2022-04-06 — I. INTRODUCTION............................................................................................................ 1. II. BACKGROUND .
Apr 6, 2022 — I. INTRODUCTION............................................................................................................ 1. II. BACKGROUND .
Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment Guidance for Industry DRAFT GUIDANCE This guidance document is being distributed for comment purposes only.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be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.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 Poonam Mishra at 301-796-1500. 49523dft.docx 10/09/18 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) November 2018 Clinical/Antimicrobial Chronic Hepatitis B Virus Infection: Developing Drugs 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: druginfo@fda.hhs.gov https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) November 2018 Clinical/Antimicrobial TABLE OF CONTENTS I. INTRODUCTION..................................................................................................1 II. BACKGROUND ....................................................................................................2 III. DEVELOPMENT PROGRAM ............................................................................3 A. General Drug Development Considerations ...................................................................3 1. Early Phase Development Considerations..........................................................................3 a. Pharmacology/toxicology development considerations ...............................................3 b. Nonclinical virology development considerations .......................................................4 c. Clinical pharmacology considerations..........................................................................5 2. Drug Development Population............................................................................................6 3. Safety Considerations..........................................................................................................7 B. Phase 3 Efficacy Trial Considerations.............................................................................7 1. Trial Design.........................................................................................................................7 a. Chronic suppressive therapy.........................................................................................7 b. Finite duration therapy .................................................................................................8 2. Trial Population ..................................................................................................................9 3. Entry Criteria ......................................................................................................................9 4. Randomization, Stratification, and Blinding .......................................................................9 5. Specific Populations ..........................................................................................................10 a. HBV/HIV-1 coinfected patients .................................................................................10 b. HBV/HDV coinfected patients...................................................................................10 c. Pediatric patients.........................................................................................................10 6. Dose Selection ...................................................................................................................12 7. Efficacy Endpoints.............................................................................................................12 8. Trial Procedures and Timing of Assessments ...................................................................13 9. Statistical Considerations..................................................................................................13 a. Analysis populations...................................................................................................13 b. Efficacy analyses........................................................................................................13 c. Handling of missing data............................................................................................14 10. Accelerated Approval (Subpart H) Considerations ......................................................14 11. Benefit-Risk Considerations..........................................................................................14 C. Other Considerations ......................................................................................................14 1. Clinical Virology Considerations......................................................................................14 2. Pharmacokinetic/Pharmacodynamic Considerations .......................................................16 3. Labeling Considerations ...................................................................................................17 GLOSSARY OF ACRONYMS ......................................................................................18 REFERENCES.................................................................................................................19 Contains Nonbinding Recommendations Draft -- Not for Implementation 1 Chronic Hepatitis B Virus Infection: 2 Developing Drugs for Treatment 3 Guidance for Industry1 4 5 6 7 8 This draft guidance, when finalized, will represent the current thinking of the Food and Drug 9 Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 10 binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 11 applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 12 for this guidance as listed on the title page. 13 14 15 16 17 I. INTRODUCTION 18 19 The purpose of this guidance is to assist sponsors in the clinical development of drugs and 20 biologics for the treatment of chronic hepatitis B virus (HBV) infection from the initial 21 investigational new drug application (IND) through the new drug application (NDA)/biologics 22 license application (BLA) and postmarketing phases.2 This draft guidance is intended to serve as 23 a focus for continued discussions among the Division of Antiviral Products (DAVP), 24 pharmaceutical sponsors, the academic community, and the public.3 Sponsors are also 25 encouraged to communicate with DAVP through the pre-IND consultation program to obtain 26 advice in the development of drugs with unique considerations based on mechanism of action, 27 novel treatment approaches, or the use of novel biomarkers.4 28 29 This guidance does not address development of vaccines or blood-derived products, as these are 30 regulated by the Center for Biologics Evaluation and Research. This guidance also does not 31 contain discussion of the general issues of statistical analysis or clinical trial design. Those 1 This guidance has been prepared by the Division of Antiviral Products in the Center for Drug 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 therapeutic biological products unless otherwise specified. 