Ask the Experts: Applying Quality by Design to Protocols
This monthly feature presents questions from clinical trial professionals with answers from experts. This month features insights from WCG Vice President of Client Delivery Cristin MacDonald.
Question: How has the regulatory push for the application of quality-by-design principles in clinical trials affected sponsors and sites?
Answer: “Quality by design” is prioritized in ICH E8(R1), calling for a comprehensive, stakeholder-inclusive approach to clinical trial design. These stakeholders include investigators and site staff, diverse patient populations, caregivers and laboratory staff, among others.
This represents a significant change for many sponsor organizations. Historically, sponsors have handled protocol design and risk assessment in a silo. If sponsors do bring in an outside perspective, it’s usually a key opinion leader. The resulting protocols often will not work in any other environment than the one the key opinion leader is familiar with and understands. This mismatch leads to financial challenges and deviations from the protocol, which results in quality issues and increased costs.
Too often, sponsors view quality initiatives through the lens of overhead costs, and it’s difficult to quantify the tangible benefits of quality. However, its absence can lead to significant financial and logistical setbacks that will increase cost and delay the project timeline.
Question: What are some of the ramifications of protocol amendments? Are there any data on this topic?
Answer: Think of a clinical trial protocol as the foundation of a building. Amending the protocol means changing the foundation. That means knocking down everything above it to fix it and then rebuilding. It involves updating the lab manual and other documents, which comes at a cost. Then comes sending out the amended protocol to all the sites with the amended informed consent form, each of which requires a new IRB review. In addition, the sponsor must ensure that all stakeholders are trained on the new protocol amendment, affecting the cost and project timeline.
It’s frustrating and costly:
- According to a 2021 Tufts Center for the Study of Drug Development (CSDD) survey, 78 percent of phase 2 protocols and 69 percent of phase 3 protocols have at least one substantial protocol amendment. CSDD estimates that sponsors spend $7 to $8 billion annually to implement these amendments.
- In a more recent report, of 952 protocols assessed by Tufts CSDD between June and October 2022, three-quarters had at least one substantial amendment.
Amendments create financial burdens and can compromise the quality of the research. One way to avoid unnecessary amendments is to spend more time at the outset thinking about the protocol and how to implement it, especially inclusion/exclusion criteria.
Question: The sponsor of a trial our site is conducting has established fairly restrictive inclusion/exclusion criteria for this trial. What impact can this have and what real life examples can you share of trials with overly stringent eligibility criteria?
Answer: Restrictive inclusion/exclusion criteria can eliminate an entire culture from participation. This limits a study’s breadth and applicability and can lead to incomplete or skewed data collection.
Consider a recent Alzheimer’s study protocol: It stated that participants could not have moved residences within three months and they cannot move for the duration of the trial. Such rigid inclusion/exclusion criteria ignore cultural nuances. In many cultures, families share the care of their elders. A person may spend time with one adult child for a few weeks and then move to another relative’s home.
In another example, a study on sexual health unintentionally excluded a significant portion of the LGBTQ+ community due to a narrow and heteronormative definition of sexual activity.
From the sponsor or CRO’s perspective, neither protocol may appear restrictive, but they immediately reveal themselves in conversations with patients, caregivers, clinicians and sites. It is imperative that sponsors begin to initiate these conversations.