Sponsors Pilot New ICH E6 R2 Initiatives


Applied Clinical Trials

In this article, Moe Alsumidaie will discuss QA updates.

Clinical quality assurance (QA) is rapidly evolving since FDA released its position on the ICH E6 R2 guidance. At ExL’s 9thAnnual Clinical Quality Oversight Forum, FDA discussed their approaches towards quality management and regulatory inspections; some sponsors are piloting novel quality management systems to ensure alignment with ICH E6 R2, whereas others are aligning QA requirements through contractual quality agreements with vendors/CROs. In this article, we will discuss QA updates.

FDA’s Perspective on Inspections

Miah Jung, from FDA’s Center for Drug Evaluation and Research (CDER), spoke about factors triggering inspections, and what FDA looks for during inspections. Jung iterated Bioresearch Monitoring (BIMO) program’s objectives, which is to monitor all facets of FDA-regulated research, and inspections cover clinical investigators, sponsors, CROs, IRBs, and non-clinical labs for good laboratory practices (GLP). Jung indicated that new drug applications (NDAs) (focus on NDA-type studies), for-cause referrals (often by anonymous reporters) and routine surveillance inspections (i.e., general surveillance of IRBs and GLPs) are common triggers for a regulatory inspection. Jung emphasized that FDA focuses on verifying data (i.e., safety and efficacy data, subject eligibility, ICF documentation, IRB review/approval documentation, protocol adherence, and drug accountability) and assurance of human subject protections (i.e., ensuring that subject welfare and rights are protected). During inspections, FDA looks for documentation around ICF versions, financial disclosure forms, 1572s, subject records, notes to file/progress reports, SOPs, and study protocol revisions. Jung categorized three finding types (a) no action indicated (NAI) (i.e., no objectionable findings), (b) voluntary action indicated (VAI) (i.e., some objectionable practices, but, does not recommend regulatory action) and the worst, (c) official action indicated (OAI) (i.e., serious objectionable practices, and regulatory action recommended). Usually, OAI findings involve, “repeated, or deliberate practices or involve submission of false information to FDA or sponsor.” Jung presented findings data; at sites, 70% of findings are NAI, 28% are VAI, and 2% are OAI; most common deficiencies with sites include protocol violations, record keeping violations, drug accountability deficiencies, and ICF deficiencies. At sponsor/CRO inspections, 67% are NAI, 30% are VAI, and 3% are OAI. Jung recommended that study personnel understand the scope of their responsibilities, create systems to support quality, ensure proper staff supervision and training, and detect errors in real-time and avoid repeating the same mistakes. FDA is also implementing risk-based inspections by identifying high-risk sites through innovative tools.

Clinical Quality Agreements

JoAnna Brodie, Director of Clinical Quality Assurance (QA) at GSK, indicated that GSK established Clinical QA Quality Agreements with CROs to ensure proper quality oversight and performance of clinical operations. According to Brodie’s perspective, the purpose of these agreements involves providing governing principles, enforcing quality deliverables, creating a framework for communications and escalation, ensuring alignment, defining roles, responsibilities, and accountabilities of QA groups, specifying quality metric thresholds, and aligning regulatory expectations. Brodie indicated that these agreements provide an additional layer of QA oversight to satisfy regulatory requirements, enhances transparency during issues resolution, ensuring inspection readiness, and measuring compliance through metrics. Brodie emphasized that these agreements need to be simple, stand-alone agreements, are not necessary to implement for all suppliers/CROs (i.e., small niche services) and must be consistent and applicable across a variety of business units and therapeutic areas to reduce confusion with suppliers/CROs.

Quality Tolerance Implementation

Melissa Suprin, Head of Quality Risk Management at Pfizer, discussed how to implement the ICH E6 R2 guidance on quality tolerance limits (QTLs). ICH E6 R2 specifies, “the sponsor should describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report (CSR).” According to Suprin’s perspective, sponsors should develop QTLs and focus on systematic issues impacting subject safety and reliability of trial results with the approach to and results from managing QTLs described in the CSR. The implementation of QTLs at Pfizer includes studies that require regulatory submissions and studies that may have an impact on subject rights, well-being, and safety. Suprin elaborated on QTL utilization in study stages including:

· Protocol design: Considering medical and statistical characteristics during study design

· Risk management: Defining QTLs in a cross-functional team during the development of the Quality Risk Management Plan (QRMP)

· Oversight: Using centralized systems to monitor performance and document action during tolerance limit deviations

· Clinical study report: Using the CSR template to document the QTL approach and actions if QTL deviations occur

Suprin also discussed how Pfizer documents QTLs. For example, they document QTL parameters and justification (i.e., as a parameter, the percent of subjects that do not meet eligibility criteria, and as justification, a high number of subjects that do not meet eligibility criteria can have a negative impact on primary study endpoints, and study data validity). Pfizer has defined and launched their QTL approach.


In summary, FDA’s quality management expectations have not changed. However, they are implementing novel methodologies to identify high-risk sites for regulatory inspections. Some sponsors are becoming more concerned with quality to the extent in which they are binding suppliers/CROs to quality metrics in the form of agreements, whereas other sponsors are piloting novel QA processes to enhance alignment with ICH E6 R2. ExL’s 3rdEuropean Clinical Quality Oversight Forum is taking place February 25-26 2019 in London. 


Moe Alsumidaie, MBA, MSF is Chief Data Scientist at Annex Clinical, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials

© 2024 MJH Life Sciences

All rights reserved.