estimate and compare the magnitude of possible placebo effects between groups. 2/18/2015 19
2/18/2015 20 Traditional Study designs
Parallel Group Design • It is of two types: 1. Group comparison parallel design: In this method, efficacy of treatment is using two groups (Treatment vs Control group). 2. Matched pair parallel design: In this method, pairs of subjects are formed possessing the same characteristics and who might be expected to respond similarly to the treatments. 2/18/2015 21
Group comparison Parallel Design Treatment Group/ Arm Control Group/ Arm • Most common clinical design. • Complete randomized design in which each patient receives one and only one treatment in a randomized fashion. 2/18/2015 22 Exp. Drug
Group comparison Parallel Design Advantages: a) It’s simple and easy to implement. b) It is universally acceptable. c) It is applicable to acute conditions. d) Analysis is less complicated and interpretation is straight forward. Disadvantages: a) It does not into account the inter- individual variability. 2/18/2015 23
Matched Pair Parallel Design Pair A Pair B Pair C Pair D • In this method, pairs of subjects are formed possessing the same characteristics and who might be expected to respond similarly to the treatments. • Matching of patients is done before randomization. 2/18/2015 24
Matched Pair Parallel Design... Advantages: a) Requires small study population. b) Can reduce variability from treatment comparison (compared with parallel froup designs). Disadvantages: a) The prognostic characteristics are not easily defined. b) Patient recruitment is slow. c) When the number of co-variates is large, this design is difficult to implement.2/18/2015 25
Cross over design  A crossover design is a modified randomized block design in which each block receives >1 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 sequence2/18/2015 26
Cross over design... Group A Group B WASH OUT PERIOD WASH OUT PERIOD 2/18/2015 27 Drug A Drug B Drug B Drug A RANDOMIZATION
Cross over design... Crossover designs may be used in clinical trials in the following situations where 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 are2/18/2015 28
Cross over design... Advantages: 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. 2/18/2015 29
Cross over design... Disadvantages: 1. Carry- over effects: The residual influence of treatments on subsequent treatment periods. Avoided by wash out period. 2. Order effects: Order in which the tt are administered affects the outcome. 3. Period effects: The diff. between the study periods. 4. Drop-outs can be higher. 2/18/2015 30
Concept of Wash-out effects AKA carry over / residual effects. It is the rest period between 2 treatment periods.  It permits the effect of previous treatment to wane off.  It should be long enough for the treatment effect to wear off so that there is no carryover effect of previous treatment to next.  It depends upon the nature of the drug. 2/18/2015 31
Williams design When there are more than two treatments to be compared, a complete crossover design is called William’s design. I. William’s design with three treatments ACB BAC CBA BCA CAB ABC II. William’s design with four treatments ADBC BACD CBDA DCAB2/18/2015 32
Split person design 2/18/2015 33 • Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present. Drug A Drug B Split Mouth Design
Split person design... 2/18/2015 34 Drug A Drug B Psoriasis patient • Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present.
Split person design... • Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present. 2/18/2015 35 Drug A Drug B Paired Organs
2/18/2015 36 Factorial designs 2× 2 Factorial design •Used when it is desired to study the influence of a number of factors on the treatments compared as well as their interaction with different treatments. + Drug A Drug B Drug A+B Neither Drug
Factorial designs...  Uses: 1. Make efficient use of clinical trial subjects by evaluating two treatments with same no. of individuals. 2. Influence of a number of factors can be studied together which might require many trials if done individually. 3. Establish dose-response characteristics of the combination of A and B when efficacy of each has been previously established.2/18/2015 37
Factorial designs...  Advantages: 1. A greater precision can be obtained in estimating the overall main factor effects. 2. Interaction between different factors can be explored. 3. Additional factors can help to extend validity of conclusions derived.  Disadvantages: 1. Difficult to analyse. 2. Large designs require large no of subjects. 3. Between subjects design lacks statistical2/18/2015 38
Add- on Design Group A Group B • A placebo-controlled trial of an experimental intervention is tested with people already receiving an established, effective treatment. 2/18/2015 39 + + Std. treatment Std. treatment Exp. Intervention
Add- on Design...  Uses: 1. Add on design is especially useful for testing of an experimental interventions that have mechanism of action different from that of established effective treatment. 2. It can be used for long term studies of treatments of conditions like heart failure since established treatment is life saving and is not being denied. 2/18/2015 40
Randomized Withdrawal Design • Here, individuals who respond (+)ly to an experimental intervention are randomized to continue receiving that intervention or to receive a placebo. • Return of symptoms in placebo group causes withdrawal of subject from that group. 2/18/2015 41 WITHDRAWN FROM STUDY Exp. Intervention
