Chronic Hepatitis D Virus Infection: Developing Drugs for Treatment 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Administrative draft guidance, not enacted legislation.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.

26502073dft.docx
09/03/19
Chronic Hepatitis D
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 Aimee Hodowanec at 240-402-5752.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2019
Clinical/Antimicrobial

Chronic Hepatitis D
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/guidance-compliance-regulatory-information/guidances-drugs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
October 2019
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 ....................................................... 3
c. 	Clinical pharmacology development considerations .................................................... 5
d. 	Efficacy considerations ................................................................................................ 5
2. Drug Development Population ............................................................................................ 5
3. Safety Considerations .......................................................................................................... 6
B. 	Phase 3 Efficacy Trial Considerations ............................................................................. 7
1. Trial Design......................................................................................................................... 7
2. Trial Population .................................................................................................................. 8
3. Randomization and Stratification ........................................................................................ 8
4. Dose Selection ..................................................................................................................... 8
5. Comparators........................................................................................................................ 9
6. Efficacy Endpoints............................................................................................................... 9
a. 	Primary endpoints ......................................................................................................... 9
b. 	Secondary endpoints................................................................................................... 10
7. Trial Procedures and Timing of Assessments ................................................................... 10
8. Statistical Considerations.................................................................................................. 10
a. 	Efficacy analyses ........................................................................................................ 10
b. 	Noninferiority trials .................................................................................................... 11
c. 	Combination regimens ................................................................................................ 11
9. Accelerated Approval (Subpart H) Considerations........................................................... 11
C. 	Other Considerations ...................................................................................................... 11
1. Clinical Virology Considerations ...................................................................................... 11
REFERENCES.................................................................................................................13

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Chronic Hepatitis D Virus Infection:	1
Developing Drugs for Treatment	2
Guidance for Industry1
3
4
5
6
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	7
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	8
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	9
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	10
for this guidance as listed on the title page.	11
12
13
14
I. 	INTRODUCTION	15
16
The purpose of this guidance is to assist sponsors in the clinical development of drugs for the	17
treatment of chronic hepatitis D virus (HDV) infection.2 Specifically, this guidance addresses the	18
Food and Drug Administration’s (FDA’s) current recommendations regarding the overall	19
development program and clinical trial designs for the development of drugs and biologics to	20
support an indication for the treatment of chronic HDV infection.	21
22
FDA encourages sponsors to communicate with the Division of Antiviral Products (DAVP)	23
through the pre-investigational new drug application (pre-IND) consultation program to discuss	24
the development of drugs with unique considerations based on mechanism of action, novel	25
treatment approaches, or the use of novel biomarkers.3 This draft guidance is intended to serve as	26
a focus for continued discussions among DAVP, pharmaceutical sponsors, the academic	27
community, and the public.4	
28
29
This guidance focuses on considerations that are specific to HDV drug development. General	30
topics in early phase drug development, statistical analysis, and clinical trial design are addressed	31
in the International Conference on Harmonisation (ICH) guidances for industry E9 Statistical	32
Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and Related	33
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, the term drug includes both human drugs and therapeutic biological products
unless otherwise specified.
3 See the FDA’s Getting Started with the Division of Antiviral Products Pre-IND Process web page at
https://www.fda.gov/drugs/pre-ind-consultation-program/getting-started-division-antiviral-products-pre-ind-process.
