FDA gives draft adjuvant trial guidance for RCC, bladder cancer

Two new draft guidances from the US Food and Drug Administration give investigators a roadmap for clinical trials of adjuvant drug or biologic therapy for two common cancers. The first of the guidances released on 1 October addresses adjuvant treatment for bladder cancer, and the other addresses adjuvant treatment of renal cell carcinoma (RCC).
 
“Currently, there is significant variability in the design, conduct, and analysis of clinical trials” that examine adjuvant treatment for renal cell carcinoma and bladder cancer, said Richard Pazdur, MD, director of FDA’s Oncology Center of Excellence in a press statement announcing the new draft guidances. “This variability negatively affects our ability to interpret trial results. Researchers need a consistent approach to eligibility criteria and imaging disease assessments to improve trials designed to facilitate development of therapies,” said Pazdur.
 
Once finalized, said Pazdur, the guidances “will assist researchers with recommendations on trial eligibility criteria, standardized imaging assessments, and determining disease recurrence that will improve interpretation of trial results for patients enrolled in clinical trials for these two cancer types."
 
Parallel elements across the guidances
The two guidances take a similar approach regarding much of the framework for trialing adjuvant drug and biologics treatments of the two diseases. “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,” said Pazdur. The workshop was held in November 2017. (RELATED: FDA finalizes guidance on broader cancer trial eligibility, Regulatory Focus 10 July 2020)
 
Both guidances are focused on trials with disease-free survival (DFS) as the primary efficacy endpoints. Each guidance also recommends that investigators discuss their thoughts regarding an appropriate comparator with FDA before proceeding.
 
For imaging assessments, the study protocol should plan for the same modality to be used for an individual patient for the duration of the trial, and for specifics of imaging be included in the protocol. Initial studies should be completed within 4 weeks of enrollment; the guidance also also recommends a blinded independent central review (BICR) of baseline scans, “to ensure the absence of metastatic disease.” Imaging frequency should be the same across arms to avoid biasing DFS assessment.
 
Guidance regarding the analytic plan for clinical trials is the same in both guidances, with advice to minimize missing data, and to specify both the primary analysis and sensitivity analyses with differen censoring rules to evaluate the impact of missing observations, imaging assessment frequency, and other factors on the results.”
 
The guidances are also parallel in recommendations for how trial results are to be interpreted, including recommendations against interim DFS analysis, in favor of a plan for formal interim analysis of overall survival, and a recognition that many factors in the trial design will factor into the magnitude of DFS improvement FDA expects to see to support approval of the drug or biologic.
 
Renal cell carcinoma-specific elements
Certain aspects of the guidances are disease-specific; for RCC, the guidance recommends that patients with non-clear cell subtypes of RCC be included, though they may need to be studied separately. The guidance also recommends clear documentation of disease stage at time of nephrectomy, and the inclusion of individuals with post-operative microscopically positive margins but no gross evidence of disease be included, if the trial arms are balanced for those considered to be at high risk of recurrence.
 
Patients who have had both radical and partial nephrectomy should be included. However, for RCC, the draft guidance recommends excluding patients with residual or recurrent malignant disease be excluded from the adjuvant therapy trials.
 
The RCC guidance also gives disease-specific criteria for determination of disease recurrence, including using biopsy to support imaging findings, when possible; and ensuring that a definition of disease recurrence takes into account localized disease as well as “overtly metastatic disease.”
 
Bladder cancer-specific elements
For bladder cancer, the guidance recommends including patients with predominant urothelial carcinoma (UC) histology, even if they have a component of variant histology, though a subgroup analysis may be required for this population. Patients with a completely non-UC histology, if included, should have their data analyzed separately.
 
The guidance recommends including patients with invasive upper-tract UC. If a trial includes patients who received neoadjuvant therapy, trialists should ensure that those patients received consensus guideline-based neoadjuvant therapy. The guidance also recommends pre-specification of criteria that define cisplatin ineligibility with specific parameters for performance and renal status, hearing loss, neuropathy and heart failure.
 
The bladder cancer guidance also gives disease-specific recommendations regarding when to biopsy suspicious lesions and how to handle patients in whom biopsy may not be safe or feasible.
 
RCC adjuvant therapy guidance
Bladder cancer adjuvant therapy guidance