logging in or signing up clinical trials and study designs... Allam.vamshi Download Post to : URL : Related Presentations : Share Add to Flag Embed Email Send to Blogs and Networks Add to Channel Uploaded from authorPOINT lite Insert YouTube videos in PowerPont slides with aS Desktop Copy embed code: Embed: Flash iPad Dynamic Copy Does not support media & animations Automatically changes to Flash or non-Flash embed WordPress Embed Customize Embed URL: Copy Thumbnail: Copy The presentation is successfully added In Your Favorites. Views: 4161 Category: Science & Tech.. License: All Rights Reserved Like it (10) Dislike it (0) Added: July 10, 2010 This Presentation is Public Favorites: 3 Presentation Description Definition Introduction Phases of Clinical Trials Design of CT Study objective Study designs Sample size Randomization Blinding techniques Conclusion Comments Posting comment... By: Allam.vamshi (19 month(s) ago) Thank you... Saving..... Post Reply Close Saving..... 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STUDY DESIGN OFCLINICAL TRIALS Contents : 2 Definition Introduction Phases of Clinical Trials Design of CT Study objective Study designs Sample size Randomization Blinding techniques Conclusion Contents Slide 3: 3 What are Clinical Trials??? Systematic CLINICAL study of new drug, which are performed in HUMANS. To discover or verify: 1. Pharmaco dynamics (how it works) 2. Pharmacokinetics (what happens to it) 3. Therapeutic effects (Efficacy) 4. Adverse reactions (Safety) From the basis of changing current medical practice. Slide 4: 4 Sponsor Phases of Clinical Trials : 5 Phases of Clinical Trials Phase I Safety (MTD) & Early Clinical Pharmacology. Performed on HEALTHY volunteers (mostly males). 20-100 subjects. (approx. 1year) Phase II Initial Efficacy & Safety. Performed in PATIENTS suffering with the disease. 100-500 (several hundreds) subjects. (approx. 2-3years) Phase III Comprehensive Efficacy & Safety Performed in PATIENTS. 1000-2500 (several thousands) subjects (large time, several years) Phase IV Post-marketing surveillance Studies Study will be conducted in large population(2500-5000 or more) & Its a MULITI CLINICAL study. Here each Phase: Cumulatively exposes greater numbers of human subjects to the drug. Collects increasing amounts of safety and efficacy data. Remember these things… : 6 Study must examine valuable and important biomedical research questions. It must be based on rigorous methodology & It must follow strong ethical principles. The probability and magnitude of risk – benefit to the participants. The population to be studied – its Size, Availability and Accessibility. Whether the disease for which new treatment is sought is severe or life threatening. Remember these things… Design of a Clinical Trial : 7 Study objective Study design Sample size Randomization Blinding Design of a Clinical Trial 1.Study Objective : 8 Researcher and statistician should jointly articulate the objective of the study. Other elements like study design, sample size and method of allocation of subjects depends on this. The objective should be clearly defined. Otherwise bias and errors may occur. Ex: While drug “X” was testing for hypertension, the bald head patients reported hair growth. (Minoxidil) In the above situation, the researcher and statistician may get confusion while collecting the data. 1.Study Objective 2.Study Designs : 9 Three main types : 1. Surveys 2. Experiments 3. Observational / Quasi-experimental. 2.Study Designs Surveys : 10 It involves measuring a set of parameters in a population group or in a sample of subjects. It is usually performed with a carefully developed and pre tested QUESTIONNAIRE. Most effective for estimatation of the frequency of parameters. Surveys Experimental study designs : 11 Here treatments are assigned to the subjects. Types of experimental Designs: 1. Simple experiment design Parallel group design 2. Repeated measures design. 3. Crossover designs a. Two-treatment, two-period crossover design b. Two-treatment, four-period crossover design c. Latin square design d. Graeco Latin square design e. Balanced Incomplete Block Design/ BIBD 4. Factorial design Experimental study designs *Simple experiments : 12 Subjects assigned as two groups. Treatment group & Control (or placebo) group. Treatment assigned to treatment group and no treatment or placebo assigned to control group. The outcome measures are compared at the end of experiment. *Simple experiments Parallel group design : 13 A homogenous group of subjects is selected using suitable selection criteria (from the total population), then subjects are randomly allocated into treatment & control groups. Ex: Total population = male + female Then the male & female subjects were separated as individual/parallel groups. Disadvantage: Inter-subject variation is not being correlated. Parallel group design Parallel group : 14 Parallel group A B C D *Repeated measure design : 15 Same as the simple experiment, but the repeated measures were taken in both, the