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Clinical trial designs - RU - 09.07.22.pptx
- 2. Contents • Introduction • Brief History • Clinical Trial • Flow • Types • Designs
- 3. History of Clinical Trials
- 4. Rhubarb • Rhubarb roots have been used as a laxative for more than 5,000 years, including in 18th- century England. • Caleb Parry, an English physician working in Bath, wanted to know whether locally grown rhubarb was as good as the more expensive Turkish variety. • In 1786, he ran a study in which he switched the type of rhubarb he gave to each patient at different times. He then compared each patient’s symptoms while eating each type of rhubarb. He concluded there was no advantage in using the Turkish version.
- 5. The 1944 patulin trial the first properly controlled multicentre trial conducted under the aegis of the British Medical Research Council
- 7. Research careful study that is done to find and report new knowledge about something the systematic investigation into and study of materials and sources in order to establish facts and reach new conclusions. (Clinical) Clinical research is medical research involving people.
- 9. Levels of Evidence Meta- analysis Systematic reviews Randomized controlled trials Cohort studies Case-control studies Case reports Expert opinions/background information
- 10. Clinical Trial • Clinical trials are a type of research that studies new tests and treatments and evaluates their effects on human health outcomes.
- 13. "If you don't want to practice medicine 10 years from now the same way we do it today then clinical research must be a priority • Animal studies are of limited value in determining the full spectrum of toxicities and predicting effectiveness of treatments in humans
- 15. Types Prevention trials Treatment trials Screening trials Diagnostic trials Quality of life trials Therapeutic Trials Non-therapeutic trials
- 16. • presence or absence of a control group • Uncontrolled trials • Controlled trials • method used to allocate • Non-randomized trials • Randomized trials • participants or investigators awareness • Open-label studies • Blind studies • result expected to be found • Superiority trials • Bioequivalence trials • Non-inferiority trials • treatment structure • Parallel trials • Cross-over trials • Sequential trials Clinical Trial Designs
- 17. • presence or absence of a control group • Uncontrolled trials • Controlled trials • method used to allocate • Non-randomized trials • Randomized trials • participants or investigators awareness • Open-label studies • Blind studies Control group A control group is comprised of people similar to the test group in all aspects that affect the outcome except for the treatment/intervention of interest. Clinical Trial Designs
- 18. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs
- 19. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 20. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 21. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 22. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 23. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 24. •presence or absence of a control group • Uncontrolled trials • Controlled trials Clinical Trial Designs Types of Control Groups 1. Placebo concurrent control 2. Dose-comparison concurrent control 3. No-treatment concurrent control 4. Active-treatment concurrent control, and 5. Historical control
- 25. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 26. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 27. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 28. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 29. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 30. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 31. • method used to allocate • Non-randomized trials • Randomized trials Clinical Trial Designs Randomization refers to the act of randomly assigning subjects in a study to different treatment groups
- 32. •participants or investigators awareness • Open-label studies • Blind studies Clinical Trial Designs
- 33. Randomized controlled trials Clinical Trial Designs Parallel group trial design Cross over design Group allocation designs
- 34. Parallel Design Simultaneous treatment and control groups Each person is randomly assigned to one treatment group Randomization removes treatment selection bias and promotes comparability of treatment groups Statistical comparisons made between treatment groups
- 35. Parallel Design National Emphysema Treatment Trial (NETT Phase Ill trial) ClinicalTrials.gov Identifier: NCT00000606 • Population - People with severe emphysema • Sample size - 1,200 • Allocation to treatment - Randomized • Treatments -Lung volume reduction surgery plus medical therapy -Medical therapy (standard therapy control)
- 36. Cross-over design • Randomization of order in which treatments are received • AB or BA • Randomization promotes balance between treatment groups in timing of exposure • Testing of both treatments in each patient • Each patient serves as his/her own control • Variability reduced because less variability within patient than between patients • Fewer patients needed
- 38. Cross-over design Limitations: • Treatment can't have permanent effects or cures • Potential carry-over effects of first-period treatment to second period • Dropouts more significant
- 39. Cross-over design Uses: • Constant intensity of underlying disease • Chronic diseases--asthma, hypertension, arthritis • Short-term treatment effects • Relief of signs or symptoms of disease
- 40. Cross-over design Effect of montelukast or salmeterol added to inhaled fluticasone on exercise- induced bronchoconstriction in children ClinicalTrials.gov Identifier: NCT00127166 Period Montelukast Salmeterol Arm Period I Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo dry powder inhaler twice daily for 4 weeks. Montelukast 5 mg oral tablet once daily and Salmeterol matching placebo DPI twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily Montelukast matching placebo oral tablet once daily and Salmeterol 50 mcg twice daily for 4 weeks. Montelukast matching placebo oral tablet once daily and Salmeterol DPI 50 mcg twice daily for 4 weeks. Inhaled Fluticasone 100 mcg twice daily Period II Throughout the study.
