2.
Submission of Investigational IVD Information Related to
433
Investigational Drugs or Biological Products
434
In codevelopment programs, as discussed above, the investigation of the IVD often occurs in
435
the context of the therapeutic product clinical development program where applicable
436
regulatory requirements for both the investigation of the therapeutic product and the
437
investigation of the IVD must be met.
40
In addition, information about the IVD might be
438
required by the therapeutic product review center if it is needed to determine whether the trial
439
can meet its stated objectives. Such considerations often raise questions from clinical trial
440
sponsors about whether IDE requirements can be fulfilled by submitting IVD information to
441
an IND.
442
443
39
21 CFR 812.2(b).
40
See 21 CFR Parts 312 and 812.
Contains Nonbinding Recommendations
Draft - Not for Implementation
14
As discussed above, if an investigational IVD presents significant risk to subjects, an IDE
444
application must be approved before the sponsor begins the therapeutic product clinical trial
445
that uses the investigational IVD.
41
Submission of IVD data to the IND will not satisfy the
446
IDE submission requirement. In general, a sponsor who wishes to streamline the IDE or IND
447
submission may cross-reference relevant information in the related IND or IDE submission
448
by providing a letter of authorization from the other sponsor giving FDA permission to refer
449
to items contained in the other submission.
42
450
451
As noted above in section III.B.1, although an IDE application is not required for an IDE-
452
exempt or non-significant risk investigational IVD,
43
submission of data supporting the
453
IVD’s analytical validity may be needed for FDA to determine whether the therapeutic
454
product clinical trial will be able to meet its stated objectives under the IND.
44
For example,
455
in such codevelopment scenarios, the test may be an integral component of the therapeutic
456
product trial inclusion/exclusion criteria, and adequate test performance may be necessary to
457
interpret trial results. If IVD information is needed, the therapeutic product review center
458
will specify the type and extent of IVD data that should be submitted to the IND. If the
459
analytical validity is critical to determining whether the clinical trial can meet its stated
460
objectives, lack of such data could be a reason to place the IND on clinical hold.
45
461
462
It is helpful to submit to the IND a short explanation of how the sponsor determined that the
463
investigational IVD was exempt or non-significant risk. If FDA has concerns or questions
464
about the sponsor’s determination, FDA may request additional information about the IVD.
465
Additionally, FDA recommends that the IND sponsor clearly indicate in its cover letter that
466
the IND submission or amendment contains investigational IVD information. This will
467
facilitate early collaboration on codevelopment programs between the therapeutic product
468
and IVD review divisions.
469
470
Note that all data related to investigational IVDs (including IDE-exempt or non-significant
471
risk IVDs) submitted in an IND may be reviewed by the relevant IVD review center at the
472
request of the appropriate therapeutic product review center if it determines that such review
473
is necessary and requests an intercenter consult. Such an intercenter consult review does not
474
require a separate submission by the sponsor.
475
476
3. IDE Applications for Investigational IVDs in Codevelopment
477
Trials
478
As described in Section III.B.1., the use of an investigational IVD in a therapeutic product
479
trial requires submission and approval of an IDE application if it is not exempt and its use
480
presents significant risk to study subjects. FDA may disapprove the IDE application under
481
41
See 21 CFR 812.20(a).
42
Examples of letters of authorization are provided in Appendix 4.
43
As noted in Section III.B.1, certain other requirements of 21 CFR Part 812 still apply.
44
21 CFR 312.42.
45
See 21 CFR 312.42(b)(1)(iv), (b)(2)(ii).
Contains Nonbinding Recommendations
Draft - Not for Implementation
15
any of the grounds specified in
21 CFR 812.30(b), or place the trial on clinical hold if the
482
investigational IVD presents an unreasonable risk to the safety of the trial subjects.
46
483
484
For investigational IVDs intended to be used in therapeutic product trials to direct the
485
management of trial subjects, the validation to support the investigational IVD should be
486
demonstrated to be sufficient to establish the reliable performance of the IVD.
