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Establishing Protocol Quality by Design Through Stakeholder Collaboration

Clinical trials face costly delays and data issues when protocols fail to incorporate a holistic viewpoint from the beginning of their development.

“Quality by design” is prioritized in ICH E8(R1) (International Council for Harmonization General Considerations for Clinical Studies Guidance), 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 which will increase cost and delay the project timeline.

As the industry grapples with complex and costly protocol amendments, inclusive stakeholder engagement not only ensures ICH E8(R1) compliance but also decreases the need for protocol amendments. Incorporating stakeholder input during the protocol design phase will pave the way for efficient, quality-focused, and culturally sensitive clinical trials.

The Problem with Amendments

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% of phase II protocols and 69% of phase III protocols have at least one substantial protocol amendment. CSDD estimates that sponsors spend $7 to $8 billion annually to implement these amendments.1
  • 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.2

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.

Examining Inclusion/Exclusion Criteria

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.

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.

Milestones that Matter

Sponsors and CROs often prioritize hitting key milestones, such as enrolling the first patient, over ensuring the quality of the protocol. Instead of planning for potential issues, problems are addressed after they arise in a retrospective manner, instead of an approach that prospectively mitigates issues. As a result, few trials finish on time. There’s a prevailing industry rush to hit early milestones, which overlooks the need for comprehensive feedback and quality assurance. This can lead to delays and additional costs down the line.

A quality-by-design approach builds in time on the front end to allow for stakeholder conversations and to identify and mitigate risks. Sponsors can shift attention from rushing to initiate the trial to focusing on developing a meticulously planned and executed trial that brings in various perspectives and leads to a successful project conclusion.

A Comprehensive, Independent Review

Reviewing a protocol from a 360-degree perspective can reduce uncertainty during study start-up, identify site readiness, flag potential obstacles to patient recruitment, and support a more robust approach to diversity, equity, and inclusion (DEI) planning. But such a review only succeeds if it’s both thorough and objective.

That’s why WCG provides a 360 Protocol Assessment to help sponsors ensure quality by design.

WCG’s subject matter experts in quality, operations, and DEI identify potential areas of risk in conjunction with its extensive network of investigators, sites, and patient advocacy groups. The assessment ensures sponsors hear from all key stakeholders. This equips them with the tools to identify and address key risks early in the trial’s planning phase, significantly reducing the need for protocol amendments.

As a neutral third party, WCG is free from external pressures and incentives related to deadlines or other external factors. When stakeholders that are close to the contractual terms of study also conduct protocol reviews, they tend to assess risk in terms of contract-related elements such as schedule and budget, rather than the nuances of scientific and project execution. Their rewards are connected to hitting milestones. This can result in a risk evaluation that’s more about logistical and contractual hurdles and less about the genuine challenges or risks inherent in the protocol. WCG enables a multi-lens review as your trusted partner.

For sponsors who want efficient, predictable, quality-focused trials that align with ICH E8(R1) guidelines, WCG’s 360 Protocol Assessment is crucial. Get comprehensive, unbiased insights from an unmatched network of experts and stakeholders. Let’s build protocols that work.

Connect with us to schedule a consultation today.


1. Getz, Ken. Doubling Down on Protocol Amendments and Deviations. March 1, 2022.
2. Protocol Amendments Continue to Increase, Report Shows. CenterWatch. March 6, 2023.

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