3 In addition to consulting guidances, sponsors are encouraged to contact the DAVP to discuss specific issues that arise during the development of chronic HBV drugs. 4 See the DAVP Pre-IND Letter of Instruction web page at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/Overview/ucm077776.htm. 1 Contains Nonbinding Recommendations Draft -- Not for Implementation 32 topics are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical 33 Trials and E10 Choice of Control Group and Related Issues in Clinical Trials, respectively.5 34 35 In general, FDA's guidance documents do not establish legally enforceable responsibilities. 36 Instead, guidances describe the Agency's current thinking on a topic and should be viewed only 37 as recommendations, unless specific regulatory or statutory requirements are cited. The use of 38 the word should in Agency guidances means that something is suggested or recommended, but 39 not required. 40 41 42 II. BACKGROUND 43 44 HBV is an enveloped DNA virus belonging to the Hepadnavirus family. The highly stable 45 covalently closed circular viral DNA (cccDNA) functions as a nonreplicative minichromosome 46 and persists throughout the lifespan of infected hepatocytes. The cccDNA is not eliminated by 47 currently available therapies that include drugs from the nucleoside/nucleotide reverse 48 transcriptase inhibitor (NrtIs) class, and pegylated interferon (IFN). 49 50 Chronic HBV (CHB) infection results in progressive liver disease ranging from asymptomatic to 51 severe disease with complications including cirrhosis, liver failure, and the development of 52 hepatocellular carcinoma (HCC). In untreated adults with CHB, the cumulative 5-year incidence 53 of cirrhosis is 8 to 20 percent; and among those with cirrhosis, the 5-year cumulative risk of 54 hepatic decompensation is 20 percent, and risk of HCC is 2 to 5 percent (Terrault et al. 2016). 55 An effective vaccine and antiviral therapies are approved for the prevention of HBV infection 56 and treatment of CHB, respectively. 57 58 Currently available therapies achieve sustained suppression of HBV DNA while on-treatment 59 with low rates of HBV surface antigen (HBsAg) loss with or without seroconversion to anti60 HBsAg (HBsAb). Sustained HBV DNA suppression is associated with serum alanine 61 aminotransferase (ALT) normalization and improvement in liver histology including regression 62 of hepatic fibrosis and cirrhosis (Chang et al. 2010; Marcellin et al. 2013; Buti et al. 2015). 63 Effective HBV therapy reduces disease-related complications such as hepatic decompensation 64 and liver failure, and decreases risk of HCC (Lok et al. 2016; Papatheodoridis et al. 2017). 65 Clearance of HBsAg is associated with reduced risk of hepatic decompensation and improved 66 survival (Terrault et al. 2016). The development of new therapies is targeted at developing 67 treatment regimens of finite duration with low risk of virologic relapse and minimal risk of liver 68 disease progression after the treatment is stopped (Lok et al. 2017). 69 70 5 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 2 Contains Nonbinding Recommendations Draft -- Not for Implementation 71 III. DEVELOPMENT PROGRAM 72 73 A. General Drug Development Considerations 74 75 This section discusses nonclinical and early phase clinical development considerations, followed 76 by issues related to the target population for drug development, assessment of activity in early 77 phase trials, and safety considerations. 78 79 1. Early Phase Development Considerations 80 81 Early clinical evaluation should follow a rational approach to provide sufficient data to establish 82 safety and antiviral activity in support of phase 3 trials. 83 84 a. Pharmacology/toxicology development considerations 85 86 Pharmacology/toxicology development considerations for single HBV drugs should follow the 87 approaches outlined in existing guidances for drug development.6 Although the ICH guidance 88 for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and 89 Marketing Authorization for Pharmaceuticals (ICH M3(R2)) recommends nonclinical 90 combination studies to support clinical trials of combination regimens for investigational drugs 91 in early stages of development (referred to in ICH M3(R2) as early stage entities), the FDA 92 recommends that for new HBV drug combinations (consisting of two or more early stage 93 investigational drugs), sponsors should discuss with the FDA whether combination toxicology 94 studies should be submitted as part of an IND to support combination clinical trials, including the 95 design of such studies. When combination toxicology studies are conducted, usually no more 96 than two drugs should be tested simultaneously in a particular arm of a toxicology study. 97 Nonclinical combination studies of an investigational drug plus an approved drug or licensed 98 biological product generally are not recommended. Therefore, unless data from nonclinical 99 studies of an investigational drug suggest a potential for serious synergistic toxicity with an 100 approved drug or licensed biological product, combination toxicology studies are not anticipated. 101 102 In general, sponsors that have clinical indications for HBV drugs with treatment durations of 6 103 months or more should conduct carcinogenicity studies.7 Sponsors developing biological 104 products should follow approaches outlined in the existing ICH guidance for industry S6 105 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals and discuss their 106 proposals for a carcinogenicity risk assessment with the FDA during clinical development to 107 facilitate a final assessment needed to support a BLA. Regarding the timing of study 108 submission, sponsors should submit carcinogenicity studies with an initial NDA. Under limited 109 circumstances, the FDA may consider allowing sponsors to initiate carcinogenicity studies (with 110 written agreement) before submitting an NDA and to submit the completed studies during the 6 See the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals, S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, and S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. 7 See the ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies of Pharmaceuticals. 3 Contains Nonbinding Recommendations Draft -- Not for Implementation 111 postmarketing period under section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act 112 (FD&C Act).8 113 114 b. Nonclinical virology development considerations 115 116 Sponsors should consider recommendations for general antiviral drug development found in the 117 guidance for industry Antiviral Product Development -- Conducting and Submitting Virology 118 Studies to the Agency. However, the development of drugs to treat CHBV infection is rapidly 119 evolving using novel approaches. Therefore, we recommend that sponsors use the pre-IND 120 consultation program to initiate preliminary discussions regarding products and development 121 plans. FDA encourages detailed reports describing the mechanism of action, antiviral activity in 122 cell culture, cytotoxicity and mitochondrial toxicity, animal models, and resistance studies. 