- 41. Group Allocation Design • Randomization unit is a group of individuals (community, school, clinic) • Individual randomization and intervention is not feasible or is unacceptable
- 43. Factorial Design Two interventions are tested simultaneously
- 44. Factorial Design Physicians' Health Study Treatment Beta-carotene Aspirin BA BP AA AA + BA AA + BP AP AP + BA AP + BP AA = Aspirin Active AP = Aspirin Placebo BA = Beta-carotene Active BP = Beta-carotene placebo
- 45. Factorial Design Physicians' Health Study Treatment Beta-carotene Aspirin BA BP AA AA + BA AA + BP AP AP + BA AP + BP AA = Aspirin Active AP = Aspirin Placebo BA = Beta-carotene Active BP = Beta-carotene placebo
- 46. Equivalence design • intervention response falls sufficiently close to control group response • How much difference can be allowed between treatments considered equivalent? • "Detectable difference" should be small • Probability of detecting difference should be large • Therefore, large sample size is needed
- 47. Equivalence design • Hypothesis testing - Flipped as compared to superiority • Ho-there is a difference between treatments • HA-there is no difference between treatments • Type I error-showing no difference when there is one • Type II error-showing a difference when there isn't one
- 48. Non-inferiority designs Whether treatment A is at least good as treatment B
- 49. Non-inferiority designs Study of an Investigational Drug for the Prevention of Thrombosis-related Events Following Knee Replacement Surgery (ADVANCE-2) ClinicalTrials.gov Identifier: NCT00452530 • Apixaban • Enoxaparin • Treatment continued for 10-14 days after surgery • Main outcome-composite of asymptomatic and symptomatic deep vein thrombosis, non-fatal pulmonary embolism, and all-cause death during treatment • defined as upper 95% confidence limit of RR (apixaban vs. enoxaparin) of 1.25 and RD of 5.6%
- 50. Non – inferiority margin
- 51. Other Design 1. n-of-1 design 1. Decision analysis-based design 2. Ranking and selection design 3. Adaptive design 4. Risk-based allocation design
- 52. Master Protocol Design A master protocol is a study protocol design with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure. basket trials, umbrella trials, and platform trials
- 53. Basket Trial - A type of clinical trial design that tests how well a new drug or other substance works in patients who have different types of cancer that all have the same mutation or biomarker. Umbrella trials - patients are enrolled with one cancer type but with different genetic changes within each tumor Super umbrella trials The combination of the bucket trials and the umbrella trials creates the “Super Umbrella Trials” Master Protocol Design
- 54. Platform trials - Multi-Arm, Multi-Stage (MAMS) design trials evaluate several interventions against a common control group and can be perpetual. • Seamless design - researchers combine the learning stage of Phase II trials and the confirmatory stage of Phase III trials and • Internal pilot design - in the case of rare diseases (few subjects), allocated to definitive study rather than a pilot study Master Protocol Design
- 55. Factors to consider in design selection Number of interventions to be compared Study objectives Treatment course and duration Carry over effects Cost and logistics Patient convenience Ethical considerations Statistical considerations Study subject availability/disease rarity Inter and intra subject variability
- 56. To demonstrate superiority, equivalence, and non-inferiority Randomized parallel arm design If the time between study inclusion and outcome assessment is short compared with recruitment time of study subjects Adaptive design If preliminary data favors one drug - adaptive randomization If there are two or more therapies of interest that can be given concurrently Factorial design, parallel arm Factors to consider in design selection
- 58. Endof Presentation… Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole No increased risk was found among rivaroxaban and dabigatran users
