Technical Assistance on VALID Act of 2018
These comments are intended only to provide technical assistance and are by no means to
be interpreted as any kind of approval or endorsement of the legislation by the Department
of Health and Human Services and its agencies or the Administration.
HHS, including FDA, CMS, and CDC, appreciates the opportunity to provide technical
assistance to the sponsors of this legislation on diagnostic reform. This document provides
feedback on the preliminary discussion draft of the Verifying Accurate Leading-edge IVCT
Development Act of 2018, or VALID, issued by Representatives Bucshon and DeGette and
Senators Bennet and Hatch, on December 6, 2018. We look forward to continuing discussion
with the sponsors and the stakeholder community as Congress works to develop this legislative
framework.
1. FDA Should Oversee IVCTs
HHS supports the proposal in VALID to task FDA with the responsibility for oversight and
assessment of the analytical and clinical validity of IVCTs. HHS maintains that FDA’s
longstanding history and experience in premarket review of diagnostics and deep knowledge of
clinical research methodology pertinent to establishing analytical and clinical validity make FDA
the appropriate Agency for jurisdiction over IVCTs.
An oversight approach should be undertaken in an efficient manner that allows labs to effectively
leverage, without duplication, the activities they already perform to comply with CLIA
requirements. To this end, we support the discussion draft language indicating that CLIAcertified labs would only need to comply with a subset of QS requirements for their IVCTs,
effectively leveraging work they already do under CLIA. HHS notes that the VALID proposal
does not duplicate CLIA requirements.
2. FDA Needs Sufficient Resources for Oversight of IVCTs
To protect the public health, it is critical that any IVCT oversight framework can be implemented
with maximum efficiency and without significant delays. This can be achieved with legislation
that is as self-implementing as possible that also avoids unnecessarily burdensome processes.
FDA must be provided with sufficient resources to stand up and run this new program and to
ensure that it is successful by allowing FDA to continue to carry out its core mission of
protecting the public health, while also ensuring timely review of medical products. We
appreciate that the sponsors included the establishment of a new user fee program in the
legislation, which we believe is intended to help ensure FDA has appropriate resources. We
include some comments on the user fee language later in this document for the sponsors’
consideration.
The Comprehensive Test Information System (CTIS) is a key resource needed for efficient
oversight, while also bringing much needed transparency to patients and healthcare providers
about the tests they are using. CTIS would include information about every IVCT, including
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 analytical and clinical validity, and provide both test developers and FDA with a single system
that could be used for notification, submissions, and adverse event reporting. Each IVCT would
be assigned a unique number to enable tracking across all processes, and the system would be
searchable across all fields, including by test uses and test developers. Further, CTIS would help
FDA monitor tests in the postmarket space, which is especially important in a framework where
the majority of tests are not reviewed individually premarket. No such system currently exists to
provide information about all tests being offered in the United States. The availability of this
information would help patients and healthcare providers to make informed medical decisions.
This system would also provide clarity for test developers around how FDA is evaluating IVCTs
similar to their own.
3. Flexible Regulatory Pathways
HHS supports the regulatory pathways outlined in VALID. We continue to believe that riskbased classification of all IVCT test groups is not necessary. Elimination of classification will
reduce the administrative burden on the Agency and will streamline the path to market. Risk
should be a key factor in determining the regulatory requirements for a given test; however, other
factors should also be considered, particularly those outlined in the exemptions described in the
applicability section and the ability to identify measures to mitigate risk. The following flowchart
outlines HHS’s thinking, which is consistent with VALID, regarding the premarket requirements
for a given IVCT:

2

 As indicated in the flowchart above, there are four potential categories an individual IVCT may
fall into for premarket requirements:
1. Premarket Exempt
2. Precertification of eligible tests (voluntary pathway)
3. Abbreviated Premarket review (for platforms; collection articles; and IVCTs eligible for
precertification for which the developer did not choose the voluntary precertification
pathway)
4. Full Premarket review for IVCTs not eligible for precertification

