[Federal Register Volume 91, Number 52 (Wednesday, March 18, 2026)]
[Proposed Rules]
[Pages 12966-12972]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2026-05322]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 892
[Docket No. FDA-2025-N-5995]
Effective Date of Requirement for Premarket Approval Applications
for Blood Irradiators Intended To Prevent Metastasis
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed amendment; proposed order.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to require
the filing of a premarket approval application (PMA) for blood
irradiators intended to irradiate intraoperatively salvaged blood for
cancer patients undergoing surgery to assist in prevention of
metastasis, which are unclassified, preamendments devices. FDA is
summarizing its proposed findings regarding the degree of risk of
illness or injury designed to be eliminated or reduced by requiring the
devices to meet PMA requirements of the Federal Food, Drug, and
Cosmetic Act (FD&C Act) and the benefits to the public from use of the
devices.
DATES: Either electronic or written comments on the proposed order must
be submitted by May 18, 2026. FDA intends that, if a final order based
on this proposed order is issued, anyone who wishes to market blood
irradiators intended for use in the irradiation of intraoperatively
salvaged blood for cancer patients undergoing surgery to assist in the
prevention of metastasis must submit a PMA prior to the last day of the
30th calendar month beginning after the month in which the
classification of the device in class III became effective. See section
III for the effective date of any final order that may publish based on
this proposed order. See section VI of this document for
[[Page 12967]]
more information about submitting a PMA.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of May 18, 2026. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2025-N-5995 for ``Effective Date of Requirement for Premarket
Approval Applications for Blood Irradiators Intended to Prevent
Metastasis.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
FOR FURTHER INFORMATION CONTACT: Julie Sullivan, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 3658, Silver Spring, MD 20993-0002, 240-402-4973,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The FD&C Act, as amended, establishes a comprehensive system for
the regulation of medical devices intended for human use. Section 513
of the FD&C Act (21 U.S.C. 360c) established three classes of devices
reflecting the regulatory controls needed to provide reasonable
assurance of their safety and effectiveness. The three classes of
devices are class I (general controls), class II (special controls),
and class III (premarket approval).
Under section 513(d)(1) of the FD&C Act, devices that were in
commercial distribution before the enactment on May 28, 1976, of the
1976 amendments (Medical Device Amendments of 1976, Pub. L. 94-295)
(generally referred to as ``preamendments devices'') are classified
after FDA (we or the Agency) has: (1) received a recommendation from
the appropriate device classification panel (which are part of the FDA
Medical Devices Advisory Committee); (2) published the panel's
recommendation and a proposed regulation classifying the device for
comment; and (3) published a final regulation classifying the device.
FDA has classified most preamendments devices under these procedures.
A person may market a preamendments device that has been classified
into class III through premarket notification procedures, without
submission of a PMA until FDA issues an administrative order under
section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) requiring premarket
approval.
Section 515(f) of the FD&C Act provides an alternative pathway for
meeting the premarket approval requirement. Under section 515(f),
manufacturers may meet the premarket approval requirement if they file
a notice of completion of a product development protocol (PDP) approved
under section 515(f)(4) of the FD&C Act and FDA declares the PDP
completed under section 515(f)(6)(B) of the FD&C Act. Accordingly, the
manufacturer of a preamendments class III device may comply with a call
for PMAs by filing a PMA or a notice of completion of a PDP. In
practice, however, the option of filing a notice of completion of a PDP
has rarely been used. For simplicity, although the PDP option remains
available to manufacturers in response to a final order under section
515(b) of the FD&C Act, this document will refer only to the
requirement for filing and obtaining approval of a PMA.
Section 515(b)(1) of the FD&C Act sets forth the process for
issuing a final order. Specifically, prior to the issuance of a final
order requiring premarket approval for a preamendments class III
device, the following must occur: (1) publication of a proposed order
in the
[[Page 12968]]
Federal Register; (2) a meeting of a device classification panel
described in section 513(b) of the FD&C Act; and (3) consideration of
comments from all affected stakeholders, including patients, payors,
and providers.
Section 515(b)(2) of the FD&C Act provides that a proposed order to
require premarket approval shall contain: (1) the proposed order; (2)
proposed findings with respect to the degree of risk of illness or
injury designed to be eliminated or reduced by requiring the device to
have an approved PMA, and the benefit to the public from the use of the
device; (3) an opportunity for the submission of comments on the
proposed order and the proposed findings; and (4) an opportunity to
request a change in the classification of the device based on new
information relevant to the classification of the device.
