n March 19, 2019, the Union Ministry for Health and Family Welfare published the new Drugs and Clinical Trials Rules, 2019 (New Rules) which is expected to build a robust regulatory and clinical research ecosystem in the country and promote the conduct of ethical and quality clinical trials which, in turn, will benefit patients in India by providing early access to medicines for unmet medical needs.

These New Rules are applicable to all stakeholders like pharmaceutical companies, study sponsors, investigators, academic research institutions, and ethics committees who are involved in conduct of clinical trials, bioequivalence and bioavailability studies, and academic health research.

It is interesting to note that the word “oversight” appears several times in the New Rules. Although the number of mentions may not be that significant, it is the spirit of the oversight of research activities by stakeholders that gets a lot of attention in the New Rules.

Patient Safety and Data Integrity

These components of the New Rules indicate that it is the collective responsibility of sponsors, investigators, and ethics committees to ensure patient safety and data integrity in clinical trials.

• In the First Schedule under General Principle and Practises for Clinical Trial, Principle Number 2 mentions “The sponsor and investigator share the responsibilities for the protection of trial subject together with ethics committee.”
• The Third Schedule explicitly clarifies sponsor, investigator, and ethics committee responsibilities in the conduct of clinical trials.
• Rule 25 Section (xvii) mentions “the sponsor and the investigator shall maintain the data integrity of the data generated during clinical trial.”

While the earlier version of the regulation had also appreciated, in principle, the importance of ensuring patient safety and data integrity in clinical trials, the new regulation formalizes this a bit more by placing greater emphasis on the stakeholders’ (sponsors, investigators, and ethics committees) oversight and supervisory activities.

Effective oversight of clinical trial activities by the respective stakeholders is key to ensure regulatory compliance; thus, it is imperative for sponsors, investigators, and ethics committees in India to implement comprehensive, meaningful oversight of their trial-related duties and functions.

Ethics Committee Oversight

The New Rules devote an entire chapter (Chapter III) to the role of ethics committees in clinical trials, bioavailability, and bioequivalence studies, and describes their functions and responsibilities in the Third Schedule, which illustrates the gravity of the oversight responsibility with which these committees are entrusted.

As specified in Rule 11 (ii) the ethics committee should “make at appropriate intervals, an ongoing review of the clinical trials for which it has accorded approval and such review may be based on periodic study progress reports furnished by the investigators or monitoring and internal audit reports furnished by the sponsor or by visiting the study sites.” The new regulatory regime clearly expects ethics committees in India to evolve in response to their duty to review and monitor research after according their initial approval to the trial.

Oversight by Ethics Committees

Ethics committees must integrate oversight (monitoring) into every stage of their operations. Structured review of research proposals can help identify potential cases of bioethical concerns or research misconduct at the very beginning. In addition to reviewing the ethical aspects (e.g., benefit-risk ratio), these committees should also consider reviewing:

• investigator’s plans for obtaining informed consent from participants,
• patient recruitment plans, and
• patient recruitment trend, study progress report, and the nature of Adverse Events (AEs).

Additionally, periodic site visits to review the informed consent process and interviewing patients can provide a great deal of insight into study conduct and fortify monitoring efforts. As specified in Schedule III, ethics committees should operate per standard operating procedures and maintain a detailed record of their proceedings; these documents are subject to Regulatory Authority inspection.

Oversight by Investigators

The Third Schedule of the New Rules specifies that the investigator shall be responsible for trial conduct according to the protocol and Good Clinical Practices (GCP) Guidelines; and for compliance specified in Table 4, which includes these and other Commitments:

1. I agree to personally conduct or supervise the clinical trial at my site.
2. I agree to ensure that all associates, colleagues and employees assisting in the conduct of the study are suitably qualified and experienced and they have been informed about their obligations in meeting their commitments in the trial.
3. I agree to maintain adequate and accurate records and to make those records available for audit or inspection.

The Third Schedule also states that “Standard operating procedures are required to be documented by the investigators for the tasks performed by them.”

These commitments/responsibilities are not very different from the responsibilities stated in ICH-GCP E6(R2) guidelines:

• Supervise individuals or parties to whom trial-related duties and functions are delegated (section 4.2.5).
• Ensure individuals and parties are qualified and implement procedures to ensure integrity of study tasks and data (4.2.6).
• Maintain adequate and accurate source documents and trial records (4.9.0).