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 The second and third pathways (i.e., precertification and abbreviated premarket review) would
be applicable to the same population of IVCTs (precertification-eligible IVCTs); it would be up
to developers to choose the pathway they prefer. It may be helpful to incorporate terms such as
“abbreviated premarket review” and “full premarket review” into VALID to distinguish the
differences in premarket submission contents.
The VALID discussion draft outlines explicit criteria for determining if a test is exempt from
premarket review, as well as some explicit criteria for determining eligibility for precertification
or abbreviated review. For the small portion of tests that do not meet these criteria, premarket
review is required unless FDA determines that sufficient mitigating measures to ensure analytical
and clinical validity of such tests exist. In such cases, FDA would have the flexibility to use the
provisions in Sec 587F Regulatory Pathway Designation to move some such tests into
precertification eligibility or a low risk exemption. FDA anticipates that the regulatory
requirements for a given category of tests may be adjusted over time, as it gains more experience
with such tests. HHS believes this framework would allow FDA to continuously re-evaluate the
appropriate level of oversight for these tests based on growing scientific knowledge and clinical
experience.
The small proportion of tests that would generally need premarket review, unless Section 587F is
invoked, are:
•
•
•
•

tests that are high-risk, as these have a greater potential to cause patient harm in the event
of a false result;
tests that are first-of-a-kind, as these have never been reviewed by FDA and therefore, the
risks and potential mitigations are unknown until the first review is complete;
tests that are cross-referenced, as these must be developed and validated for use with
another medical product, necessitating inter-Center review; and
tests that are offered direct to consumer or for home use, as these require review of the
ability of a lay user to understand test results provided directly to the user, and in the case
of home use, to perform the test themselves.

In addition, we agree that certain tests related to the safety of the blood and tissue supply,
including tests that are intended for use in the determination of donor eligibility, donation
suitability or compatibility between donor and recipient; hemolytic disease of newborns, or
diagnosing or monitoring of human retroviruses or human retrovirus infections, would need
premarket review.
Risk remains a key driver of regulatory pathway in the proposed framework, but risk does not
directly correlate with the regulatory pathway. This is similar to the existing medical device
framework in which we have some Class 1 devices that are “reserved” and require premarket
notification and some Class 2 devices that are exempt from premarket notification. Given the
lack of direct correlation between risk and regulatory pathway, HHS believes the risk
classification process is not necessary in this framework and would only delay implementation.

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 4. Definition of Low Risk
On page 10, lines 8-10, clause (ii) says that a test can be low risk if an undetected inaccurate
result “could cause non-life threatening injury or injury that is medically reversible, or delay
necessary treatment.” We suggest combining this language with subparagraph (B) at lines 11-17
(as suggested below) so that such tests can only be considered low risk if the above criteria is
met and “mitigating measures are sufficient to prevent such inaccurate results, detect such
inaccurate results prior to any adverse patient impact or adverse public health impact, or
otherwise sufficiently mitigate the risk associated with such inaccurate result.” Suggested edits to
“Low-Risk” definition:
“(8) LOW-RISK.—
“(A) Subject to subparagraph (B), tThe term ‘low-risk’, with respect to an
in vitro clinical test or category of in vitro clinical tests, means that an
undetected inaccurate result from such in vitro clinical test, or such category of
in vitro clinical tests, when used as intended—
“(iA) would cause minimal or no harm or disability, or immediately
reversible harm, or would lead to only a remote risk of adverse patient
impact or adverse public health impact; or
“(iiB) could cause non-life threatening injury or injury that is
medically reversible, or delay necessary treatment, . “(B) Such term does
not include an in vitro clinical test if and mitigating measures are sufficient
to prevent such inaccurate result, detect such inaccurate result prior to any
adverse patient impact or adverse public health impact, or otherwise
sufficiently mitigate the risk associated with such inaccurate result.
5. Certain Provisions Related to Blood and Tissues
On page 16, line 22, through page 17, line 6, paragraph (2)(C), refers to the continued authority
of the Secretary with respect to human blood and cell and tissue establishments. We note that
some cell and tissue establishments are regulated solely under Section 361 of the Public Health
Service Act, and as such we recommend that section 361 be included on page 17, lines 5 and 6,
as follows:
“(C) BLOOD AND TISSUE.—Nothing in this subchapter shall be
construed to modify the authority of the Secretary with respect to
laboratories, establishments, or other facilities to the extent they are
engaged in the propagation, manufacture, or preparation, including filling,
testing, labeling, packaging, and storage, of blood, blood components,
human cells, tissues, or tissue products under this Act or section 351 or
361 of the Public Health Service Act.

