Guidelines for Clinical Trials at AIIMS
Background: Medical research is becoming increasingly important given the ever-growing burden of diseases and the urgent need to find new ways to improve the health of the people. One of the major objectives of the All India Institute of Medical Sciences is research. Faculty, scientists, and postgraduates students are all engaged in clinical and basic science research. The research environment is quite vibrant at the institute. There are at present >600 extramural and intramural funded projects being undertaken by the faculty and scientists at the institute. In addition, there are many investigator initiated non-funded research studies being conducted by the faculty and postgraduates.
Reasons for fresh thinking and guidelines: In recent years, there has been a debate about certain unethical practices in conducting clinical trials in India. In this regard, the Hon’ble Supreme Court of India (SCI) has also passed certain orders to curb such unethical practices. The regulatory body i.e. Central Drugs Standard Control Organization (CDSCO), under the Ministry of Health & Family Welfare, Government of India (GOI) has also introduced many new guidelines and initiated many new processes for proper conduct of clinical trials in India with the overwhelming emphasis on the safety of trial participants. In view of the changing scenario and fresh inputs from the CDSCO and the SCI, it has become imperative that the AIIMS also follows these guidelines and all the stakeholders are apprised of the new rules/regulations/guidelines in this regard. The following issues are pertinent in this regard:
What is a Clinical Trial? Although any study that aims to evaluate the effectiveness and safety of any drug/device/procedure can be labelled as a clinical trial, the Drug & Cosmetic Act 1940 (amended 2005, 2008) and Drug & Cosmetic Rules 1945 (amended 2005), GOI has defined a clinical trial as follows:
Definition of Clinical trial (Rule 122DAA): For the purpose of this part, “Clinical trial” means 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.
Definition of ‘new drug’ (Rule 122E): For the purpose of this Part, ‘new drug’ shall mean and include:
(a) A drug, as defined in the Act including bulk drug substance which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labelling thereof and has not been recognized as effective and safe by the licensing authority mentioned under rule 21 for the proposed claims:
Provided that the limited use, if any, has been with the permission of the licensing authority.
(b) A drug already approved by the Licensing Authority mentioned in Rule 21 for certain claims, which is now proposed to be marketed with modified or new claims, namely, indications, dosage, dosage form (including sustained release dosage form) and route of administration.
(c) A fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage, dosage form (including sustained release dosage form) and route of administration. (See items (b) and (c) of [Appendix VI] to Schedule Y.)
Explanation: For the purpose of this rule−
(i) all vaccines shall be new drugs unless certified otherwise by the Licensing Authority under Rule 21;
(ii) a new drug shall continue to be considered as new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier.
Major Changes in Rules/Regulations/Guidelines: Recently, major changes have been introduced for conducting ‘clinical trials’. It has become mandatory for all the investigators of a clinical trial in India to follow these rules/regulations/guidelines regarding the following issues:
(i) Obtaining permission to start a clinical trial
(ii) Registration of trial (Where
(iii) Obtaining consent of a trial participant
(iv) Monitoring of a clinical trial
(v) Reporting of Serious Adverse Reaction (SAE)
(vi) Compensation to be paid in case of SAE
Obtaining permission to start a clinical trial: It is mandatory to seek and get approval for any new clinical trial by the CDSCO (DCGI office). A proposal for a new clinical trial has to be submitted to the CDSCO. The proposal will be reviewed by a Technical Review Committee (TRC). If the TRC approves the proposal, it should be submitted to the Institute Ethics Committee (IEC) by the investigator for ethical approval.
Registration of trial: Once the proposal is approved, the clinical trial protocol must be registered at the ICMR Clinical Trial Registry www.ctri.in before its initiation.
Obtaining consent of a trial participant: As per the SCI order and the CDSCO order, audio-visual recording of the consent taking process must be done in addition to the written informed consent. Confidentiality must be maintained and such recordings must be preserved.
Monitoring of a clinical trial: All clinical trials must be monitored periodically. There should be a data safety monitoring board (DSMB) at the institution level that is expected to monitor the adverse events occurring in a clinical trial. It is the responsibility of the investigator to report all adverse events in a clinical trial to the IEC and to DSMB. The DSMB will also report the findings to the IEC on its own.