Section 515(b)(3) of the FD&C Act provides that FDA shall, after
the close of the comment period on the proposed order,\1\ consideration
of comments received, and a meeting of a device classification panel
described in section 513(b) of the FD&C Act, issue a final order to
require premarket approval or publish a document terminating the
proceeding together with the reasons for such termination. If FDA
terminates the proceeding, FDA is required to initiate reclassification
of the device under section 513(e) of the FD&C Act, unless the reason
for termination is that the device is a banned device under section 516
of the FD&C Act (21 U.S.C. 360f).
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\1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ACTION caption for these documents to indicate
that they ``propose to amend'' the Code of Federal Regulations. This
editorial change was made in accordance with the Office of the
Federal Register's interpretations of the Federal Register Act (44
U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and
parts 21 and 22), and the Document Drafting Handbook.
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A preamendments class III device may be commercially distributed
without a PMA until 90 days after FDA issues a final order requiring
premarket approval for the device, or 30 months after the
classification of the device in class III under section 513 of the FD&C
Act becomes effective, whichever is later (section 501(f)(2)(B) of the
FD&C Act (21 U.S.C. 351(f)(2)(B)). Elsewhere in this issue of the
Federal Register, FDA is proposing to classify blood irradiators
intended for use in the irradiation of intraoperatively salvaged blood
for cancer patients undergoing surgery to assist in the prevention of
metastasis (blood irradiators intended to prevent metastasis) into
class III. Therefore, if the proposed classification regulation and the
order to require PMAs are finalized at the same time, a PMA for blood
irradiators intended to prevent metastasis must be filed within the 30-
month period because that will be the later of the two time periods. If
a PMA is not timely filed for such devices, then the device would be
deemed adulterated under section 501(f) of the FD&C Act.
Also, a preamendments device subject to the order process under
section 515(b) of the FD&C Act is not required to have an approved
investigational device exemption (IDE) (see part 812 (21 CFR part 812))
until the date identified by FDA in the final order requiring the
filing of a PMA for the device (assuming it complies with other
applicable FDA requirements). At that time, an IDE is required prior to
interstate distribution of the device only if a PMA has not been filed.
If the manufacturer, importer, or other sponsor of the device submits
an IDE application and obtains FDA approval, the device may be
distributed for investigational use. If a PMA is not filed by the later
of the two dates, and the device is not distributed for investigational
use under an IDE or otherwise exempt from the PMA requirements, the
device is subject to enforcement action.
II. Regulatory History of the Devices
After the enactment of the Medical Device Amendments of 1976, FDA
undertook an effort to identify and classify all preamendments devices
in accordance with section 513(d) of the FD&C Act. Consistent with the
FD&C Act, FDA held a Radiological Devices Panel meeting regarding the
classification of blood irradiators, with product code ``MOT,'' on
April 12, 2012 (2012 Panel) (Ref. 1). However, the 2012 Panel focused
specifically on blood irradiators intended to irradiate blood and blood
products to prevent transfusion-associated graft-versus-host disease
(blood irradiators intended to prevent TA-GVHD), including those
intended to inactivate leukocytes and/or lymphocytes to prevent TA-
GVHD. The materials considered by the 2012 Panel noted that one device
had been cleared at the time for the prevention of metastasis, but the
classification of blood irradiators intended to prevent metastasis was
not discussed at the 2012 Panel (Ref. 1).
On November 7, 2023, FDA held a Radiological Devices Panel meeting
regarding the classification of blood irradiators intended to prevent
metastasis (2023 Panel) (Ref. 2). FDA held the 2023 Panel to obtain
input on the risks to health and benefits of blood irradiators intended
to prevent metastasis. During the 2023 Panel meeting, FDA presented
proposed risks to health for these devices. FDA identified risks which
included some of the same risks that had been identified during the
2012 Panel for blood irradiators intended to prevent TA-GVHD relating
to the device's hardware and software and some unique risks based on
the device's intended use to prevent metastasis. FDA noted that based
on available information, long-term safety risks related to the
device's intended use are unclear. In addition, there appears to be a
lack of clinical data to demonstrate a clear clinical benefit from use
of blood irradiators intended to prevent metastasis. The 2023 Panel was
asked to recommend to FDA whether blood irradiators intended to prevent
metastasis should be classified into class III (premarket approval),
class II (special controls), or class I (general controls).
