Clinical Trial

Clinical trials in layman’s language mean any investigation on human subjects carried out by pharmaceutical experts in order to discover or verify the clinical and pharmacological effects of any investigational medicinal product(s) and/or to identify any adverse reactions of such medicinal products(s) and/or to study such investigational medicinal product(s) with the object of ascertaining its safety and/or efficacy. Like any standard scientific and research activity, clinical trials are carried out with a definite aim through well- defined procedure and under closed conditions.

Applicable laws and regulatory framework:

Governed by well established guidelines and directives at international level like

EU regulations and directives,
ICH- Good Clinical Practices (GCP) guidelines,
Recommendations of World Medical Association Declaration of Helsinki, Guidelines for Good Pharmacoepidemiology Practices and ICMR guidelines.
Not Legally binding (soft law)

India – regulation of clinical trials by

Central Drugs Standard Control Organization (CDSCO) (headed by Director Control General of India) is the primary authority
“Drugs and Cosmetics Act, 1940” (along with the rules framed there under) is the principal legislation. S
Schedule Y of the Drugs and Cosmetics Rules, 1945 (“Rules”) provides for the detailed conditions, and compliances relating to clinical trials in India.

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Trial Stages

		Objectives
(Phase I):	Human Pharmacology non-therapeutic objectives estimation of safety and tolerability with the into human	To Evaluate Maximum tolerated dose:Pharmacokinetics- drug’s absorption, distribution, metabolism and excretion Pharmacodynamics- drug blood levels (pharmacokinetic/ pharmacodynamic studies) Early Measurement of Drug Activity – secondary objective.,
Phase II	Therapeutic exploratory trials	evaluate the effectiveness of a drug for a particular indication or indicationsconducted in a group of patientsa relatively homogeneous populationto determine the dose(s) and regimen for Phase III trialsevaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease)
Phase III):	Therapeutic confirmatory trials	to confirm the preliminary evidence accumulated in Phase II dose-response relationships (relationships among dose, drug concentration in blood and clinical response),
Phase IV	Post Marketing Trial	go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.

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Clinical Trial related regulations

For drug discovered in India
- clinical trials are required to be carried out inIndia right fromPhase I
For new drug substances discovered outside india
- To submit Phase I data
- permission maybe granted to repeat
  - Phase I trials and/or
  - to conduct Phase II trials and
  - Subsequently Phase III trials
- Concurrently with other global trials for that drug.

Responsibilities of Sponsor:

responsible for implementing and maintaining quality assurance systems to ensure that the clinical trial is conducted and data generated, documented and reported in compliance with the protocol and Good Clinical Practice (GCP) Guidelines issued by the Central Drugs Standard Control Organization, Directorate General of Health Services, Government of India as well as with all applicable statutory provisions.

Responsibilities of the Investigator(s)

Should possess appropriate qualifications, training and experience and should have access to such investigational and treatment facilities as are relevant to the proposed trial protocol.
A qualified physician (or dentist, when appropriate) who is an investigator or a sub-investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
Laboratories used for generating data for clinical trials should be compliant with Good Laboratory Practices.
Responsible for the conduct of the trial according to the protocol and the GCP Guidelines shall report all serious and unexpected adverse events to the Sponsor within 24 hours and to the Ethics Committee that accorded approval to the study protocol within 7 working days of their occurrence.

Responsibilities of the Ethics Committee:

reviews and accords its approval to a trial protocol to safeguard the rights, safety and well being of all trial subjects

Ethics committee

At least 7 members
a Chairperson (who is from outside the institution)
Atleast 5 members with the following representations:
- Basic medical scientists (preferably one pharmacologist).
- clinicians
- legal expert
- Social scientist / representative of non-governmental voluntary agency / philosopher / ethicist / theologian or a similar person
- Lay person from the community.
At least one member whose primary area of interest / specialization is nonscientific and at least one member who is independent of the institution / trial site.

Controversy

According to information from the health ministry, 1542 deaths were reported in clinical trials between 2010 and 2012. However, only 54 of these were attributed directly to the trials.
The approvals for clinical trials are usually given by India’s drug regulator, Central Drugs Standard Control Organization
- January ruling – the Supreme Court revoked the powers of the regulator to approve trials for new chemical entities (or molecules) because of irregularities in the process. It banned clinical trials for new chemical entities unless these were personally vetted and cleared by the Union health secretary.
Program for Appropriate Technology in Health (PATH)
- “Alleged Irregularities in the Conduct of Studies Using Human Papilloma Virus (HPV) Vaccine by PATH in India”PATH + Bill and Melinda Gates Foundation (BMGF) + Western Institutional Review Board (WIRB)donations from Merck Sharp and Doh me (MSD)+ Glaxo SmithKline (GSK), in partnership with Indian Council of Medical Research (ICMR) and along with the governments of Andhra Pradesh and Gujarat, through the national vaccinationprogramme, delivered and administered HPV vaccines to 10-14-year-old girls in Khammam (A.P.) and Vadodara (Gujarat) districts.Some girls died under Trialquestions the role of the ICMR, DCGI, EC members and PATH.
- PATH demesne – It is not clinical trial but demonstration project.