[Federal Register Volume 79, Number 226 (Monday, November 24, 2014)]
[Pages 69860-69863]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-27713]



Food and Drug Administration

[Docket Nos. FDA-2011-D-0360 and FDA-2011-D-0357]

Framework for Regulatory Oversight of Laboratory Developed Tests; 
Public Workshop; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public workshop; request for comments.


    The Food and Drug Administration (FDA) is announcing the following 
public workshop entitled ``Framework for Regulatory Oversight of 
Laboratory Developed Tests (LDTs).'' The purpose of this workshop is to 
discuss FDA's proposal for a risk-based framework for addressing the 
regulatory oversight of a subset of in vitro diagnostic devices (IVDs) 
referred to as laboratory developed tests (LDTs), which are intended 
for clinical use and designed, manufactured and used within a single 
laboratory, and provide an additional opportunity for public comment
    Dates and Times: The 2-day public workshop will be held on January 
8, 2015, from 8:30 a.m. to 5:30 p.m. and on January 9, 2015 from 8:30 
a.m. to 5:30 p.m.
    Location: The public workshop will be held at the Natcher Center at 
the National Institutes of Health Campus, 9000 Rockville Pike, Bldg. 
45, Auditorium, Bethesda, MD 20814. For parking and security 
information, please refer to http://www.nih.gov/about/visitor/.
    Contact Person: Allen Webb, Center for Devices and Radiological 
Health, Food and Drug Administration, Bldg. 66, Rm 5675, 10903 New 
Hampshire Ave., Silver Spring, MD 20993, 240-402-4217, 
[email protected].
    Registration: Registration is free and available on a first-come, 
first-served basis. Persons interested in attending this public 
workshop must register online by December 12, 2014, at 4 p.m. Early 
registration is recommended because facilities are limited and, 
therefore, FDA may limit the number of participants from each 
organization. If time and space permits, onsite registration on the day 
of the public workshop will be provided beginning at 8 a.m.
    If you need special accommodations due to a disability, please 
contact Susan Monahan, (email: [email protected] or phone: 301-
796-5661) no later than December 19, 2014.
    To register for the public workshop, please visit FDA's Medical 
Devices News & Events--Workshops & Conferences calendar at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. 
(Select this meeting/public workshop from the posted events list.) 
Please provide complete contact information for each attendee, 
including name, title, affiliation, email, and telephone number. If you 
are unable to register online, please contact Susan Monahan (see 
Registration.) Registrants will receive confirmation after they have 
been accepted and will be notified if they are on a waiting list.

[[Page 69861]]

    Streaming Webcast of the Public Workshop: This public workshop will 
also be Webcast. Persons interested in viewing the Webcast must 
register online. Early registration is recommended because Webcast 
connections are limited. Organizations are requested to register all 
participants, but to view using one connection per location. Webcast 
participants will be sent technical system requirements and connection 
access information after registration and prior to the meeting. If you 
have never attended a Connect Pro event before, test your connection at 
To get a quick overview of the Connect Pro program, visit http://www.adobe.com/go/connectpro_overview. (FDA has verified the Web site 
addresses in this document, but FDA is not responsible for any 
subsequent changes to the Web sites after this document publishes in 
the Federal Register.) The Webcast will be recorded and posted on FDA's 
Web site after the meeting.
    Requests for Oral Presentations: This public workshop includes 
topic-focused public comment sessions. During online registration you 
may indicate if you wish to present during a public comment session, 
and which topics you wish to address. FDA has included general topics 
in this document. FDA will do its best to accommodate requests to make 
public comment. Individuals and organizations with common interests are 
urged to consolidate or coordinate their presentations, and request 
time for a joint presentation, or submit requests for designated 
representatives to participate in the focused sessions. Following the 
close of registration, FDA will determine the amount of time allotted 
to each presenter and the approximate time each oral presentation is to 
begin, and will select and notify participants by December 17, 2014. 
All requests to make oral presentations must be received by the close 
of registration on December 12, 2014. If selected for presentation, any 
presentation materials must be emailed to Allen Webb (see Contact 
Person) no later than January 6, 2015. No commercial or promotional 
material will be permitted to be presented or distributed at the public 
    Comments: In order to permit the widest possible opportunity to 
obtain public comment, FDA is soliciting either electronic or written 
comments on all aspects of the public workshop topics. The deadline for 
submitting comments related to this public workshop is February 2, 
    Regardless of attendance at the public workshop, interested persons 
may submit either electronic comments regarding this document to http://www.regulations.gov or written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852. It is only necessary to send one set of 
comments. Identify comments with the docket number found in brackets in 
the heading of this document. In addition, when responding to specific 
questions as outlined in section II of this document, please identify 
the question you are addressing. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday, and will be posted to the docket at http://www.regulations.gov.
    Transcripts: Please be advised that as soon as a transcript is 
available, it will be accessible at http://www.regulations.gov. It may 
be viewed at the Division of Dockets Management (see Comments). A 
transcript will also be available in either hardcopy or on CD-ROM, 
after submission of a Freedom of Information request. Written requests 
are to be sent to the Division of Freedom of Information (ELEM-1029), 
Food and Drug Administration, 12420 Parklawn Dr., Element Bldg., 
Rockville, MD 20857. A link to the transcripts will also be available 
approximately 45 days after the public workshop on the Internet at 
http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/default.htm. (Select this public workshop from the posted events list).


