Welcome to today’s 

FDA/CDRH Webinar

Thank you for your patience while we register all 

of today’s participants.

If you have not connected to the audio portion of the 

webinar, please do so now:

Dial: 877-917-9491

International: 1-212-287-1619 

Passcode: 5995433

Conference Number:PWXW9340376 1 
Principles for Codevelopment

of an In Vitro Companion 

Diagnostic Device with a 

Therapeutic Product 

August 18, 2016

Christopher Leptak, MD, PhD

Office of New Drugs

Center for Drug Evaluation and Research

Pamela Bradley, PhD

Personalized Medicine Staff

Office of In Vitro Diagnostics and Radiological Health

Center for Devices and Radiological Health 2 
Principles for Codevelopment of an In 

Vitro Companion Diagnostic Device 

with a Therapeutic Product 

• The FDA published draft guidance on July 15, 2016

• Tri-center guidance from CBER, CDER and CDRH

• Open comment period through Oct. 13, 2016

• Purpose of today’s webinar is to facilitate public 

feedback 

• Public comments submitted to the docket will be 

considered in finalization of the guidance

3 
Overview of Webinar 

• Presentation of draft guidance ~40 min

– Christopher Leptak, CDER

– Pamela Bradley, CDRH

• Q&A ~20 min

– Sheryl Kochman, CBER

– Elizabeth Mansfield, CDRH 

– Michael Pacanowski, CDER

4 
Companion Diagnostics

• The FDA issued final guidance “In Vitro Companion Diagnostic 

Devices” Aug. 2014

• Defined companion diagnostic (CoDx) as IVD that provides 

information that is essential for the safe and effective use of a 

corresponding therapeutic product

• Described CoDx uses: 

– Identify population most likely to benefit or most at risk of adverse 

reaction.

– Monitor response to adjust treatment.

– Identify population for whom product is known to be safe and effective.

• Clarified that, in general, the FDA expects contemporaneous 

regulatory approvals of the CoDx and therapeutic product

• Described other regulatory requirements (labeling, etc.)

• Did not provide a “how-to”

5 
Draft Guidance:

Principles for Codevelopment of an In Vitro 

Companion Diagnostic Device with a 

Therapeutic Product

• Intended to provide the “how to” –- the practical 

aspects of codevelopment to support the design and 

implementation of successful codevelopment 

programs.

• The guidance describes:

– General principles to guide codevelopment to support obtaining 

contemporaneous marketing authorization 

– Certain regulatory requirements 

– Considerations for therapeutic product clinical trial that 

includes investigation of an IVD CoDx

– Submission process for the therapeutic product and CoDx 6 
Codevelopment Guidance 

Topics

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling Considerations

• Postmarket Considerations

7 
Codevelopment 

• Codevelopment does not require simultaneous development of CoDx and 

therapeutic product from beginning to end.

• Biomarker discovery (↓) and test development can occur at any point during the 

therapeutic product development process.

• Whether initiated at the outset of development or at a later point, codevelopment

should generally be conducted in a way that will facilitate obtaining 

contemporaneous marketing authorizations for the therapeutic product and the 

associated IVD companion diagnostic. 

Preclinical Early Pivotal

Therapeutic 

Product 

Development

IVD

Development

FDA CO

-APPROVAL

↓ ↓ ↓ ↓

8 
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

9 
Clinical Trial Design

• When a clinical trial is properly designed to establish 

the safety and effectiveness of a therapeutic product 

in a population based on measurement or detection 

of a marker, the results of the clinical trial can also 

be used to establish the clinical validity of the IVD 

companion diagnostic

• Considerations:

– Mechanistic rationale for selecting the marker

– The nature of the disease

– Level of characterization in the test-negative population

– Prospective-retrospective analyses 10
Biomarker Based Clinical Trial 

Designs 

+ Obtain information from all 

subjects

+ Assess predictive vs. 

prognostic

+ May include futility analysis

+ May stack enrollment toward 

biomarker positive (e.g., 80/20)

- Large trial

+ More efficient (if biomarker is 

predictive or prognostic)

