By Penelope Przekop, MSQA, RQAP-GCP
Following the May 19, 2023 ICH Assembly endorsement of ICH E6(R3) final draft, every sponsor should understand and accept that regardless of delegating GCP tasks, duties, or functions, they retain overall responsibility for the activities. Sponsors have made tremendous progress in executing and documenting oversight in recent years. However, sponsor oversight remains a challenge.
The integrity, strength, and reliability of the pharmaceutical industry of the future depends on us to strengthen and maintain clear boundaries for sponsor and vendor roles and responsibilities. Regulators know this and are doing their part. We must do ours.
One way to do our part is to strengthen sponsor involvement in monitoring activities. Sponsors should have an active, documented role in the finalization of monitoring reports. Mock regulatory inspections, inspection readiness activities, and other quality assurance (QA) support scenarios have consistently shown that the process for – and documentation of – sponsor review of monitoring reports generated by clinical vendors is ineffective or does not exist. Even if written procedures, client-specific guidelines, or monitoring plans state that the sponsor reviews monitoring reports, there is strong evidence that a gap exists across the industry.
What CROs Often Say About Sponsor Review
Imagine you are an auditor, and a sponsor has engaged you to audit their primary CRO. After reading the related CROs processes and the monitoring plan, which includes sponsor review of monitoring reports, you spend 5 hours assessing selected monitoring reports. Based on your review, you now have a list of questions and issues due to 1) lack of clarity in reports and 2) information gleaned from the reports. Now you’re ready to ask questions and request additional documentation.
The following are real-world verbal and written responses (paraphrased from the recent experiences of QA professionals, including my own) by CRO staff when auditors asked how, when, who, and how often the sponsor reviews monitoring reports, how is feedback received, how they make corrections, etc.
- There is no written process, but our monitoring plan says that the sponsor reviews the reports. Please speak with them.
- Having a process would take too long and impact timeliness. That will affect our bonuses.
- We provide final monitoring reports to the sponsor (via CTMS, eTMF, etc.); they can review them in a time frame that works for them. If there’s an issue, they just let us know.
- We don’t allow changes to final monitoring reports.
- We don’t allow addendums to monitoring reports. They may have a spreadsheet. The sponsor didn’t engage us to track their review of monitoring reports.
- If they want us to do anything else with final reports, there will be an added charge.
- Our policy is to not share draft monitoring reports with the sponsor. They get the final version. But once final, the report cannot be changed.
Mock inspections of sponsors often elicit responses equally as vague that include the verbal assurance that monitoring reports, or a subset, are reviewed.
If It's Not Documented, Did It Happen? If It Did, Was It Good Enough?
If sponsors are reviewing monitoring reports, why are issues with the reports identified during audits and mock inspections? After receiving responses such as those above, the obvious next request is, “Please provide documentation of sponsor review of monitoring report(s).” There is no documentation available in most cases. Sometimes, the response is that the issues are discussed in meetings, which leads to a request for meeting minutes. Those rarely include specifics regarding sponsor review of monitoring reports that can be linked to a specific report or issue that has been identified.
There is a 100% chance that auditors and regulatory inspections will request monitoring reports for review. This is because monitoring reports are the most detailed source of information about what happened at investigators’ sites, as well as how well the sponsor actively monitored and ensured compliance, data integrity, and patient safety during the study and many other required items.
Numerous statements in the ICH E6(R3) draft clarify sponsor responsibilities during clinical trials, regardless of delegation to vendors. Many sponsors are questioning how they can have more direct and impactful oversight. The three examples below relay why a stronger focus on sponsor review of monitoring reports is an obvious and practical answer.
1. Documented review of monitoring reports demonstrates a strong commitment to oversight.
A documented process for sponsor review and documentation to demonstrate it has occurred is a solid action a sponsor can take to demonstrate it follows these two ICH E6(R3) statements:
Part II, 10.1 The sponsor may transfer, or the investigator may delegate some or all their tasks, duties, or functions (hereafter referred to as activities), but they retain overall responsibility for their respective activities.
Part III, 3.9.2 The sponsor should ensure that trial processes are conducted in compliance with the trial protocol and related documents as well as with applicable regulatory requirements and ethical standards.
There are other valuable ways to demonstrate sponsor oversight and that should continue; however, without a solid process for review of monitoring reports, documenting that review, and having a feedback loop, sponsors are cutting out an obvious direct line of sight into their clinical trial. Reading information in, or realizing that information is omitted from, monitoring reports provides information as straight-from-the-source as a sponsor can get.
2. Clinical trials should be designed and conducted by qualified individuals.
ICH E6(R3) Section II, 5.1 states that individuals with different expertise and training may be needed across all phases of a clinical trial, such as physicians, scientists, ethicists, technology experts, trial coordinators, monitors, auditors, and statisticians. Individuals involved in a trial should be qualified by education, training, and experience to perform their respective task(s).
Well designed and written final monitoring reports provide assurance to sponsors that monitors are qualified and that those reviewing their reports are qualified to spot issues and ensure they are corrected. Experienced industry managers know that while the CV and training records are critical documentation that show an individual is qualified by education, training, and experience, it is their actual deliverables that solidify and confirm that they are qualified and capable of delivery on the promise of their CV, first impression, and interview process. Too many sponsors assume that monitors and clinical trial managers are qualified based on a CV rather than the actual deliverables produced.
