A. General
226
Ideally, the need for an IVD companion diagnostic would be identified early in the course of
227
therapeutic product development so that an analytically validated test can be prospectively
228
incorporated into the design of the therapeutic product clinical trials. For example, the
229
therapeutic product development program may be designed from the earliest phases of
230
nonclinical development to treat a specific subpopulation identified by testing with an IVD.
231
If the need for an IVD companion diagnostic was at first uncertain or unknown, emerging
232
data from early-phase clinical trials of a therapeutic product may identify an important safety
233
issue or a differential efficacy response that justifies inclusion, exclusion, or changing
234
management (e.g., dosing) of certain subpopulations, identified by an IVD, in subsequent
235
clinical trials or clinical use. In both cases, development of the IVD would be
236
contemporaneous with development of the therapeutic product, allowing for
237
contemporaneous marketing authorization of the therapeutic product and the IVD companion
238
diagnostic.
239
240
On the other hand, important safety or efficacy issues related to a particular subpopulation
241
identified by testing with an IVD may not arise until late in the course of therapeutic product
242
development. In such cases, approval of the therapeutic product could be delayed until an
243
appropriate IVD companion diagnostic receives marketing authorization. As described in the
244
guidance on “In Vitro Companion Diagnostic Devices,” in certain circumstances, FDA will
245
consider the timing of the therapeutic product approval after discussion with sponsors (see
246
also Section III.F.2. of this guidance).
15
247
248
Although codevelopment as a process does not require simultaneous development of the IVD
249
companion diagnostic and the therapeutic product from beginning to end, the availability of
250
an IVD with “market-ready” analytical performance characteristics (i.e., a test that is
251
completely specified with complete analytical validation
16
and meets the therapeutic product
252
sponsor’s expectations for performance) is highly recommended at the time of initiation of
253
clinical trial(s) intended to support approval of the therapeutic product. The trial will
254
determine whether the developmental IVD companion diagnostic
17
demonstrates adequate
255
clinical performance characteristics to support the safe and effective use of the therapeutic
256
15
See note 3. FDA may decide to approve a therapeutic product even if an IVD companion diagnostic is not
yet approved, granted a de novo request or cleared when the therapeutic product is intended to treat a serious or
life-threatening condition for which no satisfactory available therapy exists and the benefits from the use of the
therapeutic product are so pronounced as to outweigh the risks from the lack of an IVD companion diagnostic
with marketing authorization. This will be determined by FDA during product review.
16
For the purposes of this document, analytical validation is the demonstration that the IVD can accurately and
reliably detect or measure the analyte it is intended to detect or measure.
17
For the purposes of this document, the term developmental IVD companion diagnostic is used to refer to a
version of the test that is under investigation. This could be a prototype clinical trial assay (CTA) (see also
Section III.C.3.), an intermediate version of the test, or even the version of the test that will ultimately be
submitted for FDA review.
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product. Whether initiated at the outset of development or at a later point, codevelopment
257
should generally be conducted in a way that will facilitate obtaining contemporaneous
258
marketing authorizations for the therapeutic product and the associated IVD companion
259
diagnostic.
260
261
Given that the need for an IVD companion diagnostic may become apparent at different
262
points in the development of the therapeutic product, sponsors should be aware of and plan
263
for the various opportunities for interactions with the Agency, and requirements for
264
submissions to the Agency. Sponsors with IVD-related questions may use the Pre-
265
Submission (Pre-Sub) program to seek feedback from CDRH or CBER at any time in the
266
codevelopment process.
18
Similarly, therapeutic product development questions may be
267
directed to the appropriate therapeutic product review center (CDER or CBER).
19
In either
268
scenario, the review centers will typically consult one another to ensure coordinated review.
269
See Appendix 1 for additional information on critical points in the codevelopment process.