123 Additionally, sponsors are advised to provide the following nonclinical virology data for 124 investigational drugs developed specifically for the treatment of CHB. 125 126 Resistance and cross-resistance 127 128 HBV does not generally grow well enough in cell culture to select for resistant virus. We 129 recommend that resistance assessments be performed for all animal studies that assess the 130 antiviral activity of an investigational drug in infected animals and that a resistance monitoring 131 plan be included in the protocols for all clinical trials that will treat patients with CHB. 132 133 Amino acid substitutions or nucleotide mutations associated with the development of 134 resistance to an investigational drug should be determined by sequencing the drug target 135 and validated by introducing resistance-associated substitutions or mutations into the 136 HBV genome using site-directed mutagenesis, and determining the fold-shift in 137 susceptibility. Results from these studies help identify resistance pathways; and support 138 the drug's proposed mechanism of action. Lack of a shift in susceptibility does not 139 exclude a resistance association for a specific substitution or mutation that occurs in 140 multiple independent events. 141 142 Cross resistance should be assessed to determine if resistance against approved HBV drugs 143 confers resistance to the drug being developed and vice versa. The development of cross- 144 resistance to HBV vaccine epitopes should be assessed. 145 146 Considerations for antisense oligonucleotides and siRNA investigational drugs 147 148 Knockdown of viral protein expression via antisense oligonucleotides and small interfering RNA 149 (siRNA) is an active area for the development of antiviral drugs. These drugs, which have a 150 nucleic acid target, present potential off-target binding at mismatched sequences that could lead 151 to species-specific toxicities not detected in classical toxicity studies. Therefore, we recommend 152 that the following bioinformatics studies be conducted for drugs that use a nucleic acid target. 153 The studies should: 8 See also the guidance for industry Postmarketing Studies and Clinical Trials -- Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act. 4 Contains Nonbinding Recommendations Draft -- Not for Implementation 154 155 Identify potential off-target matches in the human transcriptome, regardless of tissue 156 expression; for each of these, describe available information on mouse knockouts and 157 human genetic diseases. A plan for monitoring for significant off-target effects should be 158 included in clinical trial protocols. 159 160 Determine the conservation among the investigational off-target human genes with their 161 respective mouse genes that are three or fewer mismatched bases different from the drug 162 to determine if these sites are sufficiently conserved in the mouse such that toxicities 163 related to off-target matches would be present in mice. 164 165 Identify potential off-target matches in the human mitochondrial transcriptome. 166 167 Determine the variation within the off-target matches in the transcriptomes of different 168 populations in the United States to assess whether different populations would be more 169 susceptible to off-target effects than others. 170 171 Determine the effect of different mismatches with respect to off-target effects (i.e., 172 comparing purine to purine versus other mismatches). 173 174 Targeting host factors 175 176 For drugs targeting host factors, polymorphisms in the gene encoding the target should be 177 assessed to determine if the drug will be more effective or less effective in different populations. 178 If a nonclinical assay to assess the drug effect is available, multiple samples from each of the key 179 racial groups in the United States should be evaluated to determine whether race may be a factor 180 contributing to efficacy. Samples should be collected during clinical trials to determine the virus 181 genotype of patients who respond less favorably to treatment. 182 183 c. Clinical pharmacology considerations 184 185 In general, dose selection for early efficacy trials should be predicted to provide plasma drug 186 exposures that exceed by several-fold the protein binding-adjusted, cell culture EC50 value of the 187 drug for the relevant HBV genotype/subtype. The dose selection should also consider the safety 188 data from the previous phase 1 trials and animal studies. 189 190 Sponsors should refer to the appropriate clinical pharmacology guidances for industry to inform 191 the need and design of drug-drug interaction studies and PK studies in patients with renal or 192 hepatic impairment.9 We encourage sponsors to conduct these studies, if needed, early in 9 See the guidance for industry Pharmacokinetics in Patients With Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. See also the draft guidances for industry Clinical Drug Interaction Studies -- Study Design, Data Analysis, and Clinical Implications; In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies, and Pharmacokinetics in Patients With Impaired Renal Function -- Study Design, Data Analysis, and Impact on Dosing and Labeling. When final, these guidances will represent the FDA's current thinking on these topics. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 5 Contains Nonbinding Recommendations Draft -- Not for Implementation 193 development to inform the management of drug interactions and the inclusion of patients with 194 renal and hepatic impairment in phase 3 trials as appropriate. See section III.B.6., Dose 195 Selection, for dose selection for phase 2 and 3 trials and section III.C.2., 196 Pharmacokinetic/Pharmacodynamic Considerations, for other PK and pharmacodynamic 197 considerations. 198 199 2. Drug Development Population 200 201 Therapies should be developed for use in a wide range of patients with CHB including pediatric 202 populations. 203 204 Early phase clinical trials should focus on the adult population without cirrhosis. Initial trials can 205 be conducted in treatment-naïve HBV e antigen positive (HBeAg-positive) patients with active 206 disease, or in HBeAg-positive or HBV e antigen negative (HBeAg-negative) patients who are 207 virally suppressed on NrtIs. In addition to endpoints discussed in section III., B., Phase 3 208 Efficacy Trial Considerations, sponsors can evaluate exploratory endpoints in early phase trials 209 to gather data to inform and support the choice of appropriate endpoints in late phase trials 210 particularly those evaluating treatments of finite durations. Some of these exploratory endpoints 211 may include the following: 212 213 · Change in quantitative HBsAg (qHBsAg) concentration at various time points on- 214 treatment 215 · HBeAg concentration 216 · HBV RNA 217 · HBV core-related antigen (HBcrAg) 218 · cccDNA quantification 219 · HBsAg fragments 220 · HBsAg-anti-HBs immune complex 221 222 Also depending on the drug's mechanism of action, liver biopsy findings can be used in certain 223 proof-of-concept studies to confirm a novel mode of action and/or to validate surrogate markers 224 of antiviral activity. 