Antiviral Product Development--Conducting and Submitting Virology Studies to the Agency: Guidance for Submitting HCV Resistance Data

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Attachment to
Guidance on Antiviral Product
Development 	— 	Conducting
and Submitting Virology
Studies to the Agency
Guidance for Submitting HCV
Resistance Data
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

Contains Nonbinding Recommendations
GUIDANCE FOR SUBMITTING
HCV RESISTANCE DATA
Sponsors are encouraged to use the following sample format for submitting HCV 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 and the endpoint isolates of virologic failures and
discontinuations 2 — 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 HCV. 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, 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:
•
•
•
•
•
•
•
HCV RNA (log10 copies/mL) at baseline
HCV RNA (log10 copies/mL) at predefined time points (e.g., week 24 and week 48), one
column for each time point including baseline
HCV RNA (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)
Follow-up for determination of sustained virologic response
Indication of data were censored for reasons other than virologic failure (e.g., discontinuation
because of adverse event)
HCV RNA (log10 copies/ml) from additional time points can be included
Note: We recommend that sponsors analyze HCV RNA with a sensitive and specific HCV RNA
assay with lower limits of quantification in the range of less than 100 copies/mL (IU/mL).
III. Genotypic Data:
•
•
HCV subtype (e.g., 1a, 1b, 2)
Genotype information for all the replicases 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 WT standard sequence indicated (i.e., blanks
indicate no change) and known polymorphisms are indicated with an asterisk.
Example (Table 1 highlights how genotype information can be displayed, but does not include
all column headings previously suggested.)
Table 1. Example of Genotype Information Display
Patient # 	Isolate 	Subtype 	E414 	F415 	D416 	L417
001 	BL 	1
001 	WK48 	1 	Y
001 	FU 	1
002 	BL 	1
002 	WK48 	1 	Y
002 	FU 	1 	Y
BL = baseline
WK48 = week 48
FU = follow-up
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)
•
•
2

Contains Nonbinding Recommendations
•
•
•
•
•
•
•
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 EC 50 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
EC50 value at follow-up for investigational product
Fold change values in EC 50 value at follow-up compared to reference strain for
investigational product
Fold change in EC50 value at follow-up compared to baseline for investigational product
2. 	Information on approved and other investigational anti-HCV products (if available)
Fold change in EC50 value of baseline compared to reference strain for each of the
approved and other investigational anti-HCV 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-HCV 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-HCV products (if
available)
Example (Table 2 highlights how phenotype information can be displayed.)
•
•
•
Table 2. Example of Phenotype Information Display
t
Other Agents in Same
Agent X 	Agent Class*
EC50 	Ref strain 	Δ resis 	Δ resis 	Δ resis 	Δ resis
value 	EC50 	from ref 	from BL 	from ref 	from BL
Sample 	Agent X 	value 	Agent X 	Agent X 	Agent Y 	Agent Y
Agent X
Baseline
Endpoin
	
	
	

Agent X = candidate agent
BL = baseline
Endpoint = predefined time point for endpoint assessment (e.g. week 24, week 48, failure or discontinuation)
Δ 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 Δ resis from ref and Δ resis from BL should be included for all approved and other
investigational anti-HCV products (if available)
3