270
B. Regulation of Investigational IVDs and Therapeutic Products
271
If a therapeutic product sponsor plans to utilize the results from an IVD in decisions on how
272
to enroll, assign or manage subjects in a therapeutic product clinical trial, and the IVD used
273
for that purpose has not already received marketing authorization for that specific intended
274
use (e.g., to select patients for treatment with a therapeutic product, including the
275
corresponding specimen type and target population), the IVD use in that context would be
276
investigational. If an investigational IVD is to be used in a therapeutic product clinical trial,
277
the requirements of the Investigational Device Exemption (IDE) regulation at 21 CFR Part
278
812 would need to be addressed. As outlined in the sections that follow, the specific set of
279
IDE regulatory requirements that apply to an investigational IVD depends on the level of risk
280
that its use presents to study subjects.
20
281
282
In codevelopment trials, applicable regulatory requirements for investigation of the
283
therapeutic product also must be met.
21
Investigational New Drug (IND) sponsors must
284
provide a description of any endpoints, including laboratory test results, that are used to
285
assess the effectiveness of the drug or biological product in human subjects and the
286
monitoring in place to mitigate risks.
22
FDA can place a trial on clinical hold (i.e., prohibit
287
the sponsor from conducting the trial) under certain circumstances.
23
For example, the trial
288
18
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
).
19
FDA guidance, “Formal Meetings between the FDA and Sponsors or Applicants”
(
http://www.fda.gov/downloads/Drugs/Guidances/ucm153222.pdf
) describes the types of meetings available
during therapeutic product development.
20
FDA intends to release guidance that addresses the topic of investigational IVDs used in clinical
investigations of therapeutic products in the near future, which will include information about determining
investigational IVD risk.
21
See 21 CFR Part 312.
22
21 CFR 312.23(a)(6)(iii)(g).
23
21 CFR 312.42 and 21 U.S.C. 360j(g).
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may be placed on clinical hold if participation would pose unreasonable and significant risks
289
to human subjects, or the IND does not contain sufficient information to assess the risks to
290
subjects.
24
In addition, a trial may be placed on hold if the investigational plan is clearly
291
deficient in design to meet its stated objectives, which may include uncertainty about the
292
analytical validity of an IVD being used to enroll subjects into the trial.
25
The party taking
293
responsibility for the investigational IVD (also referred to in this document as the sponsor of
294
the investigational IVD) – whether it is the manufacturer of the investigational IVD or the
295
sponsor of the therapeutic product trial that includes an investigational IVD – should ensure
296
that the applicable requirements of the IDE regulation are met. The IDE application (if one
297
is required) should be submitted to the appropriate IVD review center by the entity that takes
298
responsibility for the investigational IVD.
299
300
1.
Risk Assessment and IDE Requirements
301
Because the IDE requirements that apply to an investigational device, including IVDs,
302
depend on the risk presented by the device, FDA expects the sponsor of the investigational
303
IVD to assess the risk presented to study subjects by use of the investigational IVD in the
304
context of the therapeutic product clinical trial. If the investigational IVD is not a significant
305
risk device as defined in 21 CFR 812.3(m) and the investigational IVD is not exempt under
306
21 CFR 812.2(c), then the abbreviated requirements described in 21 CFR 812.2(b) apply,
307
including the requirement to provide to the reviewing institutional review board (IRB) a brief
308
explanation of why the IVD is not significant risk.
26
If the IRB disagrees with the sponsor
309
and concludes that the investigation involves a significant risk device, the IRB is required to
310
notify the investigator and where appropriate, the sponsor.
27
Sponsors can also seek a risk
311
determination from CDRH or CBER through the Pre-Sub program.
28
Note that FDA’s
312
determination will supersede that of the sponsor or IRB.
29
313
314
It is important to be aware that assessment of risk as it applies to the use of an investigational
315
IVD in the context of a clinical trial is distinct from risk classification for the purposes of
316
marketing authorization, which determines the type of premarket submission required on the
317
basis of an IVD’s intended use and other factors.
