US Regulation of In Vitro

Diagnostic Devices (IVDs)

SoGAT- Clinical Diagnostic

NIBSC, June 25, 2008

Francisco Martínez Murillo, PhD

Office of In Vitro Diagnostic Device Evaluation (OIVD)

Center for Devices and Radiological Health (CDRH)

US Food and Drug Administration (FDA)

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Highlights

• Regulatory process

• Device requirements

• Review challenges

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FDA’s Mission

Get safe and effective

devices to market as

quickly as possible

Ensure that devices

on the market are

safe and effective

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• Class I: common, low risk devicese.g., vitamin A deficiency test

– General Controls

– Most exempt from premarket submission

Risk-Based Regulation of IVDs

Substantial Equivalence

Safe & Effective vs Pred.

510(k) sect. of the Act

Evidence of Safety and Effectiveness

Impact on patient

Controlled clinical trials

Device stands on its own

• Class II: moderate riske.g. prognosis, monitoring in already diagnosed

cancer patients

– Special Controls

– Premarket Notification [510(k)]

• Class III: most complex, highest riske.g. cancer diagnosis or screening

– Safety, effectiveness, supported by valid scientific evidence

– Premarket Approval [PMA]

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General & Special Controls

• General Controls– Register and List

– Follow cGMP

• Design Control

– Report device failures

– System for remedying

device failures

• Special Controls– Premarket notification

– Guidelines/guidance

– Performance standards

– Tracking requirements

– Postmarket surveillance

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Key Elements of a Submission

• Intended use/indications for use

• Device description

• Analytical validation

• Clinical validity/clinical utility

• Instrument and software validation, if applicable

• Labeling (package insert)

• Manufacturing, design controls, quality system

requirements (QSRs/cGMP) (For PMA)

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Major Review Issues

• Analytical performance– How reliably and correctly test measures analyte

• Clinical performance– How reliably test measures clinical condition

• Labeling– Intended use, directions for use, warnings, limitations,

interpretation of results, performance summary

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Challenges for the Review

• Lack of “gold standards”/performance standards

• Cutting edge new technology - multiplex, bioinformatics, nanotechnology

– Paucity of standard methods and materials

• New biological/clinical knowledge

– Changes in practice of medicine

• Overt and latent bias

• Issues of traceability

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IVDs and Standards

• Determination of analytical sensitivity

• Viral load/NAT detection vs. infectivity

• Determination of IU vs. SI

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Lack of Standards/Ref. Materials

• Microbiology

– TB (NAT and infectivity)

– Malaria, WNV. Parasites (Chagas, Trypanosomiasis)

– CMV, EBV, VZV, HSV

• Chemistry

– Glucose

– Troponin

• Immunology

– PSA/AFP (for low level)

– Other specific cancer, allergen, autoimmune marker

– Copy number

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Current Tentative Solutions

• Analytical calibration related to infective units

• Clinical performance referred to a cleared device

• Clinical performance related to clinical truth

(clinical trial outcome)

• Use of consensus of literature

• Composite reference + other lab tests/clinical history

• Use of recognized reference panels (CDC)

• Generation of Standards by accredited organization

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Quest for Standards

• Standards already in documentation

– Founding member of NCCLS (CLSI)

– QSReg (21 CFR 820) (~ISO 13485/9100)

• Traceability-Commutability-Robustness

• Working with NIST

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Handling the Challenges

• Regulatory trail is well lit - Literature, Guidance

• Broad menu of flexible regulatory tools

- Pre-IDE - Exempt

- IDE - de novo

- 510(k) - Real time

- PMA - Expedited

• Review not outcome oriented

• Mandate to be least burdensome

• New scientific resources/programs

• Evidence, risk, and knowledge base

Eye on Public Health

Risk-Based Regulation

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Transparency

www.fda.gov/cdrh/oivd

www.fda.gov/cdrh/devadvice

• Guidance

– Documents/Recommendations

• Regulation

– Device Requirements

• Databases

– 510(k)/PMA/GGP/CLIA

e-mail: Francisco.Martinez@fda.hhs.gov

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Supplementary Information

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FREQUENTLY USED WEBSITES – June 2007

21 CFR Parts 1 - 1499 www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm

510(k) Paradigm www.fda.gov/cdrh/ode/parad510.html

CDRH Databases www.fda.gov/cdrh/databases.html

CDRH Home Page www.fda.gov/cdrh/

Code of Federal Regulations (CFR) www.fda.gov/cdrh/devadvice/365.html

Consumer Information/CDRH www.fda.gov/cdrh/consumer

Device Advice www.fda.gov/cdrh/devadvice/

Device Specific Contacts www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfReferral/referral.cfm