4 In addition to consulting FDA guidances, sponsors are encouraged to contact DAVP to discuss specific issues that
arise during the development of drugs for the treatment of HDV infection.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
Issues in Clinical Trials (May 2001).5 The draft guidance for industry Chronic Hepatitis B Virus	34
Infection: Developing Drugs for Treatment (November 2018) also contains information that is	35
relevant to HDV drug development.6	
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. 	BACKGROUND	45
46
HDV is a replication-defective virus that uses the hepatitis B virus (HBV) surface antigen	47
(HBsAg) as its envelope protein. Therefore, HDV infection only occurs in the setting of	48
concurrent HBV infection (Wranke and Wedemeyer 2016). According to the World Health	49
Organization, an estimated 15–20 million people worldwide are living with HBV/HDV co-	50
infection.7 Subsequently, a meta-analysis reported a much higher worldwide HBV/HDV co-	51
infection prevalence of 62–72 million (Chen et al. 2019). Areas of high HDV prevalence include	52
Eastern and Mediterranean Europe, the Middle East, Central and North Asia, the Amazon basin,	53
and parts of Africa (Chen et al. 2019). HDV prevalence is thought to be relatively low in the	54
United States overall, but may be increased in certain subpopulations, such as in persons who	55
inject drugs and in persons born in, or who have lived in, countries where the disease is endemic.	56
Population-based data from the National Health and Nutrition Examination Survey estimated	57
that the anti-HDV antibody prevalence among adults in the United States is 0.15 percent (Patel et	58
al. 2019). There are eight recognized genotypes of HDV (1 to 8); the globally prevalent genotype	59
1 is the predominant genotype in the United States.	60
61
Relative to HBV monoinfection, HBV/HDV co-infection may be associated with more severe	62
liver disease, leading to increased rates of cirrhosis, hepatocellular carcinoma, hepatic	63
decompensation, and liver failure (Fattovich et al. 1987; Romeo et al. 2009). Although currently	64
available HBV therapies are effective in suppressing HBV replication, the rate of HBsAg loss	65
remains low (Tang et al. 2018). In the absence of HBsAg loss, HDV infection persists.	66
Therefore, therapies directly targeting HDV may be of clinical benefit. At present there are no	67
drugs approved for the treatment of chronic HDV infection, although pegylated interferon-alpha	68
(PEG-IFN-α) is commonly used. However, PEG-IFN-α is associated with significant toxicity	69
and sustained virologic response rates (defined as undetectable HDV RNA levels 6 months after	70
5 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.
6 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents.
7 See the World Health Organization’s Hepatitis D web page at https://www.who.int/en/news-room/fact-
sheets/detail/hepatitis-d.

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
treatment) of only 25 to 30 percent (Erhardt et al. 2006; Wedemeyer et al. 2011). In addition, late	71
virologic relapses are common following treatment with PEG-IFN-α, and it is not known if HDV	72
sustained clearance can be achieved in the setting of persistent HBsAg positivity (Heidrich et al.	73
2014).	74
75
Because chronic HDV infection is considered serious and life-threatening and there are no	76
approved treatments, investigational anti-HDV drugs may be eligible for FDA’s expedited	77
programs, such as fast track, breakthrough therapy, and priority review designations.8	
78
79
80
III. 	DEVELOPMENT PROGRAM	81
82
A. 	General Drug Development Considerations	83
84
This section discusses nonclinical and early phase clinical development considerations, including	85
the evaluation of antiviral activity and resistance, issues related to the target population for drug	86
development, and safety considerations.	87
88
1. 	Early Phase Development Considerations	89
90
Early clinical evaluation should provide sufficient data to establish safety and antiviral activity in	91
support of phase 3 trials.	92
93
a. 	Pharmacology/toxicology development considerations	94
95
Sponsors should refer to the following guidance documents for nonclinical development	96
considerations:	97
98
• 	Guidance for industry Chronic Hepatitis B Virus Infection: Developing Drugs for	99
Treatment	100
101
• 	ICH guidance for industry M3(R2) Nonclinical Studies for the Conduct of Human	102
Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010)	103
104
• 	ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-	105
Derived Pharmaceuticals (May 2012)	106
107
• 	ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies	108
of Pharmaceuticals (March 1996)	109
110
b. 	Nonclinical virology development considerations	111
112
Sponsors should consider recommendations for general antiviral and HBV drug development	113
addressed in the guidances for industry Antiviral Product Development — Conducting and	114
