Development of Treatments for Localized Prostate Cancer in Patients Eligible for Active Surveillance: U.S. Food and Drug Administration Oncology Center of Excellence Public Workshop.

PURPOSE: The following is a summary of discussion at a United States FDA (Food and Drug Administration) public workshop reviewing potential trial designs and end points to develop therapies to treat localized prostate cancer. MATERIALS AND METHODS: The workshop focused on the challenge that drug and device development to treat localized prostate cancer has been limited by the large trial sizes and lengthy timelines required to demonstrate an improvement in overall or metastasis-free survival and by the lack of agreed on alternative end points. Additionally, evolving treatment paradigms in the management of localized prostate cancer include the widespread use of active surveillance of patients with low and some intermediate risk prostate cancer, and the availability of advances in imaging and genomics. RESULTS: The workshop addressed issues related to trial design in this setting. Attendees discussed several potential novel end points such as a delay of morbidity due to radiation or prostatectomy and pathological end points such as Gleason Grade Group upgrade. CONCLUSIONS: The workshop provided an open forum for multiple stakeholder engagement to advance the development of effective treatment options for men with localized prostate cancer.

SPARED Collaboration: Patient Selection for Partial Gland Ablation in Men with Localized Prostate Cancer.

PURPOSE: The SPARED CRN (Study of Prostate Ablation Related Energy Devices Coordinated Registry Network) is a private-public partnership between academic and community urologists, the FDA (U.S. Food and Drug Administration), the Medical Device Epidemiology Network and device manufacturers to examine the safety and effectiveness of technologies for partial gland ablation in men with localized prostate cancer. MATERIALS AND METHODS: We report on a recent workshop at the FDA with thought leaders to discuss a critical framework for partial gland ablation, focusing on patient selection, surgical planning, followup, study design and appropriate comparators in terms of adverse events and cancer control outcomes. We summarize salient points from experts in urology, oncology and epidemiology that were presented and discussed in an open forum. RESULTS: Given the challenges in achieving patient and physician equipoise to perform a randomized trial, as well as an inherent paradigm shift when comparing partial gland ablation (inability to assess prostate specific antigen recurrence) to whole gland treatments, the group focused on objective performance criteria and goals as a platform to guide the creation of single arm studies in the SPARED CRN. CONCLUSIONS: This summit lays the foundation for prospective, multi-center data collection and evaluation of novel medical devices and drug/device combinations for partial gland ablation.

Prostate Ablation Using High Intensity Focused Ultrasound: A Literature Review of the Potential Role for Patient Preference Information.

PURPOSE: The FDA (Food and Drug Administration) recently allowed the marketing of 2 high intensity focused ultrasound devices for prostate tissue ablation indications after previous rejections for a prostate cancer indication due to insufficient data on clinical effectiveness or direct patient benefit. We reviewed the safety and effectiveness of high intensity focused ultrasound and knowledge regarding patient preferences, such as tolerance for adverse events associated with high intensity focused ultrasound ablation of tissue, in men with prostate cancer. This may inform decision making for device developers and the FDA. MATERIALS AND METHODS: We searched PubMed® and gray literature, including FDA reports for relevant data on 1) the safety and effectiveness of primary and salvage high intensity focused ultrasound of localized prostate cancer in studies performed in or outside the United States and 2) patient preference information on high intensity focused ultrasound related safety and effectiveness outcomes. RESULTS: We found no high intensity focused ultrasound effectiveness data relevant to clinical decision making, such as overall or prostate cancer specific survival, in the United States. Long-term effectiveness data from outside the United States were sparse and outcomes varied. We also found no patient preference data on high intensity focused ultrasound treatment in men with prostate cancer. CONCLUSIONS: The lack of long-term high intensity focused ultrasound oncological data in an American population has brought new challenges to prostate cancer stakeholders, including clinicians, patients and the FDA. Patient preference information from future patient studies on high intensity focused ultrasound could provide additional information to patients, clinicians, and current and prospective device developers. In addition, it can be used by regulators in benefit-risk evaluations of this class of treatment devices.

Development of a Nationally Representative Coordinated Registry Network for Prostate Ablation Technologies.

PURPOSE: The accumulation of data through a prospective, multicenter coordinated registry network is a practical way to gather real world evidence on the performance of novel prostate ablation technologies. Urological oncologists, targeted biopsy experts, industry representatives and representatives of the FDA (Food and Drug Administration) convened to discuss the role, feasibility and important data elements of a coordinated registry network to assess new and existing prostate ablation technologies. MATERIALS AND METHODS: A multiround Delphi consensus approach was performed which included the opinion of 15 expert urologists, representatives of the FDA and leadership from high intensity focused ultrasound device manufacturers. Stakeholders provided input in 3 consecutive rounds with conference calls following each round to obtain consensus on remaining items. Participants agreed that these elements initially developed for high intensity focused ultrasound are compatible with other prostate ablation technologies. Coordinated registry network elements were reviewed and supplemented with data elements from the FDA common study metrics. RESULTS: The working group reached consensus on capturing specific patient demographics, treatment details, oncologic outcomes, functional outcomes and complications. Validated health related quality of life questionnaires were selected to capture patient reported outcomes, including the IIEF-5 (International Index of Erectile Function-5), the I-PSS (International Prostate Symptom Score), the EPIC-26 (Expanded Prostate Cancer Index Composite-26) and the MSHQ-EjD (Male Sexual Health Questionnaire for Ejaculatory Dysfunction). Group consensus was to obtain followup multiparametric magnetic resonance imaging and prostate biopsy approximately 12 months after ablation with additional imaging or biopsy performed as clinically indicated. CONCLUSIONS: A national prostate ablation coordinated registry network brings forth vital practice pattern and outcomes data for this emerging treatment paradigm in the United States. Our multiple stakeholder consensus identifies critical elements to evaluate new and existing energy modalities and devices.