225 226 CHB is a global disease, and clinical trials are often conducted in multiple countries. Under 21 227 CFR 312.120, the FDA will accept a well-designed, well-conducted, non-IND foreign study as 228 support for an IND or application for marketing approval if the trial was conducted in 229 accordance with good clinical practice and if the FDA is able to validate the data from the trial 230 through an onsite inspection, if necessary. When sponsors rely on foreign data, these should be 231 supported with information about predominant virus genotypes and subtypes in the region(s). 232 Development programs should include a sufficient number of U.S. patients to ensure 233 applicability of data to the U.S. population. The FDA strongly encourages sponsors to discuss 234 the anticipated number of women and racial representation that will be included in the 235 submission to support an NDA or BLA at the end-of-phase 2 meeting. 236 6 Contains Nonbinding Recommendations Draft -- Not for Implementation 237 3. Safety Considerations 238 239 In general, we recommend that initial marketing applications for drugs intended to treat CHB 240 contain a safety database of about 1,000 to 1,500 patients exposed to the proposed dose and 241 duration of treatment. Depending on the drug safety profile and concerns identified during the 242 development process, a larger database or long durations of post-treatment follow-up may be 243 needed. 244 245 In addition to routine safety monitoring, specific criteria for monitoring for hepatitis flares or 246 HBV reactivation should be well-defined in the clinical trial protocols. Clinical protocols should 247 include predefined algorithms for data collection in the setting of significant hepatic events to 248 ensure that the relevant data are available for further assessment and adjudication of these cases 249 to differentiate between potential etiologies. The outcomes for all serious hepatic events should 250 be systematically evaluated during clinical development. Evaluation by an independent 251 adjudication committee is encouraged. 252 253 For a drug approved for use in patients without cirrhosis or with compensated cirrhosis, the 254 database needed to extend use to the decompensated cirrhotic population would depend on the 255 safety profile of the investigational drug and the overall benefit-risk profile for the indicated 256 population. Similarly, obtaining safety data in other subpopulations, such as in patients 257 coinfected with hepatitis D virus (HDV), may be important for certain clinical development 258 programs. We encourage sponsors to discuss with the FDA safety-related considerations, 259 including but not limited to the size of the safety database, before the initiation of phase 3 trials. 260 261 B. Phase 3 Efficacy Trial Considerations 262 263 Sponsors can submit an NDA/BLA to support marketing approval of a drug in a single patient 264 population. Such an application should include at least two adequate and well-controlled trials 265 conducted in the proposed population. Alternatively, sponsors can choose to pursue an 266 indication for different populations (e.g., a trial in treatment-naïve patients and a second trial in 267 patients who are virally suppressed on NrtIs). In these situations, the NDA should contain at 268 least one adequate and well-controlled trial in each patient population, with adequate supporting 269 data. 270 271 1. Trial Design 272 273 Randomized and well-controlled trials are recommended to establish efficacy because of the 274 heterogeneity of the natural course of CHB. Appropriate trial designs depend on whether the 275 therapeutic is intended for chronic suppressive therapy or therapy of finite duration as discussed 276 below. 277 278 a. Chronic suppressive therapy 279 280 A randomized controlled trial with an approved active control arm with the primary efficacy 281 endpoint of undetectable HBV DNA (defined as less than lower limit of quantification (LLOQ), 282 target not detected (TND)) after 48 weeks on-treatment could be conducted in HBeAg-positive 7 Contains Nonbinding Recommendations Draft -- Not for Implementation 283 patients and HBeAg-negative patients. The active comparator should be an antiviral drug that is 284 recommended for treatment of CHB and reflects current practice at the time of trial initiation. 285 The patient population could be treatment-naïve or previously treated patients with detectable 286 HBV DNA. 287 288 b. Finite duration therapy 289 290 The appropriate trial design depends on the patient population being studied and the treatment 291 regimen being evaluated. 292 293 Virally suppressed on NrtIs 294 295 To evaluate the primary efficacy outcome of sustained HBV DNA suppression off-treatment 296 with HBsAg loss in patients with active disease (HBeAg-positive or HBeAg-negative CHB) who 297 are virally suppressed on NrtIs, sponsors can consider an add-on superiority trial against placebo 298 with current NrtI treatment regimen as the background therapy. The primary efficacy endpoint 299 of HBsAg loss and sustained HBV DNA suppression should be assessed at the 6-month post- 300 treatment time point with additional follow-up to monitor for durability of response (i.e., 301 sustained HBV DNA suppression and HBsAg loss) off-treatment. 302 303 Alternatively, an outcome of sustained HBV DNA suppression off-treatment without HBsAg 304 clearance can be evaluated after a finite treatment duration using a superiority trial design 305 comparing the investigational drug plus an NrtI to an NrtI alone. 306 307 Sponsors should use the following criteria for stopping NrtI therapy at the end of the 308 investigational treatment period: (1) applied equally across treatment arms; (2) well-defined in 309 the protocol; and (3) stringent, such as HBsAg loss or substantial HBsAg decline or marked 310 reduction in other important biomarkers identified in phase 2 trials. It is expected that few 311 patients would meet such criteria on the placebo arm. The use of biomarkers as a trigger for 312 treatment interruption should be discussed with the FDA in advance of trial initiation. 