The 2023 Panel reviewed the list of risks to health provided by FDA
for blood irradiators intended to prevent metastasis and agreed with
the risks to health identified by FDA. The 2023 Panel also identified
several additional risks to health posed by the device's intended use.
The 2023 Panel agreed with FDA that the list of risks to health
identified for this device type may not be exhaustive due to the
limited reported clinical use of blood irradiators when used for the
prevention of metastasis. The 2023 Panel also agreed that the benefits
of irradiating intraoperatively salvaged blood for cancer patients
undergoing surgery is unknown based on lack of scientific evidence.
The 2023 Panel recommended that blood irradiators intended to
prevent metastasis be classified into class III because there was a
lack of available evidence to determine that general and special
controls are sufficient to provide reasonable assurance of safety and
effectiveness, and these devices present a potential unreasonable risk
of illness or injury given the lack of probable benefit. FDA agrees
with the Panel's recommendation that blood irradiators intended for the
prevention of metastasis be classified into class III subject to PMA.
It is also FDA's position that there is a lack of available evidence to
determine that general and special controls are sufficient to provide
reasonable assurance of the device's safety and effectiveness, and that
the device presents a potential unreasonable risk of illness or injury.
Elsewhere in this issue of the Federal Register, FDA is proposing
to classify blood irradiators intended to prevent metastasis into class
III. FDA has tentatively determined that requiring
[[Page 12969]]
PMA approval, in addition to general controls, will provide reasonable
assurance of the safety and effectiveness of these devices. The
proposed classification action would also establish the identification,
classification, and regulatory controls for blood irradiators intended
to prevent TA-GVHD. These devices have been subject to premarket review
through a premarket notification (510(k)) submission and have been
cleared for marketing if FDA considers the device to be substantially
equivalent to a legally marketed predicate in accordance with section
513(i) of the FD&C Act. To date, FDA has cleared 16 of these devices
and cleared only two devices of the device type that will be subject to
the PMA requirements. For these two devices, the prevention of
metastasis is a second intended use for the device in addition to the
intended use to prevent TA-GVHD.
III. Dates New Requirements Apply
If FDA finalizes the proposed classification of blood irradiators
intended to prevent metastasis, these devices will be classified into
class III. In accordance with sections 501(f)(2)(B) and 515(b) of the
FD&C Act, FDA is proposing to require that a PMA be filed with the
Agency for blood irradiators intended to prevent metastasis by the last
day of the 30th calendar month beginning after the month in which the
classification of the device in class III becomes effective.
An applicant whose product was in commercial distribution before
May 28, 1976, or whose product has been found to be substantially
equivalent to such a product, may continue marketing such class III
product during FDA's review of the PMA, provided that a PMA is timely
filed. FDA intends to review any PMA for the device within 180 days.
FDA cautions that under section 515(d)(1)(B)(i) of the FD&C Act, the
Agency may not enter into an agreement to extend the review period for
a PMA beyond 180 days, unless the Agency finds that ``. . . the
continued availability of the device is necessary for the public
health.''
Moreover, manufacturers must cease distribution of blood
irradiators intended to prevent metastasis upon receiving a denial
decision rendered on a PMA. In such circumstances, to resume
distribution of devices for this indication, these manufacturers must
receive PMA approval for their devices. However, the product may be
distributed for investigational use only if the requirements of the
investigational device exemptions regulations in part 812 are met. The
requirements for investigational use of significant risk devices
include submitting an IDE application to FDA for review and obtaining
approval. An IDE application under 21 CFR 812.30 is required to be
approved before an investigation of the device may be initiated or
continued. FDA, therefore, recommends that IDE applications be
submitted to FDA at least 30 days before the date a PMA is required to
be filed to avoid interrupting investigations.
IV. Devices Subject to This Proposal
Blood irradiators intended to prevent metastasis are used to
irradiate intraoperatively salvaged blood ex vivo from cancer patients
undergoing surgery to assist in the prevention of metastasis. Blood
lost during surgery is collected using a suction device and may be
processed or filtered before the blood irradiator is used to irradiate
the blood to prevent the proliferation of cancer cells that may be
present. The blood is then reinfused to the same patient either
intraoperatively or post-operatively in an autologous blood
transfusion. These devices include an x-ray or a sealed radiation
source. FDA currently regulates these unclassified devices as devices
requiring a 510(k) submission under product code MOT.
