With The State Of CRO Monitoring, Industry Must Course Correct

By Penelope Przekop, MSQA, RQAP-GCP

In 1962, the U.S. Kefauver-Harris Drug Amendments included a key new provision requiring that, in addition to the pre-market safety demonstrations mandated by the 1938 Food, Drug, and Cosmetic Act, new drugs demonstrate efficacy prior to marketing. This provision required controlled trials to substantiate claims of efficacy.

In 1963, the FDA established investigational drug regulations, which introduced new procedures to strengthen control over investigational new drugs. Given the new efficacy requirement, the 1963 Act required pharmaceutical products to be developed, evaluated, and manufactured by controlled processes within controlled environments. The FDA established a simple equation to demonstrate safety and efficacy: qualified professionals execute established written procedures with quality control (QC) measures under sponsor leadership oversight, which relied on quality assurance (QA) practices to monitor status, identify gaps, implement corrective actions, etc. That equation is still required today.

By 1990, it all came together. ICH published its first guidelines to support global alignment. Big Pharma generally understood and respected the QC and QA concepts inherent in the IND regulations. But, just as Big Pharma was falling into lockstep with regulators’ proven, control-based equation, outsourcing swung in and the industry swooned, clearing the field for new and exciting cost-saving business approaches.

It all sounded good. Much of it was! Yet, 30 years later, there is a growing tide of sponsor dissatisfaction and despair with one of our most fundamental QC measures designed to provide oversight: monitoring. Many sponsors feel trapped in an outsourcing rut with no way out.

Monitoring Is Quality Control

Monitoring is a critical QC step in the clinical development process. Clinical monitors do not execute clinical trials; that responsibility falls to the principal investigators and their staff. Therefore, when a sponsor outsources monitoring, it is outsourcing QC. Delegating this level of control without proper oversight and direct management may increase the risks to patient safety, data integrity, inspection outcomes, budget, and long-term success.

This article focuses on monitoring; however, to talk about monitoring, we must briefly address the role of QA. Compounding the challenge, sponsors are outsourcing, scaling back, or delaying QA activities, further weakening their oversight capabilities. Clinical auditors ensure that required processes with QC measures (i.e., monitoring) are established and that all QC activities have been executed appropriately on behalf of sponsor leadership because the buck stops with them.

Due to the transformation of our industry, the proven, control-based equation that inspired the long-standing FDA regulations is no longer adding up.

What’s Really Happening Out There?

Sponsors struggle to manage outsourced monitoring services provided by small and large CROs. Despite a rise in quality and customer satisfaction awards for CROs, dissatisfaction with CRO monitoring has led to the following common behind-the-scenes scenarios:

• Sponsor 1 moves monitoring from large CRO A to large CRO B.
• Sponsor 2 moves monitoring from large CRO B to large CRO A.
• Sponsor 3 moves monitoring from small CRO C to large CRO A.
• Sponsor 3 moves monitoring from large CRO A to small CRO C.
• Sponsor 4 moves monitoring from ex-U.S. CRO to U.S. CRO.
• Sponsor 5 moves monitoring from U.S. CRO to ex-U.S. CRO.

Is your head spinning? It should be. In all cases, ongoing operational issues and audit observations driving sponsors to shift from one CRO to another are similar across the industry. Those issues include:

1. Low-quality monitoring reports; overfocus on timeliness at the expense of quality
2. CRO-required generic monitoring report templates that lack detail and protocol-specific information
3. CRO refusal to allow or enable sponsor review of draft monitoring reports
4. Lack of processes to address sponsor final report review comments
5. Check-the-box monitoring report reviews conducted by peers or project managers, rather than experienced monitors
6. High turnover of monitors and poor handover processes
7. Abbreviated site monitoring visits; lack of monitor-site coordinator interaction
8. Insufficient documentation of escalation for open site issues
9. Inexperienced monitors unable to adequately identify site issues or address site staff questions
10. Inability of monitors to assist sites with audit observations, which are often issues that should have been noted during monitoring visits

The Industry Can Course Correct

Sponsors can begin course correction by following the solutions recommended below. Solutions that require CRO collaboration may appear to be quicker, lower-cost fixes that enable sponsors to avoid major infrastructure changes. Based on recent industry history, this is not the case. Carefully weigh the long-term outcomes when considering the time and money inherent in each solution.

Remember that patient safety and data integrity should always be the true drivers behind sponsor decisions. Consider the following recommendations in tandem with the many sponsor-specific factors at play.

Solutions That Require CRO Agreement:

• Establish more stringent qualifications for monitoring report reviewers.
• Require CROs to formally document monitoring report review, including review comments and their resolution.
• Insist on sponsor review of monitoring reports prior to finalization.
• Require CROs to use the sponsor’s protocol-specific monitoring report templates.
• Develop sponsor monitoring and clinical operations SOPs and require your CROs to follow them.

Solutions Sponsors Can Independently Implement:

• Require CRO to ensure monitors address the sponsor's final report comments in the next monitoring report.
• Enhance qualification standards for monitors, including the provision of writing samples (e.g., redacted monitoring reports).
• Ensure creation and execution of protocol-specific QA plans for all Phase 1 – 3 clinical trials.
• Hire experienced contract monitors to conduct co-monitoring visits following a regular schedule; incorporate co-monitoring into the overall monitoring plan.
• Utilize CRO monitors while retaining in-house staff for key clinical trial management activities, such as development and oversight of monitoring-related plans (i.e., monitoring plan, deviation plan, etc.).

The Ultimate Decision

Bring monitoring back in-house to reinstate sponsor QC over clinical trials.

Considering the current disjointed clinical trial process and the complexity of oversight, it is time for sponsors to reclaim the critical QC power of monitoring. Sponsors can continue struggling through endless meetings, negotiations, and work orders, or the industry can finally say “Enough is enough” and reestablish sponsor responsibility for monitoring — the most fundamental QC activity in drug development. The industry may have come full circle regarding monitoring.

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.