Bacillus Calmette-Guérin-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biological Products for Treatment : Draft Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

BCG-Unresponsive
Nonmuscle Invasive Bladder
Cancer: Developing Drug
and Biological Products for
Treatment
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact Sundeep Agrawal (CDER/OCE)
sundeep.agrawal@fda.hhs.gov , or (CBER) Office of Communication, Outreach and
Development, 800-835-4709 or 240-402-8010
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence (OCE)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2024
Clinical/Medical
Revision 1

BCG-Unresponsive
Nonmuscle Invasive Bladder
Cancer: Developing Drug
and Biological Products for
Treatment
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4 th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353
Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Communication, Outreach and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010
Email: ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Oncology Center of Excellence (OCE)
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
August 2024
Clinical/Medical
Revision 1

Contains Nonbinding Recommendations
i
TABLE OF CONTENTS
I. 	INTRODUCTION .................................................................................................................. 1
II. 	DEVELOPMENT PROGRAM ........................................................................................... 2
A. 	Early Product Development ..................................................................................................... 2
B. 	Late Phase Development........................................................................................................... 3
1. Dosage Selection ........................................................................................................................ 3
2. Trial Population and Entry Criteria ............................................................................................ 3
3. Single-Arm versus Randomized, Controlled Trial Design ............................................................ 5
4. Efficacy Endpoints ...................................................................................................................... 7
5. Trial Procedures and Timing of Assessments............................................................................... 9
6. Statistical Considerations ........................................................................................................... 9
7. Risk-Benefit Considerations ...................................................................................................... 10
C. 	Other Considerations.............................................................................................................. 10
1. Risk Management Considerations ............................................................................................. 10
2. Nonclinical Safety Considerations............................................................................................. 10

Contains Nonbinding Recommendations
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1
BCG-Unresponsive Nonmuscle Invasive Bladder Cancer:	1
Developing Drug and Biological Products for Treatment	2
Guidance for Industry1
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
14
I. 	INTRODUCTION	15
16
This guidance provides recommendations for the development of drug and biological products2	17
for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle	18
invasive bladder cancer (NMIBC) and is intended for pharmaceutical sponsors, the academic	19
community, and other interested parties.3 This guidance discusses pathological diagnosis and	20
staging, risk stratification, and trial design, including assessment of appropriate clinical	21
endpoints.	22
23
The specific recommendations for trial design and endpoints contained herein focus on BCG-	24
unresponsive NMIBC. While some general principles may apply across bladder cancer contexts,	25
sponsors should discuss with the FDA their development plans for drugs intended to treat other	26
forms of NMIBC or muscle invasive, locally advanced, or metastatic bladder cancer.	27
28
This guidance addresses select statistical and clinical trial design issues specific to BCG-	29
unresponsive NIMBC. These topics are further addressed in the ICH guidances for industry E9	30
1 This guidance has been prepared by the Division of Oncology 1 in the Center for Drug Evaluation and Research
(CDER) and the Oncology Center of Excellence (OCE) in cooperation with the Center for Biologics Evaluation and
Research (CBER) at the Food and Drug Administration.
2 For the purposes of this guidance, all references to drug or drugs include both human drug and biological products
unless otherwise specified.
3 In addition to consulting guidances, sponsors should contact the division to discuss specific issues that arise during
the development of drugs for the treatment of BCG-unresponsive NMIBC.

