Attachment to 

 
Guidance on Antiviral Product Development  

Conducting and Submitting Virology Studies to the 

Agency 

 
Guidance for Submitting HIV-1 
 
Resistance Data 

 
DRAFT GUIDANCE  
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
document.  Submit electronic comments to http://www.regulations.gov.  Submit written 
comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD  20852. All comments should be identified with 
the docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document contact Lisa K. Naeger at 301-796-0771.  
 
 
This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) 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)  

 
February 2014 
	
Clinical/Antimicrobial 
	
 
Revision 1
	
10935dft.doc  
 
02/04/14  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1
	
1  Guidance for Submitting HIV-1 Resistance Data  
2 
  
3  Sponsors are encouraged to use the following sample format for submitting HIV-1 resistance 

4  data. 

5   
6  One dataset combines patient data, endpoint data, genotypic data, and phenotypic data.  There 
7  are a number of ways datasets can be subdivided (i.e., by clinical study, baseline isolates, or 
8  virologic failure isolates) and this should be discussed with the Division of Antiviral Products 
9  (DAVP) before submission.  To identify any potential formatting problems as early as possible, 
10  all sponsors are encouraged to submit preliminary (or mock) resistance datasets to the DAVP 
11  before assembling formal clinical trial resistance datasets.  
12   
13  For each study, we recommend constructing datasets as SAS transport files containing the 
14  following information: 
15   
16     One record (row) per patient per isolate (e.g., baseline, failure, and other time points).  

17 
  
18     Data in columns (with suggested column headings shown below) on all isolates.  

19 
  
20     Genotypic data should be provided on the corresponding record for each patient isolate for 
21  baseline isolates of all patients in treatment-experienced studies, and the endpoint isolates of 
22  patients who are classified as virologic failures and discontinuations in all studies.  In 
23  treatment-naive studies, a baseline sample should be collected and stored from all patients for 
24  future phenotypic and genotypic analysis of virologic failures.   
25   
26     Phenotypic data should be provided on the corresponding record for each patient isolate for 
27  baseline isolates and the endpoint isolates of patients who are classified as virologic failures 
28  and discontinuations. In treatment-experienced studies, it is recommended that baseline 
29  phenotypic data be obtained for all patients. 
30   
31  The specific criteria for defining virologic failures should be discussed with the DAVP and 
32  may include multiple primary and secondary protocol endpoints.  The endpoints for 
33  virologic and resistance outcome analyses should be consistent. 
34   
35  Standardization of Column Headings and Variables for HIV-1 Resistance Datasets  
36   
37  Sponsors should consult with the DAVP in advance if considering alternative approaches to any 
38  of the recommended column headings, variables, or definitions. 
39   
40  Sponsors collecting and submitting next generation sequencing (NGS) data should consult with  
41  DAVP early in the experimental design process, as additional guidance will be necessary.  To 
42  initiate discussions with DAVP, sponsors should provide the details of their planned NGS 
                                                 
