Clinical trials

What is a Clinical Trial?

A clinical trial is a type of research that studies new tests and treatments and evaluates their effects on human health outcomes. People volunteer to take part in clinical trials to test medical interventions including drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments and preventive care.

In India, CDSCO(The Central Drugs Standard Control Organisation) is responsible for approval of New Drugs, Conduct of Clinical Trials, laying down the standards for Drugs, control over the quality of imported Drugs in the country and coordination of the activities of State Drug Control Organizations by providing expert advice with a view of bring about the uniformity in the enforcement of the Drugs and Cosmetics Act.

Official Definitions

Drugs and Cosmetics Rules, 1945

122DA defines clinical trial as, a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and/or adverse effects with the objective of determining safety and/or efficacy of the new drug;

New Drugs and Clinical Trials Rules, 2019

Defines "clinical trial" in relation to a new drug or investigational new drug means any systematic study of such new drug or investigational new drug in human subjects to generate data for discovering or verifying its,—

(i) clinical or;

(ii) pharmacological including pharmacodynamics, pharmacokinetics or;

(iii) adverse effects,

with the objective of determining the safety, efficacy or tolerance of such

drug or investigational new drug;

Case Laws

Swasthya Adhikar Manch v. Union of India

This case is one of the most significant regarding clinical trials in India. The Supreme Court addressed various issues related to clinical trials, including:

• The need for stricter regulations
• Compensation for trial participants
• Informed consent procedures
• Ethical considerations in conducting trials

Jacob Puliyel vs Union of India

This judgement reiterated that, the principles and guidelines for protection of trial subjects as described in Third Schedule as well as Good Clinical Practices guidelines shall be followed in conduct of any clinical trial.

The Third Schedule of the New Drugs and Clinical Trials Rules 2019 outlines the key aspects of conducting clinical trials, including the conduct of the trial, obtaining informed consent, and defining the responsibilities of the Sponsor, Investigator, and the Ethics Committee.

Consent of the human participants is a must and Table 3 of Third Schedule provides essential elements of informed consent. Essential elements are as follows:

(i) A study involving research must be explained in terms of its purpose. (ii) The expected duration of subject participation should be disclosed. (iii) Procedures, including invasive ones, must be clearly described. (iv) Risks or discomforts foreseeable to the subject should be outlined. (v) Benefits that may be reasonably expected for the subject or others should be stated. (vi) Any alternative procedures or therapies available should be disclosed. (vii) Confidentiality of subject records and access should be described. (viii) Trial treatment schedule and random assignment probability in randomized trials should be provided. (ix) Financial compensation and medical management details should be explained in the case of injury during the trial. (x) Contact information for trial-related queries, subject rights, and injury events should be given. (xi) Any prorated payment for subject participation should be anticipated. (xii) Subject responsibilities during the trial should be outlined. (xiii) The voluntary nature of participation, the right to withdraw at any time, and no penalty for refusal should be stated. (xiv) There is a possibility that the investigational product may not have the intended effect. (xv) In placebo-controlled trials, the placebo will not have a therapeutic effect. (xvi) Any other relevant information should be included.

And only after having been informed of all aspects of the study Informed consent should be documented by means of a written, signed and dated Informed Consent Form (ICF), as prescribed in Schedule Y, (Appendix-V) under the provisions of the Drugs and Cosmetic Rules, 1945.

Accordingly, it is the responsibility of the ethics committee that reviews and accords its approval to a trial protocol to safeguard the rights, safety and well-being of all trial subjects, among several others. All forms of medical research including clinical trials are required to be overlooked by an independent ethics committee. All ethics committees for the purpose of medical research must be registered with the Clinical Trial Registry of India (“CTRI”) maintained by the ICMR.

National Ethical Guidelines for Biomedical Health Research Involving Human Participants 2017

These guidelines by The Indian Council of Medical Research defines clinical trial as, any research/study that prospectively assigns human participants or groups of humans to one or more health-related intervention(s) to evaluate the effects on health outcomes. The intervention could be drugs, vaccines, biosimilars, biologics, phytopharmaceuticals, radiopharmaceuticals, diagnostic agents, public health interventions, socio-behavioural interventions, technologies, devices, surgical techniques or interventions involving traditional systems of medicine, etc.

Legal Provisions related to clinical trials

The Drugs and Cosmetics Act, 1940 and Rules, 1945

This is the primary legislation governing clinical trials in India.

Key provisions include:

Rule 122A: Outlines the application process for permission to import or manufacture new drugs for clinical trials.

Rule 122B: Specifies the requirements for conducting clinical trials.

Rule 122 DAA: Deals with the pre-submission meetings for clinical trials.

Rule 122 DAB : Compensation in case of injury or death during clinical trial.

