Attachment to 

 
Guidance on Antiviral Product Development  

Conducting and Submitting Virology Studies to 

the Agency 

 
Guidance for Submitting HCV 
 
Resistance Data 

 
DRAFT GUIDANCE
 
 
 
  This guidance attachment is being distributed for comment purposes only.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This draft guidance, when finalized, will represent the Food and Drug Administrations (FDAs) 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 2013 

Clinical Antimicrobial 
 
 
Revision 1
  
I:\10421dft.doc 
02/04/13  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
1 
Guidance for Submitting HCV Resistance Data  
1 
2   
3   
4   
5  STANDARDIZATION OF COLUMN HEADINGS AND VARIABLES FOR HCV 
6  RESISTANCE DATASETS2   
7   
8  Points to Consider 
9     The column headings, variables, and definitions  provided in this attachment can be used as a 
10  guide by sponsors of hepatitis C virus (HCV) direct-acting antiviral (DAA) clinical trials 
11  when assembling electronic datasets of HCV virology and drug resistance data.  We  
12  recommend submitting final datasets as SAS transport files (.xpt). 
13   
14     The recommendations in this attachment are not intended to be applicable to all situations.  
15  Sponsors should consult with the Division of Antiviral Products (DAVP) in advance when 
16  more detailed guidance is needed, or if considering alternative approaches to any of the 
17  recommended column headings, variables, or definitions.  Given the rapid pace of HCV 
18  DAA drug development, we expect continued evolution in trial designs and technologies 
19  used for collection of genotypic and phenotypic resistance data, and we intend to update this 
20  attachment frequently as new information accumulates. 
21   
22     Sponsors should use this attachment for submission of data from phase 3 and larger phase 2b 
23  efficacy trials. Sponsors can use this attachment for the submission of HCV virology and 
24  resistance data from other clinical trials, although in most cases data from early-stage clinical 
25  trials can be submitted in the form of study reports.  
26   
27     There are a number of ways datasets can be subdivided (i.e., by clinical trial, genotype, 
28  subtype) and this should be discussed with the DAVP before submission of datasets. 
29   
30     As detailed in section III., Genotypic Data, separate resistance datasets should be constructed 
31  to report amino acid sequence data from  patient populations according to their HCV 
32  genotype or subtype. 
33   
34     To identify any potential formatting problems as early as possible, all sponsors are 
35  encouraged to submit preliminary (or mock) resistance datasets to DAVP before assembling 
36  formal clinical trial resistance datasets. 
37   
38   
                                                 
1 This attachment is being revised to  provide  the current  format, recommended  definitions, standardization of 
column headings and variables, and recommended data for submission of HCV resistance  datasets. 
 