8 See the guidance for industry Expedited Programs for Serious Conditions — Drugs and Biologics (May 2014).

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
Submitting Virology Studies to the Agency (June 2006), and Chronic Hepatitis B Virus Infection:	115
Developing Drugs for Treatment, including recommendations for studies of mechanism of	116
action, determination of antiviral activity in cell culture, cytotoxicity, and mitochondrial toxicity.	117
118
Sponsors should also consider the following recommendations specific for HDV drug	119
development:	120
121
• 	Antiviral activity determination in cell culture: To assess the breadth of activity of the	122
investigational drug, the effective drug concentration at which virus replication is	123
inhibited by 50 and 90 percent (EC50 and EC90 values) should be determined against	124
different genotypes of HDV, including genotype 1, in cell culture. If EC50 values vary	125
significantly across genotypes, indicating a lack of conservation of the drug target, the	126
breadth of activity against genotype 1 should also be determined by testing multiple	127
geographically and temporally distinct isolates of this genotype.	128
129
• 	Cell culture combination antiviral activity: Cell culture combination antiviral activity of	130
an investigational drug against HDV should be determined with approved drugs for HBV	131
and for HDV (when anti-HDV drugs are approved) to determine the likelihood of	132
antagonism when used in combination for the treatment of HBV/HDV infection.	133
Sponsors should assess the effect of approved drugs for HBV on the activity of the	134
investigational HDV drug, and conversely, the effect of the investigational HDV drug on	135
the activity of approved HBV drugs.	136
137
• 	Activity in animal models:9 Animal models of HDV infection may be important for	138
assessing the antiviral activity of investigational drugs, given the difficulty in propagating	139
the virus in cell culture. Sponsors should consider the following recommendations related	140
to animal models:	141
142
− 	Animal models for consideration may include immunocompromised mice with	143
chimeric human/mouse livers and transgenic mice expressing human sodium	144
taurocholate cotransporting polypeptide (NTCP) receptor and HBsAg (Winer et al.	145
2018). The woodchuck model using HDV pseudotyped with woodchuck hepatitis	146
virus envelope proteins can be considered for drugs that do not specifically target the	147
HDV/HBV envelope protein or human NTCP receptor (Aldabe et al. 2015).	148
149
− 	If studies are conducted in animal models to support an HDV treatment program, we	150
recommend including time course plots of viral load (RNA) and antigen expression	151
data for each animal. We recommend testing different HDV/HBV genotypes and	152
assessing resistance development where feasible.	153
154
• 	Evaluating HDV resistance: FDA encourages sponsors to investigate resistance in	155
nonclinical models of infection where feasible, although such studies may be challenging	156
9 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible. FDA
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be
suitable, adequate, validated, and feasible. FDA will consider if the alternative method could be assessed for
equivalency to an animal test method.

Contains Nonbinding Recommendations
Draft — Not for Implementation
5
given the limitations of propagating HDV in cell culture and animal models and the	157
dependency of HDV on HBV envelope proteins for infection.	158
159
• 	Evaluating HDV cross-resistance: If a drug for treatment of HDV infection is approved	160
and HDV variants resistant to the drug are identified, these variants should be assessed	161
for susceptibility to the investigational drug. Likewise, HDV variants resistant to the	162
investigational drug should be assessed for susceptibility to any approved drugs for HDV.	163
164
c. 	Clinical pharmacology development considerations	165
166
Studies to characterize pharmacokinetics including the effect of extrinsic (e.g., drug-drug	167
interaction studies, food effect studies) and intrinsic factors (e.g., pharmacokinetic studies in	168
subjects with renal impairment or hepatic impairment) should be conducted early in development	169
to inform the trial design for phase 2 and phase 3 trials. Sponsors should consider	170
recommendations in the pertinent guidances for industry.	171
172
d. 	Efficacy considerations	173
174
In early clinical trials, the sponsor should measure HDV RNA levels during a short treatment	175
period (i.e., one to three months, depending on the drug’s mechanism of action) to assess	176
activity. The sponsor should assess changes in alanine aminotransferase (ALT) as a key	177
secondary endpoint.	178
179
2. 	Drug Development Population	180
181
Development programs should include a diverse and representative clinical trial population, and	182
sponsors should consider the following points related to trial populations:	183
184
• 	HDV infection is a global disease with the greatest burden of infection occurring in	185
Eastern and Mediterranean Europe, the Middle East, the Amazon Basin, and parts of Asia	186
and Africa.	187
188
− 	Under 21 CFR 312.120, FDA will accept data from a well-designed, well-conducted,	189
non-IND foreign trial as support for an IND or application for marketing approval if	190
the trial was conducted in accordance with good clinical practice and if FDA is able	191
to validate the data from the trial through an onsite inspection, as necessary.10	
192
193
− 	Although foreign data may be acceptable as a sole basis for marketing approval under	194
certain circumstances (see 21 CFR 314.106), FDA encourages sponsors to include	195
U.S. patients in development programs to provide additional experience relevant to	196
the U.S. population.	197
198
10 For additional information, see the guidance for industry and FDA staff FDA Acceptance of Foreign Clinical
Studies Not Conducted Under an IND: Frequently Asked Questions (March 2012).

