The problem with not following QbD prior to commercial production is that it is extremely difficult to insert or force quality into a suboptimal process.  Doing so leads to awkward and inefficient practices, duplicative efforts and “Band-Aid” approaches to quality. Building a quality pharmaceutical begins with building quality into the research and development phase.

One may argue that QbD is already built into R&D through clinical quality assurance (QA). While QA certainly is an important part of clinical research, it does not build quality into the process. Because it is traditionally conducted as an assessment at one point in time, it does not provide a continuous assessment over the course of the trial and therefore cannot be considered as part of the process.

What can pharmaceutical companies do to build quality into research and development? They can implement a third-party quality oversight program. Quality oversight upholds the principles of QbD, because it is performed over the course of the trial and it represents a simultaneous exchange of information that allows for real-time corrective and preventive action (CAPA).

What is quality oversight?
Third-party quality oversight provides an unbiased and objective assessment of the vendor contract research organization (CRO) work effort. Sponsors utilize many processes to evaluate the quality of their clinical trial data; however, the bias that may exist in a long-term relationship between a sponsor and its clinical trial CRO makes it more difficult for the sponsor to adequately assess the vendor CRO’s performance. Third-party quality oversight eliminates this bias and provides reliable information in real time.

An optimally structured quality oversight program should not result in any duplication of effort on the part of the sponsor. Quality oversight is all about processes and adherence to contractual and regulatory requirements. It is not about co-monitoring or re-auditing the study.

Quality oversight builds quality into a clinical trial by ensuring that CRO performance meets FDA and other regulatory body requirements and that the work also meets FDA expectations.

Let’s take a closer look.

Ensure that CRO performance meets FDA requirements
While sponsors always have been responsible for the quality of their vendors’ work, it is now clear that sponsors also are being held directly accountable for that quality. Nowhere is this more evident than in the case of recent FDA warning letters issued to top-quality pharmaceutical firms for failure to oversee the activities of their vendors.

Problems don’t have to reach warning letter status to attract the attention of regulatory authorities. Several sponsors have reported that FDA investigators are specifically asking how the sponsor oversees the activities and assures the quality of its clinical vendors. This is a legitimate question and one that industry sources expect will gain more currency as part of the inspectional process. Third-party quality oversight answers this question.

Ensure that the work meets FDA expectations
FDA’s good clinical practice (GCP) requirements are quite thin—most are expectations of ethical and scientific quality standards rather than codified regulations. So how can a sponsor successfully navigate what could become a mine field of expectations? By retaining an expert with significant experience in FDA submissions.

The quality oversight provider should have extensive experience in GMP as well as GCP in order to bring GMP-quality methodology to the clinical process. The quality oversight team should be comprised of senior clinical research associates with significant experience in this type of activity. Through accrued experience, the quality oversight provider should thoroughly examine the CRO work effort and authoritatively weigh its adherence to FDA expectations.

Incorporating QbD into research and development through third-party quality oversight of clinical trials helps pharmaceutical companies ensure that FDA requirements and expectations have been met long before a drug enters commercial production. Entering production without this assurance can mean costly delays and unnecessary re-work.

This article appeared in Pharmaceutical Compliance Monitor on January 16, 2012.

Even before reaching warning letter status, problems are attracting the attention of regulatory authorities. FDA investigators are asking how sponsors oversee the activities and assure the quality of work performed by their clinical vendors. Quality oversight answers this question.

A third-party quality oversight program provides an unbiased and objective assessment of the CRO’s work effort. It eliminates the inherent bias that may exist in a long-term relationship between a sponsor and its CRO—a bias that makes it difficult for the sponsor to adequately assess the CRO’s performance.

An optimal quality oversight program provides real-time assessment and reporting of CRO field activity; it is not about co-monitoring or re-auditing, and it is not clinical quality assurance. Rather, it provides a comprehensive assessment of the CRO’s overall process and performance.

