GUIDE TO BIORESEARCH MONITORING INSPECTIONS
OF IN VITRO DIAGNOSTIC DEVICES
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.