Randomized Withdrawal Design...  Advantage: This trial design minimizes the amount of time that individuals receive a placebo.  Disadvantages: 1. Carry over effects. 2. Difficulties in assessing whether the underlying disease process is still active. 3. Long lag times to adverse events if 2/18/2015 42
Early escape design Intervention Arm Placebo Arm • Participants are removed from the study if symptoms reached a defined level or they fail to respond to a defined extent. • The patient could then be switched over to another therapy, including the test treatment if 2/18/2015 43 Exp. Intervention Predefined negative efficacy criterion
Early escape design...  Advantages: 1. It minimizes an individual’s duration of exposure to a placebo. 2. Ethically justifiable.  Disadvantages: 1. Complex statistical analysis. 2. Difficulties in assessing whether underlying disease is active or not (like Randomised withdrawal design). 2/18/2015 44
2/18/2015 45 Study designs for Small Populations
Study designs for small populations  Defined as <50 possible patients recruited in 5years with multicentre∕ multinational recruitment. 1. Rare diseases 2. Unique study populations (e.g. Astronauts) 3. Individually tailored therapies 4. Environments that are isolated 5. Emergency situations 6. Public health urgency 7. Restricted resources coupled with an important need 2/18/2015 46
N- of- 1 Design  They are cross over trials in which one participant receives the experimental and the control interventions.  Typically the number of pair of interventions varies from two to seven.  The number of interventions is not pre specified so that the clinician and the patient can decide to stop at will. 2/18/2015 47
N- of- 1 Design...  Indications: 1. If an RCT has shown that some patients are unresponsive to treatment. 2. If there is doubt about whether a treatment is really providing benefit to the patient. 2/18/2015 48
Decision Analysis based Design Outcome Intervention A Intervention B Beneficial outcome 1. Utility (0-1) 2. Probability 1. Utility (0-1) 2. Probability Adverse Outcome 1. Utility (0-1) 2. Probability 1. Utility (0-1) 2. Probability •Utility are numeric values assigned to each outcome which reflects the “desirability of the event”. • Probability are the “chances of event to occur”. •Decision analysis combines the probability with utility to calculate an “expected utility”. 2/18/2015 49
Decision Analysis based Design...  Thus decision analysis is used during the planning phase to structure the question.  One obtains best estimates of for each probability and utility.  Sensitivity analysis is done where potential important values (utility and probability) are changed over a likely range to create a model structure.  This design is dependent upon on the assumptions made about parameter values and model structure.2/18/2015 50
Adaptive design 2/18/2015 51  These designs are used when an RCT clearly begin to favour one intervention over another.  Advantage: Over time more patients will be assigned to the more successful treatment.  Disadvantages: 1. In most trials, patients are heterogeneous with respect to important prognostic factors.
Adaptive design 2. It does not protect against bias introduced by changes in the types of patients entering into trial overtime. Adaptive designs can be of two types: 1. Sequential designs 2. Rolling designs 2/18/2015 52
Sequential Design  Here the participants are sequentially enrolled in the study and are assigned a treatment (usually at random).  The efficiency, safety and efficacy of the experiment is improved by changing the rules as the study progresses.  Various for sequential designs are: 1. Up & down methods (Most Common) 2. Stochastic approximation methods 3. Maximum likelihood methods 4. Bayesian methods 2/18/2015 53
Sequential Design... 2/18/2015 54 Abandon the Study If low dose is ineffective and High dose is effective If low dose is effective and High dose has ADRs If both low dose and High dose are ineffective Low dose High dose Up & down method
Sequential Design...  Problems with sequential designs: 1) Uncertainty of sample size. 2) Duration of trial cannot be stipulated in advance. 3) Resources (funding). 2/18/2015 55
Rolling design • Design that can roll on continually by introducing new treatment options from the evidence accumulated, dropping those of either proven efficacy or if found not to be effective. • Make use of intermediate endpoints (in contrast to the traditionally used endpoints that require longer patient follow-up). 2/18/2015 56
Intervention A Intervention B Control Group 2/18/2015 57 Discontinue Intervention B Subsequent recruitment favours beneficial profiles Randomized recruitment to control arm continues Drug A Drug B Std. drug
Risk based Allocation Design • This design allows individuals at higher risk or with greater disease severity to benefit from a potentially superior experimental treatment. •Advantages: Ethically more justifiable. •Disadvantage: It is a non-randomized design. 2/18/2015 58 Individuals with higher risk or greater disease severity Individuals with lesser risk or lesser disease severity Potentially superior Experimental treatment Relatively inferior Experimental treatment
2/18/2015 59 Miscellaneou s Study designs
Cluster Randomized Design Cluster/ Group A Cluster/ Group B Cluster/ Group C • For assessment of non-therapeutic interventions such as lifestyle intervention or new educational programs for smoking cessation. • Randomization can be performed on intact social units- family, school, worksites, athletic teams, etc. •Randomization is done at cluster level rather2/18/2015 60 Intervention A Intervention B Intervention C
