Principles for Codevelopment of an 1 In Vitro Companion Diagnostic



Yüklə 0,62 Mb.
Pdf görüntüsü
səhifə6/6
tarix26.02.2017
ölçüsü0,62 Mb.
#9737
1   2   3   4   5   6

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

 See FD&C Act section 505(b)(5) and FDA’s “Guidance for Industry: Special Protocol Assessment” for 



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Draft - Not for Implementation 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

 See FDA’s Manual of Policies and Procedures: “Good Review Practice: Review of Marketing Applications 



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

  

1171



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. 

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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

 

1266



                                                 

88

 See FDA website: 



http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubm

issions/PremarketApprovalPMA/ucm142714.htm. 

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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

 See note 3. 



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.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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

G. Labeling Considerations 

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.

 

 

1375



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.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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.

 


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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

 More information about the Pre-Sub program can be found in the FDA guidance “Requests for Feedback on 



Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration 

Staff” 


(

www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf

).  


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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


Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

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

  Sample Data Collection/Case Report Forms  



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

  Site information (including name, street address, city, state, zip code, name of 



1596

contact, and telephone number) 

1597

o

  Statement of location of line data (e.g., at the site or with sponsor) 



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

  • General
  • Regulation of Investigational IVDs and Therapeutic Products
    • Risk Assessment and IDE Requirements
    • Submission of Investigational IVD Information Related to Investigational Drugs or Biological Products
    • IDE Applications for Investigational IVDs in Codevelopment Trials
  • Planning Ahead for IVD Validation in Potential Codevelopment Programs
    • Expectation for Analytical Validation Prior to Investigational IVD Use in Therapeutic Product Trials
    • New Intended Uses for IVDs
    • IVD Prototypes in Early-Phase Therapeutic Product Clinical Trials
    • Using Research Use Only Components as Part of a Test System
    • Prescreening for Eligibility for Therapeutic Product Clinical Trials
    • Preanalytic Procedures and Testing Protocols
    • Planning Ahead for Analytical Validation Studies
  • Therapeutic Product Clinical Trial Design Considerations
    • General Considerations for Early Therapeutic Product Development
    • General Considerations for Late Therapeutic Product Development
    • Prognostic and Predictive Markers
    • Prospective-Retrospective Approaches
    • Considerations for Identifying Intended Populations
  • Considerations for IVD Development in Late Therapeutic Product Development
    • Training Samples Sets versus Validation Samples Sets
    • Effect of Changes to the Test Design
    • IVD Bridging Studies
    • Special Protocol Assessments
  • Planning for Contemporaneous Marketing Authorizations
    • Coordinating Review Timelines
    • When Contemporaneous Marketing Authorization is Not Possible
    • Shipment and Verification of an IVD Companion Diagnostic Prior to Marketing Authorization
  • Labeling Considerations
    • Claims for IVD Companion Diagnostics Based on Use in Trial
  • Postmarketing Considerations
  • APPENDIX 1: Critical Points of the Codevelopment Process
  • APPENDIX 2: Subject Specimen Handling Considerations
  • APPENDIX 3: BIMO Information to Submit in a PMA
  • APPENDIX 4: Letters of Authorization

Yüklə 0,62 Mb.

Dostları ilə paylaş:
1   2   3   4   5   6




Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©www.azkurs.org 2022
rəhbərliyinə müraciət

    Ana səhifə