30
A determination that an investigational
318
IVD is exempt under 21 CFR 812.2(c) or presents non-significant risk for investigational
319
device regulatory purposes (and therefore, is subject to the abbreviated requirements under
320
21 CFR 812.2(b)) does not mean that contemporaneous marketing authorizations for the IVD
321
and therapeutic product will not be needed. In other words, even if a clinical trial is designed
322
in such a way that investigational use of the IVD is exempt under 21 CFR 812.2(c),
323
contemporaneous marketing authorization of the IVD with the therapeutic product would be
324
24
21 CFR 312.42.
25
21 CFR 312.42 (b)(2)(ii).
26
21 CFR 812.2(b)(1)(ii).
27
21 CFR 812.66.
28
See note 18.
29
21 CFR 812.2(b)(1) and 812.20(a).
30
21 U.S.C. 360c.
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needed if FDA determines that the IVD is essential for the safe and effective use of the
325
therapeutic product.
326
327
Codevelopment clinical trial designs can incorporate use of an investigational IVD in ways
328
that are categorized by the IDE regulation as 1) exempt, 2) significant risk, and 3) non-
329
significant risk. Each category has specific requirements under the IDE regulation. These
330
requirements are described in the following sections.
331
332
i. Exempt Investigational IVDs
333
An investigational IVD may be exempt from the requirements of the IDE regulation (with the
334
exception of 21 CFR 812.119, Disqualification of a Clinical Investigator), if certain criteria
335
under 21 CFR 812.2(c)(3) are met, including that the testing is not used as a diagnostic
336
procedure without confirmation of the diagnosis by another, medically established diagnostic
337
product or procedure.
31
Examples of possible uses meeting this exemption criterion typically
338
seen in codevelopment programs are 1) when test results from an investigational IVD used in
339
a trial are used only for exploratory analyses and do not determine what treatment subjects
340
receive, and 2) when samples are collected prospectively and analyzed retrospectively
341
according to a pre-specified analysis plan (see Section III.D.4. in this guidance). Neither of
342
these uses relies on the investigational IVD for a diagnosis used to direct treatment of the
343
subjects enrolled in the therapeutic product clinical trial. Sponsors may use the Pre-Sub
344
program to consult with the FDA center responsible for regulating the IVD to resolve
345
questions about whether a particular investigational use would be considered exempt under
346
21 CFR Part 812.
347
348
Another criterion for exemption under 21 CFR 812.2(c)(3) is that the testing must not require
349
invasive sampling that presents significant risk to the subject. The use of surplus samples of
350
body fluids or tissues from invasive sampling being performed for non-investigational
351
purposes, such as in the normal course of medical care, is considered noninvasive.
32
352
Sponsors may use the Pre-Sub program to discuss specific sampling procedures with the
353
appropriate center (CDRH or CBER) if there are questions about whether the testing requires
354
invasive sampling that presents significant risk to subjects.
33
355
356
When sponsors are pursuing a codevelopment program and the developmental IVD
357
companion diagnostic is IDE-exempt, sponsors are strongly urged to use the Pre-Sub
358
program at the appropriate review center (CBER or CDRH) to discuss the IVD development
359
plan and other IVD-specific issues, particularly before launching a trial intended to support
360
the IVD’s marketing authorization. This interaction opportunity will help align FDA and
361
sponsors on the proposed IVD development process. Therapeutic product development
362
sponsors should also note that although an IDE application is not required for an IDE-exempt
363
investigational IVD, the therapeutic product review center may require submission of data
364
31
See 21 CFR 812.2(c) for full criteria pertaining to exempted investigations.
32
21 CFR 812.3(k).
33
Noninvasive sampling procedures are defined in 21 CFR 812.3(k) and include sampling methods such as
urine collection, buccal swabs, and saliva collection. Under 21 CFR 812.3(k), blood sampling that involves
simple venipuncture is also considered noninvasive.
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supporting the IVD’s analytical validity to determine whether the investigation conducted
365
under the IND will be able to meet its stated objectives (see Section III.B.2.).
366
367
ii. Non-exempt Investigational IVDs
368
If a developmental IVD companion diagnostic (which is investigational) used in the
369
therapeutic product trial does not meet the criteria for exemption under 21 CFR 812.2(c), the
370
IVD will be considered either significant risk or non-significant risk, depending on the risk
371
its use presents to trial subjects.