2 See the Glossary of  Abbreviations and Acronyms at the end of this attachment. 
1 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
39  RECOMMENDED COLUMN HEADINGS, VARIABLES, AND DEFINITIONS 
40   
41  NULL = blank cell 
42   
43  I. Patient Data: 
44   
45     USUBJID: Unique subject identification number (ID number should be unique for all 
46  studies) 
47   
48     STUDYID: Study identification number 
49   
50     IL28MET: IL28B single nucleotide polymorphism (SNP) genotype assay name or other 
51  method identifier 
52   
53     IL28POL: IL28B SNP analyzed (rs12979860, rs8099917, or other as appropriate; 
54  genotypes relationship to response to Peg-IFN/RBV should be identified in column notes 
55  (e.g., for rs12979860 CC>CT>TT)). The rs number, if available, should always be used to 
56  identify the SNP analyzed. If multiple IL28B SNPs are analyzed and reported, additional 
57  columns can be added to identify the different SNPs (e.g., IL28POL1, IL28POL2). 
58   
59     IL28GEN: IL28B SNP genotype result (CC, CT, TT, GG, GT, or other polymorphism  
60  genotype result).  If multiple IL28B SNPs are analyzed and reported, additional columns can 
61  be added to report the results of the different SNPs analyzed (e.g., IL28GEN1, IL28GEN2 
62  corresponding to IL28POL1, IL28POL2). 
63   
64     ARM: Treatment group 
65   
66     LEADINFL: Subject received a protocol regimen that includes an initial lead-in period of 
67  one or multiple drugs before receiving full regimen (e.g., 4-week Peg-IFN/RBV lead-in (Y or 
68  N)) 
69   
70     RGTFL: Subject received an abbreviated duration of therapy according to the protocol, 
71  based on achieving a protocol-defined early response (Y or N; OTHER should be used if 
72  subject did not follow protocol guidelines (e.g., discontinued before response-guided therapy 
73  (RGT) decision point); NULL if no RGT in arm or trial)   
74   
75     VISIT: (SCREENING, BASELINE, DAY#, WEEK#, FOLLOWUP WK#).  Visit windows 
76  should be as defined in protocol or statistical analysis plan. 
77   
78     VISITDY: Study day, protocol-defined, relative to initiation of protocol treatment.  Counting 
79  should be continued upwards into Peg-IFN/RBV tail, rollover, or follow-up phases.  Baseline 
80  = Day 1 or Day 0 should be indicated in column notes.  
81   
82     ISOLDTC: Date of isolate.  Time of isolate can be included as appropriate (e.g., if multiple 
83  samples collected at different times in same day). 
84   
2 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
85     ISOLID: Unique identifier for isolate analyzed (e.g., barcode or other means to identify 
86  specific isolate) 
87   
88     FUDY: Day of isolate from end-of-treatment.  Last day of treatment considered FUDY = 0 
89  (NULL if pre-treatment or on-treatment time point). 
90   
91     RFSTDTC: Start date of protocol treatment 
92   
93     RFENDTC: End date of protocol treatment (actual end date, not planned end date) 
94   
95     HCVHIST: Anti-HCV treatment exposure history.  See recommended terms and definitions 
96  in Table 1. 
97   
98  Table 1. Recommended Controlled Terms and Definitions for Documenting Previous HCV 
99  Treatment Exposure History for the HCVHIST Column*  
NAIVE-ALL   Naive to all anti-HCV treatment  
P/R 
Previously treated with Peg-IFN/RBV, but naive to HCV DAAs 
EXPERIENCED  
P/R PLUS DAA  Previously treated with Peg-IFN/RBV in combination with 1 or more HCV 
EXPERIENCED  DAAs 
DAA  Previously exposed to 1 or more HCV DAAs (including short courses of DAA 
EXPERIENCED  monotherapy), but never treated with Peg-IFN/RBV 
DAA AND P/R  Previously treated with Peg-IFN/RBV and HCV DAAs, but never in the form  
EXPERIENCED  of a Peg-IFN/RBV/DAA combination regimen  
OTHER**   Treatment history not captured by any of the above definitions.   
100  *  Note:  Peg-IFN can refer to  any pegylated interferon (e.g.,  -2a,  -2b,  ); specific Peg-IFN exposure is defined 
101  elsewhere (e.g., CMTRTIFN). 
102  **  Sponsors should consult with the DAVP before using this variable, because it may be appropriate to create an 
103  additional treatment history definition.  
104   
105     CMTRTIFN: Previous HCV interferon (IFN) therapeutic products (e.g., PEGASYS, 
106  PEGINTRON). NULL if no previous IFN products. 