47
487
488
With respect to codevelopment trials, FDA typically requests that the IDE application
489
include the types of information described below, as applicable:
48
490
· A description of the IVD cutoff value(s) (i.e., clinical decision points) when such
491
values are essential for the use of the IVD in the trial.
492
· A description of the preanalytical (specimen handling, storage and pre-assay
493
treatment) and analytical studies, and results from studies designed to demonstrate the
494
reliability of the assay, particularly around the cutoff value(s).
495
· A description of and results from other analytical studies that support the conclusion
496
that use of the IVD does not expose subjects to unreasonable risk of harm, e.g.,
497
precision, limits of detection/quantitation, specificity/cross-reactivity, accuracy
498
(comparison to a reference method and/or IVD).
499
· The clinical trial protocol, either through direct submission or by reference to the
500
appropriate IND.
49
501
C. Planning Ahead for IVD Validation in Potential
502
Codevelopment Programs
503
This section discusses various aspects of IVD companion diagnostic development that
504
typically are important to consider early in the codevelopment process.
505
506
1. Expectation for Analytical Validation Prior to Investigational
507
IVD Use in Therapeutic Product Trials
508
Although there is significant flexibility in the type of test to be used, and test design changes
509
are permissible between therapeutic product clinical trial phases, it is still important to
510
understand the critical analytical performance characteristics
50
of early prototype tests. The
511
analytical validation studies that evaluate critical performance parameters should be
512
completed in advance of using the test in a trial that is intended to provide the clinical
513
46
21 U.S.C. 360j(g)(8).
47
Sponsors may use the Pre-Sub program (see note
18) to help determine which studies are needed and the
degree of rigor that should be applied to each study. Additionally, sponsors may consider various resources for
information about proper performance validation, e.g., guidelines issued by the Clinical and Laboratory
Standards Institute (CLSI).
48
Note that the contents of the IDE application are specified in full in 21 CFR 812.20, 812.25, and 812.27.
49
A letter of authorization to cross-reference should also be provided when referencing an IND.
50
For the purposes of this document, an analytical performance characteristic refers to a property of a test that
is used to describe its quality with respect to measuring the analyte, e.g., accuracy, precision, analytical
sensitivity, analytical specificity, reproducibility.
Contains Nonbinding Recommendations
Draft - Not for Implementation
16
evidence in support of IVD companion diagnostic claims. Using an analytically validated test
514
is important to protect clinical trial subjects, to be able to interpret trial results when a
515
prototype test is used, and to help to define acceptable performance characteristics for the
516
development of the candidate IVD companion diagnostic.
517
518
When a significant risk investigational IVD is to be used in a clinical trial for a therapeutic
519
product, an evaluation to demonstrate that the IVD is sufficiently analytically robust,
520
particularly around the test’s clinical decision point(s),
51
where necessary, should be
521
conducted prior to using the IVD in the therapeutic product clinical trial. This evaluation
522
should be submitted in an IDE application (see Section III.B. of this guidance for discussion
523
of significant risk investigational IVDs). For investigational IVDs that are determined to be
524
non-significant risk or are exempt under 21 CFR 812.2(c) (and therefore do not require
525
submission of an IDE application) and when submission of IVD information is not needed by
526
the therapeutic product review center as part of the IND (as described in Section III.B.2.),
527
FDA recommends that sponsors perform the same types of validation prior to using the IVD
528
in the therapeutic product trial, even though FDA will not review the data prior to initiation
529
of the clinical trial.
530
531
2. New Intended Uses for IVDs
532
In some codevelopment programs, the developmental IVD companion diagnostic may be an
533
IVD with previous FDA marketing authorization. However, as stated in Section III.B, when
534
the IVD is put to a new use (e.g., a test is used for a new specimen type, a new population, or
535
to select treatment with a new drug), the IVD is considered investigational and the sponsor
536
must comply with the applicable requirements of the IDE regulation.
