FDA’s new regulatory paradigms for in vitrodiagnostic devicesM Robinowitz and S I Gutman

Food and Drug Administration, Rockville, Maryland, USA

This is a summary of the FDA’s response to new statutory

requirements imposed by the US Congress through the

FDA Modernization Act (FDAMA) of 1997. Congress

intends to facilitate the development of new, safe and

effective drugs and medical devices by requiring the FDA

to accept the least burdensome route to market, consistent

with no decrease in the level of reasonable safety and

effectiveness. This will balance premarket review with

appropriate postmarket surveillance and increase the pre-

market interaction of the FDA with the manufacturers of

drugs and medical devices.

Appendices describing the role of the Center for Devices

and Radiologic Health of the FDA in the development cycle

of medical devices, and the overall benefits and disadvan-

tages of this regulation are given later.

Websites are provided for access to the original

documents from the FDA and through links to other

government agencies and stake-holders in medical products.

These can be viewed at: http://fda.gov (FDA as a whole),

[FDA Center for Devices and Radiologic Health (CDRH)]

http://fda.gov/cdrh.

In vitro diagnostic devicesIn 1938, Congress passed the Federal Food, Drug and

Cosmetic Act of 1938 (The Act). FDA was given ‘after-the-

fact’ authority, but Congress recognized that this was

inadequate. In 1938, there were very few types of medical

devices and these were brought under the regulation using

a drug model.

In 1976, Congress passed the Federal Food, Drug, and

Cosmetics Act Amendments to address the concerns that

medical devices required specific legislation and regulation.

Congress extended for the first time the regulatory authority

of the FDA to oversee manufacturers of all types of medical

devices. The FDA was given the authority to ensure that

medical devices will not be marketed in the USA unless there

is premarketing evidence that they are reasonably safe and

effective for their intended use.

In vitro diagnostic devices (IVDs) are considered medical

devices for regulatory purposes. They are defined as ‘‘an

instrument, apparatus, implement, machine, contrivance,

in vitro reagent or other similar article that is used for

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 in humans’’.

The FDA was given premarket review authority, i.e.

premarket notification [510(k)] and premarket approval

(PMA) application. It was instructed to classify medical

devices with the assistance of advisory panels. The definition

of ‘‘device’’ was amended to make it more distinct from

drugs. The FDA was also given additional regulatory power

[good manufacturing practices (GMP), reporting require-

ments, enforcement power].

510(k) is intended for new versions of well-established

IVD reagents, test kits, or test systems, that are substantially

equivalent to a legally-marketed IVD for the same clinical

intended use. PMA is required for IVD reagents, test kits, or

test systems that are novel and not well-established. The

IVD manufacturer sponsors adequate studies based on valid

scientific evidence to support the PMA. The FDA reviews

the study results, but does not repeat the studies. Then an

FDA advisory panel makes a recommendation for approval

or disapproval. The FDA Commissioner makes the final

decision.

The Safe Medical Devices Act of 1990(SMDA)The SMDA of 1990 expanded the 1976 authorities. SMDA

requires a clearance order before marketing a medical

device, a 510(k) summary or 510(k) statement, and Class

III certification and summaries.

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MedWatch and adverse event reportingIn 1993, a new unified FDA-wide post-market reporting

system, MedWatch, was established, so that adverse

reactions to any drug or medical device can be reported on

a 24h basis, with minimal paperwork from any healthcare

provider. MedWatch can be reached through http://

www.fda.gov.mdrforms.htm, telephone in the USA is (800)

FDA-1088, fax 800 FDA-0178.

In 1996, the FDA broadened its mandatory require-

ments for reporting serious device failures, i.e. failures

causing death or likely to be life-threatening to make the

reporting as timely as possible. Now healthcare professionals

and healthcare facilities are required to report to the FDA, in

addition to the existing reporting requirements for medical

device manufacturers.

FDAMAFDAMA authorizes the FDA to issue exemptions from

active regulation for some low-risk medical devices. FDA, in

response to FDAMA, has adopted re-engineering and

reform measures, to update the classification of medical

devices according to a risk-based approach.