Device Standards Program www.fda.gov/cdrh/stdsprog.html

DSMICA Staff Directory www.fda.gov/cdrh/dsma/dsmastaf.html#contents

Electronic Products Radiation Control www.fda.gov/cdrh/radhealth/

Establishment Registration and U.S. Agent www.fda.gov/cdrh/devadvice/341.html

Export of Medical Devices from U.S. www.fda.gov\cdrh\devadvice\39.html

FDA Home Page www.fda.gov/

FDA’s Centers Small Business Contacts www.fda.gov/ora/fed_state/Small_Business/sb_guide/centerco.htm

Federal Food, Drug, and Cosmetic Act www.fda.gov/opacom/laws/fdcact/fdctoc.htm

Global Harmonization www.ghtf.org

Good Guidance Practices (GGP) www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfggp/search.cfm

Index of CDRH Web Documents www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/topicindex/topindx.cfm

International Program www.fda.gov/cdrh/international/

Medical Device Exemptions www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm

Medical Device Foreign Regulators www.ita.doc.gov/td/health/regulations.html

Medical Device Listing www.fda.gov/cdrh/devadvice/342.html

Medical Device Reporting Home Page www.fda.gov/cdrh/mdr/index.html

Medical Device User Fee and Modernization www.fda.gov/cdrh/mdufma

Act of 2002 (MDUFMA)

MEDWATCH www.fda.gov/medwatch/index.html

Premarket Approval http://www.fda.gov/cdrh/devadvice/pma/

Premarket Notification (510(k)) www.fda.gov/cdrh/devadvice/314.html

Quality Systems www.fda.gov/cdrh/devadvice/32.html

Reuse of Single Use Devices www.fda.gov/cdrh/reprocessing/

Third Party Inspection Programs www.fda.gov/cdrh/ap-inspection/index.html

Third Party Review Program www.fda.gov/cdrh/thirdparty

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FDA Guidance Documents

• Factor V Leiden DNA Mutation Detection Systems – March 2004http://www.fda.gov/cdrh/oivd/guidance/1236.html

• Instrumentation for Clinical Multiplex Test Systems – Class II Special Controls Guidance Document – March 2005http://www.fda.gov/cdrh/oivd/guidance/1546.html

• Drug-Diagnostic Co-Development Concept Paper – April 2005http://www.fda.gov/cder/genomics/pharmacoconceptfn.pdf

• RNA Preanalytical Systems (RNA Collection, Stabilization and Purification Systems for RT-PCR used in Molecular Diagnostic Testing) -- September 2005. http://www.fda.gov/cdrh/oivd/guidance/1563.html

• CFTR Gene Mutation Detection Systems – October 2005. http://www.fda.gov/cdrh/oivd/guidance/1564.html

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FDA Guidance Documents

• RNA Preanalytical Systems (RNA Collection, Stabilization and Purification Systems for RT-PCR used in Molecular Diagnostic Testing) -- September 2005. http://www.fda.gov/cdrh/oivd/guidance/1563.html

• CFTR Gene Mutation Detection Systems – October 2005. http://www.fda.gov/cdrh/oivd/guidance/1564.html

• Pharmacogenetic Tests and Genetic Tests for Heritable Markers – February 2006. http://www.fda.gov/cdrh/oivd/guidance/1549.html

• Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable – April 2006. http://www.fda.gov/cdrh/oivd/guidance/1588.html

• In Vitro Diagnostic Multivariate Index Assays – September 2006. http://www.fda.gov/cdrh/oivd/guidance/1610.html

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FDA Guidance Documents

• Quality Control Material for Cystic Fibrosis Nucleic Acid Assays – January 2007. http://www.fda.gov/cdrh/oivd/guidance/1614.html

• Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests – March 2007. http://www.fda.gov/cdrh/osb/guidance/1620.html

• Gene Expression Profiling Test system for Breast Cancer Prognosis – May 2007.

http://www.fda.gov/cdrh/oivd/guidance/1627.html

• Drug Metabolizing Enzyme Genotyping System - Class II Special Controls Guidance Document

http://www.fda.gov/cdrh/oivd/guidance/1551.html

• In Vitro Diagnostic (IVD) Device Studies – Frequently Asked Questions

http://www.fda.gov/cdrh/oivd/guidance/1587.html

• Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices

http://www.fda.gov/cdrh/ode/guidance/337.html