1. INTERVENTIONAL STUDIES “CLINICAL TRIALS” “Experimental Studies” A. Prof. Dr Faris Al-Lami MB,ChB MSc PhD FFPH

2. Objectives Define interventional studies Identify strengths, limitations and types of bias Types of interventional studies Steps of conducting interventional studies Define blocking, randomization, compliance, blinding, placebo, factorial design

3. “CLINICAL TRIALS” Provide data of the highest quality Resemble controlled experiments done in laboratories. Similar to cohort studies, individuals included on the basis of exposure status, BUT the difference: the investigators themselves will allocate the exposure (Active investigator in interventional studies versus passive in cohort studies)

4. Investigator Determines Exposure Status

5. Interventions amenable to be studied using clinical trials Life style Diet Drugs Operational factors Surgical procedures Rehabilitation

6. “CLINICAL TRIALS” Strengths: 1. The gold standard of epidemiological studies. 2. Can detect mild to moderate differences (10-20%) 3. Can control and manipulate many confounding factors

7. “CLINICAL TRIALS” Strengths: 4. Can demonstrate the temporal relationship between exposure and outcome with the highest degree of confidence 5. Randomized trial can yield the strongest and the most direct epidemiological evidence to judge on causal association

8. “CLINICAL TRIALS” Major limitations: It does not represent the real life situation, (because in life you can not allow one factor to operate, while other factors are kept constant).

9. “CLINICAL TRIALS” Types: 1.Therapeutic (Secondary Prevention) Trials: conducted among patients with certain disease to determine the ability of an agent or procedure to diminish symptoms, prevents recurrence or decrease risk of death from that disease e.g.: CASS on AP, or MI patients, end point is the total CHD mortality Breast CA studies: radical versus simple mastectomy, end point recurrence and five year mortality

10. “CLINICAL TRIALS” 2. Preventive (Primary Preventive) Trial: It involves the evaluation of whether an agent or procedure reduces the risk of developing disease among those free from that condition at enrolment. This study can be done on healthy individuals at usual or high risk of development of a particular disease. e.g.: Polio vaccine versus placebo In Coronary Primary Prevention Trial, a cholesterol lowering drug (versus placebo) used healthy men with high cholesterol level.

11. “CLINICAL TRIALS” Therapeutic trials are always done on individuals while preventive trials can be done on individuals or the whole population as in Dental Caries study.

12. Problems of Intervention Studies 1.Ethical: Always there should be some doubt in the beneficial or harmful effect of an agent or procedure to be tested. A known beneficial agent should not be withholding from affected individuals Similarly, a known harmful agent should not be allocated and this can be tested indirectly through its removal as stopping smoking.

13. Problems of Intervention Studies 2. Feasibility: The widespread adoption of certain measures by the general population make it difficult to find sufficient number who can avoid such a measure or treatment believed to be beneficial for the total duration of a trial even if there is no strong evidence to support this belief (Vitamin supplement).

14. Problems of Intervention Studies 3. Cost: This is higher than in observational analytic studies.

15. Phase I Phase I Clinical pharmacology & toxicity Human volunteers Hospital study Phase II Phase II Initial clinical investigation for treatment effects Patients Hospital study Phase III Phase III Full-scale evaluation Patients Hospital study Phase IV Phase IV Post-marketing surveillance Phases of trial

16. Informed consent: Participants must clearly understand requirements in trial. Receiving a placebo, should be free to refuse to participate or withdraw Stopping rule : should be stated before start of trial -Clinical efficacy of test treatment -Toxicity of test treatment -External ( independent ) experts to do this Ethical issues in clinical trials

17. Good Clinical Practices (GCP) GCP are international ethical and scientific standards setting the minimum requirements for the development, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials that involve the participation of human subjects

18. Selection of Study Population Reference population: o It is the general group to whom the results of the investigation can be applicable. o This could be the general population as a whole or restricted by sex, race, geography. o The reference reflected the generalizability of the results. e.g.: Physician Health Study which examines the role of B carotene in prevention of cancer involves US physicians aged > 40 years. The results can be reflected to non physicians and outside USA.

19. Selection of Study Population The experimental population is the actual population on whom the trial is conducted. This should be: 1.Large to achieve the necessary sample size (e.g.: IV streptokinase therapy for AMI, a multicentric study involving 15 countries that enrol 22,000 in two years)

20. The experimental population 2. It is essential to choose an experimental population that will experience a sufficient number of end points or outcomes of interest to permit comparison between various treatments or procedures with reasonable period. (e.g.: Primary prevention effect of aspirin in prevention of CV mortality, it is better to use men >40 years of age, than to use women <40 years).

21. The experimental population 3.The need to have complete and accurate follow up information for the duration of the trial (e.g.: Physician Health Study)

22. The experimental population Once the experimental population defined, subjects are invited and informed about the: Aim of the study Possible benefits and side effects of intervention The possibility of having only a placebo. Those willing to participate must be screened for eligibility according to predetermined criteria.

