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BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry

BCG-Unresponsive

Nonmuscle Invasive Bladder

Cancer: Developing Drugs

and Biologics 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DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.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be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit electronic comments to http://www.regulations.gov. Submit written comments to the Division of Dockets Management (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 (CDER) V. Ellen Maher at 301-796-5017 or (CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402- 8010.

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016 Clinical/Medical

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1152293dft.docx 10/19/16

BCG-Unresponsive

Nonmuscle Invasive Bladder

Cancer: Developing Drugs

and Biologics 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., 4th Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

and/or

Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, rm. 3128
Silver Spring, MD 20993-0002
Phone: 800-835-4709 or 240-402-8010; Email: This e-mail address is being protected from spambots. You need JavaScript enabled to view it
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services Food and Drug Administration
Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

November 2016 Clinical/Medical

I. II.

A. B.

TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1 DEVELOPMENT PROGRAM ....................................................................................... 2 Early Phase Development ..............................................................................................................2 Late Phase Development ................................................................................................................3

1. 2. 3. 4. 5. 6. 7. 8. 9.

  1. Accelerated Approval (Subpart H and Subpart E) Considerations.............................................7

  2. Risk-Benefit Considerations.........................................................................................................7

General Considerations ...................................................................................................................3 Trial Population and Entry Criteria.................................................................................................3 Randomization, Stratification, and Blinding ....................................................................................5 Dose Selection ..................................................................................................................................5 Single-Arm vs. Randomized, Controlled Trial Design .....................................................................5 Efficacy Endpoints............................................................................................................................5 Trial Procedures and Timing of Assessments ..................................................................................6 Endpoint Adjudication......................................................................................................................7 Statistical Considerations.................................................................................................................7

C. Other Considerations .....................................................................................................................8

1. Risk Management Considerations....................................................................................................8

2. Nonclinical Safety Considerations ...................................................................................................8

REFERENCES.............................................................................................................................. 9

Contains Nonbinding Recommendations

Draft — Not for Implementation

  1. 1 BCG-Unresponsive Nonmuscle Invasive Bladder Cancer:

  2. 2 Developing Drugs and Biologics for Treatment

  3. 3 Guidance for Industry1

4 5 6

7 8 9

10 11 12 13

14
15
16
17
I. INTRODUCTION 18

  1. 19  The purpose of this guidance is to assist sponsors in the clinical development of drugs, including

  2. 20  biologics, for the treatment of patients who have bacillus Calmette-Guerin (BCG)-unresponsive

  3. 21  nonmuscle invasive bladder cancer (NMIBC).2 The definition described by Lerner et al. 2015 is

  4. 22  used to identify the patient population with BCG-unresponsive disease. This guidance is

  5. 23  intended for pharmaceutical sponsors, the academic community, and the public and provides a

  6. 24  framework, based on current Food and Drug Administration (FDA) thinking, to facilitate the

  7. 25  development of drugs to treat this patient population.3 The pathological diagnosis and staging,

  8. 26  risk stratification, and trial design, including assessment of appropriate clinical endpoints, are

  9. 27  discussed. These issues were discussed at the Food and Drug Administration/American

  10. 28  Urological Association Bladder Cancer Workshop held on May 6, 2013, and in more recent

  11. 29  publications (Jarow, Lerner, et al. 2014; Jarow, Maher, et al. 2015).

30

  1. 31  Many of the general principles elucidated in this guidance also apply to development of drugs for

  2. 32  other forms of nonmuscle invasive bladder cancer. Nevertheless, the specific recommendations

  3. 33  for trial design and endpoints contained herein may not necessarily apply, and sponsors are

  4. 34  encouraged to discuss development plans with the FDA for drugs intended to treat other forms of

  5. 35  NMIBC or for muscle invasive, locally advanced, or metastatic bladder cancer.

36

1 This guidance has been prepared by the Division of Oncology Products 1 in the Center for Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and Drug Administration.

2 For the purposes of this guidance, all references to drugs include both human drugs and biological products unless otherwise specified.

