Principles for Codevelopment of an 1 In Vitro Companion Diagnostic
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4. Special Protocol Assessments 1105
Special Protocol Assessment (SPA) is a process that ideally results in agreements between 1106
the sponsor of a drug or biological product 73 and the division responsible for reviewing the 1107 application. The SPA provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act) 1108 apply to clinical trial protocols intended to form the primary basis for demonstration of 1109 effectiveness in support of a new drug application (NDA), biologics license application 1110 (BLA), or efficacy supplements to approved NDAs or BLAs; the SPA provisions do not 1111 apply to IVD protocols. 74
1112 1113
In codevelopment programs, an SPA submission may include questions regarding certain 1114
clinical trial design elements related to a drug or biological product, including an IVD’s 1115
effect on interpretation of product data. However, a SPA submission should not include 1116
questions related to aspects of the IVD’s performance (i.e., IVD data collection that is 1117
independent of the drug or biological product). In general, questions about the drug or 1118
biological product should be directed to the therapeutic product review center, and questions 1119
about the IVD should be directed to the appropriate IVD review center. FDA expects that 1120
the therapeutic product and IVD review centers will consult each other on crossover issues. 1121
73 The SPA provisions apply to agreements between FDA and the sponsor of an investigation or an applicant for approval for a drug under FD&C Act section 505(b) or for a drug that is also a biological product under section 351 of the Public Health Service Act. See 21 U.S.C. 355(b)(5).
74
additional information on SPAs ( http://www.fda.gov/downloads/Drugs/.../Guidances/ucm080571.pdf ).
Contains Nonbinding Recommendations Draft - Not for Implementation
32 1122 Sponsors should note that alterations to an IVD (e.g., changed cut-off value, altered scoring 1123 system, addition of analytes) or changes in the performance characteristics of an IVD (e.g., 1124 sensitivity, specificity) may affect the type or interpretation of the data collected in the 1125 therapeutic product trial. In some cases, these IVD changes could negatively affect the 1126 ability to interpret the therapeutic product data and could necessitate amending or revising 1127 the terms of the SPA agreement, as described in the SPA guidance. For example, IVD 1128 alterations might change the characteristics of the enrolled patient population or could alter 1129 the threshold for a positive outcome used as a primary endpoint. 1130 1131
If an IVD is altered or replaced with a different technology after the trial has begun, 1132
interpretation of therapeutic product data may be negatively impacted. Under section 1133
505(b)(5)(C)(ii) of the FD&C Act, such changes may be considered a substantial scientific 1134
issue essential to determining the safety or efficacy of the therapeutic product, identified after 1135
the trial has begun, and may lead to rescission of the SPA agreement.
1136
F. Planning for Contemporaneous Marketing Authorizations 1137
When an IVD companion diagnostic is essential for the safe and effective use of a 1138
therapeutic product, FDA intends to make every effort to coordinate the review so that the 1139
therapeutic product and the companion diagnostic can receive marketing authorization at the 1140
same time. To achieve contemporaneous marketing authorizations, FDA recommends that 1141
the IVD and therapeutic product sponsors plan ahead to assure coordination of the 1142
therapeutic product and IVD submissions. 1143
1144 1. Coordinating Review Timelines 1145
To support contemporaneous marketing authorizations for the therapeutic product and 1146
IVD companion diagnostic, consideration should be given to the differences in review 1147
timelines for the different products. NDAs and BLAs (and their supplements) are 1148
reviewed under standard review timelines or under priority review timelines if the criteria 1149
for priority review are met. 75 Review times may be shortened even further for a 1150 marketing application of a breakthrough therapy-designated product. 76 In addition, 1151 rolling review may be available for applications for therapeutic products designated as 1152 fast track or breakthrough therapy. 77 Review of PMAs can be placed on hold if 1153 deficiencies are identified during review of the submission, e.g., if FDA determines that 1154
75 See FDA’s guidance for Industry “Expedited Programs for Serious Conditions – Drugs and Biologics” ( http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf ). 76
for Breakthrough Therapy-Designated Drugs and Biologics That Are Receiving an Expedited Review” (http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/Manu alofPoliciesProcedures/UCM407009.pdf). 77 See note 75. Contains Nonbinding Recommendations Draft - Not for Implementation
33 supplemental testing is necessary. 78 Unless care is taken to assure that the submission for 1155 the IVD companion diagnostic is timely and complete, the sponsor may incur delay in the 1156 total time to marketing authorization of the IVD companion diagnostic, which may in 1157 turn affect the timing of the approval of the corresponding therapeutic product. The 1158 points discussed below are intended to help sponsors manage timing aspects for the 1159 separate submissions. 1160 1161
i. Modular PMA 1162
In most cases, the modular PMA approach will allow the most flexibility for IVD companion 1163
diagnostic submissions. For “traditional” PMAs, an applicant submits all components of a 1164
PMA, as outlined in 21 CFR 814.20, simultaneously. A “modular” PMA process allows an 1165
applicant to submit discrete sections, or modules, of the PMA as they are completed. 79 Using 1166 the modular PMA process, the IVD companion diagnostic sponsor submits analytical data, 1167 manufacturing data, and other information required under 21 CFR 814.20, while collecting, 1168 compiling and analyzing the clinical data. When the clinical data are complete, the data are 1169 submitted in the final module of the PMA, and the 180-day “PMA review clock,” under 21 1170 CFR Part 814, begins on that date. 80