Contains Nonbinding Recommendations
Draft — Not for Implementation
6
• 	FDA encourages sponsors to discuss their enrollment strategies and plans for phase 2 and	199
phase 3 trials with DAVP. Eligibility criteria should allow the clinical trial population to	200
reflect the diversity of the patients who will be using the drug if the drug is approved.11	
201
202
• 	Sponsors should conduct initial trials to define antiviral activity and dose-response in	203
patients without cirrhosis or with compensated cirrhosis, as these patients are at lower	204
risk of imminent clinical progression or decompensation. In the later stages of drug	205
development, enrollment of patients with decompensated liver disease may be considered	206
(see section III.B.2., Trial Population).	207
208
• 	In the absence of a serious safety signal in adults, it may be appropriate to enroll	209
adolescent patients (for the purpose of this guidance, ages 12 to younger than 18 years of	210
age) concurrently with adults in phase 3 trials and to make every effort to obtain	211
confirmatory pharmacokinetic and safety data from a cohort in this age group as part of	212
the data included at the time of filing of the original new drug application or biologics	213
license application.	214
215
3. 	Safety Considerations	216
217
An initial marketing application should include adequate safety data, such as the following, to	218
allow for a benefit-risk assessment of the drug:	219
220
• 	Safety data from 300 to 500 patients exposed to the proposed drug dose and treatment	221
duration (or greater) may be adequate; however, the size of the safety database could be	222
smaller for investigational drugs that demonstrate substantial efficacy and safety	223
compared to available therapies. Nonclinical or clinical safety signals may necessitate a	224
larger safety database or the conduct of additional safety studies. For a drug approved for	225
use in patients without cirrhosis or with compensated cirrhosis, the safety database	226
needed to extend use of the drug to the decompensated cirrhotic population would depend	227
on the safety profile of the investigational drug and the overall benefit-risk profile for the	228
indicated population.	229
230
• 	Clinical trial protocols should include predefined algorithms for data collection in the	231
setting of significant hepatic events, such as ALT flares or reactivation of HDV or HBV.	232
FDA encourages use of an independent adjudication committee to evaluate significant	233
hepatic events to determine whether the events represent drug-related toxicity, flares	234
related to viral reactivation, or immunologic responses to virologic infection.	235
236
• 	Severe acute exacerbations of HDV and HBV infection may occur after antiviral therapy	237
is discontinued. Hepatic function should be monitored closely with both clinical and	238
laboratory follow-up for at least several months in patients who discontinue anti-HDV	239
and/or anti-HBV therapy. In certain circumstances, resumption of antiviral therapy may	240
be warranted. The sponsor should adequately monitor and evaluate these concerns in the	241
11 For additional information, see the draft guidance for industry Enhancing the Diversity of Clinical Trial
Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs (June 2019). When final, this guidance
will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
7
development program and convey, as appropriate, these concerns in proposed drug	242
labeling.	243
244
B. 	Phase 3 Efficacy Trial Considerations	245
246
1. 	Trial Design	247
248
No drugs have been approved for the treatment of chronic HDV infection. Therefore, a double-	249
blind, placebo-controlled trial is the FDA’s preferred trial design for a phase 3 clinical trial.	250
251
Alternative trial design options include the following:	252
253
• 	Three-arm, randomized, controlled trial comparing investigational drug, standard-of-care	254
treatment, and placebo.	255
256
− 	Although PEG-IFN-α has not been approved by FDA for the treatment of chronic	257
HDV infection, it is used in clinical practice and is considered the standard-of-care in	258
some parts of the world. As such, the use of PEG-IFN-α as a comparator in a clinical	259
trial may be acceptable. However, the treatment effect of PEG-IFN-α over placebo	260
has not been well established; therefore, superiority of the investigational drug versus	261
placebo should be demonstrated to support efficacy. The comparison between PEG-	262
IFN-α and placebo can establish the effect of PEG-IFN-α, and the comparison	263
between the investigational drug and PEG-IFN-α can help to evaluate the efficacy	264
and the safety profile of the investigational drug.	265
266
• 	Randomized, controlled trial in which subjects are randomized to the investigational drug	267
(immediate treatment group) or placebo for a prespecified duration followed by open	268
label treatment with investigational drug (deferred treatment group). Effectiveness would	269
be demonstrated by showing an early significant improvement over the placebo control.	270
271
• 	Randomized, controlled superiority trial comparing the investigational drug plus	272
standard-of-care treatment to standard-of-care treatment alone (i.e., an add-on trial). In	273
this case, although effectiveness is demonstrated, it would have been shown only when	274
the investigational drug is added to the standard-of-care treatment; the sponsor would not	275
know whether the investigational drug has an effect when used alone.	276
277
• 	Randomized, controlled superiority trial comparing different doses and/or durations of	278
