Principles for Codevelopment of an 1 In Vitro Companion Diagnostic

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. 

 

Contains Nonbinding Recommendations 

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9 

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). 

Contains Nonbinding Recommendations 

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10 

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. 

Contains Nonbinding Recommendations 

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11 

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.

 

Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

12 

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. 

Contains Nonbinding Recommendations 

Draft - Not for Implementation 

 

 

13 

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