- 59. References • National Academies of Sciences, Engineering, and Medicine. 2001. Small Clinical Trials: Issues and Challenges. Washington, DC: The National Academies Press. https://doi.org/10.17226/10078. • Fogel RB, Rosario N, Aristizabal G, Loeys T, Noonan G, Gaile S, Smugar SS, Polos PG. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Ann Allergy Asthma Immunol. 2010 Jun;104(6):511-7. • Nair B. Clinical Trial Designs. Indian Dermatol Online J. 2019 Mar-Apr;10(2):193-201. doi: 10.4103/idoj.IDOJ_475_18. PMID: 30984604; PMCID: PMC6434767. • Fundamentals of clinical trials. Lawrence M • Research Methodology. WHO
- 60. References • https://www.nejm.org/doi/full/10.1056/NEJMoa2102137 • https://www.annallergy.org/article/S1081-1206(10)00375-3/fulltext • https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(86)91157-8/fulltext • https://www.nejm.org/doi/full/10.1056/nejm198907203210301 • https://www.nejm.org/doi/full/10.1056/nejmoa1006885 • https://www.annalsofoncology.org/article/S0923-7534%2819%2945984-X/fulltext • https://theconversation.com/the-fascinating-history-of-clinical-trials-139666
- 61. References • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1592068/ • https://watermark.silverchair.com/dyh028.pdf?token=AQECAHi208BE 49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAArowggK2B • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149409/
Editor's Notes
- The world's first clinical trial is recorded in the “Book of Daniel” in The Bible.1 This experiment resembling a clinical trial was not conducted by a medical, but by King Nebuchadnezzar a resourceful military leader.1 During his rule in Babylon, Nebuchadnezzar ordered his people to eat only meat and drink only wine, a diet he believed would keep them in sound physical condition.1 But several young men of royal blood, who preferred to eat vegetables, objected. The king allowed these rebels to follow a diet of legumes and water — but only for 10 days. When Nebuchadnezzar's experiment ended, the vegetarians appeared better nourished than the meat-eaters, so the king permitted the legume lovers to continue their diet.1 This probably was the one of the first times in evolution of hum
- he results were striking: 55 of the 95 patients given patulin recovered during the trial, compared to only eight of the 85 patients in the placebo control group. (The article does not explain how this imbalance in the numbers of patients in the two groups could have arisen using ‘alternation’.)
- The results of the trial showed that streptomycin was helpful. During the first six months after admission to the study, there were four deaths among 55 patients who had been allocated streptomycin, compared with 15 among 52 patients allocated to bed rest alone, and this difference was reflected in radiological and other improvements. During the subsequent six months, the radiological and mortality differences were less marked (there eight more deaths in the streptomycin group and nine more in the groups treated with bed rest alone).
- Observational studies are hypothesis-generating studies, and they can be further divided into descriptive and analytic. Descriptive observational studies provide a description of the exposure and/or the outcome, and analytic observational studies provide a measurement of the association between the exposure and the outcome. Experimental studies, on the other hand, are hypothesis testing studies.
- Observational studies are hypothesis-generating studies, and they can be further divided into descriptive and analytic. Descriptive observational studies provide a description of the exposure and/or the outcome, and analytic observational studies provide a measurement of the association between the exposure and the outcome. Experimental studies, on the other hand, are hypothesis testing studies.
- Clinical Trial means a systematic study of any new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic), and/or adverse effects with the objective of determining safety and/or efficacy of the new drug.