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2
Statistical Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and	31
Related Issues in Clinical Trials (May 2001), respectively.4	
32
33
This guidance, when finalized, will replace the final guidance titled BCG-Unresponsive	34
Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment published	35
in February 2018.	36
37
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	38
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	39
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	40
the word should in Agency guidances means that something is suggested or recommended, but	41
not required.	42
43
44
II. 	DEVELOPMENT PROGRAM	45
46
A. 	Early Product Development	47
48
Sponsors should conduct nonclinical studies to assess toxicity in animal models (see section	49
II.C.2., Nonclinical Safety Considerations).5 We also recommend that sponsors conduct	50
nonclinical studies to demonstrate antitumor activity in NMIBC and to select the dose and	51
schedule of the investigational drug to be evaluated in the first-in-human (FIH) trial. For	52
intravesical therapy, six weekly installations have become a standard dosing regimen for patients	53
with NMIBC, but few data are available to support this approach; therefore, alternative schedules	54
may be appropriate. Once sponsors complete nonclinical studies, we recommend that sponsors	55
design a FIH trial to evaluate safety, tolerability, pharmacokinetics, and antitumor activity and	56
also explore the dose- and exposure-response relationships, if feasible, to select the dosage(s) to	57
be evaluated in subsequent trials. One option to assess antitumor activity is in patients with	58
marker lesions that can be safely left in place after resection of other areas of NMIBC.	59
60
Sponsors developing investigational drugs for BCG-unresponsive NMIBC should also consider	61
assessing antitumor activity in a small number of patients who are awaiting radical cystectomy	62
for BCG-unresponsive NMIBC. With this approach, only a limited window of time is available	63
for observation of antitumor activity because surgery should not be delayed. In addition, these	64
trials should not interfere with the use of any planned neoadjuvant systemic chemotherapy.	65
66
67
4 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs guidance web page at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
5 We support the principles of the “3Rs” to reduce, refine and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable,
adequate, validated, and feasible. We will consider if such an alternative method could be assessed for equivalency
to an animal test method.

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B. 	Late Phase Development	68
69
1. 	Dosage Selection	70
71
Dosage selection is critical to an optimal benefit-risk balance and to the success of a late phase	72
trial. Sponsors should consider the nonclinical data and clinical data, such as safety, tolerability,	73
activity, and pharmacokinetics, to obtain an understanding of the dose- and exposure-response	74
relationships of intravesically and systemically administered investigational drugs when	75
selecting dosages to be evaluated in late phase trials. The acceptability of toxicities may be	76
different in an earlier disease setting, such as NMIBC, compared to a later line setting; therefore	77
different and/or lower dosages may be appropriate. A strong rationale for the choice of the	78
dosage(s) to be evaluated should be provided before initiating late phase trials. Dosage	79
optimization is further addressed in the draft guidance for industry Optimizing the Dosage of	80
Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases	81
(January 2023).6	82
83
2. 	Trial Population and Entry Criteria	84
85
Given the importance of defining a homogenous population of patients with BCG-unresponsive	86
disease for the purposes of determining available therapy and interpreting clinical trial results,	87
sponsors should specifically define the trial entry criteria in the trial protocol and document in	88
detail the NMIBC treatment history in the case report forms.	89
90
For the purposes of this guidance, BCG-unresponsive disease is defined as being at least one of	91
the following:	92
93
• 	Persistent or recurrent Carcinoma in Situ (CIS) alone or with recurrent Ta/T1	94
(noninvasive papillary disease/tumor invades the subepithelial connective tissue) disease	95
within 12 months of completion of adequate BCG therapy	96
97
• 	Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG	98
therapy	99
100
• 	T1 high-grade disease at the first evaluation following an induction BCG	101
course7	
102
103
For the purposes of this guidance, adequate BCG therapy is defined as at least one of the	104
following:	105
106
• 	At least five of six doses of an initial induction course plus at least two of three doses of	107
6 When final, this guidance will represent the FDA’s current thinking on this topic.
7 Steinberg RL, Thomas LJ, Mott SL, and O’Donnell MA, 2016, Bacillus Calmette-Guérin (BCG) Treatment
Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition of BCG Unresponsive Disease,
Bladder Cancer, 2:215–224.