Cluster Randomized Design...  Although the trials adopt a cluster randomization, the analysis of data completely ignores this fact and uses subject as the unit of analysis.  Thus, the unit of analysis may not be necessarily the same as the unit of randomization. 2/18/2015 61
Enrichment Design Enrichment phase Randomizatio n phase • Phase of manipulation of dose levels of a therapeutic agent for identification of patients with drug efficacy is Enrichment phase. • The patients with drug efficacy identified at enrichment phase are randomized to receive either efficacious dose of drug or matching placebo. 2/18/2015 62
Placebo Challenging design  For treatment of erection dysfunction, a design that consists of a :- 1. “Titration phase” for achieving optimal dose and 2. “Crossover active treatment phase” with two placebo challenges (i.e., pre- and post-treatment) is often considered.  Design of this kind is a placebo- challenging design.2/18/2015 63
Placebo Challenging design.. 1. In-clinic evaluation (double-blind placebo- challenging) 2. Three-month home treatment 3. In-clinic evaluation (double- blind placebo- 2/18/2015 64 Titration phase Active drug Active drug Placebo Placebo Active drug Active drug
Blinded reader designs  A clinical trial for evaluation of medical imaging products with blinded imaging evaluation is said to have a blinded reader design.  It is not feasible to blind the investigators who administer the investigational medical imaging agents.  So effectiveness of medical imaging drug products should be evaluated based on the images by readers (usually trained radiologists) obtained with the investigational agents or controls under2/18/2015 65
Trial with Zelen’s design  Here, the patients are randomised before they give consent to participate in the trial.  Those who are allocated to standard treatment group are not told that they are part of the trial.  Those who are allocated to the experimental intervention group are told that they are part of the trial. If they refuse to participate in the trial, they are given the standard treatment but analysed as if they had received the experimental intervention.2/18/2015 66
Trial with Zelen’s design...  Advantages: 1. Almost all eligible individuals are included in the trial. 2. Allows the evaluation of true effect of experimental intervention in patients.  Disadvantages: 1. Open trials. 2. The statistical power of the study gets compromised if large no of patients choose the standard treatment. 2/18/2015 67
Trial with Zelen’s design... 2/18/2015 68
Trial with Zelen’s design...  There is ethical concerns of not telling patients that they have been randomised to receive the standard treatment.  So, the original Zelen’s design can be modified by informing participants of the group to which they have been allocated and by offering them opportunity to switch the group.  Disadvantages: 1. Lack of blinding 2/18/2015 69
Trial with Zelen’s design... 2/18/2015 70
Trial with Wennberg’s design  In this design, eligible individuals are randomised to: 1. “Preference group” where patients can choose between exp. or std. treatment at will. 2. “RCT group” where patients are randomised between both arms.  Rarely used.  They are likely to be more frequently used as consumer participation in healthcare decisions and research is increasing.2/18/2015 71
Trial with Wennberg’s design... 2/18/2015 72 Preference Group RCT Group ELIGIBLE INDIVIDUALS Std. drug Exp. drug Std. drug Exp. drug
2/18/2015 73 Trial with comprehensive cohort design • A comprehensive cohort trial is a study in which all participants are followed up, regardless of their randomisation status. 1. If a person agrees for RCT, he is randomised to one of the study interventions. 2. If a person does not agree for RCT, he is given his intervention of choice and followed up as if he were a part of a cohort study. •At the end, the outcomes of RCT and cohort study are compared to assess their similarities
Trial with comprehensive cohort design 2/18/2015 74 Outcomes of Cohort studies and RCT group are then compared Cohort Group RCT Group ELIGIBLE INDIVIDUALS Std. drug Exp. drug Std. drug Exp. drug
Designs using historical controls  Very rarely, a new treatment is given to all patients and result are compared with the past (historical controls).  It is almost always unacceptable even for disease like leukaemia because: 1. Standards of diagnosis and treatment change with time 2. Severity of some diseases fluctuates  An exception to this rule is the case- control study 2/18/2015 75
Factors in choosing clinical trials designs 1. Chronology of events: Chronological effects may be very important in any trial design, but particularly in cross over design. 2. Subject convenience: Lengthy trials requiring multiple visits and involving washout periods may compromise patient compliance. 3. Trial cost: Very lengthy trials may not be routinely feasible due to prohibitive costs2/18/2015 76
Trial designs phase wise  Phase I CT: All patients receive the drug, thus an unblinded, open label trial is suitable.  Phase II through III CT: Parallel designs, Cross over, Factorial designs are most commonly used.  Phase IV CT: Non experimental (observational) designs- These include epidemiologic designs such as case control or cohort studies.2/18/2015 77
2/18/2015 78 Knowledge is the root and practice is the bough and there is no bough without a root behind it, although roots may be found which can as yet boast no boughs. Moses Maimonides Thank you for your patience!!

