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Abstract
- Clinical Trials as Topic
- Urinary Bladder Neoplasms
- Guidelines as Topic
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Introduction
For over two decades, therapeutic developments for non-muscle invasive bladder cancer (NMIBC) remained stagnant, with very few treatment options. The absence of consensus on key aspects of clinical trial design, including disease state definitions, trial endpoints, and outcome definitions, hindered effective data interpretation and progress. NMIBC is a heterogeneous disease that requires a dynamic, ongoing classification to account for the timing of previous treatments and recurrences, along with tumor staging. Accordingly, significant effort was placed on developing a standardized nomenclature to classify BCG failures and recurrences, to permit meaningful comparisons among patients and treatment outcomes.1
The therapeutic landscape of NMIBC began to shift after the US Food and Drug Administration (FDA) issued guidance in 2018 that provided a much-needed framework for the design of clinical trials, referencing the sentinel publication by the International Bladder Cancer Group (IBCG) in 2016.1–3 This guidance engendered more uniform clinical trials, aiming to define a clear pathway for regulatory approval. Defining patients who were “BCG unresponsive” and endorsing a single-arm trial design for registration purposes (a suitable control other than radical cystectomy did not exist) catalyzed unprecedented progress in therapeutic development. The FDA approved two new therapeutic agents for the treatment of NMIBC for the first time in over 20 years, marking a significant milestone in bladder cancer research and treatment. Pembrolizumab was approved by the FDA in 2021, followed by nadofaragene firadenovec in 2022.4 5
Owing to an increased understanding of bladder cancer biology, therapeutic development in bladder cancer has become highly active across the disease continuum. In metastatic bladder cancer, eight new drugs have been approved since 2016, including five immune checkpoint inhibitors, two antibody-drug conjugates, and one fibroblast growth factor receptor (FGFR)-targeted agent. As the competition for trials increases, there is an urgent need to ensure that trials are conducted synergistically and resources (especially the most precious resource—the patient) are harnessed efficiently to generate the most valuable data to advance the field.
New comprehensive guidance from the SITC and IBCG
Building on the success of the 2016 IBCG guidance, the Society for Immunotherapy of Cancer (SITC) and IBCG decided to collaborate and expand this approach to develop guidance encompassing all bladder cancer disease states.6 SITC and IBCG gathered a multidisciplinary, international panel of clinical trial experts that included perspectives from medical oncology, pathology, urology, statistics, and patient advocacy. Throughout the development process, the patient’s voice and consideration of the patient’s journey were integral considerations during the panel deliberation and final recommendation formation.
To develop the recommendations within the SITC-IBCG guidance, the expert panel engaged in an explicit and transparent process of consensus generation, including surveying that followed a modified Delphi process, a closed consensus meeting of the expert panel, and open communication and debate during the iterative manuscript review. The draft guidance was also presented during an open session at the 2021 Bladder Cancer Advocacy Network Think Tank, providing a formal opportunity for external review and public input. The panel actively monitored the field at all stages of manuscript development and initiated additional consensus-generation activities as needed as new and emerging evidence became available to ensure the SITC-IBCG recommendations were as up to date as possible at the time of publication.
The result of these efforts is a comprehensive guidance document that provides specific recommendations for designing bladder cancer clinical trials according to disease stage and treatment modality, as well as outlines uniform eligibility criteria and controls. Within this document, the expert panel also proposes primary and secondary endpoints and critical values for effect size or response rate thresholds to aid in sample size calculations. The published SITC-IBCG recommendations are outlined in figure 1.6
Summary of recommendations from SITC and IBCG reproduced from Kamat et al.6 IBCG, International Bladder Cancer Group; SITC, Society for Immunotherapy of Cancer.
Standardization of clinical trial design
The SITC-IBCG recommendations are clear and comprehensive, providing a robust standard for clinical trials across the spectrum of bladder cancer disease settings. Notable general considerations include calling for designs with demonstrated superiority to current standards and more specific terminology to define recurrences and progression (eg, progression should always be counted as a recurrence event). With the patient perspective in mind, the panel also emphasized including objective quality of life endpoints with attention to cost and therapeutic burden.
Standardizing clinical trial design offers numerous advantages. It enhances transparency and reproducibility, promotes rigorous methodology, and improves the quality and reliability of data. This can enhance the relevance of trial results, supporting regulatory approval and clinical adoption of new therapies. Moreover, standardization results in more comparable and robust datasets suitable for meta-analysis and reduces redundancy across trials.
By promoting consistency and comparability in trial definitions and design, we can build on previous research instead of repeating it and optimize resource allocation, ultimately streamlining the drug development process. This is not to undermine the need for unique and innovative trials but rather to lay a uniform foundation that can be tailored to different research questions.
The benefits of a standardized approach to clinical trials extend beyond scientific rigor. Uniform definitions and eligibility criteria simplify trial identification and enrollment, making it easier for clinicians and patients. Likewise, the consensus of the trial blueprint fosters clinician buy-in, which can accelerate patient accrual. The nadofaragene firadenovec trial is an example of this, in which many investigators collaborated to recruit 157 patients in less than 3 years within the USA.5 Lastly, consistent design enhances trial credibility within the general medical community. This not only increases the likelihood that the findings will be accepted but also can facilitate implementation into clinical practice, leading to better patient outcomes.
Conclusion
In conclusion, establishing clinical trial design guidance through collaborative efforts and expert consensus represents a pragmatic and necessary shift in clinical research. A standardized approach to clinical trial design enhances transparency and credibility, paving the way for increased acceptance among clinicians, regulatory bodies, and the scientific community at large. We strongly urge the global research community, stakeholders, and regulatory bodies to advocate for and adopt a standardized approach to clinical trial design. The path charted by the IBCG and FDA and further expanded by SITC and IBCG should mark the dawning of comprehensive clinical trial design guidance in all disease states.
Ethics statements
Patient consent for publication
Footnotes
Twitter @AmandaMyersMD, @MattGalsky
Contributors All authors contributed to drafting the work or revising it critically for important intellectual content and final approval of the version to be published.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests AAM: Nothing to disclose. AMK: Consulting fees: Abbott Molecular, Arquer, ArTara, Asieris, Astra Zeneca, BioClin Therapeutics, Biological Dynamics, BMS, Cepheid, Cold Genesys, Eisai, Engene, Ferring, FerGene, Imagin, Incyte DSMB, Janssen, MDxHealth, Medac, Merck, Pfizer, Photocure, ProTara, Roviant, Seattle Genetics, Sessen Bio, Theralase, TMC Innovation, US Biotest, Urogen; Contracted research: Adolor, BMS, Fergene, FKD Industries, Heat Biologics, Merck, Photocure, SWOG/NIH; Patent: CyPRIT (Cytokine Predictors of Response to Intravesical Therapy) Joint with UT MD Anderson Cancer Center. AK: Nothing to disclose. MDG: Consulting fees: Inovio, NuMab, Janssen, Merck, Glaxo Smith Kline, Genentech, Bristol-Myers Squibb, Seattle Genetics, Dracen, Dragonfly, Astellas, Novartis, Pfizer, Astra Zeneca, Incyte, Dendreon, Lilly, EMD Serono, Aileron Therapeutics; Ownership interest: RAPPTA Therapeutics.
Provenance and peer review Commissioned; externally peer reviewed.