Bioresearch Monitoring Inspections of In Vitro Diagnostics Devices

 

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TABLE OF CONTENTS

 

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

 

 

INTRODUCTION

 

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).

 

 

NATURE, SCOPE, AND PURPOSE

 

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."

 

 

DEFINITION

 

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.

 

 

EXEMPTIONS FROM 21 CFR 812

 

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).

 

 

LABELING REQUIREMENTS

 

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).

 

 

PROHIBITED LABELING INFORMATION

 

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.

 

 

SPECIMEN TESTING AND SAMPLING REQUIREMENTS

 

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.

 

 

THE SPONSOR'S INVESTIGATIONAL PLAN

 

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.

 

 

PROPOSED INTENDED USE OF THE IVD AND THE CLINICAL DATA

 

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.

 

 

PERFORMANCE CHARACTERISTICS AND THE CLINICAL DATA

 

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.

 

 

FACTORS AFFECTING THE QUALITY OF THE RESULTS

 

OF THE CLINICAL INVESTIGATION

 

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.

 

 

CONCLUSION

 

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

 

 

REFERENCES

 

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.

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