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 In addition, we agree, as set forth in page 4, lines 6-12, of the discussion draft, that it is important
that FDA be able to regulate blood, blood components, or human cells or tissues that are used as
components of such tests under existing authorities until they are released to be incorporated into
an IVCT. This would help to ensure that certain protections currently in place for these products,
including donor screening and eligibility requirements, are applied to such components.
However, on a technical note, we believe it would be more accurate to delete the reference to
interstate commerce, as some blood or tissue establishments may also be the developer of test
and, therefore, may not place the blood, blood component, or tissue in interstate commerce. We
recommend you revise the text as follows:
“(A) Blood, blood components, or human cells or tissues, from the time of
donation or recovery of such article, including determination of donor
eligibility, as applicable, until such time as the article is released into
interstate commerce as a component or part of an in vitro clinical test by
the establishment that collected such article.
6. Applicability for Emergency Use
On page 24, lines 2-3, clause (i) refers to the Secretary making “a declaration under section
564(b) for an in vitro clinical test.” Section 564(b) states that “[t]he Secretary may make a
declaration that the circumstances exist justifying the authorization under this subsection for a
product on the basis of – . . . (C) a determination by the Secretary that there is a public health
emergency, or a significant potential for a public health emergency, that affects, or has a
significant potential to affect, national security or the health and security of United States
citizens living abroad, and that involves a biological, chemical, radiological, or nuclear agent or
agents, or a disease or condition that may be attributable to such agent or agents.” Given the
declaration is for the public health emergency, and not the product, you may wish to consider the
following edits in lines 1-9:
“If the Secretary makes a declaration under section 564(b), for an in vitro clinical test
that was offered for clinical use under an exemption under subsection (b), (c), (d),
(e), (f), (g), (h), or (k) of section 587AB prior to the declaration, such test may
continue to be offered for clinical use after such declaration only if –”
7. Grandfathering
HHS supports the exemption from premarket review, quality system requirements, and most
labeling requirements for grandfathered tests, as described in VALID. As written on page 28
lines 9-14, the provision exempts a grandfathered IVCT when it is run for the first time in a
different lab within the same corporate organization and under common ownership by the same
parent corporation. HHS suggests that this concept should also be applied to CDC’s laboratory
networks. You may wish to consider the following additional text in this provision:
“…is performed in the same laboratory in which it was developed, or by another such
laboratory for which a certificate is in effect under section 353 within the same corporate
organization and having common ownership by the same parent corporation, or by a
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 laboratory within a public health laboratory network coordinated or managed by the
Centers for Disease Control and Prevention;”
8. Public Health Surveillance Activities
HHS encourages the adoption of the definition of Public Health Surveillance published in the
Common Rule (45 CFR 46.102(l)(2)). For your consideration, suggested redlines to page 38
lines 10-23 follow:
‘‘(i) PUBLIC HEALTH SURVEILLANCE ACTIVITIES
(1) IN GENERAL.—The provisions of this subchapter shall not apply to a test
intended to be used solely for public health surveillance.
(2) DEFINITION.—In this subsection, the term ‘public health surveillance’
means ongoing systematic activities, including collection, analysis, and
interpretation of health-related data, essential to planning, implementing, and
evaluating public health practice. activities, including the collection and testing
of information or biospecimens, conducted, supported, requested, ordered,
required, or authorized by a public health authority. Such activities are limited to
those necessary to allow a public health authority to identify, monitor, assess, or
investigate potential public health signals, onsets of disease outbreaks, or
conditions of public health importance (including trends, signals, risk factors,
patterns in diseases, or increases in injuries from using consumer products). Such
activities include those associated with providing timely situational awareness and
priority setting during the course of an event or crisis that threatens public health
(including natural or man-made disasters).
(3) EXCLUSION.—An in vitro clinical test is not excluded from the provisions
of this subchapter if it that is either intended for use in making clinical decisions
for individual patients or other purposes not described in paragraph (2) or whose
if the test’s individually identifiable results may are intended to be reported back
to an individual patient or the patient’s health care provider even if also intended
for public health surveillance purposes.
9. Premarket Review to Ensure Analytical Validity of Platforms
HHS supports the requirement in VALID for premarket review of platforms.
All platforms that are exempt from premarket notification requirements today (e.g., clinical
chemistry analyzers, mass spectrometers, and next generation sequencing instruments) are
currently reviewed when an assay using such platform is submitted to the FDA. This is described

