What is clinical trial? Methodological experimentation of investigational drugs or devices (like stents ) in human beings/ (volunteers/patients)
DRUG DEVELOPMENT PROCESS Chemistry Synthesis & Purification Formulation Animal Pharmacology Animal Toxicity (Short / Long term) Studies in Humans Drug Authorities Market
PHASE I TRIALS1. Initial studies to determine the metabolism and pharmacologic actions of drugs in humans, the side effects associated with increasing doses, and to gain early evidence of effectiveness; may include healthy participants and/or patients.2. In phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
PHASE II TRIALS1. Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks.2. In phase II trials, the experimental study drug or treatment is given to a larger group of people (100- 300) to see if it is effective and to further evaluate its safety.
PHASE III TRIALS1. Intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling.2. In phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.
PHASE IV TRIALS Post-marketing studies conducted to describe additional information including the drugs risks, benefits, and optimal use.
Randomized Controlled Trials Participants randomly allocated to either study drug OR another like a different drug or placebo Follow up is for a specified period Analyses in terms of outcomes defined at the outset Objective of randomization is to rule out bias on part of investigator ( doctor ) for a specific treatment. 1 2 3 4 5 6 7 8 9 10 A A B B B A A B B A
Cohort Studies Two or more groups of people are selected on the basis of their exposure to a particular agent Subsequently followed up to see how many from each group develop the ‘outcome’ For example: smokers ( one group ) and non-smokers ( other group ) are selected and followed-up for a period of say 5 years to see how many from the smoker group and non-smoker group develop bronchitis( outcome )
Case Control Studies Patients with a particular disease are identified and matched with controls Data is collected on past exposure to a possible causal agent For example, diabetic patients (one group) and non-diabetics (other group ) otherwise matching with each other are selected and evaluated for a risk factor (say obesity) for diabetes.
Cross-sectional Surveys Data are collected at a single time e.g. Lipid profiles of 25 year old males in Ahmedabad
Case Reports Medical history of a single patient Not very reliable as evidence Conveys information which might have been lost
Terms : Systematic reviews: Summarize primary studies according to a systematic scientific methodology Meta-analyses: Integrate numerical data from more than one study/trial on a single product and analyze data Guidelines: Conclusions from primary studies on clinical decisions For example JNC (Joint National Committee ) VII Guidelines on hypertension, NCEP ATP III ( National Cholesterol Education Program Adult Treatment Plan ) Guidelines on dyslipidemia management
Terms (Cont…) Placebo controlled: Subjects in control group receive a placebo whereas subjects in other group receives drug Treatment controlled: Subjects in control group receive a standard treatment whereas subjects in other group receives drug under investigation.
Single blind: Patients do not know which treatment they are receiving Double blind: The investigators and the patient both do not know which of the two treatment options is being administered
Terms (Cont…) Multicenter trial: A clinical trial conducted according to a single protocol at more than one site and thus by more than one investigator
Hierarchy of Evidence: In terms of clinical evidence ,Systemic reviews & meta-analyses have rated as the highest evidence followed by randomized controlled trials.
Systematic reviews and meta- analysesRandomized controlled trials Cohort studies Case-control studies Cross-sectional surveys Case reports
Q. 6) Define the following terms:Meta-analysis:Placebo-controlled studyDouble-blind study:Multi-centric study:
Absolute Risk Reduction (ARR ) &Relative Risk Reduction (RRR) AbsoluteRisk Reduction ARR is the difference in the event rate between treatment group and control groups
Relative Risk Reduction The proportional reduction in rates of bad outcomes between experimental and control participants in a trial
P Value P value: The probability of any particular outcome having arisen by chance. Arbitrarily a P value of less than 1 in 20 (expressed as P<0.05, odds of 20 to 1) is taken as "statistically significant" and a P value of less than 1 in 100 (P<0.01) as "statistically highly significant”.
Confidence Interval The range of numerical values in which we can be confident (to a probability, such as 90 or 95%) that the value being estimated will be found. A 95% CI is the range of values within which we can be 95% sure that the true value for the whole population lies. RRR=26.9%, 95% CI, Confidence intervals indicate the strength of evidence. The narrower the confidence interval, the more precise is the estimate of effect. The larger the trial size, the narrower the interval.
Points to look for Who funded the research? Where was it published? How large was the patient population? How long was the population studied? How much at variance are the results of this research with other studies? How sweeping did the studys findings appear to be? What recommendations accompany the study, and who is making them?