Clinical trial design, Trial Size, and Study Population

Freshers in clinical research and regulatory affairs must go through this presentation. It will help you to understand the basis of clinical trial design as per European guidelines, which is the most preferred reference guideline. Initially, I also faced many problems to understand this concept. A student who is studying a clinical research diploma can also use this presentation for their basic understanding.

1. Clinical T rial Design, Trial Size, and Study Population Shubham A. Chinchulkar (Regulatory Affairs) M.Tech (Pharm.) National Institute of Pharmaceutical education and Research (NIPER) [email protected] 1

2. The appropriate study design should be chosen to provide the desired information Examples for study design :- Parallel group The most common clinical trial design for confirmatory trials in which each arm being allocated different treatment Two separate treatment arms, A and B, are given so that one group receives only treatment arm A while another group receives only treatment arm B It include the investigational product at one or more doses and one or more control treatments (placebo or comparator) In case of other design additional features (covariates, repeated measurements over time, interactions between design factors, protocol violations, dropouts (see Glossary) and withdrawals) of trial complicate the analysis and interpretation Clinical Trial Design Screening Treatment A Treatment B Treatment C 2

3. 2. Crossover Design Each subject is randomised to a sequence of two or more treatments and hence acts as his own control for treatment comparisons It reduces the number of subjects Usually the number of assessments needed to achieve a specific power 2×2 crossover design - subject receives each of two treatments in randomised order in two successive treatment periods, often separated by a washout period To demonstrate the bioequivalence of two formulations of the same medication 3

4. Variations like each subject receives a subset of n(>2) treatments or ones in which tr eatments are repeated within a subject In the 2×2 design the carryover effect cannot be statistically distinguished from the interaction between treatment and period and the test for either of these effects lacks power because the corresponding contrast is 'between subject‘ It is important to avoid carryover (he effect of the treatment from the previous time period on the response at the current time period) Adequate knowledge of both the disease area and the new medication will helps to avoid carryover The disease under study should be chronic and stable The relevant effects of the medication should develop fully within the treatment period and washout periods should be sufficiently long Complications of analysis and interpretation arising from the loss of subjects, carryover leads to difficulties in assigning adverse events When losses of subjects from the trial are expected to be small, then only we can use crossover design 4

5. 3. Factorial Designs T wo or more treatments are evaluated simultaneously through the use of varying combinations of the treatments The simplest example is the 2×2 factorial design in which subjects are randomly allocated to one of the four possible combinations of two treatments, A and B say A alone; B alone; both A and B; neither A nor B Specific purpose of examining the interaction of A and B The statistical test of interaction may lack power to detect an interaction if the sample size was calculated based on the test for main effects It is important when this design is used for examining the joint effects of A and B, in particular, if the treatments are likely to be used together 5

6. It is use to establish Dose-response characteristics of the simultaneous use of treatments C and D In some cases 2x2 design may be used to make efficient use of clinical trial subjects This Strategy has proved to be particularly valuable for very large mortality trials 4. Dose escalation - The guiding principle for dose escalation in phase I trials is to avoid exposing too many patients to subtherapeutic doses while preserving safety and maintaining rapid accrual 5. Fixed dose-dose response - To characterize the dose response 6

7. To achieve clinical study objective – Appropriate comparators (Reference product) Adequate numbers of subjects Primary and secondary endpoints and plans for their analyses should be clearly stated The protocol should specify procedures for the follow-up of patients who stop treatment prematurely 3.2.2.1 Selection of subjects Stage of development and the indication to be studied are the crucial parameters to select the subjects in clinical trials E.g . Normal healthy subjects, cancer patients or other special populations in early phase development In early stages of clinical trials the variability of groups of patients or healthy volunteers studied is limited to a narrow range by strict selection criteria Further, as drug development proceeds the selection get broadened 7

8. Trial subjects should not participate concurrently in more than one clinical trial but there can be justified exceptions Subjects should not be enrolled repetitively in clinical trials without time off treatment adequate to protect safety and exclude carry-over effects Women of childbearing potential should be using highly effective contraception to participate in clinical trials For male subjects, potential hazards of drug exposure in the trial to their sexual partners or resulting progeny should be considered When drugs involved in trials are potentially mutagenic or toxic to reproductive system, then appropriate contraception provision should be include 3.2.2.2 Selection of Control Group Trials should have an adequate control group Comparison may be made with placebo, active controls or diff. doses of drug under investigation The objective of the trial decides the comparator 8

9. 3.2.2.3 Number of subjects The size of a trial is affected by - Disease to be investigated Objective of the study The study endpoints Statistical assessments of sample size should be based on - Expected magnitude of the treatment effect Variability of the data The specified (small) probability of error Secondary endpoints Generally larger database is required to establish the safety of drug Always be large enough to provide a reliable answer to the questions addressed Primary objective of the trial responsible to decide subject number 9

10. Following points should be specified for determining the sample size – Primary variable – Primary Objective T est statistic – T-test N ull hypothesis - T he population  mean  of the treatment and control groups is assumed to be the same until an effect estimate (which reaches some prespecified statistical threshold) is observed The probability of erroneously rejecting the null hypothesis (the type I error) Probability of erroneously failing to reject the null hypothesis (the type II error) Approach to dealing with treatment withdrawals and protocol violations The method by which the sample size is calculated should be given in the protocol and basis for calculation also should be provided The deviations from these assumptions are also important in sample size calculation In confirmatory trials, assumptions should normally be based on published data or on the results of earlier trials 10

11. Sample size calculations should refer to the number of subjects required for the primary analysis If this is the full analysis set, the effect size need to reduce compared to the protocol The exact sample size in a group sequential trial cannot be fixed in advance because it depends upon the play of chance in combination with the chosen stopping guideline and the true treatment difference When event rates are lower than anticipated or variability is larger than expected, methods for sample size re-estimation are available without unbinding data or making treatment comparisons Role of Independent Data Monitoring Committee (IDMC ) It is established by the sponsor to assess at intervals the progress of a clinical trial , safety data , and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial IDMC should have written operating procedures and maintain records of all its meetings , including interim results; these should be available for review when the trial is complete The IDMC is a separate entity from an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC) IDMC include clinical trial scientists knowledgeable in the appropriate disciplines including statistics 11

12. References https:// www.ema.europa.eu/en/documents/scientific-guideline/ich-e-8-general-considerations-clinical-trials-step-5_en.pdf https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-9-statistical-principles-clinical-trials-step-5_en.pdf 12