By Megan Marshall, Halloran Consulting Group
Quality, as it relates to clinical trials, is defined as an absence of errors that matter to decision-making. Therefore, quality by design (QbD) literally translates into an absence of errors that matter to decision-making by design. This proactive approach to quality continues to gain global and regulatory support. In fact, on May 8, 2019, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) released a draft revision of ICH E8 (R1), General Considerations for Clinical Studies.1 The guideline is being revised after 22 years of existence and will now contain an entire section on embedding quality measures into the design of clinical studies. It is glaringly apparent that regulatory agencies are pushing clinical trial sponsors to adopt a stronger culture of quality through the principles of QbD. This focus on designing trials through a quality lens enforces the fact that an organizational culture of quality is more important now than ever before.
1. What Is The True Cost Of Quality?
In the ever-fast-moving world of clinical trials, meeting milestones and accelerating timelines are always at the forefront of decision-makers’ minds. It would be extremely naïve to think that this deeply engrained attitude would dissipate overnight, even with the push from regulatory bodies. However, it is important to reflect on the immense amount of risk a sponsor takes on when running a poorly designed clinical trial. With poor design comes poor execution, and with poor execution comes a significantly increased risk to the safety of patients and reliability of your trial results. This ultimately leads to the chance that potentially lifesaving therapies won’t make it into the hands of patients who desperately need them. The probability of risks becoming issues decreases significantly when you take a proactive and data-driven approach to clinical trial design. Transferring your resources from downstream corrective activities to upstream proactive risk identification, mitigation, and contingency planning will ultimately save a significant amount of time, money, and resources and allows you to avoid metaphorical fire drills during the more crucial parts of clinical trial conduct and submission activities.
2. What Does Proactive Clinical Trial Design Look Like?
One of the more fundamental questions to ask yourself when proactively designing the trial is: Does this make sense? Are your clinical trial objectives clear? Does the design of your trial make sense for what you are trying to prove? QbD encourages sponsors to home in on the factors that are critical to the quality of the trial. This approach pushes sponsors to consider whether study objectives can be met, without an undue burden on patients, with the chosen design. Study designs should be operationally feasible and avoid unnecessary complexity and unnecessary data collection.1 ICH E8 (R1) challenges sponsors to engage patients early in the study design process to contribute to identifying these factors. Is it feasible and/or necessary to have a patient return to the clinical for labs once a week? Is this something that patients with a given medical condition will be able to easily comply with? Considering what data will be most meaningful to generate valuable information will be critical to ensuring success. Proactive clinical trial design takes a “work smarter, not harder” approach to design.
3. How Do Organizations Make This Shift To QbD?
As with any new initiative, successfully implementing QbD will take organizational buy-in. That starts with creating a culture that supports quality conversations that go beyond following procedures. Quality management focus moves from assurance of conformity by the QA function to demonstration by study team members that process performance and quality are managed over the life cycle of the clinical trial. A culture of quality encourages dialogue around the design of clinical studies and challenges stakeholders to take an out-of-the-box approach that focuses on what matters. It is important to move away from standardized trial design and think about each trial as unique. This will call for an organization to be transparent about its risks, program, and study level. The culture of risk management should support this conversation and see an opportunity for improvement, rather than a cause of delayed timelines. This culture will also push stakeholders to consider activities that are essential to the study. We often see that in an effort to ensure every base is covered, organizations overcomplicate the design of the clinical study. For example, inclusion/exclusion criteria for some trials have become so robust that we start to question whether research is being performed on a realistic population. Take out the complexity and streamline your trial to provide clearly established objectives. This culture also encourages collaboration by both internal and external stakeholders. Embrace the opinions of the patients and physicians who will participate in the conduct of the study. Learn and understand what makes sense from their perspective and what is really feasible to perform. This is also an opportunity to engage with regulatory authorities and allow them to weigh in on those factors critical to quality (i.e., patient populations, procedures, or endpoints).
4. How Do We Elevate Our Current Process?
While many organizations are currently taking steps to ensure the quality of their clinical trials, it is generally coming from a reactionary place. Quality indicators such as performance metrics, monitoring, audits, and data trending are all important activities, but they aren’t enough to ensure the quality of a clinical trial. By only operating in a reactive or retrospective state, we are often waiting for issues to occur in order to make change. QbD enables organizations to be proactive by considering critical quality factors prior to potential issues occurring. This ultimately saves time and resources and can enable an organization to avoid unnecessary costly protocol amendments throughout the course of the clinical trial. Proactively approaching clinical trial design is not something that has a standard procedure but rather encourages stakeholders to use past organizational knowledge, experience, and common sense to drive the decision-making. This should be part of a continuous learning process that allows organizations to build on accumulated experience and knowledge and continually improve. While a clinical study absent from error is as likely as a snowstorm in the desert, there needs to be a cross-organization emphasis to better position companies to enhance performance, credibility and sustainability of clinical study design from trial conception. This requires proactive planning and continuous review and improvement of risk management process and critical to quality factors.
While the clinical trial process may never reach perfection, QbD is a process that could take you closer to that goal. By being methodical and really taking the opportunity to assess trial design, you are making a conscious effort to avoid trial-damaging issues down the road. Ultimately, by making the commitment to embracing QbD, organizations can become better equipped to successfully navigate through clinical trials, ensuring they can make a positive impact in patients’ lives.
- ICH E8 (R1): General Considerations for Clinical Trials – Draft Guidelines
About The Author:
Megan Marshall has more than three years of experience in quality assurance and clinical diagnostics, focusing in immunology and infectious disease testing. At Halloran, she is responsible for writing and evaluating procedures, identifying and executing process improvements, and assisting with CAPA development and various audits. Prior to joining Halloran, Marshall was employed by Oxford Immunotec, working as a quality assurance specialist, providing support across a diverse operations group that included diagnostics, device manufacturing, and R&D. Within this role she was responsible for various tasks that ensured compliance within the quality management system that included procedural reviews, internal/external auditing, supplier quality, CAPA and risk management, and driving continuous improvements.