[Federal Register Volume 72, Number 143 (Thursday, July 26, 2007)]
[Pages 41081-41083]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 07-3660]



Food and Drug Administration

[Docket No. 2006D-0347]

Draft Guidance for Industry and Food and Drug Administration 
Staff; In Vitro Diagnostic Multivariate Index Assays; Availability

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.


SUMMARY:  The Food and Drug Administration (FDA) is announcing the 
availability of a revised draft guidance entitled ``In Vitro Diagnostic 
Multivariate Index Assays.'' FDA is issuing this revised draft guidance 
to address the definition and regulatory status of a class of In Vitro 
Diagnostic Devices referred to as In Vitro Diagnostic Multivariate 
Index Assays (IVDMIAs). The revised draft guidance also addresses 
premarket and postmarket requirements with respect to IVDMIAs. The 
initial draft of this guidance was issued September 7, 2006.

DATES:  Submit written or electronic comments on this draft guidance by 
August 27, 2007.

ADDRESSES:  Submit written requests for single copies of the draft 
guidance document entitled ``In Vitro Diagnostic Multivariate Index 
Assays'' to the Division of Small Manufacturers, International, and 
Consumer Assistance (HFZ-220), Center for Devices and Radiological 
Health, Food and Drug Administration, 1350 Piccard Dr., Rockville, MD 
20850 or to the Office of Communication, Training, and Manufacturers 
Assistance (HFM-40), Center for Biologics Evaluation and Research 
(CBER), Food and Drug Administration, 1401 Rockville Pike, suite 200N, 
Rockville, MD 20852-1448. Send one self-addressed adhesive label to 
assist that office in processing your request, or fax your request to 
240-276-3151. See the SUPPLEMENTARY INFORMATION section for information 
on electronic access to the draft guidance.
    Submit written comments concerning this draft guidance to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic 
comments to http://www.fda.gov/dockets/ecomments. Identify comments 
with the docket number found in brackets in the heading of this 

FOR FURTHER INFORMATION CONTACT: Courtney Harper, Center for Devices 
and Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 240-276-0694.
    For further information concerning the guidance as it related to 
devices regulated by CBER: Martin Ruta, Center for Biologics Evaluation 
and Research, Food and Drug Administration, 1401 Rockville Pike, 
Rockville, MD 20852, 301-827-3518.


I. Background

    In the Federal Register of September 7, 2006 (71 FR 52800). FDA 
published a notice of availability of the initial draft guidance to 
address the definition and regulatory status of a class of in vitro 
diagnostic devices referred to as ``In Vitro Diagnostic Multivariate 
Index Assays (IVDMIAs).'' The initial draft guidance also addressed 
premarket and postmarket requirements with respect to IVDMIAs.
    An IVDMIA, as defined in the draft guidance document, is a device 
within the meaning of the Federal Food, Drug, and Cosmetic Act (the 
act). Some IVDMIAs are laboratory-developed tests (LDTs); laboratory-
developed IVDMIAs are a specific subset of LDTs. While FDA has stated 
that ``clinical laboratories that develop (in-house) tests

[[Page 41082]]