Patient Preferences for Benefit and Risk Associated With High Intensity Focused Ultrasound for the Ablation of Prostate Tissue in Men With Localized Prostate Cancer.

INTRODUCTION: Food and Drug Administration must make decisions about emerging high intensity focused ultrasound (HIFU) devices that may lack relevant clinical oncologic data but present with known side effects. This study aims to capture patients' perspective by quantifying their preferences regarding the available benefit and important side effects associated with HIFU for localized prostate cancer. MATERIALS AND METHODS: Preferences for HIFU outcomes were examined using a discrete choice experiment survey. Participants were asked to choose a preferred treatment option in 9 choice questions. Each included a pair of hypothetical treatment profiles that have similar attributes/outcomes with varying levels. Outcomes included prostate biopsy outcome and treatment-related risks of erectile dysfunction (ED) and urinary incontinence (UI). We calculated the maximum risk of side effect patients were willing to tolerate in exchange for increased benefit. Preferences were further explored via clinical and demographic data. RESULTS: About 223 subjects with a mean age of 64.8 years completed the survey. Respondents were willing to accept a 1.51%-point increase in new ED risk for a 1%-point increase in favorable biopsy outcome. They were also willing to accept a 0.93%-point increase in new UI risk for a 1%-point increase in biopsy outcome. Subjects who perceived their cancer to be more aggressive had higher risk tolerance for UI. Younger men were willing to tolerate less ED risk than older men. Respondents with greater than college level of education had a lower risk tolerance for ED or UI. CONCLUSIONS: Results may inform development and regulatory evaluation for future HIFU ablation devices by providing supplemental information from the patient perspective.

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC. OBJECTIVE: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies. METHODS: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment. RESULTS: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure. CONCLUSIONS: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.

Development and Usability Testing of a Mobile Application to Monitor Patient-Reported Outcomes after Stress Urinary Incontinence Surgery.

OBJECTIVE: To develop and perform a usability testing of a mobile application (app) with representative users of surgeons and female patients undergoing stress urinary incontinence (SUI) surgery. METHODS: A mobile app was developed with the Medical Device Epidemiology Network (MDEpiNet) High-Performance Integrated Virtual Environment (HIVE) to streamline the collection of patient-reported outcomes following SUI surgery using validated questionnaires. It was designed as a collaborative effort with the Women's Health Initiative (WHI), including patient and surgeon involvement. The app evaluation questions addressed the user's rating on the clarity and length of the questions and the comfort level in using the interface for patients to report post-operative outcomes and surgeons to review them. RESULTS: A total of twenty patients and 5 surgeons tested the mobile app and reported their experience and level of satisfaction. The average patient experience score was 9 out of ten, with ten being the best. Eleven patients (55%) were interested in replacing in-person follow-up visits with the app. The surgeons reported an average user experience score of 8.6 out of ten. Four surgeons (80%) were interested in replacing in-person visits with the app. The combined experience score between all users was 8.9 out of ten. Fifteen out of twenty-five users (60%) showed interest in replacing in-person visits with the app. CONCLUSION: The mobile app for SUI captured important patient-reported outcomes with a high satisfaction reporting from patients and surgeons.

Advancing the Real-World Evidence for Medical Devices through Coordinated Registry Networks.

Objectives: Generating and using real-world evidence (RWE) is a pragmatic solution for evaluating health technologies. RWE is recognized by regulators, health technology assessors, clinicians, and manufacturers as a valid source of information to support their decision-making. Well-designed registries can provide RWE and become more powerful when linked with electronic health records and administrative databases in coordinated registry networks (CRNs). Our objective was to create a framework of maturity of CRNs and registries, so guiding their development and the prioritization of funding. Design setting and participants: We invited 52 stakeholders from diverse backgrounds including patient advocacy groups, academic, clinical, industry and regulatory experts to participate on a Delphi survey. Of those invited, 42 participated in the survey to provide feedback on the maturity framework for CRNs and registries. An expert panel reviewed the responses to refine the framework until the target consensus of 80% was reached. Two rounds of the Delphi were distributed via Qualtrics online platform from July to August 2020 and from October to November 2020. Main outcome measures: Consensus on the maturity framework for CRNs and registries consisted of seven domains (unique device identification, efficient data collection, data quality, product life cycle approach, governance and sustainability, quality improvement, and patient-reported outcomes), each presented with five levels of maturity. Results: Of 52 invited experts, 41 (79.9%) responded to round 1; all 41 responded to round 2; and consensus was reached for most domains. The expert panel resolved the disagreements and final consensus estimates ranged from 80.5% to 92.7% for seven domains. Conclusions: We have developed a robust framework to assess the maturity of any CRN (or registry) to provide reliable RWE. This framework will promote harmonization of approaches to RWE generation across different disciplines and health systems. The domains and their levels may evolve over time as new solutions become available.