Regardless of what someone’s CV and training records reflect, sponsors have the right and responsibility to question the quality of what is being delivered to them. The sponsor is not only ultimately responsible, but they are also the customer of those monitoring their studies. Providers have an obligation to provide the level of quality promised and appropriate customer service.
3. Sponsors must incorporate quality into clinical trial design, including timely escalation of issues.
Quality by design (QbD) includes a process for documented sponsor review. Designing quality into any process also includes steps that enable identification of where things go wrong. Escalation pathways have been adopted throughout the industry over the last decades; however, auditors and mock inspectors continue to identify issues that were not properly escalated via review of monitoring reports.
Monitoring reports are the first line of defense and should be a focus for sponsors. Monitoring reports include information critical to the quality of the trial and are a key tool to manage risk. The process of sponsor review of monitoring reports can be considered early communication and a route of escalation, along with those established through clinical operations, quality assurance, and senior management processes. Monitoring reports should be corrected when the sponsor identifies issues, and monitors should receive feedback as part of their ongoing development. Further, if the monitoring report has been reviewed by the CRO prior to provision to the sponsor, those who are reviewing the reports must also receive feedback in terms of what they should be identifying during their review.
The following ICH E6(R3) statements support why sponsor review of monitoring reports is a logical and practical process for our industry:
Part III 3.1.2 Sponsors should incorporate quality into the design of the clinical trial by identifying factors that are critical to the quality of the trial and by managing risks to those factors.
Part III 3.6.7 A sponsor may transfer any or all of the sponsor’s trial-related activities to a service provider; however, the ultimate responsibility for the sponsor’s trial-related activities, including protection of participants’ rights, safety and well-being, and reliability of the trial data, resides with the sponsor. Any service provider used for activities should implement appropriate quality management and report to the sponsor any incidents that might have an impact on the safety of trial participants or/and trial results.
Part III 3.9.6 The sponsor should ensure appropriate and timely escalation and follow-up of issues to allow the implementation of appropriate actions in a timely manner.
Part II 6.3 Strategies should be implemented to avoid, detect, and address serious noncompliance with GCP, the trial protocol and applicable regulatory requirements to prevent recurrence. The quality and amount of the information generated in a clinical trial should be sufficient to provide confidence in the trial’s results and support good decision making.
Monitoring is a critical part of any strategy to avoid, detect, and address serious noncompliance with GCP, the trial protocol, and applicable regulatory requirements to prevent recurrence. If monitoring reports cannot or do not capture details in a clear, comprehensive, logical manner, they will be unable to provide documentation that this occurred. In addition, if they do relay ongoing compliance issues that are not being escalated, the sponsor may only be aware of this through review of the monitoring reports.
Proactive Actions For Sponsors
Following are a few actions sponsors can proactively take to ensure their review of monitoring reports serves as a successful tool for not only conducting oversight but documenting it.
- Clearly define sponsor expectations for monitoring report templates and for writing skills. A CRO saying that they cannot alter a less-than-ideal monitoring report template because “it’s the template” is an example of the CRO not allowing the sponsor to exercise their oversight.
- Relay that the quality of monitoring reports is equally important to the timeliness. Our industry’s focus on timeliness has slowly degraded our respect for quality. It’s time to change that, and this is one way to do it. Request that the details around sponsor review be included in monitoring plans as opposed to the statement, “The sponsor shall review monitoring reports.”
- Communicate any disappointment you have in the quality of the deliverables presented to you, whether it’s a monitoring report or a clinical plan. You are the customer, and the services provided should meet your expectations.
- Ensure monitoring reports not only capture noncompliance but also capture escalation, follow-up, and resolution of those issues within time frames designated in the monitoring plan. Numerous examples have been noted during audit and inspection where issues remained open for double and triple the times required with no indication of sponsor involvement.
Sponsor oversight is not a “check the box” activity. Too many vendors are taking the reins by putting timeliness above quality, whether intentional or not. Sponsors must take the lead to get back into the driver’s seat. As an industry, we must be willing to sacrifice time, when necessary, to ensure ongoing data integrity and patient safety now and in the decades to come.
About The Author:
Penelope Przekop is a corporate quality management expert. Throughout her 30+ year career, she has worked with numerous Fortune 100 pharma companies, including Pfizer, Merck, Lilly, and Glaxo Smith Kline, and held leadership positions at Novartis, Covance, Wyeth, and Johnson & Johnson. She is the founder and CEO of PDC Pharma Strategy, a firm that provides corporate compliance, quality assurance, and pharmacovigilance consulting and services. She is an author whose books include Six Sigma for Business Excellence (McGraw-Hill) and 5-Star Career: Define and Build Yours Using the Science of Quality Management (Productivity Press). Przekop earned a BS in biology from Louisiana State University and an MS in quality systems engineering from Kennesaw State University. She is a graduate of the Smith College Program for Women’s Leadership and the Rutgers University Senior Leadership Program for Professional Women.