1172 When implemented appropriately, the modular PMA approach allows the applicant to resolve 1173 deficiencies identified by the IVD review center earlier in the review process, making the 1174 final review more likely to be completed concurrently with review of the therapeutic product. 1175 1176
ii. Premarket Review Submissions 1177
As with all medical devices, FDA will apply a risk-based approach to determine the 1178
appropriate regulatory pathway (e.g., a PMA or a premarket notification submission 1179
(510(k))) for a specific IVD companion diagnostic for its intended use. A Class III IVD 1180
companion diagnostic that obtains FDA approval is typically approved for a specimen type, 1181
target population and therapeutic product. If an approved IVD companion diagnostic is to be 1182
used for additional specimen types, target populations or therapeutics, the sponsor can submit 1183
a PMA supplement for the new intended use. Other types of changes may also require a 1184
PMA supplement. 81 The type of PMA supplement is dependent on the type of change and 1185 the nature of the review required. FDA recommends that sponsors consult with the 1186 appropriate IVD review division to discuss the appropriate type of submission. 1187 1188
If FDA has previously classified a legally marketed (predicate) IVD companion diagnostic 1189
78 See FDA’s guidance for industry and FDA staff “FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals” ( http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm089733.htm ). 79 See FDA guidance “Premarket Approval Application Modular Review” ( http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0897 67.pdf ) for additional information about the modular PMA review process, including instructions and provisions for modular PMAs.
80 Upon receipt of the final module, FDA makes its filing decision based on whether the last module includes all the information necessary to complete the PMA as required by 21 CFR 814.20. If FDA files the PMA, the filing date is the date that the application became complete, typically the receipt date of the last module.
81 21 CFR 814.39. Contains Nonbinding Recommendations Draft - Not for Implementation
34 as a Class II (non-exempt) device, a new IVD companion diagnostic may obtain marketing 1190
authorization if FDA determines, through review of a premarket notification (510(k)) 1191
submission, that the new IVD companion diagnostic is substantially equivalent to the 1192
predicate. 82,83
If no appropriate predicate is available, a new IVD companion diagnostic is 1193
considered Class III and subject to premarket approval by operation of law. 84 However, if 1194 FDA believes that a reasonable assurance of safety and effectiveness for a new IVD 1195 companion diagnostic may be provided by general controls or general and special controls, 1196 FDA may identify the test as eligible for the de novo process. 85 Devices eligible for the de 1197 novo process may obtain marketing authorization if FDA determines, through review of a de 1198
novo request for classification, that general controls or general and special controls provide a 1199
reasonable assurance of safety and effectiveness. Devices that are classified into Class I or 1200
Class II through the de novo process may be marketed and used as predicates for future 1201
510(k) submissions. Changes to a Class I or Class II device that could significantly affect the 1202
safety or effectiveness of the device or a major change or modification in its intended use 1203
require a new premarket submission (e.g., a 510(k) or in some instances a PMA). 86
1204 1205
iii. Bioresearch Monitoring Inspections and Manufacturing Inspections 1206
There are two types of inspections that can occur in the context of a PMA submission: 1207
bioresearch monitoring (BIMO) inspections and manufacturing inspections. The BIMO 1208
program conducts inspections of clinical investigations to ensure the protection of research 1209
subjects and the integrity of data submitted in support of the PMA. Sponsors should 1210
anticipate the Agency’s need to inspect clinical trial sites with respect to both the therapeutic 1211
product and the IVD companion diagnostic. When an IVD companion diagnostic PMA is 1212
reviewed, CDRH/CBER BIMO personnel have the authority to inspect the clinical trial 1213
enrollment sites; however, the inspections of clinical enrollment sites will usually be 1214
coordinated by the lead therapeutic product review center (i.e., CDER Office of Scientific 1215
Investigations or the CBER Division of Inspections and Surveillance) and may be performed 1216
by the FDA’s Office of Regulatory Affairs. Nonetheless, the IVD manufacturer should still 1217
submit information about the clinical testing sites, including clinical line data, to the PMA for 1218
BIMO review. 87 FDA will coordinate review and inspections of clinical sites, as needed, 1219 among the appropriate review center(s). 1220 1221
To facilitate IVD-related BIMO activities, PMA applicants should submit BIMO information 1222
that is organized together, in its own section, or otherwise easily identifiable. BIMO 1223
information typically includes lists of the clinical investigators with contact information, all 1224
82 21 U.S.C. 360c(i). 83 See FDA guidance “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)]” ( http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM28 4443.pdf ) for more information about substantial equivalence. 84 See sections 513(f)(1) and 515(a) of the FD&C Act (21 U.S.C. 360c(f)(1) and 360e(a)). 85 See section 513(f)(2) of the FD&C Act (21 U.S.C. 360c(f)(2)). 86 21 CFR 807.81(a)(3). 87 A therapeutic product company can submit the data either in a master file or in the NDA/BLA, which can then be referenced by the IVD manufacturer in the PMA, as a means to include the clinical line data in the PMA review while maintaining confidentiality of the data; see Section III.F.1.iv and v.