107   
108     CMTRTRBV: Previous HCV ribavirin (RBV) therapeutic products (e.g., COPEGUS, 
109  REBETOL). NULL if no previous RBV products. 
110   
111     PRVDAA1: Previous HCV DAA therapeutic products (e.g., BOCEPREVIR, 
112  TELAPREVIR). Additional columns should be added as needed to provide information on 
113  multiple DAA exposures (e.g., PRVDAA2, PRVDAA3).  NULL if no previous DAA 
114  products. 
115   
116     PRVDAA1D: Approximate duration of PRVDAA1 exposure (actual, not planned), using the 
117  following categories: 1 WEEK, >1-4 WEEKS, >4-12 WEEKS, >12-24 WEEKS, >24 
118  WEEKS. Additional columns should be added as needed for additional DAA exposures.  
119  UNKNOWN can be used if necessary, although efforts should be made to capture this 
120  information.  NULL if no previous DAA exposure. 
3 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
121   
122     PRVDAA1T: Approximate time since previous exposure to DAA1, using the following 
123  categories:   1 MONTH, >1-3 MONTHS, >3-6 MONTHS, >6-12 MONTHS, >1-2 YEARS, 
124  >2-4 YEARS, >4 YEARS. Additional columns should be added as needed for additional 
125  DAA exposures.  UNKNOWN can be used if necessary, although efforts should be made to 
126  capture this information.  NULL if no previous DAA exposure. 
127   
128     EXPERCAT: Previous response category; see recommended terms and definitions in Table 
129  2. Note: If multiple prior treatments, response category during most recent DAA-containing 
130  treatment regimen takes precedence.  Alternatively, prior responses used for determining trial 
131  eligibility can take precedence.  Additional descriptive information should be provided to the 
132  DAVP as appropriate. 
133   
134  Table 2. Recommended Controlled Terms and Definitions for Documenting Previous 
135  Treatment Responses for the EXPERCAT Column*  
NAIVE-ALL   Naive to all anti-HCV treatment 
P/R NULL  <2 log  IU/mL reduction in HCV RNA at Week 12 of a Peg-IFN/RBV 
10
RESPONDER  regimen 
P/R WEEK 4  <1 log  IU/mL decline from baseline at Week 4 futility rule and 
10
FUTILITY  discontinued therapy before Week 12 of a Peg-IFN/RBV regimen 
P/R PARTIAL  2 log  IU/mL reduction in HCV RNA at Week 12, but not achieving HCV 
10
RESPONDER  RNA target not detected at end-of-treatment with a Peg-IFN/RBV regimen.  
Can include subjects who met 24-week virologic futility rule.  
P/R  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during treatment with a 
Peg-IFN/RBV regimen. 
P/R RELAPSER  HCV RNA target not detected at end-of-treatment with a Peg-IFN/RBV 
  regimen, but HCV RNA quantifiable (LLOQ) during follow-up 
P/R+DAA  HCV RNA detected at end-of-treatment with a regimen that included one or 
NONRESPONDER  more HCV DAAs dosed in combination with Peg-IFN/RBV.  Can include 
  subjects who met protocol-defined virologic futility rule (except for 
breakthrough which is captured elsewhere).   
P/R+DAA  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during the DAA dosing 
period with a regimen that included one or more HCV DAAs dosed in 
combination with Peg-IFN/RBV. 
P/R TAIL  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during Peg-IFN/RBV tail 
dosing period that followed a Peg-IFN/RBV/DAA(s) dosing period. 
P/R+DAA  HCV RNA target not detected at end-of-treatment with a regimen that 
RELAPSER   included one or more HCV DAAs dosed in combination with Peg-
  IFN/RBV, but HCV RNA quantifiable (LLOQ) during follow-up 
136  continued 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
137  Table 2, continued 
DAA  HCV RNA detected at end-of-treatment with a regimen that included only 
NONRESPONDER  HCV DAAs (can also include RBV, but not IFNs).  Can include subjects 
  who met protocol-defined virologic futility rule (except for breakthrough, 
which is captured elsewhere). 
DAA  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during treatment with a 
regimen that included only HCV DAAs (can also include RBV, but not 
IFNs). 
DAA RELAPSER   HCV RNA target not detected at end-of-treatment with a regimen that 
  included only HCV DAAs (can also include RBV, but not IFNs), but HCV 
RNA quantifiable (LLOQ) during follow-up 
138  *Notes: 
139     The recommended terms and  definitions  for  EXPERCAT are identical to those for NONRECAT. 
 