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 in our Replacement Reagent and Instrument Family Policy1 as follows: “Although most
automated clinical analyzers by themselves are class I and exempt from 510(k),
reagent/instrument systems are considered “combination devices.” FDA’s Guidance on the
CDRH Premarket Notification Review Program provides: In its review of the 510(k), the Center
will subject the “combination device” to the same sorts of questions and documentation
requirements that are applied to a single device. When such a device is found to be [substantially
equivalent to the predicate device], it combines devices from different classes and is classified in
the highest of the predicate device classifications unless the combined devices are regulatable as
separate articles, e.g., they are detachable. In that case, the separately regulatable articles will be
regulated in separate classes.” One example of this in practice is FDA’s recent clearance for a
thyroid hormone assay run on a clinical chemistry analyzer where we reviewed and cleared both
the assay and the platform, even though the platform is exempt on its own. 2 While review of
platforms in the context of assays that utilize them works under FDA’s current framework that
includes premarket review of moderate and high risk assays, the focus of oversight is shifted
under the VALID framework such that most assays would not be subject to individual premarket
review, making a model where platforms are not individually reviewed dangerous.
FDA premarket review of platforms, as proposed in the discussion draft, is necessary because of
the potential for inaccurate test results due to platform issues. As provided under the proposed
regulatory framework, a wide variety and large number of tests could be run on a platform under
precertification (or other exemption), and therefore it is necessary to ensure that platforms are
analytically valid. Without this review, we would be concerned about the broad public health
impact of platforms being used for many types of tests for which the platform is potentially
invalid or outside of its specifications. FDA has seen such issues impact test results, in some
cases resulting in a safety alert3 or recalls4. These examples illustrate the importance of the
platform to the assay results.
We also believe that a stand-alone review of platforms covering all marketed functionalities will
be more efficient than reviewing limited functionality of a platform in the context of each
submission for each assay run on the platform. One-time platform review would include
analytical validation across all functionalities, labeling, software validation, electromagnetic
1

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM598031
.pdf
2
For example, see https://www.accessdata.fda.gov/cdrh_docs/reviews/K162606.pdf
3
For example, see http://wayback.archiveit.org/7993/20171115052211/https:/www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm518830.htm
4
For examples, see https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=165791,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=164973,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=165298,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=158468,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfres/res.cfm?id=155029,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfres/res.cfm?id=129116,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=147815,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=99600,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=88235,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=33671,
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRES/res.cfm?id=35321

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 compatibility and electrical safety; however, platforms would only be required to have Quality
System (QS) documentation on file and they would not be subject to premarket review of QS
documentation or preapproval inspection, nor would the developer be required to provide raw
data by default. Premarket review of platforms would enable developers to market their
platforms as FDA-authorized for other test developers to incorporate into their IVCTs, regardless
of whether those IVCTs are exempt from premarket review. Further, developers would be
required to utilize only those platforms that are FDA-authorized.
Recognizing that platforms are a significant investment for laboratories, we continue to support
allowing a 5-year grace period for development of new IVCTs on platforms that have not been
authorized by FDA, as is currently proposed in VALID.
Also recognizing that some entities develop both platforms and assays, we are amenable to
language clarifying that developers may submit concurrent submissions for platforms and
IVCTs, leveraging the same data sets as applicable (i.e., for the single representative assay). For
example, a developer could submit concurrent submissions for a precertification ineligible test, a
platform, a collection article, and a precertification, or any subset of combinations. This set of
concurrent submissions would use the precertification ineligible test as the representative assay
for the platform, collection article, and precertification, provided it appropriately covers the
scope of all submissions leveraging it. This would allow the developer to leverage the same AV
and CV data from a single representative assay and receive: (1) approval for a precertification
ineligible IVCT, (2) approval for a platform, (3) approval for a collection article, and (4)
precertification for the specified technology. In this example, the developer would submit the
assay validation in their full premarket submission and include a reference to this submission for
the representative assay requirements in the other three submissions (i.e., for the platform,
collection article and precertification). This could streamline premarket submission and review
for developers and FDA while maintaining an appropriate level of oversight.
10. Data requirements
The Department supports the discussion draft’s approach for ensuring FDA is able to obtain
enough information to make regulatory decisions, as this is critical for protecting the public
health. HHS believes that submission of summary data in a premarket application is appropriate
for most tests, but FDA must be able to obtain additional information if needed without undue
burden, particularly to evaluate the relatively small proportion of tests that would require full
premarket review. For certain tests, FDA’s ability to determine whether a test is analytically and
clinically valid depends on its ability to review the underlying raw data. In FDA’s experience
reviewing IVDs, it has seen a variety of serious issues during premarket review that were only
identified because FDA was able to review the raw data.
11. Streamlined, Efficient Approach to Modifications
HHS supports the requirements regarding modifications in VALID. We note that under the
proposed regulatory framework, FDA would be reviewing less than half of the modifications we
currently review prior to implementation. HHS believes this approach is appropriate as it will
give FDA a premarket check on the most impactful modifications and still require
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 documentation to design control files for all modifications, which would be subject to postmarket
review upon inspection.
Specifically, precertified developers would be able to modify their tests without submitting
anything to FDA for review, as long as the modification did not cause the test to fall outside the
scope of the precertification or render the test ineligible for the program. For the small proportion
of tests for which premarket review is required or for which the developer elects abbreviated
premarket review, FDA would incorporate review of prospective change protocols in initial
submissions that would enable timely improvements and other important changes to tests without
requiring premarket review of the modification. Such prospective change protocols could
potentially cover certain types of modifications relating to specimen type or stability, addition of
new clinical context of use or new target variants, among others.
FDA needs clear authority to review modifications to such tests outside of an approved change
protocol if the modifications adversely affect performance, change performance claims, or
constitute a change in intended use as described by the seven key notification elements:
substance(s) measured, specimen/sample type(s), test method, disease or condition for which the
test is intended for use, intended patient population, test purpose, and context of use. Such
modifications impact the analytical and clinical validity of a test or could result in an entirely
new intended use.
12. Least Burdensome
HHS supports the least burdensome provisions provided in brackets beginning on page 64.
13. Priority Review and Breakthrough
HHS supports the concept of priority review in VALID, which is consistent with existing
breakthrough provisions for medical devices. The breakthrough provisions instituted by 21st
Century Cures have already led to successful authorizations of in vitro diagnostics, including the
Foundation One CDx oncopanel and the Banyon Biomarkers blood test for traumatic brain
injury. HHS supports leveraging the existing criteria and framework in VALID. For your
convenience, HHS notes some potential drafting issues for your consideration.
•
•