Risk is defined as the probability of occurrence of a hazard

which may expose a patient to harm. For in vitro diagnostic

laboratory tests, hazards are the consequences resulting from

false positive, or false negative test results. The FDA is

actively reassessing and updating the existing Class I, II, and

III (low, moderate and high-risk respectively) for each type of

IVD. The result is that some low risk products have been

removed from active regulation. Manufacturers of exempted

devicesmust comply with general controls, but do not have to

submit 510(k) applications. FDA and the medical device

industry can now use these resources to focus on higher risk

products, without any unreasonable lowering of the level of

assurance of safety and effectiveness for IVDs.

FDA down-classified some class III IVDs because they

are sufficiently well-characterized by scientifically-valid

information to support clearance by premarket notifications

[(510(k)] and no longer require PMA. These down-classified

IVDs have guidelines or standards in place that can serve as

special controls. They include immunohistochemistry kits

and serum tumor markers for monitoring the recurrence of

tumors and response to therapy.

Analyte Specific Reagent RuleAlthough the FDA has the authority to regulate clinical

laboratories that develop house-developed IVDs (home-

brew tests) as manufacturers of medical devices, it has chosen

not to regulate clinical laboratories as manufacturers.

Instead, the FDA has issued the Analyte Specific Reagent

Rule (ASR), which became effective on November 23, 1998.

FDA’s goal for the ASR Rule is to encourage the develop-

ment, manufacture, marketing, and distribution of the major

components of in-house (home-brew) assays that will be

reasonably safe and effective as the major building blocks of

in-house developed test systems.

ASRs are defined as ‘‘antibodies, specific receptor

proteins, nucleic acid sequences, and similar biological

reagents which through chemical binding or reaction with

substances in specimen are intended for identification and

quantification of an individual chemical substance or ligand

in biological specimens.’’ These are the active ingredients

that can be used to develop and run an in-house in vitro

diagnostic test.

The ASR Rule clarifies the regulatory status of in-house

tests. Only the minimum level of regulations will be required

for ASRs because they will be made in compliance with the

FDA’s Quality Systems Regulations (QSR) and the perfor-

mance characteristics of the finished test system will be the

responsibility of the clinical laboratory director.

The ASR Rule does not apply to finished test-kits or test-

systems. It does not apply to research-use-only (RUO) or

investigational-use-only (IUO) reagents, nor to all or parts

of RUO, or IUO test-kits or test-systems.

FDA’s ASR Rules require manufacturers to:

n Register and list.

n Meet Quality System Requirements (QSRs) which

include good manufacturing practices.

n Report adverse events.

n Restrict distribution, use, and labeling of the ASRs.

n The safety and effectiveness of ASRs has not been

established so no performance claims will be allowed in

the product labeling.

The ASR Rule is a response to the following assump-

tions. In-house-developed laboratory tests are performed

commonly for a variety of tests. In-house tests in the USA

must be performed in compliance with CLIA regulations for

personnel standards, record keeping and documentation of

test-performance characteristics. In most instances, this

limits the development of in-house test systems to high

complexity clinical laboratories.

Use of ASRs is limited to clinical laboratories that meet

the CLIA designation of a high-complexity laboratory. FDA

354 M Robinowitz and S I Gutman

requires that laboratories use ASRs in their in-housedeve-

loped test systems. The exception is if the reagent that meets

the definition of ASR is made within the laboratory itself and

is not from a commercial or non-commercial source outside

of the laboratory. FDA requires that the test report sent to

the patient’s clinician for an in-house-developed test system

must include the following mandatory disclaimer statement:

‘‘This test was developed and its performance characteristics

were developed by (Laboratory Name). It has not been

cleared or approved by the US Food and Drug

Administration.’’

FDAs ASR Rules allow an explanatory discretionary

statement by the clinical laboratory director to accompany

the mandatory disclaimer. For example, the FDA allows

inclusion of the following statement drafted by the College

of American Pathologists: ‘‘This test does not require FDA

approval’’. These statements document that the responsi-

bility for development of the test system and validation of

the performance characteristics are the responsibility of the

clinical laboratory and not that of the manufacturer.

Research use only andinvestigational use only reagents,test kits and test systems‘‘Research Use Only’’ (RUO) reagents, test kits and test

systems are not ASRs. RUOs are intended for basic scientific

studies. They are not to be used for patient diagnosis or

management because the safety and effectiveness of these

products has not been established. FDA does not regulate

research products and does not require that manufacturers

of RUOs comply with QSR good manufacturing practices.