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Designs of clinical trials

  • 1.
    Designs of ClinicalTrials Dr. Prashant Shukla Junior Resident Dept of Pharmacology
  • 2.
    Contents  Definition  Bias-ways to reduce it.  Classification of clinical trials  Individual designs: Traditional Study designs Study designs for small populations  Miscellaneous trials 2/18/2015 2
  • 3.
    Clinical Trials  (Asper the revised Schedule ‘Y’ of the Drugs & Cosmetic Act 2005). 122-DAA. Definition of Clinical trial It is a systematic study of new drug(s) in human subjects to generate data for discovering and/or verifying the clinical, pharmacological, and/or adverse effects with the objective of determining their safety and/or efficacy of the new drugs. 2/18/2015 3
  • 4.
    Key elements ofClinical Trials The acronym PICO is used by health professionals to convey all elements of the clinical scenario in an orderly fashion:  P - Patient, Population of patients, Problem  I - Intervention (a therapy, test)  C - Comparison (another therapy, placebo)  O - Outcome (survival, response)2/18/2015 4
  • 5.
    Bias  Bias isa systematic error contained in the study design, conduct or interpretation of a study. Whereas extensive lists of particular bias forms exist, there are two basic forms of bias: 1. Selection bias occurs if study populations are selected in an erroneous way that comparison groups are not comparable. 2. Information bias occurs if measurements are different between2/18/2015 5
  • 6.
    Techniques to avoidbias The two most important techniques are: 1. Randomisation of subjects. 2. Blinding of subjects as well as investigator. 3. Monitoring of clinical trial. 4. Checking original source documents. 5. Source data verification. 6. Clinical data management. 7. Quality control (QC) and Quality assurance (QA) procedures. 2/18/2015 6
  • 7.
    Randomisation  It aimsto obviate systematic differences between groups due to factors other than intervention.  It gives each patient a known (or equal) chance of being assigned to any of the groups.  The most common methods of randomisation are: 1. Simple randomization 2. Blocked randomization 3. Stratified randomization 4. Cluster randomization2/18/2015 7
  • 8.
    Blinding  Single- blinddesign:  Double- blind design:  Triple- blind design: 2/18/2015 8
  • 9.
    TYPES OF CLINICALTRIALS  Superiority Trials: compare a std treatment or intervention with a new or alternative approach anticipated to be more effective.  Inferiority Trials: An alternative therapy (perhaps one that is cheaper, less toxic or easier to administer) is suggested to replace the standard provided its efficacy is no worse than the std.  Equivalence: Test treatment is required to be neither less nor more efficacious than 2/18/2015 9
  • 10.
    Did investigator assign exposure? Experimentalstudy Observational study Analytical study Random allocation Comparison group? YES NO Descriptiv e study NO YES RCT Non- rando mize d YE S NO Cohort Study Case- control Cross- sectiona l2/18/2015 10
  • 11.
    How to categorizeclinical trials?  Number of participating centers: 1. Single center vs Multicenter 2. National vs International  Control group: 1. Non comparative 2. Historical controls 3. Concurrent controls 4. “Self” controls 2/18/2015 11
  • 12.
    How to categorizeclinical trials?  Randomization: 1. Non- randomized 2. Simple randomized 3. Balanced (stratified) randomized trials 4. Cluster randomized trials  Blinding (Masking): 1. Open label or non- blinded trial 2. Single blinded 3. Double blinded 4. Triple blinded 5. Double dummy 2/18/2015 12
  • 13.
