Introduction to clinical research

What is clinical research?

 Organized research on human beings
Intended to provide adequate information on the drug use as a therapeutic agent on its
safety and efficacy.
 Also referred to as Clinical trial management

Clinical research - position in drug development

Drug development
Discovery research
Formulation and development

Clinical development (trials)

Commercialization

When do we need clinical trials?

new drugs
for new uses of existing drugs,
medical devices,
new drug delivery systems etc.
Evidence to prove the efficacy and safety in human beings.
Only a well designed clinical study on a defined population can give meaningful
results- (positive or negative) about any therapeutic intervention

The need for organized study

EVALUATION OF DRUG X FOR OSTEOARTHRITIS
How many patients improved?
-approximately 150 /200
What was the percentage of improvement?
80-90%

CLINICAL TRIAL -I

Any drop outs?

-May be 10-12
Reasons?
-may be they did not get symptomatic relief???
Any side effects?
-Gastritis,headache,diarrhoea etc.
CLINICAL TRIAL - II
EVALUATION OF DRUG Y FOR OSTEOARTHRITIS
How many patients improved?
If the criteria of 40% is considered as improvement, 150/200 showed
improvement(p<.01)

What was the percentage of improvement?

100 patients 40-50%
40 patients 50-60%
10 patients 60-70%

Any drop outs?

There were 10 drop outs due to following reasons
3 -gastritis
4- no improvement
3 -reasons not known

Any side effects?

Gastritis,
headache,
diarrhoea etc.
tingling and numbness
1,2,3, were due to the drug.

OUTCOME
Clinical trial-1
Trial poorly designed
No definite outcome,
Results ambiguous

Clinical trial –2
Trial well designed, organised and conducted
Definite outcome.
Results- conclusive.

Scope of clinical research?

Total cost of the drug development
900 million US $

Total time taken for the drug development

10-12 years

2/3rds of the cost and time is spent on clinical trials.

Historical review-
19TH CENTURY

Ancient pharmacy practice

Drugs given on trial and error basis
Practicing physician decided all.

History: The concept of Ethics

20th CENTURY

Growth of Pharma industry

1947 Nuremberg code after the trials by the Nazi physicians
Emphasized on the informed consent

History: The concept of Ethics

1950s Proper testing of drugs on human beings started
The concept of randomised controlled clinical trials appeared.

Historical review: Ethics

Emphasized on the informed consent

WMA (world medical association)-1964-guidance to physicians and other participants in medical

research involving human subjects

Further growth in ethical issues

WMA (1964) (World Medical Association) guidance to physicians and other
participants in medical research involving human subjects
Declaration of Helsinki
Thalidomide disaster brought about an exponential growth in Pharmaceutical
legislation

Ethical issues today

International conference on hormonisation- Good clinical practices
(ICH-GCP) Guidelines
Institutional review board/Institutional ethics committee
Patients informed consent

Regulatory guidelines today

Drugs and cosmetics act 1940
schedule-Y
Indian GCP guidelines
ICMR Guidelines
WHO Guidelines
ICH-GCP Guidelines
Clinical research then and now
CLINICAL RESEARCH 50 YEARS AGO
- investigator driven informal activity

CLINICAL RESEARCH NOW

Multidisciplinary, multinational,multibillion dollar global business governed by many
complex and interrelated regulations and guidelines.

Clinical research -a multi-disciplinary approach

Sponsor
Investigators
Monitors
Auditors and the quality control personnel.
Biostatisticians.
Data management group.
Regulatory Affairs.
Reporting and Documentation medical writing.
Business development group

Players in Clinical Research Industry

Pharma companies
Clinical/contract research organisations(CROs)
Biotech companies
Central diagnostic laboratories
Clinical research training institutes

Understanding clinical research

New drug development
Drug discovery and development
Clinical trials

NEW DRUG DEVELOPMENT PROCESS

Drug discovery
Synthesis
Drug designing
Target validation(Preliminary in-vitro screening)
Pharmacological assays

Drug development
Safety
Efficacy
Kinetics
Formulation
PRECLINICAL STUDIES
Include studies conducted on Experimental animals for safety and efficacy

Toxicity studies
Acute toxicity studies LD50
Sub- acute toxicity studies
Chronic toxicity studies
Special toxicity studies-carcinogenecity,teratogenecity genotoxicity,effects on fertility
and reproduction

Efficacy studies
In- vitro assays-Studies conducted using only animal tissues or cells or enzyme
systems
In- vivo assays-Experiments using whole animals

CLINICAL TRIAL PHASES

Phase-I- Clinical pharmacology,safety of new drugs
Phase-II-safety and efficacy of new drug in patients,exploratory trial.
Phase-III-multicentric confirmatory trial.
Phase-IV-post- marketting surveillance

Who conducts the clinical trial?

Investigators
Principal investigator
Co-investigator

Who participates in the trial?

Subjects
Healthy Human Volunteers
Patients

Ethical issues and guidelines

International conference on harmonization(ICH)
Good clinical practice(GCP)
Independent ethics committee IEC
Institutional Review board IRB
Informed consent

Good clinical practice

It is the international standard for conducting the clinical trials which lays down the
standard for
Design
 Conduct
Monitoring
Termination
Analysis and Documentation.

Informed consent
A written free consent of the subjects to participate in a clinical trial after receiving
complete information about the new product

Regulatory requirements
Drugs and cosmetics act 1940
Schedule-Y
DCGI Drug controller General of India
US-FDA United states-Food and drug administration act.
MHRA Medicinal and health care products regulatory agency

MONITORING
Overseeing the progress of a clinical trial
Ensuring that it is conducted according to the approved protocol, GCP, SOPs and the
regulatory requirements.
Usually done by Clinical research associates.

Quality control and quality assurance

Internal department of the CRO
Avoids unnecessary risks to the patients.
Essential to improve the quality of all the processes of the trial.

AUDIT
Systematic and independent examination of the trial related documents and activities
Checks whether the trial is going on as per the protocol,GCP,SOP.
Whether reported accurately or not

PHARMACOVIGILANCE
Collection of data on adverse effects of the drugs that are already in the market

PHARMACOEPIDEMIOLOGY
Collection of data in terms of both efficacy and safety after being prescribed to large number of
patients.

OUTSOURCING
Outside source utilisation for conducting a clinical study.
Transferring part of the activity of drug development to any other independent
organisations (contractual research organisations).

STANDARD OPERATING PROCEDURES

 Written instructions to achieve uniformity in the performance.

FRAUD
Generation of a false data with an intention to deceive.

MISCONDUCT
Behaviour which falls short of good ethical or scientific standards(-carelessness)

BIOAVALABILITY STUDIES
To understand how much of drug is available for action.

Bioequivalence studies.
Conducted for new formulations,
Compare the new formulation of any established drug with the existing formulation.

Data management,analysis and validation

Organised collection of accurate data from the clinical trial,
Capture the data from the data base
To provide a clean data to the statistician to facilitate analysis.

BIOSTATISTICS
During the protocol designing
to calculate number of patients to be included in the trial(sample size)
randomisation
review of data and
For the final analysis of results by applying suitable statistical methods.

DOCUMENTATION AND REPORTING

Record any event or step in the data management
Necessary for retrospective analysis
for the purpose of audit

MEDICAL WRITING
To prepare reviews on the drug based on the available literature.
Preperation of research papers.
Medico-marketting literature.

SUMMARY
Clinical research is an integral part of drug development
Unlike the past, today the process has gained a unique position due to the regulatory
requirements and ethical guidelines available globally..
Designing, conducting,monitoring, appropriate quality assurance and data
management determine the success of the clinical research.