. 2023 Sep 25;9(3):271-286.

doi: 10.3233/BLC-230056. eCollection 2023.

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer

Elaine Chang¹, Noah M Hahn², Seth P Lerner³, Jaleh Fallah¹, Sundeep Agrawal¹, Ashish M Kamat⁴, Vishal Bhatnagar⁵, Robert S Svatek⁶, Adnan A Jaigirdar⁷, Peter Bross⁷, Neal Shore⁸, Max Kates⁹, Karen Sachse¹⁰, Jamie R Brewer¹, Michael A O'Donnell¹¹, Gary D Steinberg¹², Charles J Viviano¹³, Erik Bloomquist¹, Maria J Ribal¹⁴, Matthew D Galsky¹⁵, Richard Oliver^{1

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24}, Peter C Black¹⁶, Hikmat Al-Ahmadie¹⁷, Kenneth Brothers¹⁸, Kamal Pohar¹⁹, Colin P Dinney⁴, Zhou Feng¹, Tracy M Downs²⁰, Sima P Porten²¹, Angela B Smith²², Rick Bangs¹⁰, Sarah P Psutka²³, Neeraj Agarwal²⁴, Laleh Amiri-Kordestani¹, Daniel L Suzman¹, Richard Pazdur⁵, Paul G Kluetz⁵, Chana Weinstock¹

Affiliations

¹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
² Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³ Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Oncology Center of Excellence, Food and Drug Administration, Silver Spring, MD, USA.
⁶ Department of Urology, University of Texas Health San Antonio, San Antonio, TX, USA.
⁷ Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁸ Department of Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA.
⁹ Department of Urology, Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Bladder Cancer Advocacy Network, Bethesda, MD, USA.
¹¹ Department of Urology, University of Iowa, Iowa City, IA, USA.
¹² Goldstein Bladder Cancer Program, NYU Langone Health, NYU Urology Associates, New York, NY, USA.
¹³ Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, USA.
¹⁴ Uro-Oncology Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
¹⁵ Hematology-Oncology, Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA.
¹⁶ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Pathology and Laboratory Medicine, Genitourinary Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁸ National Cancer Institute Bladder Cancer Task Force, Bethesda, MD, USA.
¹⁹ Department of Urology, The Ohio State University, Columbus, OH, USA.
²⁰ Department of Urology, University of Virginia, Charlottesville, VA, USA.
²¹ Department of Urology, University of California San Francisco, San Francisco, CA, USA.
²² Department of Urology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
²³ Department of Urology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA.
²⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

PMID: 38993184
PMCID: PMC11181701
DOI: 10.3233/BLC-230056

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer

Elaine Chang et al. Bladder Cancer. 2023.

. 2023 Sep 25;9(3):271-286.

doi: 10.3233/BLC-230056. eCollection 2023.

Authors

Affiliations

¹ Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
² Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
³ Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Urology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Oncology Center of Excellence, Food and Drug Administration, Silver Spring, MD, USA.
⁶ Department of Urology, University of Texas Health San Antonio, San Antonio, TX, USA.
⁷ Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA.
⁸ Department of Urology, Carolina Urologic Research Center, Myrtle Beach, SC, USA.
⁹ Department of Urology, Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁰ Bladder Cancer Advocacy Network, Bethesda, MD, USA.
¹¹ Department of Urology, University of Iowa, Iowa City, IA, USA.
¹² Goldstein Bladder Cancer Program, NYU Langone Health, NYU Urology Associates, New York, NY, USA.
¹³ Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD, USA.
¹⁴ Uro-Oncology Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
¹⁵ Hematology-Oncology, Icahn School of Medicine at Mount Sinai/Tisch Cancer Institute, New York, NY, USA.
¹⁶ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Department of Pathology and Laboratory Medicine, Genitourinary Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁸ National Cancer Institute Bladder Cancer Task Force, Bethesda, MD, USA.
¹⁹ Department of Urology, The Ohio State University, Columbus, OH, USA.
²⁰ Department of Urology, University of Virginia, Charlottesville, VA, USA.
²¹ Department of Urology, University of California San Francisco, San Francisco, CA, USA.
²² Department of Urology, University of North Carolina, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
²³ Department of Urology, University of Washington, Seattle Cancer Care Alliance, Seattle, WA, USA.
²⁴ Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

PMID: 38993184
PMCID: PMC11181701
DOI: 10.3233/BLC-230056

Abstract

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.

Keywords: BCG; BCG-unresponsive; anti-neoplastic agents; clinical trial design; regulatory.