the investigational drug.	279
280
After approval of a drug for the treatment of HDV infection, a randomized, controlled superiority	281
or noninferiority trial comparing the investigational drug against an active comparator is	282
appropriate.	283
284

Contains Nonbinding Recommendations
Draft — Not for Implementation
8
2. 	Trial Population	285
286
Sponsors should include the following virologic and clinical characteristics in patient eligibility	287
criteria:	288
289
• 	Documentation of chronic HDV infection, defined as positive serum anti-HDV	290
antibodies	291
292
• 	Quantifiable HDV RNA of at least 6-month duration	293
294
• 	Receiving HBV treatment in accordance with current treatment guidelines. Patients who	295
qualify for HBV treatment should be on a stable regimen for at least 3 months with	296
documented HBV DNA suppression before initiating the HDV investigational therapy.	297
298
Sponsors should enroll sufficient numbers of patients in the trials who are infected with HDV	299
genotype 1 to assess efficacy in this population.	300
301
Sponsors should consider the following when enrolling patients without cirrhosis or with	302
compensated cirrhosis:	303
304
• 	The presence or absence of cirrhosis at trial entry should be documented. The use of a	305
noninvasive modality to define the presence or absence of cirrhosis in a trial should be	306
supported by references that summarize the performance characteristics and sensitivity	307
and specificity of the modality for its intended purpose in the proposed population.	308
309
• 	FDA recommends that sponsors exclude patients with decompensated cirrhosis or a	310
history of any prior hepatic decompensation event until data on the safety and	311
effectiveness of a given therapy in patients without cirrhosis and with compensated	312
cirrhosis are obtained.	313
314
3. 	Randomization and Stratification	315
316
If multiple subpopulations are included in the same trial, sponsors can consider stratifying groups	317
at randomization based on key variables such as presence or absence of cirrhosis, baseline HDV	318
RNA level, and genotype/region.	319
320
4. 	Dose Selection	321
322
FDA encourages sponsors to use quantitative clinical pharmacology approaches that leverage	323
prior information to optimize dose selection for phase 3 trials. These approaches are addressed in	324
other guidances for industry.12	
325
326
12 See the guidance for industry Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory
Applications (April 2003) and the draft guidance for industry Population Pharmacokinetics (July 2019) (when final,
this guidance will represent the FDA’s current thinking on this topic).

Contains Nonbinding Recommendations
Draft — Not for Implementation
9
5. 	Comparators	327
328
See section III.B.1., Trial Design, for a description of potential comparators for use in different	329
trial designs.	330
331
6. 	Efficacy Endpoints	332
333
a. 	Primary endpoints	334
335
FDA anticipates that initial approvals for anti-HDV drugs will be based on a surrogate endpoint	336
that is reasonably likely to predict clinical benefit. An appropriate surrogate endpoint for the	337
treatment of HDV should provide evidence of both a decline in virologic replication and an	338
improvement in associated liver inflammation as evident by biochemical response (see section	339
III.B.9., Accelerated Approval (Subpart H) Considerations, for additional information regarding	340
approval under the accelerated approval pathway). For FDA, the following surrogate endpoint	341
could reasonably predict clinical benefit and could be considered to support an accelerated	342
approval:	343
344
• 	The proportion of trial patients with undetectable serum HDV RNA (defined as less than	345
the lower limit of quantification (LLOQ), target not detected (TND)) and ALT	346
normalization.	347
348
There are some data suggesting that a 2-log10 decline in HDV RNA is associated with clinical	349
benefit (Farci et al. 2004; Yurdaydin et al. 2019); therefore, in certain situations, such as for	350
drugs that are intended to be used as chronic suppressive therapy, a greater than or equal to 2-	351
log 10 decline in HDV RNA and ALT normalization on-treatment could be considered an	352
acceptable surrogate endpoint reasonably likely to predict clinical benefit (see section III.B.9.,	353
Accelerated Approval (Subpart H) Considerations). The sponsor can request a Type C formal	354
meeting to discuss the use of a novel surrogate endpoint as the primary basis for drug approval.13	
355
356
The timing of the primary endpoint assessment (whether on-treatment, at the end-of- treatment,	357
or off-treatment after a specified duration of follow-up) will depend on the treatment strategy	358
used (i.e., finite duration of therapy versus chronic suppressive therapy) for a specific drug. FDA	359
encourages the sponsor to discuss its proposed primary efficacy endpoint and the timing of the	360
endpoint assessment with DAVP.	361
362
Approval based on a surrogate endpoint reasonably likely to predict clinical benefit will require	363
subsequent confirmation using a clinical endpoint. FDA’s preferred clinical endpoint is	364
improvement in clinical outcomes such as decrease in progression to cirrhosis, progression to	365
decompensated liver disease, liver transplantation, hepatocellular carcinoma, and liver-related	366
death. These clinical outcomes should be collected as long-term follow-up data.	367
368
13 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA
Products (December 2017). When final, this guidance will represent the FDA’s current thinking on this topic.