140     Other protocol-defined or  retrospectively  defined responses can be used  as appropriate, and should be 

141  discussed in advance with the  DAVP. 

142     Peg-IFN can refer to any pegylated interferon (e.g.,  -2a,  -2b,  ). 

143     For DAA-containing treatment regimens, breakthrough should take  precedence.  Exceptions to this 

144  guideline should be discussed  in advance with the DAVP. 
  
145     UNKNOWN can  be  used if  necessary, although efforts should  be made to capture this information. 
 
146 
  
147     EXTRTIFN: Concomitant HCV IFN treatment drugs (e.g., PEGASYS, PEGINTRON).  
148  NULL if no concomitant IFN. 
149   
150     EXTRTRBV: Concomitant RBV HCV treatment drugs (e.g., COPEGUS, REBETOL).  
151  NULL if no concomitant RBV. 
152   
153     HCVGTSC: HCV subtype at screening (e.g., 1a, 1b, 2a, 2b, 2c, 3a, 3b, 4a, 4b, 4c, 4d, 4e, 5a, 
154  6a). Mixed infections should be reported as Gt/Gt (e.g., 1a/1b). 
155   
156     HCVGTAN: HCV subtype for analysis (e.g., 1a, 1b, 2a, 2b, 2c, 3a, 3b, 4a, 4b, 4c, 4d, 4e, 5a, 
157  6a; NA (not assigned); or NULL (if not done (i.e., screening method used for analysis))).  
158  Mixed infections should be reported as Gt/Gt (e.g., 1a/1b). 
159   
160     HCVGTSCM: Assay used for determining HCV genotype/subtype at screening (e.g., 
161  TRUGENE, VERSANTLIPA2.0, VERSANTLIPA1.0, NS3 SEQUENCE, NS3_4A 
162  SEQUENCE, NS5A SEQUENCE, NS5B SEQUENCE) 
163   
164     HCVGTANM: Assay used for determining HCV genotype/subtype for analysis (e.g., 
165  TRUGENE, VERSANTLIPA2.0, VERSANTLIPA1.0, NS3 SEQUENCE, NS3_4A 
166  SEQUENCE, NS5A SEQUENCE, NS5B SEQUENCE) or NULL 
167   
168     HBVCOINF: HBV co-infected (Y or N) 
169   
170     HIVCOINF: HIV co-infected (Y or N) 
171   
5 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
172     CIRRFL: Subject has cirrhosis as defined in protocol (Y or N)  
173   
174  II. Endpoint Data: 
175   
176  Note regarding reporting of HCV RNA viral load data:  For the purposes of populating the 
177  viral load data described below, HCV RNA viral load results of target not detected should be 
178  reported using the term NOT DETECTED.  HCV RNA viral load results of detectable/<LLOQ 
179  should be reported using the term DETECTED <LLOQ. 
180   
181     VLMET: HCV RNA viral load assay name and version 
182   
183     VLVEND: Name of vendor, contract laboratory, or other central laboratory conducting HCV 
184  RNA viral load assessments 
185   
186     VLLOQ: lower limit of quantitation for HCV RNA viral load assay 
187   
188     VLOD: limit of detection for HCV RNA viral load assay 
189   
190     VLBL: HCV RNA (IU/mL) at baseline 
191   
192     LOGVLBL: HCV RNA (log  IU/mL) at baseline 
10
193   
194     HCVVL: HCV RNA (IU/mL) at all time points from protocol, one row for each time point.  
195  HCV RNA (IU/ml) from additional time points not specified in protocol can also be included 
196  (e.g., virologic breakthrough confirmatory sample, retest sample).  Imputed data should not 
197  be reported; only observed data should be reported. 
198   
199     LOGHCVVL: HCV RNA (log  IU/mL) at all time points from protocol, one row for each 
10
200  time point.  HCV RNA (log  IU/ml) from additional time points not specified in protocol 
10
201  can also be included (e.g., virologic breakthrough confirmatory sample, retest sample).  
202  Imputed data should not be reported; only observed data should be reported. 
203   
204     HCVVL(TIME): Individual column headings for HCV RNA measurements (IU/mL) at 
205  selected visit times of interest. Each column represents a single time  point of interest.  In the 
206  example shown in Table 3, the selected time points of interest are:  Treatment Weeks (W) 4, 
207  8, 12, 24, and 48, and Follow-Up Weeks (F) 12 and 24.  These time points can be adjusted or 
208  reduced as appropriate depending on the trial design.  Time points/results for RGT decision 
209  making should be included as time points of interest.  Visit windows defined in protocol or 
210  statistical analysis plan should be used.  If there are multiple discordant results in a visit 
211  window of interest, the results should be reported according to statistical analysis plan.  Cells 
212  should be NULL for any time points that are not applicable for individual subjects, or where 
213  data are not available. 
214   
215     VLEOT: HCV RNA (IU/mL) at end-of-treatment; this usually is duplicate data for subjects 