Subsection “a” on page 66 lines 12 and 14-15 refer to granting of approval under
subsection “f”; this subsection “f” on page 69 lines 20-23 refers to annual reporting
requirements and does not mention approval.
Subsection “c” on page 67 line 21 refers to “breakthrough approval or approval under
this section”; however, an approval process is not currently described in this section.

Subsection “e” on page 69 line 18 includes a placeholder for “Breakthrough In Vitro Clinical
Tests.” HHS would support a provision that enables a time-limited approval based on probable
clinical validity, provided the approval would automatically lapse if clinical validity was not
established and full approval obtained within a specified timeframe.

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 14. Precertification is a Key Component of a New Flexible Regulatory Framework
HHS continues to believe that a precertification pathway provides a flexible option for eligible
developers with eligible tests, and supports its inclusion in VALID. The feasibility of the overall
regulatory framework depends on inclusion of the precertification pathway to enable efficient
FDA oversight of a large volume of tests. Under precertification, FDA would evaluate test
developers and their processes for developing certain tests to ensure that current and future tests
developed under that precertification are analytically and clinically valid. Precertification would
benefit test developers who would be able to bring new tests to market under a precertification
quickly, patients who would have access to these tests more quickly, and FDA which would be
able to appropriately focus resources to best protect the public health. HHS believes that
precertification is an efficient and appropriate way to provide oversight for certain categories of
tests.
HHS supports the VALID proposal that the scope of an individual precertification be limited to
all eligible IVCTs within a single technology. Accordingly, a single precertification scope could
cover many test groups. For example, a developer could request a precertification scope covering
the use of polymerase chain reaction (PCR) on a variety of sample types and in different clinical
areas, such as diagnosing infectious diseases from microbial DNA and/or germline diseases from
human DNA. Although HHS’s prior TA suggested limiting the scope by both technology and
medical subspecialty, HHS agrees that many medical specialties can be addressed in a single
precertification provided they are stated up front by the developer, supported by appropriate
procedures for establishing clinical validity, and contemplated in the selection of a representative
assay for purposes of recertification.
Potential risks associated with allowing precertified developers to market eligible tests without
FDA premarket review are mitigated by key provisions in VALID: The requirement for periodic
re-certification with a new representative assay would enable FDA to monitor a developer’s
ongoing application of its procedures to developing and validating tests appropriately. The
requirement for transparency regarding IVCT intended use and performance in the CTIS would
enable FDA and the public to efficiently monitor the tests introduced under precertification and
the developer’s claims associated with them. This powerful database combined with adverse
event reporting requirements would enable FDA to identify issues. Finally, if issues do arise, the
provisions for temporary suspension and withdrawal of precertification would allow FDA to
address them appropriately.
VALID includes requirements for annual reports to Congress for the first five years of the
program as well as a public meeting between the fourth and fifth annual report. HHS appreciates
the need for transparency and accountability as this novel program is implemented. Since much
of the data requested in the Report to Congress would be publicly available through CTIS, we
recommend that FDA provide a public update published on its website, instead of through a
Report to Congress, to ensure all affected stakeholders have the opportunity to review and
comment on the update.