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maintenance therapy	108
109
• 	At least five of six doses of an initial induction course plus at least two of six doses of a	110
second induction course	111
112
For patients who received partial doses or less than adequate doses of BCG therapy as prior	113
treatment, or who received different substrains of BCG therapy not approved in the United	114
States, see Section IIC3 for additional considerations.	115
116
Patients with BCG-unresponsive NMIBC are unlikely to benefit from further therapy with BCG	117
and represent a unique population for the study of new therapies. The standard of care for these	118
patients has been radical cystectomy; however, many of these patients prefer to avoid cystectomy	119
despite the potential risk of progression to muscle-invasive or metastatic disease. Patients who	120
elect not to undergo cystectomy can enter into trials of investigational therapies. Informed	121
consent documents should clearly communicate the risk of tumor progression and/or recurrence,	122
including progression to metastatic disease. Further, sponsors should evaluate these patients at	123
defined intervals to identify persistent or recurrent disease with adequate time to allow patients to	124
discontinue investigational drugs and proceed to other therapies.	125
126
Patients with BCG-unresponsive NMIBC include those who experienced recurrence with either	127
papillary disease or CIS or both and who have completely resected disease, resected disease with	128
CIS, or CIS alone at trial entry. The 2004 World Health Organization/International Society of	129
Urologic Pathology classification system is the preferred system for tumor grading. This system	130
categorizes tumors as papillary urothelial neoplasm of low malignant potential, low-grade, or	131
high-grade.8 Before initiating the trial, sponsors should assess and discuss with the FDA the need	132
for central pathology review of tissue and urine cytology to determine patient eligibility and	133
patient outcomes.	134
135
Because the methods of a urologist performing the cystoscopy can affect both patient eligibility	136
and outcome, sponsors should ensure that all participating urologists perform and document their	137
bladder examinations according to the protocol. Investigators should fully characterize a	138
patient’s disease status at or before trial entry, for example through mandatory templated	139
biopsies in patients with CIS. Sponsors should also obtain urine cytology. The FDA considers	140
use of biomarkers for further risk stratification exploratory at this time. To fully define the extent	141
of disease at trial entry, sponsors should have patients with T1 disease undergo resection of the	142
base of the lesion (the biopsy should contain muscle fibers) before trial entry to ensure the	143
absence of muscle-invasive disease. Furthermore, for patients with high-risk disease undergoing	144
transurethral resection of their bladder tumors, we recommend pelvic examination under	145
anesthesia to rule out the presence of locally advanced disease. Sponsors should use imaging by	146
computerized tomography or magnetic resonance to further evaluate patients for the presence of	147
locally advanced disease.	148
149
8 Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, and Epstein JL, 2010, Non-Invasive Papillary Urothelial
Neoplasms: The 2004 WHO/ISUP Classification System, Pathol Int, 60(1):1–8.

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Sponsors should collect data on the patient’s previous anticancer therapies, the dose and timing	150
of administrations, and the patient’s responses to each therapy. If a patient has met criteria for	151
BCG-unresponsive disease at any time during their treatment course, sponsors can consider that	152
patient to have BCG-unresponsive NMIBC regardless of whether BCG was the most recent	153
therapy to which the patient was exposed (i.e., not newly BCG-unresponsive). Duration of the	154
disease-free interval following the most recent therapy prior to recurrence should be recorded, as	155
a prolonged versus a short disease-free interval may reflect different underlying biology.	156
Sponsors are responsible for providing evidence to demonstrate that the patient met “BCG	157
unresponsive” criteria, even if this occurred substantially prior to enrollment. Sponsors should	158
attempt to enroll patients who reflect the clinically relevant patient population that will take the	159
drug if it is approved.	160
161
3. 	Single-Arm versus Randomized, Controlled Trial Design	162
163
Whether the patient has active disease at the time of trial enrollment is a key consideration for	164
the recommended trial design and endpoints used to evaluate the effectiveness of an	165
investigational drug treating BCG-unresponsive NMIBC. For patients without active disease	166
(disease was resected at or before trial entry), the FDA recommends a randomized, controlled	167
trial design using a time-to-event primary endpoint such as recurrence-free survival.	168
169
In contrast, patients with CIS at trial entry can be studied in either a randomized, controlled trial	170
or a single-arm trial. In the absence of pharmacologic intervention or cystectomy, BCG-	171
unresponsive CIS (a type of NMIBC), with or without resected disease, will persist and progress,	172
making complete response (CR) an interpretable endpoint in the single arm setting. In BCG-	173
unresponsive NMIBC with CIS at trial entry, a single-arm clinical trial with CR rate as the	174
primary endpoint, supported by duration of response, can provide primary evidence of	175
effectiveness to support a marketing application. Sponsors can include patients with completely	176
resected lesions and no evidence of CIS in these single-arm trials but should not include them in	177
the evaluation of the primary efficacy endpoint (e.g., CR rate). However, sponsors should	178
include these patients in the safety analysis.	179
180
Single-arm trials are appropriate in clinical settings where a randomized, controlled trial (RCT)	181
is either unethical or not feasible. Randomizing patients with BCG-unresponsive NMIBC to a	182
placebo as a concurrent control raises ethical concerns. Currently, single-arm trials may be	183
appropriate for assessment of therapies for patients with BCG-unresponsive disease (CIS with or	184
without resected papillary disease) because the standard of care has been radical cystectomy and	185
attainment of a durable CR may represent clinical benefit by allowing some patients to delay or	186
forgo radical cystectomy. Sponsors should use randomized trials in clinical settings in which a	187
control arm is feasible and/or a time-to-event endpoint is appropriate.	188
189
When deciding between a single-arm versus randomized, controlled trial design in patients	190
with BCG-unresponsive CIS (with or without resected papillary disease), sponsors should	191
consider the following:	192
193

