Attachment to 
 
Guidance on Antiviral Product 
Development  Conducting 
and Submitting Virology 
Studies to the Agency 
 
 
 
Guidance for Submitting HBV  
Resistance Data 
 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
June 2006 
Clinical Antimicrobial 
 
  Contains Nonbinding Recommendations 
GUIDANCE FOR SUBMITTING  
HBV RESISTANCE DATA 
 
Sponsors are encouraged to use the following sample format for submitting HBV resistance data. 
 
One dataset combines patient data, endpoint data, genotypic data, and phenotypic data.  There 
are a number of ways datasets can be subdivided (i.e., by clinical study, baseline isolates, or 
virologic failure isolates) and this should be discussed with the division before submission.  
 
For each study, we recommend constructing datasets as SAS transport files containing the 
following information:   
 
  One record (row) per patient per isolate (e.g., baseline, failure, and other time points).  
  Data in columns (with suggested column headings shown below)1 on all isolates. 
  Genotypic data for baseline isolates of all patients and the endpoint isolates of virologic 
failures and discontinuations2  on the corresponding record for each patient isolate.   
  Phenotypic data for baseline isolates and the endpoint isolates of virologic failures and 
discontinuations2  on the corresponding record for each patient isolate.  We recognize the 
difficulty of phenotypic analysis of HBV.  Sponsors are strongly encouraged to appropriately 
collect and store samples for later analysis if warranted.  If the pathway to resistance as 
defined by genotypic analysis is straightforward (e.g., lamivudine), phenotypic analysis may 
not be necessary.  We recommend that sponsors consult with the division to determine 
whether phenotypic analysis should be conducted.  
 
The specific criteria for defining virologic failures should be discussed with the division and 
may include multiple primary and secondary protocol endpoints.  The endpoints for 
clinical virologic and resistance outcome analyses should be consistent. 
 
Information to Include with Suggested Column Headings1  
 
I. Patient Data: 
 
  Patient identification number (ID number should be unique for all studies) 
  Isolate (e.g., baseline, week 24, week 48, discontinuation.  Multiple isolates should be 
numbered.) 
  Date of isolate 
  Study day (number of days since the patient started the study product) 
  Previous therapeutic products where available 
  Treatment group 
  Censored for analysis (yes or no) 
 
                                                 
1 In the SAS transport files, column headings can be given abbreviated column names to fit the SAS format; 
however, it is suggested that a description of column names be provided to the reviewer in the submission. 
 
2 Samples should be collected from rebound and failure isolates for analysis when the patient is receiving the study 
product. 
1  Contains Nonbinding Recommendations 
II. Endpoint Data: 
 
  HBV DNA (log  copies/mL) at baseline 
10
  HBV DNA (log  copies/mL) at predefined time points (e.g., week 24 and week 48), one 
10
column for each time point including baseline 
  HBV DNA (log  copies/mL) at time of loss of virologic response or discontinuation because 
10
of adverse event 
  Endpoint assessment (e.g., log  change in viral load from baseline)   
10
  Indication of data were censored for reasons other than virologic failure (e.g., discontinuation 
because of adverse event) 
  HBV DNA (log  copies/ml) from additional time points can be included 
10
 
Note: We recommend that sponsors analyze HBV DNA with a sensitive and specific HBV DNA 
assay with a lower limit of quantification less than 1,000 copies/mL. 
 
III. Genotypic Data:  
 
  HBV subtype 
  Genotype information for all the RT or relevant coding region sequenced, one amino acid per 
column with the wild-type (WT) amino acid as column heading identified using the one 
amino acid abbreviation.  Changes from the baseline sequence should be indicated (i.e., 
blanks indicate no change) and known polymorphic amino acid residues flagged in the 
column heading. 
 
Example (Table 1 highlights how genotype information can be displayed, but does not include 
all column headings as previously suggested.) 
 
Table 1.  Example of Genotype Information Display 
Patient #  Isolate  Subtype  rtY203  rtM204  rtD205  rtD206
001  BL  A         
001  WK48  A    V     
002  BL  C         
002  WK48  C    I     
003  BL  A         
004  BL  B    V     
BL = baseline 
WK48 = week 48 
 
IV. Phenotypic Data:  
 
1.  Information on the investigational product 
  Baseline EC  value for investigational product 
50
  EC  value of reference strain for investigational product (a widely available standard 
50
laboratory strain is recommended as the reference strain) 
  Fold change of baseline EC  value compared to EC  value of reference strain of 
50 50
investigational product 
2  Contains Nonbinding Recommendations 
  EC  value at time of endpoint assessment or failure for investigational product  
50
  Fold change values in EC  value at time of endpoint assessment or failure compared to 
50
reference strain for investigational product 
  Fold change in EC  value at time of endpoint assessment or failure compared to baseline 
50
for investigational product 
 
2.  Information on approved and other investigational anti-HBV products (if available) 
  Fold change in EC  value of baseline compared to reference strain for each of the 
50
approved and other investigational anti-HBV products (if available) 
  Fold change in EC  value at time of endpoint assessment or failure compared to 
50
reference strain for each of the approved and other investigational anti-HBV products (if 
available) 
  Fold change in the EC  value at time of endpoint assessment or failure compared to 
50
baseline for each of the approved and other investigational anti-HBV products (if 
available) 
 
Example (Table 2 highlights how phenotype information can be displayed, but does not include 
all column headings previously suggested.) 
 
Table 2.  Example of Phenotype Information Display 
     
    Other Agents in Same 
  Agent X  Class* 
  EC   Ref strain   resis   resis   resis   resis 
50
  value  EC   from ref  from BL  from ref  from BL 
50
Sample  Agent  value  Agent X  Agent X  Agent Y  Agent Y 
X  Agent X 
Baseline             
Endpoint             
Agent X = candidate agent 
BL = baseline 
Endpoint = predefined time point for endpoint assessment (e.g., week 24, week 48, failure or 
discontinuation) 
 resis = fold resistance change, e.g.,    EC  value of sample with Agent X  
50
EC  value of reference (or baseline) strain with Agent X 
50
Ref strain = reference strain (or WT) 
*Note: The  resis from ref and  resis from BL should be included for all approved and other 
investigational anti-HBV products (if available).  
3