216  who complete protocol-specified treatment (i.e., duplicate with Week 48, if a 48-week 
6 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
217  treatment duration).  Based on actual end-of-treatment, not planned end-of-treatment, for 
218  subjects who discontinued early. 
219   
220     LOGVLEOT: HCV RNA (log  IU/mL) at end-of-treatment (Note:  Not shown in Table 3 
10
221  example).  Based on actual end-of-treatment, not planned end-of-treatment, for subjects who 
222  discontinued early. 
223   
224     VLEOTFL: HCV RNA target not detected at end-of-treatment (Y or N, NULL if not  
225  available) 
226   
227  Table 3. Example Illustrating Formatting of HCV RNA Viral Load Data*   
228   
229  *Note:  In this  example, HCV RNA viral load assessments were conducted at SCREENING, BASELINE, DAY 2,  
230  DAY 4, WEEKS 1,  2, 4, 8,  12, 16, 20, 24, 28, 36, and 48, EOT (e.g.,  can be a duplicate of Week 48  if a 48-week 
231  treatment course is completed), and FOLLOW-UP Weeks 4, 8,  12, and 24.  HCVVL and LOGHCVVL data are 
232  provided for each  of these time points, with each time point  representing a unique row.  The RESISTFL and related  
233  columns (described in section  III., Genotypic Data) will be  used to flag time point(s) where resistance assessments 
234  were performed.  HCV RNA  viral load  data  for select time points of interest are also  provided in column format.  
235   
236     SVR2FL: Sustained virologic response (SVR) at Week 2 after end-of-treatment (Y or N, or 
237  NULL). Use visit window defined in protocol or statistical analysis plan.  NULL used if visit 
238  not specified in protocol or data missing.  Do not impute Y or N.  Currently, we define SVR 
239  based on HCV RNA <LLOQ.  
240   
241     SVR4FL: Sustained virologic response at Week 4 after end-of-treatment (Y or N, or NULL).  
242  Visit window defined in protocol or statistical analysis plan should be used.  NULL should 
243  be used if visit not specified in protocol or data missing.  Y or N should not be imputed.  
244  Currently, we define SVR based on HCV RNA <LLOQ. 
245   
246     SVR12FL: Sustained virologic response at Week 12 after end-of-treatment (Y or N, or 
247  NULL). Visit window defined in protocol or statistical analysis plan should be used.  NULL 
248  should be used if visit not specified in protocol or data missing.  Y or N should not be 
249  imputed.  Currently, we define SVR based on HCV RNA <LLOQ. 
250   
251     SVR24FL: Sustained virologic response at Week 24 after end-of-treatment (Y or N, or 
252  NULL). Visit window defined in protocol or statistical analysis plan should be used.  NULL 
7 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
253  should be used if visit not specified in protocol or data missing.  Y or N should not be 
254  imputed.  Currently, we define SVR based on HCV RNA <LLOQ. 
255   
256     EFFICFL: Achieved primary efficacy endpoint as defined in protocol and statistical analysis 
257  plan, including sponsor-imputed results (Y or N). 
258   
259     VR1FL: Protocol-defined virologic response, intended for RGT decisions or key protocol
260  defined endpoints; additional column headings can be added if other protocol-defined 
261  responses are used (e.g., VR2FL, VR3FL); the definition of the protocol-defined response(s) 
262  should be included as notes to the column heading(s).  Additional descriptive information 
263  should be provided to the DAVP as needed to define the virologic responses (Y or N). 
264   
265     NDSTDY: Study day of first documented result of HCV RNA NOT DETECTED.  NULL 
266  should be used if never achieved HCV RNA not detected. 
267   
268     NONRECAT: Nonresponder category for currently tested therapy as defined by the 
269  protocol.  See recommended terms and definitions in Table 4. 
270   
271     DISCTXFL: A flag used to indicate subject discontinued from protocol treatment (Y or N) 
272   
273     DISCTXVL: HCV viral RNA load when subject discontinued protocol treatment (e.g., NOT 
274  DETECTED, DETECTED <LLOQ, specific IU/mL, or NULL for those who did not 
275  discontinue treatment early) 
276   
277     DISCREAS: Reason for early protocol treatment discontinuation (ADVERSE EVENT, 
278  DEATH, STOPPING RULE, LACK OF EFFICACY, LOST TO FOLLOW-UP, 
279  NONCOMPLIANCE WITH STUDY DRUG; OTHER; PHYSICIAN DECISION; 
280  PREGNANCY; PROGRESSIVE DISEASE; PROTOCOL VIOLATION; SCREEN  