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• 	Standard of care intravesicular and systemic treatments exist for patients with BCG-	194
unresponsive NMIBC allowing for an RCT design. An RCT is preferrable and can	195
provide stronger evidence of effectiveness, allow for evaluation of both CIS and	196
papillary disease, and generate comparative safety data.	197
198
• 	Lack of a comparator arm can make differentiating drug-related adverse events from	199
those due to the underlying disease or other causes challenging. An inability to	200
adequately characterize toxicity in a single-arm trial can have important implications on	201
the assessment of overall risk-benefit.	202
203
• 	When the investigational therapy consists of more than one drug, assessing the	204
contribution of effect of each drug to the combination therapy is not possible in a	205
single-arm study. Sponsors should adequately assess the need for each drug to a	206
combination therapy, as ineffective drugs may introduce excess toxicity without	207
improving efficacy outcomes. Sponsors should discuss considerations around	208
contribution of each drug of a combination therapy with the FDA.	209
210
• 	Time-to-event endpoints are uninterpretable in a single-arm trial. Evaluating clinically	211
relevant long-term outcomes assessed as time-to-event endpoints (e.g., cystectomy-free	212
interval time to progression) in a randomized trial allows for characterization of these	213
endpoints that assess clinical benefit that is important to patients.	214
215
• 	Variability in key aspects of trial conduct at screening and follow up (e.g., use of	216
advanced cystoscopy techniques, use of mandatory templated versus directed biopsies,	217
operator-dependent conclusions on cystoscopy findings, frequency of focal CIS being	218
completely resected by screening transurethral resection of bladder tumor (TURBT)	219
alone) can result in challenges in assessment of disease status, evaluation of the primary	220
endpoint, and interpretation of trial results.	221
222
Randomization allows for the balancing of known and unknown prognostic and other clinical	223
factors and may mitigate issues related to variability that may occur in the conduct of a single-	224
arm trial, allowing for better interpretation of trial results. Additional considerations for	225
designing a randomized clinical trial in patients with BCG-unresponsive CIS (with or without	226
resected papillary disease) include:	227
228
• 	Sponsors should consider use of a superiority design.	229
230
• 	Control arms should be selected from best available therapy applicable to a U.S. patient	231
population.	232
233
• 	Sponsors should stratify the randomization and analysis of trials that include patients	234
with CIS based on the type of disease (CIS alone or CIS with resected papillary disease)	235
at trial enrollment.	236

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• 	Sponsors should stratify the randomization and analysis of trials that include patients	237
with resected papillary disease by the type of disease (e.g., Ta, T1, and grade) at trial	238
enrollment.	239
240
• 	Sponsors should consider whether blinding is feasible.	241
242
• 	Using a randomized trial design comparing an intravesical agent(s) to systemic therapy	243
may require additional considerations that should be discussed with the FDA prior to	244
trial initiation.	245
246
• 	Sponsors should discuss the plan of formal hypothesis testing for efficacy endpoints and	247
other statistical considerations with the FDA when designing such a trial.	248
249
4. 	Efficacy Endpoints	250
251
The primary efficacy endpoint in single-arm trials of patients with BCG-unresponsive NMIBC	252
with CIS should be CR rate. Sponsors should consider the CR rate in the context of the duration	253
of response. The CR rate can only be determined in those patients who have disease at trial entry	254
(patients with CIS) with or without resected papillary disease. Because partial response has not	255
been defined in this disease setting, sponsors should not use it as a response criterion. Sponsors	256
should discuss with the FDA the minimum duration of follow-up (and, thus, the minimum	257
duration of response) before submitting an application.	258
259
For single-arm trials of patients with BCG-unresponsive disease, the FDA defines a CR as at	260
least one of the following:	261
262
• 	Negative cystoscopy and negative (including atypical) urine cytology	263
264
• 	Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative	265
cytology	266
267
For intravesical therapies with limited systemic absorption, the FDA includes, in the definition of	268
a CR, negative cystoscopy with malignant urine cytology if both a) cancer is found in the upper	269
tract or prostatic urethra and b) mandatory templated bladder biopsies are negative.	270
271
Intravesical instillation does not deliver the investigational drug to the upper tract or prostatic	272
urethra. Therefore, the development of disease in these areas cannot be attributed to a lack of	273
activity of the investigational drug. Thus, sponsors can consider patients with new malignant	274
lesions of the upper tract or prostatic urethra who have received intravesical therapy to have	275
achieved a CR in the primary analysis. However, sponsors should record these lesions and	276
conduct sensitivity analyses in which these patients are not considered to have achieved a CR. A	277
large proportion of patients with upper tract or prostatic urethral recurrence or progression	278
despite efficacy within the bladder will be considered in the overall risk-benefit assessment.	279
280

