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Risk-Based Monitoring: Pfizer and BMS Seek Clarity on FDA Draft Guidance

Posted 15 May 2019 | By Zachary Brennan 

Risk-Based Monitoring: Pfizer and BMS Seek Clarity on FDA Draft Guidance

Pfizer and Bristol-Myers Squibb (BMS) recently raised questions with and sought further clarity from the US Food and Drug Administration (FDA) on a draft guidance related to the risk-based monitoring (RBM) of clinical trials.

The eight-page RBM draft guidance, released in March, comes in the form of eight questions and answers. It expands on guidance from August 2013, known as “Oversight of Clinical Investigations--A Risk-Based Approach to Monitoring,” by providing additional guidance on planning a monitoring approach, developing the content of monitoring plans and addressing and communicating monitoring results.

But companies commenting on the draft Q&A questioned some of the terminology and how FDA inspections would work with RBM.

For instance, BMS asked FDA if the term “monitoring plan” is appropriate given the fact that other industry-wide guidance (from TransCelerate and Avoca) refer to this concept as Risk Monitoring Plan or Risk Management Plan (RMP).

“The term RMP is also much closer to ISO31000 and other cross-industry quality principles of interest as intended in the original RBM Guidance of 2013. This Q&A Guidance document does not specifically address monitoring activities that can occur on-site and the related documents. As such in this Guidance the term ‘monitoring plan’ conveys the impression that only traditional GCP [good clinical practice] on-site monitoring visit reports are intended here,” BMS said.

BMS suggests renaming the “monitoring plan” as “Risk Monitoring Plan” and that FDA include concepts such as remote and central monitoring in such a plan.

Pfizer, meanwhile, explains how there is limited experience industry-wide with regulatory inspections when the trial is monitored in a risk-based approach.

“Pfizer recommends providing additional information related to how inspectors are prepared and best practices for inspections in RBM. To encourage robust adoption of risk-based approaches across industry, we suggest that FDA take proactive steps to diminish any perception that an individual inspector may be unwilling to accept this strategy,” Andrew Emmett, Pfizer’s FDA liaison and head of US regulatory policy, wrote.

He also encouraged FDA to establish indicators for how it would measure the success of a risk-based approach.

“If the Agency intends to measure success through the same parameters of inspection readiness and quality that are used today for non-Risk-Based approach, Pfizer suggests including this language in the guidance,” he wrote.

Pfizer also suggested that FDA work with the Clinical Trials Transformation Initiative (CTTI) to gather data and determine whether the factors noted in the draft as potentially important are important to quality outcomes, before issuing the final guidance.

Pfizer further called on FDA to discuss risk-based monitoring “in the context of a comprehensive study level quality risk management plan (ICH E6 Section 5). Risk-based monitoring offers options for added controls for those risks identified during study quality risk management, but RBM is not the driver for overall quality risk management. The guidance suggests the control (monitoring) is the driver. Any issue found during monitoring is a ‘realized risk’ and can only be mitigated once discovered.

"The goal of an overall risk plan for the study is to proactively identify risks and implement changes that prevent the identified risks from being realized. Where that is not possible, other controls can be used, like monitoring activities, to mitigate the consequences of issues or errors. The overall risk management plan is mentioned, but risk assessment is not for the sole purpose of defining risk-based monitoring, as discussed in Q1, since it has broader applicability and benefits,” Pfizer said.

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