Elsewhere in this issue of the Federal Register, FDA is proposing
to classify blood irradiators intended to prevent metastasis into class
III. Blood irradiators are identified as follows: A blood irradiator
device is a prescription device used to deliver a controlled radiation
dose to blood or blood products. This generic type of device includes
an x-ray or a sealed radiation source. Blood irradiators are class III
when intended to irradiate intraoperatively salvaged blood in cancer
patients undergoing surgery to assist in the prevention of metastasis.
In accordance with section 515(b)(2)(C) and (D) of the FD&C Act,
interested persons are being offered the opportunity to comment or
request a change on the Agency's proposed classification of blood
irradiators intended to prevent metastasis published elsewhere in this
Federal Register.
V. Proposed Findings With Respect to Risks and Benefits for Blood
Irradiators Intended To Prevent Metastasis
As required by section 515(b) of the FD&C Act, FDA is publishing
its proposed findings regarding: (1) the degree of risk of illness or
injury designed to be eliminated or reduced by requiring that these
devices have an approved PMA and (2) the benefits to the public from
the use of the devices. These findings are based on the reports and
recommendations of the 2023 Panel, and any additional information that
FDA has obtained. Additional information regarding the risks can be
found below, as well as in the proposed rule published elsewhere in
this issue of the Federal Register, proposing to classify these devices
into class III.
Based on this information, FDA has identified the following risks
to health of blood irradiators intended to prevent metastasis:
Damage to blood or blood components from radiation:
Irradiation of whole blood and red blood cells causes damage to red
blood cells and lymphocytes within the blood. Radiation damages the
membrane of red blood cells leading to higher concentrations of
potassium in plasma, hemolysis (destruction of red blood cells), and
decreased red blood cell viability and survival.
Unintended radiation exposure to the operator and others:
\2\ Device malfunction, lack of adequate maintenance, inadequate
shielding, or safety control or interlock failure could allow the
operator to access the radiation source resulting in physical injury
and/or exposure of the operator or other nearby persons to radiation.
Exposure to ionizing radiation has been shown to increase cancer risk
(Ref. 3). Insufficient presence of safety controls or interlocks within
irradiator design may result in unintended exposure.
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\2\ The original 2023 Panel materials denoted this risk as
``Unintended radiation exposure to the operator and public''. We
have updated the title of this risk to health to expressly reflect
other persons who may be at risk of such exposure (e.g., patients,
bystanders); the description of this risk to health is identical to
what was included in the 2023 Panel materials.
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Electrical shock: \3\ Electrical malfunction of the device
or operator contact with an energized portion may result in electrical
shock or burn. This can occur when there are insufficient or
malfunctioning safety controls or interlocks.
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\3\ The original 2023 Panel materials denoted this risk as
``Electrical shock or burn.'' We have updated the title of this risk
to health to be consistent with the similar risk discussed for blood
irradiators intended to prevent TA-GVHD in the proposed rule; the
description of this risk to health is identical to what was included
in the 2023 Panel materials.
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Mechanical or crush injury: Blood irradiators contain
shielding materials to prevent excess radiation emission outside the
device causing the device itself and many components to be heavy.
Operator inattention or placement of body parts where they can be
impinged by the device may result in physical injury to the operator.
[[Page 12970]]
Presence of proliferative malignant cells in re-transfused
blood due to incorrect dose or improper dose of radiation delivered:
Incorrect dose of radiation identified to be effective or improper dose
of radiation delivered due to operator error, device malfunction, lack
of adequate maintenance, or lack of dosimetry or quality assurance
checks, may result in tumor cell survival leaving proliferative (i.e.,
able to function, grow, and divide) tumor cells present in the blood.
Worsened control of oncologic disease or patient
prognosis: Irradiating blood or blood components may cause an immune
response that negatively impacts cancer outcome or patient recovery or
survival.
Delayed or lack of re-transfusion of irradiated blood or
blood components: Use of the device inherently delays re-transfusion
and lengthens the duration of the operating procedure with larger
volumes of blood irradiated adding a larger amount of additional
operating procedure time. Device malfunction, including from
mechanical, electrical, or software malfunctions, or operator error
could lead to improper or no irradiation of the blood or blood
components, which could add additional delay if the malfunction or
error results in the salvaged blood not being suitable for re-
transfusion into the patient. Delay in re-transfusion could increase
risk to patients depending on their blood volume at any given point in
the procedure. Longer operating times are associated with increased
risks, including prolonged exposure to anesthesia and greater risk of
infection.
