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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 
26502073dft.docx 
09/03/19   
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:  
2  Developing Drugs for Treatment 
3  Guidance for Industry1 
4   
5   
6   
7  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
8  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
9  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
10  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
11  for this guidance as listed on the title page. 
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  The purpose of this guidance is to assist sponsors in the clinical development of drugs for the 
18  treatment of chronic hepatitis D virus (HDV) infection.2 Specifically, this guidance addresses the 
19  Food and Drug Administrations (FDAs) current recommendations regarding the overall 
20  development program and clinical trial designs for the development of drugs and biologics to 
21  support an indication for the treatment of chronic HDV infection.  
22   
23  FDA encourages sponsors to communicate with the Division of Antiviral Products (DAVP) 
24  through the pre-investigational new drug application (pre-IND) consultation program to discuss 
25  the development of drugs with unique considerations based on mechanism of action, novel 
26  treatment approaches, or the use of novel biomarkers.3 This draft guidance is intended to serve as 
27  a focus for continued discussions among DAVP, pharmaceutical sponsors, the academic 
28  community, and the public.4 
29   
30  This guidance focuses on considerations that are specific to HDV drug development. General 
31  topics in early phase drug development, statistical analysis, and clinical trial design are addressed 
32  in the International Conference on Harmonisation (ICH) guidances for industry E9 Statistical 
33  Principles for Clinical Trials (September 1998) and E10 Choice of Control Group and Related 
                                                 
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 FDAs 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. 
 
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34  Issues in Clinical Trials (May 2001).5 The draft guidance for industry Chronic Hepatitis B Virus 
35  Infection:  Developing Drugs for Treatment (November 2018) also contains information that is 
36  relevant to HDV drug development.6  
37   
38  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
39  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
40  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
41  the word should in Agency guidances means that something is suggested or recommended, but 
42  not required. 
43   
44   
45  II.  BACKGROUND 
46   
47  HDV is a replication-defective virus that uses the hepatitis B virus (HBV) surface antigen 
48  (HBsAg) as its envelope protein. Therefore, HDV infection only occurs in the setting of 
49  concurrent HBV infection (Wranke and Wedemeyer 2016). According to the World Health 
50  Organization, an estimated 1520 million people worldwide are living with HBV/HDV co-
51  infection.7 Subsequently, a meta-analysis reported a much higher worldwide HBV/HDV co-
52  infection prevalence of 6272 million (Chen et al. 2019). Areas of high HDV prevalence include 
53  Eastern and Mediterranean Europe, the Middle East, Central and North Asia, the Amazon basin, 
54  and parts of Africa (Chen et al. 2019). HDV prevalence is thought to be relatively low in the 
55  United States overall, but may be increased in certain subpopulations, such as in persons who 
56  inject drugs and in persons born in, or who have lived in, countries where the disease is endemic. 
57  Population-based data from the National Health and Nutrition Examination Survey estimated 
58  that the anti-HDV antibody prevalence among adults in the United States is 0.15 percent (Patel et 
59  al. 2019). There are eight recognized genotypes of HDV (1 to 8); the globally prevalent genotype 
60  1 is the predominant genotype in the United States. 
61   
62  Relative to HBV monoinfection, HBV/HDV co-infection may be associated with more severe 
63  liver disease, leading to increased rates of cirrhosis, hepatocellular carcinoma, hepatic 
64  decompensation, and liver failure (Fattovich et al. 1987; Romeo et al. 2009). Although currently 
65  available HBV therapies are effective in suppressing HBV replication, the rate of HBsAg loss 
66  remains low (Tang et al. 2018). In the absence of HBsAg loss, HDV infection persists. 