3 In addition to consulting guidances, sponsors are encouraged to 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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This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

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Draft — Not for Implementation

  1. 37  This guidance does not contain discussion of the general issues of statistical analysis or clinical

  2. 38  trial design. Those topics are addressed in the ICH guidances for industry E9 Statistical

  3. 39 Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical

  4. 40 Trials, respectively.4

41

  1. 42  In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

  2. 43  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

  3. 44  as recommendations, unless specific regulatory or statutory requirements are cited. The use of

  4. 45  the word should in Agency guidances means that something is suggested or recommended, but

  5. 46  not required.

47
48
49
II. 50
51
52

  1. 53  Nonclinical studies and early phase development should be conducted to demonstrate antitumor

  2. 54  activity and determine the optimal dose and schedule of the investigational drug. Although six

  3. 55  weekly instillations of intravesical therapy has become a standard approach for the treatment of

  4. 56  NMIBC, there are few data available to support this approach. Antitumor activity may be

  5. 57  demonstrated in animal models and/or in patients with marker lesions or those who are scheduled

  6. 58  for cystectomy.

59

  1. 60  Marker lesions are small areas (less than 3 centimeters (cm)) of low-grade papillary lesions that

  2. 61  are biopsied and left in place. These lesions then can be examined for complete response to the

  3. 62  investigational drug. The number of patients involved in such studies should be small, and these

  4. 63  patients should be closely followed with resection of residual lesions after response has been

  5. 64  determined. In addition to the assessment of drug activity in low-grade disease, sponsors should

  6. 65  consider assessment of activity of the investigational drug in patients with BCG-unresponsive

  7. 66  disease before late phase development.

67

  1. 68  Another option to assess antitumor activity is to administer an investigational drug to patients

  2. 69  who are awaiting cystectomy. This allows examination of activity against higher risk disease

  3. 70  and over the entire surface of the bladder. With this approach, there is only a limited window

  4. 71  available for observation of antitumor activity because surgery should not be delayed. Further,

  5. 72  these studies should not interfere with the use of neoadjuvant systemic chemotherapy whenever

  6. 73  appropriate.

74

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 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

DEVELOPMENT PROGRAM A. Early Phase Development

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75 B. 76
77
1. 78

Contains Nonbinding Recommendations

Draft — Not for Implementation

Late Phase Development

General Considerations

  1. 79  A key consideration for the recommended trial design and endpoints used to evaluate

  2. 80  effectiveness for an investigational drug used to treat NMIBC is whether the patient has active

  3. 81  disease at the time of enrollment. The preferred trial design in patients without active disease

  4. 82  (disease was resected at or before trial entry) is a randomized, controlled trial using a time-to-

  5. 83  event endpoint of recurrence-free survival. In contrast, patients with disease at trial entry, such

  6. 84  as patients with carcinoma in situ (CIS), can be studied in either a randomized, controlled trial or

  7. 85  single-arm trial. The natural history of BCG-unresponsive NMIBC (CIS with or without

  8. 86  resected disease) is that, in the absence of a pharmacologic intervention or cystectomy, CIS will

  9. 87  almost always persist. In this setting, a single-arm clinical trial with complete response rate as

  10. 88  the primary endpoint can provide primary evidence of effectiveness to support a marketing

  11. 89  application.

90

  1. 91  The use of systemic, as opposed to intravesical, therapy has been proposed for the treatment of

  2. 92  patients with NMIBC. Given the potential for the increased risks associated with the use of

  3. 93  systemic therapies, initial trials should be limited to patients with few treatment options. Patients

  4. 94  with BCG-unresponsive disease are appropriate because their treatment options are limited and

  5. 95  the current alternative is cystectomy.

96
97
2. Trial Population and Entry Criteria
98
99 The trial entry criteria should be specifically defined in the trial protocol and well documented in

100 the case report forms.
101
102 NMIBC includes the following stages (Edge, Byrd, et al. 2010): 103

  1. 104

  2. 105

  3. 106

107

  1. 108  The 2004 World Health Organization/International Society of Urologic Pathology classification

  2. 109  system is the preferred system for tumor grading. This system categorizes tumors as papillary

  3. 110  urothelial neoplasm of low malignant potential, low-grade, or high-grade (Miyamoto, Miller, et

  4. 111  al. 2010).