313 314 Treatment-naïve 315 316 An outcome of sustained HBV DNA suppression off-treatment with HBsAg loss can be 317 evaluated to demonstrate superiority to an active control or placebo in treatment-naïve patients in 318 whom a treatment is currently not indicated per treatment guidelines. In certain patient 319 populations (e.g., for patients in the immune-tolerant phase with mild necroinflammation or 320 fibrosis) comparison with placebo may be feasible as current treatment guidelines do not 321 recommend treatment for these patients. 322 323 In any of the trial design scenarios, it may be appropriate for patients in the placebo group to be 324 rolled over to active investigational drug before the completion of the trial (e.g., at the 325 prespecified interim analysis). This should be discussed with the FDA before trial enrollment. 326 327 Sponsors considering a noninferiority (NI) trial design should discuss in advance their trial 328 designs and justifications of the proposed NI margin based on historical evidence of treatment 8 Contains Nonbinding Recommendations Draft -- Not for Implementation 329 effect of the active control. In general, the active comparator in an NI trial should be an FDA- 330 approved drug that is considered the standard of care for the specific indication and population 331 being studied. A detailed protocol and statistical analysis plans (SAPs) should be submitted for 332 review. 333 334 2. Trial Population 335 336 Patients fulfilling one of the following two criteria for CHB should be enrolled (Centers for 337 Disease Control and Prevention 2012): 338 339 (1) Negative immunoglobulin M (IgM) antibodies to HBV core antigen (IgM anti-HBc) 340 AND a positive result on one of the following tests: HBV surface antigen (HBsAg), 341 HBV e antigen (HBeAg), or nucleic acid test for hepatitis B virus DNA (including 342 qualitative, quantitative, and genotype testing); or 343 344 (2) Positive HBsAg result or positive nucleic acid test for HBV DNA (including qualitative, 345 quantitative, and genotype testing) or positive HBeAg on two occasions at least 6 months 346 apart (any combination of these tests performed 6 months apart is acceptable). 347 348 Sponsors should consider evaluating drug efficacy in key CHB subpopulations, including 349 but not limited to the following: 350 351 HBeAg-positive and HBeAg-negative patients 352 Patients with cirrhosis 353 Patients with decompensated liver disease 354 355 3. Entry Criteria 356 357 The presence or absence of cirrhosis at study entry should be documented. The use of a 358 noninvasive modality to define presence or absence of cirrhosis in a trial protocol should be 359 supported by references that summarize performance characteristics and sensitivity and 360 specificity of the modality for identifying patients with cirrhosis. Patients with history of and 361 current evidence of HCC should be excluded. 362 363 4. Randomization, Stratification, and Blinding 364 365 Sponsors should conduct randomized, double-blind trials whenever feasible to reduce the 366 likelihood of potential biases. In general, trials should be designed to evaluate the effect of 367 investigational therapies in patients with key disease characteristics. If feasible, patient 368 subpopulations should be studied separately. If multiple patient populations are included in the 369 same trial, consideration should be given to stratifying groups at randomization based on 370 variables such as HBeAg status, HBsAg level, presence or absence of cirrhosis, HBV DNA 371 level, treatment history, and HBV genotype; and to ensure adequate number of patients in each 372 stratum to provide informative data. 373 9 Contains Nonbinding Recommendations Draft -- Not for Implementation 374 5. Specific Populations 375 376 a. HBV/HIV-1 coinfected patients 377 378 The overall treatment goals for HBV/HIV coinfected patients remain identical to those described 379 for the HBV-monoinfected population. The concurrent use of HIV antiretroviral drugs that are 380 also effective against HBV may have implications for treatment cessation with finite duration 381 HBV therapies and possibly confound interpretation of efficacy outcome. Because of the various 382 interactions between HIV and HBV therapies, we recommend sponsors discuss their plans and 383 obtain feedback from the FDA regarding trials in coinfected patients. 384 385 b. HBV/HDV coinfected patients 386 387 Infection with HDV only occurs in the setting of concurrent HBV infection (Wranke and 388 Wedemeyer 2016). Approximately 15 million people worldwide are living with HBV/HDV 389 coinfection (World Health Organization 2017). Relative to HBV monoinfection, HBV/HDV 390 coinfection leads to more severe liver disease resulting in a greater risk of cirrhosis, HCC, and 391 hepatic decompensation/failure. 392 393 The ultimate goal in treating HBV/HDV coinfected patients is clearance or long-term 394 suppression of both viruses. CHB treatment leading to loss of HBsAg may ultimately lead to the 395 clearance of HDV infection (Wranke and Wedemeyer 2016). HDV superinfection frequently 396 leads to spontaneous suppression of HBV (Huang and Lo 2014) and the effect of specific HBV 397 therapies on the interplay between the two viruses cannot be predicted. Recommendations for 398 studies in HBV/HDV coinfection are beyond the scope of this guidance and development plans 399 should be discussed directly with the FDA. 400 401 c. Pediatric patients 402 403 Pediatric assessments are required under section 505B of the FD&C Act as part of the overall 404 drug development program for a "new active ingredient, new indication, new dosage form, new 405 dosing regimen, or new route of administration,"10 unless those assessments are waived.11 406 Sponsors are required to submit pediatric study plans no later than 60 days after an end-of-phase 407 2 meeting or such other time as may be agreed upon by the FDA and the sponsor.12 408 409 In the absence of a serious safety signal in adults, sponsors should enroll adolescents 410 concurrently (for the purpose of this guidance, 12 to younger than 18 years of age) with adults in 411 phase 3 trials and make every effort to obtain confirmatory PK and safety data from a cohort in 412 this age group as part of the data included at the time of filing of the original NDA/BLA.13 10 See section 505B(a)(1)(A) of the FD&C Act; 21 U.S.C. 355c(a)(1)(A). 11 See section 505B(a)(5) of the FD&C Act. 12 See section 505B(e)(2)(A)(ii) of the FD&C Act; see also the draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans. When final, this guidance will represent the FDA's current thinking on this topic. 10 Contains Nonbinding Recommendations Draft -- Not for Implementation 413 Because progressive liver disease is uncommon in young children with HBV infection, it is 414 generally not recommended to include patients younger than 2 years in most development 415 programs. Further, treatment generally is not recommended in children younger than 2 years of 416 age as per current treatment guidelines (Terrault et al. 2016). Sponsors should discuss their plans 417 for pediatric assessments with the review division and be aware of timing and content 418 requirements for pediatric study plans under section 505B(e) of the FD&C Act. 419 420 In general, pediatric clinical trials can be initiated after phase 2 adult data characterizing the 421 safety profile and preliminary evidence of efficacy are available. Typically, the non-adolescent 422 pediatric population (for the purpose of this guidance, 2 to younger than 12 years of age) is 423 divided into several groups or cohorts according to age or weight for enrollment into trials. 