Induction of a new cancer due to irradiation of the blood
or blood components: Irradiation of nucleated cells may result in
malignant transformation as ionizing radiation exposure causes DNA
damage that may result in downstream biologic effects (e.g., mutation,
cell killing or carcinogenesis) (Ref. 4). Permanent DNA damage could
result in the cells becoming malignant. Quantitative risk assessment of
this phenomenon occurring in irradiated blood for the prevention of
metastasis has not been performed. If blood salvage and processing,
including irradiation, occurs multiple times, blood cells may be
exposed to ionizing radiation multiple times. If those cells are
returned into the body this could result in induction of a new cancer.
Risks associated with usability including irradiating the
salvaged blood outside the operating room, and the potential for blood
to be incorrectly labeled or misidentified: Included in this risk to
health are issues with operating the device in a way that results in an
incorrect blood product being given to the patient. For example, should
blood irradiation be performed in a manner where blood or blood
products from multiple patients are irradiated at one time, if the bags
are labeled with the wrong patient information, or are thought to be
irradiated, but are not, this could result in the patient receiving a
transfusion of the wrong blood. This could include operator error or
inadequate usability testing of the points of interaction between the
device and the operator, including displays and instructions for use.
A. Summary of Data
FDA conducted a query of the Manufacturer and User Facility Device
Experience (MAUDE) database and the Medical Device Report (MDR)
database from 1984 through September 25, 2023, to identify adverse
events related to use of blood irradiators, with product code MOT,
which includes blood irradiators intended to prevent TA-GVHD and blood
irradiators intended to prevent metastasis. The query resulted in the
identification of five unique MDRs related to blood irradiators during
that time period. No direct adverse events to patients were reported.
FDA also conducted a query of Accidental Radiation Occurrences (AROs)
reports during this time period. There were no AROs reported for
devices under product code MOT. The MDR and ARO analyses showed few
device malfunctions over the lifetime of use for these devices.
Following these queries, FDA received one report of adverse events
related to high current safety interlock system switch failures
reported to result in superficial (first-degree) burns. FDA conducted
updated queries for MDRs on July 7, 2025, and for AROs on November 7,
2024 and August 4, 2025. No additional reports were identified.
FDA reviewed recalls reported under product code MOT from November
2002 to June 22, 2025. There were two recalls for devices under product
code MOT during that time period. The first recall was to complete a
cooling system retrofit to preclude overheating and failure of the
device. The recall was terminated May 13, 2012.\4\ The second recall
was for non-compliance with the associated performance standards within
21 CFR Subchapter J Radiological Health. Specifically, the device
failed to comply with the performance standard for cabinet x-ray
systems (21 CFR 1020.40) \5\ because an interlock was not directly
linked to the door. To address this issue, the company completed
repairs during annual routine preventive maintenance visits at the
users' sites to minimize downtime, and the recall was terminated August
1, 2017.
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\4\ For details about termination of a recall see 21 CFR 7.55.
\5\ A blood irradiator that includes an x-ray source meets the
definition of a cabinet x-ray system found in Sec. 1020.40(b)(3)
because it consists of an x-ray tube installed in an enclosure
intended to contain at least that portion of material, in this case
blood or blood components, being irradiated, provides radiation
attenuation, and excludes personnel from its interior during
generation of x radiation.
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Additionally, FDA conducted a systematic literature review for
articles published between January 1, 2002, and April 20, 2023, to
identify and gather relevant published information regarding the safety
and effectiveness of blood irradiators intended to prevent metastasis.
The review identified 10 articles which were determined to be relevant
to the safety and effectiveness of blood irradiators used to prevent
metastasis. (Ref. 2, Executive Summary at pp. 11-12). No articles
provided information on the safety assessment of blood irradiators
intended to prevent metastasis. No articles definitively evaluated the
effect of salvaged blood irradiation on tumor recurrence or metastasis.