67  Therefore, therapies directly targeting HDV may be of clinical benefit. At present there are no 
68  drugs approved for the treatment of chronic HDV infection, although pegylated interferon-alpha 
69  (PEG-IFN-) is commonly used. However, PEG-IFN- is associated with significant toxicity 
70  and sustained virologic response rates (defined as undetectable HDV RNA levels 6 months after 
                                                 
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 FDAs 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 Organizations Hepatitis D web page at https://www.who.int/en/news-room/fact-
sheets/detail/hepatitis-d. 
 
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71  treatment) of only 25 to 30 percent (Erhardt et al. 2006; Wedemeyer et al. 2011). In addition, late 
72  virologic relapses are common following treatment with PEG-IFN-, and it is not known if HDV 
73  sustained clearance can be achieved in the setting of persistent HBsAg positivity (Heidrich et al. 
74  2014). 
75   
76  Because chronic HDV infection is considered serious and life-threatening and there are no 
77  approved treatments, investigational anti-HDV drugs may be eligible for FDAs expedited 
78  programs, such as fast track, breakthrough therapy, and priority review designations.8 
79   
80   
81  III.  DEVELOPMENT PROGRAM 
82   
83  A.  General Drug Development Considerations 
84   
85  This section discusses nonclinical and early phase clinical development considerations, including 
86  the evaluation of antiviral activity and resistance, issues related to the target population for drug 
87  development, and safety considerations.    
88   
89  1.  Early Phase Development Considerations  
90   
91  Early clinical evaluation should provide sufficient data to establish safety and antiviral activity in 
92  support of phase 3 trials.  
93   
94  a.  Pharmacology/toxicology development considerations 
95   
96  Sponsors should refer to the following guidance documents for nonclinical development 
97  considerations: 
98   
99    Guidance for industry Chronic Hepatitis B Virus Infection: Developing Drugs for 
100  Treatment 
101   
102    ICH guidance for industry M3(R2) Nonclinical Studies for the Conduct of Human 
103  Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010) 
104   
105    ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-
106  Derived Pharmaceuticals (May 2012) 
107   
108    ICH guidance for industry S1A The Need for Long-Term Rodent Carcinogenicity Studies 
109  of Pharmaceuticals (March 1996) 
110   
111  b.  Nonclinical virology development considerations 
112   
113  Sponsors should consider recommendations for general antiviral and HBV drug development 
114  addressed in the guidances for industry Antiviral Product Development  Conducting and 
                                                 
8 See the guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014).  
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115  Submitting Virology Studies to the Agency (June 2006), and Chronic Hepatitis B Virus Infection: 
116  Developing Drugs for Treatment, including recommendations for studies of mechanism of 
117  action, determination of antiviral activity in cell culture, cytotoxicity, and mitochondrial toxicity.  
118   
119  Sponsors should also consider the following recommendations specific for HDV drug 
120  development: 
121   
122    Antiviral activity determination in cell culture: To assess the breadth of activity of the 
123  investigational drug, the effective drug concentration at which virus replication is 
124  inhibited by 50 and 90 percent (EC  and EC  values) should be determined against 
50 90
125  different genotypes of HDV, including genotype 1, in cell culture. If EC  values vary 
50
126  significantly across genotypes, indicating a lack of conservation of the drug target, the 
127  breadth of activity against genotype 1 should also be determined by testing multiple 
128  geographically and temporally distinct isolates of this genotype. 
129   
130    Cell culture combination antiviral activity: Cell culture combination antiviral activity of 
131  an investigational drug against HDV should be determined with approved drugs for HBV 
132  and for HDV (when anti-HDV drugs are approved) to determine the likelihood of 
133  antagonism when used in combination for the treatment of HBV/HDV infection. 
134  Sponsors should assess the effect of approved drugs for HBV on the activity of the 
135  investigational HDV drug, and conversely, the effect of the investigational HDV drug on 
136  the activity of approved HBV drugs. 
