NIH Grant Awards as a Metric of Clinical and Translational Research Training Effectiveness

The number of clinical research training programs has increased over the past 5–10 years, but few studies have quantitatively evaluated the effectiveness of these programs. The goal of this study was to evaluate the clinical and translational research training program at the University of Cincinnati by comparing the number of National Institutes of Health grants awarded to pediatric fellows who graduated from the MS degree program between 1995 and 2013 versus fellows who did not pursue an MS degree. Among 394 pediatric fellows, 16 of 81 (20%) MS alumni were awarded at least one NIH grant, as compared with 28 of 313 (9%) fellows who did not obtain an MS degree (p < 0.02). In multivariable analysis, MS alumni were more than three times as likely to have received at least one grant than were non‐MS fellows (OR = 3.5, 95% CI [1.7–7.2]; C‐statistic = 0.71) and MS alumni were more likely to obtain at least one K‐series (OR = 4.1, 95% CI [1.6–10.2]; C‐statistic = 0.74), M‐series (OR = 11.8, 95% CI [3.4–41.4]; C‐statistic = 0.81), or R‐series (OR = 10.1, 95% CI [2.4–42.8]; C‐statistic = 0.74) grant than were non‐MS fellows. These findings suggest that graduate training in clinical and translational research prepares graduates for the highly competitive field of clinical and translational research.     

Mentoring in Clinical‐Translational Research: A Study of Participants in Master's Degree Programs

Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of master''s‐level trainees in clinical‐translational research training programs. A cross‐sectional online survey of recent graduates of clinical research master''s program was conducted. Of 73 surveys distributed, 56.2% (n = 41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master''s programs and the impact it had on their professional development. Overall the majority (≥75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical‐translational research. Fewer trainees perceived effective mentoring in career development and work‐life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with ≥2 mentors compared to those with solo mentoring (SM). In addition, trainees with ≥2 mentors perceived having effective mentoring in more mentoring aspects (median: 14.0; IQR: 12.0–15.0) than trainees with SM (median: 10.5; IQR: 8.0–14.5). Results from this survey suggest having ≥2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical‐translational training.     

Designing and Implementing INTREPID,an Intensive Program in Translational Research Methodologies for New Investigators

Senior housestaff and junior faculty are often expected to perform clinical research, yet may not always have the requisite knowledge and skills to do so successfully. Formal degree programs provide such knowledge, but require a significant commitment of time and money. Short‐term training programs (days to weeks) provide alternative ways to accrue essential information and acquire fundamental methodological skills. Unfortunately, published information about short‐term programs is sparse. To encourage discussion and exchange of ideas regarding such programs, we here share our experience developing and implementing INtensive Training in Research Statistics, Ethics, and Protocol Informatics and Design (INTREPID), a 24‐day immersion training program in clinical research methodologies. Designing, planning, and offering INTREPID was feasible, and required significant faculty commitment, support personnel and infrastructure, as well as committed trainees.     

Association of Learning Styles with Research Self‐Efficacy: Study of Short‐Term Research Training Program for Medical Students

Purpose

With a growing need for developing future physician scientists, identifying characteristics of medical students who are likely to benefit from research training programs is important. This study assessed if specific learning styles of medical students, participating in federally funded short‐term research training programs, were associated with research self‐efficacy, a potential predictor of research career success.

Method

Seventy‐five first‐year medical students from 28 medical schools, selected to participate in two competitive NIH‐supported summer programs for research training in aging, completed rating scales to evaluate learning styles at baseline, and research self‐efficacy before and after training. We examined associations of individual learning styles (visual‐verbal, sequential‐global, sensing‐intuitive, and active‐reflective) with students’ gender, ranking of medical school, and research self‐efficacy.

Results

Research self‐efficacy improved significantly following the training programs. Students with a verbal learning style reported significantly greater research self‐efficacy at baseline, while visual, sequential, and intuitive learners demonstrated significantly greater increases in research self‐efficacy from baseline to posttraining. No significant relationships were found between learning styles and students’ gender or ranking of their medical school.

Conclusions

Assessments of learning styles may provide useful information to guide future training endeavors aimed at developing the next generation of physician‐scientists.     