    How to categorizeclinical trials?  Purpose: 1. Treatment trials 2. Prevention trials 3. Screening trials 4. Quality of life trials 5. Compassionate use trials 6. Genetics trials 2/18/2015 13
  • 14.
    How to categorizeclinical trials? Trial format: 1. Traditional designs for clinical trials A. Parallel group trials B. Cross over trials C. Factorial design D. Add on design E. Randomized withdrawal design F. Early escape design 2. Special Design issues for small clinical trials A. N- of- 1 design B. Sequential design C. Decision analysis- based design D. Adaptive design E. Risk based allocation design2/18/2015 14
  • 15.
    How to categorizeclinical trials?  Trial format (contd.): 3. Miscellaneous Designs A. Cluster randomized design B. Enrichment design C. Placebo Challenging design D. Blind Reader design E. Trial with Zelen’s design F. Trial with Wennberg’s design G. Trial with Comprehensive cohort design H. Design using historical controls I. Rolling design 2/18/2015 15
  • 16.
    Factors to considerin selecting a clinical trial design 2/18/2015 16 Study population and indication Treatment duration Carry over effects Cost and logistics Patient convenience Statistical considerations
  • 17.
    Role of Placeboin Clinical trials  No standard treatment exists.  Standard treatment is ineffective.  Standard treatment is inappropriate for the particular clinical trials.  The placebo is reportedly effective in treating the disease.  The disease is mild and lack of treatment is not considered to be medically important. 2/18/2015 17
  • 18.
    Role of Placeboin Clinical trials...  The placebo is given as an add-on treatment to an already existing regimen that is not sufficient to treat patients.  The disease process is characterized by frequent spontaneous exacerbations and remission(e.g., peptic ulcer).  “Escape clauses” or points are 2/18/2015 18
  • 19.
    Run in period Beforerandomization of patients a run-in (or lead-in) period of placebo, no active treatment, dietary control, or active maintenance therapy is usually employed. Advantages: 1. It acts as a washout period to remove effects of previous therapy. 2. It can be used to obtain baseline data and to evaluate if patient fulfills study entry criteria. 3. It can be used as a training period for patients, investigators, and their staff. 4. It helps in identifying placebo responders. 5. It provides useful information regarding patient compliance. 6. It can be used to estimate and compare the magnitude of possible placebo effects between groups. 2/18/2015 19
  • 20.
  • 21.
    Parallel Group Design •It is of two types: 1. Group comparison parallel design: In this method, efficacy of treatment is using two groups (Treatment vs Control group). 2. Matched pair parallel design: In this method, pairs of subjects are formed possessing the same characteristics and who might be expected to respond similarly to the treatments. 2/18/2015 21
  • 22.
    Group comparison Parallel Design TreatmentGroup/ Arm Control Group/ Arm • Most common clinical design. • Complete randomized design in which each patient receives one and only one treatment in a randomized fashion. 2/18/2015 22 Exp. Drug
  • 23.
    Group comparison Parallel Design Advantages: a)It’s simple and easy to implement. b) It is universally acceptable. c) It is applicable to acute conditions. d) Analysis is less complicated and interpretation is straight forward. Disadvantages: a) It does not into account the inter- individual variability. 2/18/2015 23
  • 24.
    Matched Pair ParallelDesign Pair A Pair B Pair C Pair D • In this method, pairs of subjects are formed possessing the same characteristics and who might be expected to respond similarly to the treatments. • Matching of patients is done before randomization. 2/18/2015 24
  • 25.
    Matched Pair ParallelDesign... Advantages: a) Requires small study population. b) Can reduce variability from treatment comparison (compared with parallel froup designs). Disadvantages: a) The prognostic characteristics are not easily defined. b) Patient recruitment is slow. c) When the number of co-variates is large, this design is difficult to implement.2/18/2015 25
  • 26.
    Cross over design A crossover design is a modified randomized block design in which each block receives >1 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 sequence2/18/2015 26
  • 27.
    Cross over design... GroupA Group B WASH OUT PERIOD WASH OUT PERIOD 2/18/2015 27 Drug A Drug B Drug B Drug A RANDOMIZATION
  • 28.
    Cross over design... Crossoverdesigns may be used in clinical trials in the following situations where 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 are2/18/2015 28
  • 29.
    Cross over design... Advantages: 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. 2/18/2015 29
  • 30.