PubMed Disclaimer

Conflict of interest statement

E.C., J.F., S.A., V.B., A.A.J., P.B., K.S., J.R.B., E.B., R.O., K.B., Z.F., T.M.D., R.B., D.L.S., L.A.K., R.P., P.G.K., and C.W. have no conflicts of interest to report. N.M.H., S.P.L., A.M.K., R.S.S., M.A.O., M.J.R., M.D.G., P.C.B., K.P., C.P.D., R.B., and S.P.P. (Psutka) are Editorial Board members of this journal, but were not involved in the peer-review process nor had access to any information regarding its peer-review. N.M.H. receives consulting compensation from AstraZeneca, Merck, BioGears, Seattle Genetics, Mirati, Incyte, RemGen, Janssen, Pfizer, EMD Serono, Verity Pharmaceuticals, Huron Consulting, Guidepoint, Natera, Protara Therapeutics, Astellas Pharma; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, Pieris, Inovio, Principia Biopharm, Incyte, and Ikena Oncology; and speaking honorarium from Medscape. S.P.L. reports clinical trial involvement with Aura Bioscience, FKD, JBL (SWOG), Genentech (SWOG), Janssen (SWOG), Merck (Alliance), QED Therapeutics, UroGen, Vaxiion, Viventia; is on the advisory board or a consultant for Aura Bioscience, BMS, C2iGenomics, Ferring, Incyte, Pfizer/EMD Serono, Protara, Stimit, UroGen, Vaxiion, Verity; has a patent for a TCGA classifier; and receives honoraria from Grand Rounds Urology and UroToday. A.M.K. reports clinical trial involvement with FKD, Merck, Bristol Myers Squibb, Photocure, SWOG, Adolor, Heat Biologics, Janssen, Taris, Seattle Genetics; reports laboratory research with NIH, SPORE, AIBCCR, PCORI; is on the advisory board or a consultant for TMC Innovation, Arquer Diagnostics, Asieris, Astellas, Biological Dynamics, BMS, CG Oncology, Cystotech, Eisai, Engene, Ferring, InCyte, Imvax, Imagin Medical, Janssen, Medac, Merck, Nonagen, Photocure, ProTara, Pfizer, Roche, Seattle Genetics, Sessen Bio, Theralase, US Biotest, Urogen Inc; is on the editorial board of European Urology Oncology; Journal of Urology, UroToday; is president of International Bladder Cancer Network and International Bladder Cancer Group; and has a joint patent with UT MD Anderson Cancer Center for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy). R.S.S. is a consultant for CG Oncology and Verity Pharma; and receives research support from Japanese BCG Laboratories and Merck. N.S. is a consultant for AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, Astra Zeneca, AuraBiosciences, Bayer, BMS, Bioprotect, Boston Scientific, Clarity, Dendreon, Exact Imaging, FizeMedical, CG Oncology, Genentech/Roche, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myriad, Nonagen, Novartis, Nymox, Pacific Edge, Palette Life, Photocure, Pfizer, PlatformQ, Profound Medical, Promaxo, Propella, Protara, Sanofi, Specialty Networks, Telix, Tolmar, Urogen, and Vessi. M.K. receives grant funding from the American Cancer Society; is a consultant for Merck, Pfizer, Seagen/Astellas, Photocure, Aura, BMS, Nanology, and Janssen; and holds a patent for Nanoparticle Formulations for Enhanced Drug Delivery to the Bladder. M.A.O. receives grant/research/clinical trial support from Abbot Molecular, Photocure, Urogen; and is a consultant or on the advisory board for Fidia Pharmaceuticals, Sesen Bio, Merck, Theralase, and Urogen. G.D.S. is a member of the Clinical Trial Protocol Committee for Merck, BMS, Janssen, CG Oncology, Pfizer, PhotoCure, Fidia, Seagen, Protara; is or has been a scientific advisor /consultant with CG Oncology; PhotoCure; Merck; Taris Biomedical (Now Janssen); Fidia Farmaceuticals; Urogen, Ferring; Fergene, Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; Epivax Therapeutics; EnGene Bio; Astellas; SeaGen; Verity Pharmaceuticals, Protara, xCures, Nonagen, Nanology, Imvax, Asieris; and has equity stock/options with Epivax Therapeutics, Urogen, CG Oncology, Engene Bio. M.J.R. has intellectual property with Fina Biotech and is or has been a meeting participant or lecturer for Roche, AstraZeneca, and Bayer. M.D.G. receives research funding from Bristol Myers Squibb, Novartis, Dendreon, Astra Zeneca, Merck, Genentech; and is on the advisory board or a consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie, Analog Devices. P.C.B is a member of the advisory board or equivalent with AbbVie, AstraZeneca, Astellas, Bayer, BMS, EMD-Serono, Ferring, Fergene, Janssen, Merck, miR Scientific, Nonagen, NanOlogy, Pfizer, Photocure, Prokarium, Protara Therapeutics, QED Bioscience, Roche, Sanofi, Sesen Bio, STIMIT, TerSera, Tolmar, Urogen, Verity; is a member of a Speaker’s bureau with Janssen, Minogue, Ferring, TerSera, Pfizer; has received a grant or honorarium from iProgen; and shares a patent with Veracyte. H.A. provides consultation to AstraZeneca, Flare Therapeutics and Paige.AI. K.P. receives consulting fees from Photocure. C.P.D. reports compensation for Scientific/Advisory Committee Member for AstraZeneca Pharmaceuticals, UroGen Pharma (formerly Theracoat Ltd.); consulting fees from STIMIT Corporation; consulting fees from General Atlantic; board member position for DF/HCC Kidney Cancer SPORE Advisory Board; research funding from Cancer Prevention Research Institute of Texas (CPRIT), Department of Defense (DoD), and NIH/NCI. S.P.P. (Porten) receives research support from Photocure, consulting compensation from Pacific Edge, grant funding from PCORI, BCAN, AHRQ, Genentech, Merck, and is on the advisory board for AstraZeneca. A.B.S. receives grant funding from PCORI, BCAN, AHRQ, Genentech, and Merck. S.P.P. (Psutka) reports being on Practice Guidelines Committee (Upper Tract Urothelial Carcinoma) of the American Urological Association (AUA), being AUA Core Curriculum Sr. Editor (2019-2023) and Senior Consultant (2023-); is or has been on Scientific Advisory Boards for Merck (Past), ImmunityBio (Past), Janssen (Current); has received travel funding/honoraria from Medtronic (Past), AstraZeneca (Past); receives research funding from PRIME Education, INC, Bladder Cancer Advocacy Network, National Institute on Aging, and is on the editorial boards for European Urology. N.A. receives research funding to institution from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.