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35 testing sites with relevant information about the analytical or clinical testing performed at 1225
each site, and the associated IRBs (see Appendix 3). BIMO will also confirm that the line 1226
data received in the submission matches the data obtained at the testing site. Therefore, 1227
information about the location of records should be included in the submission. 1228
1229 For IVD PMAs, submission of manufacturing information for review is required, and FDA 1230 will usually conduct manufacturing inspections at the IVD manufacturing site(s). For IVD 1231 companion diagnostics, FDA will attempt to schedule inspections as early as possible in the 1232 application review process so that inspection results are available to inform the IVD review 1233 division and to allow time for the sponsor/manufacturer to address any significant inspection 1234 findings. 1235 1236
To achieve timely inspections, FDA recommends that PMA applicants use the modular PMA 1237
process for premarket submission and discuss the contents and timeline for the components 1238
of the submission with the review division prior to the submission. Submission of the 1239
manufacturing module as early as possible helps to allow sufficient time for the review 1240
division to assist the manufacturer to assure that all necessary documentation is in place 1241
ahead of scheduling the manufacturing inspection. This is particularly important when the 1242
manufacturing of the IVD companion diagnostic is done outside the U.S., as inspections in 1243
other countries may take longer to schedule. 1244
1245 iv. Master Files 1246
For various reasons, such as to address a bridging study, additional information from the 1247
therapeutic product trial that is not included in the NDA or BLA (and is therefore not 1248
accessible through a letter of authorization (see Section III.F.1.v.)) may need to be sent to the 1249
appropriate IVD review center for review. If the therapeutic product sponsor does not want 1250
its data, or a subset of the data, to be shared with the IVD sponsor (i.e., the party that would 1251
normally submit IVD data and information), the therapeutic product sponsor has the option to 1252
submit the data directly into a master file (MAF), which is accessible to the IVD review 1253
center but not accessible to the IVD sponsor. A MAF allows the therapeutic product 1254
sponsor’s proprietary information to undergo confidential review by FDA, without sharing 1255
the information with the IVD sponsor. 1256
1257 When submitted in support of a PMA, the data in a MAF will be reviewed by FDA and the 1258 MAF holder (i.e., the therapeutic product sponsor) will receive, if appropriate, a MAF 1259 deficiency letter. Additionally, with the MAF holder’s consent, the PMA applicant will 1260 receive a major deficiency letter that states a MAF deficiency letter has been sent to the MAF 1261 holder. FDA will not conduct any additional PMA review until all deficiencies, including 1262 those in the MAF, have been addressed. The MAF holder should send its response to the 1263 deficiencies to the MAF. The PMA applicant should reference the MAF when sending its 1264 own response to its major deficiencies letter. For further information about MAFs, refer to 1265 information available from the FDA website or contact CDRH or CBER. 88
88 See FDA website: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubm issions/PremarketApprovalPMA/ucm142714.htm.
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36 1267 v. Letters of Authorization 1268
In most cases, the marketing authorizations of the therapeutic product and the IVD 1269
companion diagnostic are dependent on each other. Therefore, the review staff from each 1270
center assigned to review the respective applications will consult with the other center on 1271
issues that may affect the review. For this reason, the therapeutic product and IVD sponsors 1272
may need to submit letters of authorization, authorizing the other applicant to refer to the 1273
corresponding NDA, BLA or PMA (or other IVD premarket submission if applicable) in 1274
support of the other applicant’s product. See Appendix 4 for sample letters of authorization. 1275
1276 vi. Priority Review 1277
IVD companion diagnostic submissions may qualify for priority review if the criteria in 21 1278
U.S.C. 360e(d)(5) are met. Generally, CDRH and CBER have granted priority review status 1279
to IVD companion diagnostic submissions, particularly when the IVD companion diagnostic 1280
is the first-of-a-kind. The IVD companion diagnostic sponsor may formally request priority 1281
review for the IVD or FDA may grant priority review on its own initiative. FDA review staff 1282
will manage the priority review of the submission through the mechanism outlined in FDA 1283
guidance “Priority Review of Premarket Submissions for Devices.” 89 Sponsors should 1284 consider their responsibilities for priority review as described in the same document. 1285 Although the guidance indicates that FDA will take most PMAs granted priority review to an 1286 advisory panel, FDA does not intend to take IVD companion diagnostic PMAs to panel 1287 unless the scientific issues associated with the candidate IVD companion diagnostic warrant 1288 panel review. Note that the current policies of CDER and CBER for advisory committee 1289 consideration of therapeutic product applications will remain in place. 1290 1291
For therapeutic products, priority review may be granted for a product that treats a serious 1292
condition and, if approved, would provide a significant improvement in safety or 1293
effectiveness. 90 This more rapid review process may make it difficult to achieve 1294 contemporaneous marketing authorization of the associated IVD companion diagnostic. 1295 Therapeutic product sponsors should ensure that their IVD companion diagnostic sponsor 1296 partners are aware of the potential for therapeutic product priority review and are prepared to 1297 submit their PMA in a timely fashion. 1298 1299
vii. Therapeutic Products Receiving Accelerated Approval 1300
FDA may decide to grant accelerated approval of a therapeutic product, if the therapeutic 1301
product treats a serious condition, generally provides a meaningful advantage over available 1302
therapies, and demonstrates an effect that either (1) is on a surrogate endpoint that is 1303
reasonably likely to predict clinical benefit, or (2) is on a clinical endpoint that can be 1304
measured earlier than irreversible morbidity or mortality (IMM) and that is reasonably likely 1305
to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint). 91
1306 1307
89 Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm089643.htm.