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Systemic therapies are expected to have a treatment effect throughout the urinary tract.	281
Therefore, a patient who received systemic therapy cannot be considered to have a CR if the	282
patient has a malignant lesion(s) in the upper tract or prostatic urethra.	283
284
For the purposes of determining the duration of a CR, the FDA defines a recurrence as findings	285
on follow-up that no longer meet the above definition for a CR. The protocol should provide a	286
plan for the evaluation of patients with suspicious urine cytology. Suspicious cytology does not	287
include the presence of atypical cells. This plan should specify how a suspicious urine cytology	288
will affect the initial definition of CR and the duration of CR. For example, the plan may include	289
repeat cytologies or mandatory templated bladder biopsies. Regardless of the prespecified plan,	290
all investigators should evaluate suspicious urine cytology in the same manner.	291
292
The method for assigning the dates of response and recurrence should be prespecified and	293
consistently applied. For example, a patient with an ongoing response and suspicious cytology	294
who later meets the criteria for recurrence without an intervening negative biopsy and/or	295
negative or atypical cytology should be considered to have recurred on the date of the initial	296
suspicious cytology.	297
298
One of the potential benefits of therapy for patients with BCG-unresponsive NMIBC is to avoid	299
cystectomy. The development of low-risk/low-grade papillary lesions does not affect the	300
decisions regarding cystectomy because these patients can be treated with transurethral resection	301
alone. Therefore, for the purposes of these trials, sponsors should consider patients with low-	302
risk/low-grade lesions to have achieved a CR and to have maintained this response (following	303
resection of these low risk/low-grade papillary lesions) in the primary analysis. However,	304
sponsors should record these lesions and the incidence and timing of TURBT and conduct	305
sensitivity analyses in which these patients are not considered to have achieved a CR.	306
307
Although delay in radical cystectomy is considered a direct patient benefit, the variations in	308
patient and health care provider preferences can confound the interpretation of this endpoint in	309
randomized trials and particularly in single-arm trials. Trials should consider defining	310
prespecified objective criteria for recommendation to undergo radical cystectomy. In all cases,	311
sponsors should collect cystectomy as an event, which may provide supportive evidence of	312
effectiveness. In addition, sponsors should document TURBT and disease progression to muscle-	313
invasive and/or metastatic disease.	314
315
The trial design should prespecify whether patients with CIS who do not achieve a CR at their 3-	316
month assessments should discontinue the investigational drug(s) because of the risk of	317
progression. Sponsors should consider the patient’s disease history, type of disease present at 3	318
months (e.g., T1), and the mechanism of action of the investigational drug(s). At 3 months,	319
patients with BCG-unresponsive CIS at study entry who are at a particularly high risk of	320
progression (e.g., new, T1 high-grade disease with or without CIS at first assessment) should	321
discontinue the investigational drug(s). Sponsors should discuss these issues with the FDA	322
during the development of the trial design.	323
324

