BACKGROUND: Trial informativeness describes the likelihood of a clinical trial to have a meaningful impact on clinical practice, research, or policy decisions. A dedicated scientific review process for protocols at the post-funding stage is not common, yet is an opportunity to enhance trial informativeness. The Bill and Melinda Gates Foundation (BMGF), one of the largest funders of clinical trials, created a group called Design, Analyze, Communicate (DAC). DAC's first completion of an expert scientific review of a grantee's trial protocol was in 2020. We categorized and quantified areas of scientific review feedback provided for 52 clinical trial protocols submitted to DAC over a 3-year period. Most trials planned to study treatment interventions and included at least one trial site in a low- and middle-income country. Feedback themes offer insight into areas of trial design weakness. METHODS: We conducted a retrospective analysis of protocol review feedback provided by DAC to grantees. Reviews were completed by BMGF between 2020 and 2022. A qualitative content analysis was conducted by developing a codebook of clinical trial methodology topics and subtopics and systematically coding free-text review feedback. Manual text classification of individual feedback statements enabled quantification and frequency analysis of review feedback. RESULTS: A total of 1537 individual recommendations were made across all 52 protocols. The median number of recommendations per protocol was 28 (range: 13 to 52), covering a wide range of issues related to clinical trial design, implementation, analysis, and impact. Nearly half of all recommendations (47%) were characterized by the review team as high priority. The areas with the highest frequency of recommendations were statistics and data analysis, trial procedures, and intervention/dose. CONCLUSIONS: This study provides a taxonomy of scientific review feedback topic areas that can be used to categorize clinical trial design topics. The high number of recommendations per protocol review across several distinct topic areas highlights the need for a scientific review to enhance trial informativeness. This review must take place prior to trial initiation and review teams should include statistical and trial design expertise with additional expertise tailored to the trial/intervention type and phase.