Teaching Translational Research to Medical Students: The New York University School of Medicine's Master's of Science in Clinical Investigation Dual‐Degree Program

To develop the next generation of translational investigators, New York University School of Medicine (NYUSOM) and the NYU‐NYC Health and Hospitals Corporation Clinical and Translational Science Institute (NYU‐HHC CTSI) developed the Master''s of Science in Clinical Investigation dual‐degree (MD/MSCI) program. This 5‐year program dedicates 1 year to coursework and biomedical research, followed by a medical school/research overlap year, to prepare students for academic research careers. This paper details the MD/MSCI program''s curriculum and approach to mentorship, describes the research/professional interests of students, and reports student productivity. In the first 4 years of the program (2010–2014) 20 students were matriculated; 7 (35%) were women, and 12 (60%) research projects were in surgical specialties. To date, 14 students have applied to residency, and half pursued surgical residency programs. Our students have produced 68 accepted abstracts, 15 abstracts in submission, 38 accepted papers, and 24 papers in submission. Despite the time‐limited nature of this program, additional training in research design and implementation has promoted a high level of productivity. We conclude that dual‐degree training in medicine and translational research is feasible for medical students and allows for meaningful participation in valuable projects. Follow‐up is warranted to evaluate the academic trajectory of these students.     

Rigor and reproducibility training for first year medical students in research pathways

AbstractIn the Spring of 2020, we launched a rigor and reproducibility curriculum for medical students in research training programs. This required class consisted of eight, 2‐h sessions, which transitioned to remote learning in response to the coronavirus disease 2019 (COVID‐19) epidemic. The class was graded as pass/fail. Flipped classroom techniques, with multiple hands‐on exercises, were developed for first‐year medical students (MD/PhD [n = 9], Clinical and Translational Research Pathway (CTRP) students [n = 9]). Four focus groups (n = 13 students) and individual interviews with the two instructors were conducted in May 2020. From individual interviews with instructors and focus groups with medical students, the course and its components were favorably reviewed. Students thought the course was novel, important, relevant, and practical—and teaching strategies were effective (e.g., short lectures, interactive small group exercises, and projects). Most students expressed concerns about lack of time for course preparation. Sharper focus and streamlining of preparation work may be required. Pre‐ and post‐student self‐assessments of rigor and reproducibility competencies showed average post‐scores ranging from high/moderate to strong understanding (n = 11). We conclude that rigor and reproducibility can be taught to first‐year medical students in research pathways programs in a highly interactive and remote format. Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

The rigor and reproducibility crisis calls for robust training of scientists in best practices for enhancing the research rigor.

• WHAT QUESTION DID THIS STUDY ADDRESS?

We evaluated a curriculum to develop physician‐scientists skilled at documenting research workflow from idea generation to publication with reproducibility in mind.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Highly interactive exercises, coupled with a hands‐on replication group project provide a pathway for students to gain competencies important to the improvement of rigor and reproducibility in scientific research. Rigor and reproducibility can be taught in a highly interactive format and using a remote format.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Formal training is needed to raise awareness of the reproducibility crisis and improve the rigor of research conducted. If techniques taught are used, the transparency and reproducibility of clinical and translational science will be improved.     

Building Leadership among Laboratory‐Based and Clinical and Translational Researchers: The University of California,San Francisco Experience

In 2005 the University of California, San Francisco (UCSF) implemented the Scientific Leadership and Management (SLM) course, a 2‐day leadership training program to assist laboratory‐based postdoctoral scholars in their transition to independent researchers managing their own research programs. In 2011, the course was expanded to clinical and translational junior faculty and fellows. The course enrollment was increased from approximate 100 to 123 participants at the same time. Based on course evaluations, the number and percent of women participants appears to have increased over time from 40% (n = 33) in 2007 to 53% (n = 58) in 2011. Course evaluations also indicated that participants found the course to be relevant and valuable in their transition to academic leadership. This paper describes the background, structure, and content of the SLM and reports on participant evaluations of the course offerings from 2007 through 2011.     

The Rockefeller University Graduate Tracking Survey System

Background

It is essential to track the careers and accomplishments of the graduates of translational research training programs to assess the impact of the programs and to improve them. The major obstacle is the lack of a convenient method to collect the information in a comprehensive and standardized manner.

Methods

We have developed a Web‐based electronic Graduate Tracking Survey System (GTSS) that prepopulates the graduate''s information on publications, grants, patents, and clinical trials from public data sources, thus insuring a uniform data format, facilitating survey completion, and facilitating the aggregation of data at individual or multiple sites. GTSS questions are designed to assess whether trainees make important contributions that improve human health, and to track related “surrogate” career development indicators of likely future success.

Results

The GTSS has been in use at Rockefeller University since 2011 and has been adopted by 21 other Clinical and Translational Science Award programs.