90 For additional information on priority review, see note 75.
91 For additional information, see note 75. Contains Nonbinding Recommendations Draft - Not for Implementation
37 If the therapeutic product sponsor intends to seek accelerated approval, the clinical trial 1308
intended to support approval should be designed in a way to appropriately validate the 1309
candidate IVD companion diagnostic. 1310
1311 For drugs and biological products granted accelerated approval, postmarketing confirmatory 1312 trials have been required to verify and describe the clinical benefit. For a therapeutic product 1313 (as described in this guidance) granted accelerated approval, it is likely that the 1314 postmarketing confirmatory trial(s) will also include the IVD companion diagnostic. If 1315 labeling claims are expanded based on such studies, the applicant should consider whether 1316 the intended use of the IVD companion diagnostic will require modification. A modification 1317 to the intended use of an IVD typically requires submission of a new device application or a 1318 supplement. 92
1319 1320 2. When Contemporaneous Marketing Authorization is Not Possible 1321
As stated in the IVD companion diagnostic guidance, 93 although there is an expectation 1322 for contemporaneous marketing authorizations for the therapeutic product and its IVD 1323 companion diagnostic, FDA recognizes there may be circumstances that prevent this. 1324 FDA will resolve each situation on a case-by-case basis, taking into account the specific 1325 circumstance surrounding the use of the therapeutic product and the characteristics of the 1326 IVD companion diagnostic. 1327 1328
3. Shipment and Verification of an IVD Companion Diagnostic 1329
Prior to Marketing Authorization 1330
In most cases, a laboratory will need time to set up and verify a new IVD before it can be 1331
used for routine clinical testing. As a result, there could be a significant delay before patients 1332
could benefit from an IVD that has just received marketing authorization. For an IVD 1333
companion diagnostic, such a delay could mean patients are unable to receive the 1334
corresponding therapeutic product during this period of time, even if both products receive 1335
contemporaneous marketing authorization. 1336
1337 To ensure immediate patient access to the therapeutic product upon approval, IVD 1338 companion diagnostic manufacturers may wish to ship the IVD to laboratories for setup and 1339 verification, after its design has been finalized and clinical trials have been completed but 1340 prior to its marketing authorization. 94 As long as use of the IVD companion diagnostic is 1341 limited to setup and verification only, is not otherwise used for diagnosing patients, and 1342 otherwise meets the criteria in 21 CFR 812.2(c)(3), FDA will consider it to be an exempt 1343
92 If the IVD companion diagnostic that was originally approved with the therapeutic product is used in the postmarket studies, the type and content of the submission will depend on the specifics of the trial, see also Section III. F.1.ii. of this guidance.
93
94 Note that changes to the IVD may occur during the premarket review process (e.g., manufacturing changes, labeling changes, or other changes), such that a laboratory may need to perform additional verification activities with the version of the IVD companion diagnostic that receives marketing authorization.
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38 investigational device per the IDE regulation. Sponsors should be aware that they are still 1344
subject to: 1345
· 21 CFR 809.10(c), requiring appropriate labeling of the IVD companion diagnostic as 1346
“Investigational Use Only.” Once the IVD is authorized, the manufacturer may 1347
provide new labeling consistent with the marketing authorization. 1348
· 21 CFR 812.119, governing the disqualification of clinical investigators. 1349
Laboratories that participate in these activities are considered study sites until the 1350
IVD companion diagnostic receives marketing authorization. 1351
1352 As an IVD companion diagnostic is considered investigational prior to marketing 1353 authorization, any use for diagnosis of patients outside of the scope of an investigation 1354 conducted according to 21 CFR Part 812 is generally not permitted. FDA may inspect study 1355 sites or take other appropriate action should it obtain information that the IVD companion 1356 diagnostic is being used for diagnosis outside of the scope of the investigation. FDA 1357 recommends that manufacturers communicate with laboratories about permitted uses of the 1358 IVD companion diagnostic and maintain records documenting the laboratories that have 1359 received it. FDA recognizes that laboratories may wish to determine whether setup and 1360 verification of a particular IVD companion diagnostic is a worthwhile activity, and does not 1361 consider speculative discussions about the price of the IVD for this purpose prior to 1362 marketing authorization to be commercialization or to otherwise violate 21 CFR 812.7. 1363
1364
The labeling of a therapeutic product/IVD companion diagnostic pair should be consistent. 95
1365 The IVD companion diagnostic’s labeling should specify those particular analytes (e.g., gene 1366 variants, expression patterns, protein expression) that are specified in the therapeutic product 1367 labeling. For example, if a therapeutic product is indicated for a population that has a 1368 particular spectrum of gene variants, the IVD companion diagnostic generally should be 1369 indicated for the detection of all the variants in the spectrum. 1370 1371
1. Claims for IVD Companion Diagnostics Based on Use in Trial 1372
There are several types of claims that may be generated for an IVD companion diagnostic, 1373
based on how the IVD was used 96 in the major efficacy therapeutic product trial(s). The 1374 types of claims and the trial designs that support them are discussed below.