treatment group as well as the control group. Here the results are some more accurate than simple experiments. *Repeated measure design *Crossover designs : 16 Each subject will get two or more treatments successively. Before switching over to the next treatment, each subject is brought back to original status as before the 1st treatment. Ex: drugs used to for Arthritis & Hypertension. (when the treatment stopped, then the disease condition riverback to original status) This method minimizes the “inter-subject variation”. Requires less no. of subjects to get meaningful results. But the only disadvantage is, increased no. of study periods leads to subject drop outs & longer duration. Time gap between stoppages of the two treatments is called “WASH OUT PERIOD”. The wash out period is generally taken as 10half-lives, thus 99.9% elimination may occurs. If in any case, after washout period, the effect of 1st treatment shows its impact on next treatment then its called as TREATMENT-PERIOD INTERACTION. *Crossover designs Two-treatment, Two-period crossover design : 17 Two-treatment, Two-period crossover design Each subject gets 2 treatments (ex: A&B). i.e: 1st treatment with A & next 2nd with B. In Two-periods: 1st period with A & next 2nd period with B. Mainly used in BE studies/ comparison of two same drugs of different manufacturers. Two-treatment, Four-period/ Switchover design : 18 Two-treatment, Four-period/ Switchover design First the 2 treatments were given as like the “TT-TP method’, but after 2nd wash out period again the treatment will be repeated. This is study gives more accurate results then “TT-TP method”. Ex: In females, some diseases associated with menstruation cycles (Ovulatory / Non-ovulatory cycles). Latin square design : 19 Latin square design If each subject has to involve in three or greater than three treatments, then Latin square design will be used. Here in 1st period 3 groups of subjects will be allocated as A, B & C. In 2nd & 3rd periods, treatment will be given in a cyclic order like A→B, B→C & C→A. Used mainly for BE studies & Agriculture studies Graeco Latin square design : 20 Graeco Latin square design Used when the measuring of treatments as well as factors is required in a study. Possible only if the no. of treatments & no. of factors are exactly same. Here subjects assigned to different combinations of treatments & factors. Ex: if we take A,B &C as treatments and X,Y & Z as factors, In 1st period the treatment groups assigned as AX, BY,CZ groups. After that, it continues like Latin Square Design. Mainly used to study Drug-drug & Drug-food interactions. Balanced Incomplete Block Design (BIBD) : 21 Balanced Incomplete Block Design (BIBD) In case of four or more than four treatments are given to a subject, the drawing of blood sample will be unethical in many aspects (it may cause health problems/ weakness to the subject). If four treatments A,B,C&D has to be measured, then 6 pairs of treatments will be performed in a subject group. Like: A-B, A-C, A-D, B-C, B-D & C-D Another subject group is arranged exactly in the opposite direction and conduct another study, at last compare the results. The main advantage of this method is EACH SUBJECT RECIEVES ONLY TWO TREATMENTS. *Factorial design : 22 *Factorial design To estimate the effect of main treatment & other factors simultaneously. In a specific case of 2 treatments A & B, The groups taken as: Given neither A (A=0) nor B (B=0) Given A alone (A=1) & not B (B=0) Given B alone (B=1) & not A(A=0) Given both A (A=1) & B (B=1) DRUG B A Level B=1 B=0 A=0 A=1 Observational/Quasi-experimental study designs : 23 Useful in the circumstances where experiments are either infeasible or unethical. Here the subject who receives the treatment / risk factor is not under the control of investigator. Instead the investigator measures and analyzes the effects or out comes. Observational/Quasi-experimental study designs Observational study designs : 24 Types of observational studies: Cohort study/ Follow up study: The subjects are selected on the basis of whether they are exposed to the risk factor/treatment & then followed to determined which ones get disease. RISK FACTORS DISEASE 2. Case control study/ Backward study: Opposite direction to the Cohort study, i.e The subjects are selected on the basis of whether they have the disease and are then studied to which ones had been exposed to the risk factor/treatment. DISEASE RISK FACTORS Observational study designs 3.Sample size : 25 3.Sample size It is a critical feature in designing a clinical trial. If few subjects were chosen, it may not give accurate outcome / the results are not trusty. If large no. of subjects were taken, then the time span and cost of the study will increases highly. So an adequate no. of subjects were selected for the study. But “Unfortunately there is no way of guaranteeing an adequate sample size”. The experienced investigator can only make an educated guess about the suitable adequate sample size. Randomization : 26 Randomization Here