- Clinical trial separate therapies which are true advances from false leads and clinical impression. Also identify risk of therapy
- 1937 - Liquid formulation of sulfa drug sold with diethylene glycol, killing > 100 1961 Case reports of thalidomide (approved in Europe) causing server birth defects and deaths
- 1937 - Liquid formulation of sulfa drug sold with diethylene glycol, killing > 100 1961 Case reports of thalidomide (approved in Europe) causing server birth defects and deaths
- clinical trial” in relation to a new drug or investigational new drug means any systematic study of such new drug or investigational new drug in human subjects to generate data for discovering or verifying its,- (i) clinical or; (ii) pharmacological including pharmacodynamics, pharmacokinetics or; (iii) adverse effects, with the objective of determining the safety, efficacy or tolerance of such new drug or investigational new drug;
- Screening or early detection QOL or supportive trials
- Regarding the presence (or absence) of a control group as comparator to the investigational treatment According to the method used to allocate participants to a treatment or control group, we will have: Based on participants' or investigators' awareness of the treatment group to which participants have been allocated, we will have Based on the significance of the result expected to be found between treatment and control groups Based on the treatment structure
- A control group is comprised of people similar to the test group in all aspects that affect the outcome except for the treatment/intervention of interest. Controls are selected on the basis of comparability to the target population or the population at risk. This group is essential to demonstrate that a treatment or intervention is superior, less costly, or associated with fewer complications compared to the standard practice. Besides helping in the assessment of safety and efficacy, a control group discriminates outcomes caused by the treatment or intervention of interest from those caused by other factors, such as natural course of disease, patient or observer expectations, or other treatments.
- This design incorporates no control arm. This design is usually utilized to determine pharmacokinetic properties of a new drug (Phase 1 trials). Uncontrolled trials are known to produce greater mean effect estimates than a controlled trial, thereby inflating the expectations from the intervention. There is a threat of inherent bias and results are considered less valid than RCT. Another issue is use of this design in spontaneously resolving maladies that might again overstate the effect
- Placebo designs if asked….
- Different doses or regimens of same treatment are used as active arm and control arm in this design. The purpose is to establish a relationship between dose and efficacy/safety of the intervention. This design may include active and placebo groups also in addition to the different dose groups. No intervention will be administered in control arm in this design. Study end points must be objective in this design. The downsides are potential for observer bias and difficulty in blinding in this design
- This design involves comparison of a new drug to a standard drug or compare combination of new and standard therapies vis a vis standard therapy alone. A therapeutic modality that should preferably be the current standard of care against which the active drug to be studied is compared with. This design can be used to demonstrate equivalence, non-inferiority, and superiority. This design is most ethical whenever approved drugs are available for the disease under study. The Declaration of Helsinki mandates the use of standard treatment as controls
- Source of controls are external to the present study and were treated at an earlier time (earlier therapeutic gold standard) or in a different setting. The advantage of historical controls is in studying rare conditions where sample size generation is difficult. The downside is that no randomization or blinding is possible in this design. A disadvantage is that the co-interventions evolve in due course of time thereby reducing the comparability of the present intervention versus historic control. Another deficiency of this design is the difference between baseline characteristics of subjects in trial arm versus historical arm.
- Medical charts Patient registry Previous clinical trial EXONDYS 51 (eteplirsen) that treats duchenne muscular dystrophy Eteplirsen's proposed mechanism of action is to bind to dystrophin pre-mRNA and alter the exon splicing of the RNA so that more almost full-length dystrophin is made
- Placebo control, no-treatment control (suitable where objective measurements are felt to make blinding unnecessary), and dose-comparison control studies are all study designs in which a difference is intended to be shown between the test article and some control
- Eliminates selection bias. Balances arms with respect to prognostic variables (known and unknown). Forms basis for statistical tests, a basis for an assumption-free statistical test of the equality of treatments. In general, a randomized trial is an essential tool for testing the efficacy of the treatment.
- Unpredictability Each participant has the same chance of receiving any of the interventions. Allocation is carried out using a chance mechanism so that neither the participant nor the investigator will know in advance which will be assigned. 2. Balance • Treatment groups are of a similar size & constitution, groups are alike in all important aspects and only differ in the intervention each group receives 3. Simplicity • Easy for investigator/staff to implement
- nclination or prejudice for or against person or treatment group election bias, performance bias, attrition bias, detection bias and reporting bias. – only if asked
- he common types of randomization include (1) simple, (2) block, (3) stratified and (4) cluster randomization – only if asked Simple Randomization This method is equivalent to tossing a coin for each subject that enters a trial, such as Heads = Active, Tails = Placebo. It is simple and easy to implement and treatment assignment is completely unpredictable. However, it can get imbalanced in treatment assignment, especially in smaller trials. Imbalanced randomization reduces statistical power.