Conclusions

The GTSS provides an efficient and convenient mechanism to track the graduates of a wide variety of training programs. It has the potential to aggregate standardized data across institutions, thus providing benchmarks for the assessment of individual training programs and data for program improvement.     

Impact of Professional Student Mentored Research Fellowship on Medical Education and Academic Medicine Career Path

Context

This study explores the long‐term impact of the Professional Student Mentored Research Fellowship (PSMRF) program at the University of Kentucky College of Medicine (UKCOM) on medical students’ research productivity and career paths.

Methods

Demographic characteristics, academic profiles, number of publications and residency placements from 2007 to 2012 were used to assess 119 PSMRF graduates against a comparison cohort of 898 UKCOM (non‐PSMRF) students.

Results

PSMRF students had higher MCAT scores at admission (31.5 ± 0.6 vs. 30.6 ± 0.2, p = 0.007) and achieved higher USMLE Step 1 scores (228 ± 4.2 vs. 223 ± 1.5, p = 0.03) than comparison group. PSMRF students were more likely to publish PubMed‐indexed papers (36.7% vs. 17.9%, p < 0.0001), achieve AOA status (19.3% vs. 8.5%, p = 0.0002) and match to top 25 US News and World Report residency programs (23.4% vs. 12.1%, p = 0.008). A greater proportion of PSMRF fellows matched to top tier competitive specialties (23% vs. 14.2%, p = 0.07), however this difference was not statistically significant.

Conclusions

The PSMRF program shows a significant increase in enrollment, as well as positive associations with indicators of success in medical school and subsequent quality of residency program.     

Summer Research Training for Medical Students: Impact on Research Self‐Efficacy

There is a well‐documented shortage of physician researchers, and numerous training programs have been launched to facilitate development of new physician scientists. Short‐term research training programs are the most practical form of research exposure for most medical students, and the summer between their first and second years of medical school is generally the longest period they can devote solely to research. The goal of short‐term training programs is to whet the students’ appetite for research and spark their interest in the field. Relatively little research has been done to test the effectiveness of short‐term research training programs. In an effort to examine short‐term effects of three different NIH‐funded summer research training programs for medical students, we assessed the trainees’ (N = 75) research self‐efficacy prior to and after the programs using an 11‐item scale. These hands‐on training programs combined experiential, didactic, and mentoring elements. The students demonstrated a significant increase in their self‐efficacy for research. Trainees’ gender, ranking of their school, type of research, and specific content of research project did not predict improvement. Effect sizes for different types of items on the scale varied, with the largest gain seen in research methodology and communication of study findings.     

From Genes to Community: Exploring Translational Science in Adolescent Health Research: Proceedings from a Research Symposium

Addressing complex adolescent health problems such as youth violence and teen pregnancy requires innovative strategies to promote protective social environments, increase healthier behaviors, and reduce the impact of health risk behaviors into adulthood. Multilevel, interdisciplinary, and translational approaches are needed to address these challenges in adolescent health. In May 2012, a group of adolescent health researchers participated in a 1‐day research symposium titled “From Genes to Community: Exploring Translational Science in Adolescent Health Research,” sponsored by the Clinical and Translational Science Institute (CTSI) of the University of Pittsburgh and the Division of Adolescent Medicine, Children''s Hospital of Pittsburgh of the University of Pittsburgh Medical Center. The research symposium offered opportunities for adolescent health researchers to share examples of translational research as well as to identify potential collaborations to promote translational research. This and subsequent issues of Clinical and Translational Science will include papers from this symposium. The studies and reviews presented range from how basic biobehavioral sciences such as functional neuroimaging and decision science can be made relevant for intervention development as well as improving strategies for community‐partnered knowledge transfer of cutting‐edge research findings to promote adolescent health and well‐being. Clin Trans Sci 2012; Volume 5: 480–481     

Training the Next Generation of Research Mentors: The University of California,San Francisco,Clinical & Translational Science Institute Mentor Development Program

Mentoring is a critical component of career development and success for clinical translational science research faculty. Yet few programs train faculty in mentoring skills. We describe outcomes from the first two faculty cohorts who completed a Mentor Development Program (MDP) at UCSF. Eligibility includes having dedicated research time, expertise in a scientific area and a desire to be a lead research mentor. A post‐MDP survey measured the program''s impact on enhancement of five key mentoring skills, change in the Mentors‐in‐Training (MIT) self‐rated importance of being a mentor to their career satisfaction, and overall confidence in their mentoring skills. Since 2007, 29 MITs participated in and 26 completed the MDP. Only 15% of the MITs reported any previous mentor training. Overall, 96% of MITs felt that participation in the MDP helped them to become better mentors. A majority reported a significant increase in confidence in mentoring skills and most reported an increased understanding of important mentoring issues at UCSF. MITs reported increased confidence in overall and specific mentoring skills after completion of the MDP. The MDP can serve as a model for other institutions to develop the next generation of clinical‐translational research mentors.     