52
Additionally,
537
submission of the appropriate premarket application will be required to support an IVD
538
companion diagnostic (if a companion diagnostic is needed) for the new intended use,
539
demonstrating, among other things, that the IVD has adequate performance characteristics
540
for the new intended use.
FDA recommends that sponsors consult early with the appropriate
541
IVD review center on the likely regulatory pathway so that the sponsor can adequately
542
prepare for the appropriate submission (see also Section III.F.1.ii. of this guidance).
543
544
3. IVD Prototypes in Early-Phase Therapeutic Product Clinical
545
Trials
546
Early on in therapeutic product development programs, a test may be developed or contracted
547
by the therapeutic product sponsor solely for the purpose of testing in the therapeutic product
548
51
FDA is aware that sponsors may sometimes consider adaptive cutoff designs in trials. Adaptive cutoff
designs in trials that are intended to support therapeutic product approval should be discussed with FDA prior to
initiating the trial. For additional discussion, see FDA draft guidance “Adaptive Design Clinical Trials for
Drugs and Biologics”
(
www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf
).
FDA draft guidance represents FDA’s proposed approach on this topic. When final, this guidance will
represent the FDA’s current thinking on this topic.
52
See 21 CFR Part 812.
Contains Nonbinding Recommendations
Draft - Not for Implementation
17
trial (i.e., the sponsor does not intend to market the test for clinical use). Such a test is often
549
referred to as a clinical trial assay (CTA). The CTA is generally a prototype IVD designed
550
to support the selection of subjects or to investigate a hypothesis related to outcome on the
551
basis of the test result. CTAs may be used to assess prediction of benefit/harm, appropriate
552
safe/effective dose, or other test-driven safety or efficacy use under the appropriate
553
investigational use requirements (see Section III.B.). A CTA used in the early-phase clinical
554
trials, or a new design of the CTA, is often further developed as the candidate IVD
555
companion diagnostic if the early-phase clinical trials of the therapeutic product yield
556
promising results.
557
558
When a CTA is used to inform the management of clinical trial subjects (e.g., enrollment,
559
assignment to treatment arm, dose, etc.), FDA recommends that a single testing protocol be
560
used in the trial, and that the CTA be fully specified (i.e., all components, protocols,
561
instrumentation, etc. are specified and fixed) without any changes during its use in the trial.
562
If multiple testing sites are used (e.g., use of regional test centers or testing in different
563
countries), a single testing protocol should be used at all sites. To assure that results are not
564
affected by site of testing, FDA recommends that the sponsor evaluate comparability of test
565
results among potential sites prior to initiating trial testing at those sites. This can be
566
achieved through a site qualification scheme or other mechanism. The use of multiple assay
567
protocols, different technologies or a method that lacks reproducibility across labs could
568
result in variable test performance and lack of comparability among test results. Such
569
variability in CTAs could compromise the ability of the therapeutic product clinical trial to
570
demonstrate an effect of treatment or to determine whether the test can appropriately identify
571
the subjects for whom the therapeutic product is intended to provide benefit.
572
573
4. Using Research Use Only Components as Part of a Test System
574
In early-phase therapeutic product trials, as mentioned above, prototype CTAs may be used
575
prior to development of a candidate IVD companion diagnostic. In some cases, especially
576
for new analytes, it may be necessary to make use of products that are labeled “For research
577
use only. Not for use in diagnostic procedures.”
53
Products that are intended for research use
578
only (RUO) and labeled in this way are not required to be designed or manufactured with the
579
level of control required for investigational use or clinical diagnostic use, and they are not
580
evaluated by FDA.