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 15. Presubmissions
HHS supports the presubmission provisions beginning on page 95, including the bracketed
language allowing presubmission discussions to cover regulatory pathways and investigational
plans.
16. National Security Considerations for Registration and Notification and for
Publication of Approval Orders
HHS supports the transparency that will be afforded to all stakeholders through the
Comprehensive Test IT System as well as the safeguard against public disclosure of sensitive
information that could compromise national security. We suggest the following revisions to
improve clarity and consistency within the legislation.
With respect to publication of approval orders on page 56, we suggest:
“(D) PUBLICATION.—The Secretary shall publish each order approving
an application pursuant to this paragraph on the public website of the Food and
Drug Administration and make publicly available a summary of the data used
to grant the approval, except to the extent the Secretary determines that such
order relates to national security or countermeasures or data is restricted from
disclosure pursuant to statutory provisions other than this section.
With respect to registration and notification on page 104, we suggest:
“(3) The registration and notification information requirements described in
subsections (a) and (b) shall not apply to the extent the Secretary determines that such
information relates to national security or countermeasures or is restricted from
disclosure pursuant to another statute, including information relating to national
security or countermeasures.

17. Quality System (QS) Regulation
HHS supports the discussion draft’s approach of requiring QS to ensure that the tests developed
are of sufficient quality and meet the developer’s specifications. The QS requirements help to
ensure that IVCTs perform as intended and establish mechanisms to detect quality problems and
promptly address any issues that may arise.
For developers that are CLIA-certified, FDA would only evaluate a subset of the QS
requirements: design controls, purchasing controls, receiving and acceptance activities, CAPA,
and records (including the subsections that fall under records in 21 CFR 820, such as complaint
files). This subset of FDA QS requirements is necessary to ensure the design and development
of high quality tests.

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 HHS suggests the addition of “distribution” to the list of IVCT activities to which the quality
system requirements of the section should apply (page 107 lines 1-10):
‘‘(1) IN GENERAL.—The quality system requirements applicable under this section
shall, including applying or amending part 820 of title 21 of the Code of Federal
Regulations as provided in subsection (a)(4)—
‘‘(A) apply only with respect to the design, development, validation, production,
manufacture, preparation, propagation, distribution, or assembly of an in vitro
clinical test, offered under this subchapter;”
HHS supports the provision that allows developers to share protocols with other laboratories
within the same corporate organization. HHS suggests enabling CDC to utilize this provision for
all of their laboratory networks. HHS also suggests explicitly stating that laboratories that run
protocols developed by another laboratory within their corporate organization, or within the
public health laboratory network, must do so without modification to meet this provision. For
your consideration, redlines to this section which begins on page 109 are provided:
‘‘(3) QUALITY SYSTEM REQUIREMENTS FOR CERTAIN LABORATORIES
DISTRIBUTING PROTOCOLS WITHIN ORGANIZATIONS OR PUBLIC HEALTH
NETWORKS.—
‘‘(A) With regard to establishing quality system requirements under this Act,
including applying or amending part 820 of title 21 of the Code of Federal
Regulations as provided in subsection (a)(4), quality system requirements
applicable to the developer and in vitro clinical test distributed under
subparagraph (B) shall consist of the following provided that the conditions of
subparagraph (B) are met:
‘‘(i) The requirements in paragraph (2).
‘‘(ii) The labeling requirements in subparagraph (1)(L).
‘‘(iii) The requirement to maintain records of the laboratories to which the
test protocol is distributed.
‘‘(B) To be eligible for subparagraph (A), the following conditions must be met—
‘‘(i) the laboratory distributing the protocol is certified by the Secretary
under section 263a of title 42 of the United States Code and meets the
requirements for performing high-complexity testing;
‘‘(ii) the laboratory develops its own in vitro clinical test or modifies
another developer’s in vitro clinical test in a manner described in section
587(6); and
‘‘(iii) the laboratory distributes the test protocol for such test only to
another laboratory that—
‘‘(I) is certified by the Secretary under section 263a of title 42 of
the United States Code and meets the requirements for performing
high-complexity testing; and‘‘
(II) is within the same corporate organization and having common
ownership by the same parent corporation; or as applicable, is
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 within the Laboratory Response N a laboratory within a public
health laboratory network of coordinated or managed by the
Centers for Disease Control and Prevention.; and
(III) implements the test protocol without further modification.
18. FDA Must have Strong General Postmarket Authorities
HHS appreciates that the discussion draft provides FDA strong general postmarket authorities.
Under the proposed regulatory framework, the ability of FDA to continue to fulfill its mission of
protecting the public health depends on FDA’s ability to monitor tests in the postmarket setting
and enforce when necessary. HHS believes that the shift away from premarket review for most
tests necessitates clear, workable postmarket monitoring and enforcement authorities, such as
postmarket surveillance, adverse event reporting, inspections, recalls, corrections and removals.
It is also critical for FDA to have reasonable enforcement standards, including, when necessary,
the ability to require a premarket submission for tests offered under an exemption or to revoke an
exemption. FDA must have the ability to address problematic IVCTs, including those that may
be grandfathered, when they are not analytically or clinically valid, do not have sufficient valid
scientific evidence to support analytical and clinical validity, have false or misleading labeling or
advertising, and where there is a reasonable potential that the IVCT will cause death or serious
adverse health consequences, including by causing the absence, delay, or discontinuation of
appropriate medical treatment.
19. Restricted IVCTs
HHS supports the provisions for Restricted IVCTs beginning on page 122. We note there is a
placeholder for “Labeling and advertising of a restricted IVCT.” HHS suggests the following
language for this subsection which is consistent with current medical device provisions:
“(1) The label, labeling, and advertising of an in vitro clinical test to which restrictions
apply under subsection (a) shall bear such appropriate statements of the restrictions as the
Secretary may prescribe in the approval, [breakthrough approval], precertification, or
regulation, as applicable.
“(2) Except in extraordinary circumstances, the Secretary shall not require prior approval
of the content of any advertisement, and no advertisement of a restricted in vitro clinical
test, published after the effective date of this section shall, with respect to the matters
specified in this section or in orders or regulations issued hereunder, be subject to the
provisions of sections 12 through 15 of the Federal Trade Commission Act (15 U.S.C.
§§52-55). This subparagraph shall not be applicable to any printed matter which the
Secretary determines to be labeling as defined in section 201(m).
20. Investigational Use
HHS supports the provision in VALID for exemptions for Investigational Use. For studies of
IVCTs that are nonsignificant risk, HHS does not believe a submission to the Secretary is
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 necessary, consistent with current practice. We suggest the following edits on page 135 of
VALID to clarify this:
“(B) In the case of an in vitro clinical test, the investigational use of which
does not pose a significant risk—
“(i) the sponsor of such investigation shall comply with—
“(I) conduct such investigation in compliance with an
investigational plan and labeling the requirements specified in
paragraphs (3)(A), (3)(B), and (5)(A)(iii); and
“(II) ensure each investigator obtains informed consent under
part 50 subject to the exceptions set forth in paragraphs (5)(A)(iii)(I)
and (II) and (5)(B)(iii); and
“(III) comply with such other requirements as the Secretary may
determine to be necessary for the protection of the public health and
safety, including the monitoring of investigations conducted with
such test, the establishment and maintenance of records, or the
submission to the Secretary of reports of data obtained as a result of
the investigational use of the in vitro clinical test during the period
covered by the exemption; and
“(IV) maintain records with respect to all requirements in this
subparagraph.
“(ii) the sponsor may rely on any exception or exemption identified in
paragraph (5)(B) or as established by the Secretary in regulations issued
under subsection (b).

