Clinical trials are a massive undertaking, that involves multiple processes. The sponsor of the trial is responsible for the safety of trial participants and the credibility of the data generated during the trial. The investigator is responsible for ensuring that the participants are recruited as per the applicable regulations, and their medical safety.

Sponsor

The sponsor of a trial implements ongoing monitoring and management of the trial.

1. Monitoring

Monitoring is defined as the act of oversight of a trial, to ensure that it is conducted, recorded and reported in compliance with the trial protocol, applicable regulatory and ethical requirements, Good Clinical Practice (GCP) guidelines and Standard Operating Procedures (SOP). Monitoring is a key aspect of quality control in a trial. It also helps ensure that the trial sites are ready for an inspection by the regulatory agency (CDSCO).  The main purpose of monitoring is to verify the following on an ongoing basis:

• The rights and well-being of all trial participants are protected
• The data generated is accurate, complete and verifiable from source documents
• The conduct of the trial is in compliance with the currently approved protocol and amendments (if any), with GCP, and with the applicable regulatory requirement(s).

It is the responsibility of the sponsor to ensure that the trial is adequately monitored. The sponsor may have its own monitors, or may outsource the monitoring task to a Contract Research Organisation (CRO).

A CRO is an organisation to which the sponsor may transfer or delegate some or all of the tasks, duties and/or obligations regarding a clinical trial or study. All such contractual transfer of obligations should be defined in writing. A CRO may be a scientific body, which is commercial, academic or other.

The sponsor should ensure that a systematic, prioritized, risk-based approach is developed for monitoring the trial. This should reflect the risks identified based on considerations such as the objective, purpose, design including patient population and intervention, complexity, blinding, size and endpoints of the trial.

Quality control or monitoring, should be applied to each stage of data handling to ensure reliability of the data and results generated. The monitoring strategy should be such, that it facilitates the effectiveness and efficiency of monitoring. The sponsor may select either on-site monitoring, or a combination of on-site and centralized monitoring, or only centralized monitoring (if justified). The rationale for the chosen strategy must be documented (monitoring plan).

On-Site Monitoring: On-site monitoring involves visits to the trial sites, by a monitor, who checks compliance. One of the key functions of a monitor is to ensure that the data being collected is verifiable and accurate (via source data verification), and that the site is complying with all applicable regulations, GCP, SOPs and the protocol.

Centralized or Remote Monitoring: Centralized monitoring is the remote evaluation of data, performed in a timely manner, at a location other than the study site. It provides additional monitoring capabilities that can complement and reduce the extent and/or frequency of on-site monitoring, and help distinguish between reliable and potentially unreliable data.

Risk-based approaches that focus on the most critical data elements and processes necessary to achieve study objectives, are increasingly used compared to visits to clinical sites and 100% source data verification. Incorporation of centralized monitoring practices, where appropriate, helps improve a sponsor’s ability to ensure the quality of clinical trial data.

In most clinical trials, a combination of centralized and targeted on-site monitoring may be used. This method allows an optimum utilisation of resources, whilst ensuring data quality and participant safety.

Monitor

The monitor is a person appointed by the sponsor or the CRO, for monitoring and reporting the progress of a trial, and for verification of data. The monitor ensures that the trial is conducted, recorded and reported in accordance with the protocol, SOPs, GCP and applicable regulatory and ethical requirements. The monitor should be adequately qualified, trained and experienced. It is essential for the monitor to be thorough with the protocol, investigational product (IP), participant information sheet, SOPs, GCP, and applicable regulatory requirements. Following are the key responsibilities of a monitor:

• Verify that the investigator(s) have adequate qualification, expertise and the resources to carry out the trial. The monitor should also ensure that the investigator will be available for the proposed duration of the trial.
• Ascertain that the required institutional facilities (laboratories, equipment, staff, space for storage, etc.) are available throughout the trial.
• Verify or make provisions to ensure the following:
  • Only eligible participants are enrolled in the trial.
  • Sufficient amount of IP is available at the site, and is stored in appropriate conditions.
  • IP is supplied to only to eligible participants at the specified dose(s) and time(s).
  • The receipt, use, return and disposal of IP at the site is controlled and documented as prescribed.
  • The protocol and all approved amendments (if any) are followed.

