Path Forward from the Recent FDA Workshop - Using MS for

Path Forward from the Recent FDA Workshop - Using MS for Proteomic

and Peptide Analysis

Doug Jeffery, Ph.D.

U.S. Food and Drug AdministrationCenter for Devices and Radiological Health (CDRH)

Office of In Vitro Diagnostics and Radiological Health (OIR)Division of Immunology and Hematology (DIHD)

doug.jeffery@fda.hhs.gov240-402-6648 1

October 5, 2016

FDA Organizational Structure

Office of the Commissioner

Legal and Legislative

Offices

Policy and Management

Offices

CVMCFSANNCTRCTP CBER CDERCDRH

OEROSBOSELODE OIR OMOOC

Office of In Vitro Diagnostics and Radiological Health

Office of Device Evaluation

June 13, 2014

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History of FDA Outreach with the Clinical LC-MS Community

Mock Pre-Submissions

Attendance and Presentations at

LC-MS Conferences:

AACC, AACC/MSSS,

MSACL, HUPO, ASMS

FDA/CDRH Mass Spectrometry Interest Group

Scientific Seminar Series

- Nine speakers in 2015/2016 from Academia and Industry talking about clinical applications of LC-MS

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*http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm486484.htm

**https://www.regulations.gov/docketBrowser?rpp=25&po=0&dct=PS&D=FDA-2016-N-0610&refD=FDA-2016-N-0610-0002

Please visit the website (link* below) to find the following:

o Agenda and Speaker Listo Archive of Webcast, including video

and audio of the entire dayo Written transcript of entire workshopo Speaker Presentationso FDA Discussion Paper o Public Comments**

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“The goal of this public workshop is to facilitate discussion with the clinical LC-MS community around specific analytical questions pertaining to the validation of LC-MS-based in vitro diagnostic products (IVDs) that identify and/or quantify specific proteins and peptides”

Goal of the Workshop

FDA/CDRH/OIRSponsor

ManufacturerDeveloper

Communication

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Speakers and Topics Presenter Affiliation Topic

Andy Hoofnagle University of Washington Keynote: Using MS to Help Patients

Chris Shuford Laboratory Corporation of America

Peptide Selection and Digestion

Jeff Whiteaker Fred Hutchinson Cancer Research Center

Affinity Enrichment of Peptides and Proteins

Mark Lowenthal National Institutes of Standards and

Technology

Selection of Calibrators and Internal Standards

Jarrett Egertson University of Washington Skyline: A Platform for Targeted Assay Development and Execution

Randy Julian Indigo Bioautomation Software Requirements for Real-World Clinical Settings

FDA Invited Speakers FDA Regulatory Considerations for Instruments and Software; Overview of Regulatory Processes and FDA Submissions

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Panel One DiscussionPanel Member Affiliation

Lorin Bachmann Virginia Commonwealth University

Cory Bystrom Cleveland Heart Lab

Dan Chan Johns Hopkins University

Russ Grant Laboratory Corporation of America

Andy Hoofnagle University of Washington

Alan Rockwood ARUP Labs

Ravinder Singh Mayo Clinic

Victoria Zhang University of Rochester

The panel addressed six questions posed by the FDA to stimulate discussion of analytical validation of LC-MS

assays in their labs

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Brief Review of the Discussion Paper

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Topics in Discussion Paper

o Precision/reproducibilityo Linearity o Carryovero Detection limit (LoB, LoD, LoQ)o Analytical specificityo Critical IVD components (instruments, reagents)o Calibrators, controls and internal standardso Comparator methods

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CDRH-Recognized Guidelines for IVDsClinical and Laboratory Standards Institute (CLSI)

Use of CDRH-recognized guidelines can make performance testing and submission review faster and more efficient

Precision Analytical Sensitivity

AND MANY MORE!http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

Liquid Chromatography-Mass Spectrometry Methods

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General Recommendations for Analytical Performance Testing

Use Recognized CLSI Guidelines

Use Real Patient Samples from the Intended Use

Population

Test Samples that Cover the Analytical Measuring Range

and at Medical Decision Points

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Panel One Discussion Questions

Panel Members

Lorin Bachmann

Cory Bystrom

Dan Chan

Russ Grant

Andy Hoofnagle

Alan Rockwood

Ravinder Singh

Victoria Zhang

1. Are study designs for validation different for LC-MS devices? What about for multiplexed LC-MS devices?

2. How do you re-validate assays after changing a key component?

3. What are appropriate internal standards, calibrators, and controls for LC-MS devices?

4. What types of method comparison studies do you perform?

5. How are raw data and processed data managed?

6. How do you evaluate and control sample collection and handling?

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Are study designs for validation different for LC-MS devices? What about for multiplexed LC-MS devices?

a. Tests should be fit for purposeb. Tests should be robust enough for validation just like any other

type of assay c. Individual analytes should be independently validated in a

multiplexed test

Panel Question #1

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How do you re-validate assays after changing a key component?

a. Critical components need to be identified during test development

b. A change in critical components, e.g., new LC column or antibody, probably requires full re-validation

Panel Question #2

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What are appropriate internal standards, calibrators, and controls for LC-MS devices?

a. As with any test, internal and external standards are fit-for-purpose, controls matrix-matched

b. Traceability and value assignment key for calibrators and controls

Panel Question #3

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What types of method comparison studies do you perform?

When possible, a method comparison is done, but LC-MS assays don’t always agree with immunoassays

Panel Question #4

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How are raw data and processed data managed? What information should be part of a submission to the FDA?

It is important to provide all the raw and processed data so that users of the test can evaluate the data

Panel Question #5

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How do you evaluate and control sample collection and handling?

a. Appropriate sample handling depends on how and where the sample is collected and what the analyte is

b. Tube type can affect the performance of the test

Panel Question #6

Conclusion and Next Steps

1. We plan to publish a workshop review paper2. We continue our outreach efforts with the

clinical LC-MS community3. Please come and talk with us!

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Thanks to:

• Speakers and Panelists• Workshop organizing committee:

o Julia Lathrop, DIHDo Yvonne Shea, DMDo Matt Humbard, DCTDo Jinong Li, DCTD

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