I. Background

    In 1976, Congress enacted the Medical Device Amendments (MDA), 
which amended the Federal Food, Drug, and Cosmetic Act (the FD&C Act) 
to create a comprehensive system for the regulation of medical devices 
intended for use in humans. At that time, the definition of a device 
was amended to make explicit that it encompassed in vitro diagnostic 
devices (IVDs): ``The term `device'. . .means an instrument, apparatus, 
implement, machine, contrivance, implant, in vitro reagent, or other 
similar or related article. . . .'' (section 201(h) of the FD&C Act (21 
U.S.C. 321(h)). The definition of device applies equally to IVDs 
manufactured by conventional device manufacturers and those 
manufactured by laboratories. An IVD, therefore, meets the device 
definition irrespective of where and by whom it is manufactured.
    Since the implementation of the MDA of 1976, FDA has exercised 
enforcement discretion so that the Agency has generally not enforced 
applicable provisions under the FD&C Act and FDA regulations with 
respect to LDTs, a subset of IVDs that are intended for clinical use 
and designed, manufactured, and used within a single laboratory.
    In 1976, LDTs were mostly manufactured in small volumes by local 
laboratories. Many laboratories manufactured LDTs that were similar to 
well-characterized, standard diagnostic devices, as well as other LDTs 
that were intended for use in diagnosing rare diseases or for other 
uses to meet the needs of a local patient population. LDTs at the time 
tended to rely on the manual techniques used by laboratory personnel. 
LDTs were typically used and interpreted directly by physicians and 
pathologists working within a single institution that was responsible 
for the patient. In addition, historically, LDTs were manufactured 
using components that were legally marketed for clinical use (i.e., 
general purpose reagents, immunohistochemical stains, and other 
components marketed in compliance with FDA regulatory requirements).
    Although some laboratories today still manufacture LDTs in this 
``traditional'' manner, the landscape for laboratory testing in 
general, and LDTs along with it, has changed dramatically since 1976. 
Today, LDTs are often used in laboratories that are independent of the 
healthcare delivery entity. Additionally, LDTs are frequently 
manufactured with components and instruments that are not legally 
marketed for clinical use and also rely more heavily on complex, high-
tech instrumentation and software to generate results and clinical 
interpretations. Moreover, technological advances have increased the 
use of diagnostic devices in guiding critical clinical management 
decisions for high-risk diseases and conditions, particularly in the 
context of personalized medicine.
    Business models for laboratories have also changed since 1976. With 
the advent of overnight shipping and electronic delivery of information 
(e.g., device results), a single laboratory can now easily provide 
device results nationally and internationally. Today, many new LDT 
manufacturers are large corporations that nationally market a limited 
number of complex, high-risk devices, in contrast to 1976 when hospital 
or public health laboratories used a wide range of devices that were 
generally either well characterized and similar to standard devices; 
used to diagnose rare diseases; or designed specifically to meet the 
needs of their local patients. Together, these changes

