Seminar on CLINICAL TRIALS

Presented byY.SRUTHI

M.Pharmacy –II semDEPARTMENT OF INDUSTRIAL PHARMACY

UNIVERSITY COLLEGE OF PHARAMACEUTICAL SCIENCES

KAKATIYA UNIVERSITYWARANGAL-506009

Contents• Introduction on Drug Development Process• Understanding Clinical Trials• Types of clinical trials• Clinical trial protocol• Regulatory bodies governing clinical trials• Ethics in Clinical Drug Research• Phases of clinical trials• Study Designs• Clinical Trials in India• References

New chemical Entity

Preclinical studies

Investigational New Drug Application

Preclinical studies plusProduct formulationMfg & controlsPackage & label designLT animal toxicity

Clinical trialsPhase IPhase IIPhase III New Drug Application

SubmissionFDA reviewPre approval plant inspectionFDA action

Post marketingPhase IV,Clinical pharmacology/toxicology, Adverse drug reactions &product defects reporting, product line extension

Schematic representation of new drug development process

These are biomedical or health related research studies in human beings that follow a predetermined protocol.

CLINICAL TRIALS

Understanding Clinical trials

•Why participate in a clinical trial?•Who can participate in a clinical trial?•What happens during a clinical trial?•What are the risks and benefits of participating

in a clinical trial?•What should people consider before

participating in a trial?

Types of clinical trials:

•Treatment trials•Prevention trials•Diagnostic trials•Screening trials•Quality of life trials

The clinical protocolContents:•Statement of purpose and objective of the study•Outline of the investigational plan and design including the kind of control group and methods to minimize bias on the part of the subjects, investigators and analysts.•Estimate the number of patients to be involved.•Basis for subject selection, including inclusion and exclusion criteria•Description of dosing plan, including dose levels, route of administration and duration of patient exposure.

…contd

•Description of the patients observations, measurements and tests to be used•Clinical procedures, lab tests and monitoring to be used to minimize patient’s risk.•Names, addresses and credentials of the principal investigator and sub-investigators.•Location and description of research facilities.•Approval of authorized IRB

Regulatory bodies governing clinical trialsFDA-The Food, Drug and Cosmetics Act, as regulated through Title

21 of the U.S Code of Federal regulations, requires a new drug to be approved by the Food and Drug administration.

Advisory Committee-The FDA often seeks the opinion of outside experts to aid the agency in making decision on approvability of the drug .One or more advisory committee comprising scientific experts from academic medicine, a consumer representative, biostatistician and other members deemed to be important

Institutional Review Boards-A committee governing the conduct of clinical trials at the local institution.Members who have the professional competence in scientific, legal, regulatory and moral perspective are included.

•Clinical trials in India are regulated by Schedule Y of the Drug and Cosmetics Rules, 1945.

•The Central Drugs Standard Control Organization (CDSCO), headed by the Drugs Controller General (India) (DCG(I)), discharges the functions allocatedto the Central Government (similar to the US Federal Government) under the Drugs and Cosmetics Act,1940.

•DCG(I), along with the Indian Council of Medical Research (ICMR) have adopted international regulatory guidelines and issued Indian versions of the same. • ICMR issued the Ethical Guidelines for Biomedical Research on HumanSubjects in 2000 and Indian GCP guidelines were released by CDSCO in December 2001. The Drug Technical Advisory Board (DTAB), the highesttechnical body under the Drugs & Cosmetics Act, has endorsed adoption of GCP guidelines for streamlining clinical studies in India.

•The clinical protocol must be reviewed and approved by an IEC of, at minimum, seven members, including a medical scientist, a clinician, a statistician, a legal expert, a social scientist and a common person from the community.

Scenario in India

Ethics in clinical drug research•Ethical principlesAutonomyBenficence/nonmaleficenceFidelityInformed consentDistributive justice•Ethical code:The code of NurembergThe Helsinki code•Ethical research questionsDrug testing in Healthy volunteersDrug testing in pediatricsDrug testing in womenDrug testing in prisonersDrug testing in mentally disabled

Phases of clinical trialsPhase I Phase II Phase III Phase IV

Population Healthy volunteers

Target diseased patients

Target diseased patients

Mixed

Sample size 20-80 200-300 100-1000 >1000

Duration Several months

Several months-years

Several years

Ongoing

Conclusions

Safety, tolerability,PK & PD

Efficacy,short term safety

Safety, effectiveness and dosage

Long term adverse effects

Design of a clinical trial

•Study objective•Sample size•Randomization•Blinding•Study design

•Randomized:•Controlled•Blinded studies:oOpen:oSingle blindoDouble blindoTriple blind:

Randomized controlled double blinded studies-A method to reduce bias

Study designs1.Surveys---------by simple questionnaire 2.Experimental

Parallel study design Simple parallel designStratified parallel design

Cross over study designComplete cross over design Balanced Incomplete Block Design Latin Square Design Factorial design 3.Observational studies Case control studiesCohort studies(prospective & retrospective) Cross sectional studies

Simple parallel•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

•Experimental studies

Stratified parallel•First all the subjects are divided into 2 specific groups (strata) on the basis of some predefined factor.So, 2 or more “Stratas” will be formed.