    Cross over design... Disadvantages: 1.Carry- over effects: The residual influence of treatments on subsequent treatment periods. Avoided by wash out period. 2. Order effects: Order in which the tt are administered affects the outcome. 3. Period effects: The diff. between the study periods. 4. Drop-outs can be higher. 2/18/2015 30
  • 31.
    Concept of Wash-outeffects AKA carry over / residual effects. It is the rest period between 2 treatment periods.  It permits the effect of previous treatment to wane off.  It should be long enough for the treatment effect to wear off so that there is no carryover effect of previous treatment to next.  It depends upon the nature of the drug. 2/18/2015 31
  • 32.
    Williams design When thereare more than two treatments to be compared, a complete crossover design is called William’s design. I. William’s design with three treatments ACB BAC CBA BCA CAB ABC II. William’s design with four treatments ADBC BACD CBDA DCAB2/18/2015 32
  • 33.
    Split person design 2/18/201533 • Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present. Drug A Drug B Split Mouth Design
  • 34.
    Split person design... 2/18/201534 Drug A Drug B Psoriasis patient • Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present.
  • 35.
    Split person design... •Occasionally, it is possible to administer the two interventions at the same time. •Very similar to that of the cross-over trial, except there is no equivalent to the periods or to the wash-out although a carry-over (now termed carry-across) effect is likely to be present. 2/18/2015 35 Drug A Drug B Paired Organs
  • 36.
    2/18/2015 36 Factorial designs 2×2 Factorial design •Used when it is desired to study the influence of a number of factors on the treatments compared as well as their interaction with different treatments. + Drug A Drug B Drug A+B Neither Drug
  • 37.
    Factorial designs...  Uses: 1.Make efficient use of clinical trial subjects by evaluating two treatments with same no. of individuals. 2. Influence of a number of factors can be studied together which might require many trials if done individually. 3. Establish dose-response characteristics of the combination of A and B when efficacy of each has been previously established.2/18/2015 37
  • 38.
    Factorial designs...  Advantages: 1.A greater precision can be obtained in estimating the overall main factor effects. 2. Interaction between different factors can be explored. 3. Additional factors can help to extend validity of conclusions derived.  Disadvantages: 1. Difficult to analyse. 2. Large designs require large no of subjects. 3. Between subjects design lacks statistical2/18/2015 38
  • 39.
    Add- on Design GroupA Group B • A placebo-controlled trial of an experimental intervention is tested with people already receiving an established, effective treatment. 2/18/2015 39 + + Std. treatment Std. treatment Exp. Intervention
  • 40.
    Add- on Design... Uses: 1. Add on design is especially useful for testing of an experimental interventions that have mechanism of action different from that of established effective treatment. 2. It can be used for long term studies of treatments of conditions like heart failure since established treatment is life saving and is not being denied. 2/18/2015 40
  • 41.
    Randomized Withdrawal Design • Here,individuals who respond (+)ly to an experimental intervention are randomized to continue receiving that intervention or to receive a placebo. • Return of symptoms in placebo group causes withdrawal of subject from that group. 2/18/2015 41 WITHDRAWN FROM STUDY Exp. Intervention
  • 42.
    Randomized Withdrawal Design...  Advantage:This trial design minimizes the amount of time that individuals receive a placebo.  Disadvantages: 1. Carry over effects. 2. Difficulties in assessing whether the underlying disease process is still active. 3. Long lag times to adverse events if 2/18/2015 42
  • 43.
    Early escape design InterventionArm Placebo Arm • Participants are removed from the study if symptoms reached a defined level or they fail to respond to a defined extent. • The patient could then be switched over to another therapy, including the test treatment if 2/18/2015 43 Exp. Intervention Predefined negative efficacy criterion
  • 44.
    Early escape design... Advantages: 1. It minimizes an individual’s duration of exposure to a placebo. 2. Ethically justifiable.  Disadvantages: 1. Complex statistical analysis. 2. Difficulties in assessing whether underlying disease is active or not (like Randomised withdrawal design). 2/18/2015 44
  • 45.
    2/18/2015 45 Study designsfor Small Populations
  • 46.
    Study designs forsmall populations  Defined as <50 possible patients recruited in 5years with multicentre∕ multinational recruitment. 1. Rare diseases 2. Unique study populations (e.g. Astronauts) 3. Individually tailored therapies 4. Environments that are isolated 5. Emergency situations 6. Public health urgency 7. Restricted resources coupled with an important need 2/18/2015 46
  • 47.
    N- of- 1Design  They are cross over trials in which one participant receives the experimental and the control interventions.  Typically the number of pair of interventions varies from two to seven.  The number of interventions is not pre specified so that the clinician and the patient can decide to stop at will. 2/18/2015 47
  • 48.
