Introduction . . Pg 1

Nature, Scope, & Purpose . . Pg 1

Definition . . Pg 1

Exemptions from 21 CFR 812 . . Pg 1

Labeling Requirements. . .Pg 2

Prohibited Labeling Information . . Pg 2

Specimen Testing & Sampling Reqmnts. . .Pg 2

The Sponsor's Investigational Plan . . Pg 3

Proposed Intended Use of the IVD and

Clinical Data . . Pg 4

Performance Characteristics and the

Clinical Data . . Pg 5

Factors Affecting the Quality of the Results of

the Clinical Investigation . . Pg 5

Conclusion . . Pg 5

References . . Pg 6

The purpose of this document is to provide

a written reference for Food and Drug

Administration (FDA) Investigators conducting

bioresearch monitoring (BIMO) inspections

involving in vitro diagnostic (IVD) devices. The

following material presents key aspects of

existing compliance approaches to BIMO IVD

inspections.

This guide was prepared by the FDA, Office

of Regulatory Affairs (ORA) and the Center for

Devices and Radiological Health (CDRH) with

input from the Center for Biologics Evaluation

and Research (CBER).

The purpose of bioresearch monitoring

inspections is to ensure that data and

information contained in premarket applications

are scientifically valid and accurate. Another

objective of the program is to ensure that

human subjects are protected from undue

hazard or risk during the course of scientific

investigations. Legal authority for these

inspections is found in Section 704 of the

Federal Food, Drug and Cosmetic Act (the Act)

which gives FDA authority to inspect facilities

where devices are "held."

IVD 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 Act.

Section 21 CFR 812.2(c)(3) exempts

investigations of IVD devices from the specific

regulations of 21 CFR 812, Investigational

Device Exemptions, under certain conditions.

Furthermore, because these are clinical

investigations, good laboratory practices (GLP)

regulations do not apply and should not be

used as a basis for citations on the form

FDA-483. Although the design control section

of the Quality System Regulation applies to

investigational devices, Quality System

Regulation deviations should only be cited

during Quality System Regulation inspections.

In order to be exempt from 21 CFR 812 the

sponsor must comply with the labeling

requirements of 21 CFR 809.10(c) and the

testing requirements of 21 CFR 812.2(c)3).

IVDs shipped solely for research purposes

must be labeled: "For Research Use Only, Not

for use in diagnostic procedures." If an IVD is

labeled "For Research Use Only," the research

that may be performed is limited to the

laboratory research phase needed to identify

test kit methods, components, and analytes to

be measured. An IVD labeled for research use

as described above is mislabeled if used for a

clinical study for even one patient if the results

are reported to the patient's physician or to

the patient's medical records. Research use

devices are not to be used to assess the

patient's condition regardless of whether or not

a confirmatory test or procedure is used.

IVDs shipped for clinical investigations must

be labeled: "For Investigational Use Only. The

performance characteristics of this product

have not been established. The regulations

define an investigation as a clinical investigation

or research involving one or more subjects to

determine the safety or effectiveness of a

device. (See draft CPG Commercialization of

In Vitro Diagnostic (IVD) Devices Labeled for

Research Use Only or Investigational Use Only,

dated January 5, 1998. This CPG will not be

implemented until finalized).

Labeling cannot include any representation

that the IVD is safe or effective because this is

a determination that only the FDA can make

based on the review of data gathered through

the clinical investigation and supplied by the

sponsor to FDA.

Labeling cannot include performance

characteristics or expected range because they

will be established by the research and/or

clinical investigation.

The testing must be noninvasive, must not

require an invasive sampling procedure that

presents significant risk, must not introduce

energy into the patient, and must not be used

as a diagnostic procedure without confirmation

of the diagnosis by an established diagnostic

product or procedure.

21 CFR 812.3(k) defines noninvasive devices

or procedures as those that do not penetrate

or pierce the skin, mucous membranes, ocular

cavity or urethra or do not enter body orifices

beyond specified limits. However, the

regulation defines simple venipuncture to obtain

blood specimens and the use of surplus samples

of body fluids or tissues left over from samples

taken for non-investigational purposes as

noninvasive.

Procedures like amniocentesis, lumbar

puncture, and tissue biopsy, are examples of

invasive sampling procedures that present

significant risk. If they are performed solely for

the investigation, then the IVD would not be

exempt from the IDE regulations. If samples

from these procedures are left over from

samples originally taken for non-investigative

purposes, then the sampling is considered

noninvasive. However, the initial procedure

should have been indicated for the patient's

condition by current medical practice and not

performed to obtain specimens surreptitiously

for the clinical investigation.

In order to be exempt from 21 CFR 812,

the investigational device cannot be used as a

diagnostic procedure without confirmation of

the diagnosis by another, medically established

diagnostic product or procedure. Disease

diagnosis usually involves a number of

observations and factors including signs and

symptoms, medical history, and a battery of

tests. There are few tests that are

pathognomonic, i.e., are considered "gold

standards," for diagnosis of a disease and,

therefore, the diagnosis is established from a

number of factors. Moreover, a sponsor or

investigator may consider the investigational

IVD to be more accurate, precise, sensitive,

specific, etc., than current medically established

products or procedures. This is generally the

goal for producing a new product.

