n a recent Global Forum interview, FDA India Office Director Sarah McMullen reflected on her vision and in-country experience in India. As Director McMullen explained, India is one of the world’s largest producers of generic drugs, with 40% of generics in the US coming from India, and many of the bioavailability and bioequivalence (BA/BE) studies done to support those applications are conducted in India. Approximately 30% of FDA’s foreign trial inspections are done in India, per this interview, with the majority of those relating to BA/BE trials. She mentioned that although this has led to India being a key player in the global pharmaceutical industry and a major supplier of affordable medications worldwide, it is disheartening to continue to see clinical trial conduct issues in India.

Regulatory inspections performed in India to evaluate Good Clinical Practice (GCP) compliance have highlighted such deficiencies. US FDA inspections at 43 Indian sites showed deficiencies with Voluntary Action Indicated (VAI) at 18 sites (search FDA Data Dashboard for Inspections). These findings have been identified as: 1. Protocol noncompliance; 2. Inadequate record-keeping; and 3. Consent issues and deficiencies in IRB notification. For-cause inspections conducted by the Central Drugs Standard Control Organization (CDSCO) showed similar compliance deficiencies in ethics approval, consent, and safety reporting.

This reinforces the need to focus on data quality at clinical sites and steps needed to develop self-reliant sites. Maintaining study documentation and source documents is essential for ensuring data integrity, accuracy, and compliance with GCP guidelines and regulatory requirements. This compliance is the heart and soul of any clinical study; however, due to the demands of conducting clinical trials, site teams may sometimes postpone necessary maintenance, leading to errors or omissions.

Source documents serve as the original records of data collected during the trial; site files contain essential documentation related to the conduct of the study at that specific investigational site. However, poor maintenance of these documents throughout the lifecycle of a clinical trial can lead to frequent on-site monitoring, endless action items, for-cause audits, reduced site team motivation, and high staff turnover. This is a problem for which sites need a solution.

Empowering trial sites with an internal quality review process can potentially ensure that trials are conducted with integrity and accuracy. However, recognizing the challenges trial sites face such as understaffing and busy schedules, it is critical that sponsors and CROs collaborate with sites and support establishing effective review processes. The following systematic approaches can empower trial sites to establish and implement an effective internal quality review process:

1. Document Identification and Classification: Sponsors/CROs can train trial sites to identify essential study documents crucial for maintaining compliance as per regulatory guidelines, GCP, and sponsor/CRO requirements and classify these documents based on their importance and relevance to the trial (i.e., before initiation, during the trial, and after closeout). Sponsors and CRO monitors can facilitate this training at the time of site initiation and reinforce it during on-site monitoring visits.
2. Establish Clear Standards and Criteria: Sponsors should also assist sites in defining clear standards and criteria for the quality review of essential study documents such as Informed Consent forms and process documentations, log sheets and forms, study site visit documentation, study drug dispensing, protocol deviations, and so on. This should include parameters such as accuracy (confirm that data on log sheets and forms matches source documents); completeness (confirm that all required fields are completed and relevant information captured); consistency (e.g., date format or pen ink [using the same pen as the original for corrections where possible, and never using pencil or erasable or water-soluble ink to write down and record information], investigator and/or Study Coordinator’s signature format, data correction method); compliance with regulations and protocols; and adherence to formatting and ALCOA-C (Attributable, Legible, Contemporaneous, Original, Accurate, Complete) Good Documentation requirements. Sponsors may offer templates, checklists, or examples of best practices to serve as a foundation for defining review parameters. The International Conference on Harmonization (ICH) Good Clinical Practice (GCP) E6 provides details of standards to be met along with relevant definitions.
3. Designated Review Team: Site should assign a dedicated review team or individual(s) responsible for conducting quality reviews of essential study documents. Sponsors/CROs should provide comprehensive training and development opportunities for review team members to ensure they are equipped with the knowledge and skills required for effective document review. This may include training on regulatory requirements, GCP guidelines, document management best practices, and specific protocol requirements.
4. Review Schedule and Frequency: Through training workshops, sponsors/CROs can assist sites to adopt risk-based criteria and help optimize the effectiveness and efficiency of the internal quality review process. This includes establishing a review schedule which outlines when and how often essential study documents will be reviewed. Consider conducting reviews once per quarter at least. This targeted approach ensures that resources are allocated where they are most needed, ultimately enhancing the quality and integrity of clinical trial data and supporting successful study outcomes. Sites can adopt the following risk-based criteria to decide which studies to include in the IQR:

4a. Study complexity and phase
4b. Upcoming monitoring visits and sponsor audits
4c. Level and rate of recruitment
4d. Protocol deviation or other issues with the study
4e. Experience of staff involved in the study.