1 This  guidance is being revised to provide the current format, recommended definitions, standardization of column  
headings and variables, and recommended  data for submission of  HIV resistance datasets.   
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Draft  Not for Implementation  
43  analyses, including the performance characteristics of the assay and bioinformatics software to 
44  be used for analysis. 
45   
46  Information to Include With Suggested Column Headings 
47   
48  I. Patient Data:  
49   
50     USUBJID: Unique subject identification number (ID number should be unique for all 
51  studies). 
52   
53     STUDYID:  Study identification number. 
54   
55     ARM: Treatment group.  
56   
57     VISIT: (e.g., SCREENING, BASELINE, DAY#, WEEK#, FOLLOWUP WK#).  Visit 
58  windows should be as defined in the protocol or statistical analysis plan. 
59   
60     VISITDY: Study day (planned), protocol-defined, relative to initiation of protocol 
61  treatment.   
62   
63     ISOLDY: Study day (actual) of isolate, relative to initiation of protocol treatment.   
64   
65     ISOLID: Unique identifier for isolate analyzed.  
66   
67     ISOLDTC:  Date of isolate. 
68   
69     EXTRTHIV: Concomitant HIV-1 treatment drugs. 
70   
71     HIVHIST: Previous therapeutic products (listing of all previous antiretrovirals (ARVs)).  
72   
73     PRVARV1:  Previous HIV-1 ARV product (e.g., AMPRENAVIR, ATAZANAVIR).  
74  Additional columns should be added as needed to provide information on multiple ARV 
75  exposures (e.g., PRVARV2, PRVARV3).  NULL if no previous ARV products. 
76   
77     HIVGTSC: HIV-1 clade/genotype at screening. 
78   
79     HBVCOINF: Hepatitis B virus co-infected (Y or N). 
80   
81     HCVCOINF: Hepatitis C virus co-infected (Y or N). 
82   
83  II. Endpoint Data: 
84   
85     HIVVLBL:  HIV-1 ribonucleic acid (RNA) (copies/mL) at baseline (identify assay in 
86  column heading description). 
87   
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88     LOGVLBL: HIV-1 RNA (log  copies/mL) at baseline.  
10
89   
90     HIVVL: HIV-1 RNA (copies/mL) at time points in protocol (e.g., Week 24 and Week 48); 
91  one row for each time point.  HIV-1 RNA (copies/mL) from additional time points not 
92  specified in protocol can also be included. 
93   
94     LOGHIVVL: HIV-1 RNA (log  copies/mL) at all time points from protocol, one row for 
10
95  each time point.  HIV-1 RNA (log  copies/ml) from additional time points not specified in 
10
96  protocol can also be included. 
97   
98     HIVVL(TIME):   Individual column headings for HIV-1 RNA measurements (copies/mL) at 
99  selected visit times as appropriate depending on trial design. Each column represents a 
100  single time point of interest.  For example, Treatment Week 4 (HIVVLW4).   
101   
102     HIVVLEOT: HIV-1 RNA (copies/mL) at end of treatment (including loss of virologic 
103  response; (i.e., virologic failure)) or discontinuation because of adverse event).  
104   
105     LOGVLEOT: HIV-1 RNA (log  copies/mL) at end of treatment (based on actual end of 
10
106  treatment, not planned end of treatment). 
107   
108     EFFICFL: Achieved primary efficacy endpoint as defined in protocol and statistical analysis 
109  plan (Y or N).  
110   
111     NONRECAT: Failure or Nonresponder category for currently tested therapy as defined by 
112  the protocol (e.g., REBOUND, NEVER SUPPRESSED, DISCONTINUED WHILE 
113  SUPPRESSED, DISCONTINUED BEFORE SUPPRESSED). 
114   