424 Weight, rather than age, is the preferred criterion for enrollment because dosing 425 recommendations for most antiviral drugs are weight-based. In addition, within clinical studies, 426 sponsors should enroll the cohorts in parallel rather than in series, unless a drug has a specific 427 safety or drug disposition factor that warrants a different approach. 428 429 Sponsors should discuss with the FDA initial pediatric PK data and results of available modeling 430 and simulation before dose selection for pediatric treatment trials. Partial pediatric extrapolation 431 of efficacy may be acceptable for HBV drugs because antiviral effects are sufficiently similar 432 between adult and pediatric populations. Therefore, after critical PK parameters for a drug are 433 identified from adult data, pediatric development programs can rely on matching the relevant 434 pediatric and adult exposure parameters to demonstrate effectiveness in pediatric populations in 435 which treatment is indicated as per current treatment guidelines. Additional data should be 436 obtained to assess whether antiviral activity is comparable to that observed in adult trials. 437 438 The pediatric trials should also obtain data to support safety in pediatric populations; in general, 439 a safety database of about 100 patients receiving the proposed dose for at least 48 weeks or 440 prespecified duration for drug with finite treatment duration, and adequately distributed across 441 the pediatric population for which studies are required and not waived or deferred. If clinical 442 trials in adults have demonstrated differences in safety profile or dosing based on fibrosis stage, 443 pediatric patients should be assessed for presence or absence of cirrhosis using the most 444 appropriate modality for each study location. 445 446 Section 505B of the FD&C Act also mandates that the requisite pediatric assessments be 447 conducted using a formulation of the drug that is appropriate for each pediatric group being 448 studied.14 Adult formulations generally are considered appropriate for adolescent patients 449 (approximately 12 to 18 years of age) (Momper et al. 2013), but younger patients, who may not 450 be able to swallow pills, may require different formulations. Therefore, pediatric formulation 451 development should begin as early as possible to enable the development of appropriate pediatric 452 formulations of investigational drugs. 453 13 We note that, for applications to which section 505B applies, all pediatric assessments must be submitted with the application unless those assessments have been deferred (section 505B(a)(1)(A)). 14 See section 505B(a)(2)A) of the FD&C Act. 11 Contains Nonbinding Recommendations Draft -- Not for Implementation 454 6. Dose Selection 455 456 Sponsors are encouraged to use quantitative clinical pharmacology approaches that leverage 457 prior information to inform dose selection for phase 2 trials and optimize dose selection for 458 phase 3 trials. The results from the proof-of-concept antiviral activity trials should be used to 459 guide selection of doses to be evaluated in phase 2 dose ranging trials with a consideration to 460 avoid the risk of the development of resistant virus and potential concerns of treatment failure 461 caused by subtherapeutic exposure. To optimize the selected dose for phase 3 trials, quantitative 462 clinical pharmacology approaches can be used to predict HBV DNA reduction in the planned 463 trials. Exposure-safety analyses, based on events with plausible causality to the drug and with 464 clinical relevance, should also be evaluated. 465 466 7. Efficacy Endpoints 467 468 New therapies could be evaluated in clinical trials using any of the following efficacy endpoints: 469 470 Suppression of HBV DNA (defined as less than LLOQ, TND) on-treatment -- similar to 471 currently available chronic NrtI therapies 472 473 Sustained suppression (more than 6 months) of HBV DNA (less than LLOQ, TND) off- 474 treatment after a finite duration of therapy 475 476 Sustained suppression (more than 6 months) of HBV DNA (less than LLOQ, TND) off- 477 treatment with HBsAg loss (less than 0.05 international unit/milliliter (IU/mL)) with or 478 without HBsAb seroconversion after a finite duration of therapy 479 480 At present, utility of reduction in HBsAg from baseline (without complete clearance) for 481 assessing response to CHB therapies is unclear because of inconsistent correlations between 482 qHBsAg and clinical response (Hu et al. 2018; Thompson et al. 2010; Chan et al. 2011). 483 484 A limited number of secondary endpoint(s) (e.g., HBeAg loss, anti-HBe seroconversion in 485 HBeAg positive patients, ALT normalization) should be considered for testing using appropriate 486 statistical methods for multiplicity. Biochemical serum markers such as ALT values vary 487 between laboratories, and lack of normalization of ALT may often be confounded by presence of 488 other chronic liver diseases such as nonalcoholic fatty liver disease. 489 490 Other important endpoints: Assessing progression of liver disease 491 492 Except for patients with advanced or decompensated cirrhosis, a statistically rigorous evaluation 493 of endpoints of liver progression can be challenging because these events occur infrequently 494 until late in the course of CHB. However, treatment effects on these endpoints provide useful 495 clinical information, and trials evaluating them could be used to support an expanded indication 496 or patient population and could be summarized in appropriate sections of the label. 497 Some of the parameters or clinical outcomes that sponsors can consider include the following: 498 499 Change in Model for End Stage Liver Disease scores 12 Contains Nonbinding Recommendations Draft -- Not for Implementation 500 Change in Child-Turcotte-Pugh scores 501 Progression to liver failure requiring transplantation or resulting in death 502 Occurrence of HCC 503 504 Treatment-related regression of fibrosis or cirrhosis, as assessed by liver biopsy or noninvasive 505 methods, can also be appropriate for display in the label and should be discussed with the 506 division when protocols evaluating these endpoints are being designed. 507 508 8. Trial Procedures and Timing of Assessments 509 510 Biochemical, serological, virological, and histological endpoints can be used to assess the 511 effectiveness of therapy. For drugs with finite treatment durations, the optimal time point to 512 assess the primary efficacy endpoint of sustained virologic response is 6 months or longer after 513 cessation of therapy. Additionally, the most appropriate time point to assess efficacy endpoints 514 depend on the mechanism of action and half-life of the drug. Longer term follow-up may be 515 useful to confirm durability of treatment response and to measure clinical outcomes. 