•Later, from the individual strata, the random samples will be taken & assigned as study groups.

Complete cross over design

•Each study subject receives more than one study treatment, one after the other.• Each of the time intervals in which one of the study treatments is administered is called a period.• The continuation of the effect of one treatment into the following period is referred to as carry over effect.•Washout period: The interval between end of a treatment and beginning of the next is called as wash out period. To eliminate the carry over effect.

Balanced Incomplete Block Design

1.Each subject receives not more than two formulations.2.Each pair of formulations occur together in the same number of subjects.3.Each formulation is administered the same number of times.

SUBJECT TREATMENT I TREATMENT II

1 A B2 B A3 A C4 C A5 A D6 D A7 B C8 C B9 B D10 D B11 C D12 D C

Latin square design1. Each subject receives just once each formulation2. Each formulation is administered just once each period.Two way cross over TreatmentGroup no Subjects in group I II

1 2

1,2,3,4,5,6 7,8,9,10,11,12

A B B A

Three way cross over I II III

1 2 3

1,2,3,4,5,67,8,9,10,11,1213,14,15,16,17,18

A C B B A C C B A

Four way cross over I II III IV

1 2 3 4

1,2,3,4,5,67,8,9,10,11,1213,14,15,16,17,1819,20,21,22,23,24

A B C D B D A C C A D B D C B A

Factorial design

Many times it is possible in one trial to evaluate two or even three treatment regimens in one study. Each drug could be compared to placebo, and any interaction of the two drugs in combination could also be evaluated.

Case control studies

Investigator identifies a certain outcome in the population, then matches the diseased group to a healthy group and finally identifies differences in exposure between the two groups .

•Observational studies

Cohort studies

Prospective cohort study: Cohort is identified before the appearance of the disease.Follow a group of people who do not have the disease for a period of time and see who develop the disease.•Assemble the Cohort•Measure Predictor Variables and Potential Confounders•Follow-up the Cohort and Measure Outcomes

Retrospective cohort study: Designs the grouping after the data is collected.•Identify a Suitable Cohort•Collect Data about Predictor Variables•Collect Data about Subsequent Outcomes

In cross-sectional studies, one defines and describes disease status (or outcome),exposure(s), and other characteristics at a point of time, in order to evaluate associations between them.

Cross sectional study

Clinical trials in India

•There are numerous government funded medical and pharma institutions facilitating multi-centered trials.•India can boast of a large well trained & qualified manpower that is well versed in English.•Vast availability of clinical material.•Cost efficiency.•Alternative systems of medicine are practiced with equal fervour as allopathy.•Large patient population.

References1.Clinical Research in Pharmaceutical Development Edited by BarryBleidt, Michael Montagne

2.Clinical Trials A Practical Guide to Design, Analysis and Reporting.

3.Text Book Of Clinical Trials Second Edition Edited by David Machin

4.Designing Clinical Research Authors: Hulley, Stephen B.; Cummings, Steven R.; Browner, Warren S.; Grady, Deborah G.; Newman, Thomas B

5.Essentials Of Clinical Trials. Edited by Stephen P.Glasser

6.Fundamentals Of Clinical Research by Antonella Bacchieri ,Giovanni Della Cioppa

7.Handbook Of PHASEI/II clinical Drug Trials edited by John O’Grady,Pieter H.Jobert

8. Pharmaceutical Dosage Forms by Howard C.Ansel.Loyd V.Allen, Nicholas G.Popovich

9. Pharmacology(Fifth edition) By H.P.Rang And M.M.Dale

10.A Text Book Of pharmacology by Tripathi

11.Biopharmaceutics and Pharmacokinetics BY V Venkateshwarlu

12.www.wikipedia.org

13.www. Clinical_trials.htm

14. www.clinical trials/irb.htm

15. www.clinical trials/Clinical-Trials-of-Drugs-and-Bio-Pharmaceuticals.htm

16. http://www.fda.gov/cder/regulatory/default.html

17. www.clinical trials/understand.htm

THANK YOU