137   
138    Activity in animal models:9 Animal models of HDV infection may be important for 
139  assessing the antiviral activity of investigational drugs, given the difficulty in propagating 
140  the virus in cell culture. Sponsors should consider the following recommendations related 
141  to animal models: 
142   
143    Animal models for consideration may include immunocompromised mice with 
144  chimeric human/mouse livers and transgenic mice expressing human sodium 
145  taurocholate cotransporting polypeptide (NTCP) receptor and HBsAg (Winer et al. 
146  2018). The woodchuck model using HDV pseudotyped with woodchuck hepatitis 
147  virus envelope proteins can be considered for drugs that do not specifically target the 
148  HDV/HBV envelope protein or human NTCP receptor (Aldabe et al. 2015). 
149   
150    If studies are conducted in animal models to support an HDV treatment program, we 
151  recommend including time course plots of viral load (RNA) and antigen expression 
152  data for each animal. We recommend testing different HDV/HBV genotypes and 
153  assessing resistance development where feasible. 
154   
155    Evaluating HDV resistance: FDA encourages sponsors to investigate resistance in 
156  nonclinical models of infection where feasible, although such studies may be challenging 
                                                 
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. 
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Draft  Not for Implementation 
157  given the limitations of propagating HDV in cell culture and animal models and the 
158  dependency of HDV on HBV envelope proteins for infection. 
159   
160    Evaluating HDV cross-resistance: If a drug for treatment of HDV infection is approved 
161  and HDV variants resistant to the drug are identified, these variants should be assessed 
162  for susceptibility to the investigational drug. Likewise, HDV variants resistant to the 
163  investigational drug should be assessed for susceptibility to any approved drugs for HDV.  
164   
165  c.  Clinical pharmacology development considerations 
166   
167  Studies to characterize pharmacokinetics including the effect of extrinsic (e.g., drug-drug 
168  interaction studies, food effect studies) and intrinsic factors (e.g., pharmacokinetic studies in 
169  subjects with renal impairment or hepatic impairment) should be conducted early in development 
170  to inform the trial design for phase 2 and phase 3 trials. Sponsors should consider 
171  recommendations in the pertinent guidances for industry. 
172   
173  d.  Efficacy considerations 
174   
175  In early clinical trials, the sponsor should measure HDV RNA levels during a short treatment 
176  period (i.e., one to three months, depending on the drugs mechanism of action) to assess 
177  activity. The sponsor should assess changes in alanine aminotransferase (ALT) as a key 
178  secondary endpoint. 
179   
180  2.  Drug Development Population 
181   
182  Development programs should include a diverse and representative clinical trial population, and 
183  sponsors should consider the following points related to trial populations: 
184   
185    HDV infection is a global disease with the greatest burden of infection occurring in 
186  Eastern and Mediterranean Europe, the Middle East, the Amazon Basin, and parts of Asia 
187  and Africa. 
188   
189    Under 21 CFR 312.120, FDA will accept data from a well-designed, well-conducted, 
190  non-IND foreign trial as support for an IND or application for marketing approval if 
191  the trial was conducted in accordance with good clinical practice and if FDA is able 
192  to validate the data from the trial through an onsite inspection, as necessary.10  
193   
194    Although foreign data may be acceptable as a sole basis for marketing approval under 
195  certain circumstances (see 21 CFR 314.106), FDA encourages sponsors to include 
196  U.S. patients in development programs to provide additional experience relevant to 
197  the U.S. population. 
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). 
 
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199    FDA encourages sponsors to discuss their enrollment strategies and plans for phase 2 and 
200  phase 3 trials with DAVP. Eligibility criteria should allow the clinical trial population to 
201  reflect the diversity of the patients who will be using the drug if the drug is approved.11 
202   
203    Sponsors should conduct initial trials to define antiviral activity and dose-response in 
204  patients without cirrhosis or with compensated cirrhosis, as these patients are at lower 
205  risk of imminent clinical progression or decompensation. In the later stages of drug 
206  development, enrollment of patients with decompensated liver disease may be considered 
207  (see section III.B.2., Trial Population). 