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In addition to durable CR in patients with CIS, time-to-event endpoints, such as event-free	325
survival (EFS), may be appropriate as the primary endpoint in a randomized trial. Patients with	326
persistent CIS at the first evaluation (e.g., 3 months), or after a re-induction if permitted, should	327
be considered to have an event at the time of randomization.	328
329
For patients with papillary-only disease that was resected at or before trial entry, FDA	330
recommends a randomized, controlled trial design using a time-to-event endpoint such as	331
recurrence-free survival.	332
333
Given the differences in event definition and timing between patients with CIS and those with	334
papillary-only disease, the FDA strongly recommends that efficacy be evaluated in separate	335
cohorts. If both patients with persistent disease (i.e., CIS) and those without active disease (i.e.	336
resected papillary disease) are enrolled in the same cohort in a randomized, controlled trial	337
evaluating a time-to-event endpoint (e.g., EFS), differences in event definition and timing and	338
potential disproportionate contribution of one subgroup (patients with CIS or papillary disease)	339
to the observed efficacy results of the combined cohort may cause challenges in determination of	340
whether substantial evidence of effectiveness has been demonstrated for both populations.	341
342
5. 	Trial Procedures and Timing of Assessments	343
344
During the conduct of a clinical trial, patients with BCG-unresponsive NMIBC should be	345
followed every 3 months for 2 years, then every 6 months for 2 years, and then annually with	346
cystoscopy, directed biopsies, and urine cytology. In addition to directed biopsies, the FDA	347
recommends mandatory bladder biopsies based on a pre-specified template at a specific time	348
point(s) (e.g., at the time of assessment of the primary endpoint) in single-arm trials.9 The	349
protocol should address the number of biopsies and the biopsy sites.	350
351
If advanced (e.g., fluorescence-guided) cystoscopy is used at baseline, the same method of	352
assessment should be used at any visit(s) to document initial response, and during any directed or	353
mandatory biopsies to maintain consistency in evaluation of disease status. For cystoscopy with	354
multiple modalities (e.g., white light and fluorescence-guided), the investigator should record	355
whether a lesion is visualized on either or both modalities.	356
357
Sponsors should use central pathology review of biopsy specimens and/or cytology for all	358
patients in single-arm trials. For randomized trial designs, sponsors should consult with the FDA	359
regarding the need for central pathology review.	360
361
6. 	Statistical Considerations	362
363
For single-arm trials of patients with BCG-unresponsive NMIBC with CIS that use CR rate as	364
the primary endpoint, the lower bound of the 95 percent confidence interval around the observed	365
response rate should rule out a clinically unimportant CR rate. The median duration of CR is also	366
9 Gudjonsson S, Blackberg M, Chebil G, Jahnson S, Olsson H, Bendahl PO, Mansson W, and Liedberg F, 2012, The
Value of Bladder Mapping and Prostatic Urethra Biopsies for Detection of Carcinoma in Situ, BJU Int, 110(2 Pt
2):E41–45.

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important. A high CR rate is not meaningful if the response duration is short. The sponsor should	367
discuss with the appropriate review division the minimum duration of response prior to the time	368
of NDA or BLA submission. Patients participating in the trial should continue to be followed for	369
the development of a CR and for duration of CR.	370
371
For randomized, controlled trials of patients with BCG-unresponsive CIS that use CR rate as	372
the primary endpoint, sponsors should conduct formal hypothesis testing to compare CR rates	373
and should meet with the FDA when planning these analyses. A statistically significant and	374
clinically meaningful difference in CR rates should be supported by a clinically meaningful	375
duration of response. Sponsors should also meet with the FDA to discuss statistical	376
considerations for any endpoints other than CR rate.	377
378
7. 	Risk-Benefit Considerations	379
380
The approval of a marketing application is based, in part, on a favorable risk-benefit assessment.	381
For therapies that have greater toxicity (e.g., systemic therapies), substantially greater efficacy	382
might be needed to achieve an overall favorable risk-benefit assessment. Sponsors of clinical	383
trials using either intravesical or systemic therapy should meet with the FDA to discuss trial	384
design details.	385
386
C. 	Other Considerations	387
388
1. 	Risk Management Considerations	389
390
The FDA cannot make a decision concerning a risk management plan before reviewing the data	391
included in an NDA or BLA. Sponsors should provide a plan to assess the long-term outcomes	392
of patients receiving the investigational drug. For example, a long-term study or trial to assess	393
bladder capacity may be needed if there was a signal in premarketing studies that the	394
investigational drug caused bladder fibrosis.	395
396
2. 	Nonclinical Safety Considerations	397
398
Before sponsors initiate clinical trials in patients with BCG-unresponsive NMIBC, sponsors	399
should use nonclinical studies to optimize the dose and schedule of intravesical drugs. A	400
sponsor’s choice and use of nonclinical models will vary with the investigational drug. The	401
sponsor should discuss this with the appropriate review division. Sponsors also can use	402
nonclinical studies to ensure that systemic therapies are active at the mucosal surface of the	403
bladder and to justify the potential risks associated with systemic therapies. For drugs intended	404
for intravesical administration, sponsors can use the extent of systemic exposure in nonclinical	405
studies following intravesical administration to determine the need for evaluation of systemic	406
toxicity. If systemic exposure is low, histological evaluation may be limited to locally exposed	407
tissues. Similarly, if systemic exposure of the active substance is equivalent to or less than that of	408
an approved route of administration for the same active substance, histological evaluation also	409
may be limited to locally exposed tissues. The recommendations for and timing of additional	410
nonclinical studies depend upon the available nonclinical and clinical data, the nature of the	411

