Abstract P5-19-03: What are the barriers to assessment of ovarian toxicity in breast cancer clinical trials?
Authors: Cui Wanyuan , Phillips Kelly-Anne , Francis Prudence A , Loi Sherene , Anderson Richard A , Partridge Ann H , Keogh Louise A 
Published: March 2022

Abstract
Background Toxicity data are routinely collected in phase 3 (neo)adjuvant breast cancer (BC) clinical trials, but ovarian toxicity is infrequently assessed, despite its impact on fertility and long-term health. Thus, little is known about the ovarian effects of newer BC therapies. This results in an information gap for women when making treatment decisions. We explored the barriers to collecting ovarian toxicity data and/or including ovarian function as an endpoint in BC trials of anti-cancer drugs. Methods Semi structured interviews were conducted with key stakeholders involved in BC clinical trials (clinicians, consumers, pharmaceutical companies, drug regulatory advisors). Participants were asked detailed questions about how trial endpoints are selected, whether effects on the ovary are assessed, and barriers to and benefits of collecting ovarian function data to assess ovarian toxicity. Interviews were transcribed verbatim, coded in NVivo software and analysed using inductive thematic analysis. Results Saturation was reached after 25 interviews (9 clinicians, 7 consumers, 5 drug regulatory advisors, 4 pharmaceutical company advisors); half were female. Participants were from North America (20%), Europe (52%), Australia (24%), Asia (4%). Median age was 50 years and median time in breast cancer research or drug regulation was 16 years. The main reported barrier to the collection of ovarian toxicity data in clinical trials was that this issue was rarely considered. Reasons included that these data are considered less important than survival data and are not required for regulatory approval. Other barriers included limited resources, lack of knowledge regarding how to assess ovarian side effects and lack of relevance in certain settings (further detail in Table 1). Most participants believed assessing ovarian toxicity in trials would be beneficial to clinicians and to patients (eg. assisting treatment and family planning decisions). Strategies to increase ovarian toxicity assessment included its inclusion in clinical trial design guidelines, improving familiarity with ovarian function markers among trial design decision makers, and increased stakeholder interest. A stronger consumer voice and regulatory and clinician advocacy were regarded as important. Regarding trial endpoint selection, pharmaceutical companies were almost always identified as the main decision maker, but clinicians including cooperative trial group researchers, consumers, regulators, and statisticians were also important contributors. While most consumers and pharmaceutical company advisors felt clinicians and consumers influenced trial design, in contrast, some clinicians and regulators reported consumers and clinicians had little influence. Factors identified as important considerations in determining trial endpoints included the main goal of the trial (eg. regulatory approval), established standardised endpoints, resources, and the investigational agent studied. All pharmaceutical advisors reported that meeting the requirements for regulatory approval was the major factor considered during endpoint selection. Conclusion This qualitative analysis evaluates the barriers to including measures of ovarian function in BC clinical trials. Increased awareness, stronger advocacy and guidelines might lead to more frequent inclusion of this important endpoint in future trials that include premenopausal women with early BC.
Table 1.Emergent themes regarding ovarian toxicity assessment in BC trialsThemeDomainCategory 1: Barriers to assessment of ovarian function Not prioritisedNot discussed or thought about;Not the primary question studied by clinical trial;Less important than other endpoints/data;Not required for regulatory approval;Data not related to survival is infrequently published;More appropriate for a follow up/registry studyToo resource intensive A burden on investigators and patients;Difficult to collect good quality data;Assessment not considered feasible;Time to obtaining results too long;Too costlyLack of knowledgeLack of clinician knowledge regarding ovarian function side effects;Lack of consensus regarding which markers to assess;Lack of preclinical data suggestive of ovarian toxicityData not relevant in certain settingsConcurrent use of gonadotoxic chemotherapy;Trials mandate contraception use;Want to suppress ovarian function in some breast cancer phenotypes;Low numbers of premenopausal women enrolled;Investigational agent already known to cause ovarian toxicity/suppressionCategory 2: Perceived benefits of assessing ovarian function Data important to patientsImproved ability to make informed cancer treatment decisions;Improved ability to make fertility and ovarian preservation decisions;Infertility and early menopause are relevant and important to patients;Preservation of ovarian function is important for quality of life;To avoid potential harm to patientsData important to cliniciansImproved ability to counsel patients;Improved understanding of the investigational agent;Improved understanding of the impact of ovarian function on disease outcomes;Holistic understanding of a patient’s experience on treatment;Prospective information is more robust than retrospective dataCategory 3: Strategies to improve inclusionIncreased stakeholder interestIncreased clinician advocacy;Increased consumer voice;Increased regulatory buy in;Increased cooperative trial group interest;Increased reproductive specialist involvement;Increased pharmaceutical company interestIncreased awareness regarding ovarian function and onco-fertilityTrial design guidelines and recommendations;Increased discussion and education;Improved familiarity with ovarian markers and ease of incorporation/collection;Use of social media and internet resources
Citation Format: Wanyuan Cui, Kelly-Anne Phillips, Prudence A Francis, Sherene Loi, Richard A Anderson, Ann H Partridge, Louise A Keogh. What are the barriers to assessment of ovarian toxicity in breast cancer clinical trials? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-19-03.