Contains Nonbinding Recommendations
Draft — Not for Implementation
10
b. 	Secondary endpoints	369
370
Sponsors should consider the following secondary endpoints:	371
372
• 	Greater than or equal to 2-log 10 decline in serum HDV RNA	373
• 	HDV RNA less than LLOQ (TND)	374
• 	ALT normalization	375
• 	Histological response or change in liver stiffness	376
• 	Change in Model for End-Stage Liver Disease scores	377
• 	Change in Child-Turcotte-Pugh scores	378
379
7. 	Trial Procedures and Timing of Assessments	380
381
The optimal timing of the primary endpoint assessment is unknown. Sponsors should consider	382
the following for timing of assessments:	383
384
• 	For therapies intended to be administered indefinitely, an on-treatment assessment after a	385
predefined time period can be acceptable for efficacy.	386
387
• 	For therapies intended to be administered for a finite duration, FDA’s preferred endpoint	388
is an off-treatment assessment of efficacy.	389
390
8. 	Statistical Considerations	391
392
For recommendations and considerations on statistical analysis methods and issues, see the	393
guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and	394
Biological Products (May 1998) and the article “Statistical Considerations on Subgroup Analysis	395
in Clinical Trials” (Alosh et al. 2015).	396
397
a. 	Efficacy analyses	398
399
The preferred primary endpoints for phase 3 trials are described above in section III.B.6.,	400
Efficacy Endpoints. Sponsors should consider the following recommendations for analyzing the	401
primary efficacy endpoint:	402
403
• 	The primary analysis should compare the proportion of responders across trial treatment	404
arms. This analysis determines whether effectiveness has been demonstrated.	405
406
• 	The analysis of the primary efficacy endpoint should be performed within important	407
subgroups based on demographic and baseline characteristics (e.g., geographic region,	408
sex, race, age group, screening HDV RNA level, HDV/HBV genotypes, baseline weight	409
and body mass index, baseline ALT, baseline fibrosis/cirrhosis, (if applicable) response	410
to previous treatment regimens). The purpose of these analyses is to explore the	411
consistency of the primary efficacy endpoint result across these subgroups.	412
413

Contains Nonbinding Recommendations
Draft — Not for Implementation
11
b. 	Noninferiority trials	414
415
Because there are no approved therapies for the treatment of chronic HDV infection at this time,	416
a noninferiority trial design is not possible. In the future, should there be approved therapies for	417
the treatment of chronic HDV infection, noninferiority trials may be acceptable. Sponsors should	418
justify proposed noninferiority margins and discuss with DAVP.14	
419
420
c. 	Combination regimens	421
422
Sponsors planning to evaluate a combination regimen of two or more drugs should consult 21	423
CFR 300.50 regarding combination drugs. Additional recommendations for codevelopment of	424
two new investigational drugs can be found in the guidance for industry Codevelopment of Two	425
or More New Investigational Drugs for Use in Combination (June 2013).	426
427
9. 	Accelerated Approval (Subpart H) Considerations	428
429
For HDV infection, no surrogate endpoints have been definitively shown to predict clinical	430
benefit. Trials aimed at demonstrating the clinical benefit of an HDV therapy would likely	431
require a prolonged follow-up period. Therefore, FDA anticipates that development programs	432
may opt to pursue accelerated approval pathways based on a surrogate endpoint reasonably	433
likely to predict clinical benefit (see section III.B.6., Efficacy Endpoints). An accelerated	434
approval pathway will require confirmation of clinical benefit through a long-term extension of	435
the original trial or a subsequent additional clinical trial or trials. Sponsors should consider	436
planning for the confirmatory trial(s) during the development of the phase 3 program.	437
438
C. 	Other Considerations	439
440
1. 	Clinical Virology Considerations	441
442
Sponsors can find general recommendations for clinical virology assessments in the guidances	443
for industry Antiviral Product Development — Conducting and Submitting Virology Studies to	444
the Agency and Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment. Sponsors	445
should consider the following recommendations specific for HDV infection:	446
447
• 	Virologic Assessments	448
449
− 	For virologic assessments in clinical trials, we recommend the use of FDA-approved	450
or FDA-cleared assays, if available, and a central laboratory. If an investigational	451
assay or assays are used, the sponsor should provide performance characteristics of	452
the assay(s) determined from analytical validation studies using geographically and	453
temporally distinct isolates in addition to detailed descriptions of the methodology.	454
Viral loads should be reported in international units per milliliter (IU/mL).	455
456
14 For additional information on determining noninferiority margins, see the guidance for industry Non-Inferiority
Clinical Trials to Establish Effectiveness (November 2016).