Schedule Y: Provides detailed guidelines on clinical trials, including:

• Requirements for conducting clinical trials
• Responsibilities of sponsors, investigators, and ethics committees
• Essential documents for conduct of clinical trials
• Data elements for clinical trial-related injuries

The New Drugs and Clinical Trials Rules, 2019

These rules replaced the earlier regulations under the Drugs and Cosmetics Rules, 1945.

Key provisions include:

Chapter IV: Specifies the regulatory requirements for clinical trials.

Rule 19: Outlines the process for application for permission to conduct clinical trials.

Rule 25: Deals with the conditions for conducting clinical trials.

Rule 35: Specifies the responsibilities of the Ethics Committee.

Rule 40: Addresses the issue of compensation in case of injury or death during clinical trials.

Seventh Schedule: Provides the formula for calculating the amount of compensation.

Types of Clinical Trials

Clinical research is medical research that studies people to understand health and disease. Clinical trials or interventional and observational are two means trhough which a clinical research can be conducted.

Clinical trials(or interventional) are research studies in which researchers assign participants to get one or more interventions to test what happens in people. Because of this, clinical trials are also called interventional studies.They are, often prospective and are specifically tailored to evaluate direct impacts of treatment or preventive measures on disease.

Observational studies are research studies in which researchers simply collect information (called data) from participants or look at data that was already collected. Observational study designs, also called epidemiologic study designs, are often retrospective and are used to assess potential causation in exposure-outcome relationships and therefore influence preventive methods.

Based on Phases

Phase I (Human Pharmacology)

• This is a non-therapeutic trial and the objective is to determine the safety of a new drug and determine the maximum tolerated dose as also to determine the nature of adverse reactions that can be expected.[1]

Phase II (Therapeutic Exploratory Trials)

• Where patients are selected with a narrow inclusion criteria to find effective dose the study population is more or less homogenous. The dose used is lesser than the highest dose used in phase I. Another objective of this Phase II is evaluation of potential study endpoints, therapeutic regimens including concomitant medications and target populations, and mild versus severe disease, for further studies in Phase II or III. These objectives may be served by exploratory analyses of subsets of data and by including multiple endpoints in trials. Normally 20 - 25 patients should be studied for assessment of each dosage. These studies are usually limited to 3 - 4 centres. It is advisable to include a clinical pharmacologist as a co-investigator in such studies.[2]

Phase III (Therapeutic Confirmatory Trials)

The purpose of these trials is to obtain adequate data about the efficacy and safety of drugs in a larger number of patients of either sex in multiple centres usually in comparison with a standard drug and / or a placebo if a standard drug does not exist for the disease under study. This is to validate efficacy and safety found in Phase II. On successful completion of phase III trials permission is granted for marketing of the drug.Studies in Phase III may also further explore the dose-response relationship to drug concentration in blood and clinical response, use of the drug in wider populations, in different stage of disease, or the safety and efficacy of the drug in combination with other drug (s). These studies carried out in Phase III complete the prescribing information needed to support adequate instructions for use of the drug.[3]

Phase IV

The Phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. These trials may not be necessary for approval of new drug for marketing but may be required by the Licensing Authority for optimizing its use.[4]

Two Approaches

• Academic Clinical Study/research:

Clinical study/research of a drug already approved for a certain claim and initiated by any investigator, academic or research institution for a new indication or new route of administration or new dose or new dosage form, where the results of such a study/research are intended to be used only for academic or research purposes and not for seeking approval of the Central Licensing Authority or regulatory authority of any country for marketing or commercial purpose.

• Adaptive Clinical Study/research:

An adaptive design is defined as a clinical study/research design that allows for prospectively planned modifications to one or more aspects of the design based on real time data generated from participants in the study/research.

Variations

Medical Devices Rules 2017 also defines clinical trials through specific medical devices and defines the same in the following manner;

“academic clinical study” means a clinical study conducted for academic purpose on a medical device for the approved or a new intended use, new material of construction, new improved design or new population;

“clinical investigation” means the systematic study of an investigational medical device in or on human participants to assess its safety, performance or effectiveness;

Clinical Trials Around the World

United States

Clinical trials in the U.S. are governed by the FDA (Food and Drug Administration) and conducted under Good Clinical Practice (GCP) guidelines. Under FDA regulations, an Institutional Review Board is a group that has been formally designated to review and monitor biomedical research involving human subjects.

Food and Drug Administration (FDA)

The Food and Drug Administration (FDA) defines research studies in which people volunteer to help find answers to specific health questions. When carefully conducted, they are the safest and fastest way to find new treatments and ways to improve health.

The National Institutes of Health (NIH)

It defines clinical trials as follows : A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. It identifies a wide range of clinical trials such as Mechanistic, exploratory or developmental, pilot or feasibility, other interventional, behavioural and basic experimental.  