FDA restricts manufacturers of RUOs from making any

claims for clinical performance in labeling or advertisements

and they are required to label their products ‘‘For Research

Use Only. Not for use in diagnostic procedures’’. RUO

products may be used in laboratory research that is entirely

unrelated to the development of IVDs, or RUOs may be the

first phase in the development of an IVD that will be

commercialized.

‘‘Investigational Use Only’’ (IUO) reagents, test kits,

or test systems are intended to be used only in a limited

number of applied scientific studies to establish, under

protocol, the safety and effectiveness of these products.

These studies are part of the support for premarketing

clearance or approval by the FDA. IUOs may be used for

patient diagnosis and management only if a confirmatory

test or clinical procedure is used for the patient diagnosis

and management. During the premarketing phase, manu-

facturers of IUOs are not required to be under QSR good

manufacturing practices.

FDA’s Compliance Policy Guide (CPG)FDA’s Center for Devices and Radiologic Health Office for

Compliance has developed a Compliance Policy Guide

(CPG) to establish boundaries for the use of RUO and

IUO reagents, test kits and test systems which can be seen at

http://www.fda.gov/cdrh/comp/ivddrfg.html. The intent of

the CPG is to not impede medical research, while assuring

reasonable safety and effectiveness for in vitro diagnostic

reagents, test kits and test systems used for patient diagnosis

and management. The CPG will not become a final rule

until the end of a phase-in period for IVD manufacturers

and clinical laboratories.

Labeling of FDA-cleared andapproved in vitro diagnostic testkits and test systems‘‘For In Vitro Diagnostic Use’’ is the product label

allowed by FDA regulations for in vitro diagnostic reagents,

test kits and test systems that have been cleared or approved

by the FDA in the package insert, user manual, and

advertising. FDA requires that cleared and approved

IVDs comply with the labeling regulation 21 CFR 809.10.

(http://www.fda.gov/cdrh) This includes the intended

use/indications for use of the device, performance charac-

teristics (accuracy, precision, sensitivity, and specificity), test

protocol, expected values and limitations of the test.

FDA’s new regulatory paradigms for in vitro diagnostic devices 355

Appendix 1 The development cycle fordiagnostic medical devices

Table 1. The six-tiered model: a conceptual con-

tinuum for efficacy (Modified from Thornbury-

Fryback)[1]

Level 1. Technical efficacy: the design specifica-tions of the device.

Level 2. Diagnostic accuracy efficacy: the analyticperformance with ideal specimens andspecimens from the target population.

Level 3. Diagnostic thinking efficacy: the influ-ence of the test result on the differentialdiagnosis of the clinician.

Level 4. Therapeutic efficacy: the influence of thetest result on the selection of therapy andmanagement of the patient.

Level 5. Patient outcome efficacy: the benefit ofthe test result to the clinical outcome ofthe individual patient, e.g., quality of life,morbidity, mortality.

Level 6. Societal efficacy: the benefit of the testresults to society weighed against othertechnologies and requirements of societyas a whole.Successful performance for each levelrequires success at the previous level.FDA review for lVD test kits requiresdocumentation of Levels 1 and 2.

If sponsors want to promote claims for Levels 3, 4, and/or 5, theseclaims must be supported by valid scientific evidence. The FDAdoes not have statutory authority to perform technologicalassessments to support Level 6.

Appendix 2 FDA’s Center forDevices and Radiologic HealthBenefits of FDA regulation of in vitro diagnosticdevicesOffice of device evaluation

n Scientific review of Manufacturer’s premarket submis-

sions and claims—not bench testing or repeat trials.

Objective review.

n Controls for conflicts of interest.

n Organized data gathering.

n Setting thresholds.

n Single market/level playing-field.

Office of compliance

n Enforcement of statutes and regulations.

n Oversight of medical device industry.

n Truth in labeling.

n Quality systems (QSR) incorporating good manufactur-

ing practices (cGMP).

n Global harmonization.

Office of surveillance and biometrics

n Post-market surveillance.

n Quality systems for good manufacturing practices

(cGMP).

n Medical device reporting by manufacturer.

n MedWatch mandatory reporting by institutions and

practitioners.

n Voluntary reporting by public.

n Post-market discretionary studies.

