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 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 

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-naive 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-naive 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 EC  value for investigational product 
50
	   Baseline EC  value of reference strain for investigational product 
50
	   Fold resistant change of baseline EC  value compared to EC  value of reference strain 
50 50
of investigational product 
	   EC  value at time of endpoint assessment or failure for investigational product  
50
	   Fold change 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 
	   Replication capacity (if available) 
 
2. 	  Information on approved and other investigational anti-HIV products (if available) in the 
same class 
	   Fold change in EC  value of baseline compared to reference strain for each of the 
50
approved and other investigational anti-HIV 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-HIV products (if 
available) 
	   Fold change in EC  value at time of endpoint assessment or failure compared to baseline 
50
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 products class with same target protein (e.g., NRTIs and NNRTIs)  
	   Fold change in EC  value of baseline compared to reference strain for approved and 
50
other investigational products (if available) outside the investigational products class  
	   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 products (if available) 
outside the investigational products class 
	   Fold change in EC  value at time of endpoint assessment or failure compared to baseline 
50
for each of the approved and other investigational products (if available) outside the 
investigational products class 
 
4.	   Information on other antiretroviral products in the regimen 
	   Fold change in EC  value of baseline compared to reference strain for other 

50
antiretroviral products in the regimen, one column per product 

	   Fold change in EC  value at time of endpoint assessment or failure compared to 
50
reference strain for other antiretroviral products in the regimen, one column per product 
	   Fold change in EC  value at time of endpoint assessment or failure compared to baseline 
50
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  
 
       
  Agent X  Other Agents in the  Other Agents Outside 
  Same Class*   Agent Class*  
  EC   Ref      resis   resis   resis   resis   resis 
50 
  value  strain  resis  from BL  from ref  from BL  from ref  from BL 
Sample  Agent  EC   from   Agent X  Agent Y  Agent Y  Agent A  Agent A 
50 
X  value  ref 
Agent  Agent 
X  X 
Baseline                 
Endpoint                 
Agent X = candidate agent 

 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) 

Endpoint = predefined time point for endpoint assessment (e.g., week 24, week 48, failure or discontinuation) 

*Note: The  resis from ref and   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): 
 
	   Patients C   
min 
	   Serum adjusted IQ (inhibitory quotient = C /serum adjusted EC value) 
min 50 
5