208   
209    In the absence of a serious safety signal in adults, it may be appropriate to enroll 
210  adolescent patients (for the purpose of this guidance, ages 12 to younger than 18 years of 
211  age) concurrently with adults in phase 3 trials and to make every effort to obtain 
212  confirmatory pharmacokinetic and safety data from a cohort in this age group as part of 
213  the data included at the time of filing of the original new drug application or biologics 
214  license application. 
215   
216  3.  Safety Considerations 
217   
218  An initial marketing application should include adequate safety data, such as the following, to 
219  allow for a benefit-risk assessment of the drug: 
220   
221    Safety data from 300 to 500 patients exposed to the proposed drug dose and treatment 
222  duration (or greater) may be adequate; however, the size of the safety database could be 
223  smaller for investigational drugs that demonstrate substantial efficacy and safety 
224  compared to available therapies. Nonclinical or clinical safety signals may necessitate a 
225  larger safety database or the conduct of additional safety studies. For a drug approved for 
226  use in patients without cirrhosis or with compensated cirrhosis, the safety database 
227  needed to extend use of the drug to the decompensated cirrhotic population would depend 
228  on the safety profile of the investigational drug and the overall benefit-risk profile for the 
229  indicated population.  
230   
231    Clinical trial protocols should include predefined algorithms for data collection in the 
232  setting of significant hepatic events, such as ALT flares or reactivation of HDV or HBV. 
233  FDA encourages use of an independent adjudication committee to evaluate significant 
234  hepatic events to determine whether the events represent drug-related toxicity, flares 
235  related to viral reactivation, or immunologic responses to virologic infection. 
236   
237    Severe acute exacerbations of HDV and HBV infection may occur after antiviral therapy 
238  is discontinued. Hepatic function should be monitored closely with both clinical and 
239  laboratory follow-up for at least several months in patients who discontinue anti-HDV 
240  and/or anti-HBV therapy. In certain circumstances, resumption of antiviral therapy may 
241  be warranted. The sponsor should adequately monitor and evaluate these concerns in the 
                                                 
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 FDAs current thinking on this topic. 
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242  development program and convey, as appropriate, these concerns in proposed drug 
243  labeling. 
244   
245  B.  Phase 3 Efficacy Trial Considerations 
246   
247  1.  Trial Design 
248   
249  No drugs have been approved for the treatment of chronic HDV infection. Therefore, a double-
250  blind, placebo-controlled trial is the FDAs preferred trial design for a phase 3 clinical trial.  
251   
252  Alternative trial design options include the following:  
253   
254    Three-arm, randomized, controlled trial comparing investigational drug, standard-of-care 
255  treatment, and placebo.  
256   
257    Although PEG-IFN- has not been approved by FDA for the treatment of chronic 
258  HDV infection, it is used in clinical practice and is considered the standard-of-care in 
259  some parts of the world. As such, the use of PEG-IFN- as a comparator in a clinical 
260  trial may be acceptable. However, the treatment effect of PEG-IFN- over placebo 
261  has not been well established; therefore, superiority of the investigational drug versus 
262  placebo should be demonstrated to support efficacy. The comparison between PEG-
263  IFN- and placebo can establish the effect of PEG-IFN-, and the comparison 
264  between the investigational drug and PEG-IFN- can help to evaluate the efficacy 
265  and the safety profile of the investigational drug.  
266   
267    Randomized, controlled trial in which subjects are randomized to the investigational drug 
268  (immediate treatment group) or placebo for a prespecified duration followed by open 
269  label treatment with investigational drug (deferred treatment group). Effectiveness would 
270  be demonstrated by showing an early significant improvement over the placebo control. 
271   
272    Randomized, controlled superiority trial comparing the investigational drug plus 
273  standard-of-care treatment to standard-of-care treatment alone (i.e., an add-on trial). In 
274  this case, although effectiveness is demonstrated, it would have been shown only when 
275  the investigational drug is added to the standard-of-care treatment; the sponsor would not 
276  know whether the investigational drug has an effect when used alone. 
