By Laurie Halloran
September 11, 2012 | Guest Commentary | Regulators are paying increased attention to sponsors within the realm of vendor oversight. Clinical Trial Sponsors must include vendor oversight in any assessment of inspection readiness on their mid-stage development programs, and once the gaps have been identified, apply preventative actions across all outsourced programs in development.
FDA regulations and ICH-GCP Guidelines mandate sponsor oversight of all clinical research activities where transfer of regulatory obligations has occurred with external parties through contractual agreement. They also require qualified individuals to manage the delegated activities.
FDA and ICH Guidelines on Sponsor Obligations
- Drug accountability and disposition
- Obtaining information from the investigator (Form 1572)
- Clinical Protocol
- Financial disclosure information (Part 54)
- Selecting monitors
- Investigator brochure
- Secure compliance from or terminate noncompliant investigators
- Halting study in case of unreasonable risk to subjects
- Recordkeeping and record retention
- FDA inspection access
- IND Safety reports (21 CFR §312.32)
These duties have taken on more vital meaning as the dynamics of developing products in a global environment coupled with the increased complexity of protocols, medicine, regulations, and the heightened financial constraints of all development-stage companies has become the new norm.
Gone are the days where the highest enrolling site(s) in a pivotal trial could be prepped by the sponsor for a well-timed inspection after submission of a new marketing application (NDA, BLA or PMA). The new “normal” for sponsors is that they must be ready for a potential inspection at any time during the clinical phases of development, and be prepared that virtually any of the vendors involved in the process are potential inspection targets.
A perfect storm exists because of an increased level of clinical research outsourcing, coupled with the globalization of clinical trials, especially within the emerging regions with sponsors’ relatively inexperienced teams. Inadequate sponsor oversight of CROs results in heightened risk, where at best the data will be inadequate to support a submission, and at worst, the wrong patients will be exposed to unproven therapy without the sponsor awareness or recognition that this liability is occurring. Without oversight, a complicated protocol may not be interpreted correctly by the CROs, ineligible subjects may be recruited, and/or unqualified investigators may be employed (PDF).
Any of these events will ensure the program will not withstand inspection scrutiny, but they won’t be identified until after the fact when it is too late to correct them. To avoid late identification of these negative events and underperformance, a CRO needs an oversight program comprised of comprehensive training, clearly set expectations, and quality control of deliverables.
A perfect example of what often happens as a result of inadequate oversight occurred recently with one of our clients. Enrollment into our client’s global pivotal vaccine trial was very rapid, and data had to be collected quickly due to both the design of the study and urgent public health needs for the product. Because their CRO had a large team (and experienced mid-stream turnover), instructions on data collection up to a key interim analysis were inadequately understood by the global team.
At some sites, misunderstandings about what should be collected were so pervasive, the resulting data were unacceptable. It was insufficient to make definitive conclusions, but by the time the poor data quality was recognized, it was so late into the trial that the clean-up was costly and time consuming, resulting in a delayed submission. If the data quality had been monitored throughout the entire program through consistent oversight, the delay and cost to our client would have been avoided, and both time and money would have been saved.
Regulators want to see sponsors set quality expectations for outsourced work, and during an inspection, they expect to see evidence of the ongoing evaluation of those vendors on quality with respect to deliverables. These themes complement those of EMA with its focus on building in quality risk management throughout the entire development process.
To Be, or Not To Be….Ready
Frequently, sponsors who outsource management and execution of their clinical trials don’t have an opportunity to look at the vendor’s integrated activities using a systematic approach. As it is almost impossible to prepare for a sponsor/monitor inspection with a reactive approach, sponsors should conduct a gap analysis specifically focused on the outsourced clinical trial model both internally and with vendors to proactively identify the areas of risk. If there are potential compliance issues, the sponsor should trigger a corrective and preventative plan to adopt an integrated system.
|Figure 1: Quality Process
|Adapted from http://www.iso.org/iso/iso_catalogue/management_standards/understand_the_basics.htm
Another key question is: Do you thoroughly document the transferred responsibilities and the evidence that your vendors and research sites understand both their roles and the study particulars? If you have not clearly defined and documented how site evaluation and selection is conducted and set clear, documented expectations on protocol training, related eligibility tests may not be communicated during the project kick-off meeting, and opportunities for poor decisions abound. Moreover, this critical baseline activity will not be captured in historical records that can be reviewed post-facto to determine decision-making surrounding the sites’ selection.
The use of a standardized tool to set expectations that begin contractually and include both performance and relationship management is being applied in many of our client companies.
Aptly called Oversight Plans, they facilitate a proactive approach between sponsor and vendors to discuss and define assumptions at the contractual stage, set expectations at the kick-off stage, and manage them throughout the entire program. Oversight Plans ensure that both minimum performance expectations and the sponsor/vendor relationship are clearly defined and not only managed by all parties, but documented for future inspection retrieval, and stored to create institutional knowledge that is transferrable to future projects.
Getting into the details at the beginning of the trial, and documenting what has been decided will be the best way to begin and continue the relationship, and to ensure a smoothly managed clinical trial.
Sponsor/monitor Warning Letters (ICON/J&J and Pfizer/K-force) listed above. Available at
Link One: www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm193156.htm
Link Three: www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm208976.htm.
Laurie Halloran is the President and CEO of Halloran Consulting Group. She can be reached at email@example.com.