5. Process Workflow/Instruction: Site should develop a standardized workflow or work instructions for the quality review process which outlines each step involved, the roles and responsibilities of review team members, and documentation requirements. Sponsors/CROs may handhold sites to identify the key steps involved, such as document collection, review, verification, correction, and approval, and develop corresponding work instructions.
6. Checklist or Review Tool: Site should create a checklist or review tool that aligns with established standards and criteria for document quality review. This tool should include specific items to be assessed for each document type, such as completeness of signatures, version control, and accuracy of content. Sponsors/CROs can assist sites in creating or reviewing the checklist and ensuring that required study items are captured.
7. Documentation and Tracking: Implement a system for documenting and tracking the quality review process, including the results of each review, any identified issues or discrepancies, and actions taken to address them. Sites should establish a document tracking log to monitor the status of each document undergoing quality review to track such key information as document name, version, review date, reviewer(s), review findings, and status of any corrective actions. Sites can obtain feedback on the same from the sponsor/CRO during their periodic site visits and refine as required.
8. Training and Continuous Improvement: Experienced site team members should provide training internally on the quality review process, including the use of review tools and adherence to established standards. They can additionally encourage feedback from the sponsor, CRO, and internal team members to identify opportunities for process improvement and refinement. Training and continuous improvement initiatives facilitated by sponsors/CROs play a crucial role in enhancing the effectiveness and efficiency of clinical trial operations at trial sites.

For example, clinical sites can run an internal quality review pilot program for three months and then proceed to develop a Work Instruction and Standardized Form for conducting reviews. Key documents for reviews can be Investigator Site Files (e.g., delegation logs, training records, updated CVs and licenses, GCP certificate, ethics and regulatory documentation, and adverse event/serious adverse event [AE/SAE] reports; and Source Documents (e.g., signed consent forms, documentation of consent/reconsent, study visit documentation, lab reports, study drug dispensing records, etc.). The result of a pilot program at sites has been encouraging, and more examples of applying this approach are needed and encouraged. In this pilot, study staff are more aware of maintaining study documentation and Site files are better maintained, creating added value for the sponsors. While experienced and staffed sites may be better positioned to implement internal quality review processes, it’s important for all trial sites to prioritize quality assurance activities to ensure the integrity and reliability of study data. Sponsors and CROs can provide support and resources to help less experienced or understaffed sites establish effective quality review processes and build their capacity over time.

How an IQR Process Can Benefit Trial Sites

1. Proactive Identification of Issues: This proactive approach enables trial sites to identify and address documentation issues early on, before they escalate into more significant compliance problems or audit findings.
2. Continuous Improvement: By conducting regular internal reviews, trial sites can establish a culture of continuous improvement in documentation practices. Feedback from the IQR process can be used to identify areas for enhancement, implement corrective actions, and optimize documentation processes over time.
3. Enhanced Compliance: Implementing an IQR process helps trial sites ensure compliance with regulatory requirements, GCP guidelines, and internal standard operating procedures (SOPs). By systematically reviewing source documents and ISFs, trial sites can mitigate compliance risks and maintain high-quality documentation standards.
4. Stakeholder Confidence: Implementing an IQR process demonstrates a commitment to quality and compliance, instilling confidence in stakeholders such as sponsors, regulatory authorities, and study participants. Transparent documentation practices supported by the IQR process contribute to trust and credibility in the clinical trial process.

The clinical trial site is where much of the action occurs in a clinical trial. An Internal Quality Review process can be an effective tool in addressing challenges related to maintaining the quality of documentation in clinical trials. By embodying these practices, a trial site can elevate itself from “good” to “great,” enhance its professional reputation, and position itself as a leader in clinical research even without heavy reliance on external trial monitors.

While implementing an internal quality review process can be resource-intensive, the benefits of improved data quality, regulatory compliance, and patient safety may justify the investment. Moreover, sponsors and CROs can provide support and guidance to trial sites to streamline the implementation process, allocate resources effectively, and maximize efficiency in quality assurance activities. As trial sites become more experienced and proficient over time in conducting internal quality reviews, the process may become more streamlined and integrated into routine operations.

Sponsors/CROs should also collaborate with trial sites to develop scalability plans that outline how the quality review process can be scaled up as needed. This may involve phased implementation, training and guidance, pilot testing, and continuous improvement to ensure smooth expansion across multiple sites.