+ Potentially exposes fewer 

patients to ineffective therapy

- May hinder enrollment

- No information about markernegative 11
Enrichment Strategies

• Draft guidance Enrichment Strategies for 

Clinical Trials to Support Approval of Human 

Drugs and Biological Products

– Published December 2012

– Guidance: 

http://www.fda.gov/downloads/Drugs/GuidanceCo

mplianceRegulatoryInformation/Guidances/UCM3321

81.pdf

– Webinar: 

http://www.fda.gov/Drugs/ucm343578.htm

12
Prospective-Retrospective 

Approaches 

• A prospectively-defined retrospective analysis of trial 

outcomes according to the test result

• Requires a pre-specified plan to collect specimens 

and analyze patient outcomes based on the IVD result

• Discuss acceptability of approaches with the FDA

13
Considerations for Identifying 

Intended Populations

• Ensure adequate representation of markers in study 

population

• Pre-specified cutoff values are essential for the 

analysis of use of the IVD in a clinical trial

14
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

15
Requirements for Investigational 

Products

• Both the therapeutic product and the IVD may be 

investigational

• Both have own regulatory requirements

– Therapeutic Product: Investigational New Drug, 21 CFR 312

– IVD: Investigational Device Exemption (IDE) Regulation, 21 CFR 

812

• Compliance with one set of requirements doesn’t 

fulfill compliance with the other

16
Investigational IVDs

• An IVD is investigational if used for a purpose that 

has not already received marketing authorization for 

that specific intended use 

• IDE regulatory requirements depends on the level of 

risk that its use presents to study subjects

– Exempt 

– SR or NSR

17
Investigational IVD 

Risk Determination

Is IVD 

exempt

from IDE 

requirements? 

Does IVD 

use pose 

significant 

risk as 

defined in 

21 CFR 

812.3(m)?

Approval of an IDE 

submission required 

prior to the trial 

proceeding 

Comply with abbreviated 

requirements, incl. 

provide IRB with 

explanation of why the 

IVD is not significant risk

For example:

•Used for exploratory 

purposes (not treatment 

decisions) or 

retrospective analyses

•AND uses non-invasive 

sampling

18

yes 

no
Submission of Information about 

the test

• Significant risk

– IVD information in IDE submission

– IDE can cross-reference other submissions to streamline

• Nonsignificant risk

– IDE submission not required

– If adequate test performance is necessary to interpret trial 

results, some IVD information may need to be included in IND

19
IDE submissions

• IVD cutoff value(s) 

• Preanalytical and analytical studies designed to 

demonstrate the reliability of the assay, particularly 

around the cutoff value(s) 

• Other analytical studies that support the conclusion 

that use of the IVD does not expose subjects to 

unreasonable risk of harm

• Clinical trial protocol

20
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

21
The test is important

• Problems with the test could:

– Compromise the ability of the trial to demonstrate an effect of 

treatment. 

– Compromise the ability to determine whether the test can 

appropriately identify the subjects for whom the therapeutic 

product is intended to provide benefit. 

22
Problems 

• Test not adequately analytically validated prior to 

use in trial

• Multiple tests with different performance used in 

trials

• Tests changed during trials

• Bias from prescreening

23
Some suggested solutions

• The FDA recommends making sure the IVD is 

analytically validated prior to use in clinical trials

– Sufficiently analytically robust, particularly around the test’s 

clinical decision point(s).

– You should complete analytical validation studies that evaluate 

critical performance parameters prior to using the test in a 

trial that is intended to provide the clinical validation.

– You should use test with “market-ready” performance in 

pivotal trials.

24
Some more recommendations

• Clinical Trials Assays (CTAs) should be fully specified 

– All components, protocols, instrumentation

• Use a single testing protocol at all sites

– Evaluate comparability of test results among potential sites 

prior to initiating testing at those sites

• Consider preanalytic reagents and instrumentation to 

be part of the test system and validate with the IVD

– Tools and reagents for DNA extraction, processing, etc. 

– Have SOPs for all steps

• You should not make changes to the test/SOP during 

the trial

25
Prescreening 

Recommendations

• Avoid enrolling subjects into a trial based on 

confirmation of a local test result. 

• Ask participating clinical sites to send forward 

specimens from all potential enrollees for testing 

with the trial test, not just positive prescreening.

• When unavoidable, be aware of the potential for 

bias, evaluate whether the expected prevalence of 

the marker is being skewed by prescreening, and 

develop approaches to adequately address potential 

selection bias.

