Recommendations

“Quality” in clinical trials is defined as the absence of errors that matter to
decision making—that is, errors which have a meaningful impact on the safety of
trial participants or credibility of the results (and thereby the care of future
patients).

CTTI recommends that quality be built into the scientific and operational design
and conduct of clinical trials (“quality by design”) as follows:

1. Create a culture that values and rewards critical thinking and open
   dialogue about quality, and that goes beyond sole reliance on tools and
   checklists.
   Encourage proactive dialogue about what is critical to quality for a particular
   trial or development program and, when needed, the development of
   innovative methods for ensuring quality. Discourage overreliance on
   checklists and inflexible “one size fits all” approaches that undermine creation
   of specific strategies and actions intended to effectively and efficiently support
   quality in a given study. Verify that quality and performance measures are
   aligned with incentives driving a culture that rewards critical thinking. For
   example, rewarding study teams who minimize the time to first patient
   enrolled may serve as a disincentive to devoting time to identifying and
   preventing errors that matter through trial design.
2. Focus effort on activities that are essential to the credibility of the study
   outcomes.
   Rigorously evaluate study design to verify that planned activities and data
   collection are essential. Streamline trial design wherever feasible. Similarly,
   deploy resources to identify and prevent or control errors that matter in the
   study; in other words, determine those study activities that are essential to
   ensure the safety of trial participants and the credibility of key study results.
   Consider whether nonessential activities may be eliminated from the study to
   simplify conduct, improve trial efficiency, and target resources to most critical
   areas.
3. Involve the broad range of stakeholders in protocol development and
   discussions around study quality.
   Engaging all stakeholders with study development is an important feature of
   quality by design. The process of building quality into the study plan may be
   informed not only by the sponsor organization but also by participation of
   those directly involved in successful completion of the study such as clinical investigators, study coordinators and other site staff, and patients. Clinical
   investigators and potential trial participants have valuable insights into the
   feasibility of enrolling patients who meet proposed eligibility criteria, whether
   scheduled study visits and procedures may be overly burdensome and lead
   to early dropouts, and the general relevance of study endpoints to the
   targeted patient population. When a study has novel features in elements
   considered critical to quality (e.g., defining patient populations, procedures, or
   endpoints), early engagement with regulators should also be considered.
4. Prospectively identify and periodically review the critical to quality
   factors.
   The CTTI Quality by Design Principles Document and Toolkit can be used to
   identify those aspects in each study that are critical to generating reliable data
   and providing appropriate protections for research participants (“critical to
   quality factors”), and to develop strategies and actions to effectively and
   efficiently support quality in these critical areas. For example, in a
   cardiovascular major morbidity outcomes trial, strategies to ensure that the
   survival status of all trial participants is captured would be critical, but source
   verifying participants’ temperature readings obtained as a part of vital sign
   assessments at routine study visits is unlikely to be considered critical to the
   successful outcome of the study. In addition, because new or unanticipated
   issues may arise once the study has begun, it is important to periodically
   review critical to quality factors to determine whether adjustments to risk
   control mechanisms are needed.

• These recommendations are based on results from CTTI’s QbD Project.
• CTTI’s Executive Committee approved the recommendations.
• Released in June 2015