281  FAILURE; TECHNICAL PROBLEMS; WITHDRAWAL BY SUBJECT); or NULL if no 
282  information available or not applicable.  Reasons should be defined according to protocol or 
283  statistical analysis plan.   
284   
285     DISCFUFL: A flag used to indicate subject discontinued from follow-up (Y or N) 
286   
287     DISCFUVL: HCV viral RNA load when subject discontinued follow-up (e.g., NOT 
288  DETECTED, DETECTED <LLOQ, specific IU/mL, or NULL for those who did not 
289  discontinue follow-up early) 
290   
291     DISCREA2: Reason for early follow-up discontinuation (ADVERSE EVENT, DEATH, 
292  STOPPING RULE, LACK OF EFFICACY, LOST TO FOLLOW-UP, NONCOMPLIANCE 
293  WITH STUDY DRUG; OTHER; PHYSICIAN DECISION; PREGNANCY; 
294  PROGRESSIVE DISEASE; PROTOCOL VIOLATION; SCREEN FAILURE; 
295  TECHNICAL PROBLEMS; WITHDRAWAL BY SUBJECT); or NULL if no information 
296  available. Reasons should be defined according to protocol or statistical analysis plan.   
297   
8 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
298     BTFL: A flag (Y or NULL) used to indicate the specific study visit with a viral load value 
299  that met the definition for protocol-defined virologic breakthrough 
300   
301     VFFL: A flag (Y or NULL) used to indicate the specific study visit in which the subject met 
302  the criteria for protocol-defined virologic failure (e.g., when the subject met a protocol
303  defined treatment futility rule, experienced virologic relapse).  Will duplicate BTFL for 
304  subjects who experienced breakthrough as the specific reason for virologic failure. 
305   
306     SVRRELFL: A flag (Y or NULL) used to indicate the specific study visit that met the 
307  criteria for a late virologic relapse. 
308   
309  Table 4. Recommended Controlled Terms and Definitions for Documenting Protocol 
310  Treatment Responses for the NONRECAT Column*  
NAIVE-ALL   Naive to all anti-HCV treatment 
P/R NULL  <2 log  IU/mL reduction in HCV RNA at Week 12 of a Peg-IFN/RBV 
10
RESPONDER  regimen 
P/R WEEK 4  <1 log  IU/mL decline from baseline at Week 4 futility rule and 
10
FUTILITY  discontinued therapy before Week 12 of a Peg-IFN/RBV regimen 
P/R PARTIAL  2 log  IU/mL reduction in HCV RNA at Week 12, but not achieving HCV 
10
RESPONDER  RNA target not detected at end-of-treatment with a Peg-IFN/RBV regimen.  
Can include subjects who met 24-week virologic futility rule.  
P/R  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during treatment with a 
Peg-IFN/RBV regimen. 
P/R RELAPSER  HCV RNA target not detected at end-of-treatment with a Peg-IFN/RBV 
  regimen, but HCV RNA quantifiable (LLOQ) during follow-up 
P/R+DAA  HCV RNA detected at end-of-treatment with a regimen that included one or 
NONRESPONDER  more HCV DAAs dosed in combination with Peg-IFN/RBV.  Can include 
  subjects who met protocol-defined virologic futility rule (except for 
breakthrough, which is captured elsewhere).   
P/R+DAA  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during the DAA dosing 
period with a regimen that included one or more HCV DAAs dosed in 
combination with Peg-IFN/RBV. 
P/R TAIL  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during Peg-IFN/RBV tail 
dosing period that followed a Peg-IFN/RBV/DAA(s) dosing period. 
P/R+DAA  HCV RNA target not detected at end-of-treatment with a regimen that 
RELAPSER   included one or more HCV DAAs dosed in combination with Peg-
  IFN/RBV, but HCV RNA quantifiable (LLOQ) during follow-up 
311  continued 
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation  
312  Table 4, continued 
DAA  HCV RNA detected at end-of-treatment with a regimen that included only 
NONRESPONDER  HCV DAAs (can also include RBV, but not IFNs).  Can include subjects 
  who met protocol-defined virologic futility rule (except for breakthrough, 
which is captured elsewhere). 
DAA  Confirmed 1 log  IU/mL HCV RNA on-treatment increase from nadir, or 
10
BREAKTHROUGH  confirmed increase in HCV RNA LLOQ if HCV RNA previously declined 
to <LLOQ (detected or not detected).  Occurred during treatment with a 
regimen that included only HCV DAAs (can also include RBV, but not 
IFNs). 
DAA RELAPSER   HCV RNA target not detected at end-of-treatment with a regimen that 
  included only HCV DAAs (can also include RBV, but not IFNs), but HCV 
RNA quantifiable (LLOQ) during follow-up 
313  *Notes: 
314     The recommended terms and definitions for NONRECAT are identical to those for EXPERCAT. 