581
582
It may be possible to use RUO products as part of a CTA if the sponsor relabels such RUO
583
products to indicate that they are for investigational use only and complies with all applicable
584
requirements under 21 CFR Part 812. As investigational devices, the products would be
585
subject to design controls under 21 CFR 820.30 if applicable,
54
but even if the products were
586
not, the test developer should put controls in place to assure that the products have
587
characteristics appropriate for the test, and the acceptance criteria are defined and met for all
588
53
Additional information about RUO labeling can be found in FDA guidance, “Distribution of In Vitro
Diagnostic Products Labeled for Research Use Only or Investigational Use Only”
(
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm253307.htm
).
54
See 21 CFR 812.1.
Contains Nonbinding Recommendations
Draft - Not for Implementation
18
units used. Additional controls may also be appropriate to assure that test performance is
589
reliable.
590
591
Sponsors should be aware that if they intend to seek FDA marketing authorization of an IVD
592
companion diagnostic, all components of the test system, including the preanalytical
593
components, should be included in validation and comply with the appropriate IVD
594
regulations, including labeling. Therefore, when materials or instrumentation that are
595
initially labeled as RUO are used in sample handling, extraction, processing, or any other
596
step in the testing procedure, sponsors should pay special attention to how the required
597
procedural step(s) will be carried out with the candidate IVD companion diagnostic, and
598
should plan to bring forth all test components for marketing authorization with that
599
candidate.
600
601
A component of a test system that is initially labeled RUO or “For investigational use only”
602
(IUO) may receive marketing authorization for use with a test system by demonstrating,
603
among other things, that its performance is appropriate for the particular test system. The
604
design and manufacture of the component must also comply with applicable requirements
605
under the Quality System regulation
55
(for devices reviewed under a premarket approval
606
application (PMA), these requirements must be met prior to approval). Therefore, an IVD
607
companion diagnostic sponsor should include all components in the test system under its
608
quality system and should describe their performance in the premarket submission for the
609
IVD companion diagnostic.
610
611
5. Prescreening for Eligibility for Therapeutic Product Clinical
612
Trials
613
Technological and scientific advances have led to the development and validation of a wide
614
assortment of tests that are frequently performed in the course of patient care to inform
615
treatment decisions. There is often no assurance that these tests (referred to as local tests) are
616
standardized or interchangeable. Increasingly, physicians are also using test results to make
617
recommendations about participation in marker-driven therapeutic product clinical trials, a
618
process that is essentially “prescreening” subjects for eligibility. Among the most important
619
are tests that, prior to entry of individuals into a clinical trial, identify a population that has a
620
higher likelihood of response. These tests are then used to predictively enrich the population.
621
This greatly enhances the ability of the study to show an effect but may also limit the
622
indicated population that is potentially eligible for treatment with a therapeutic product.
623
624
Prescreening can create particular problems for sponsors attempting to evaluate a novel
625
therapeutic product’s safety and efficacy in an intended population, as well as for the IVD
626
manufacturer attempting to provide an unbiased demonstration of performance of the IVD
627
companion diagnostic. Prescreening may result in a biased clinical trial population that does
628
not represent the population that would be selected by the IVD companion diagnostic in real-
629
55
21 CFR Part 820.
Contains Nonbinding Recommendations
Draft - Not for Implementation
19
world testing. Thus, planning to enroll subjects into a trial based on confirmation of a local
630
test result is strongly discouraged.
631
632
One way for sponsors to avoid potential bias from prescreening is to educate the participating
633
clinical sites about the importance of sending forward specimens from all potential enrollees
634
for testing with the trial test, rather than forwarding just those specimens from subjects that
635
are identified based on a prescreening test. By testing all samples from the intent-to-
636
diagnose (ITD) population, the IVD sponsor can determine the true performance of the IVD,
637
as well as assure that the therapeutic product clinical trial is not compromised by a trial
638
population that is skewed toward a non-representative population.
639
640
When prescreening is unavoidable, such as in oncology where molecular profiling is
641
common, sponsors should be aware of the potential for bias, take steps to evaluate whether
642
the expected prevalence of the marker is being skewed by prescreening, and develop
643
approaches to adequately address potential selection bias.
644
645
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