1376
95 Appropriate labeling for an IVD companion diagnostic and the corresponding therapeutic product is further described in the guidance “In Vitro Companion Diagnostic Devices” ( http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM26 2327.pdf ).
96 Examples of uses of IVDs include: selection of the treatment population, exclusion of patients likely to suffer severe adverse reactions, stratification of the various trial arms to ensure balanced representation of the treatment/control arms, and selection of dose in treatment arms.
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39 i. Predictive Claims 1377
Predictive claims 97 for IVD companion diagnostics should be supported by evidence that 1378 clinical benefit accrues only to, or primarily to, a population defined by the IVD result (i.e., 1379 only test-positive or test-negative patients), or that serious adverse reactions are confined to a 1380 population defined by the IVD result. The evidence to support a claim for prediction of 1381 clinical benefit is generally derived from studies in which both test-positive and test-negative 1382 subjects are enrolled. Each test-defined subset is split and then randomized to 1383 “investigational therapy” and “control/placebo therapy” arms (e.g., Figure 1A). This type of 1384 design will demonstrate whether the IVD result is predictive of therapeutic response. It may 1385 be possible, with appropriate pre-specification of the expected treatment by test result 1386 interaction, to support predictive claims using a prospective-retrospective trial design (see 1387 Section III.D.4.). Note that the evidence to support a claim for prediction of serious adverse 1388 reactions may require different approaches from that for prediction of effectiveness, if it is 1389 considered unethical to place subjects who are considered more likely to have a serious 1390 adverse reaction in the investigational therapeutic product arm. 1391 1392
It is not possible to support prediction claims for the IVD when only test-positive or test- 1393
negative subjects are selected for enrollment in a trial because there will be no information 1394
about safety and efficacy in the population that is not treated (e.g., Figure 1B). 1395
1396 ii. Selection Claims 1397
Trial designs in which only test-positive (or test-negative) subjects are selected for 1398
enrollment in a trial (e.g., Figure 1B) typically support IVD companion diagnostic claims for 1399
patient selection. For a selection claim, if the major efficacy trial demonstrates adequate 1400
safety and effectiveness of the therapeutic product within the population selected by the IVD, 1401
the IVD is considered to be “clinically validated” in that it selected a population that benefits 1402
from the therapeutic product. 1403
1404 iii. Monitoring Claims 1405
IVD companion diagnostics for patient monitoring help select the dosage of a therapeutic 1406
product during treatment, or indicate when therapy should be modified or discontinued to 1407
avoid harm. An IVD companion diagnostic for monitoring may be required because the 1408
therapeutic product demonstrates important safety issues and/or a lack of efficacy (that 1409
presents a risk of serious harm to the patient) when administered to a patient outside of the 1410
established therapeutic window. Monitoring to determine when to discontinue therapy (e.g., 1411
when a patient is not expected to achieve any additional benefit but could incur harm) may 1412
also be an IVD companion diagnostic claim. Trial designs to support IVD companion 1413
diagnostic monitoring claims are beyond the scope of this guidance, and FDA recommends 1414
discussing such approaches with the Agency. 1415
97 In the context of this guidance document, the term “predictive” or “prediction” indicates whether the test result can be used to predict a patient’s response to a therapeutic product. This is distinct from the term’s use in other contexts, such as for microbiology tests.