Figures

**Fig. 1**
BCG-Naïve HR NMIBC Direct Comparison Clinical Trial Design. Abbreviations: BCG: Bacillus Calmette-Guerin; EFS: event-free survival; HR NMIBC: high-risk non-muscle invasive bladder cancer; R: randomize; SOC: standard of care; Tx: treatment.

**Fig. 2**
BCG-Naïve HR NMIBC Add-On Clinical Trial Design. Abbreviations: BCG: Bacillus Calmette-Guerin; EFS: event-free survival; HR NMIBC: high-risk non-muscle invasive bladder cancer; R: randomize; SOC: standard of care; Tx: treatment.

**Fig. 3**
Randomized Platform Common Control Trial Design. Abbreviations: BCG: Bacillus Calmette-Guerin; CIS: carcinoma *in situ*; HR NMIBC: high-risk non-muscle invasive bladder cancer; R: randomize; SOC: standard of care; Tx: treatment.

**Fig. 4**
Two-Trial Design Simulation Investigating Papillary (Ta/T1) and CIS Patients Separately. Abbreviations: BCG: Bacillus Calmette-Guerin; CIS: carcinoma *in situ*; CR: complete response; EFS: event-free survival; HR NMIBC: high-risk non-muscle invasive bladder cancer; SOC: standard of care; Tx: treatment.

**Fig. 5**
One-Trial Design Simulation Investigating Papillary (Ta/T1) and CIS Patients Simultaneously. Abbreviations: BCG: Bacillus Calmette-Guerin; CIS: carcinoma in situ; CR: complete response; EFS: event-free survival; HR NMIBC: high-risk non-muscle invasive bladder cancer; SOC: standard of care; Tx: treatment.

**Fig. 6**
Abbreviations: BCG: Bacillus Calmette-Guerin; FDA: Food and Drug Administration; NMIBC: non-muscle invasive bladder cancer; U.S.: United States.

See this image and copyright information in PMC

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Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer

Affiliations

Advancing Clinical Trial Design for Non-Muscle Invasive Bladder Cancer

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

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Medical