The FDA has issued draft guidance documents for drug and biologic development in the adjuvant treatment of renal cell carcinoma (RCC) and bladder cancer, with recommendations for clinical trials concerning eligibility criteria, methodology, and use of disease-free survival as an end point.
"The FDA has actively encouraged a more uniform approach to developing clinical trials to evaluate adjuvant treatments for renal cell carcinoma and bladder cancer, including hosting a public workshop in partnership with the National Cancer Institute and releasing draft guidances on clinical trial eligibility for these cancer types," stated Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research, in a press release. "Today, we are releasing draft guidances which, if finalized, would provide recommendations on development of adjuvant treatments in patients with renal cell carcinoma and bladder cancer."
"Significant variability exists in the design, conduct, and analysis of trials for the adjuvant treatment of renal cell carcinoma, including the eligibility criteria, radiological disease assessments, the definition of disease recurrence, and the date used to define the disease-free survival end point," state the authors of the RCC draft guidance. "Consistency in these aspects within and across trials may facilitate interpretation of trial results."
The RCC draft guidance includes several trial eligibility criteria recommendations. Patients with non–clear cell RCC subtypes, including those with a sarcomatoid component, should be included in trials, although it may be appropriate to place such patients in a cohort separate from patients with clear cell histologies in order to account for differences in treatment response. In addition, patients with microscopically positive soft tissue or vascular margins without gross residual disease should be included, provided that the clinical trial ensures that the number of patients at high risk of recurrence is balanced between study arms using stratified randomization procedures. Patients who have undergone radical or partial nephrectomy should also be included in trials, whereas patients with residual or recurrent malignant disease should be excluded.
The guidance recommends a blinded independent central review (BICR) of baseline scans prior to study entry in order to ensure that there is no metastatic disease. In addition, the trial protocol should require documentation of tumor stage, nodal and vascular involvement, and the number of lymph nodes sampled at the time of nephrectomy in order to ascertain that eligibility criteria have been met.
The guidance specifies that an appropriate choice of comparator, one consistent with standards of care and with community practice patterns, should be discussed with the FDA prior to the study's initiation.
Regarding imaging assessments, initial imaging studies should be completed within four weeks of trial enrollment. When disease-free survival is used as an end point, the study protocol should specify acceptable methods of imaging acquisition, display, and radiological interpretation technique to be used in its determination. Imaging assessment frequency should be the same across all treatment arms to avoid biasing the assessment of disease-free survival.
In assessing disease-free survival, the definition of disease recurrence should address the development of localized disease in the absence of overtly metastatic disease. The determination of disease recurrence should be based on assessment by BICR, with radiological findings suggestive of recurrence supported by tumor biopsies to confirm malignant disease whenever possible. In case biopsy is not possible, the radiological definition of recurrence by site should be prespecified. The algorithm for assigning date of recurrence should also be prespecified and should be applied with consistency.
Importantly, interim analyses of disease-free survival are not recommended, as immature data can misrepresent the magnitude of improvement.
Similar to the RCC guidance, the bladder cancer guidance was written to address "significant variability… in the design, conduct, and analysis of trials for the adjuvant treatment of bladder cancer."
Regarding eligibility, patients with predominant urothelial carcinoma (UC) histology and a component of variant histology should be included, with subset analyses performed if enough patients with a component of variant histology are enrolled in the trial. Patients with purely non-UC histology, such as those with mixed endocrine or small cell tumors, should be analyzed separately if they are included in the trial. Patients with microscopically positive margins without gross residual disease should be included, provided that the trial ensures that the number of patients at high risk of recurrence is balanced between study arms using stratified randomization procedures. Patients with invasive upper-tract UC should be included in trials. Patients with residual or recurrent malignant disease should be excluded.
A BICR of baseline scans prior to study entry is recommended to ensure that there is no metastatic disease. The study protocol should require documentation of tumor stage, grade, extent, and number of lymph nodes sampled at the time of cystectomy to ensure that eligibility criteria have been met.
If the trial protocol permits enrollment of patients who received neoadjuvant therapy prior to study entry, criteria should ensure that the neoadjuvant therapy that patients received is consistent with standard-of-care treatment. Eligibility criteria for those who received neoadjuvant treatment that was not consistent with current consensus guidelines should be based on post-cystectomy pathologic stage and prespecified in the protocol.
Eligibility criteria defining cisplatin ineligibility should be prespecified, including Eastern Cooperative Oncology Group (ECOG) performance status of 2, creatinine clearance under 60 mL/min, hearing loss of grade 2 or higher, neuropathy of grade 2 or higher, or New York Heart Association (NYHA) class III heart failure.
The bladder cancer guidance contains similar recommendations to the RCC guidance regarding the choice of comparator, protocol regarding imaging studies, and criteria and methodology for determining disease recurrence.
"New high-grade non–muscle-invasive tumors and all new muscle-invasive bladder cancer tumors that develop in the remaining urothelium following resection should be disease-free-survival–defining events," write the authors of the draft guidance. "The designation of all other non–muscle invasive tumors as evidence of disease recurrence should be discussed with the FDA prior to study initiation and prespecified in the protocol."
Trials should specify planned use of urine cytology for post-operative surveillance in patients with remaining urothelium and should specify the test used, testing interval, and endoscopic surveillance procedures.
As in the RCC guidance, the bladder cancer guidance states that interim analyses of disease-free survival are not recommended.
Regarding disease-free survival as an end point, "the trial design (eg, add-on design, active versus placebo control) and conduct, toxicity profile observed, study population, and the overall benefit-risk evaluation all factor into the magnitude of improvement in disease-free survival required to support drug approval," state both the RCC and bladder cancer guidances. "While FDA approval does not require demonstration of an overall survival benefit, the protocol and statistical analysis plan should include a plan for a formal interim analysis of overall survival at the time of final disease-free survival analysis… In addition, FDA expects continued follow-up to allow conduct of the final overall survival analysis."
The FDA guidance documents do not establish legally enforceable responsibilities; they are recommendations but not requirements, except in cases where specific regulatory or statutory requirements are cited. Members of the public can submit comments on the draft guidances for both RCC and bladder cancer until December 1, 2020.
For More Information
US Food & Drug Administration (2020). Renal cell carcinoma: developing drugs and biologics for adjuvant treatment: draft guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/renal-cell-carcinoma-developing-drugs-and-biologics-adjuvant-treatment
US Food & Drug Administration (2020). Bladder cancer: developing drugs and biologics for adjuvant treatment: draft guidance for industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bladder-cancer-developing-drugs-and-biologics-adjuvant-treatment
Image credit: Nephron. Licensed under CC BY-SA 3.0