1. Experimental Studies Dr Amna Rehana Siddiqui Assistant Professor Department of Community and Family Medicine

2. 2 Learning Objectives To understand: What are experimental studies? The value of clinical trials The basic methodology of RCTs Advantages and disadvantages of RCTs

3. Types of Study Designs DesignStudy Type Case reportObservational - Descriptive Case seriesObservational - Descriptive Cross sectionalObservational - Descriptive/Analytic Case controlObservational - Analytic CohortObservational - Analytic Clinical trialExperimental - Analytic 3

4. 4  Intervention studies are similar in approach to cohort studies except that the investigator directly control exposure.  Similar to laboratory experiments except living populations are the subjects  They are the ultimate step in testing causal hypotheses.

5. DEVELOP DISEASE DO NOT DEVELOP DISEASE DEVELOP DISEASE NOT EXPOSED EXPOSED DO NOT DEVELOP DISEASE Defined population NON-randomized Designs of a COHORT Study 5

6. With Outcome Without Outcome With Outcome NOT EXPOSED instead to PLACEBO EXPOSED to Drug or New therapy WithoutOutcome Defined population Randomized Design of a Clinical Trial 6

7. What are Clinical Trials ? A clinical trial is an organized research study designed to investigate new methods of – preventing, – detecting, – diagnosing, or – treating an illness or disease Modification of natural history of disease New approaches to treatment and interventions to determine whether a new method of treatment is superior to the standard (currently approved) treatment of the ailment. In some instances, clinical trials attempt to improve a patient’s quality of life

8. 8  New treatments - pharmaceutical agents, devices, surgical procedures - are being developed every day.  Before an intervention becomes standard practice, assessment of its efficacy and safety in comparison to standard therapy should be undertaken. Why Clinical Trials are Important

9. Why are They Important? To determine whether a new method of treatment is superior to the standard (currently approved) treatment of the ailment. Clinical trials are extremely important in discovering new techniques to fight disease. For example, many of the advances in breast cancer detection and treatment resulted from clinical trials. These advances include: – screening mammography – use of chemotherapy before or after breast surgery, – use of radiation after lumpectomy, and – cancer treatment drugs (tamoxifen, Herceptin, etc.)

10. Size of Tumors Found by Mammography and Breast Self-Exam Average-size lump detected with routine mammogram (0.43 inches / 1.1 cm) Average-size lump detected with first mammogram (0.59 inches / 1.5 cm) Average-size lump found by regularly practicing breast self-exam (0.83 inches / 2.1 cm) Average-size lump found accidentally (1.42 inches / 3.6 cm

11. 11 Types of Experimental studies: 1.Preventive trials: e.g. Vaccine or any procedure that reduces the risk of development of a particular disease. 2. Therapeutic trials: to diminish symptoms, prevent recurrence, or decrease risk of death from that disease. Incidence rate of outcome is compared among those who received the new therapy/vaccine (exposed) and those who received the placebo (non-exposed).

12. 12 Pre-clinical trials in animals and lab. Testing drugs in human Phases of testing new agent

13. 13 Pre-clinical trials  Before clinical trials of any medication in human subjects are undertaken, considerable research in experimental animals is essential. It includes pharmacological and toxicological studies. Aims: to establish that the new agent is effective and may be suitable for human use. to estimate roughly the dose to be used in man.

14. 14 Clinical trials of new agents in human pass through 4 phases Phase I: Aims: to find a safe tolerated dose in man to test effects on body functions under close supervision. It is carried out on (20 to 25) of healthy volunteers They receive small doses of new drugs This phase is of short duration (one or two months) It is performed by clinical pharmacologists. Testing drugs in human

15. 15 Phase II:  It is carried out on 20 – 200 patients with relevant disease  It lasts longer than Phase I trials (6 months to 2 years)  The purpose of Phase II is:  to assess therapeutic benefits & adverse reactions of the drug  To establish a dose range and to investigate its side effects.

16. 16 Phase III (The classical phase)  Large scale, Randomised, Controlled Trials (RCTs)  Target population: 250 – 1000 patients  Performed by Clinicians in multi-centric hospitals.  The purpose of this phase is to: assess the efficacy and safety. reduce the side effects & improve the quality of life.  Results from Phase III trials are used to evaluate whether a new product or device should be licensed for general public use.

17. 17 Phase IV: ( Post marketing Surveillance) It is a trial in normal field conditions when the drug is already available by prescription in the market. The purpose of the Phase IV trial is to assess: Effectiveness under actual field conditions Safety& acceptability Long-term side effects. Rare adverse reactions and Drug interactions

18. 18 1.The first step is to identify the reference population (the target population). The reference population is the population to which generalizations of the results of the experiment apply. 2.Second, Selection of a study population after defining inclusion/exclusion criteria. – The inclusion criteria identify the target group or subgroup that will enter the study – The exclusion criteria are chosen to minimize potential dangers (e.g. elderly patients, pregnant women, children) Design of Randomized Clinical Trials (RCTs):

19. WITH OUTCOME WITHOUT OUTCOME WITH OUTCOME NOT EXPOSED instead to PLACEBO EXPOSED to Drug or New therapy WITHOUT OUTCOME Defined population Randomized Design of a Clinical Trial 19 Consenters

20. 20 3.Getting ‘informed consent’ from the participants before they are subjected to experiments. 4.Random allocation of subjects to the experiment and control groups, 5.Follow up for a specified period of time under strict conditions 6.The outcome of the experiment is carefully measured. The outcome may be a cure, recurrence of the disease, survival, relief of pain, or reduction in blood pressure, etc. 7.The outcome measures are compared between the groups using appropriate statistical methods.