277   
278    Randomized, controlled superiority trial comparing different doses and/or durations of 
279  the investigational drug.  
280   
281  After approval of a drug for the treatment of HDV infection, a randomized, controlled superiority 
282  or noninferiority trial comparing the investigational drug against an active comparator is 
283  appropriate.  
284   
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285  2.  Trial Population 
286   
287  Sponsors should include the following virologic and clinical characteristics in patient eligibility 
288  criteria: 
289   
290    Documentation of chronic HDV infection, defined as positive serum anti-HDV 
291  antibodies 
292   
293    Quantifiable HDV RNA of at least 6-month duration 
294   
295    Receiving HBV treatment in accordance with current treatment guidelines. Patients who 
296  qualify for HBV treatment should be on a stable regimen for at least 3 months with 
297  documented HBV DNA suppression before initiating the HDV investigational therapy. 
298   
299  Sponsors should enroll sufficient numbers of patients in the trials who are infected with HDV 
300  genotype 1 to assess efficacy in this population. 
301   
302  Sponsors should consider the following when enrolling patients without cirrhosis or with 
303  compensated cirrhosis: 
304   
305    The presence or absence of cirrhosis at trial entry should be documented. The use of a 
306  noninvasive modality to define the presence or absence of cirrhosis in a trial should be 
307  supported by references that summarize the performance characteristics and sensitivity 
308  and specificity of the modality for its intended purpose in the proposed population.  
309   
310    FDA recommends that sponsors exclude patients with decompensated cirrhosis or a 
311  history of any prior hepatic decompensation event until data on the safety and 
312  effectiveness of a given therapy in patients without cirrhosis and with compensated 
313  cirrhosis are obtained. 
314   
315  3.  Randomization and Stratification 
316   
317  If multiple subpopulations are included in the same trial, sponsors can consider stratifying groups 
318  at randomization based on key variables such as presence or absence of cirrhosis, baseline HDV 
319  RNA level, and genotype/region.  
320   
321  4.  Dose Selection 
322   
323  FDA encourages sponsors to use quantitative clinical pharmacology approaches that leverage 
324  prior information to optimize dose selection for phase 3 trials. These approaches are addressed in 
325  other guidances for industry.12 
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 FDAs current thinking on this topic).   
 
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327  5.  Comparators 
328   
329  See section III.B.1., Trial Design, for a description of potential comparators for use in different 
330  trial designs. 
331   
332  6.  Efficacy Endpoints 
333   
334  a.  Primary endpoints 
335   
336  FDA anticipates that initial approvals for anti-HDV drugs will be based on a surrogate endpoint 
337  that is reasonably likely to predict clinical benefit. An appropriate surrogate endpoint for the 
338  treatment of HDV should provide evidence of both a decline in virologic replication and an 
339  improvement in associated liver inflammation as evident by biochemical response (see section 
340  III.B.9., Accelerated Approval (Subpart H) Considerations, for additional information regarding 
341  approval under the accelerated approval pathway). For FDA, the following surrogate endpoint 
342  could reasonably predict clinical benefit and could be considered to support an accelerated 
343  approval: 
344   
345    The proportion of trial patients with undetectable serum HDV RNA (defined as less than 
346  the lower limit of quantification (LLOQ), target not detected (TND)) and ALT 
347  normalization.  