Research Participant‐Centered Outcomes at NIH‐Supported Clinical Research Centers

Background

Although research participation is essential for clinical investigation, few quantitative outcome measures exist to assess participants’ experiences. To address this, we developed and deployed a survey at 15 NIH‐supported clinical research centers to assess participant‐centered outcomes; we report responses from 4,961 participants.

Methods

Survey questions addressed core aspects of the research participants’ experience, including their overall rating, motivation, trust, and informed consent. We describe participant characteristics, responses to individual questions, and correlations among responses.

Results

Respondents broadly represented the research population in sex, race, and ethnicity. Seventy‐three percent awarded top ratings to their overall research experience and 94% reported no pressure to enroll. Top ratings correlated with feeling treated with respect, listened to, and having access to the research team (R ² = 0.80–0.96). White participants trusted researchers more (88%) than did nonwhite participants collectively (80%; p < 0.0001). Many participants felt fully prepared by the informed consent process (67%) and wanted to receive research results (72%).

Conclusions

Our survey demonstrates that a majority of participants at NIH‐supported clinical research centers rate their research experience very positively and that participant‐centered outcome measures identify actionable items for improvement of participant''s experiences, research protections, and the conduct of clinical investigation.     

Perceptions of Pediatric Emergency Medicine Fellows and Program Directors about Research Education

Pediatric emergency medicine (PEM) fellows who entered training after January 1995 are required to complete three years of fellowship training. Additionally, they are required to receive instruction in related basic sciences and to demonstrate research competence. OBJECTIVES: To determine: 1) whether PEM fellows and program directors perceive their programs as providing adequate training in research principles, 2) the manner in which these principles are taught, and 3) the commitment of fellows and program directors to research and research training. METHODS: Pediatric emergency medicine fellows who participated in the Fourth Annual PEM Fellows Conference (Miami, Florida, March 1997) were surveyed. The survey was then extended via mail to all PEM fellows and program directors in the United States and Canada. RESULTS: A total of 159 of the 220 fellows (72%) in the United States and Canada returned completed questionnaires. Fifty-three of 70 PEM fellows (76%) who attended the conference completed questionnaires, and 106 of 167 fellows (63%) who did not attend the conference responded by mail. Fifty-three of the 63 program directors (84%) returned completed questionnaires. Of 159 responding fellows, 86 (54%), and of 53 responding program directors, 29 (58%) reported that their programs lacked adequate training in one or more of the surveyed research areas. Thirteen program directors (25%) reported no formal research training in their curricula. Programs that included formal research training were perceived to have higher overall quality than programs that failed to offer such formal training. Sixty-six of 158 responding fellows (42%) anticipated an ongoing commitment to research in their careers. One hundred fourteen of 153 responding fellows (75%) indicated that, if given the option, they would have pursued a two-year "clinical track" PEM board certification that did not include a research requirement. CONCLUSIONS: More than half of surveyed PEM fellows and program directors perceived important deficiencies in research education within their training programs. Further research is necessary in order to evaluate the validity of these perceptions.     

Pharmacokinetic/pharmacodynamic modeling for dose selection for the first‐in‐human trial of the activated Factor XII inhibitor garadacimab (CSL312)

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein–kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first‐in‐class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first‐in‐human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose‐related PD effects were observed (e.g., a mechanism‐based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically‐based pharmacokinetic (mPBPK) models with target‐mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa‐mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Models based on physiology and mechanisms of action can be highly useful in translating pharmacokinetic/pharmacodynamic (PK/PD) data from animal studies to expectations in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This analysis sought to select doses for investigation in a phase I, first‐in‐human trial of garadacimab (CSL312), a first‐in‐class, fully human, immunoglobulin G4 monoclonal antibody that targets FXIIa.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This analysis demonstrated how a mechanism‐based PK/PD model describing the relationship between drug administration and pharmacologic response observed in cynomolgus monkeys was generated and extrapolated to select doses for investigation in a phase I, first‐in‐human trial of garadacimab. The detailed explanation of the modeling and extrapolation methodology used in this study provides guidance to future researchers selecting doses for phase I, first‐in‐human trials of monoclonal antibodies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This study highlights the importance and utility of insightful, physiologic, and mechanistic mathematical modeling in conjunction with robust animal data for translation of PK/PD and accurate prediction of first‐in‐human dosing for clinical trials.     