112

  1. 113  Tumor stage and grade can be used to categorize an individual patient’s risk of recurrence and

  2. 114  progression. The following risk categories are commonly employed (Persad, Lamm, et al.

  3. 115  2008):

116
117
118
119

Ta: Noninvasive papillary disease
T1: Tumor invades the subepithelial connective tissue Tis: Carcinoma in situ

Low-risk tumors: include all of the following features: small-volume (less than 3 cm), low-grade, pathological Ta lesions with no evidence of CIS

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Intermediate-risk tumors: include those that cannot be categorized as low-risk or high- risk

High-risk tumors: include any of the following features: T1 lesions, high-grade disease, tumors larger than 3 cm, multiple or recurrent lesions, and CIS

125

  1. 126  For the purposes of this guidance, BCG-unresponsive disease is defined as (Lerner, Dinney, et al.

  2. 127  2015):

128
129
130
131
132
133
134
135

  1. 136  Most patients with intermediate- or high-risk NMIBC are treated with an induction course (six

  2. 137  weekly instillations) with or without maintenance (three weekly instillations at 3 and 6 months

  3. 138  and every 6 months thereafter for 1 to 3 years) of BCG (Lamm, Blumenstein, et al. 2000). Some

  4. 139  tumors recur on therapy or after a short disease-free interval. Patients with BCG-unresponsive

  5. 140  disease are extremely unlikely to benefit from further therapy with BCG and represent a unique

  6. 141  population for study of new therapies.

142

  1. 143  To fully define the extent of disease at study entry, patients with T1 disease should undergo

  2. 144  repeat resection or biopsy of the base of the lesion before study entry to ensure the absence of

  3. 145  muscle-invasive disease (T2). Furthermore, patients with high-risk disease should undergo

  4. 146  pelvic examination under anesthesia and imaging by computerized tomography or magnetic

  5. 147  resonance imaging to rule out locally advanced disease. Patients with BCG-unresponsive

  6. 148  disease can have completely resected disease, resected disease with CIS, or CIS alone at study

  7. 149  entry. Patients should be staged before enrollment. Staging should include the use of bladder

  8. 150  mapping and random biopsies in patients with CIS or high-grade papillary disease (Gudjonsson,

  9. 151  Blackberg, et al. 2012). Urine cytology also should be obtained and evaluated.

152

  1. 153  Data should be collected concerning previous anticancer therapies, the dose and timing of

  2. 154  administration, and the patient’s response to each therapy. Patient sex, age, and race should be

  3. 155  considered when enrolling patients in any clinical trial. In NMIBC, an effort should be made to

  4. 156  include women and patients of all races. Because bladder cancer rarely occurs in children, a

  5. 157  pediatric waiver request may be appropriate.

158

  1. 159  The role of central pathology in establishing patient eligibility should be discussed with the

  2. 160  responsible review division. Fluorescence-guided cystoscopy also may be used to aid in patient

  3. 161  selection. Whether white light or fluorescence-guided cystoscopy is used at baseline, the same

  4. 162  method of assessment should be employed throughout the study of that individual patient.

163

120 121
122
123
124

Persistent high-grade disease or recurrence within 6 months of receiving at least two courses of intravesical BCG (at least five of six induction doses and at least two of three maintenance doses); or

T1 high-grade disease at the first evaluation following induction BCG alone (at least five of six induction doses)

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Contains Nonbinding Recommendations

Draft — Not for Implementation

164 3. Randomization, Stratification, and Blinding 165

  1. 166  Because the urologist performing the cystoscopy can affect both patient eligibility and outcome,

  2. 167  sponsors should consider randomization by study site. In either a randomized or single-arm trial,

  3. 168  sponsors should ensure that all participating urologists perform and document their examination

  4. 169  of the bladder according to the protocol. Moreover, for either randomized or single-arm trials,

  5. 170  sponsors should provide a plan to examine the effect of the urologist/investigator site on patient

  6. 171  staging and outcome.