348   
349  There are some data suggesting that a 2-log  decline in HDV RNA is associated with clinical 
10
350  benefit (Farci et al. 2004; Yurdaydin et al. 2019); therefore, in certain situations, such as for 
351  drugs that are intended to be used as chronic suppressive therapy, a greater than or equal to 2-
352  log decline in HDV RNA and ALT normalization on-treatment could  be considered an 
10 
353  acceptable surrogate endpoint reasonably likely to predict clinical benefit (see section III.B.9., 
354  Accelerated Approval (Subpart H) Considerations). The sponsor can request a Type C formal 
355  meeting to discuss the use of a novel surrogate endpoint as the primary basis for drug approval.13 
356   
357  The timing of the primary endpoint assessment (whether on-treatment, at the end-of- treatment, 
358  or off-treatment after a specified duration of follow-up) will depend on the treatment strategy 
359  used (i.e., finite duration of therapy versus chronic suppressive therapy) for a specific drug. FDA 
360  encourages the sponsor to discuss its proposed primary efficacy endpoint and the timing of the 
361  endpoint assessment with DAVP. 
362   
363  Approval based on a surrogate endpoint reasonably likely to predict clinical benefit will require 
364  subsequent confirmation using a clinical endpoint. FDAs preferred clinical endpoint is 
365  improvement in clinical outcomes such as decrease in progression to cirrhosis, progression to 
366  decompensated liver disease, liver transplantation, hepatocellular carcinoma, and liver-related 
367  death. These clinical outcomes should be collected as long-term follow-up data. 
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 FDAs current thinking on this topic. 
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369  b.  Secondary endpoints 
370   
371  Sponsors should consider the following secondary endpoints:  
372   
373    Greater than or equal to 2-log  decline in serum HDV RNA 
10
374    HDV RNA less than LLOQ (TND) 
375    ALT normalization  
376    Histological response or change in liver stiffness 
377    Change in Model for End-Stage Liver Disease scores 
378    Change in Child-Turcotte-Pugh scores 
379   
380  7.  Trial Procedures and Timing of Assessments 
381   
382  The optimal timing of the primary endpoint assessment is unknown. Sponsors should consider 
383  the following for timing of assessments:  
384   
385    For therapies intended to be administered indefinitely, an on-treatment assessment after a 
386  predefined time period can be acceptable for efficacy. 
387   
388    For therapies intended to be administered for a finite duration, FDAs preferred endpoint 
389  is an off-treatment assessment of efficacy.  
390   
391  8.  Statistical Considerations 
392   
393  For recommendations and considerations on statistical analysis methods and issues, see the 
394  guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
395  Biological Products (May 1998) and the article Statistical Considerations on Subgroup Analysis 
396  in Clinical Trials (Alosh et al. 2015).  
397   
398  a.  Efficacy analyses 
399   
400  The preferred primary endpoints for phase 3 trials are described above in section III.B.6., 
401  Efficacy Endpoints. Sponsors should consider the following recommendations for analyzing the 
402  primary efficacy endpoint: 
403   
404    The primary analysis should compare the proportion of responders across trial treatment 
405  arms. This analysis determines whether effectiveness has been demonstrated.  
406   
407    The analysis of the primary efficacy endpoint should be performed within important 
408  subgroups based on demographic and baseline characteristics (e.g., geographic region, 
409  sex, race, age group, screening HDV RNA level, HDV/HBV genotypes, baseline weight 
410  and body mass index, baseline ALT, baseline fibrosis/cirrhosis, (if applicable) response 
411  to previous treatment regimens). The purpose of these analyses is to explore the 
412  consistency of the primary efficacy endpoint result across these subgroups.  
413   
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414  b.  Noninferiority trials 
415   
416  Because there are no approved therapies for the treatment of chronic HDV infection at this time, 
417  a noninferiority trial design is not possible. In the future, should there be approved therapies for 
418  the treatment of chronic HDV infection, noninferiority trials may be acceptable. Sponsors should 
419  justify proposed noninferiority margins and discuss with DAVP.14  
420   
421  c.  Combination regimens 
422   
423  Sponsors planning to evaluate a combination regimen of two or more drugs should consult 21 
424  CFR 300.50 regarding combination drugs. Additional recommendations for codevelopment of 
425  two new investigational drugs can be found in the guidance for industry Codevelopment of Two 
426  or More New Investigational Drugs for Use in Combination (June 2013). 