26
Recommendations for Analytical 

Validation Studies to Support 

Submission

• Know what studies are relevant and plan ahead

– e.g., analyte stability studies 

• Collect and bank adequate samples

• Not all AV studies need clinical trial specimens 

– But should be same target population

– Validation studies with contrived samples are appropriate in 

some cases

27
Recommendations for 

Banking Samples

• Bank specimens for future AV studies, bridging 

studies

• Bank intent-to-diagnose population, not just enrolled

• Consider accessibility to samples in foreign countries

• Consider informed consent policies for all uses of 

samples (e.g., retesting)

• Thorough specimen annotation is needed

• Consider lability issues when storing specimens; may 

need to store purified/extracted analyte

28
Training vs. Validation

• The set of clinical samples used to design an IVD and 

establish the clinical decision point(s) and assay 

cutoff(s) is referred to as the “training set.” 

• Testing should be conducted with a second set of 

independent clinical samples and with the final IVD 

to validate (i.e., the “validation set”). 

• If changes are made to the IVD based on results from 

the validation set, then this dataset effectively 

becomes a new training set for the modified IVD, 

which should then be validated with an additional set 

of samples. 29
Recommendations for IVD 

Bridging Studies

• Statistical Plan to assess concordance and discordance 

between 2 tests using the same samples from trial 

subjects.

• Takes into account discordance, missing samples and 

effect on drug efficacy.

• Retest population should be representative of the 

intended use population for the device and adequately 

reflect the characteristics that affect test performance. 

• Re-analysis of the trial for effectiveness of device is 

potentially biased if subset not representative.

• Plan to analyze worst case scenario for missing data with 

sensitivity analysis. 30
The Pre-Submission Program

• As soon as you know there is codevelopment intent, 

we recommend using the Pre-submission Program for 

feedback about IVD issues

• Pre-sub program

– An opportunity to ask questions and conduct discussions 

• Clinical or analytical study protocol review

• Appropriate regulatory pathway

– A formal written request from a sponsor for FDA feedback 

31
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

32
Coordinating Review 

Timelines

• Submissions

– Drugs – New Drug Application (NDA)

– Biologics – Biologics License Application (BLA)

– CoDx will likely be Class III and require a Premarket Application 

(PMA) 

• Statutory timelines differ for therapeutic products 

and IVDs

• In practice, IVD review keeps to therapeutic product 

timelines 

– Therapeutic product expedited review/accelerated approval 

shorten timelines 33
What Helps Expedite 

IVD Review

• IVD priority review

• Modular PMA

– Allows issues to be identified & addressed along the way

– Manufacturing inspection – submit this module early

– BIMO inspection – organize information in the PMA

• Master Files

• Letters of Authorization

34
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

35
Labeling 

• Product labels should be consistent with each other

• IVD claims based on the trial design

– Prediction: supported by evidence that clinical benefit accrues 

only to, or primarily to, a population defined by the IVD result 

or that serious adverse reactions are confined to a population 

defined by the IVD result 

– Selection: trial designs in which only test-positive (or testnegative) subjects are selected for enrollment in a trial 

typically support IVD companion diagnostic claims for patient 

selection

– Monitoring: beyond guidance scope

36
Codevelopment Guidance

• General 

• Codevelopment Clinical Trials

• Requirements for Investigational Products

• IVD Development – Planning Ahead

• IVD Development in Later Stages of TP Development

• Coordinating Review 

• Labeling 

• Postmarket Considerations

37
Postmarketing Considerations 

• Consult the FDA when designing postmarketing

studies that involve codx. 

• For adverse events, report IVD problems to IVD 

center; therapeutic product problems to TP center. 

If not clear, or if both products could have 

contributed, report to both centers.

38
Key Points

• Use clinical trials strategy that provides evidence for 

TP and IVD; Read enrichment guidance

• Interact with the FDA early and often

• Plan ahead – collect specimens (annotate and store 

well) for AV studies, bridging studies

• Engage IVD partner as soon as possible

• Determine what IDE requirements apply to the 

investigational IVD

• Complete analytical validation studies before using 

IVD in trial

• Use test with “market-ready” performance in pivotal 

trials

39
Critical Points of the Codevelopment Process 

40
We Want Your Input

• Comments due October 13, 2016

• Docket # FDA-2016-D-1703

• Submit electronically at http://www.regulations.gov

• Submit written comments to Division of Dockets 

Management (HFA-305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 1061, 

Rockville, MD 20852. 

41
Q&A 

• Pamela Bradley, CDRH

• Sheryl Kochman, CBER

• Christopher Leptak, CDER

• Elizabeth Mansfield, CDRH

• Michael Pacanowski, CDER

42
Questions? 

Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

Slide presentation, transcript and webinar recording 

will be available at: 

http://www.fda.gov/training/cdrhlearn 

Under the heading-“In Vitro Diagnostics”

43