172

  1. 173  In a randomized trial that includes patients with CIS and resected papillary disease, patients

  2. 174  should be stratified into patients with CIS alone and patients with CIS and resected papillary

  3. 175  disease. Sponsors also should consider whether fluorescence-guided cystoscopy will be used in

  4. 176  the examination of the bladder and may choose to stratify by this variable as well. Finally,

  5. 177  sponsors should consider whether blinding is feasible in a randomized trial.

178
179
4. DoseSelection 180

  1. 181  Dose selection is critical to optimal patient treatment and to the success of a late phase trial.

  2. 182  Sponsors should consider an exploration of dose and schedule during nonclinical studies and

  3. 183  early phase clinical trials. Systemic exposure assessed in an early phase dose-selection trial may

  4. 184  help evaluate and minimize safety concerns from potential systemic exposure after intravesicular

  5. 185  administration. For investigational drugs administered systemically, it is important to consider

  6. 186  the safety profile, activity, and pharmacokinetics of the drug in patients with nonmuscle invasive

  7. 187  disease. These considerations can help guide selection of various dose levels and dosing

  8. 188  regmimens for study in the trials intended to provide primary evidence of effectiveness. The

  9. 189  doses used to treat nonmuscle invasive disease may be lower than the doses administered for the

  10. 190  systemic treatment of metastatic disease.

191
192
5. Single-Arm vs. Randomized, Controlled Trial Design 193

  1. 194  Single-arm trials are appropriate in clinical settings where a randomized, controlled trial is either

  2. 195  unethical or not feasible. Randomizing patients with BCG-unresponsive disease to a minimally

  3. 196  effective drug as a concurrent control raises ethical concerns. Because effective drugs are not

  4. 197  available and the alternative treatment is cystectomy, single-arm trials of patients with BCG-

  5. 198  unresponsive CIS disease with or without papillary disease are appropriate. In general, these

  6. 199  single-arm trials should use drugs that have shown activity in bladder cancer.

200
201
6. Efficacy Endpoints 202

  1. 203  The primary endpoint we recommend sponsors use in single-arm trials of patients with BCG-

  2. 204  unresponsive disease is the complete response rate of CIS and its 95 percent confidence interval.

  3. 205  The median duration of response also should be assessed. Complete response can be defined as

  4. 206  negative urine cytology and no lesions on cystoscopy. If random biopsies of the bladder and

  5. 207  prostatic urethra are performed, they should be negative. Partial response has not been defined

  6. 208  in this disease setting because the area involved with CIS is difficult to quantitate; therefore,

  7. 209  partial response should not be used as a response criteria in the assessment of patients with BCG-

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  1. 210  unresponsive CIS. Furthermore, partial response is not a relevant endpoint because cystectomy

  2. 211  would be indicated in patients with any remaining BCG-unresponsive CIS. Patients with both

  3. 212  CIS and completely resected lesions can be assessed using this endpoint. That is, this endpoint

  4. 213  would be used to assess the response of the remaining CIS. Adequate follow-up should be

  5. 214  provided to establish the duration of response.

215

  1. 216  A delay in cystectomy should not be used as a primary endpoint in patients with BCG-

  2. 217  unresponsive CIS. A delay of cystectomy is considered a direct patient benefit. However, in a

  3. 218  single-arm study, variability in health care provider and patient preference can makes it difficult

  4. 219  to interpret such a delay. Nevertheless, these data should be collected to provide supportive

  5. 220  evidence. Patients with completely resected lesions, in the absence of CIS, also can be included

  6. 221  in these trials but should not contribute to the primary endpoint. These patients should be

  7. 222  included in the safety analysis.

223

  1. 224  Intravesical therapy is unlikely to affect the occurrence of upper tract disease and, therefore, the

  2. 225  development of upper tract disease should not be included as an event in the assessment of the

  3. 226  duration of response. Upper tract disease should be included as an event in systemic therapy

  4. 227  trials. In both settings, the incidence of upper tract disease should be recorded and presented as a

  5. 228  separate analysis. Further, in some situations, it may be reasonable to exclude the development

  6. 229  of low-risk disease as an event. For example, a trial involving patients with BCG-unresponsive

  7. 230  disease could include only high-risk disease as an event. In this clinical setting, low-risk disease

  8. 231  would lead to transurethral resection while high-risk disease would lead to cystectomy, a much

  9. 232  different clinical outcome. Nevertheless, the low-risk recurrences and the development of upper

  10. 233  tract disease should be recorded and reported separately.