427   
428  9.  Accelerated Approval (Subpart H) Considerations 
429   
430  For HDV infection, no surrogate endpoints have been definitively shown to predict clinical 
431  benefit. Trials aimed at demonstrating the clinical benefit of an HDV therapy would likely 
432  require a prolonged follow-up period. Therefore, FDA anticipates that development programs 
433  may opt to pursue accelerated approval pathways based on a surrogate endpoint reasonably 
434  likely to predict clinical benefit (see section III.B.6., Efficacy Endpoints). An accelerated 
435  approval pathway will require confirmation of clinical benefit through a long-term extension of 
436  the original trial or a subsequent additional clinical trial or trials. Sponsors should consider 
437  planning for the confirmatory trial(s) during the development of the phase 3 program. 
438   
439  C.  Other Considerations 
440   
441  1.  Clinical Virology Considerations 
442   
443  Sponsors can find general recommendations for clinical virology assessments in the guidances 
444  for industry Antiviral Product Development  Conducting and Submitting Virology Studies to 
445  the Agency and Chronic Hepatitis B Virus Infection: Developing Drugs for Treatment. Sponsors 
446  should consider the following recommendations specific for HDV infection: 
447   
448    Virologic Assessments 
449   
450    For virologic assessments in clinical trials, we recommend the use of FDA-approved 
451  or FDA-cleared assays, if available, and a central laboratory. If an investigational 
452  assay or assays are used, the sponsor should provide performance characteristics of 
453  the assay(s) determined from analytical validation studies using geographically and 
454  temporally distinct isolates in addition to detailed descriptions of the methodology. 
455  Viral loads should be reported in international units per milliliter (IU/mL). 
456   
                                                 
14 For additional information on determining noninferiority margins, see the guidance for industry Non-Inferiority 
Clinical Trials to Establish Effectiveness (November 2016). 
11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
457    Because HDV requires the HBV envelope protein to propagate, clinical efficacy 
458  assessments should include virologic parameters for both HDV and HBV. 
459   
460    Samples for HDV and HBV quantification, genotypic, and phenotypic analysis 
461  should be obtained at multiple time points during treatment and follow-up.  
462   
463    Where feasible, we recommend determining the genotypes/subtypes of both HDV 
464  and HBV present at baseline and, hence, determine if the investigational drug exhibits 
465  antiviral activity against all the HDV/HBV genotypes/subtypes represented in the 
466  trial. 
467   
468    Resistance Assessment 
469   
470    In general, for treatment of HDV infection, virologic failure is defined as a confirmed 
471  increase in HDV RNA levels of greater than or equal to 1.0 log  IU/mL above the 
10
472  nadir value (assuming an initial response of at least 1.0 log  IU/mL compared with 
10
473  baseline) or having quantifiable HDV RNA after being less than LLOQ (TND). In 
474  general, virologic nonresponse is defined as less than or equal to 1.0-log  IU/mL 
10
475  reduction in HDV RNA levels compared with baseline. 
476   
477    Genotypic assessment of resistance should include sequencing of the HDV genome 
478  and, for drugs that act through the HBV envelope protein or NTCP receptor, 
479  sequencing of the HBsAg coding region where feasible. Any changes, including 
480  mixtures, in the amino acid sequence of the target protein (or nucleotide sequence for 
481  genome targeting drugs) present in on-treatment or follow-up samples, but not in the 
482  baseline sample, can be reported as having developed during therapy. 
483   
484    Phenotypic assessment of resistance should include analysis of HDV variants in cell 
485  culture, if feasible, and determination of loss of susceptibility to the investigational 
486  drug. 
487   
488    Before submission of resistance data, contact FDA to obtain the most recent format 
489  recommendations for submitting resistance datasets.  
490   
491    For drugs with a host target, the frequency of polymorphisms in the target in key U.S. 
492  racial groups should be reported and their effect on efficacy assessed in clinical trials. 
493   
12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
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14