Contains Nonbinding Recommendations
Draft — Not for Implementation
12
− 	Because HDV requires the HBV envelope protein to propagate, clinical efficacy	457
assessments should include virologic parameters for both HDV and HBV.	458
459
− 	Samples for HDV and HBV quantification, genotypic, and phenotypic analysis	460
should be obtained at multiple time points during treatment and follow-up.	461
462
− 	Where feasible, we recommend determining the genotypes/subtypes of both HDV	463
and HBV present at baseline and, hence, determine if the investigational drug exhibits	464
antiviral activity against all the HDV/HBV genotypes/subtypes represented in the	465
trial.	466
467
• 	Resistance Assessment	468
469
− 	In general, for treatment of HDV infection, virologic failure is defined as a confirmed	470
increase in HDV RNA levels of greater than or equal to 1.0 log 10 IU/mL above the	471
nadir value (assuming an initial response of at least 1.0 log10 IU/mL compared with	472
baseline) or having quantifiable HDV RNA after being less than LLOQ (TND). In	473
general, virologic nonresponse is defined as less than or equal to 1.0-log10 IU/mL	474
reduction in HDV RNA levels compared with baseline.	475
476
− 	Genotypic assessment of resistance should include sequencing of the HDV genome	477
and, for drugs that act through the HBV envelope protein or NTCP receptor,	478
sequencing of the HBsAg coding region where feasible. Any changes, including	479
mixtures, in the amino acid sequence of the target protein (or nucleotide sequence for	480
genome targeting drugs) present in on-treatment or follow-up samples, but not in the	481
baseline sample, can be reported as having developed during therapy.	482
483
− 	Phenotypic assessment of resistance should include analysis of HDV variants in cell	484
culture, if feasible, and determination of loss of susceptibility to the investigational	485
drug.	486
487
− 	Before submission of resistance data, contact FDA to obtain the most recent format	488
recommendations for submitting resistance datasets.	489
490
− 	For drugs with a host target, the frequency of polymorphisms in the target in key U.S.	491
racial groups should be reported and their effect on efficacy assessed in clinical trials.	492
493

Contains Nonbinding Recommendations
Draft — Not for Implementation
13
REFERENCES	494
495
Aldabe, R, L Suárez-Amarán, C Usai, and G González-Aseguinolaza, 2015, Animal Models of	496
Chronic Hepatitis Delta Virus Infection Host-Virus Immunologic Interactions, Pathogens,	497
4(1):46–65.	498
499
Alosh, M, K Fritsch, M Huque, K Mahjoob, G Pennello, M Rothmann, E Russek-Cohen, F	500
Smith, S Wilson, and L Yue, 2015, Statistical Considerations on Subgroup Analysis in Clinical	501
Trials, Stat Biopharm Res, 7(4):286–303.	502
503
Chen, HY, DT Shen, DZ Ji, PC Han, WM Zhang, JF Ma, WS Chen, H Goyal, S Pan, and HG	504
Xu, 2019, Prevalence and Burden of Hepatitis D Virus Infection in the Global Population: A	505
Systematic Review and Meta-Analysis, Gut, 68:512–21.	506
507