516 517 9. Statistical Considerations 518 519 In general, a detailed protocol and SAP stating the trial hypotheses, analysis methods, and all 520 other relevant details should be provided to DAVP before trial initiation. For statistical analysis 521 methods and issues, see the FDA guidances for industry Providing Clinical Evidence of 522 Effectiveness for Human Drug and Biological Products and Non-Inferiority Clinical Trials to 523 Establish Effectiveness and the FDA White Paper Statistical Considerations on Subgroup 524 Analysis in Clinical Trials (Alosh et al. 2015). 525 526 a. Analysis populations 527 528 All patients who are randomized and received at least one dose of assigned therapy during the 529 trial should be included in the primary efficacy analysis. Any possibility of randomized patients 530 who do not receive treatment in either or both arms should be minimized. 531 532 b. Efficacy analyses 533 534 The primary analysis should compare the proportion of responders across trial treatment arms. 535 This analysis determines whether effectiveness has been demonstrated. 536 537 For subgroup analyses, the analysis of the primary efficacy endpoint should be performed within 538 important demographic and baseline characteristics (e.g., geographic region, sex, race, age 539 group, HBV genotype, HBeAg status, screening HBV DNA, baseline weight, and body mass 540 index, baseline ALT, baseline fibrosis/cirrhosis, and (if applicable) prior response to previous 541 treatment regimens). The purpose of these analyses is to explore the consistency of the primary 542 efficacy endpoint result across these subgroups. 543 13 Contains Nonbinding Recommendations Draft -- Not for Implementation 544 Treatment-by-region interaction should be investigated and reported to assess consistency of the 545 efficacy results. Treatment-by-HBeAg status interaction should also be investigated if HBeAg- 546 positive and -negative patients are enrolled in the trial. 547 548 c. Handling of missing data 549 550 Sponsors should make every attempt to limit discontinuation of patients from the trial. When the 551 loss is unavoidable, sponsors should explain the causes of missing data and attempt to determine 552 the final status of a patient who does not complete the protocol. Analyses excluding patients 553 with missing data or other post-treatment outcomes can be biased because patients who do not 554 complete the trial may differ substantially in both measured and unmeasured ways compared to 555 patients who remain in the trial. The primary method of handling missing data in the analysis 556 should be prespecified in the protocol or the SAP. Sensitivity analyses should demonstrate that 557 the primary analysis results are robust to the assumptions regarding missing data. 558 559 10. Accelerated Approval (Subpart H) Considerations 560 561 For CHB, HBV DNA suppression with or without HBsAg loss is considered a validated 562 surrogate endpoint that has been demonstrated to predict clinical outcomes; and this endpoint 563 could be used to support a traditional approval. Sponsors should discuss plans to use any 564 surrogate endpoints that are reasonably likely to predict clinical benefit to support accelerated 565 approval with the FDA. 15 After accelerated approval, postmarketing confirmatory trials have 566 been required to verify and describe the anticipated effect on irreversible morbidity or mortality 567 or other clinical benefit.16 568 569 11. Benefit-Risk Considerations 570 571 A thorough and comprehensive benefit-risk assessment ensures that the benefits outweigh 572 potential risks to the intended population. Benefit-risk assessment takes into consideration 573 demonstrated therapeutic effect of the new drug, and observed safety profile in the context of 574 underlying disease and current treatment options available for the indication. 575 576 C. Other Considerations 577 578 1. Clinical Virology Considerations 579 580 Samples for HBV quantification, genotypic, and phenotypic analysis should be obtained at 581 different time points during treatment and follow-up. Timing of sample collection should be 582 based on initial observations of potency, and on-treatment and off-treatment durability. The 583 genotypes and phenotypes of baseline and virologic failure isolates should be determined 584 (virologic failure defined as a confirmed increase of greater than or equal to 1 log10 HBV DNA 585 copies/mL above nadir, quantifiable HBV DNA after being less than LLOQ, or never achieved 586 HBV DNA levels less than LLOQ). Genotypes of baseline and on-therapy virologic failure 15 See section 506(c) of the FD&C Act; 21 CFR part 314, subpart H; 21 CFR part 601, subpart E. 16 See 21 CFR 314.510; 21 CFR 601.41. 14 Contains Nonbinding Recommendations Draft -- Not for Implementation 587 isolates should be compared and newly emerged drug resistance-associated 588 substitutions/mutations should be identified. HBV DNA from patients with genotypic resistance 589 to the investigational drug should be cloned in an HBV genome background and susceptibility to 590 the investigational drug should be determined. 591 592 There are 10 recognized HBV genotypes (genotypes A through H) as well as subtypes 593 identified for genotypes A through F. The different HBV genotypes/subtypes encode 594 distinct viral proteins and may exhibit differential responses to an investigational drug, 595 which could confound efficacy results in clinical trials if the drug is only effective against 596 some genotype/subtypes. Therefore, we recommend determining the genotypes/subtypes 597 of HBV infection present at baseline to determine if the investigational drug exhibits 598 antiviral activity against all HBV genotypes/subtypes. The assay, with performance 599 characteristics, used to genotype the HBV samples in enrolled patients should be 600 included with the clinical trial protocol. It may be important to confirm the 601 genotype/subtype by phylogenetic analysis. 602 603 For resistance analyses, any changes, including mixtures, in the amino acid sequence of 604 the target protein, or DNA sequence for genome targeting drugs, present in on-treatment 605 or follow-up samples, but not in the baseline sample, can be reported as having developed 606 during therapy. In addition, baseline samples should be analyzed to identify HBV 607 genetic polymorphisms that are associated with differential antiviral activity against the 608 investigational drug. Sponsors should consult the FDA early for the most current format 609 for submission of resistance data and if Next Generation Sequencing (NGS) will be used. 610 611 There is a risk of the development of resistance against an antiviral drug that targets 612 similar viral proteins in different virus species in patients coinfected with HIV and HBV. 613 Because of this risk, we recommend assessing for the development of resistance and 614 cross-resistance in the viral proteins of both HIV-1 and HBV when appropriate. 