All Adverse Events (AE) and Serious Adverse Events (SAE) that occur during a clinical trial should be recorded and reported appropriately, to ensure the safety of all trial participants. It is recommended that a Safety Management Plan is developed during the set-up stage of a trial, so that all safety management procedures are documented. The safety management plan should be aligned with the type of trial to be conducted, and the risks involved. Ensuring participant safety is a key responsibility of the investigator.

The first aspect of safety management is collection of data related to AEs and SAEs. The trial specific safety management plan must document the reporting procedures and timelines. The sponsor must ensure that the roles and responsibilities are clearly delegated and documented.

The key components of a safety management plan are:

• Roles and responsibilities
• Processing and data entry of AE and SAE
• Follow-up process for AE and SAE
• Causality assessment (investigator and sponsor, both).
• Safety reporting procedure
• Safety Reports
• Implications for the monitoring team
• Compensation in case of clinical trial related injury

According to Chapter VI (page 161), of the New Drugs and Clinical Trial Rules, 2019, the sponsor or its representative (who has obtained the permission to conduct the clinical trial), is responsible for providing financial compensation, if an injury or death has occurred due to any of the following (during a trial):

• AE of the investigational product
• Any procedure involved in the trial
• Violation of the approved protocol, scientific misconduct or negligence
• Failure of the investigational product to provide the intended therapeutic effect
• Use of a placebo, in a placebo-controlled environment
• AE due to concomitant medication excluding standard care, necessitated as part of the protocol
• For injury to a child in-utero, because of the parent’s participation in a clinical trial.

Free medical management should be provided to the participant as long as required, or until it is established that the injury is not related to the clinical trial. In case the injury or death is related to the trial, financial compensation must be given according to CDSCO’s rule, over and above any expenses incurred due to the medical management of the participant. More information about the compensation formula are available in Chapter VI (page 161) and Seventh Schedule (page 234) of the New Drugs and Clinical Trial Rules, 2019.

Safety Reporting

The sponsor of a clinical trial is responsible for the on-going safety evaluation of the investigational product or study intervention.

Safety reports are submitted to the regulatory agency, the ethics committee, oversight groups, and the sponsor throughout the lifecycle of a trial. These reports are requested by the respective groups or committees to ensure participant safety and quality of trial conduct. For instance, at a predefined frequency, a progress or status report needs to be submitted to the Data and Safety Monitoring Board (DSMB) and/or safety update to the regulatory agency.

The sponsor of the trial should ensure that these reports are developed and submitted to the relevant committees and regulatory authority, on time (as applicable).

Adverse Event

Any untoward medical occurrence (including a symptom or disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a participant, that does not necessarily have a relationship with the treatment given. It is the responsibility of the investigator to ensure the medical management of trial participants, for any adverse events. Information about the AEs are captured as a part of CRF data. Status or progress reports sent to oversight committees during trial conduct should include information about adverse events in a trial.

Adverse Drug Reaction (ADR)

In case of approved pharmaceutical products Adverse Drug Reaction (ADR) is a noxious and unintended response at doses normally used or tested in humans. In case of new unregistered pharmaceutical products (or those products which are not yet approved for the medical condition for which they are being tested), ADR is a noxious and unintended response(s) at any dose. In clinical trials, an untoward medical occurrence seemingly caused by overdosing, abuse or dependence, and interaction with other medicinal products, is also considered as an ADR.

The sponsor should ensure that sufficient AE and ADR reporting forms available at all clinical sites before the trial can commence.

Serious Adverse Event (SAE)

An AE or ADR that is associated with death, inpatient hospitalisation (in case the trial or study was being conducted on out-patients), prolongation of hospitalisation (in case the trial or study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening.