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40 H. Postmarketing Considerations 1416
Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), 1417
postmarketing requirements can be used to assess a therapeutic product’s safety in a given 1418
patient population. If a therapeutic product’s use in a patient population is determined by an 1419
IVD companion diagnostic, the therapeutic product and IVD sponsors should seek input from 1420
the appropriate centers to ensure that such postmarketing clinical trials are designed to meet 1421
stated objectives. 1422
1423 For adverse reactions that occur when an IVD companion diagnostic and a therapeutic 1424 product are used together, reportable events that can be reasonably attributed only to IVD 1425 performance problems must be reported in accordance with 21 CFR Part 803, while those 1426 reportable events that are reasonably attributed only to the therapeutic product must be 1427 reported to the therapeutic product center in accordance with 21 CFR 314.80 or 600.80. For 1428 reportable events that can be attributed to both products, or when it is not clear which product 1429 may have caused the problem, report the event in accordance with both regulations. 1430 1431
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41 APPENDIX 1: Critical Points of the Codevelopment 1432
Process 1433
Efficient codevelopment of a therapeutic product with an IVD companion diagnostic requires 1434
coordination of the development programs of the two products, including interactions with 1435
all relevant FDA review divisions (see Figure A1). 1436
1437 Figure A1. 1438 1439
1440 Therapeutic product development typically advances through a series of clinical trial phases 1441 and includes predictable points of interaction with the FDA (e.g., specified meetings and 1442 submissions). 98 IVD development, on the other hand, is typically not linear and many 1443 analytical validation studies may take place without prior FDA involvement. In 1444 codevelopment programs, the clinical validity of the IVD is typically assessed in the 1445 therapeutic product clinical trials. 1446 1447
Sponsors of developmental or candidate IVD companion diagnostics may use the Pre-Sub 1448
program at any point during IVD development, to discuss any aspect of the development 1449
program, including the appropriateness of analytical or clinical protocols and possible 1450
regulatory pathways, among other things. 99
1451
1452
98 See FDA guidance, “Formal Meetings between the FDA and Sponsors or Applicants” ( http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf).
99
Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff”
( www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf ).
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42 The Pre-IND, End-of-Phase 1 (EOP1) and End-of-Phase 2 (EOP2) meetings for a therapeutic 1453
product are critical times to discuss plans for a therapeutic product’s development. If the 1454
therapeutic product review center determines that an analytically validated test is necessary 1455
to meet the stated objectives of the clinical trial, FDA may not allow the trial to proceed 1456
without an adequately validated test. If the IVD sponsor has not initiated interaction with the 1457
appropriate IVD review center by the time the therapeutic product sponsor holds key 1458
milestone meetings, FDA strongly recommends that the IVD sponsor do so at that time. 1459
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43 1460 APPENDIX 2: Subject Specimen Handling 1461
Considerations 1462
An appropriate sample acquisition plan is critical to a successful codevelopment strategy. 1463
Sponsors may find it helpful to consider resources on biospecimen reporting, such as the 1464
Biospecimen Reporting for Improved Study Quality (BRISQ) recommendations. 100
1465
1466 1. Banking Samples 1467
FDA strongly recommends that sponsors collect and bank (where analytes are stable under 1468
banking conditions) the specimens from all subjects tested for participation in the trial when 1469
possible, regardless of whether a specific IVD companion diagnostic intended for 1470
commercialization will be used in the clinical trial. There are two primary reasons for 1471
banking specimens: (1) diagnostic indications with respect to a specific therapeutic product 1472
require a correlation between the candidate IVD companion diagnostic test results with 1473
subject specimens and the subject status; and (2) analytical performance of the IVD is 1474
demonstrated with subject specimens. For these reasons and others, it is important to 1475
consider a specimen banking plan when contemplating codevelopment programs. 1476
1477 2. Sample or Analyte Specifications 1478
An ideal specimen banking plan should be structured around obtaining specimens from all 1479
subjects who are tested for possible enrollment into a marker-driven or marker-stratified 1480
therapeutic product trial, whether or not the subjects were actually enrolled, with the 1481
exception of those who were excluded from the trial due to not meeting other inclusion 1482
criteria for the trial. The availability of samples from all subjects in the ITD population 1483
allows the test developer to meet analytical performance study requirements, such as 1484
determining accuracy of the test. Analytical validation with specimens also allows for an 1485
adequate evaluation of test performance with the variables present in the major efficacy 1486
therapeutic product trial(s) and likely to be present in clinical care when the therapeutic 1487
product is approved. This includes, but is not limited to, the mode of collection (e.g., 1488
surgical resection, core needle biopsy), anatomical sites of collection (e.g., primary, 1489
metastatic), histology and stage. Additionally, if changes are made to the test, or the CTA is 1490
not the candidate IVD companion diagnostic, the samples will need to be retested with the 1491
candidate for the purpose of assessing efficacy of the therapeutic product based on the results 1492
obtained with the test version intended for commercialization. 1493
1494 Sponsors should plan to bank both the specimen and any processed specimen (e.g., DNA 1495 extractions) used for the initial testing. The banked tissue is useful for the analytical 1496 performance studies since most performance studies should include the preanalytic steps. 1497 The processed samples, such as DNA extractions, are useful in the event that the sample 1498 needs to be retested for a demonstration of concordance between the CTA and the candidate 1499
