FDA’s Approach to Regulation of In Vitro Diagnostic Tests

Elizabeth Mansfield, PhDOIVD/CDRH/FDA

elizabeth.mansfield@fda.hhs.gov

Overview

• IVD regulation• Laboratory developed test policy

– IVDMIA– Revisit of policy

• RUO/IUO labeling• Personalized Medicine• Codevelopment/companion Dx

What FDA regulatesFFDCA Part 201(h) Devices• The term "device" (…) means an instrument, apparatus, implement,

machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is--– (1) recognized in the official National Formulary, or the United States

Pharmacopeia, or any supplement to them,– (2) intended for use in the diagnosis of disease or other conditions, or in

the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

– (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

IVDs are devices• 21 CFR 809.3(a)

– In vitro diagnostic products are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae.Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body. These products are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act.

IVD regulation Cliff Notes• Regulation by risk

– Risk defined by possible harm to patient of unrecognized incorrect result

– Three classes from high to low risk• Compliance with general controls

– Registration/listing, GMPs, premarket review, postmarket controls, etc

• Labeling– Instructions for use, etc.

Current Structure• Office of In Vitro Diagnostic Device Evaluation

and Safety (OIVD) in Center for Devices and Radiologic Health (CDRH

• Four review divisions– Chem/tox– Micro (virology/bacteriology)– Immunology/hematology– Radiology

• One Personalized Medicine Staff serves all divisions

Laboratory Developed Tests• Bifurcation in oversight of IVD devices

– FDA + CLIA– CLIA only

• LDTs (CLIA only pathway)– No record of who is offering what– No premarket review– No requirement for clinical validation– No postmarket requirements– Taking on higher risk, more complex tests

LDTs: the problem

• Can be used as a loophole– Bad, unvalidated, or fraudulent tests on

market with minimal control– High risk tests with unknown performance in

use• Creates an unlevel playing field

– Traditional Dx manufacturers have higher hurdle than LDT manufacturers

Enforcement Discretion

• LDTs: Currently, – Self-defined by labs– No way to know what’s out there– No regulatory definition of LDT– More-or-less blanket approach by FDA

Time for Change

• Blanket enforcement discretion no longer appropriate– risk-based approach to regulation

• Need to see what is being offered– No registry of LDTs exists

• Need an approach to regulation that serves public health

Public meeting on LDTs• FDA announces public meeting and intent to

make changes (FDA-2010-N-0274)– Public meeting July 19-20, 2010– Intent to establish risk-based oversight framework for

all tests– General expectations at this time

• Registration and listing period will be needed• Risk-based phase in (highest risk first)• Avoid disruption to access

– Low or no bar for certain tests (rare disease, etc)

The book is not written yet• Seeking input on:

– Risk assessment paradigm– Oversight mechanisms for LDTs

• Evaluation of necessary info to assure safety and effectiveness

• Encourage innovation• Avoid total disruption of marketplace• Provide fair field of play

– Timing

LDTs:Benefits/harms

• Possible benefits– Tests available for small populations– Rapid test development and deployment– May save system $$$

• Possible harms– Patients, healthcare providers relying on useless tests– Labs think they validate better than they really do– Puts traditional mfrs with controlled design, product

development, manufacture processes at disadvantage = they don’t play

Benefits/harms explored

• Emergency use authorization for H1N1 outbreak– Devices for diagnosing 2009 H1N1 needed

urgently– Device regulatory bar lowered– EUA not required to offer test– Multiple applicants from traditional and LDT

manufacturing sectors

2009 H1N1• FDA makes EUA template available with

minimum info/data requirements– “fill in the blanks” approach– Low data burden

• Result– Several devices deemed appropriate– Labs—more than one had improperly designed test

(already being offered), not enough validation– Mfrs—more than one “not ready for prime time”

IVDMIA

• FDA’s effort to ensure certain types of difficult-to-validate tests came under regulatory scrutiny– Easy to overfit data– Easy to introduce bias– Easy to choose incorrect validation strategy– Easy to get to market if an LDT

Problems We’ve Seen• Inappropriate sample size• Overfit data• Bias, bias, bias• Tests not independently validated• Lack of control mechanisms

– Reagents– Processes– Samples

RUO/IUO Labeling

• Manufacturers inappropriately marketing devices marked:– For research use only. Not for use in

diagnostic procedures (RUO)– For investigational use only. The performance

characteristics of this product have not been established (IUO)

Legitimate Uses of RUO/IUO

• RUO– Research to determine characteristics of

devices to be developed– Basic scientific research

• IUO– Controlled investigations to gather

performance data on products• Informed consent, IRB

RUO Inappropriate Marketing

• Labeling– Includes intended use

• See 21 CFR 801.4 on intent– Includes clinical information– Includes clinical interpretation guidelines– References diagnostic use

• Sold for clinical use

IUO Inappropriate Marketing

• Sold for clinical use outside investigation• “investigation” has no protocol, no ending

criteria

Novel Technologies• aCGH—public meeting on validation and

regulatory issues• Whole genome sequencing—still evolving

quickly• Proteomics—may offer new and

accessible markers• Highly multiplexed diagnostics—validation

and review timing issues

Personalized Medicine

• How will OIVD handle novel technologies• What is different about codevelopment• What are the regulatory requirements for

companion diagnostics• Other policy areas around emerging

diagnostic issues

Approach to Novel Issues• Different programs available

– VXDS: scientific discussion only; discuss discovery/science issues related to use in drug development, etc

• Not for regulatory issues• Not an early diagnostic meeting

– preIDE: early diagnostic consultation• CDRH program, but can add consults from other centers• Evaluation of validation plans in context of intended use

– Intended use– Analytical validation– Enrollment strategies– etc

Codevelopment

• “Coordinated” development of a drug with a diagnostic that identifies a specific treatment population– Response/non-response– Adverse events– Dose required for safety and efficacy– Population in which the drug was trialed

Regulatory Issues in Codevelopment

• Test and therapeutic review processes– Test subject to IDE/IND– Review of one or two applications?– Labeling

• Drug reference to FDA approved test• Device with specific intended use

• Approval– Intercenter agreement– Timing

• Change management– Test performance– Technology– Labeling

Codevelopment

• Codevelopment guidance– Most likely “non-directive” but providing

information about differences in approach for drug and diagnostic development

– Every drug/diagnostic combination will have different issues

– Planned draft publication in 2010– Not directly related to biomarker guidance

Codev guidance• Codevelopment guidance approach

– Will describe:• general principles and provide information• when a diagnostic must be available in order for drug (or new

label) to be approved• risk/benefit determinations around requiring or

recommending a diagnostic in labeling• recommendations for timing of diagnostic development in

drug development cycle• how drug and diagnostic performance evidence will be

reviewed

Companion Diagnostics

• Those diagnostic devices that are required in order to select appropriate patients for treatment with a therapy– Established performance of drug depends on

diagnostic test result– Known performance of diagnostic needed– Premarket approval indicated– Business model of test offering not critical

Other Issues

• RUO to IVD transition for instrumentation, reagents

• Intercenter coordination for codeveloped products

• Quality systems for laboratories

Thanks!

• Questions?• Elizabeth Mansfield• elizabeth.Mansfield@fda.hhs.gov• 301-796-4664