Experimental Studies Dr Amna Rehana Siddiqui Assistant Professor

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

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

Types of Study Designs Design Study Type Case report Observational - Descriptive Case series Observational - Descriptive Cross sectional Observational - Descriptive/Analytic Case control Observational - Analytic Cohort Observational - Analytic Clinical trial Experimental - Analytic 3

¯ 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. 4

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

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

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

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

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. )

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

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). 11

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

Pre-clinical trials Ø 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. 13

Testing drugs in human 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. 14

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

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

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 17

Design of Randomized Clinical Trials (RCTs): 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) 18

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

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

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

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

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

Original Table Shown For Your Interest 24

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). 25

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

Methods of Blinding v Masking is achieved by ensuring that all treatments appear identical (form & shape of drugs). v A placebo is used for the comparison group if the objective is to evaluate a new drug in comparison with no treatment. v 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

Relative Risk: Measure of Effect Size Group outcome Total Positive Negative Intervention a b a +b Control c d c +d 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)) 29

Pravastatin Study Results (NEJM 1996) Outcome # Placebo # Pravastatin Death CHD 274 13. 2 % 212 Fatal MI 10. 2% 207 10% 157 7. 5% Stroke 78 3. 8 % 54 2. 6% Calculate RR for all 30

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

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. 32

• 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). 33

Selecting Study Design from Last Lecture 34