Quality oversight is well-aligned with the FDA’s Clinical Trials Transformation Initiative and, as it is accepted as a critical trial process by a large number of firms, will increase its positive impact. It also is aligned with the FDA’s call for industry to be more innovative in its clinical trial work. A trial-specific, formal quality oversight plan could be part of any prospective trial review conducted under the agency’s pilot initiative for adaptive clinical trials.

Most important, a solid, metrics-driven quality oversight report can greatly facilitate the inspection process, particularly when FDA investigators ask “How do you, sponsor, know that the CRO is doing what it is supposed to be doing?”

This article appeared in the October 2011 CenterWatch Monthly.

Beaufort Solution: Beaufort helped the company resolve ASR compliance issues with the pre-IDE submission and crafted an appropriate pre-IDE submission and project plan. Prior to mediating the pre-IDE meeting with the FDA, Beaufort helped the company develop a presentation and assisted with a dress rehearsal.

Beaufort Solution: After identifying pathways to a Class II device classification, Beaufort prepared a strategic regulatory plan for the test kit, enabling the company to satisfy regulatory requirements in a cost-effective manner.  Beaufort drafted a pre-IDE filing, including a clinical trial plan, and provided coaching to the client as they prepared for their pre-IDE meeting with the FDA.  After successful meetings with FDA officials, the company relies on Beaufort for continued support as necessary, including assisting with pre-clinical and clinical trial activities.

Beaufort Solution: These actions included a review and revision of their Quality Document System, a review of their Computer System Validation (CSV) Plan, and performing Vendor Audit Assessments.  Beaufort performed an in-depth review of the company’s current document system, including meetings with all key stakeholders.  This review led us to suggest several alternative document structures.  The final project deliverables included an SOP Assessment Report, complete Document Index, revised SOPs, Flow Diagrams, Glossary of Terms and Definitions, and an SOP Writing Style Guide.

Beaufort Solution: Beaufort conducted these audits on behalf of the company.  They allowed the company to make informed decisions as a clinical trial sponsor. This client has since requested Beaufort’s additional support in developing a Quality System and assisting with their 510(k) submissions.

Beaufort Solution: The client sought assurance that clinical data was valid and could support a PMA submission.  Lacking sufficient internal resources, the client selected Beaufort to conduct the assessments.  Beaufort planned and audited two clinical sites and worked with the client to gain historical information regarding site staff and data collection. Beaufort recommended performing an audit of the sponsor’s Trial Master File prior to auditing clinical sites, thus ensuring that the sponsor held required regulatory documents for each site.  Beaufort provided audit reports and held subsequent discussions with the client, enabling them to make informed decisions regarding the integrity of data associated with the clinical trial.  The output of these audits provided the client assurance that their required study files were in order for potential FDA inspection following the submission of the PMA.

Beaufort Solution: Realizing they had insufficient internal resources, the Quality Assurance division sought assistance in transitioning from a paper-based document system to a software-based document control system.  Beaufort performed an initial review of their system to identify any existing gaps.  This effort included review of approximately 670 SOPs and 350 forms for content including obsolete references; document relevance; assignment of appropriate ownership/responsibility; and potential for SOP deletion, modification, or combination.  In addition, Beaufort worked closely with functional areas to gain an understanding of the numerous processes and how they were potentially linked. This assignment led to a follow-on SOP project.

Beaufort Solution: The company’s products range from early detection and prevention of diseases to diagnosis, treatment, and treatment monitoring and this was the first time they had turned to outside resources to fill their needs.  Beaufort developed a turn-key clinical trial management plan, beginning with site identification/qualification and essential document development for three separate clinical trials.  In parallel, Beaufort performed a formal Risk Analysis Plan to ensure the project team was aware of the potential risks involved in performing three clinical trials within the very short timeframe required by the client.  The plan identified potential risks, mitigating factors, and planned corrective actions if identified risks occurred.  Beaufort initiated site identifications/qualifications and prepared the Project Operations