    N- of- 1Design...  Indications: 1. If an RCT has shown that some patients are unresponsive to treatment. 2. If there is doubt about whether a treatment is really providing benefit to the patient. 2/18/2015 48
  • 49.
    Decision Analysis based Design OutcomeIntervention A Intervention B Beneficial outcome 1. Utility (0-1) 2. Probability 1. Utility (0-1) 2. Probability Adverse Outcome 1. Utility (0-1) 2. Probability 1. Utility (0-1) 2. Probability •Utility are numeric values assigned to each outcome which reflects the “desirability of the event”. • Probability are the “chances of event to occur”. •Decision analysis combines the probability with utility to calculate an “expected utility”. 2/18/2015 49
  • 50.
    Decision Analysis based Design... Thus decision analysis is used during the planning phase to structure the question.  One obtains best estimates of for each probability and utility.  Sensitivity analysis is done where potential important values (utility and probability) are changed over a likely range to create a model structure.  This design is dependent upon on the assumptions made about parameter values and model structure.2/18/2015 50
  • 51.
    Adaptive design 2/18/2015 51 These designs are used when an RCT clearly begin to favour one intervention over another.  Advantage: Over time more patients will be assigned to the more successful treatment.  Disadvantages: 1. In most trials, patients are heterogeneous with respect to important prognostic factors.
  • 52.
    Adaptive design 2. Itdoes not protect against bias introduced by changes in the types of patients entering into trial overtime. Adaptive designs can be of two types: 1. Sequential designs 2. Rolling designs 2/18/2015 52
  • 53.
    Sequential Design  Herethe participants are sequentially enrolled in the study and are assigned a treatment (usually at random).  The efficiency, safety and efficacy of the experiment is improved by changing the rules as the study progresses.  Various for sequential designs are: 1. Up & down methods (Most Common) 2. Stochastic approximation methods 3. Maximum likelihood methods 4. Bayesian methods 2/18/2015 53
  • 54.
    Sequential Design... 2/18/2015 54 Abandonthe Study If low dose is ineffective and High dose is effective If low dose is effective and High dose has ADRs If both low dose and High dose are ineffective Low dose High dose Up & down method
  • 55.
    Sequential Design...  Problemswith sequential designs: 1) Uncertainty of sample size. 2) Duration of trial cannot be stipulated in advance. 3) Resources (funding). 2/18/2015 55
  • 56.
    Rolling design • Designthat can roll on continually by introducing new treatment options from the evidence accumulated, dropping those of either proven efficacy or if found not to be effective. • Make use of intermediate endpoints (in contrast to the traditionally used endpoints that require longer patient follow-up). 2/18/2015 56
  • 57.
    Intervention A InterventionB Control Group 2/18/2015 57 Discontinue Intervention B Subsequent recruitment favours beneficial profiles Randomized recruitment to control arm continues Drug A Drug B Std. drug
  • 58.
    Risk based AllocationDesign • This design allows individuals at higher risk or with greater disease severity to benefit from a potentially superior experimental treatment. •Advantages: Ethically more justifiable. •Disadvantage: It is a non-randomized design. 2/18/2015 58 Individuals with higher risk or greater disease severity Individuals with lesser risk or lesser disease severity Potentially superior Experimental treatment Relatively inferior Experimental treatment
  • 59.
  • 60.
    Cluster Randomized Design Cluster/Group A Cluster/ Group B Cluster/ Group C • For assessment of non-therapeutic interventions such as lifestyle intervention or new educational programs for smoking cessation. • Randomization can be performed on intact social units- family, school, worksites, athletic teams, etc. •Randomization is done at cluster level rather2/18/2015 60 Intervention A Intervention B Intervention C
  • 61.
    Cluster Randomized Design... Although the trials adopt a cluster randomization, the analysis of data completely ignores this fact and uses subject as the unit of analysis.  Thus, the unit of analysis may not be necessarily the same as the unit of randomization. 2/18/2015 61
  • 62.
    Enrichment Design Enrichment phase Randomizatio n phase •Phase of manipulation of dose levels of a therapeutic agent for identification of patients with drug efficacy is Enrichment phase. • The patients with drug efficacy identified at enrichment phase are randomized to receive either efficacious dose of drug or matching placebo. 2/18/2015 62
  • 63.