234
235
7. Trial Procedures and Timing of Assessments 236

  1. 237  During the conduct of a clinical trial, patients with NMIBC should be followed every 3 months

  2. 238  with cystoscopy, directed biopsies, and urine cytology. The definition of complete response

  3. 239  should be included in the protocol and should include the absence of lesions on cystoscopy or

  4. 240  negative, for cause, biopsies along with negative urine cytology. Random biopsies at a specific

  5. 241  time point(s) are not needed, but sponsors can choose to incorporate these into the study design.

  6. 242  The number of random biopsies and the biopsy sites should be defined in the protocol.

243

  1. 244  With either approach, it is important to ensure that all participating urologists perform and

  2. 245  document their examination of the bladder in a similar manner. A detailed protocol, as well as

  3. 246  investigator meetings and trial initiation visits, can be used to standardize this approach.

247

  1. 248  Follow-up of urine cytology is critical in patients with BCG-unresponsive NMIBC. The clinical

  2. 249  protocol should provide an algorithm for further workup of positive and indeterminate cytology.

  3. 250  In addition, the clinical protocol should provide a statement of what constitutes an event. For

  4. 251  example, the protocol would state whether a patient with no visible lesions, positive urine

  5. 252  cytology (i.e., the presence of malignant cells), and negative random biopsies would still be

  6. 253  considered to have a complete response. Note that the definition of an event used in the clinical

  7. 254  trial setting may differ from the actual management of the patient.

255

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256 8. Endpoint Adjudication 257

  1. 258  Sponsors should consult with the appropriate review division concerning the need for central

  2. 259  pathology review of all patients, or in a representative sample, to assess and adjudicate the

  3. 260  endpoint.

261
262
9. Statistical Considerations 263

  1. 264  For single-arm trials that use complete response rate as the primary endpoint, the lower bound of

  2. 265  the 95 percent confidence interval around the observed response rate should rule out clinically

  3. 266  unimportant complete response rates on treatment. The median duration and lower bound of the

  4. 267  95 percent confidence interval for duration of complete response are also important. A high

  5. 268  complete response rate is not meaningful if the duration is short.

269

  1. 270  Either early phase evidence of effect size or data from historical controls can be employed to

  2. 271  calculate the sample size of the single-arm trial; however, a prespecified response rate

  3. 272  (performance goal) is not required. The natural history of CIS is well understood, and the

  4. 273  complete response rate is negligible in the absence of therapy.

274
275
10. Accelerated Approval (Subpart H and Subpart E) Considerations 276

  1. 277  A development program that assesses complete response rate in a single-arm trial may be

  2. 278  appropriate for traditional approval or it may require a confirmatory trial postapproval.5

  3. 279  A confirmatory, randomized trial in the same population often is not possible (e.g., BCG-

  4. 280  unresponsive patients). It may be possible to provide confirmatory evidence of effectiveness in

  5. 281  a different patient population. For example, a drug that demonstrates a complete response rate in

  6. 282  patients with BCG-unresponsive disease also may be effective in patients who do not develop

  7. 283  a complete response following their initial induction course of BCG. Patients could then be

  8. 284  randomized to additional BCG or additional BCG plus the investigational drug. The need for

  9. 285  a confirmatory trial and its design can be discussed at a separate, end-of-phase 2 meeting held

  10. 286  during the conduct of a single-arm trial. On occasion, long-term follow-up from the same trial

  11. 287  can satisfy a confirmatory study obligation under accelerated approval.

288
289
11. Risk-Benefit Considerations 290

  1. 291  The approval of a marketing application is based on a favorable risk-benefit assessment. The

  2. 292  key elements in the planning and conduct of these trials have been outlined above. For therapies

  3. 293  that have greater toxicity (e.g., systemic therapies), substantially greater efficacy might be

  4. 294  needed to achieve an overall favorable risk-benefit assessment. Sponsors of clinical trials using

  5. 295  either intravesical or systemic therapy are encouraged to meet with the FDA to discuss details of

  6. 296  their trial designs.

