Preclinical and Clinical Trial Requirements
Preclinical and clinical trial requirements in India. Prepared in association with Nishith Desai & Associates, a leading law firm in India, this is an extract from The Pharma Legal Handbook: India, available to purchase here for GBP 75.
1. Are clinical trials required to be conducted locally as a condition (stated or implicit) for marketing approval?
If the drug or biological satisfies the definition of new drug (see Chapter 1 Question 3 above for definition), or if a notified medical device satisfies the definition of investigational medical device (see Chapter 1 Question 3 above for definition), then a clinical trial is required to be conducted locally as a pre-condition for marketing approval, in order to prove its safety and efficacy on Indian population.
However, if the investigational medical device is imported from United States of America, United Kingdom, Australia, Canada, Japan or the European Union, then the requirement to undertake local clinical trial may be waived on the submission of a free sale certificate from the relevant jurisdiction.
In all other cases, there is no requirement to undertake clinical trial before marketing of products in India.
2. How are clinical trials funded?
The clinical trials may be funded directly by the sponsor of the trial, irrespective of whether the sponsor is incorporated in India or not. The clinical trials are run by a team of investigators chosen by the sponsor, and the team is led by a principal investigator who is also chosen by the sponsor. The sponsor is permitted to pay the investigators directly for their services. The sponsor also selects a site for trial to provide in-patient and other facilities. The sponsor is permitted to make payment to the site as well. Sometimes, when the investigators are employees of the site, the sponsor makes payment directly to the site and the site then redistributes the payment to the investigators.
3. What are the requirements for preclinical and clinical trial protocols? Who must approve the protocols?
The preclinical trials (or studies on animals) are regulated by The Prevention of Cruelty to Animals Act, 1960 (“PCA Act”) and The Breeding of and Experiments on Animals (Control and Supervision) Rules, 1998 (“BEACS Rules”) made under the PCA Act. The BEACS Rules stipulate that any protocol for preclinical studies must ensure that
- animals lowest on the phylogenetic scale which may give scientifically valid results should be first considered for any experimental procedure
- the experiment should be designed using minimum number of animals to give statistically valid results at 95% degree of confidence,
- replacement alternatives not involving experiments on animals have been given due and full consideration
- sound justification is provided where alternatives not involving experiments on animals, though available, are not used
Before conducting any experiment animals, an experiment specific permission of the Committee for Purpose of Control and Supervision of Experiments on Animals (“CPCSEA”) or an Institutional Animals Ethics Committee (“IAEC”) recognized by CPCSEA is required. The CPCSEA or IAEC reviews each protocol for meeting the requirements stipulated above, amongst other things.
With respect to clinical trial protocols, the New Drugs and Clinical Trial Rules, 2019 (“CT Rules“) – a set of rules framed under the D&C Act prescribes a lot of requirements. The format of the protocol, along with the requirements, is published under Table 2, Third Schedule of the CT Rules – a set of rules framed under the D&C Act.. Some of the notable requirements are study rationale, study design, subject eligibility, study treatment and background of the principal investigator.
The protocol is submitted to the DCGI along with the application for permission to conduct the clinical trial. The ethics committee of the trial is also required to approve the clinical trial prior to its commencement. You may note that any change or update to the clinical trial protocol is required to be approved by the ethics committee before it can be implemented as part of the trial, except when such change in necessary to be implemented in the interest of the patient health and safety.
4. What are the requirements for consent by participants in clinical trials?
Voluntary informed consent is an essential requirement of the subject recruitment process. Prior to obtaining consent from a study subject, the investigator is required to provide information about the study in an easy-to-understand, non-technical manner, both verbally and by using a Patient Information Sheet (“PIS”). The consent of the study subject is required be obtained in writing in an ‘Informed Consent Form’ (“ICF”), the format for which is prescribed under the D&C Rules. The ICF is required to be submitted to the DCGI as part of the application for permission to conduct the clinical trial, while the ethics committee is also required to accord its approval prior to commencement of the trial.
In instances where the participants are unable to give consent (such as unconscious persons or minors), the legal representatives of the study subjects may do so on their behalf. If the subject or the legal representative is unable to read/write, an impartial witness is required to be present during the process and their signatures should be recorded on the form too.
Appendix V to Schedule Y of DCR enlists all the essential information the study subject or his legal representatives must be provided with prior to obtaining consent. The list of essential information includes explanation with respect to the purpose and duration of the study, any expected risks or discomfort the subject may face, alternate procedures or therapies available to the subject and anticipated payment if any
The D&C Rules also mandate audio-visual recording of the informed consent process in case of vulnerable subjects who volunteer to participate in trial involving a new chemical or molecular entity. The recording must contain the entire process of obtaining consent including the process of providing information and any questions that the prospective study subject may ask. However, in cases of clinical trials for anti-HIV drugs and anti-Leprosy drugs, only an audio recording of the process shall suffice.
Vulnerable subjects include those who are part of a hierarchical structure (e.g. prisoners, armed forces personnel, staff and students of medical, nursing and pharmacy academic institutions), patients with incurable diseases, unemployed or impoverished persons, patients in emergency situation, ethnic minority groups, homeless persons, nomads, refugees and minors.
5. May participants in clinical trials be compensated?
Participants in clinical trials may be compensated. If any compensation is to be paid to the prospective study subject, such study subject must be made aware of it while obtaining consent. However, the Ethical Guidelines for Biomedical Research on Human Subjects state that compensation “should not be so large or the medical services so extensive as to induce prospective subjects to consent to participate in research against their better judgment.”
21. How are participants in clinical trials protected and indemnified against any harm that arises as a result of participation in the trial?
The sponsor of a clinical trial is responsible for paying compensation to a study subject or his/her legally acceptable representatives in case the study subjects suffers an injury or death which is related to the trial and arose because of:
- Adverse effects of the investigational product;
- Violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;
- Failure of investigational product to provide intended therapeutic effect, where, the standard care, though available, was not provided to the subject as per the clinical trial protocol;
- Use of placebo in a placebo-controlled trial where, the standard care, though available, was not provided to the subject as per the clinical trial protocol;
- Adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
- For injury to a child in-utero because of the participation of parent in clinical trial;
- Any clinical trial procedures involved in the study.
The sponsor is also obligated to provide for medical management to the study subject for all injuries suffered by the study subject during the course of the trial until it is proven that the injury was not connected to the clinical trial.
Most sponsors obtain a clinical trial insurance to gives the protection against claims for compensation from study subjects or their legally acceptable representatives.