    Placebo Challenging design For treatment of erection dysfunction, a design that consists of a :- 1. “Titration phase” for achieving optimal dose and 2. “Crossover active treatment phase” with two placebo challenges (i.e., pre- and post-treatment) is often considered.  Design of this kind is a placebo- challenging design.2/18/2015 63
  • 64.
    Placebo Challenging design.. 1.In-clinic evaluation (double-blind placebo- challenging) 2. Three-month home treatment 3. In-clinic evaluation (double- blind placebo- 2/18/2015 64 Titration phase Active drug Active drug Placebo Placebo Active drug Active drug
  • 65.
    Blinded reader designs A clinical trial for evaluation of medical imaging products with blinded imaging evaluation is said to have a blinded reader design.  It is not feasible to blind the investigators who administer the investigational medical imaging agents.  So effectiveness of medical imaging drug products should be evaluated based on the images by readers (usually trained radiologists) obtained with the investigational agents or controls under2/18/2015 65
  • 66.
    Trial with Zelen’sdesign  Here, the patients are randomised before they give consent to participate in the trial.  Those who are allocated to standard treatment group are not told that they are part of the trial.  Those who are allocated to the experimental intervention group are told that they are part of the trial. If they refuse to participate in the trial, they are given the standard treatment but analysed as if they had received the experimental intervention.2/18/2015 66
  • 67.
    Trial with Zelen’sdesign...  Advantages: 1. Almost all eligible individuals are included in the trial. 2. Allows the evaluation of true effect of experimental intervention in patients.  Disadvantages: 1. Open trials. 2. The statistical power of the study gets compromised if large no of patients choose the standard treatment. 2/18/2015 67
  • 68.
    Trial with Zelen’sdesign... 2/18/2015 68
  • 69.
    Trial with Zelen’sdesign...  There is ethical concerns of not telling patients that they have been randomised to receive the standard treatment.  So, the original Zelen’s design can be modified by informing participants of the group to which they have been allocated and by offering them opportunity to switch the group.  Disadvantages: 1. Lack of blinding 2/18/2015 69
  • 70.
    Trial with Zelen’sdesign... 2/18/2015 70
  • 71.
    Trial with Wennberg’sdesign  In this design, eligible individuals are randomised to: 1. “Preference group” where patients can choose between exp. or std. treatment at will. 2. “RCT group” where patients are randomised between both arms.  Rarely used.  They are likely to be more frequently used as consumer participation in healthcare decisions and research is increasing.2/18/2015 71
  • 72.
    Trial with Wennberg’sdesign... 2/18/2015 72 Preference Group RCT Group ELIGIBLE INDIVIDUALS Std. drug Exp. drug Std. drug Exp. drug
  • 73.
    2/18/2015 73 Trial withcomprehensive cohort design • A comprehensive cohort trial is a study in which all participants are followed up, regardless of their randomisation status. 1. If a person agrees for RCT, he is randomised to one of the study interventions. 2. If a person does not agree for RCT, he is given his intervention of choice and followed up as if he were a part of a cohort study. •At the end, the outcomes of RCT and cohort study are compared to assess their similarities
  • 74.
    Trial with comprehensivecohort design 2/18/2015 74 Outcomes of Cohort studies and RCT group are then compared Cohort Group RCT Group ELIGIBLE INDIVIDUALS Std. drug Exp. drug Std. drug Exp. drug
  • 75.
    Designs using historical controls Very rarely, a new treatment is given to all patients and result are compared with the past (historical controls).  It is almost always unacceptable even for disease like leukaemia because: 1. Standards of diagnosis and treatment change with time 2. Severity of some diseases fluctuates  An exception to this rule is the case- control study 2/18/2015 75
  • 76.
    Factors in choosingclinical trials designs 1. Chronology of events: Chronological effects may be very important in any trial design, but particularly in cross over design. 2. Subject convenience: Lengthy trials requiring multiple visits and involving washout periods may compromise patient compliance. 3. Trial cost: Very lengthy trials may not be routinely feasible due to prohibitive costs2/18/2015 76
  • 77.
    Trial designs phasewise  Phase I CT: All patients receive the drug, thus an unblinded, open label trial is suitable.  Phase II through III CT: Parallel designs, Cross over, Factorial designs are most commonly used.  Phase IV CT: Non experimental (observational) designs- These include epidemiologic designs such as case control or cohort studies.2/18/2015 77
  • 78.
    2/18/2015 78 Knowledge isthe root and practice is the bough and there is no bough without a root behind it, although roots may be found which can as yet boast no boughs. Moses Maimonides Thank you for your patience!!