This
guidance represents the Food and Drug Administration’s (FDA’s)
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
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)
on all isolates.
·
Genotypic data for baseline isolates of all patients
and the endpoint isolates of virologic failures and
discontinuations
— 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)
II.
Endpoint Data:
·
HBV DNA (log10 copies/mL) at baseline
·
HBV DNA (log10 copies/mL) at predefined
time points (e.g., week 24 and week 48), one column for each time
point including baseline
·
HBV DNA (log10 copies/mL) at time of loss
of virologic response or discontinuation because of adverse event
·
Endpoint assessment (e.g., log10 change
in viral load from baseline)
·
Indication of data were censored for reasons other
than virologic failure (e.g., discontinuation because of adverse
event)
·
HBV DNA (log10 copies/ml) from additional
time points can be included
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 EC50 value for investigational
product
·
EC50 value of reference strain for
investigational product (a widely available standard laboratory
strain is recommended as the reference strain)
·
Fold change of baseline EC50 value
compared to EC50 value of reference strain of
investigational product
·
EC50 value at time of endpoint assessment
or failure for investigational product
·
Fold change values in EC50 value at time
of endpoint assessment or failure compared to reference strain for
investigational product
·
Fold change in EC50 value at time of
endpoint assessment or failure compared to baseline for
investigational product
2.
Information on approved and other investigational anti-HBV
products (if available)
·
Fold change in EC50 value of baseline
compared to reference strain for each of the approved and other
investigational anti-HBV products (if available)
·
Fold change in EC50 value at time of
endpoint assessment or failure compared to reference strain for
each of the approved and other investigational anti-HBV products
(if available)
·
Fold change in the EC50 value at time of
endpoint assessment or failure compared to 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
|
Agent X |
Other Agents in Same Class* |
Sample |
EC50 value
Agent X |
Ref strain
EC50 value
Agent X
|
D resis
from ref
Agent X
|
D resis
from BL
Agent X
|
D resis
from ref
Agent Y
|
D resis
from BL
Agent Y
|
Baseline |
|
|
|
|
|
|
Endpoint |
|
|
|
|
|
|
Agent X = candidate agent
BL = baseline
Endpoint = predefined time point
for endpoint assessment (e.g., week 24, week 48, failure or
discontinuation)
D resis = fold
resistance change, e.g., EC50 value of sample
with Agent X
EC50 value of reference
(or baseline) strain with Agent X
Ref strain = reference strain (or
WT)
*Note: The
D
resis from ref and
D resis from BL
should be included for all approved and other investigational
anti-HBV products (if available).