1. 25/5/2009 Dr. Salwa Tayel 1

2. 25/5/2009 Dr. Salwa Tayel2 Associate Professor Family and Community Medicine Department King Saud University By

3. 25/5/2009 Dr. Salwa Tayel3 Learning Objectives To understand: To understand: What are experimental studies? What are experimental studies? The value of clinical trialsThe value of clinical trials The basic methodology of RCTsThe basic methodology of RCTs Advantages and disadvantages of RCTsAdvantages and disadvantages of RCTs

4. 31/1/2009 Dr. Salwa Tayel4 Study designs A. Experimental - study factor is manipulated by the investigator B. Observational – no manipulation of study factor by the investigator Descriptive: Case report, Case series, Correlation studies, Cross-sectional studies Descriptive: Case report, Case series, Correlation studies, Cross-sectional studies Analytic: (have a comparison group); Case control, Cohort study Analytic: (have a comparison group); Case control, Cohort study

5. Types of Study Designs DesignStudy Type Case reportObservational - Descriptive Case seriesObservational - Descriptive Cross sectionalObservational - Descriptive Case controlObservational - Analytic CohortObservational - Analytic Clinical trialExperimental - Analytic 515/12/2010Cohort studies

6. 25/5/2009 Dr. Salwa Tayel6  Experimental 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.

7. 25/5/2009 Dr. Salwa Tayel7  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. Back ground

8. 25/5/2009 Dr. Salwa Tayel8 WHAT ARE CLINICAL TRIALS?  Clinical trials)are research activities that involve the administration of a therapeutic or a preventive regimen to humans to evaluate its safety and efficacy.  Clinical trials (Experimental studies) are research activities that involve the administration of a therapeutic or a preventive regimen to humans to evaluate its safety and efficacy.  Experimental studies are the best epidemiological study design to prove causation.

9. 25/5/2009 Dr. Salwa Tayel9 Types of Experimental studies: 1. Preventive trials These evaluate whether a preventive agent (e.g. Vaccine) or procedure reduces the risk of development of a particular disease. We compare incidence rate among exposed and non-exposed.

10. 25/5/2009 Dr. Salwa Tayel10 2. Therapeutic trials: Carried out among patients with a particular disease, to determine the ability of an agent or procedure to diminish symptoms, prevent recurrence, or decrease risk of death from that disease.

11. 25/5/2009 Dr. Salwa Tayel11 Values of Clinical trials Clinical trials are useful for evaluating:  New drugs or other treatments for disease.  New medical/health care technology.  New methods of prevention.  New programs for screening and diagnosis.  New methods of providing health care.  New health care policies.

12. 25/5/2009 Dr. Salwa Tayel12 Pre-clinical trials in animal and lab. Pre-clinical trials in animal and lab. Testing drugs in human Testing drugs in human Phases of testing new agent

13. 25/5/2009 Dr. Salwa Tayel13 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 establish that the new agent is effective and may be suitable for human use. to estimate roughly the dose to be used in man.to estimate roughly the dose to be used in man.

14. 25/5/2009 Dr. Salwa Tayel14 Clinical trials of new agents in human pass through 4 phases Phase I: Aims: to find a safe tolerated dose in manto find a safe tolerated dose in man to test effects on body functions under close supervision.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 drugsThey receive small doses of new drugs This phase is of short duration (one or two months)This phase is of short duration (one or two months) It is performed by clinical pharmacologists.It is performed by clinical pharmacologists. Testing drugs in human Testing drugs in human

15. 25/5/2009 Dr. Salwa Tayel15 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. 25/5/2009 Dr. Salwa Tayel16 Phase III (The classical phase)  Large scale, Randomised, Controlled Trials (RCTs)  Target population: 250 – 1000 patients  Performed by Clinicians in mhospitals.  Performed by Clinicians in multi-centric hospitals.  The purpose of this phase is to: assess the efficacy and safety.assess the efficacy and safety. reduce the side effects & improve the quality of life.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. 25/5/2009 Dr. Salwa Tayel17 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 Effectiveness under actual field conditions Safety& acceptability Safety& acceptability Long-term side effects. Long-term side effects. Rare adverse reactions and Rare adverse reactions and Drug interactions Drug interactions

18. 25/5/2009 Dr. Salwa Tayel18 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 studyThe 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)The exclusion criteria are chosen to minimize potential dangers (e.g. elderly patients, pregnant women, children) Design of Randomized Clinical Trials (RCTs):

19. 25/5/2009 Dr. Salwa Tayel19 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.

