CLINICAL TRIALSPRESENTED BY

DR.PALLAVI BHAILUMEPG STUDENT

Clinical research design

No intervention InterventionObservational ExperimentalComparison

group

NoYes

Analytical study (case

control, cohort)

Descriptive study

Random allocation

Yes NoRandomize

d controlled

trial

Non-Randomised

Type

s of

exp

erim

enta

l stu

dies

Preventive or prophylactic study –e.g. Study of vaccines or risk

factor

Therapeutic or clinical trials

Community (field) trial -Community wide basis e.g.

fluoridation trial for prevention of tooth decay.

Clinical Trials are the best way to test whether a treatment is effective and better than other treatments (or no treatment).

Randomized controlled trials are best suited for testing new treatments.

STEPS OF A RCT1.Preparing a protocol.

a)The medicine to be researched , selection of patients , diagnostic criteria , dose of drug , duration of treatment , method of randomization , method of blinding , etc.b)Developed and approved before enrollment of subjects from the institutional ethics committee

2.Selection of reference & experimental populations:

Reference population –the population / group to whom an

investigator expects the result to be applicable.

all human beings or subgroups women , smokers etc

Experimental population- actual population in which the study

will be carried out.

INFORMED CONSENT- Legally and ethically to inform

• Medicine its cost , possible toxic effects and benefits.

• By accepting to participate in the study he is willing to subjects himself for new treatment that is under trial.

• He can withdraw from trial without giving any reason and without any fear of loosing the benefits he has received till that time.

3.Randomization –

Statistical procedure by which the participants are allocated in

to groups usually called ‘study’ and ‘control’ group.

Types

A]Simple randomization

B]Systematic randomization

C]Stratified randomization

4.Intervention

Deliberate application or withdrawal or reduction of a suspected

causal factor.

5.Follow up

The period of follow up is predetermined and documented in

the protocol.

6.Assessment

Positive results-benefits –reduced incidence or severity.

Negative results –severity & frequency of side effects and

complication including death.

Bias Selection bias

Bias due to subject variation

Observer bias

Investigator bias

Attrition bias

Good study design - minimizing all possible sources of bias

Blinding Single blind

Double blind

Triple blinding

Open label

Types of study designs Randomized controlled trials

Non randomized controlled trials

Concurrent parallel design

Group getting new medicine continues to get the new medicine and

control group continues to get standard treatment

this is the usual format of rct.

Eligibilit

y assesse

dConsent Randomize

d

Test drug

Control

Cross over type design

a.Each patient gets both drugs the order in which the patient gets

each drug is randomized

b.Each patient serves as his own control

c.Avoids between participant variation in estimating intervention

effect

• Requires a small sample size

A(NEW MEDICINE)

A

B(STANDARD MEDICINE) BA followed by BB followed by A

Run in

Wash out period

Factorial design-

- two or more interventions.

- Allows study of interactive effects.

Disadvantages1. Complexity of trial design2. Complexity of statistical analysis

Clinical trial using historical controls

A new intervention is used in a series of participants and results

are compared to the outcome in a previous series of

comparable population , the historical controls.

Withdrawal study

Participant on particular treatment are taken off therapy or have

dosage reduced.

The study is used to assess response to discontinuation or

reduction.

Group allocation design

Also called cluster randomisation design.

A group of individual , a clinic or community.

Hybrid design

if substantial data is available from historical controls.

Smaller proportion of participants is allocated to either group and

study is conducted to see the effect of medicine.

Double dummy technique

Randomize

Placebo

Placebo

-refers to type of placebo -drugs are adminstered by different routes (e.g.injection nd pills)-In order to keep participants from knowing which treatment arm they are in

Clinical trial is an organized research , conducted on human beings to investigate the safety and efficacy of a drug.

Clinical trial may be done for various purposes.

Common types

• 1.prophylactic trial e.g immunization• Safety trials e.g.side effects of oral

contraceptics & injectacbles

• Therapeutic trials e.g drug treatment , surgical procedure

• Risk –factor trials ,e.g proving the etiology of a disease by inducing it with the agent in animals / withdrawing the agent

NEW DRUG DEVELOPMENT PROCESS

Drug discovery requires two basic steps , i.e. RESEARCH & DEVELOPMENT.

