Lecture 4. Analytical Interventional Studies

Transcription

1 Lecture 4 Analytical Interventional Studies By the end of this lecture the student will be able to : Identify the concept of analytical Interventional studies Identify the concept of clinical trials and preventive trials Identify different phases of a clinical trial. Identify the concept of Randomization, blinding and the different types of Blinding Identify some ethical considerations while conducting clinical trials Identify the different types of clinical trials. Identify statistical issues and analysis conducted from clinical trials. A. Clinical Trials It is one of the interventional studies. It is a prospective study to assess the effect of one or more intervention (therapeutic) in a group of patients against a control in human beings. A controlled clinical trial compares the outcomes of a treated group with a comparable group of patients receiving the control treatment. The intervention being tested is often a drug treatment, but may also be a non-drug treatment such as surgery. In evaluation of new interventions, the new drug or procedure should pass through four phases of clinical trial. Phase one: Pharmacology and Toxicology -To assess drug safety, not effectiveness. -Performed on small number of healthy humans. Phase Two: Initial investigation of treatment Effect: -To assess Efficacy and safety -Performed on small scale of affected humans Phase Three: Clinical Evaluation of treatment -To assess Effectiveness -Performed on a large scale. Phase Four: Post marketing Surveillance -Monitoring long term adverse effects. The following description is for phase 3 clinical trial or clinical trials in short. The objectives of a clinical trial are usually: a) To assess the efficacy and effectiveness of a new intervention or drug. b) To assess the side effects and tolerance of patients to the new drug or intervention. c) To help establish the role of the new drug or intervention in clinical practice.

2 Some important consideration in designing controlled clinical trial 1. The protocol The protocol specifies the aims and objectives of the study, questions to be answered, criteria for the selection of study and control groups, size of the sample, procedures. 2. Selection of study groups by Randomization. Randomization is a statistical procedure by which the participants are allocated into groups usually called study and control groups, to receive or not to receive a new preventive or therapeutic intervention. Randomization is an attempt to eliminate selection bias and allow for proper comparison. 3. Blinding: to avoid placebo effect, regression to the mean and investigator bias. Blinding can be done in three ways: Single blind trial: The trial is so planned that the participant is not aware whether he/she belongs to the study group or control group. b. Double blind trial: The trial is so planned that neither the doctor nor the participant is aware of the group allocation and the treatment received. c. Triple blind trial: This goes one step further. The participant, the investigator, and the person analyzing the data are all not aware blind. NB: the two drugs should be identical in shape, color, taste and the container (if possible). 4. Assessment The final step in clinical trial is assessment in terms of positive results as reduction in incidence rate or severity of the disease or increase in survival time. Also, negative results as adverse events among treated and control groups. Bias may arise from errors of assessment of the outcome due to human factors (blind assessment). a. Bias from participant Who may subjectively feel better or report improvement if they knew that they were receiving a new form of treatment. b. Observer bias: when measuring the outcome of a therapeutic trial the investigator may be influenced if he knows beforehand the particular therapy to which the patient has been subjected. c. Evaluation bias that is the investigator may subconsciously give a favorable report of the outcome of the trial. All previous types of bias can be reduced by blinding technique.

3 Ethical issues The Helsinki declaration which was revised by The World Medical Association (WMA) many times up to 2000 has listed some ethical issues. Stopping rules or when to stop the trial: i) If severe and unexpected side effects or complications occur. ii) If the benefit from the intervention becomes evident and undeniable. Standard of care protocol Should be applied to all participants in both groups Informed Consent Should be read, agreed upon and signed by each participant. The rationale of the informed consent is to safeguard the individual and to ensure that patients play an active role in decisions about their treatment. Patients Random Allocation Study group(new treatment) Outcome Follow up Control group(standard treatment or placebo) Outcome Compare outcome Schematic Diagram for controlled clinical trial Types of clinical trials 1. One Arm clinical trial: One group of patients will receive the treatment, without control. We will assess the effect of treatment without comparative placebo effect. 2. Two arms clinical trial: This is the classical clinical trial. It is also called controlled clinical trial. One group will receive the new treatment; meanwhile the other group will receive the old treatment or the placebo. Placebo is an inert compound randomly allocated to subjects in a clinical trial.

4 Placebo arm is a true control for an intervention: -Assess relative effect of intervention relative risk - Assess risk for adverse events Placebo arms are not ethical if there is an established standard treatment/management. 3- Cross over Clinical trial: Group A will receive the new treatment and group B will receive the old treatment or the placebo. Evaluation of the results in each group is done. After a washout period, the effect of the first administration is supposed to be washed out, group A will receive the old treatment and group B will receive the new treatment. In this type of clinical trials comparison of each group will be carried with the same group. 4- Sequential Clinical trial Only one group will receive the treatment and the placebo alternatively. Group A.New treatment.evaluation of effects washout period..group A..old treatment.. Evaluation of effects. Both the cross-over and the sequential designs of the clinical trials attempt to remove biases introduced from known or unknown difference between the two groups. B. Preventive Trials The term "Preventive trials" implies trials of primary preventive measures e.g. vaccines and chemo-prophylactic drugs. It is similar to controlled clinical trial. Other types of preventive trials are: risk factor trials e.g. the major risk factors of coronary heart disease are elevated blood cholesterol, smoking, hypertension and sedentary life. So, interventions were used to evaluate the effect of elimination or reduction of one single risk factor each time e.g. smoking or multifactor, are both needed. Notes: 1. There are many other types of clinical trials as non- randomized trials and non-comparative trials. 2. There are many studies can be classified as natural experiments e.g. Atomic bombing of Japan, earthquakes etc. Statistical issues in clinical trials 1. Sample Size: A. Determined for primary study outcome. B. Must account for multiple comparisons.

5 C. Sample Size should account for loss to follow up cases (censored). 2. Analysis: 1. Fundamental measures are Relative Risk (RR), efficacy and Number needed to treat. Relative Risk: = Incidence rate in treatment group/incidence rate in placebo/control group which measure the reduced risk of developing the disease after receiving the treatment. Absolute Risk Reduction (ARR) = (Incidence rate in control gr- Incidence rate in treatment gr). Number needed to treat (NNT)= 1/ARR Which is the number of patients needed to be treated with the new treatment to have one favorable outcome. Example: 200 hypertensive males are randomly allocated to treatment A (100 patients) and a placebo (100 patients) after three months of treatment, 70 of the treated groups and 50 of the placebo group showed persistent normal blood pressure. The incidence rate among treated =30% The incidence rate among Controls=50% The risk ratio= 30/50= 0.6, so the treatment is successful. Absolute risk reduction= 50-30=20% Number needed to treat=1/0.2=5, which means that you need to treat 5 cases to have an extra one favorable outcome or corrected blood pressure in this example.