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
INFLUENZA RESISTANCE DATA
Sponsors are
encouraged to use the following sample format for submitting
influenza resistance data for microbiology review. Sponsors
should begin these analyses in the earliest clinical stages of
product development so that sample collection, storage, and
analyses are well established at the time of the initiation of
pivotal studies. If sponsors wish to submit additional
information, they are encouraged to discuss these suggestions with
the division in advance.
One dataset combines patient data, virologic data, genotypic data, and
phenotypic data.
Selected clinical outcome data can also be included for
exploratory analysis (we recommend discussion with the division to
establish the format for including these data in the dataset).
There are a number of ways datasets can be subdivided (i.e., by
clinical study1, baseline isolates, or designated later
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.
·
For
treatment studies, a row should be included for the initial
isolate obtained before starting study drug (baseline isolate),
even if virologic studies (e.g., culture, PCR) are negative. In
cases where an assay was negative, insert <LLOQ (lower limit of
quantification) or <LOD (limit of detection) where the specific
numerical value of the LLOQ or LOD is inserted, as appropriate.
Other isolates to be included for treatment studies, and inclusion
and designation of isolates for prophylaxis studies, should be
discussed with the division.
·
Data in
columns (with suggested column headings shown below)
on all isolates.
·
In
studies where both treatment and prophylaxis are evaluated, a
column should be included identifying the patient as treatment or
prophylaxis group.
·
In most
studies it is anticipated that all isolates for virologic analysis
will be obtained using the same methodology (e.g., nasal washing,
nasopharyngeal swab, throat swab) that will be described in the
protocol and study report. If there is a reason for use of more
than one method in the same study, discussion with the division is
recommended.
·
Genotypic
data should be provided for (at a minimum) baseline isolates of
all patients and the predetermined time points of isolate
collection on the corresponding record for each patient isolate.
·
Phenotypic data should be provided for (at a minimum)
baseline isolates and the predetermined time points of isolate
collection on the corresponding record for each patient isolate.
The FDA recognizes the difficulty of phenotypic analysis of
influenza virus and the lack of clinical validation of current
assays. Sponsors are strongly encouraged to appropriately collect
and store isolates for later analysis. If the pathways to
resistance as defined by genotypic analysis are straightforward,
phenotypic analysis, after consultation with the division, may not
be necessary.
·
Depending
on the timing of serum specimens for antibody determination
relative to isolates obtained for viral isolation, the most
appropriate incorporation of serologic results into the dataset
should be discussed with the division.
Information to Include with Suggested Column Headings
I. Patient
Data:
·
Patient
identification number (ID number should be unique to all clinical
studies of the product)
·
Isolate (e.g.,
baseline, day 2 (with day 0 being the start of product
administration), discontinuation. Multiple isolates from the same
visit should be numbered (e.g., baseline 1, baseline 2)). All
isolates should be included even if negative for PCR and cell
culture.
·
Date of isolate
·
Days of study product
treatment on day isolate obtained
·
Days off study
product treatment on day isolate obtained
·
Previous therapeutic
products, if any
·
Treatment group
(e.g., specific dose, active control, placebo)
·
Indication if data
were censored (e.g., discontinuation because of adverse event)
II.
Virologic Data (culture and PCR results and quantification as appropriate):
·
Baseline measurement
(e.g., log10 influenza RNA copies/mL of nasal wash at
baseline, log10 TCID50/mL). (For
therapeutic studies, after onset of illness and before receipt of
study product.)
·
Measurements using
the same units at predefined time points (e.g., day 2),
one column for each time point including
baseline (i.e., the measurement throughout the course of infection
is repeated for each isolate)
·
Measurements from
additional time points can be included
III.
Genotypic Data (for baseline isolates of all patients and
predetermined time points):
·
Subtype for influenza
A isolates (e.g., H1N1, H3N2); insert “B” for influenza B to
confirm typing
·
Genotype information for all the relevant coding regions
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 WT standard sequence indicated (i.e.,
blanks indicate no change). Known polymorphic amino acid residues
should be flagged with an asterisk in the column heading. For
neuraminidase inhibitors, genotype information for both the
neuraminidase and hemagglutinin proteins would be relevant.
Example
(Table 1 highlights how genotype information should be displayed
but does not include all column headings previously suggested.)
Table 1. Example of Genotype Information Display
Patient # |
Isolate |
Subtype/Type |
C-291 |
R292 |
D-293 |
N-294 |
001 |
BL |
H3N2 |
|
|
|
|
001 |
Day 2 |
H3N2 |
|
K |
|
|
001 |
Day 5 |
H3N2 |
|
K |
|
|
002 |
BL |
H1N1 |
|
|
|
|
002 |
Day 2 |
H1N1 |
|
|
|
|
002 |
Day 3 |
H1N1 |
|
|
|
|
BL = baseline
IV.
Phenotypic Data (minimally for baseline isolates and
predetermined time points):
1. Candidate product
- Baseline EC50
value for candidate product
- EC50
value of reference strain for candidate product (the reference
strain should be a widely available standard lab strain)
- Fold change
of baseline EC50 value compared to EC50
value of reference strain of candidate product
- EC50
value at time of subsequent assessment as appropriate for
candidate product
- Fold change
values in EC50 value at time of subsequent assessment
as appropriate compared to reference strain for candidate
product
- Fold change
in EC50 value at time of subsequent assessment as
appropriate compared to baseline for
candidate product
2. Approved or investigational
products in the same class
- Fold change
in EC50 value of baseline
compared to reference strain for each of the approved or
investigational products in the same class
- Fold change
in EC50 value at time of subsequent assessment as
appropriate compared to reference
strain for each of the approved or investigational
products in the same class
- Fold change
in the EC50 value at time of subsequent assessment as
appropriate compared to baseline
for each of the approved or investigational products in the same
class
Example
(Table 2
highlights how phenotype information should be displayed.)
Table 2. Example of Phenotype
Information Display
|
Product X |
Other Products in Same Product Class* |
Isolate |
EC50 value Product X |
Ref strain
EC50 value
Product X
|
D
resis
from ref
Product X
|
D resis from BL
Product X
|
D
resis
from ref
Product Y
|
D
resis
from BL
Product Y
|
Baseline |
|
|
|
|
|
|
Day x |
|
|
|
|
|
|
Product X = candidate product"
BL = baseline
Day x = predefined
time point for subsequent assessment as appropriate (e.g., day 2,
day 5)
D resis = fold resistance
change, e.g.: EC50 value of baseline isolate with
Product X
EC50 value of reference strain with Product
X
Ref strain =
reference strain (or WT)
*Note: The
D resis from ref and
D resis from BL should be
included for all approved anti-influenza products.