Erhardt, A, W Gerlich, C Starke, U Wend, A Donner, A Sagir, T Heintges, and D Haussinger,	508
2006, Treatment of Chronic Hepatitis Delta with Pegylated Interferon-Alpha2b, Liver Int,	509
26(7):805–810.	510
511
Farci, P, T Roskams, L Chessa, G Peddis, AP Mazzoleni, R Scioscia, G Serra, ME Lai, M Loy, L	512
Caruso, V Desmet, RH Purcell, and A Balestrieri, 2004, Long-Term Benefit of Interferon Alpha	513
Therapy of Chronic Hepatitis D: Regression of Advanced Hepatic Fibrosis, Gastroenterology,	514
126(7):1740–1749.	515
516
Fattovich, G, S Boscaro, F Noventa, E Pornaro, D Stenico, A Alberti, A Ruol, and G Realdi,	517
1987, Influence of Hepatitis Delta Virus Infection on Progression to Cirrhosis in Chronic	518
Hepatitis Type B, J Infect Dis, 155(5):931–935.	519
520
Heidrich, B, C Yurdaydin, G Kabacam, BA Ratsch, K Zachou, B Bremer, GN Dalekos, A	521
Erhardt, F Tabak, K Yalcin, S Gurel, S Zeuzem, M Cornberg, CT Bock, MP Manns, and H	522
Wedemeyer, 2014, Late HDV RNA Relapse After Peginterferon Alpha-Based Therapy of	523
Chronic Hepatitis Delta, Hepatology, 60(1):87–97.	524
525
Patel, EU, CL Thio, D Boon, DL Thomas, and AAR Tobian, 2019, Prevalence of Hepatitis B	526
and Hepatitis D Virus Infections in the United States, 2011–2016, Clin Infect Dis, 69(4):709–	527
712.	528
529
Romeo, R, E Del Ninno, M Rumi, A Russo, A Sangiovanni, R de Franchis, G Ronchi, and M	530
Colombo, 2009, A 28-Year Study of the Course of Hepatitis Delta Infection: A Risk Factor for	531
Cirrhosis and Hepatocellular Carcinoma, Gastroenterology, 136(5):1629–1638.	532
533
Tang, LSY, E Covert, E Wilson, and S Kottilil, 2018, Chronic Hepatitis B Infection: A Review,	534
JAMA, 319(17):1802–1813.	535
536
Wedemeyer, H, C Yurdaydin, GN Dalekos, A Erhardt, Y Cakaloglu, H Degertekin, S Gurel, S	537
Zeuzem, K Zachou, H Bozkaya, A Koch, T Bock, HP Dienes, and MP Manns, 2011,	538

Contains Nonbinding Recommendations
Draft — Not for Implementation
14
Peginterferon Plus Adefovir Versus Either Drug Alone for Hepatitis Delta, N Engl J Med,	539
364(4):322–331.	540
541
Winer, BY, E Shirvani-Dastgerdi, Y Bram, J Sellau, BE Low, H Johnson, T Huang, G	542
Hrebikova, B Heller, Y Sharon, K Giersch, S Gerges, K Seneca, MA Pais, AS Frankel, L	543
Chiriboga, J Cullen, RG Nahass, M Lutgehetmann, JE Toettcher, MV Wiles, RE Schwartz, and	544
A Ploss, 2018, Preclinical Assessment of Antiviral Combination Therapy in a Genetically	545
Humanized Mouse Model for Hepatitis Delta Virus Infection, Sci Transl Med, 10(447):	546
eaap9328.	547
548
Wranke, A and H Wedemeyer, 2016, Antiviral Therapy of Hepatitis Delta Virus Infection —	549
Progress and Challenges Towards Cure, Curr Opin Virol, 20:112–118.	550
551
Yurdaydin, C, Z Abbas, M Buti, M Cornberg, R Esteban, O Etzion, EJ Gane, RG Gish, JS	552
Glenn, S Hamid, T Heller, C Koh, P Lampertico, Y Lurie, M Manns, R Parana, M Rizzetto, S	553
Urban, and H Wedemeyer, on behalf of Hepatitis Delta International Network (HDIN), 2019,	554
Treating Chronic Hepatitis Delta: The Need for Surrogate Markers of Treatment Efficacy, J	555
Hepatol, 70(5):1008–1015.	556