Further, the articles showed a lack of consensus on the specific dose
to use, and for which cancer type and surgical procedure. FDA also
conducted an additional literature search on September 23, 2024 for
articles published since the prior search using the same search terms
and filters and found no additional articles relevant to the safety and
effectiveness of blood irradiators intended to prevent metastasis
published since the prior search. Consequently, FDA tentatively
concludes there is inadequate information characterizing the safety and
effectiveness of blood irradiators intended to prevent metastasis to
establish special controls. The 510(k) clearances of these devices were
based solely on nonclinical information and determinations of
substantial equivalence to a preamendments device. In light of the
available information regarding the risks to health with no information
supporting the benefit of these devices, general controls, including
the 510(k) requirement, appear inadequate to support a reasonable
assurance of safety and effectiveness for these devices.\6\
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\6\ The first blood irradiator that included an intended use to
prevent metastasis was found to be substantially equivalent to a
previously cleared device (i.e., the predicate), which has an
intended use for the prevention of TA-GVHD only. At this time, FDA
does not have records identifying a preamendments device with an
intended use other than to prevent TA-GVHD. As reflected in this
proposed order, and for the reasons described in section V, FDA is
proposing to separately classify these two device types.
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[[Page 12971]]
On November 7, 2023, FDA convened the Radiology Device Panel (2023
Panel) described in section II (Ref. 2). The 2023 Panel members agreed
that there is a lack of clinical data to demonstrate a clinical benefit
regarding the use of blood irradiators intended to prevent metastasis.
The 2023 Panel noted that it is unclear whether risks to health related
to the device's intended use can be exhaustively identified. The 2023
Panel consensus was that blood irradiators intended to prevent
metastasis present an unreasonable risk of illness or injury to the
patient, especially given the lack of probable benefit. Additionally,
the 2023 Panel consensus was that special controls could not be
established to mitigate the risks to health associated with the device
given the very limited data available. As such, the panelists agreed
that blood irradiators intended to prevent metastasis should be
classified as class III.
B. Benefits of the Device
As radiation is able to cause DNA damage in radiation-sensitive
cancer cells and prevent those cells from proliferating (Ref. 5), the
purported benefit of the use of blood irradiators intended to prevent
metastasis is to prevent cancer cells present in the irradiated
intraoperatively salvaged blood from causing metastasis after being
reinfused into the patient. However, available evidence is inadequate
to draw any definitive conclusions about the safety or effectiveness of
this intended use (Ref 2). FDA is not aware of clinical evidence
supporting the benefit of the use of blood irradiators intended to
prevent metastasis. FDA is proposing a PMA be filed to require that
manufacturers demonstrate that a reasonable assurance of safety and
effectiveness exists for blood irradiators intended to prevent
metastasis.
C. Risks to Health
The risks associated with blood irradiators intended to prevent
metastasis includes damage to blood or blood components from radiation,
unintended radiation exposure to the operator and public, electrical
shock, mechanical crush or injury, presence of proliferative malignant
cells in re-transfused blood due to incorrect dose or improper dose of
radiation delivered, worsened control of oncologic disease or patient
prognosis, delayed or lack of re-transfusion of irradiated blood or
blood components, induction of a new cancer due to irradiation of the
blood components, and risks associated with usability including
irradiating the salvaged blood outside the operating room and the
potential for blood to be incorrectly labeled or misidentified.
FDA agrees with the 2023 Panel that there is a lack of probable
benefit for these devices based on available information and has
tentatively determined that blood irradiators intended to prevent
metastasis present a potential unreasonable risk of illness or injury.
FDA does not believe the special controls proposed for blood
irradiators intended to prevent TA-GVHD are sufficient to provide
reasonable assurance of safety and effectiveness for blood irradiators
intended to prevent metastasis. FDA has identified additional risks to
health posed by the intended use for prevention of metastasis for which
it does not have adequate information to establish special controls.
Additionally, FDA agrees with the 2023 Panel that the identified risks
for this intended use may not be exhaustive. FDA further agrees that
because insufficient information exists to determine that general and
special controls are sufficient to provide reasonable assurance of the
safety and effectiveness, blood irradiators intended to prevent
metastasis should be class III subject to PMA.
VI. PMA Requirements
A PMA for blood irradiators intended to prevent metastasis must
include the information required by section 515(c)(1) of the FD&C Act
and 21 CFR 814.20. Such a PMA should also include a detailed discussion
of the risks identified in section V, as well as a discussion of the
effectiveness of the product for which premarket approval is sought. In
addition, a PMA must include all data and information on the following:
(1) any risks known, or that should be reasonably known, to the
applicant that have not been identified in this document; (2) the
effectiveness of the device that is the subject of the application; and
(3) full reports of all preclinical and clinical information from
investigations on the safety and effectiveness of the device for which
premarket approval is sought (see section 515(c)(1)(A) of the FD&C Act;
21 CFR 814.20(b)(8)).
A PMA must include valid scientific evidence to demonstrate
reasonable assurance of the safety and effectiveness of the blood
irradiator to prevent metastasis for its intended use (see 21 CFR
860.7(c)(1)). FDA defines valid scientific evidence in 21 CFR
860.7(c)(2).