20. 25/5/2009 Dr. Salwa Tayel20 Experimental Design time Study begins here (baseline point) Study population Intervention Control outcome no outcome outcome no outcome baseline future RANDOMIZATION

21. 25/5/2009 Dr. Salwa Tayel21 Design of a Randomized Controlled Clinical trial With outcome Without outcome With outcome Without outcome Treatment group (New therapy) Control group Control group (Standard therapy) Participant(consenters) Randomization Follow up

22. 25/5/2009 Dr. Salwa Tayel22 Random allocation  Random  Random allocation is the method of assigning patients to treatment groups.  Each  Each subject has an equal chance of being assigned to any group in the study  All  All groups in a study are similar in all characteristics  It  It avoids selection bias bias on the part of the investigator or the patient.

23. 25/5/2009 Dr. Salwa Tayel23 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).

24. 25/5/2009 Dr. Salwa Tayel24 IIIIt is a method of concealing (hiding) knowledge of treatment assignment to reduce bias in measuring outcome. AAAA Single masked study – subjects are unaware of whether they are in the experimental or control group study. AAAA Double masked study – the subject and the observer are unaware of the subject’s group allocation. AAAA Triple masked study – the subject, observer and data analyst are unaware of the subject’s group allocation. Masking or "blinding"

25. 25/5/2009 Dr. Salwa Tayel25 MMMMasking is achieved by ensuring that all treatments appear identical (form & shape of drugs). AA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AA placebo is an inactive agent made to seem identical to the active agent in terms of appearance and mode of administration. Methods of Blinding

26. 25/5/2009 Dr. Salwa Tayel26 Relative Risk TotaloutcomeGroup NegativePositive a +b baIntervention c +d dcControl

27. 25/5/2009 Dr. Salwa Tayel27 Measures of effect size Relative risk (RR) Is the ratio of the incidence of a given outcome in experimental group compared to that in the control group ( a/(a + b)) / (c /( c + d)) Interpretation of RR?

28. 25/5/2009Dr. Salwa Tayel28 RR=(118/164) / (74/164) =0.719/0.451=1.59 Intervention Outcome Total CureNot cured Intervention (experimental) 11846164 Control group7490164 Calculate size of effect of the intervention

29. 25/5/2009 Dr. Salwa Tayel29 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)

30. 25/5/2009 Dr. Salwa Tayel30 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.

31. 31/1/2009 Dr. Salwa Tayel31 Mention type of study design Subjects were children enrolled in a health maintenance organization. At 2 months, each child was randomly given one of two types of a new vaccine against rotavirus infection. Parents were called by a nurse two weeks later and asked whether the children had experienced any of a list of side-effects. Subjects were children enrolled in a health maintenance organization. At 2 months, each child was randomly given one of two types of a new vaccine against rotavirus infection. Parents were called by a nurse two weeks later and asked whether the children had experienced any of a list of side-effects.

32. 25/5/2009 Dr. Salwa Tayel32 Are exposure and disease linked? ExposureDisease

33. 25/5/2009 Dr. Salwa Tayel33 Descriptive Studies Case-control Studies Cohort Studies Develop hypothesis Investigate it’s association to outcomes Define it’s risk with exposures Clinical trials Test link experimentally Increasing Knowledge of Disease/Exposure Knowledge of Exposure/Disease

34. 25/5/2009 Dr. Salwa Tayel34 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. 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). With increasing certainty comes increasing complexity and attention to detail (and increasing expense, time, and cooperation).

35. 31/1/2009 Dr. Salwa Tayel35 What type of study design to choose? It 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. 31/1/2009 Dr. Salwa Tayel36 What type of study design to choose? It depends on:  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. 25/5/2009 Dr. Salwa Tayel37 Thank you Bibliotheca Alexandrina The End Website http://faculty.ksu.edu.sa/73234/default.aspx salwatayel@hotmail.com