从护理论文发表现状认识护理本科生科研能力的培养

目的通过对临床本科护士科研能力、积极性和近年来护理论文撰写和发表现状的回顾,探析导致本科护士科研能力不强的相关因素和培养方法。方法调查1999—2003年毕业于原上海第二医科大学护理系87名本科护士的个人自身发展需求、论文撰写和发表情况;分析2001—2003年刊登于国内3种核心护理期刊的571篇护理论著。结果在68名临床本科护士中,将从事护理科研作为自身发展首位意向的为6人（8．82%）;所撰写的护理论著在护理核心期刊的刊出率为11．33%。在回顾的已刊出论著中,属前瞻性研究为38．18%,实验性研究为23．99%;研究样本数小于或等于100例的为57．44%;有统计学处理和描述的为58．67%。结论应通过多途径提高本科护士的科研能力,包括完善护理科研课程体系的建设、适度培养学生的科研能力、提高护理师资科研素质、加强本科护士职后科研能力的培养。     

Provider's Perspectives on Building Research and Quality Improvement Capacity in Primary Care: A Strategy to Improve Workforce Satisfaction

Objectives

Safety‐net populations are underrepresented in research and quality improvement (QI) studies despite the fact that safety‐net providers are uniquely positioned to engage in translational research. This study aimed to understand the current level of interest in, experience with, predicted career satisfaction associated with, and barriers experienced in conducting research and QI among primary care providers (PCPs) at 18 safety‐net practices in the Boston, Massachusetts area.

Methods

The Harvard Catalyst Safety‐net Infrastructure Initiative partnered with staff at a large academic public hospital system, including 15 primary care sites, to develop and administer an online survey. This survey was then adapted and administered at three other academically affiliated community health centers.

Results

Of the 260 providers surveyed, 136 (52%) responded. Nearly 80% reported interest in conducting either QI projects or clinical research and 95% of them believed it would enhance their career satisfaction. However, 63% did not report prior experience or training in research or QI and 93% reported at least one barrier to engagement.

Conclusion

While supporting safety‐net PCPs’ engagement in research and/or QI may improve career satisfaction there are numerous barriers that must be addressed to achieve this goal.     

Partnership‐Driven Resources to Improve and Enhance Research (PRIMER): A Survey of Community‐Engaged Researchers and Creation of an Online Toolkit

Objective: This project aimed to develop an open‐access website providing adaptable resources to facilitate best practices for multisite research from initiation to closeout. Methods: A web‐based assessment was sent to the leadership of the Clinical and Translational Science Award (CTSA) Community Engagement Key Functions Committee (n= 38) and the CTSA‐affiliated Primary Care Practice‐based Research Networks (PBRN, n= 55). Respondents rated the benefits and barriers of multisite research, the utility of available resources, and indicated their level of interest in unavailable resources. Then, existing research resources were evaluated for relevance to multisite research, adaptability to other projects, and source credibility. Results: Fifty‐five (59%) of invited participants completed the survey. Top perceived benefits of multisite research were the ability to conduct community‐relevant research through academic–community partnerships (34%) and accelerating translation of research into practice (31%). Top perceived barriers were lack of research infrastructure to support PBRNs and community partners (31%) and inadequate funding to support multisite collaborations (26%). Over 200 resources were evaluated, of which 120 unique resources were included in the website. Conclusion: The PRIMER Research Toolkit (http://www.researchtoolkit.org) provides an array of peer‐reviewed resources to facilitate translational research for the conduct of multisite studies within PBRNs and community‐based organizations. Clin Trans Sci 2011; Volume 4: 259–265     

Model‐based dose selection to inform translational clinical oncology development of WNT974, a first‐in‐class Porcupine inhibitor

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. The conventional approach for dose selection in small‐molecule oncology trials is based on the maximum tolerated dose (MTD).

• WHAT QUESTION DID THIS STUDY ADDRESS?

How to inform the clinical development path and selection of the recommended dose for expansion (RDE) for a first‐in‐class oncology molecule.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A model‐based approach can be effectively used to integrate pharmacokinetic (PK), pharmacodynamic and safety data and inform RDE selection in oncology drug development.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This model‐based approach integrated population PK and exposure–response analyses of biomarker and safety to determine the RDE, rather than the conventional MTD approach. The strategy can be applied to support translational clinical oncology development, and dose selection in early oncology trials to inform later phase clinical development and study design.