we can say it as “The probability that allows every subject to get equal treatment.” To minimize or avoid bias and errors. Randomization techniques: 1. Simple randomization 2. Stratified randomization 3. Factorial randomization 4.Randomization *Simple Randomization : 27 We can simply say that it is like “different color balls drawn from a basket”. Here, first the subjects satisfying selection criteria as defined in the study protocol are identified. Later, from the above group subjects are chosen in random manner. *Simple Randomization Slide 28: 28 Group.A Group.B SIMPLE RANDOMIZATION *Stratified Randomization : 29 First all the subjects are divided into 2 specific groups (STRATA) on the basis of some predefined factor. So, 2 or more “Stratas” will formed. Later, from the individual strata, the random samples will be taken& assigned as study groups. *Stratified Randomization Slide 30: 30 STRATIFIED RANDOMIZATION Group.A Group.B Group.A Group.B MALE-STRATA FEMALE STRATA Factorial Randomization : 31 If two or more than two factors to be considered in the study, then this method is used. Ex: Comparison of response pattern with two treatments in depressed as well as non depressed male and female subjects. Here, 1. The total no. of subjects are identified. 2. Classify them as Male & Female (factor-sex) 3. Further classify both of them as Depressed & NonDepressed (2nd factor-disease status) 4. Randomize subjects from each type. Male – Depressed Male – Non depressed Female – Depressed Female – Non depressed Factorial Randomization Slide 32: 32 FACTORIAL RANDOMIZATION FACTORS MALE SEX DEPRESSED NON DEPRESSED FEMALE D I S E A S E S T A T E A B A B Blinding : 33 Blinding If the investigator, statistician and subject knows about the treatment which has given, then there is a chance to misinterpretation of result, Thus bias and errors may occur. To prevent this, “BLINDING” is used. Types of studies on the basis of blinding: 1. Open/No blinding . 2. Single Blind 3. Double Blind 4. Triple blind Methods of achieving double blinding: 1. Matching 2. Double dummy technique 5.Blinding Blinding : 34 Open/ No blinding: Investigator, patient & statistician all are aware of treatment Single blind: One party, either the patient or the investigator aware of treatment. (Mostly the investigator will be aware.) Double blind: Neither the investigator nor the patient are aware of treatment. Triple blind: Investigator, subject and the statistician is also not aware of treatment. Blinding Methods of achieving Double blinding : 35 Matching: If two treatments are available in the form of tablets then matching both tablets in terms of colour/shape/size. Double Dummy Technique: If two treatments available in different forms like tablet(A) & capsule(B), then all subjects are given both 1tablet & 1capsule. 1. Here subjects assigned to treatment “A” will get original drug containing tablet and a placebo capsule. 2. Subjects assigned to treatment “B” will get original drug containing capsule and a placebo tablet. Methods of achieving Double blinding Conclusion : 36 A wide variety of clinical trial designs have been developed and adopted over the past 25 years. Designing a clinical trial is a creative and rigorous process that requires attention to a large number of details, each of which can determine the SUCCESS or FAILURE of the project. For the planning and execution of clinical research to be successful, the investigator must be fully aware of the many aspects that must be planned so that all are addressed as early as possible in research process. Conclusion References : 37 Amberson Jb, Jr.McMohan Bt, Pinner M A Clinical trail of sanocrysin in pulmonary tuberculosis, AmRev Tuberic 1931;24:401-35 Doll R. clinical trials: retrospect and prospect, stat Med 1982;1:337-44 Meinert CL. Clinical trials: Design, conduct, analysis. NY1986. SHAPIRO SH, LOUIS TA (Eds). Clinical trials: issues and approaches. NY 1983. S.K. Gupta, Basic principles of Clinical research and Methodology. ICRI, India 2007. Anello C. Statistical Issues In Comparative Clinical Trials, Drud inf., 1983;17:55. Armitage P. Statistical Methods in medical research. NY: Willy & sons. FDA guidelines: http://www.fda.gov/cder/regulatory/default.html References References : 38 References 9. Hill AB. Principles of Medical Statistics, 9th edn, London. The Lancet 1971. 10. Hill A.E. Nunn A.J., FOX W. “Matching the quality of Agents Employed in Double-Blind controlled Clinical Trials.” 1976;352 ICH: http://www.ifpma.org/ich.html. Pockok S.J. Allocation of Patients to Treatment in Clinical Trials, Biometrics, 1979;35:183. Pockok S.J. Clinical Trials: A Practical Approach. NY1983 Spriet A, Dupin spriet T, Simon P. Methodology of Clinical Trials. 2nd edn. Basel 1994; Karger. Storer BE. Design and Analysis of Phase I clinical trials, Biometrics 1989;45;925-37. Vere DW. Ethics of Clinical Trials. In Good CS, ed: The Principles and Practice of Clinical Trials, Edinburgh, Churchill Livingstone, 1976. 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