Registry and Data

In the US, Clinical trials can be accessed through ClinicalTrials.gov maintained by the National Library of Medicine (NLM), this is the most comprehensive database of clinical trials conducted in the U.S. and around the world. Trials can be searched by condition, drug/intervention, location, phase, and sponsor accompanied with many other filters.

Additionally, FDA Clinical Trials Searchis a database of Federally and privately supported studies available through clinicaltrials.gov.

NIDA Data Share website is an electronic environment that allows data from completed clinical trials to be distributed to investigators and the public in order to promote new research, encourage further analyses, and disseminate information to the community.This website was created in order to make the NIDA Clinical Trial data available to as wide an audience as possible. As studies are completed and their data become available, this web site will be linked to those data. The following information will be posted per protocol:

1. Study protocol
2. Reference to study publication of primary outcome
3. Data sets (SAS and ASCII )
4. Annotated case report forms
5. Define file (also known as Data Dictionary)
6. Study-specific de-identification notes

European Union

The European Union defines Clinical trials as scientifically controlled studies undertaken in humans to establish or confirm the safety and effectiveness of investigational medicinal products (IMPs). They are governed by the Clinical Trials Regulation( Regulation of the European Parliment and of the Council on clinical trials on medicinal products for human use and repealing Directive).

The Clinical Trials Regulation differentiates between Clinical study and Clinical Trials as follows:

Article 2. 2(1) ‘Clinical study’ means any investigation in relation to humans intended:

1. to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products;
2. to identify any adverse reactions to one or more medicinal products; or
3. to study the absorption, distribution, metabolism and excretion of one or more medicinal products;

with the objective of ascertaining the safety and/or efficacy of those medicinal products;

Article 2. 2(2) ‘Clinical trial’ means a clinical study which fulfils any of the following conditions:

1. the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned;
2. the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or
3. diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.

Registry and data

European Union Clinical Trials Register (EUCTR)

The EUCTR provides protocol and results information for

• Interventional clinical trials approved in the EU/EEA under the Clinical Trials Directive 2001/20/EC.

• Clinical trials conducted outside the EU/EEA that are linked to European pediatric-medicine development.

This register enables to search for information in the EudraCT database.

Clinical Trials Information System (CTIS)

Established under Regulation 536/2014, CTIS ensures public accessibility of data for interventional clinical trials approved within or transitioned to this regulation. One can search for clinical trials beased on various criteria.

World Health Organisation

The World Health Organization also has an International Clinical Registry platform (ICTRP). It defines clinical trials for the purpose of registration as, “any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. Clinical trials may also be referred to as interventional trials. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc. This definition includes Phase I to Phase IV trials.”

India

In India, clinical trials must be registered with the Clinical Trials Registry (CTRI). It ensures that all clinical trials conducted in India are prospectively registered, i.e. before the enrolment of the first participant. It is a free and online public record system for registration of clinical trials being conducted in India.

Research

Handbook for Good Clinical Research Practice.

The handbook aims to ensure the integrity of clinical data and the safety of trial participants worldwide by outlining the ethical and scientific standards that should be followed throughout the entire process of designing, conducting, recording, and reporting trials involving human subjects. It highlights the importance of transparency and adherence to regulatory guidelines.

Clinical Trials and Biomedical Research in India: Legal and Regulatory Framework [Report].

This report provides a detailed and in-depth analysis of the legal and regulatory framework surrounding clinical trials and biomedical research conducted in India. It meticulously outlines recent policy changes, highlights key ethical considerations, sheds light on the pivotal role played by regulatory bodies such as CDSCO in overseeing and monitoring the intricacies of clinical trials, upholding participant safety standards, and safeguarding the overall integrity of research practices within the country.

Clinical Trials in India: A way Towards Improvement?

This paper critically assesses the current state of clinical trials in India, highlighting key concerns such as ethical issues, inadequate participant protection, and a lack of regulatory oversight. It offers suggestions to enhance the trial framework, increase transparency, and build public trust, with the aim of fostering a more robust and ethical clinical trial environment in the country.

The report of the Prof. Ranjit Roy Chaudhury Expert Committee to Formulate Policy and Guidelines for Approval of New Drugs.

This landmark report from the Prof. Ranjit Roy Chaudhury Expert Committee, commissioned by the Government of India, addresses the pressing need for comprehensive reforms in the processes pertaining to new drug approvals. In an effort to enhance the transparency and credibility of the regulatory framework, the committee proposes more stringent guidelines for conducting clinical trials. Moreover, the recommendations focus on reinforcing the infrastructure for ethical review mechanisms to ensure the protection of human subjects involved in these trials. Additionally, an emphasis is placed on fostering capacity building initiatives to guarantee that the entire process of approving new drugs is rooted in scientific rigor and upholds the utmost ethical standards.