Reporting timelines for SAE in India

All SAEs occurring in clinical trials must be reported as per the details provided in Table 5 of the Third Schedule (page 218) in the New Drugs and Clinical Trial Rules, 2019. The reporting timelines mandated by CDSCO are as follows:

• It is the responsibility of the investigator to report all SAE(s) to CDSCO, the sponsor (or its representative who has obtained the approval from CDSCO), and the Ethics Committee (EC) – within 24 hours of its occurrence (Initial Report).
• The sponsor (or its representative), must forward their reports on SAE, after due analysis to CDSCO, EC, and the head of the institution where the SAE has occurred, within fourteen calendar days of the knowledge of occurrence of SAE.
• The investigator is also required to submit their report on SAE, after due analysis to CDSCO, EC, and the head of institute (where the SAE has occurred), within fourteen days of reporting the SAE (Follow-up Report).
• The EC forwards its report after due analysis and their recommendation on financial compensation (if any – determined in accordance to the formula specified in the Seventh Schedule of the New Drugs and Clinical Trial Rules, 2019) to CDSCO, within 30 calendar days of occurrence of SAE.
• The Central Licensing Authority (CLA), i.e., , CDSCO forwards the reports of the investigator, sponsor or representative, and the EC to the Chairperson of the expert committee.
• The expert committee (appointed by the DCGI) examines the reports and gives its recommendations to CLA, within 60 days of receipt of the reports of the SAE. In case of a clinical trial or BA or BE related death, the expert committee shall also make recommendations on the quantum of compensation, to be paid by the sponsor or their representative.
• The CLA makes the final decision on the quantum of compensation to be paid by the sponsor or his/her representative within 90 days of the receipt of the report of the SAE.
• The sponsor or his/her representative shall pay the amount of compensation within 30 calendar days of receiving the order from CLA.

The table below summarises the reporting timelines for SAE:

The prescribed format for reporting SAEs is available in Table 5 of the Third Schedule (page 218), of the New Drugs and Clinical Trial Rules, 2019. This document may be used as a template for SAE reporting.

SUSAR (for global clinical trials):

In the case of global clinical trials, or trials with an international sponsor, the investigator will also be required to report Serious Unexpected Serious Adverse Reaction (SUSAR) in a format prescribed by the Council for International Organizations of Medical Sciences (CIOMS). The CIOMS working group has published guidelines and the prescribed format, which can be accessed here. This is also known as expedited safety reporting in clinical trials. The ICH E2A recommend the following timeframes:

• For fatal or life-threatening Unexpected ADRs: Fatal or life-threatening unexpected ADRs occurring in clinical investigations, qualify for very rapid reporting. The regulatory agencies must be notified within 7 calendar days after first knowledge, by the sponsor, followed by a complete report within the next 8 days (i.e., 15 days after first knowledge of event).
• All other serious, unexpected ADRs: Serious, unexpected ADRs that are not fatal or life-threatening, must be filed within 15 calendar days after first knowledge of the sponsor, that the case meets the criteria for expedited reporting.

The minimum criteria for reporting and the format (data elements for inclusion in expedited reports) are available in ICH E2A.

References, resources and further reading

• New Drugs and Clinical Trial Rules, 2019, G.S.R. 227(E), Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, available online (last accessed on 03.04.2019).
• More information about Serious Adverse Events on CDSCO’s website, last accessed on 26.02.2019.
• Good Clinical Practices for Clinical Research in India, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2001, available online (last accessed on 26.02.2019).
• ICH Harmonised Guideline, Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), current step 4 version, dated 9^th November 2016, available online (last accessed on 26.02.2019).
• Format for Serious Adverse Event Reporting in Biomedical Health Research, published by the Indian Council of Medical Research, 2018, available online (last accessed on 26.02.2019).
• Management of safety information from clinical trials, Report of CIOMS working group IV, 2005, available online (last accessed on 26.02.2019).
• Format for Serious Adverse Event Reporting in clinical trials, published by the Indian Council of Medical Research, 2018, available online (last accessed on 26.02.2019).
• MRC Clinical Trials Unit at University College London SOP for Safety Management, version 8.0, 2017.
• Gogtay, N. J., Ravi, R. & Thatte, U. M., Regulatory requirements for clinical trials in India: What academicians need to know, Indian Journal of Anaesthesia, 2017, version 61, number 3, pages 192-99, available online (last accessed on 26.02.2019).
• Lahiry, S., Sinha, R., Choudhury, S., Mukherjee, A., Chetterjee, S., Paradigm shift in clinical trial regulations in India, Indian Journal of Rheumatology, 2018, version 13, pages 51-55, available online (last accessed on 14.03.2019).
• ICH Harmonised Tripartite Guideline, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, E2A, current step 4 version, dated 27^th October 1994, available online (last accessed 13.03.2019).