21. WITH OUTCOME WITHOUT OUTCOME WITH OUTCOME Standard Therapy / PLACEBO EXPOSED to Drug or New therapy WITHOUT OUTCOME Defined population Randomized Design of a Clinical Trial 21 Consenters

22. 22 Random allocation  Random allocation is the method of assigning patients to treatment groups.  Each subject has an equal chance of being assigned to any group in the study  All groups in a study are similar in all characteristics  It avoids selection bias on the part of the investigator or the patient.

23. Baseline characteristics of patients in Placebo and Pravastatin groups (NEJM 1996) CharacteristicPlacebo Pravastatin 1.Mean Age (yrs) 59+ 9 59+ 9 2.Male Sex (%) 86 86 3.Race White (%) 92 93 4.Current Smoker (%) 21 21 5.Hypertension (%) 34 34 6.Diabetes Mellitus (%) 15 14 7.Body Mass Index (Mean) 28+ 4 28+ 4 8.Angina (%) 20 21 9.Medication Aspirin (%) 83 83 * 10.Oral Hypoglycemic agent (%) * 7 5 23

24. 24 Original Table Shown For Your Interest

25. 25 Value of Randomization Successful randomization tends to create comparison groups that are similar in terms of both known and unknown factors that may be related to outcome (e.g. gender, age group, disease stage, or other prognostic factor).

26. 26 IIt is a method of concealing (hiding) knowledge of treatment assignment to reduce bias in measuring outcome. AA Single masked study – subjects are unaware of whether they are in the experimental or control group study. AA Double masked study – the subject and the observer are unaware of the subject’s group allocation. AA Triple masked study – the subject, observer and data analyst are unaware of the subject’s group allocation. Masking or "blinding"

27. MMasking is achieved by ensuring that all treatments appear identical (form & shape of drugs). AA placebo is used for the comparison group if the objective is to evaluate a new drug in comparison with no treatment. AA placebo is an inactive agent made to seem identical to the active agent in terms of appearance and mode of administration; having same color, weight, shape, and odour,; exactly similar to the intervention medicine Methods of Blinding

28. 28  In evaluations of new surgical procedures, it is more difficult to apply blinding.  It is obvious to which group the patient has been allocated.  Thus, masking in such settings may be limited to the individuals who are assessing the outcome.  For example, in a clinical trial of eye surgery, the technician measuring visual acuity would be masked as to treatment assignment to avoid bias in administration of the visual acuity test.

29. 29 Relative Risk: Measure of Effect Size TotaloutcomeGroup NegativePositive a +bbaIntervention c +ddcControl Relative risk (RR): Ratio of the incidence of a given outcome in experimental group compared to that in the control group ( a/(a + b)) / (c /( c + d))

30. Pravastatin Study Results (NEJM 1996) Outcome#Placebo# Pravastatin Death CHD27413.2 %21210.2% Fatal MI 207 10% 157 7.5% Stroke 78 3.8 % 54 2.6% Calculate RR for all 30

31. 31 More scientifically valid (time relation is clearly established). More scientifically valid (time relation is clearly established). Advantages of RCTS Unbiased allocation of subjects through randomization. (No Selection Bias) Unbiased allocation of subjects through randomization. (No Selection Bias) Unbiased assessment of outcomes through blinding. (No measurement bias) Unbiased assessment of outcomes through blinding. (No measurement bias)

32. 32 Disadvantages of RCTS  Require large sample size.  Time consuming and expensive.  Non-compliance to treatment assignment  Attrition (Losses to follow-up) may affect validity of results.  Ethical issues may arise.

33. 33 In summary, there is a hierarchy of studies from ones that open up a question to ones that may be the definitive answer or very close to that. With increasing certainty comes increasing complexity and attention to detail (and increasing expense, time, and cooperation).

34. Selecting Study Design from Last Lecture 34

35. Choice of study design depends on:  What is the research question/objective (to describe or to test a hypothesis) descriptive versus analytic designs  Available knowledge about the condition If new condition with little information; Case-control  Disease incidence If Rare choose Case-control If Common choose Prospective cohort

36.  Time span between exposure and outcome If long latency choose Case-control If Short choose Prospective cohort  Resources and Time available for study if yes (Prospective cohort)  Quality of data from various sources Uniformly available and objective data are available (e. g. birth weight for premature babies) choose case-control Often there are multiple approaches which will all work

37. Case controlCohortAspect Quick Relatively cheap Small - Long Expensive Larger Present Logistic of the study 1. Time 2. Cost 3. Sample size 4. Ethical problem Best - Best - Best - Type of investigation 1. Rare disease 2. Disease with long latency period 3. Rare exposure 4. Multiple outcome 5. Several risk factors

38. Case controlCohortAspect Always present Present Not certain Little Not a problem - Certain Problematic Problems 1. Selection bias 2. Recall bias 3. Temporal relationship 4. Attrition problem 5. Change in environment, behaviour Can not be calculated Approximation (OR) Can not be calculated Can not be determined Can be calculated Can be determined Measurements 1. Incidence rate 2. Relative risk 3. Attributable risk 4. Dose-response relationship