315     Other protocol-defined or  retrospectively  defined responses can be used  as appropriate, and should be 

316  discussed in advance with the  DAVP. 

317     Peg-IFN can refer to any pegylated interferon (e.g.,  -2a,  -2b,  ). 

318     For DAA-containing treatment regimens, breakthrough should take  precedence.  Exceptions to this 

319  guideline should be discussed in  advance with  the  DAVP. 

320 
  
321  III. Genotypic Data:
   
322 
  
323  General Information: 

324 
  
325     There are a number of ways datasets can be subdivided (e.g., clinical trial, genotype, 
326  subtype). This should be discussed with the DAVP before submission of datasets. 
327   
328     Separate resistance datasets can be constructed to report amino acid sequence data from  
329  patient populations according to their HCV genotype.  Data from HCV genotype 1 
330  populations can be assembled in separate datasets for HCV genotype 1a- and 1b-infected 
331  patient populations or submitted in a single dataset, even if using different subtype-specific 
332  reference strains for reporting amino acid sequences.  Non-genotype 1 HCV data can be 
333  reported according to HCV genotype in separate resistance datasets using genotype-specific 
334  reference strains. Again, this should be discussed with the DAVP before submission of 
335  datasets. 
336   
337     Subject sequence data should be reported using subtype-specific reference strains (see Table 
338  5). 
339   
10 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
340  Table 5. Reference Strains for Reporting of Amino Acid Sequence Data  
HCV Genotype  Reference Strain  GenBank Accession ID  
Genotype 1a  H77  NC_004102  
Genotype 1b  Con1  AJ238799  
Other genotype 1 subtypes, mixed 
H77  NC_004102  
subtypes, or subtype unknown 
Genotype 2  JFH-1  AB047639  
Genotype 3  S52  GU814263  
Genotype 4  ED43  GU814265  
Genotype 5  SA13  AF064490  
Genotype 6  EUHK2  Y12083  
341   
342  Reporting Amino Acid Substitutions: 
343   
344     Genotype information for all relevant coding regions sequenced should be reported using one 
345  amino acid position per column:  
346   
347  COLUMN HEADING FORMAT EXAMPLE: N30XXX (e.g., N30155, N4A0030, 
348  N5A0002, N5B0200) 
349   
350     Changes from the prototypic reference sequence (Table 5) should be indicated for each 
351  reported sequence. Blank cells indicate no change from prototypic reference strain sequence.  
352  Mixed populations of WT/Variant or Variant/Variant should be reported as such (e.g., 
353  R155R/K reported as R/K; R155K/T reported as K/T). 
354   
355     To report insertions in subject sequence data relative to the prototypic reference strain used to 
356  generate the dataset, additional columns should be added where appropriate.  For example, a 
357  5-amino acid stretch that includes a 3-amino acid insertion between NS3 position 131 and 
358  132 should be reported under the column headings N30131, N30131A, N30131B, N30131C, 
359  and N30132. 
360   
361     To report deletions in subject sequence data relative to the prototypic reference strain used to 
362  generate the dataset, X should be reported for appropriate positions. 
363   
364     Missing sequence data caused by poor sequence quality or other technical problems should 
365  be reported as a question mark (?) for appropriate positions.  Efforts should be made not to 
366  have stretches of missing sequence information caused by poor sequence quality or other 
367  technical problems.      
368   
369     A composite of all substitutions emerging on treatment should be reported (i.e., POST-BL 
370  ALL). For datasets that include genotypic data for multiple post-baseline time points for 
371  individual subjects, a single row (one row per subject) should be added that reports the 
372  composite of all substitutions detected post-baseline relative to standard reference.  This row 
373  should be indicated by a VISIT term of POST-BL ALL, as shown in Table 6.   
374   
11 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
375  Table 6. Recommendation for Reporting POST-BL ALL Composite  
376  Substitution Data   
377   
378   
379  Reporting Reference Strain Information: 
380   
381     The amino acid sequences of the specific reference strains used for reporting of the data 
382  should be reported in the top rows of the dataset (see example in Table 7).  Below each 
383  reference strain sequence, sponsors should include two additional rows to indicate the 
384  following: 
385   
386  -  Percent conservation at each amino acid position (from large HCV sequence databases) 
387  for the genotype/subtype included in the dataset 
388   
389  -  Summary of the most common variants (comprising ~5 percent or more of variants 
390  available in sequence databases) at the amino acid position in decreasing frequency 
391   
392     The following is additional information regarding the reporting of reference strain, percent 
393  conservation, and variant information: 
394   
395  -  The USUBJID column can be used to designate rows for reference strains (REFERENCE 
396  NAME), percent conservation (GT CONSERVATION), and common variants (GT 
397  VARIANTS) (see Table 7).   
398   
399  -  Both public databases and internal data (e.g., baseline sequences from trial) can be used 
400  to report percent conservation and common variants.  Internal data may be valuable in the 
401  event that inadequate sequence data are available in the public domain for certain HCV 
402  genotypes. 
403   
404  -  Database sequences used should be from subjects with no known previous exposure to 
405  therapies that target the region of interest.  No more than one sequence per subject. 
406   
407  -  It is not necessary to continually update database sequence information for percent 
408  conservation and most common variants each time a new resistance dataset is assembled 
409  and submitted to the DAVP unless a large volume of sequence data has recently become 
410  available for certain HCV genotypes that previously had only limited available sequence 
411  data. 
412   
413  -  When reporting genotype 1a and 1b sequences all in the same dataset, there will be a total 
414  of six rows that provide the necessary background information for the reference strains,  
12 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
415  percent conservation, and common variants.  Percent conservation and common variants 
416  should be calculated separately for subtype 1a and subtype 1b.   
417   
418  -  For non-genotype 1 populations, database sequences used to report percent conservation 
419  and common variants within a given HCV genotype should be comprised of HCV 
420  subtypes that are reasonably representative of the HCV subtypes included in the clinical 
421  trial. 
422   