are acting as manufacturers of medical devices and are subject to FDA 
jurisdiction under the Act,'' 62 FR 62243 to 62249 (November 21, 1997), 
the agency has generally exercised enforcement discretion over most 
standard LDTs. However, in the draft guidance, FDA recognizes that 
IVDMIAs include elements that are not among the primary ingredients of 
standard LDTs (e.g., complex, unique, interpretation functions). 
IVDMIAs thus do not fall within the scope of LDTs over which FDA has 
generally exercised enforcement discretion.
    IVDMIAs raise significant issues of safety and effectiveness. These 
types of tests are developed based on observed correlations between 
multivariate data and clinical outcome, such that the clinical validity 
of the claims is not transparent to patients, laboratorians, and 
clinicians who order these tests. Additionally, IVDMIAs frequently have 
a high risk intended use. FDA is concerned that patients and healthcare 
practitioners are relying upon IVDMIAs with high risk intended uses to 
make critical healthcare decisions without any independent assurance 
that the IVDMIA has been properly clinically validated, and without any 
ability to assess whether the test yields clinically valid results.
    With this revised draft guidance document, FDA seeks to identify 
IVDMIAs as a discrete category of device, and to clarify that, even 
when offered as LDTs, IVDMIAs must meet pre- and post-market device 
requirements under the act and FDA regulations, including premarket 
review requirements in the case of most class II and III devices.
    FDA received and considered approximately 60 sets of comments on 
the initial draft guidance document, including comments provided at a 
public meeting that was held on February 8, 2007. After taking the 
comments into consideration, the FDA has updated the draft guidance 
document to provide clarifications as needed.
    Certain comments on the initial draft guidance document requested 
that FDA undertake notice and comment rulemaking rather than issue a 
guidance document in order to allow sufficient opportunity for public 
input. In response to this concern, FDA extended the comment period on 
the draft guidance document from 90 days to 180 days, March 5, 2007 (71 
FR 68822), and held a public meeting to provide a forum for 
presentations and comments on the draft guidance document. The meeting 
was attended by 266 people representing a cross-section of interested 
stakeholders including industry, consumer groups, and the medical 
community. FDA has carefully considered the comments it has received. 
Many comments reflect that stakeholders construed the definition of 
IVDMIAs in the initial draft guidance document to encompass a wider 
range of tests than FDA had intended. The initial draft guidance 
document has been revised to clarify the definition of an IVDMIA and to 
provide examples of tests that the agency does and does not consider to 
be IVDMIAs. This section of the draft guidance was modified so that 
stakeholders can more easily understand the nature of tests designated 
as IVDMIAs, and manufacturers can more easily determine whether their 
tests are IVDMIAs. However, the clarifications do not alter the scope 
or intent of the definition of an IVDMIA found in the initial draft 
guidance document.
    In response to additional comments received, the revised draft 
guidance document now clarifies FDA regulatory mechanisms in general, 
such as how devices are classified and reviewed based on the risk of 
the intended use, how laboratory-developed IVDMIAs should be labeled, 
and how manufacturers can update and improve cleared or approved 
devices using existing mechanisms within the regulatory framework. 
These existing mechanisms enable manufacturers to bring innovative new 
tests to the market and ensure that they can be updated and improved as 
new scientific information becomes available. While this information is 
generally available in existing regulations, guidance documents, and on 
the FDA Web site, the revised draft guidance provides a summary of this 
information with a focus on IVDMIAs in order to assist those 
stakeholders who are not familiar with existing FDA requirements.
    In other comments, some stakeholders expressed concern that 
requiring FDA regulatory compliance for IVDMIAs has the potential to 
discourage the development of new tests for rare diseases. A 
manufacturer of an IVDMIA for a disease or condition that affects small 
patient populations may find that research and development costs exceed 
market returns. The draft guidance has been revised to indicate FDA's 
intent to exercise enforcement discretion for laboratory-developed 
IVDMIAs that are intended to diagnose rare diseases (i.e., IVDMIAs that 
meet the definition of Humanitarian Use Devices under 21 CFR part 814 
Subpart H).
    Finally, the draft guidance document clarifies that laboratories 
that manufacture IVDMIAs should follow the Medical Device Reporting 
requirements for manufacturers, 21 CFR part 803 for their IVDMIA 
device(s). As in the initial draft guidance, the revised draft guidance 
indicates that FDA intends to issue guidance to assist laboratories 
that manufacture IVDMIAs in complying with the Quality System 
regulation (QS), 21 CFR part 820. In response to comments that 
expressed concern about coming into compliance with the QS regulation, 
the revised draft guidance indicates that until such a final guidance 
is published, FDA intends to exercise enforcement discretion with 
regard to post-market QS requirement enforcement for laboratories that 
manufacture IVDMIAs, recognizing that some Clinical Laboratory 
Improvement Amendments of 1988 (CLIA' 88) requirements may partially 
fulfill corresponding QS regulation requirements.
    FDA is issuing this revised draft in order to gather significant 
new comments before issuing a final version of the guidance. Because 
the agency believes it has addressed the most important concerns raised 
by the comments it received on the initial draft, and because it is 
important to issue a final guidance to provide clarity for 
stakeholders, FDA is providing a comment period of 30 days following 
publication of this document.

II. Significance of Guidance

    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance 
represents the agency's current thinking on IVDMIAs. It does not create 
or confer any rights for or on any person and does not operate to bind 
FDA or the public. An alternative approach may be used if such approach 
satisfies the requirements of the applicable statute and regulations.

III. Electronic Access

    Persons interested in obtaining a copy of the draft guidance may do 
so by using the Internet. To receive ``In Vitro Diagnostic Multivariate 
Index Assays,'' you may either send an e-mail request to 
dsmica@fda.hhs.gov to receive an electronic copy of the document or 
send a fax request to 240-276-3151 to receive a hard copy. Please use 
the document number 1610 to identify the guidance you are requesting.
    CDRH maintains an entry on the Internet for easy access to 
information including text, graphics, and files that may be downloaded 
to a personal computer with Internet access. Updated on a regular 
basis, the CDRH home page includes device safety alerts, Federal

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Register reprints, information on premarket submissions (including 
lists of approved applications and manufacturers' addresses), small 
manufacturers' assistance, information on video conferencing and 
electronic submissions, Mammography Matters, and other device-oriented 
information. The CDRH Web site may be accessed at http://www.fda.gov/cdrh. A search capability for all CDRH guidance documents is available 
at http://www.fda.gov/cdrh/guidance.html. Guidance documents are also 
available on the CBER Internet site at http://www.fda.gov/cber/guidelines.htm or on the Division of Dockets Management Internet site 
at http://www.fda.gov/ohrms/dockets.

IV. Paperwork Reduction Act of 1995

    This draft guidance contains information collection provisions that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in the draft guidance document have been 
approved by OMB in accordance with the PRA under the regulations 
governing premarket notifications (21 CFR part 807, subpart E, OMB 
control number 0910-0120) premarket approval applications (21 CFR part 
814, OMB control number 0910-0231), investigational device exemptions 
(21 CFR part 812, OMB control number 0910-0078), quality system 
regulation (21 CFR part 820, OMB control number 0910-0073), and medical 
device reporting (21 CFR part 803, OMB control number 0910-0437). The 
labeling provisions addressed in this guidance have been approved by 
OMB under OMB control number 0910-0485.

V. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES), written or electronic comments regarding this document 
on or before August 27, 2007. Submit electronic comments to http://www.fda.gov/dockets/ecomments. Submit two paper copies of any mailed 
comments, except that individuals may submit one copy. Comments are to 
be identified with the docket number found in brackets in the heading 
of this document. Comments received may be seen in the Division of 
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.

    Dated: July 20, 2007.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 07-3660 Filed 7-23-07; 12:02 pm]