Additionally, we noted an incorrect reference in the Investigational Plan Requirements and
suggest the following edit on page 138 of VALID:
“(5) INVESTIGATION PLAN REQUIREMENTS.—
“(A) IN GENERAL.—With respect to a plan submitted under paragraph
(23)(B), the sponsor submitting such plan shall—
The following conforming edit to the Application Contents on page 136 of VALID may be
helpful:
“(2) APPLICATION CONTENTS.—An investigational use application shall
be submitted in such time and manner and contain such information as the Secretary
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 may require in regulation. The application and shall include an investigational plan
and assurances to the satisfaction of the Secretary that the sponsor involved shall,
with respect to the in vitro clinical test that is the subject of the application—
21. FDA Supports Leveraging External Expertise
The Department supports the mechanisms the discussion draft has provided to allow FDA to
leverage external expertise for oversight of IVCTs. FDA should be able to leverage external
expertise and assistance in the context of third party review and inspection to realize efficiencies,
particularly as some existing CLIA Accrediting Organizations (AOs) may seek accreditation
from FDA to conduct third party reviews or inspections, perhaps combined with CLIA
inspections. At the very least, using CLIA AOs to perform FDA inspections would allow labs to
continue to interact with the inspectors they are already familiar with.
FDA should also be able to engage with public and private sector members to proactively work
together to solve shared problems. Engagement with such continuing forums, which we have
termed “Collaborative Communities,” would allow FDA to seek input from a broad array of
stakeholders on a variety of topics, such as standards development activities and mitigating
measures.
22. Transition
HHS supports the transition provisions starting on page 184 in VALID. Specifically, we agree
that grandfathered in vitro clinical tests that meet the criteria starting on page 26 of VALID,
including being offered for clinical use at least 90 days prior to enactment, should be
“grandfathered” and exempt from premarket review and QS requirements. The 90 day window
pre-enactment is critical to prevent rush to market to obtain grandfathered status.
Developers of transitional in vitro clinical tests (as defined starting on page 186 of VALID)
offered for clinical use between 90 days pre-enactment and the effective date could choose
between voluntary compliance with medical device provisions or temporary enforcement
discretion until review of an IVCT submission (e.g., precertification, abbreviated premarket
review, or full premarket review, as applicable) is complete following the effective date.
HHS believes this is the smoothest way to transition into the new framework in a reasonable
amount of time. HHS appreciates that the discussion draft would not require simultaneous
operation of two different oversight systems for the same products.
23. User Fees
HHS appreciates the inclusion of a user fee provision in VALID, as a healthy user fee program is
critical to its success. Under user fee programs, FDA and stakeholders come together on a
regular basis for the shared purpose of advancing the field and helping patients. For example,
FDA and industry created the Dual 510(k) and CLIA Waiver by Application pathway under the
Medical Device User Fee program. This strategic pathway enables developers of tests intended
for use by lay users to conduct one clinical study and submit one submission to obtain both
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 marketing authorization and CLIA waiver status. This is more efficient for all parties and
furthers timely patient access to accurate and reliable tests. Resources from user fee programs
enable FDA staff to dedicate time to developing innovative policies such as this as well as to
interacting with sponsors for more efficient reviews of submissions.
As written in the discussion draft, FDA would not be able to use user fee funding to support all
activities under the IVCT program, particularly those outside of premarket application review. In
addition to the premarket review of in vitro clinical tests, the IVCT framework relies on an
enhanced postmarket focus for the assurance of in vitro clinical test analytical validity and
clinical validity. All activities related to IVCT oversight that provide the assurance of in vitro
clinical test analytical validity and clinical validity (e.g., registration, notification, premarket
review, precertification, adverse event monitoring, inspections, and other postmarket
surveillance activities) should be supported by a healthy user fee program in order to ensure the
workability and success of the program. To enable FDA to apply user fees to all such activities,
we suggest replacing the phrase “the process for the review of in vitro clinical tests” with
“activities related to oversight of in vitro clinical tests” throughout the section.
We are open to a novel user fee framework but note that some deviations from FDA’s existing
medical product user fee programs may have unintended consequences as described below.
•