- he common types of randomization include (1) simple, (2) block, (3) stratified and (4) cluster randomization – only if asked Simple randomization does not guarantee balance in numbers during trial. Especially, if patient characteristics change with time, (e.g. early patients sicker than later), early imbalances can't be corrected. Block randomization is often used to fix this issue.
- he common types of randomization include (1) simple, (2) block, (3) stratified and (4) clusterrandomization – only if asked Stratified random sampling is a method of sampling that involves the division of a population into smaller sub-groups known as strata. In stratified random sampling, or stratification, the strata are formed based on members' shared attributes or characteristics such as income or educational attainment. prevents imbalance between treatment groups for known factors that influence prognosis or treatment responsiveness
- A cluster randomized trial (CRT) is a trial in which individuals are randomized in groups—the group as a whole is randomized and not the individual Physicians, group practices, health plans, or even geographic regions (counties or states) can be defined as clusters.
- An additional tool that is also used to make trials more precise is “blinding.” Blinding involves taking steps to prevent patients, doctors, or other people involved in the trial (e.g., those people recording measurements) from finding out which patients got what treatment. prevent observer bias
- Gold standard
- Montelukast, compared with salmeterol, significantly reduced the mean maximum percentage decrease in FEV1 (10.6% vs 13.8%; P = .009), Attenuation and response of EIB to albuterol rescue after exercise challenge were significantly better with montelukast than with salmeterol after 4 weeks of treatment.
- "cluster randomization” Tracking Contamination
- mild vitamin A deficiency to increased mortality and suggest that supplements given to vitamin A deficient populations may decrease mortality by as much as 34%. 450 villages in northern Sumatra were randomly assigned to either participate in a vitamin A supplementation scheme (n=229) or serve for 1 year as a control (n=221). y 1992 the World Health Organization (WHO), UNICEF, the Food and Agriculture Organization of the United Nations, and the Convention on the Rights of Children had all declared the control of VAD a global goal.
- Economic reasons
- its use of a pre-randomization run-in phase Its finding that low-dose aspirin decreased the risk of a first myocardial infarction by 44% helped focus on the role of aspirin in primary prevention of coronary heart disease. physicians were then randomly assigned to receive active aspirin and active beta-carotene (n=5,517), active aspirin and beta-carotene placebo (n=5,520), aspirin placebo and active beta-carotene (n=5,519), or aspirin placebo and beta-carotene placebo (n=5,515).
- aspirin arm of the PHS several years ahead of schedule because it was clear that aspirin had a significant effect on the risk of a first myocardial infarction. 3 years of supplementation with beta-carotene produced neither benefit nor harm. These results demonstrated that beta-carotene alone was not responsible for the health benefits seen among people who ate plenty of fruits and vegetables.
- Not worse than Hypothesis is one sided (in eqivalence it both sided)
- and follow-up visits at 30 and 60 days after last treatment Designed to detect non-inferiority, Apixaban 2·5 mg twice daily, starting on the morning after total knee replacement, offers a convenient and more effective orally administered alternative to 40 mg per day enoxaparin, without increased bleeding.
- The 95% confidence interval is a range of values that you can be 95% confident contains the true mean of the population.
- Small clinical trials
- the could be seen as a wasteful approach.
- Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease
- Apixaban users had a significantly increased risk of bleeding following exposure to systemic fluconazole: odds ratio (OR) 3.5; 95% confidence interval (CI), 1.4-10.6. No increased risk was found among rivaroxaban and dabigatran users: ORs of 0.9 (95% CI, 0.2-3.0) and 1.7 (95% CI, 0.5-5.6), respectively. As to bleeding risk pertaining to topical azole exposure among apixaban, rivaroxaban, and dabigatran users, no association was found, with corresponding ORs of 0.8 (95% CI, 0.5-1.3); 1.3 (95% CI, 0.9-2.1); and 1.2 (95% CI 0.8-1.8), respectively.