115     DISCTXFL: A flag used to indicate subject discontinued from protocol treatment (Y or N). 
116   
117     DISCTXVL: HIV-1 viral RNA load when subject discontinued protocol treatment.  
118   
119     DISCREAS: Reason for early protocol treatment discontinuation (e.g., ADVERSE EVENT, 
120  DEATH, STOPPING RULE, LACK OF EFFICACY, LOST TO FOLLOW-UP, 
121  NONCOMPLIANCE WITH STUDY DRUG; PHYSICIAN DECISION; PREGNANCY; 
122  PROTOCOL VIOLATION; SCREEN FAILURE; WITHDRAWAL BY SUBJECT; 
123  OTHER); or NULL if no information available or not applicable.  Reasons are defined 
124  according to protocol or statistical analysis plan.  
125   
126     VFFL: A flag (Y or NULL) used to indicate the specific study visit in which the subject met 
127  the criteria for protocol-defined virologic failure (e.g., rebound, end of treatment).  
128   
129     VLMET:  HIV-1 RNA viral load assay name and version. 
130   
131     VLVEND:  Name of vendor, contract laboratory, or other central laboratory conducting 
132  HIV-1 RNA viral load assessments. 
133   
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134  III. Genotypic Data:2   
135   
136  Genotypic data should be provided for the HIV-1 target, one amino acid per column, with the 
137  wild-type (WT) amino acid in the column heading.  Changes from WT standard sequence should 
138  be indicated in the row (i.e., blanks indicate no change).  
139   
140  COLUMN HEADING FORMAT EXAMPLE:    
141  For reverse transcriptase (RT), RTAXXX where A = amino acid code and XXX is 
142  amino acid position (e.g., RTK065, RTK103); for protease (PR), PRAXXX (e.g., PR 
143  I084, PRL090); for integrase (IN), INAXXX. 
144   
145     Changes from the reference sequence should be indicated for each reported sequence 
146  (e.g., PRI084 change reported as V). Blank cells indicate no change from reference 
147  strain sequence. Mixed populations of WT/Variant or Variant/Variant should be reported 
148  as such (e.g., K65R/K reported as R/K; K103N/K reported as N/K). 
149   
150     To report insertions in subject sequence data relative to the reference strain used to 
151  generate the dataset, additional columns should be added where appropriate.  For 
152  example, a four-amino acid stretch that includes a two-amino acid insertion between RT 
153  position 69 and 70 should be reported under the column headings RTH069, RTH069A, 
154  RTH069B, and RTK070. 
155   
156     To report deletions in subject sequence data relative to the prototypic reference strain 
157  used to generate the dataset, a dash (-) should be reported in cell for appropriate 
158  positions.  
159   
160     For ambiguous amino acids (i.e., nucleotide information was present but amino acid 
161  could not be called due to non-interpretable translation), X should be reported for 
162  appropriate positions.  
163   
164     Missing sequence data caused by poor sequence quality or other technical problems 
165  should be reported as a question mark (?) for appropriate positions.  Efforts should be 
166  made not to have stretches of missing sequence information because of poor sequence 
167  quality or other technical problems. 
168   
169     GENOMET: Genotypic assay name. 
170   
171     GENOFAIL: A flag used to identify samples with sufficient HIV-1 RNA to be analyzed 
172  but results not reported because of poor sequence quality or other technical reasons (e.g., 
173  RT-PCR amplification not successful) (Y or NULL). 
174   
                                                 