23. Reasons for exclusion from experimental population: History of end point Contraindication to the agent Definite need to the agent

24. Experimental Population The remaining represents those willing and eligible, but they are different from non-participants in ways that may affect the rate of development of the end point under study. This is called Volunteerism, and could be associated with age, sex, socioeconomic status, education and other factors that might influence significantly the morbidity or mortality.

25. Allocation of the study regimens: After determining the eligible and willing subjects, allocation into various groups will be done. The effect of the intervention is determined by comparing it to different groups as treatment, placebo, or others.

26. Randomization To ensure maximum comparability, the allocation into various study groups is done at random (every individual has the same chance of receiving each of the possible treatments). This can be done by using random digit table, computer generated randomization list or other techniques.

27. Design of a Randomized Clinical Trial

28. Advantages of Randomization: Removal of the possibility of selection, and physician bias. Comparability with respect to all variables (known and unknown confounders) except the variable under study. The favourable impression of randomization and its confidence (Best approach)

29. Blocking When the outcome under study is varied in frequency between sexes, different age groups or different stages of the disease, it is necessary that treatment groups are equal to these characteristics, and this is called Blocking Every participant is categorized with respect to each variable and then randomization within the subgroups.

30. Selection of Subjects : Stratified Randomization

31. Maintenance and Ascertainment of Compliance After agreeing to participate, some individuals can develop side effects, forget to take the treatment or withdraw from the trial, or choose the alternative method or the intervention becomes contraindicated. This is called Non Compliance, which is related to the length and complexity of the study.

32. To enhance compliance: Inclusion of individuals who are interested and reliable such as population at high risk of developing the outcome. (In Coronary Primary Prevention Trial they included individuals with hypercholesterolemia). Frequent contact with the participants Use of Calendar pack of study medication Provision of incentives

33. Monitoring compliance Monitoring compliance is important because non compliance will decrease the statistical power of the study. The interpretation of any trial must consider the level of non compliance.

34. Monitoring compliance The level of compliance should be measured. This can be done by: Self report (as in case of exercise program or behavioural modification) Pill count of unused medication Use of a biochemical parameter.

35. Ascertainment of Outcome: It is necessary to have complete, accurate and similar methods of collection of information from both study groups. While some endpoints require short period of follow up (as the mortality after MI) others may require long follow up.

36. Blinding The ascertainment of the outcome can be affected by knowing the exposure status of the participants, especially if the outcome is subjective as side effect, or severity of the symptoms. This is called observational bias. To decrease this bias, blinding (masking) to the exposure status can be used.

37. Blinding Attempt to eliminate biases & preconceptions Single-blind –Subject masking –Use of placebo Double-blind –Subject masking and researcher masking (both the patients and the investigator who assess the outcome are unaware of the exposure status). Data collectors and data analysts Triple-blind –Subject masking, researcher masking and study sponsor masking

38. Problems with Blinding Immediate unblinding is necessary in case of emergency or serious side effects. Sometimes double blinding is not possible as in evaluation of changes in life style as exercise, smoking, or diet.

39. Placebo A placebo is used to minimize bias in ascertainment of subjective disease outcome and side effects. But this can result in placebo effect, which is the tendency of the patients to report good response to any therapy irrespective of its physiologic effect. The other effect of placebo: persons taking a drug or undergoing a medical procedure may blame this treatment for the side effects.

40. The Factorial Design It is a technique used to test two or more hypotheses at the same time. A clinical trial of two hypotheses can utilize a two by two factorial designs in which subjects are first randomized to treatment A or B to address the first hypothesis and then within each treatment group there is further randomization to treatment C or D to address the second hypothesis. A third or forth hypothesis can also be added.

41. The Factorial Design The main advantage of the factorial design is the ability to answer two or more questions in a single study with a slight increase in cost.

42. Statistical Power of Clinical Trial It depend on: 1.Sample Size should be sufficiently large (otherwise it can lead to a major scientific harm as saying that this intervention is not beneficial, while in fact it did not detect its benefit because of the small sample size). 2.Total number of end points experienced by the study population. 3. Effect of Compliance: Non-compliance will increase the similarity between the two groups, and thus inability to detect the small differences.

43. Total number of end points To achieve a sufficient number of endpoints two major strategies may be considered: 1.Selecting of high risk population based on variables like age, sex, occupation or others. 2. Length of follow up period: the planned follow up period always shows less endpoint than what is anticipated, because of the healthy volunteer effect, and sometimes secular changes. It is mandatory to extend follow up period as early as possible.

44. Analysis Relative risk is the measure of association in clinical trials. Role of chance can be minimized by having large sample size Role of bias can be minimized by randomization and blinding Role of confounder can be minimized by randomization