    The investigator(s) has received the current version of Investigator’s Brochure and the trial supplies, as required.

  • All essential documents are maintained by the investigator at site.
  • All parties involved in the trial are adequately informed of the trial and its various aspects, and follow the GCP guidelines and prescribed SOPs.
  • All parties follow their specified functions, as documented in the agreement with the sponsor and the concerned party.
  • None of the parties involved, delegate an assigned task or function to an unauthorised individual or party.
• The monitor must inform the sponsor, of any unwarranted protocol deviation, or violation of the GCP guidelines at the site(s).
• The monitor should follow a set of predetermined SOPs.
• Monitor should maintain a written record of the following:
  • Visit to the trial sites.
  • Phone calls and correspondence with the investigators and other parties (if involved).
• As part of site feasibility, the monitor should ensure that the premises and facilities are adequate, to conduct the trial.
• It is the monitor’s responsibility to observe the participant recruitment rate, and report it to the sponsor.
• The monitor should ensure that the site staff have been adequately trained and comply with the protocol, SOPs, and other aspects of the trial.
• The monitor should also assist with providing guidance on Case Record Form (CRF) completion.
• The monitor must ensure that all CRFs are completed accurately in accordance with original observations (source data verification), entries are legible, complete and dated. The monitor should verify the following:
  • Critical data, required by the protocol is reported accurately on the CRFs and is consistent with the source documents.
  • Any modification(s) with the dose and/or therapy are documented for each trial participant.
  • Medical history, adverse events and concomitant medications are reported accurately on the CRFs, in accordance to the protocol and SOPs.
  • Visits missed by the participant, or any tests or examinations that may have not been conducted during the trial must be reported on the CRFs.
• Participant drop-outs or withdrawals must be accurately reported and explained on the CRF.

Before the trial can commence, the monitoring team is also responsible for:

• Site feasibility and selection
• Site preparedness and initiation
• Site staff training.

Once recruitment has been completed at a site, the monitoring team will also carry out:

• Site close-out (close-out visit)
• Investigator Site File close-out

1. Ensure that the investigational product is retrieved and disposed or returned to the sponsor, in accordance to the protocol.

Monitoring reports

Regular trial monitoring reports that combine data from central and site monitoring are produced and used to indicate when remedial actions like additional site training or on-site visits are required, as per the monitoring plan. The monitor is expected to submit a written report to the sponsor following a site-monitoring visit. This report must include a summary of findings at the site, any protocol or GCP deviations or deficiencies (if observed) and the proposed corrective and preventive actions.

Audit

The sponsor may plan audits of clinical trial sites, as part of the Quality Assurance system of the trial. Audits are independent and separate from routine monitoring or quality control functions. Audits are planned to evaluate trial conduct, and verify compliance with the protocol, applicable regulatory guidelines, GCP guidelines, SOPs, etc. The auditors are trained professionals, who are independent of the parties involved in the trial. They record their observations, as per the sponsor’s requirements. If persistent non-compliance is observed, then, the sponsor may consider closing the site.

Site / Investigator

A qualified professional (doctor or dentist, as applicable), is responsible for all trial related medical decisions. The investigator must ensure that the participants receive appropriate medical care, for any adverse events that occur during the trial. After the completion of the trial, or if a participant drops out of the trial, arrangements must be made to provide appropriate medical care and follow-up.

