Last year, announcements appeared on the FDA, EMA, and WHO websites, that during regulatory inspections of a clinical contract research organization (CRO) in India serious violations were identified in the conduct of bioequivalence and bioavailability studies.
The outcome of these inspections didn’t just seriously impact the CRO, but also the pharmaceutical companies that subcontracted this CRO.
“The inspection found significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples..” “the sponsor […] must repeat the bioequivalence/bioavailability studies […] at an acceptable alternate study site.” FDA, April 2016
“EMA recommends suspension of medicines over flawed studies…” “Bioequivalence studies performed at the site cannot be used to support medicines approval in the EU.” EMA, July 2016
Risks in vendor management
Present-day clinical studies are increasingly complex, more globalised, and making use of new technologies. As a result, vendors are often highly specialised and pharmaceutical companies (Sponsors) make use of many different vendors in one clinical study. In turn, these vendors often subcontract activities to third party vendors. Sponsors should understand that the use of all those vendors and their subcontractors can be very risky because if one of them fails to be compliant, it can have disastrous consequences for the development of your product.
According to Good Clinical Practice (ICH E6, section 5.2.1), the Sponsor always remains ultimately responsible for the quality and integrity of a study. In the revised ICH E6 (section 5.2.2) it’s stated that Sponsor oversight is not just limited to the vendors they contract, but it also includes the vendor’s third parties.
Some examples of risks in vendor management that might seem familiar:
- Your company has a list of approved vendors, but… under time pressure, because it was requested because they know the vendor… the study team decides to contract an unapproved vendor or an approved vendor for unapproved services.
- Your qualified vendor decides to change procedures or one of their vendors without notifying you, the contract giver. This may not seem like a big deal, but what if this change involves critical study activities or software?
- During the vendor qualification audit, everything looked perfectly fine, but now your vendor doesn’t perform as expected... Serious breaches aren’t escalated, deadlines are missed, overall quality is low…
- Are we using Sponsor procedures, vendor procedures, or a combination? Confusion about the applicable procedures can lead to an inconsistent approach to study execution (document management, monitoring, reporting of deviations, etc.) and may finally lead to significant quality issues.
- Use of different vendors does not only complicate the clinical study execution and (essential document) management. It may also lead to additional data integrity risks. Are you sure that clinical study data collected in different systems finally end up in one location? Are data still reliable when they are transferred from one system to another? Is a reliable analysis of all study data possible during or at the end of the study?
Mitigating the risks
Quality agreements between Sponsor and vendors to document the responsibilities and expectations to ensure the quality of a study are quite common nowadays. Sometimes it’s already part of the contract. But does this give the assurance, that there is a robust quality system in place for your clinical study and will it make sure you don’t face any surprises at some point during or even after the study?
Risks can be further mitigated by a carefully thought-out vendor oversight approach, considering the following aspects:
Formalise your vendor management approach.
Standardising your processes in selection, qualification, contracting, managing and even ending collaboration with vendors can support your company in adequate vendor oversight. Assign a vendor manager or vendor management team, which can support your company in keeping vendor oversight. A vendor manager can manage the contracts, interact with quality assurance, and be involved in issue/conflict management.
Don’t underestimate the importance of good communication lines (and trust).
Make sure there is a detailed Sponsor-vendor and/or vendor-vendor communication plan in place. Open and transparent communication is essential for smooth execution, prompt handling in case of issues and a reliable study outcome. A relationship built on trust is essential. This is a two-way process: The vendor should be transparent and share potential issues; the contract giver should establish an open environment. Immediate repercussions will work counterproductive. Instead, focus on an action plan to mitigate any risks and improve any processes.
Vendor qualification and requalification are more than ‘just’ an audit.
- In addition to auditing the vendor’s quality system, competencies and qualifications, experience and resources, have you considered the following? Try to assess the ‘soft’ aspects of vendor quality, such as communication, reliability, collaboration and quality awareness (the quality culture). Not easy to objectify, but you may have a look at repeat business, staff turnover, quality objectives, visibility of leadership, and accessibility to staff during an audit.
- Assess vendor continuity. In other words, are you sure that the vendor still exists in a few years? Are there any signs of potential acquisitions or mergers, which could potentially influence the commitment of the vendor to your company?
- Invite a subject matter expert to accompany the auditor. The assigned auditor may not have the in-depth knowledge to assess certain aspects of the considered services. If necessary, involve the Information Technology department or consider to hire a GxP IT auditor.
Consider the potential risks in the combination of vendor activities and systems.
Don’t only consider the potential risks at the level of individual vendors, but also ensure adequate oversight of and assess potential risks in the entire chain of processes and data, from vendor to vendor, from vendor to sponsor. A systematic quality (risk) management approach will finally ensure the integrity of the entire clinical study.
When activities are outsourced, the most important task of a Sponsor is to keep good oversight, both by overseeing the individual vendors and by looking in a more systematic way at the use of different vendors in one study. Adequate vendor oversight could avoid issues, which may have any impact on the integrity of the entire study.
Blog by: Henrieke de Bie - Senior Consultant at Xendo