423  -  Descriptive information should be provided to the DAVP in the study report summarizing 
424  the source and number of sequences used for reporting this information.   
425   
426  Table 7. Recommendation for Reporting Reference Strain, 
427  Percent Conservation, and Common Variant Information in 
428  Resistance Datasets   
429   
430   
431  Reporting Clonal Nucleotide Sequence Analysis: 
432   
433     For data generated by clonal nucleotide sequence analysis (or other sensitive method), we 
434  recommend consulting with the DAVP in advance of assembling these data because a 
435  number of different formats may be appropriate for submission. 
436   
437     A separate dataset or study report should be submitted that includes more specific details of  
438  clonal analysis results (e.g., all variants detected at a specific position of interest and their 
439  percent prevalence in the population). 
440   
441  Additional column headings and terms related to genotypic data that should be included in 
442  the dataset: 
443   
444     GENORF: HCV reference strain for genotypic sequence (CON1, H77, or other as 
445  appropriate). See reference strain recommendations in Table 5. 
446   
447     GENOMET: Genotypic method (CLONAL, POPULATION) 
448   
449     GENOFAIL: A flag used to identify samples with sufficient HCV RNA to be analyzed but 
450  results not reported because of poor sequence quality or other technical reasons (e.g., RT
451  PCR amplification not successful) (Y or NULL) 
452   
453     RESISTFL: A resistance analysis flag used to identify any isolate/time point (including 
454  baseline, on-treatment, and during follow-up) with resistance analysis data reported.  This 
455  flag should allow reviewers to pull out all reported resistance data (Y or NULL). 
456   
13 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
457     RESBLFL: A flag used to identify baseline sample with resistance analysis data reported.  
458  Can indicate multiple rows per subject if multiple baseline or screening samples analyzed (Y 
459  or NULL). 
460   
461     RESEOTFL: A flag used to identify the last on-treatment isolate/time point with resistance 
462  analysis data reported. Should indicate no more than one time point per subject (Y or 
463  NULL). 
464   
465     RESFU1FL: A flag used to identify the first treatment-free follow-up isolate/time point with 
466  resistance analysis data reported.  Should indicate no more than one time point per subject (Y 
467  or NULL). 
468   
469     RESFU2FL: Flag to identify the last treatment-free follow-up isolate/time point with 
470  resistance analysis data reported.  Should indicate no more than one time point per subject (Y 
471  or NULL). 
472   
473  IV. Phenotypic Data (if available):   
474   
475  We recommend the following guidelines for submission of phenotypic resistance data generated 
476  using subject sample-derived amplicons evaluated in cell-based or biochemical phenotyping 
477  assays. Data on the effect of specific substitutions (e.g., in site-directed mutant replicons) should 
478  not be included in these datasets and can be reported in summary format in study reports.  We  
479  recommend consulting with the DAVP before finalizing phenotypic resistance data formats for 
480  submission, because additional columns/variables may be needed.   
481   
482     DRUG ABBREVIATION EC  value (e.g., DRGEC50): EC  values at baseline and post
50 50
483  baseline time points; with cell culture assay.  DRG is a placeholder for the three-character  
484  abbreviation of drug used in phenotype assay. 
485   
486     DRUG ABBREVIATION RF (e.g., DRGECRF): Fold change values in EC  value at time  
50
487  of assessment (BASELINE or ENDPOINT) compared to reference strain for DRUG, with 
488  cell culture assay.  DRG is a placeholder for the three-character abbreviation of drug used in 
489  phenotype assay. 
490   
491     DRUG ABBREVIATION BL (e.g., DRGECBL): Fold change in EC  value at time of 
50
492  endpoint assessment or failure compared to baseline for DRUG, with cell culture assay.  
493  DRG is a placeholder for the three-character abbreviation of drug used in phenotype assay. 
494   
495     DRUG ABBREVIATION IC  (e.g., DRGIC50): IC  values at baseline and post-baseline 
50 50
496  time points, with biochemical assay.  DRG is a placeholder for the three-character 
497  abbreviation of drug used in phenotype assay. 
498   
499     DRUG ABBREVIATION RF (e.g., DRGICRF): Fold change values in IC  value at time of 
50
500  assessment (BASELINE or ENDPOINT) compared to reference strain for DRUG, with  
501  biochemical assay.  DRG is a placeholder for the three-character abbreviation of drug used in 
502  phenotype assay. 
14 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
503   
504     DRUG ABBREVIATION BL (e.g., DRGICBL): Fold change in IC  value at time of 
50
505  endpoint assessment or failure compared to baseline for DRUG, with biochemical assay.  
506  DRG is a placeholder for the three-character abbreviation of drug used in phenotype assay. 
507   
508     PHENOMET: Phenotypic method (REPLICON, BIOCHEMICAL, CELL-BASED, VIRUS, 
509  SDM).  An example of a CELL-BASED method is a secreted alkaline phosphatase protease 
510  assay. 
511   
512     PHENORF: Reference strain (e.g., H77; CON1) 
513   
514     PHENFAIL: Phenotype analysis conducted but failed because of poor replication in 
515  phenotype assay (Y or NULL). 
516   
517     DRUG ABBREVIATION IQ (e.g., DRGIQ): Inhibitory quotient (C  value/serum(or 
min
518  plasma)-adjusted EC  value) (when available).  DRG is a placeholder for the three-character 
50
519  abbreviation of drug used in phenotype assay.  Method for serum or plasma protein-binding 
520  adjustment should be based on the effect of 40 percent human serum on the drug EC  value 
50
521  in a cell culture assay, or discussed in advance with DAVP if other means of adjustment are 
522  necessary. 
523   
15 
 Contains Nonbinding Recommendations 
Draft  Not for Implementation  
524  GLOSSARY OF ABBREVIATIONS AND ACRONYMS 
525   
526  DAA  direct-acting  antiviral  
527  EC  value  50 percent effective concentration (cell-based assay) 
50
528  EOT  end-of-treatment 
529  FU  follow-up 
530  GT  genotype 
531  HBV  hepatitis B virus 
532  HCV  hepatitis C virus 
533  HIV  human immunodeficiency virus 
534  IC  value  50 percent inhibition concentration (biochemical assay) 
50
535  ID  identification 
536  IU/mL  international unit/milliliter 
537  LLOQ  lower limit of quantitation 
538  LOD  limit of detection 
539  Peg-IFN  pegylated interferon (-2a, -2b or ) 
540  P/R  pegylated interferon (-2a, -2b or ) plus ribavirin 
541  RBV  ribavirin 
542  RGT  response-guided therapy 
543  RNA  ribonucleic acid  
544  SNP  single nucleotide polymorphism  
545  SVR  sustained virologic response 
546  WT  wild-type 
547   
16