Nevertheless, the diagnosis itself must be

confirmed in the established way to meet the

requirements for exemption from the IDE

regulation.

In order to obtain valid scientific data to

support its submission to the FDA and to

maintain the integrity of that data, the sponsor

should have an investigational plan including a

protocol or other effective means to

communicate procedures, etc., to its

investigators. Non-adherence to such a

protocol should be noted on an FDA 483.

Purpose:

The purpose of the plan is to establish and

support claims and information in proposed

labeling, including intended use; statements

about reagents, instruments, and specimens; the

procedure; limitations of the procedure;

expected values; and specific performance

characteristics; and to support a determination

of safety and effectiveness and/or substantial

equivalence.

Description:

Such a study must be carried out in a

scientifically sound manner. Therefore, to

assure useful results and the integrity of the

data and to be able to present their plan to an

Institutional Review Board (IRB), the sponsor

should develop an investigational plan. A good

plan will include all information, procedures,

reporting forms, etc., required by the clinical

investigator to gather valid data for the sponsor

to submit to FDA. These would include such

things as a statement of purpose, a protocol, a

description of the device, monitoring

procedures, labeling, consent materials, IRB

information, and additional records and reports.

Additional records could include a certification

program that ensures that the sponsor is

controlling the distribution of the investigational

and/or research device and is using it in

scientifically sound research and investigations.

The investigator should sign an investigator's

agreement acknowledging his/her

responsibilities.

At this phase there should be no

promotional/advertising material.

Advertisements to recruit subjects should be

reviewed by the IRB to ensure that information

is not misleading and that patient's rights and

welfare are protected.

IRB and Informed Consent:

The IRB must review and approve the

protocol and consent materials before the

study can begin. 21 CFR 56, Institutional

Review Boards, and 21 CFR 50, Informed

Consent, do not specifically exempt IVDs and,

therefore, are applicable.

Because most IVD research and

investigations do not require an IDE and are

minimal risk, the IRB may use expedited review

procedures to review most IVD research and

investigational proposals. The IRB must

document why expedited review was used for

approving the IVD investigation.

The IRB may exempt the study from

informed consent if it finds that the research

presents no more than minimal risk of harm to

subjects and involves no procedures for which

written consent is normally required. For

example, an IRB may exempt a study from

informed consent if left-over specimens will be

used, provided that patient confidentiality is

maintained.

Protocol:

While the protocol does not need FDA

approval, it is an essential tool for the sponsor

to communicate accurately to the IRB and the

clinical investigator. Although the sponsor is

exempt from labeling requirements if it meets

the requirements of 21 CFR 809.10(c), the

labeling or its equivalent supplies the clinical

investigator with important information about

the test procedure. Without a protocol, or

similar tool, the sponsor runs the risk of getting

invalid results from the investigation.

The protocol and the labeling should reflect

all the steps the clinical investigator must take

to obtain useful information for the sponsor.

They should describe such things as specimen

collection, instrumentation, reagents,

calibration, quality control, step-by-step

procedures, calculations, storage conditions,

stability of various components both before and

after opening and/or reconstituting, reporting

procedures, and the necessary reporting forms,

etc., for obtaining accurate and precise results

and communicating them to the sponsor.

For Diagnosis or Differential Diagnosis of a

Disease or Medical or Physiological Condition:

The sponsor may use the data to establish

expected values or ranges and cut-off values.

The sponsor's proposed labeling will designate

concentrations that characterize the healthy

and affected populations. These are usually

expressed as diagnostic cut-off values. This

information will determine the clinical

usefulness of the test results and will affect the

rates of true and false results. Since treatment

may be based on a diagnosis from an IVD,

expected values should be established with

accurate information. For example, an IVD to

measure blood glucose levels will have a normal

range for healthy individuals. Values outside

the normal range will be used in the diagnosis

of diabetes.

In many cases, the sponsor may simply

compare the performance of the investigational

device to a device already cleared with the

same intended use, using left-over patient

specimens. When the patient's diagnosis is

necessary, it must have been established by

some medically acceptable scientific method. In

those cases, the sponsor and investigator must

record enough of the patient's medical history

to determine the diagnosis and any other

conditions that might impinge on the

performance of the IVD.

To Monitor a Patient's Therapy or to Follow

Their Progress After Treatment:

Records should establish which patients are

on the therapy or have had the treatment. For

example, if the IVD measured a tumor marker

to assure total removal of the tumor and/or

monitor its reoccurrence, then records should

reflect the patient's diagnosis and treatment and

the pre-treatment levels of the marker.

Screening and Prognosis:

Screening is performed to identify risk

factors in health promotion and disease

prevention. For example, cholesterol screening

may be performed on a random population to

identify individuals with this risk factor for heart

disease.

Prognosis means determining the intensity

or stage of a disease and predicting the

expected course of a disease.