Investigator Strategies for Oversight Compliance

• Investigators must understand that delegation of clinical trial tasks brings along both the responsibility to ensure adequate delegate qualification to conduct the tasks, and the responsibility to supervise the delegated individuals.
• Investigators should maintain the current curriculum vitae of all individuals listed in the Delegation of Responsibility log to document their qualification to perform their tasks.
• Investigators should retain evidence that the associates/third parties that they employ are qualified to assume their responsibilities for each specific study.
• Investigators should establish contractual agreements with each third party, associate, or vendor (e.g., audio-visual recording vendor, external radiology facility, laboratory, etc.) involved in the trial, including a detailed list of tasks delegated to them.
• When an investigator engages a third party, associate, or vendor in trial-related activities, a responsible party of that entity should be listed in the site’s delegation of authority log, and that entity should maintain its own internal delegation of authority log in relation to the study.
• It is also essential that these third party entities and individuals receive and document any study-specific training pertinent to their role.
• To ensure that services performed by third party entities and individuals are appropriate and that the data they generated meet integrity expectations, the investigator should put in place an oversight/supervision plan to be implemented throughout the study.
• Investigators should also retain evidence that the supervision plan has been followed.
• Investigators should ideally maintain, for each study, a record of the location(s) of the essential documents, including source documents. The storage system used during the trial and for archiving after the trial (irrespective of the type of media used) should ideally provide clear document identification, version history, and search and retrieval functionalities.
• Most importantly, the investigator must ensure that Standard Operating Procedures for all site-related activities are in place and maintain evidence that these procedures have been followed.

Oversight by Sponsors

Based on various clauses in the New Rules and in conjunction with GCP guidelines, the sponsor bears the overall responsibility of ensuring that the clinical trial is conducted, and data generated, documented, and reported, in compliance with the protocol and GCP guidelines as well as all applicable statutory provisions. While the New Rules do not explicitly specify oversight measures that sponsors should implement, there is a tacit incumbency on the sponsor to oversee and manage compliance for all clinical trial activities, regardless of whether they are conducted in-house or through a Contract Research Organization (CRO).

However, because there is no “one size fits all” recipe for trial oversight, oversight implementation varies across sponsors based on what each sponsor perceives as “appropriate.” In this situation, the oversight principles laid down in ICH-GCP E6(R2) guidelines can be adapted to bring in an element of homogeneity in oversight activities implemented by sponsors in India.

Analysis, Strategy, Evaluation, Implementation

It is fundamental to begin by creating a detailed map of all study-related activities, all internal or external stakeholders involved in each of activity, and their roles and responsibilities. This analysis will help identify the sponsor’s specific requirements. With this clear overview of oversight requirements, the sponsor’s next step will be to evaluate various oversight models that can be designed and implemented to meet them; the optimum oversight model will aim at proactively identifying potential risks based on risk triggers to prevent non-compliance.

After the oversight strategy and model is clearly identified, the sponsor must document and effectively implement the oversight model, enabling them to examine data, monitor activities, and gain a real-time overview of the CRO’s or site’s performance throughout the study lifecycle.

General Principles for Effective CRO Oversight

• Objectively assess the CRO’s capability in the context of the sponsor’s specific requirements, including a structured assessment, before awarding a contract.
• Formalize the Sponsor-CRO relationship through a contractual agreement that addresses the following:
• Detailed list of tasks delegated to the CRO
• Sponsor’s expectations on quality, timelines, and deliverables
• Clearly defined roles and responsibilities of each party
• Communication frequencies and communication plan
• Clear expectations on data quality
• Consequences if any of the above expectations are not met
• Conduct regular CRO performance evaluations both remotely (monitoring visit report review) and onsite to ensure that the trial is monitored in compliance with the agreed upon terms.
• Make the oversight effective by defining risks and triggers.
• Document CRO oversight in an Oversight Plan.

General Principles for Effective Investigator Site Oversight

• Perform detailed feasibility study at the site level before awarding a trial.
• Create a comprehensive site monitoring plan, as specified in Indian GCP guidelines, customized based on the protocol requirements and adequate to ensure patient safety and data integrity.
• Conduct co-monitoring visits with Clinical Research Associates, including follow-up on any issues they report.
• Continuously measure site performance through the Enrolment Status Report, Data Entry Backlog Report, Query Aging Report, Adverse Events, Concomitant Medications, and other reports and metrics.
• Proactively address emerging triggers and risks.

Conclusion

As the clinical trial landscape in India rapidly evolves, its Regulatory Authority is highly committed to ensuring a robust framework that promotes the quality and ethics of clinical trials in India. The Regulatory Authority expects ALL stakeholders (sponsors, investigators, and ethics committees) to focus on planned, systematic clinical trial oversight approaches so that emerging risks can be proactively identified to ensure patient safety and data integrity. Consequently, there is also need to establish appropriate controls to prevent errors, identify potential problems, and implement mitigation measures before any problem becomes serious.

Clinical trial oversight not only represents a mandatory regulatory requirement but a strategic management requirement for all stakeholders: Integrating quality throughout the trial lifecycle through effective oversight brings in greater system efficiency, because preventing errors is always less cumbersome than identifying and implementing remediation.