Contains Nonbinding Recommendations
Draft — Not for Implementation
11
toxicities observed, and the patient population (e.g., more advanced NMIBC such as BCG-	412
unresponsive NMIBC). Sponsors should discuss this with the appropriate review division before	413
conducting a clinical trial using either a systemic or intravesicular drug in patients with BCG-	414
unresponsive NMIBC.	415
416
For recommendations on the substance and scope of nonclinical information needed to support	417
clinical trials for cell therapy and gene therapy products, see the guidance for industry	418
Preclinical Assessment of Investigational Cellular and Gene Therapy Products (November	419
2013), Clinical Considerations for Therapeutic Cancer Vaccines (October 2013), and	420
Recommendations for Microbial Vectors Used for Gene Therapy (September 2016).	421
422
3. 	BCG Supply Issues	423
424
In times of BCG supply issues or when enrollment of sufficient patients who meet the prior BCG	425
criteria in the definition of BCG unresponsive disease is not feasible, sponsors may consider	426
inclusion of patients who received less than adequate prior BCG as defined in Section IIB2,	427
partial doses of BCG, or alternative treatment schedules. Enrolling these patients will create	428
uncertainty in the interpretation of endpoints such as durable CR as assessed in a single arm trial	429
given that the outcomes in response to subsequent therapies is unknown for these patients.	430
431
Given this uncertainty, a randomized trial is recommended to allow for interpretation of results	432
if sponsors enroll a heterogenous population with respect to prior BCG received. In a	433
randomized trial, stratification is recommended to control for differences in exposure to prior	434
BCG. Sensitivity analyses should assess the effect of the variability in previous BCG exposure	435
on trial results. Labeling will reflect the enrolled population.	436
437
Currently, there are limited prospective, randomized trial data demonstrating equivalence of	438
BCG substrains not approved in the United States to those that are approved, and it is unclear	439
whether BCG substrains vary with respect to efficacy and safety and are applicable to a U.S.	440
BCG-unresponsive patient population. For regulatory purposes, different substrains of BCG are	441
not considered equivalent and each BCG substrain-derived drug product is regulated as a	442
separate product. This has implications for trial designs in the BCG-unresponsive setting for (1)	443
eligibility, as patients may be determined to be BCG-unresponsive based on prior treatment with	444
substrains not approved in the United States, and (2) trial conduct, if BCG substrains not	445
approved in the United States are used as part of combination therapy.	446
447
An adequate percentage of patients should be treated with FDA-approved BCG substrains for the	448
results of a trial to be applicable to a U.S. population. Sensitivity analyses should be conducted	449
to explore the effects of different BCG substrains on clinical efficacy and safety. Variation in the	450
safety and activity of different substrains of BCG can pose a challenge in interpreting trial	451
results. If sponsors plan to enroll patients who received prior BCG therapy with substrains not	452
approved by the FDA, they should discuss their proposal with the appropriate FDA review	453
division. Use of alternative control arms (e.g., non-BCG, reduced dose BCG, or alternative BCG	454
schedules) should be supported by a rationale that includes their expected efficacy in this patient	455
population.	456