Generally firms do not develop an IVD

specifically for screening or prognosis. IVDs

intended to diagnose or monitor are used

instead and the results translated into screening

or prognostic terms. If the intended use is, or

includes screening, then the investigation should

reflect the anticipated screening population,

generally healthy adults. If it is for prognosis,

then the screening population should consist

almost exclusively of those with the disease.

Prognostic claims should be established with

patient outcome data.

Home Use and Physician Office Lab Devices

Versus Professional Lab Devices:

If a device is intended for use outside the

professional laboratory setting, the Office of

Device Evaluation may require other types of

studies, e.g., analyses performed by the actual

users.

The FDA investigator should be alert to any

special instructions, e.g., patient instruction and

preparation, when he or she is inspecting such

studies.

Labeling:

The sponsor may use the investigational

data to support the performance characteristics

section of the product's proposed labeling. This

section of the labeling describes how well the

device performed during the clinical

investigation and describes such things as the

accuracy, precision, sensitivity, and specificity of

the IVD. The sponsor is establishing the

purported quality of the device and therefore

should assure that the data are valid.

Accuracy or bias describes how well the

IVD result compares to the actual

concentration in the patient's specimen.

Precision describes how well the IVD

repeats test results on the same material.

Sensitivity describes the lowest

concentration at which the IVD gives

acceptable results.

Specificity is the ability of the IVD to

accurately measure the analyte of interest in

the presence of potential interfering substances.

The performance characteristics should be

related to a generally accepted method and use

biological specimens from normal and abnormal

populations. The sponsor should define these

populations. Too few patients in any one

group may not provide the sponsor with the

statistical power to make a claim in their

labeling.

There are many factors that may affect the

quality and validity of the data collected to

support the claims and statements discussed

above. The sponsor and investigator should

control these factors using QC and QA

methods applicable to diagnostic and analytical

laboratories. These factors are usually

categorized as pre-analytical, analytical, and

post-analytical.

Factors:

Pre-analytical considerations center around

the patient, his or her preparation, and the

specimen.

Analytical considerations include everything

surrounding the actual measurement process.

Post-analytical considerations center around

the proper calculation and reporting of results.

Although elements of QC and QA

principles outlined in FDA's Good Laboratory

Practices or Quality Systems GMP Regulation

may apply, the regulations themselves do not.

FDA Investigators should base any inspectional

observations on whether the sponsor or clinical

investigator followed the protocol and labeling

specified for the investigation.

Although 21 CFR Part 812, Investigational

Device Exemptions (IDE), is used as guidance

when reviewing inspectional reports, the IDE

regulations themselves do not apply to in vitro

diagnostic devices and should not be used as a

reference when documenting observations on

the FDA-483.

In summary, IVDs for clinical investigations

or research must meet the labeling

requirements in 21 CFR 809.10(c). Labeling

must not contain performance claims,

diagnostic ranges, indications of safety and

effectiveness, etc. The sponsor must control

the distribution of the device to avoid the

appearance of commercializing an uncleared or

unapproved medical device. They must also

meet the requirements of 21 CFR 56,

Institutional Review Boards, and 21 CFR 50,

Protection of Human Subjects. Additionally, if a

protocol or its equivalent exists, the FDA

Investigator should assure that the clinical

investigator has followed it. The clinical

investigator should have followed the specific

inclusion and exclusion criteria for patients

assuring that the diagnosis for each patient is

accurate by a cleared IVD or other standard of

diagnosis. They should assure the integrity of

the data, specifically, that the analyses were

actually performed according to instructions

that accompany the kit and that the data were

recorded and reported accurately. Raw data

should exist to support the data submitted in

reports and applications to the Agency.

Although many of these requirements resemble

GLPs, the observations should be in terms of

adherence to the sponsor's protocol.

Should you have comments or questions

regarding In Vitro diagnostic bioresearch

monitoring inspections or this guide, please

contact Robert Fish at: Center for Devices and

Radiological Health Office of Compliance

Division of Bioresearch Monitoring Program

Enforcement Branch II, HFZ-312 28 Gaither

Road Rockville, MD 20850 (301) 594-4723

This reference is intended to be used in

conjunction with the:

-Compliance Program Guidance Manuals for

Institutional Review Boards; Sponsors,

Contract Research Organization and

Monitors; and Clinical Investigators (CP

7348.809; 7348.810; and 7348. 811),

-21 CFR Part 809 - In Vitro Diagnostic

Products for Human Use

-21 CFR Part 812.2 (c)(3), 812.3(k) - IVD

exemptions

-21 CFR Part 50 - Protection of Human

Subjects

-21 CFR Part 56 - Institutional Review

Boards

-Investigations Operations Manual (IOM),

and

-Applicable Compliance Policy Guides

(CPG) for devices (beginning with the

numbers 7124 and 7133).

Guidances are posted to the CDRH and

ORA Internet World Wide Web Home Pages

at http://www.fda.gov. See IOM Chapter 10,

References, for additional information.