372
373
Significant Risk Investigational IVDs
374
Significant risk investigational IVDs include those that are for a use that is of substantial
375
importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing
376
impairment of human health, and that present a potential for serious risk to the health, safety,
377
or welfare of a subject; or otherwise present a potential for serious risk to the health, safety,
378
or welfare of a subject.
34
For IVDs, risk presented by investigational use is defined primarily
379
by the potential consequences to the subject of an incorrect test result. When results from
380
investigational IVDs are used to make critical medical decisions in a trial, and the
381
consequence of an incorrect result presents the potential for serious risk to the health, safety,
382
or welfare of a subject in that trial, the investigational IVD would be considered a significant
383
risk device for its proposed use in the investigation. Specifically, the use of a diagnostic test
384
result to enroll subjects into a clinical trial of a therapeutic product, assign subjects in a trial
385
to different treatment arms, or select a particular therapeutic dose may pose serious risk to the
386
health, safety or welfare of subjects. For example, an incorrect test result could pose a
387
significant risk if it leads to trial subjects foregoing or delaying a treatment that is known to
388
be effective, or being exposed to higher safety risks than the control arm or standard of
389
care.
35
390
391
Before beginning an investigation using a significant risk device, the IDE regulation requires
392
the sponsor to submit an IDE application and receive FDA approval.
36,37
The sponsor must
393
also comply with other applicable requirements in 21 CFR Part 812. It is important to
394
understand that the fact that a therapeutic product clinical trial may proceed under the IND
395
regulations or be exempt from the IND regulations (e.g., because it falls within certain
396
limited exemptions for clinical investigations with approved marketed drugs)
38
does not
397
exempt the trial from IDE regulatory requirements.
398
399
Non-significant Risk Investigational IVDs
400
Non-significant risk, non-exempt investigational devices are those that do not present a
401
potential for serious risk to the health, safety, or welfare of a subject. In codevelopment
402
scenarios, a non-significant risk use of an investigational IVD usually means that an incorrect
403
34
21 CFR 812.3(m).
35
See also note 20.
36
See 21 CFR 812.20(a).
37
The components of an IDE application are described in 21 CFR 812.20, 812.25, and 812.27. See also Section
III.B.3.
of this guidance which describes some of the information that FDA typically requests in IDE
applications for codevelopment trials.
38
See 21 CFR Part 312.
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test result does not pose a potential for serious risk to subjects in a trial. For example,
404
subjects are not put at serious risk when a test result is used to assign them to different
405
stratum for the purpose of balancing the characteristics of subjects assigned to different
406
treatment arms (a process referred to as stratification) because the test result itself does not
407
determine the treatment the subject receives. Likewise, using a test to assess a baseline
408
characteristic to be used in later analyses would not pose a serious risk.
409
410
If the investigational IVD used in a therapeutic product clinical trial does not meet the
411
criteria of a significant risk device, submission of an IDE application is not required.
412
However, the abbreviated requirements for investigational devices would apply,
39
even if the
413
therapeutic product clinical trial is being conducted under an IND.
414
415
When a sponsor believes that an investigational IVD poses a non-significant risk, submitting
416
a justification for this position to the IND aids FDA in reviewing the totality of the issues.
417
418
Although an IDE submission is not required for trials using non-significant risk or exempt
419
investigational IVDs, sponsors involved in codevelopment with such IVDs are strongly urged
420
to use the Pre-Sub program to seek feedback on the IVD development plan and other IVD-
421
specific issues, particularly before a major efficacy therapeutic product trial is initiated.
422
Early interaction with CDRH or CBER may help to identify and address problems with the
423
IVD development plan before a premarket application is under review and may help to
424
facilitate contemporaneous marketing authorization of an IVD companion diagnostic with its
425
corresponding therapeutic product.
426
427
Although an IDE application is not required for non-significant risk investigational IVDs, the
428
therapeutic product review center may require submission of data supporting the analytical
429
validity of the IVD to determine whether the investigation conducted under IND will be able
430
to meet its stated objectives (see Section III.B.2.).
431
432
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