Recruitment

The investigator is responsible for ensuring that an adequate number of suitable participants are recruited in the trial, through an unbiased process. The following documents should be maintained by the investigator:

• Screening Log – to identify potential participants, that were screened for the trial
• Confidential list of all participants that have been recruited in the trial
• An enrolment log

The researcher should use only an EC approved version of the Participant Information Sheet (PIS) and Informed Consent Form(ICF), including its local translations (if applicable). Adequate information necessary for informed consent should be communicated to the participant in a language and manner easily understood by the prospective participant. It must be ensured that the participant is competent and has understood the information provided, and gives voluntary consent. If the potential participant and/or the Legally Acceptable/Authorized Representative (LAR) are illiterate, an impartial literate person must be present as a witness to the consent process. The witness should be independent of the trial.

The prospective participant should be provided with adequate opportunity to ask questions or seek clarifications regarding the trial, and to discuss with family and friends, before reaching a decision.

Documentation of the informed consent process is an essential aspect of this process. The investigator must ensure that each prospective participant signs the ICF only after going through the informed consent process of receiving the information, understanding it and voluntarily agreeing to participate in the trial. If the participant cannot sign, a thumb impression must be obtained. The ICF must also be signed and dated by the investigator / researcher administering the consent.

If the trial is planned for a paediatric population, then, the consent from the guardian must be obtained. In addition to the PIS and ICF, Assent Forms are used to provide trial related information to the prospective participant (if the participant is between the ages of 7 and 18 years) in a simple language. Assent forms ensure that the child understands the request to voluntarily participate in the trial.

Audio-Visual Recording of Consent

This is supplemented with appropriate documentation from an impartial witness. According to New Drugs and Clinical Trial Rules, 2019, an audio-video recording of the consent process is required for vulnerable participants in clinical trials of new chemical entity or new molecular entity. Vulnerability in research pertains to individuals who are relatively or absolutely incapable of protecting their own interests because of personal disability, environmental burdens or social injustice, lack of power, understanding or ability to communicate or are in a situation that prevents them from doing so.

The recording should include the process of providing the information to the prospective participant, and their understanding of the information. For clinical trials of anti-HIV or anti-Leprosy drugs, only an audio recording of the informed consent process of each individual participant is required.

In certain cases, where, written consent (with signatures or thumb impressions), is not possible, an oral or verbal consent may be taken, on approval by the EC. This process can be documented through an audio-video recording.

All audio-video recordings of the informed consent process, must be maintained in the Investigator Site File, at the site. CDSCO has published draft guidelines for audio-visual recording of consent process, and these can be accessed here.

Documentation

The investigator must ensure that the data recorded in the Case Record Forms is accurate, legible, complete, and consistent with the source documents. Generally, the sponsor ensures that the investigator and the site staff are trained and aware of the CRF completion guidelines, and Good Documentation Practices.

Communication with the Ethics Committee (EC)

The investigator should report the following to the EC and the sponsor:

• Deviations or changes in the protocol (protocol violation / deviation reporting form, published by ICMR can be accessed here).
• Changes that may increase the risks to participants, or significantly affect the conduct of the trial
• All Adverse Drug Reactions (ADRs) and Adverse Events (AEs) that are unexpected, and/or serious
• New information that may adversely affect the safety of the participants and/or conduct of the trial
• For any reported death, the investigator should supply additional information like autopsy, medical reports, etc.

References

• 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).
• The Drugs and Cosmetic Acts and Rules, 1945, as amended up to the 30^th of June 2005, Ministry of Health and Family Welfare, Government of India, available online (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).
• National Ethical Guidelines for Biomedical and Health Research involving Human Participants, Indian Council of Medical Research, 2017, 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).
• Oversight of clinical investigations – a risk-based approach to monitoring, U.S. Department of Health and Human Services, Food and Drug Administration, available online.
• Draft Guidelines on Audio-Visual Recording of Informed Consent Process in Clinical Trial, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2014, available online (last accessed on 26.02.2019).
• Draft Guidance for Industry on Reporting Serious Adverse Events occurring in Clinical Trials, Central Drugs Standard Control Organization, Ministry of Health and Family Welfare, 2011, available online (last accessed on 26.02.2019).