Reporting of Serious Adverse Reaction (SAE): As per Appendix XII, the Investigator shall report all serious and unexpected adverse events to the CDSCO, the Sponsor or his representative whosoever had obtained permission from the CDSCO for conduct of the clinical trial and the Ethics Committee, within 24 hours of their occurrence. This must be done in a pre-designed format with all the relevant details (see attachment 1). The IEC will determine the causality of the SAE as to whether it is related to the investigational drug or not. The IEC will give its opinion to the expert committee constituted by the Ministry of Health. The expert committee will also determine if the SAE is causally related to the drug and recommend suitable compensation based on a formula. The DCGI will then direct the sponsor to pay compensation to the participant or his/her relative.
Compensation to be paid in case of SAE: In case of serious adverse events of death, the reports shall be examined by an independent Expert Committee constituted by DCGI to determine if the cause of death is due to following reasons, which are considered as clinical trial related death and gives its recommendation to CDSCO. In case of clinical trial related death the committee shall also recommend the quantum of compensation to be paid by the sponsor or his representative, to CDSCO.
a) Adverse effect of investigational product(s);
b) Violation of the approved protocol, scientific misconduct or negligence by the Sponsor or his representative or the investigator;
c) Failure of investigational product to provide intended therapeutic effect;
d) Use of placebo in a placebo-controlled trial;
e) Adverse effects due to concomitant medication excluding standard care, necessitated as part of approved protocol;
f) For injury to a child in–utero because of the participation of parent in clinical trial;
g) Any clinical trial procedure involved in the study
CDSCO shall consider the recommendations of the Expert Committee and shall determine the cause of death and also the quantum of compensation in case of clinical trial related death within three months of receiving the report of SAE of death.
In cases of serious adverse event other than death, CDSCO shall determine the cause of injury, if any, due to any of the reasons mentioned above as in the case of death, which is considered as clinical trial related injury. However CDSCO has option to constitute an independent Expert Committee, wherever considered necessary, to examine such serious adverse event. In case of clinical trial related injury, CDSCO shall also determine the quantum of compensation within three months of receiving of the SAE. In case of clinical trial related injury or death, the Sponsor or his representative concerned shall pay the compensation as per the order of CDSCO within thirty days of the receipt of such order.
Advisory to the Principal Investigators of the ongoing clinical trials and potential new investigators at the AIIMS: In view of the above mentioned mandatory requirements for conducting clinical trials including the ongoing trials, the competent authority has desired that all investigators at the institute should comply with the following:
1. The investigator must obtain necessary regulatory approvals e.g. from DCGI and the IEC before starting any clinical trial.
2. The trial must be registered at the ICMR clinical trial registry website.
3. The investigators must start audio-visual recording of the consent from the participants. The recordings must be preserved and confidentiality of the subject must be maintained. CMET will provide technical assistance in this matter.
4. The investigator must report any expected SAE or suspected unexpected serious adverse reaction (SUSAR) to the IEC within 24 hours of its occurrence. The SOPs for reporting the SAE are being communicated separately.
5. The investigators must periodically submit the progress of their trials to the IEC for the purpose of monitoring of the trial.
6. The investigator must make adequate arrangements for compensation of the subjects either through the sponsor or insurance. If the trial is investigator initiated, then the investigator should make arrangement for providing compensation. As of today, no mechanism exists to pay compensation by AIIMS if the trial is not sponsored by a company/industry. It is proposed that the trials, which are funded by any government agency e.g. ICMR/DST/DBT, should either be insured or contribute a significant amount of funds for this purpose. The problem will arise if the trial is not funded by any organization. In that case, the institute will be hard pressed to pay compensation. It would therefore be advisable that faculty should take all necessary precautions and apply due diligence before embarking on any new clinical trial particularly non-funded projects till such time that there is more clarity on the issue and a mechanism is in place to deal with the issue of compensation.
Future Prospects: It is well appreciated that the research atmosphere at the institute should promote investigator initiated academic research. Rules and regulations should not curtail the academic freedom of the faculty because that is one of the most important activities expected of a faculty. However, the new regulations have been framed so that the research is conducted in a fair and proper manner, and the rights of the participants are protected. At the same time, the concerned authorities are taking steps to impress upon the regulators to make certain amendments keeping in mind the concerns of the academia so that the research at the institute is as vibrant as it should be. Till such time that there is more clarity on various issues regarding clinical trials, it is recommended that all concerned should take the suggested reforms in the right spirit. The institute has formed a sub-committee to look in to this matter in greater detail and also interact with various government agencies and regulators to make clinical research more patient and researcher friendly.