[[Page 69862]]

have resulted in a significant shift in the types of LDTs developed, 
the business model for developing them, and the potential risks they 
pose to patients.
    Because of changes in the complexity and use of LDTs and the 
associated increased risks, as described earlier, FDA believes the 
policy of general enforcement discretion towards LDTs is no longer 
appropriate. To initiate this step toward greater oversight, FDA held a 
2-day public meeting on July 19 and 20, 2010, to provide a forum for 
stakeholders to discuss issues and concerns surrounding greater 
oversight of LDTs. Comments submitted to the public docket for the July 
19 and 20, 2010, public meeting were reviewed and, as appropriate, 
incorporated into FDA's current proposed framework for regulatory 
oversight of LDTs. FDA's July 31, 2014, Notification to Congress 
concerning the Agency's intent to issue the draft guidance, ``Framework 
for Regulatory Oversight of Laboratory Developed Tests (LDTs)'' 
(Framework draft guidance document), and the accompanying draft 
guidance, ``FDA Notification and Medical Device Reporting for 
Laboratory Developed Tests (LDTs),'' was made publicly available, and 
these draft guidance documents were subsequently issued on October 3, 
2014. See 79 FR 59776 and 79 FR 59779 (October 3, 2014). These 
documents describe a risk-based framework for addressing the regulatory 
oversight of LDTs, including FDA's priorities for enforcing premarket 
and postmarket requirements for LDTs as well as the process by which 
FDA intends to phase in enforcement of FDA regulatory requirements for 
LDTs over time. As outlined in the Framework draft guidance document, 
FDA proposes to continue to exercise enforcement discretion for all 
applicable regulatory requirements for LDTs used solely for forensic 
(law enforcement) purposes as well as certain LDTs for transplantation 
when used in certified, high-complexity histocompatibility 
laboratories. Additionally, FDA proposes to exercise enforcement 
discretion for applicable premarket review requirements and quality 
systems (QS) requirements, but enforce other applicable regulatory 
requirements, including registration and listing (with the option to 
provide notification instead) and adverse event reporting, for low-risk 
LDTs (class I devices), LDTs for rare diseases, Traditional LDTs and 
LDTs for Unmet Needs, as described in the Framework draft guidance 
document. For other high- and moderate-risk LDTs, FDA proposes to 
enforce applicable regulatory requirements, including registration and 
listing (with the option to provide notification instead) and adverse 
event reporting, and phase in enforcement of premarket and QS 
requirements in a risk-based manner.
    With the publication of the draft guidances, FDA announced a public 
comment period soliciting feedback on all aspects of the guidance 
documents as well as on the following specific issues: (1) Factors for 
``Traditional LDT'' and appropriate level of enforcement discretion for 
such tests; (2) factors for considering LDTs for rare diseases; (3) 
manufacture and use of LDTs solely within a healthcare system as a risk 
mitigation supporting some continued enforcement discretion; (4) 
timeframe for phase-in enforcement of QS regulation requirements for 
those LDTs called in for enforcement of premarket review requirements 
early in the implementation period; and (5) the appropriateness of a 
single notification for the same LDT manufactured by multiple labs 
owned by a single entity.
    FDA intends to use this public workshop as a forum for open 
discussion with all stakeholders regarding these specific issues as 
well as other considerations for how to best balance patient safety and 
patient access in developing the finalized framework in a manner that 
best serves public health.

II. Topics for Discussion at the Public Workshop

    Issues to be considered during the sessions include:

Session 1: Components of a Test and LDT Labeling Considerations
     What components do FDA cleared/approved tests and LDTs 
typically include?
     What labeling considerations should be taken into account 
for LDTs?
     How does LDT labeling affect and not affect physician 
consultation with the laboratory?
Session 2: Clinical Validity/Intended Use
     What is clinical validity and how is it demonstrated for 
IVDs, including LDTs?
     How are clinical claims or intended use related to 
clinical validity?
     What types of modifications may affect the intended use or 
significantly affect the performance of a test?
Session 3: Categories for Continued Enforcement Discretion
     As a factor for consideration of continued enforcement 
discretion for premarket review and QS regulation requirements for LDTs 
for rare diseases, the proposed framework for LDTs relies on the 
definition of a humanitarian use device (HUD) in 21 CFR 814.102(a)(5). 
Under this definition, an IVD may qualify for HUD designation when the 
number of persons in the United States who may be tested with the 
device is fewer than 4,000 per year. Is this an appropriate factor for 
LDTs for rare diseases? If not, what factor should FDA consider for 
LDTs for rare diseases?
     Should enforcement discretion be limited to tests for rare 
diseases that meet the definition of an LDT (a test designed, 
manufactured and used within a single laboratory)?
     Are the following three factors the appropriate controls 
to mitigate risks due to Traditional LDTs so that continued enforcement 
discretion is appropriate with respect to premarket review and quality 
system requirements whether the test is: (1) An LDT (designed, 
manufactured and used within a single laboratory); (2) comprised of 
only components and instruments that are legally marketed for clinical 
use, which have a number of regulatory controls in place, including 
reporting of adverse events; and (3) interpreted by laboratory 
professionals who are appropriately qualified and trained as required 
by the CLIA (Clinical Laboratory Improvement Amendments) regulations 
(see, e.g., 42 CFR 493.1449), without the use of automated 
instrumentation or software for interpretation? Are these three factors 
also sufficient to support continued enforcement discretion in full 
(i.e., for all regulatory requirements rather than just for premarket 
review and quality system requirements) for this category of LDTs? 
Should FDA instead consider different factors?
     FDA has proposed the following three factors for 
consideration of continued enforcement discretion for premarket review 
and QS requirements for LDTs for Unmet Needs whether: (1) The device 
meets the definition of an LDT (a test designed, manufactured and used 
by a single laboratory); (2) there is no FDA cleared or approved IVD 
available for that specific intended use; and (3) the LDT is both 
manufactured and used by a healthcare facility laboratory (such as one 
located in a hospital or clinic) for a patient that is being diagnosed 
and/or treated at that same healthcare facility or within

