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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)
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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