615 616 For all virologic assessments in clinical trials, we recommend the use of FDA-approved 617 or FDA-cleared assays, when available, and a central laboratory. Sponsors can collect 618 results from local lab tests, identifying the assay(s) used. If investigational assay(s) are 619 used, performance characteristics of the assay(s) determined from analytical validation 620 studies using geographically and temporally distinct isolates should be provided in 621 addition to detailed descriptions of the methodology.17 Drugs that require assays to 622 identify the infected population benefiting from treatment (e.g., specific genotypes or 623 resistant populations) may require a companion diagnostic. Additional recommendations 624 can be found in the draft guidance for industry and FDA staff Principles for 625 Codevelopment of an In Vitro Companion Diagnostic Device With a Therapeutic 626 Product.18 627 17 See the IDE (Investigational Device Exemption) web page available at https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046164.htm. 18 When final, this guidance will represent the FDA's current thinking on this topic. 15 Contains Nonbinding Recommendations Draft -- Not for Implementation 628 Sponsors are encouraged to submit a resistance monitoring plan early in development. If 629 resistance evaluation in clinical trials involves NGS, we recommend that sponsors discuss 630 details of the NGS approach with the FDA. Submission of NGS data in fastq format is 631 strongly encouraged. 632 633 HBV should be genotyped for any instances where HBV DNA is detected in long-term 634 follow-up to distinguish relapse from reinfection. 635 636 2. Pharmacokinetic/Pharmacodynamic Considerations 637 638 Trials conducted in HBV-infected patients should include assessment of pharmacokinetics and the 639 relationship between drug exposure (e.g., minimum or maximum plasma concentration (Cmin or 640 Cmax), area under the curve) and virologic success and toxicity in all patients. 641 642 Sponsors can use a combination of intensive and sparse sampling throughout development to 643 characterize the pharmacokinetics of the investigational drug. For example, sponsors should 644 implement an intensive sampling schedule in early phase monotherapy trials. In longer term 645 trials, an intensive sampling schedule might not be feasible. Alternatively, sponsors can combine 646 sparse sampling from these trials with intensive PK data from earlier trials for population PK 647 analysis. Sponsors should obtain multiple sparse PK samples from as many patients as possible 648 including at the time of key virologic assessments. It is important to document dosing times and 649 plasma sampling times. 650 651 Sponsors can use the following two broad approaches to characterize the relationship between 652 drug exposure and viral kinetics or virologic suppression of the investigational drug, depending 653 on the development stage and purpose of the analysis. Both approaches allow for exploration of 654 relevant covariates. 655 656 (1) To aid the design of phase 2b or phase 3 trials, with respect to selection of the dosage 657 regimen, a mechanistic approach relating drug concentrations and viral kinetics should be 658 considered. A mechanistic modeling approach should also account for the development 659 of resistance to the investigational drug and the intended patient population. For 660 combination therapy, the potential of additive or synergistic antiviral effects can be 661 incorporated in the model to assist optimization of the dose combination. 662 663 (2) A simplified analysis relating the proportion of patients with virologic suppression or 664 virologic failure and appropriate exposure variable (e.g., minimum concentration or area 665 under the plasma drug concentration versus time curve) can be used to support evidence 666 of activity and to support dose selection. 667 668 Exposure-response safety analyses should consider the mechanistic on-target and off-target 669 effects of the investigational drug and adverse events that are more frequent in the 670 investigational drug arm. The appropriate exposure parameter and modeling approach depends 671 on the investigational drug and toxicity. 672 16 Contains Nonbinding Recommendations Draft -- Not for Implementation 673 3. Labeling Considerations 674 675 Severe acute exacerbations of HBV infection may occur after discontinuation of anti-HBV 676 therapy. Hepatic function should be monitored closely with both clinical and laboratory follow- 677 up for at least several months in patients who discontinue anti-HBV therapy. In certain 678 circumstances, resumption of anti-HBV therapy may be warranted. These concerns should be 679 adequately conveyed in drug labeling. 680 681 Development of HIV-1 resistance against anti-HBV drugs with activity against HIV-1 is a 682 potential risk that should be conveyed in labeling. 683 17 Contains Nonbinding Recommendations Draft -- Not for Implementation 684 GLOSSARY OF ACRONYMS 685 686 ALT alanine aminotransferase 687 CC50 concentration inhibiting 50 percent cell growth 688 cccDNA covalently closed circular DNA 689 CHB chronic hepatitis B 690 EC50/90 effective drug concentration inhibiting 50 or 90 percent virus replication 691 FD&C Act Federal Food, Drug, and Cosmetic Act 692 HBeAg HBV enigma antigen 693 HBsAb antibody specific to HBsAg 694 HBsAg HBV surface antigen 695 HBV hepatitis B virus 696 HBV DNA hepatitis B virus DNA 697 HCC hepatocellular carcinoma 698 HDV hepatitis delta virus 699 HIV human immunodeficiency virus 700 IFN interferon 701 IgM immunoglobulin M 702 IU international unit 703 LLOQ lower limit of quantification 704 mL milliliter 705 NrtI nucleoside/nucleotide reverse transcriptase inhibitor 706 NGS Next Generation Sequencing 707 NI noninferiority 708 PHH primary human hepatocyte 709 PK pharmacokinetic 710 qHBsAg quantitative HBsAg 711 RNA ribonucleic acid 712 rt reverse transcriptase 713 SAP statistical analysis plan 714 TND target not detected 715 WHV woodchuck hepatitis virus 716 18 Contains Nonbinding Recommendations Draft -- Not for Implementation 717 REFERENCES 718 719 Alosh M, Fritsch K, Huque M, Mahjoob K, Pennello G, Rothmann M, Russek-Cohen E, Smith 720 F, Wilson S, and Yue L, 2015, Statistical Considerations on Subgroup Analysis in Clinical 721 Trials, Stat Biopharm Res, 7:286304. 722 723 Arnold JJ, Sharma SD, Feng JY, Ray AS, Smidansky ED, Kireeva ML, Cho A, Perry J, Vela JE, 724 Park Y, Xu Y, Tian Y, Babusis D, Barauskus O, Peterson BR, Gnatt A, Kashlev M, Zhong W, 725 and Cameron CE, 2012, Sensitivity of Mitochondrial Transcription and Resistance of RNA 726 Polymerase II Dependent 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