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that facility's healthcare system. Are these factors appropriate and/or 
sufficient to both mitigate risks and to provide patient access if 
warranted? Should FDA use different factors to best balance patient 
safety and patient access?
     For the categories of Traditional LDTs and LDTs for Unmet 
Needs, one of the factors for enforcement discretion is whether the LDT 
is both manufactured and used by a healthcare facility laboratory (such 
as one located in a hospital or clinic) for a patient that is being 
diagnosed and/or treated at that same healthcare facility, or within 
the facility's healthcare system. To further clarify this factor, the 
Framework draft guidance document explains that ``healthcare system'' 
refers to a collection of hospitals that are owned and operated by the 
same entity and that share access to patient care information for their 
patients, such as, but not limited to, drug order information, 
treatment and diagnosis information, and patient outcomes. If this is 
an appropriate factor to use, are the considerations about which types 
of facilities would or would not be included within a healthcare system 
as defined by the draft guidance appropriate? Is there an alternative 
definition of healthcare system that would be more appropriate?
     Do the FDA-proposed categories for continued enforcement 
discretion appropriately encompass the LDTs that should remain under 
enforcement discretion? Should the scope of proposed categories be 
broadened or narrowed? If so, how? Should additional categories for 
continued enforcement discretion be added or proposed categories 
removed? If so, which categories? For any new proposed categories, what 
are the appropriate factors in considering enforcement discretion?
     Is the information provided detailed enough for 
laboratories to make a determination that their LDT falls within one of 
these categories of continued enforcement discretion?
Session 4: Notification and Adverse Event Reporting (MDRs)
     Will notification be adequate to provide FDA, 
laboratories, providers, patients, and other members of the public a 
comprehensive list of what tests are currently available for a specific 
intended use?
     Would it be sufficient to allow laboratory networks (i.e., 
more than one laboratory under the control of the same parent entity) 
that offer the same test in multiple laboratories throughout their 
network to submit a single notification for that test?
     Are there certain types of LDTs for which the Agency 
should neither enforce requirements for registration and listing nor 
request notification in lieu of registration and listing?
     How can FDA leverage other information in the community to 
reduce the information collection associated with notification for 
laboratories while still obtaining sufficient information to inform the 
LDT classification and prioritization process?
Session 5: Public Process for Classification and Prioritization
     How should FDA structure the advisory panels that will be 
convened to provide input to help FDA classify LDTs and prioritize them 
for enforcement of FDA premarket review requirements?
     Which stakeholders should be able to present relevant 
information or views at the panel meetings to discuss the 
classification and prioritization of LDTs?
     What factors should be considered in determining LDT 
classification and risk?
     How should the advisory panel process weigh these factors 
when providing input for classifying LDTs and prioritizing LDTs for 
enforcement of FDA premarket review requirements?
Session 6: Quality System Regulation
     How can laboratories best leverage their current processes 
and procedures, implemented to meet CLIA accreditation requirements, to 
meet the FDA QS regulation requirements in the least burdensome manner?
     Are there FDA QS requirements that differ from CLIA 
requirements that FDA should continue not to enforce for laboratories 
that make LDTs?
     What additional resources will laboratories need in order 
to assist them with implementation of the QS regulation?
     What is the appropriate timeframe for phase-in enforcement 
of QS regulation requirements in general and for design controls 

    Dated: November 17, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014-27713 Filed 11-21-14; 8:45 am]