100 Moore, HM. Biospecimen reporting for improved study quality (BRISQ). Cancer Cytopathol. 2011. 119(2):92-101.
Contains Nonbinding Recommendations Draft - Not for Implementation
44 IVD companion diagnostic. While having large amounts of homogeneous sample from each 1500
subject is ideal, it may not be achievable, especially where the sample collection method 1501
requires invasive procedures that are not part of standard clinical care for the disease or 1502
condition in question. In their sampling plan, sponsors should plan to obtain a sufficient 1503
sample volume to perform the necessary test, plus enough overage to enable retesting one or 1504
more times (where possible and ethical). 1505
1506 3. Foreign Countries 1507
Sample banking can be complicated when samples are obtained from subjects in countries 1508
that do not typically allow specimens to leave the country of origin. In designing a sample 1509
banking plan, this possibility should be carefully considered. If it is likely that a significant 1510
number of samples from a therapeutic product trial will be inaccessible due to country- 1511
specific export limitations, sponsors may try to establish a plan to both bank samples and 1512
retest in those countries. 1513
1514 4. Informed Consent 1515
The definition of human subject includes a subject’s specimens (21 CFR 812.3(p)), and thus, 1516
informed consent applies to the use of specimens. In the U.S., to use a human specimen in an 1517
investigation, legally effective informed consent must be obtained from the subject (or his 1518
legal representative). 101,102
It is good practice to outline the uses of the subject’s sample that 1519
may reasonably be anticipated, either in the therapeutic product clinical trial consent or in a 1520
separate document dedicated to the sample collection only, even if the laws and regulations 1521
in the country of origin do not specifically require it. It is also good practice to obtain 1522
samples from subjects who are not enrolled in the trial, so that the ITD population is properly 1523
represented in the banked samples. Informed consent may also be required for these 1524
samples, e.g., if the investigational IVD will be used on the samples. 1525
1526 5. Specimen Annotation 1527
Thorough sample annotation is critical to successful development of an IVD companion 1528
diagnostic. It is very important to adequately annotate specimens with relevant information 1529
that will inform both their use in the therapeutic product trial and potential later uses. 1530
Relevant information includes factors that may affect test performance and factors that may 1531
affect the therapeutic product evaluation. The latter are typically outlined as demographics 1532
and stratification factors in the clinical trial. These factors may also be evaluated as sources 1533
of bias in the event that there are missing samples in analysis of test performance that 1534
informs therapeutic product use. 1535
1536 Subject characteristics may include: 1537
101 See 21 CFR Part 50, 21 CFR Part 812, and 21 U.S.C. 360j(g)(3)(D). 102 Currently, FDA intends to exercise enforcement discretion with respect to the informed consent requirements, see note 101, under certain circumstances for IVD investigations using leftover human specimens that are not individually identifiable. See FDA guidance “Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable” ( http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0712 65.pdf ).
Contains Nonbinding Recommendations Draft - Not for Implementation
45 · Disease or condition grade, stage, severity, or other standardized measures of patient 1538
status 1539
· Previously administered therapies 1540
· Study stratification factors, e.g., age, sex, race/ethnicity, tumor size, geographical 1541
location, performance status 1542
1543 Sample characteristics may include: 1544 · Type of specimen, e.g., tumor, blood, serum, urine, plasma, tissue, saliva 1545 · If tumor sample, percent tumor/stromal/necrotic proportion 1546 · Content of potential inhibitory or cross-reactive substances, e.g., melanin 1547 · Anatomical site of collection 1548 · Collection method and container type 1549 · Primary, metastatic, normal, abnormal 1550 1551
Sample handling and preliminary preparative steps may include: 1552
· Biopsy, fine needle aspirate 1553
· Formalin-fixed paraffin embedded (FFPE), frozen, centrifuged, fractionated, 1554
extracted, macrodissected, etc. 1555
· Date of collection/handling/preparation 1556
· Storage conditions (e.g., temperature) including conditions associated with shipping 1557
to laboratory 1558
1559 6. Storage 1560
When specimens are stored for later use, the sponsor should consider the stability of the 1561
analyte(s) of interest. Some analytes are labile and require special handling or storage 1562
conditions, while others are more stable and can withstand a variety of handling and storage 1563
conditions. To the degree that the stability of the analyte in the matrix of choice is not well- 1564
defined, the sponsor should perform a thorough assessment of the anticipated handling and 1565
storage conditions to ensure that conditions are selected that will allow later informative use 1566
of the samples. It is acceptable to extract or purify the analyte(s) of interest if extraction or 1567
purification (or partial purification) is required to stabilize it. In this case, complete 1568
analytical studies will necessitate that the sponsor demonstrate that the extraction or 1569
purification can be consistently carried out in a way to assure expected test performance. 1570
FDA recommends that a single, uniformly implemented method be used in any sample 1571
handling or extraction procedures, as use of more than one method may introduce variables 1572
into the test performance that cannot be quantified. 1573
1574 Contains Nonbinding Recommendations Draft - Not for Implementation