The discussion draft limits fees to submissions, which could result in unstable funding.
FDA experienced unintended consequences with such a structure under MDUFA I that
required the MDUFA stabilization act to correct. Since that time FDA’s MDUFA
reauthorization discussions with industry first focus on a total cost for a given package of
performance goals and process improvements; then FDA works together to negotiate a
fee structure that provides such funding in a stable manner. For example, under MDUFA
FDA has facility registration fees. The relatively smaller fees on a large number of
facilities ensures more stable funding than relatively higher fees tied to less frequent
activities subject to fluctuations in frequency. A stable base is critical for the program,
since premarket submission volumes often fluctuate.

•

Submission fees have traditionally not been commensurate with the effort for the
particular submission type. Instead, the funds necessary for the entire program are
determined, and fees are assigned to particular submission types in a strategic manner,
knowing that the fees will be used to support activities across the entire program, not only
a particular submission. For example, the MDUFA IV agreement includes funding for
additional review staff to meet performance goals on Pre-Submissions. There are no fees
on Pre-Submissions themselves; the staff are supported by fees associated with facility
registrations and other submissions. The ability to consider the program and ecosystem
holistically has been useful to all parties to MDUFA reauthorization.

HHS suggests aligning the authorization timeframe with the reauthorizations for MDUFA and
PDUFA programs, which would allow them to be included in a single legislation. Further,
removing IVDs from the current MDUFA program would upset some of the assumptions of the
negotiated agreement, particularly with respect to submission volumes and their impact on fee
setting. A clean break could take place between MDUFA IV and MDUFA V, which will begin
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 on October 1, 2022. It would be most helpful if this could be anticipated at the time MDUFA V
negotiations begin in 2020, so that appropriate assumptions can be taken into consideration for
the medical device program under MDUFA V.
Further, HHS recommends removing audits from the statutory provision and leaving discussion
of such independent assessments to the user fee negotiations. We note that both MDUFA and
PDUFA programs include independent assessments, the details of which are outlined in the
Commitment Letters. This approach would allow meaningful discussion among affected
stakeholders and the ability to craft appropriately tailored provisions for an independent
assessment that fit with the overall package to be negotiated. Any such provisions for an
independent assessment could be included in the Commitment Letter to ensure accountability.

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