Disadvantages of FDA regulationn Delays marketing.

n Financial costs to conduct studies and prepare sub-

mission.

n Financial cost to prepare for GMP inspections.

n Good products may never be invented, developed or

commercialized.

Statutory limitations to FDA regulation ofmedical devicesn No cost-benefit analyses,

n No technology assessments comparing a new device with

alternative devices, or procedures.

n Usually the endpoint in the premarket studies is a

surrogate marker, rather than the clinical outcomes of

death and/or morbidity.

n No review of off-label uses of cleared or approved

devices.

n No regulation of non-commercialized home-brew or

in-house developed devices that are not intended

to be marketed outside the site where testing is

performed.

Appendix 3 Basis of FDA’sdetermination of the safety and effec-tiveness of in vitro diagnostic devices[21 Code of FederalRegulations (CFR) 860.7](http://www.fda.govlcdrh)The FDA relies upon only valid scientific evidence to

determine whether there is reasonable assurance that a

356 M Robinowitz and S I Gutman

medical device is safe and effective. Valid scientific evidence

is evidence from well-controlled investigations, partiallycon-

trolled studies, studies and objective trials without matched

controls, well-documented case histories conducted by

qualified experts and reports of significant human experience

with a marketed device, from which it can fairly and

responsibly be concluded by qualified experts that there is

reasonable assurance oE the safety and effectiveness of a

medical device under its conditions of use.

The evidence required by the FDA may vary according

to the characteristics of the medical device, including its

reliability, conditions of use, the existence and adequacy of

warnings and other restrictions, the extent of experience

with its use, and the level of education and training of the

intended user.

Isolated case reports, random experience, reports lacking

sufficient details to permit scientific evaluations and unsub-

stantiated opinions are not regarded as valid scientific

evidence to show safety or effectiveness. Such information

may be considered, however, in identifying a device that has

questionable safety and effectiveness. There is reasonable

assurance that a device is safe when it can be determined,

based upon valid scientific evidence, that the probable bene-

fits to health from use of the device for its intended uses and

conditions of use, when accompanied by adequate directions

and warnings against unsafe use, outweigh any probable

risks.

Among the types of evidence that may be required, when

appropriate, to determine that there is reasonable assurance

that a device is safe, are investigations using laboratory

animals, investigations involving human subjects and non-

clinical investigations, including in vitro studies. The safety

of a diagnostic medical device is determined by the

likelihood that the device will lead to a true result when

used according to the manufacturer’s intended use and

indications for use. Examples of intended uses of diagnostic

medical devices include screening of asymptomatic indivi-

duals, diagnosis of individuals with signs or symptoms of a

disease, confirmation of a diagnosis, prediction of therapeu-

tic response, or prognosis of natural history of disease, or

determination of risk factors of disease.

FDA’s determination of the effectiveness

of IVDs (21 CFR 860.7)

There is reasonable assurance that a device is effective when

it can be determined, based upon valid scientific evidence,

that in a significant portion of the target population, the use

of the device for its intended uses and conditions of use,

when accompanied by adequate directions for use and

warnings against unsafe use, will provide clinically-signifi-

cant results. The valid scientific evidence used to determine

the effectiveness of a device shall consist principally of well-

controlled investigations, unless the FDA Commissioner has

determined there is sufficient evidence from which to

determine the effectiveness of a device even in the absence

of well-controlled investigations. The effectiveness of a

medical device refers to how well the device performs under

average conditions of use according to the manufacturer’s

labeling (instructions, recommendations, promotions, etc.).

Effectiveness goes beyond efficacy, which is defined as the

performance of a therapy or medical device under ideal

conditions.

The essentials of a well-controlled clinical

investigation (21 CFR 860.7)

FDA considers principles that have been developed over

a period of years and are recognized by the scientific

community as the essentials of a well-controlled clinical

investigation. These principles provide the basis for the

FDA Commissioner’s determination whether there is

reasonable assurance that a device is effective based

upon well-controlled investigations and are also useful in

assessing the weight to be given to other valid scientific

evidence.

Reference1 Thornbury-Fryback National Council on Radiation Protection

and Measurements. Bethesda, MD, 1995.

FDA’s new regulatory paradigms for in vitro diagnostic devices 357