46 APPENDIX 3: BIMO Information to Submit in a PMA 1575
To facilitate the CDRH/CBER BIMO inspection of investigational testing sites in clinical 1576
trials, it is recommended that PMA applicants submit the following information, stratified by 1577
the type of study (analytical validation vs. clinical validation) from each of the testing sites: 1578
· Analytical studies for PMA (information provided by site for each study) 1579
o Site information (including name, street address, city, state, zip code, name of 1580 contact, and telephone number) 1581 o Location of source documents 1582 o Statement of location of line data (e.g., at the site or with sponsor) 1583 o Patient/subject information, unless the studies were conducted with leftover 1584 specimens that are not individually identifiable 1585 o
1586 o Investigator Agreements 1587 o Conflict of Interest/ Financial Disclosure 1588
o Informed Consent Document(s), unless the studies were conducted with 1589 leftover specimens that are not individually identifiable 1590 o Protocol Deviations 1591 o IRB information 1592 o Monitoring Plan 1593 o Line Listings (stratified by site and then subject) 1594 · Clinical testing by site (e.g., centralized testing for enrollment) 1595 o
1596 contact, and telephone number) 1597 o
1598 o Patient/subject information, if needed 1599 o Location of source documents 1600 o Case Report Forms 1601 o Investigator Agreements 1602 o Conflict of Interest/Financial Disclosure 1603 o Informed Consent Document(s) 1604 o Protocol Deviations 1605 o Line Listings (stratified by site and then subject) 1606 Contains Nonbinding Recommendations Draft - Not for Implementation
47 1607 APPENDIX 4: Letters of Authorization 1608
For efficient review of a therapeutic product and its corresponding IVD companion 1609
diagnostic, the therapeutic product sponsor and the IVD sponsor should send letters of 1610
authorization to FDA that authorize the other sponsor to cross-reference the premarket 1611
submission or incorporate the relevant content by reference. 1612
1613 The center reviewing the IVD (CDRH/CBER) needs permission from the therapeutic 1614 product sponsor to rely on the data in the NDA/BLA to support the PMA (or other device 1615 premarket submission if applicable). The letter authorizing this cross-reference should be 1616 sent to the Document Control Center of the center reviewing the IVD (CDRH/CBER) to 1617 the attention of the IVD reviewer. Also, the center reviewing the therapeutic product 1618 (CDER/CBER) needs permission from the IVD sponsor to rely on the data in the PMA 1619 (or other device premarket submission if applicable) to support the NDA/BLA. The letter 1620 authorizing this cross reference should be sent to the electronic gateway of the center 1621 reviewing the therapeutic product (CDER/CBER) to the attention of the therapeutic 1622 product reviewer. 1623 1624
Letters should clearly specify the product name, sponsor name and submission number(s) 1625
(e.g., PMA, BLA, or NDA numbers). Authorizing FDA to rely on information in the 1626
corresponding product premarket submission does not authorize FDA to share that 1627
information with the other company; the information remains confidential in accordance 1628
with the applicable laws. 103
1629
1630 Two examples of letters of authorization are provided below. 1631 1632
Example 1: An IVD sponsor authorizing CDER to refer to a PMA in support of an 1633
NDA 1634
1635 [IVD Sponsor Name] 1636 [Address] 1637 1638
[Date] 1639
1640 [CDER Reviewer] 1641 [Address] 1642 1643
Re: Authorization Letter to Cross Reference [PMA#] [IVD Name] 1644
1645 This letter authorizes CDER to refer to [IVD Sponsor Name]’s PMA [PMA number] for 1646
103 For information on FDA treatment of confidential information and what constitutes trade secret, confidential commercial or financial information, and private personal identifier information, see the FDA regulations implementing the Freedom of Information (FOI) Act in 21 CFR Part 20. See also FDA’s FOI web page at http://www.fda.gov/ RegulatoryInformation/foi/ default.htm .
Contains Nonbinding Recommendations Draft - Not for Implementation
48 [IVD Name] in support of [Drug Sponsor Name]’s NDA application [NDA number] for 1647
[Drug Name and Indication] and [Drug Name and Indication 2 (if applicable)]. 1648
1649 By copy of this letter, we authorize [Drug Sponsor Name] to incorporate information 1650 contained in the PMA by reference into their NDA submission(s) as necessary. (Optional 1651 if the IVD sponsor wishes to allow the drug sponsor to incorporate IVD information into 1652
the NDA submission.) 1653
1654 Please contact [Name] at [Phone Number] or [E-mail] with questions. 1655 1656
[Signature] 1657
[Name] 1658
[Title] 1659
1660 Example 2: A drug sponsor authorizing CDRH to refer to an NDA(s) in support of 1661
a PMA for an IVD companion diagnostic 1662
1663 [Drug Sponsor Name] 1664 [Address] 1665 1666
[Date] 1667
1668 [CDRH Reviewer] 1669 [Address] 1670 1671
Re: Authorization Letter to Cross Reference [NDA #] [Drug Name] 1672
1673 This letter authorizes the Center for Devices and Radiological Health to refer to [Drug 1674 Sponsor Name]’s New Drug Application [NDA number] for [Drug Name] in support of 1675 [IVD Sponsor Name]’s PMA [PMA number] for [IVD Name], which is intended to be 1676 used for [Intended Use]. 1677 1678
By copy of this letter, we authorize [IVD Sponsor Name] to incorporate information 1679
contained in the NDA(s) by reference into their PMA submission as necessary. (Optional 1680
if the drug sponsor wishes to allow the IVD sponsor to incorporate drug information into 1681
the PMA submission.) 1682
1683 Please contact [Name] at [Phone Number] or [E-mail] with questions. 1684 1685
[Signature] 1686
[Name] 1687
[Title] 1688 Document Outline
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