Antiviral Product Development--Conducting and Submitting Virology Studies to the Agency: Guidance for Submitting HIV 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 HIV
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
HIV RESISTANCE DATA
Sponsors are encouraged to use the following sample format for submitting HIV 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 should be provided on the corresponding record for each patient isolate for
baseline isolates of all patients in treatment-experienced studies and the endpoint isolates of
virologic failures and discontinuations in all studies.2 In treatment-naïve studies, a baseline
sample should be collected and stored from all patients for future phenotypic and genotypic
analysis of virologic failures.
Phenotypic data should be provided on the corresponding record for each patient isolate for
baseline isolates and the endpoint isolates of virologic failures and discontinuations.2 In
treatment-experienced studies, it is recommended that baseline phenotypic data be obtained
for all patients.
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 Treatment and endpoint samples should be collected when the patient is still on the study product.
1

•
•
•
•
•
•
•
•
•
Contains Nonbinding Recommendations
II. Endpoint Data:
HIV RNA (copies/mL) at baseline
HIV RNA (copies/mL) at predefined time points (e.g., week 24 and week 48), one column
for each time point including baseline (i.e. the viral load throughout the course of the study is
provided for each sample)
HIV RNA (copies/mL) at other times (e.g., loss of virologic response or discontinuation
because of adverse event)
Endpoint assessment (e.g., mean log change in viral load from baseline)
Other endpoint assessments (e.g., DAVG)
Indication of data were censored for reasons other than virologic failure (e.g., discontinuation
because of adverse event)
Outcome (i.e. responder, virologic failure, discontinuation while suppressed, discontinuation
before achieving viral suppression)
Reason for discontinuation (i.e., adverse event, pregnancy) or failure (i.e., never suppressed,
rebound)
HIV RNA (copies/ml) from additional time points can be included
III. Genotypic Data: 3
• 	Clade
• 	Genotype for the RT, protease and gp160 (for products targeting entry only), one amino acid
per column with the wild-type (WT) amino acid as column heading. Changes from WT
standard sequence indicated (i.e., blanks indicate no change).
• 	Column with total number of PI mutations in patient isolate (for baseline and endpoint
isolates). The specific mutations to include should be discussed with the division in advance.
• 	Column with total number of NRTI mutations in patient isolate (for baseline and endpoint
isolates). The specific mutations to include should be discussed with the division in advance.
• 	Column with total number of NNRTI mutations in patient isolate (for baseline and endpoint
isolates). The specific mutations to include should be discussed with the division in advance.
Example (Table 1 highlights how genotype information can be displayed, but does not include
all column headings previously suggested.)
3 Genotypic data should be provided for baseline isolates of all patients in treatment-experienced studies and the
endpoint isolates of virologic failures and discontinuations in all studies. In treatment-naïve studies, a baseline
sample should be collected and stored from all patients for future phenotypic and genotypic analysis of virologic
failures.
2

Contains Nonbinding Recommendations
Table 1. Example of Genotype Information Display
Patient # 	Isolate 	V-82 	N-83 	I-84 	I-85 	G-86 	R-87 	N-88 	L-89 	L-90 	# PI Mutations
001 	BL 	S 	M/L 	2
001 	WK48 	V 	S 	M 	3
002 	BL 	A/T 	V 	D 	M 	4
002 	WK48 	T 	V 	M 	3
003 	BL 	T 	V 	2
004 	BL 	V 	M 	2
BL = baseline
WK48 = week 48 for investigational product
IV. Protease Cleavage Sites (for protease inhibitors only):
• 	NC/p1 Gag cleavage sites: show amino acid and position of cleavage site of WT in column
headings (as above for genotype) and indicate amino acid change if mutant
• 	p1/p6 Gag cleavage sites: show amino acid and position of cleavage site of WT in column
headings (as above for genotype) and indicate amino acid change if mutant
V. Phenotypic Data:4
1. 	Information on the investigational product
• 	Baseline EC50 value for investigational product
• 	Baseline EC50 value of reference strain for investigational product
• 	Fold resistant 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 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
• 	Replication capacity (if available)
2. 	Information on approved and other investigational anti-HIV products (if available) in the
same class
• 	Fold change in EC50 value of baseline compared to reference strain for each of the
approved and other investigational anti-HIV 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-HIV products (if
available)
• 	Fold change in EC50 value at time of endpoint assessment or failure compared to baseline
for each of the approved and other investigational anti-HIV products (if available)
4 Phenotypic data should be provided for baseline isolates and the endpoint isolates of virologic failures and
discontinuations. In treatment-experienced studies, it is recommended that baseline phenotypic data be obtained for
all patients.
3

Contains Nonbinding Recommendations
3. 	Information on approved and other investigational products (if available) outside the
investigational product’s class with same target protein (e.g., NRTIs and NNRTIs)
• 	Fold change in EC50 value of baseline compared to reference strain for approved and
other investigational products (if available) outside the investigational product’s class
• 	Fold change in EC50 value at time of endpoint assessment or failure compared to
reference strain for each of the approved and other investigational products (if available)
outside the investigational product’s class
• 	Fold change in EC50 value at time of endpoint assessment or failure compared to baseline
for each of the approved and other investigational products (if available) outside the
investigational product’s class
4. 	Information on other antiretroviral products in the regimen
• 	Fold change in EC50 value of baseline compared to reference strain for other
antiretroviral products in the regimen, one column per product
• 	Fold change in EC50 value at time of endpoint assessment or failure compared to
reference strain for other antiretroviral products in the regimen, one column per product
• 	Fold change in EC50 value at time of endpoint assessment or failure compared to baseline
for other antiretroviral products in the regimen, one column per product
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
Sample
EC50
value
Agent
X
Agent X
Ref
strain
EC50
value
Agent
X
Δ
resis
from
ref
Agent
X
Δ resis
from BL
Agent X
Other Agents in the
Same Class*
Δ resis
from ref
Agent Y
Δ resis
from BL
Agent Y
Other Agents Outside
Agent Class*
Δ resis
from ref
Agent A
Δ resis
from BL
Agent A
Baseline
Endpoint
Agent X = candidate agent
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)
Endpoint = predefined time point for endpoint assessment (e.g., week 24, week 48, failure or discontinuation)
*Note: The Δ resis from ref and Δ resis from BL should be included for all approved anti-HIV products
VI. Co-Receptor Usage (for all agents targeting co-receptors):
• 	Co-receptor usage of baseline isolates. Indicate R5, X4, D for dual-tropic, M for mixed-
tropic, or D/M if the assay cannot distinguish between dual or mixed, in a column.
• 	Baseline R5 tropism assay value (e.g., RLUs).
• 	Baseline X4 tropism assay value (e.g., RLUs).
4

Contains Nonbinding Recommendations
• 	Co-receptor usage of virologic failures and end-of-study isolates (on therapy). Indicate R5,
X4, D for dual-tropic, M for mixed-tropic, or D/M if the assay cannot distinguish between
dual or mixed, in a column.
• 	R5 tropism assay value at failure or end of study (e.g., RLUs).
• 	X4 tropism assay value at failure or end of study (e.g., RLUs).
VII. Therapeutic Drug Monitoring Data (when available):
• 	Patient’s Cmin
• 	Serum adjusted IQ (inhibitory quotient = Cmin /serum adjusted EC 50 value)
5