RESEARCH -3 Sequential activities –Target selection , drug selection & product development.

Target selection –a disease to treat and then developing a model for that disease.

Drug selection – finding a drug or group of drugs that work within that model system.

When the compounds with the desired activity are

discovered , the most promising among them are

optimized to produce one or two final compounds that may

eventually become drugs.

DEVELOPMENT –

-Preclinical & Clinical development (clinical trial)

Preclinical development. Performed in the laboratory , using a wide array of

chemical and biochemical assays, cell culture models and animal models of human disease.

Develops -

Pharmacological profile

Acute toxicity

Short-term toxicity studies

Phase -4 years. Investigational New drug application-test –human If regulatory body does not disapprove it within 30days ,

then this application becomes effective and at this stage clinical trial can be initiated.

Phases of clinical trials Clinical trials on patients in different countries are

approved and monitored by different regulatory agencies , which in India , is monitored by Drug Controller of India (DCGI) under Central Drug Standard Control Organization(CDSCO).

Duration – 8-9years

Phases of Clinical Trial

PHASE l

PHASE ll

PHASE lll

PHASE lV

Phase I

First stage of testing in human subjects (20-100).

Designed to assess the initial safety ,maximum tolerance ,

Pharmacokinetics of the drug.

Time period – 3 -6months

Phase II Therapeutic Exploratory Trial. (20-300 Subjects). Efficacy in patients (primary objective) Safety issues (secondary objective) Dose and adverse reaction of drug. 6months to 2years. Phase II

› Phase IIA: Designed to assess dosing requirements› Phase IIB: Designed to study efficacy

Phase III Therapeutic confirmatory trials. (300-3000 subjects). To establish efficacy of the drug against existing

therapy in larger number of patients, method of usage etc.,.

Subtypes› Phase IIIA: to get sufficient and significant data.› Phase IIIB: allows patients to continue the

treatment, Label expansion, additional safety data.

Phase IV

Post Marketing Studies (PMS). Involves safety surveillance. Determine behavior of drug in real life situations. Evaluate action of drug in a situation of missed

dosage or over dosage.

5,000-10,000 compounds

250

5

1 Approved by FDA

Preclinical testing

Clinical testing

REGULATORY FRAMEWORK International ethical and scientific quality standard for

designing , conducting , recording and reporting of clinical trials

International conference on harmonization of technical requirement for registration of pharmaceuticals for human use – good clinical practice : consolidated guidance (ICH-GCP , 1997)

Local regulatory requirements (DCGI) Indian council of medical research (ICMR code , 2000 ) Local ethics review boards (ERBs)

Good Clinical Practice International ethical and scientific quality standard for

designing , conducting , recording and reporting of clinical trials

Rationale Of Good Clinical Practice Legal requirement for conduction of the trial. Protects the rights , integrity and confidentiality of research

subjects. Provides assurance that the data and results are credible and

accurate. Global acceptance of the data.

Ethics Review Board No clinical trial is initiated at any investigator site without

obtaining a written permission by the review board.

Sponsor / CRO

Investigator

Study subjects

REGULATORY AUTHORITY

ERB

Protocol of proposed study.

Informed consent document and its translation in vernacular language

All clinical and non clinical data of investigational product

Study advertisement an investigator’s qualification

Trial permission by DCGI/FDA

Clinical Trial Stakeholder

Conduction of clinical trial Different pharmaceutical companies , Biotechnology

companies , contract research organisation (CRO) , Research/ Academic Institutions and Cooperative Groups.

Sponsor / CRO

Investigator

Regulators

Registry of clinical trial

The Clinical Trials Registry- India (CTRI), hosted at the ICMR's National Institute of

Medical Statistics (http://nims-icmr.nic.in), is a free and online public record system

for registration of clinical trials being conducted in India that was launched on

20th July 2007 (www.ctri.nic.in).

Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI

has been made mandatory by the Drugs Controller General (India) (DCGI) (

www.cdsco.nic.in).

References

Park’s textbook of preventive and social medicine Essentials of preventive and commuity dentistry –Soben

Peter. Principles and practice of medical research by dr.J.v.Dixit Mahajan & gupta textbook of preventive and social

medicine Online sources