297

5 21 CFR part 314, subpart H, and part 601, subpart E
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298 C. 299
300
1. 301

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Other Considerations

Risk Management Considerations

  1. 302  The FDA cannot make a decision concerning a risk management plan before it reviews the data

  2. 303  included in a biologics license application or new drug application. Sponsors should provide a

  3. 304  plan to assess the long-term outcomes for patients receiving the investigational drug. For

  4. 305  example, a long-term study or trial to assess bladder capacity may be needed if there was a signal

  5. 306  in premarketing studies that the investigational drug caused bladder fibrosis.

307
308
2. NonclinicalSafetyConsiderations 309

  1. 310  Before initiating clinical trials in patients with NMIBC, we recommend that nonclinical studies

  2. 311  be used to optimize the dose and schedule of intravesicular drugs. The choice and use of

  3. 312  nonclinical models will vary with the investigational drug and should be discussed with the

  4. 313  appropriate review division. Nonclinical studies also can be used to ensure that systemic

  5. 314  therapies are active at the mucosal surface of the bladder and to justify the potential risks

  6. 315  associated with systemic therapies. For drugs intended for intravesicular administration, the

  7. 316  extent of systemic exposure in nonclinical studies following intravesicular administration can be

  8. 317  used to determine the need for evaluation of systemic toxicity. If systemic exposure is low,

  9. 318  histological evaluation may be limited to locally exposed tissues. Similarly, if systemic exposure

  10. 319  of the active substance is equivalent to or less than that of an approved route of administration

  11. 320  for the same active substance, histological evaluation also may be limited to locally exposed

  12. 321  tissues. The recommendations for and timing of additional nonclinical studies depends upon the

  13. 322  available nonclinical and clinical data, the nature of the toxicities observed, and the patient

  14. 323  population (e.g., more advanced NMIBC such as BCG-unresponsive disease). This should be

  15. 324  discussed with the appropriate review division before the conduct of a clinical trial using either a

  16. 325  systemic or intravesicular drug in patients with NMIBC.

326

  1. 327  For recommendations on the substance and scope of nonclinical information needed to support

  2. 328  clinical trials for cell therapy and gene therapy products, see the guidances for industry

  3. 329 Preclinical Assessment of Investigational Cellular and Gene Therapy Products, Clinical

  4. 330 Considerations for Therapeutic Cancer Vaccines, and Recommendations for Microbial Vectors

  5. 331 Used for Gene Therapy.6

332

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6 These guidances are available on the Cellular & Gene Therapy Guidances Web page at
http://www .fda.gov/BiologicsBloodV accines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandG eneTherapy/default.htm.

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333 REFERENCES 334

  1. 335  Edge S, Byrd S, Compton CC, Fritz AG, Greene FL, and Trotti A, editors, 2010, AJCC Cancer

  2. 336  Staging Manual, 7th ed., New York (NY): Springer-Verlag.

337

  1. 338  Gudjonsson S, Blackberg M, Chebil G, Jahnson S, Olsson H, Bendahl PO, Mansson W, and

  2. 339  Liedberg F, 2012, The Value of Bladder Mapping and Prostatic Urethra Biopsies for Detection

  3. 340  of Carcinoma in Situ, BJU Int, 110(2 Pt 2) E41–45.

341

  1. 342  Jarow JP, Lerner SP, Kluetz PG, Liu K, Sridhara R, Bajorin D, Chang S, Dinney CP, Groshen S,

  2. 343  Morton RA, O’Donnell M, Quale DZ, Schoenberg M, Seigne J, and Vikram B, 2014, Clinical

  3. 344  Trial Design for the Development of New Therapies for Nonmuscle-Invasive Bladder Cancer:

  4. 345  Report of a Food and Drug Administration and American Urological Association Public

  5. 346  Workshop, Urology, 83(2):262–264.

347

  1. 348  Jarow J, Maher VE, Tang S, Ibrahim A, Kim G, Sridhara R, and Pazdur R, 2015, Development

  2. 349  of Systemic and Topical Drugs to Treat Non-Muscle Invasive Bladder Cancer, Bladder Cancer,

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