2  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.  
4 
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Draft  Not for Implementation  
175     RESISTFL:  A resistance analysis flag used to identify any isolate/time point (including 
176  baseline, on-treatment, and during follow-up) with resistance analysis data reported.  This 
177  flag should allow reviewers to pull out all reported resistance data (Y or NULL). 
178   
179     RESBLFL:  A flag used to identify baseline sample with resistance analysis data 
180  reported (Y or NULL). 
181   
182     RESEOTFL: A flag used to identify the last on-treatment isolate/time point with 
183  resistance analysis data reported.  The flag should indicate no more than one time point 
184  per subject (Y or NULL). 
185   
186     TOTCCR5: Column with total number of CCR5 co-receptor antagonist substitutions in 
187  subject isolate (for baseline and endpoint isolates).  The specific substitutions to include 
188  should be discussed with the DAVP in advance.   
189   
190     TOTFI:  Column with total number of fusion inhibitor substitutions in subject isolate 
191  (for baseline and endpoint isolates). The specific substitutions to include should be 
192  discussed with the DAVP in advance. 
193   
194     TOTINSTI:  Column with total number of INSTI substitutions in subject isolate (for 
195  baseline and endpoint isolates).  The specific substitutions to include should be discussed 
196  with the DAVP in advance.   
197   
198     TOTNNRTI:  Column with total number of NNRTI substitutions in subject isolate (for 
199  baseline and endpoint isolates).  The specific substitutions to include should be discussed 
200  with the DAVP in advance. 
201   
202     TOTNRTI: Column with total number of NRTI  substitutions in subject isolate (for 
203  baseline and endpoint isolates).  The specific substitutions to include should be discussed 
204  with the DAVP in advance. 
205   
206     TOTPI:  Column with total number of PI substitutions in subject isolate (for baseline and 
207  endpoint isolates). The specific substitutions to include should be discussed with the 
208  DAVP in advance. 
209   
210     TOTDRG: Column with total number of target substitutions (or mutations for genome
211  targeting products) in subject isolate (for baseline and endpoint isolates) for a drug with a 
212  novel target.  DRG is a placeholder for the three-character abbreviation of drug.   
213   
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214  IV. Phenotypic Data:3   
215   
216  For the candidate drug, approved/investigational drug(s) in the same class, and 
217  approved/investigational drug(s) outside the candidate drug class with the same target protein 
218  (e.g., NNRTIs and NRTIs) or protein complex (e.g., gp120/gp41), sponsors should provide the 
219  following data: 
220   
221     DRGEC50 (i.e., DRUG ABBREVIATION EC  value):  EC  values (M) at baseline and 
50 50
222  post-baseline time points for candidate drug.  DRG is a placeholder for the three-character 
223  abbreviation of drug used in phenotype assay. 
224   
225     DRGECRF (i.e., DRUG ABBREVIATION RF):  Fold change values in EC  value at time 
50
226  of assessment (BASELINE or ENDPOINT) compared to reference strain for drug.  DRG is a 
227  placeholder for the three-character abbreviation of drug used in phenotype assay.  
228   
229     DRGECBL (i.e., DRUG ABBREVIATION BL):  Fold change in EC  value at time of  
50
230  endpoint assessment or failure compared to baseline for drug.  DRG is a placeholder for the 
231  three-character abbreviation of drug used in phenotype assay. 
232   
233     PHENOMET: Phenotypic method or assay name. 
234   
235     PHENORF: Reference strain. 
236   
237     PHENFAIL: Phenotype analysis conducted but failed because of poor replication in 
238  phenotype assay (Y or NULL). 
239   
240     DRGIQ (i.e., DRUG ABBREVIATION IQ):  Inhibitory quotient (C  value/serum or 
min
241  plasma adjusted EC  value when available).  DRG is a placeholder for the three-character 
50
242  abbreviation of drug used in phenotype assay. 
243   
244  V. Protease Cleavage Sites (for protease inhibitors only): 
245   
246     NC/p1 Gag cleavage sites:  Sponsors should show amino acid and position of cleavage site 
247  of WT in column headings (as above for genotype) and indicate amino acid change if mutant 
248  in row 
249   
250     p1/p6 Gag cleavage sites:  Sponsors should show amino acid and position of cleavage site 
251  of WT in column headings (as above for genotype) and indicate amino acid change if mutant 
252  in row 
253   
                                                 
3 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. 
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Draft  Not for Implementation  
254  VI. Co-Receptor Usage (for all products targeting co-receptors):  
255   
256     TRPBL: Co-receptor usage of baseline isolates.  Sponsors should indicate R5, X4, D for 
257  dual-tropic, M for mixed-tropic, or D/M if the assay cannot distinguish between dual or 
258  mixed, in a column. 
259   
260     TRPBLR5: Baseline R5 tropism assay value (e.g., RLUs). 
261   
262     TRPBLX4: Baseline X4 tropism assay value (e.g., RLUs). 
263   
264     TRPEOT: Co-receptor usage of virologic failures and end-of-study isolates (on therapy).  
265  Sponsors should indicate R5, X4, D for dual-tropic, M for mixed-tropic, or D/M if the assay 
266  cannot distinguish between dual or mixed, in a column. 
267   
268     TRPEOTR5: R5 tropism assay value at failure or end of study (e.g., RLUs). 
269   
270     TRPEOTX4: X4 tropism assay value at failure or end of study (e.g., RLUs). 
7