Antiviral Product Development — Conducting and Submitting Virology Studies to the Agency: Guidance for Submitting HIV-1 Resistance Data: Attachment to the Guidance: Draft Draft Guidance: This draft guidance updates the final guidance posted 6/2/06

Administrative draft guidance, not enacted legislation.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-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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s)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)
February 2014
Clinical/Antimicrobial
Revision 1
10935dft.doc
02/04/14

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1 	Guidance for Submitting HIV-1 Resistance Data1
2
3 	Sponsors are encouraged to use the following sample format for submitting HIV-1 resistance
4 	data.
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,
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:
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
 	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-naïve studies, a baseline sample should be collected and stored from all patients for
24 	future phenotypic and genotypic analysis of virologic failures.
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.
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
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
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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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 (log10 copies/mL) at baseline.
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 (log10 copies/mL) at all time points from protocol, one row for
95 	each time point. HIV-1 RNA (log10 copies/ml) from additional time points not specified in
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 (log10 copies/mL) at end of treatment (based on actual end of
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-naïve studies, a baseline
sample should be collected and stored from all patients for future phenotypic and genotypic analysis of virologic
failures.
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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 EC50 value): EC50 values (μM) at baseline and
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 EC50 value at time
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 EC50 value at time of
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 (Cmin value/serum or
241 	plasma adjusted EC50 value when available). DRG is a placeholder for the three-character
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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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).
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