To present reasonable assurance of safety and effectiveness of
blood irradiators intended to prevent metastasis, FDA tentatively
concludes that manufacturers should submit performance testing,
including clinical studies of their product, to support PMA approval.
Existing published clinical literature relevant to the product may also
be leveraged as part of the PMA submission. In addition, FDA strongly
encourages manufacturers to meet with the Agency early through the Q-
Submission Program \7\ for any assistance in preparation of their PMA.
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\7\ See FDA guidance, ``Requests for Feedback and Meetings for
Medical Device Submissions: The Q-Submission Program; Guidance for
Industry and Food and Drug Administration Staff.'' May 29, 2025,
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program.
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VII. Analysis of Environmental Impact
We have determined under 21 CFR 25.34(b) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VIII. Paperwork Reduction Act of 1995
While this proposed order contains no collection of information, it
does refer to previously approved FDA collections of information. The
previously approved collections of information are subject to review by
the Office of Management and Budget (OMB) under the Paperwork Reduction
Act of 1995 (PRA) (44 U.S.C. 3501-3521). The collections of information
in 21 CFR part 814, subparts A through E, have been approved under OMB
control number 0910-0231; and the collections of information in part
812 have been approved under OMB control number 0910-0078.
IX. Proposed Effective Date
FDA is proposing that any final order based on this proposal become
effective on the date of its publication in the Federal Register or at
a later date if stated in the final order.
X. Opportunity To Request a Change in Classification
Before requiring the filing of a PMA or notice of completion of a
PDP for a device, FDA is required by section 515(b)(2)(D) of the FD&C
Act to provide an opportunity for interested persons to request a
change in the classification of the device based on new information
[[Page 12972]]
relevant to the classification of the device. A request for a change in
the classification of blood irradiators for the prevention of
metastasis, as described in this document, should be provided in
response to the proposed rule issued elsewhere in this issue of the
Federal Register and contain the information required by 21 CFR
860.123, including new information relevant to the classification of
the device.
XI. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they are also available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. Although FDA verified the website addresses
in this document, please note that websites are subject to change over
time.
*1. Radiological Devices Panel ``April 12, 2012: Meeting Materials
FDA Generated--Blood Irradiators.'' Available at https://wayback.archive-it.org/7993/20170403223422/https:/www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/RadiologicalDevicesPanel/ucm299053.htm.
*2. Radiological Devices Panel, ``November 7, 2023: Radiological
Devices Panel of the Medical Devices Advisory Committee Meeting.''
Available at https://www.fda.gov/advisory-committees/radiological-devices-panel/2023-meeting-materials-radiological-devices-panel.
*3. National Cancer Institute. ``Risk Factors--Radiation'' (2019).
Available at: Risk Factors: Radiation--NCI (canchttps://
www.cancer.gov/about-cancer/causes-prevention/risk/radiationer.gov)
(last accessed September 5, 2025).
4. Hall EJ and Giaccia, A. (2011) Radiobiology for the Radiologist.
7th Edition, Lippincott Williams & Wilkins, Philadelphia. Chapter 2:
Molecular Mechanisms of DNA and Chromosome Damage and repair, pp.
12-34, and Chapter 10: Radiation Carcinogenesis, pp. 135-158.
5. Joiner, M. and van der Kogel, A. (Eds) (2009), Basic Clinical
Radiobiology. 4th Edition, CRC Press, London. Chapter 3: Cell Death
After Irradiation: How, When and Why Cells Die (BG Wouters), pp. 27-
40 and Chapter 7 (D Zips): Tumour Growth and Response to Radiation,
pp. 78-101.
List of Subjects in 21 CFR Part 892
Medical devices, Radiation protection, X-rays.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, we
propose that 21 CFR part 892 be amended as follows:
PART 892--RADIOLOGY DEVICES
0
1. The authority citation for part 892 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371
0
2. Amend Sec. 892.7000, as proposed to be added in Docket No. FDA-
2025-N-5996, published elsewhere in this issue of the Federal Register,
by adding paragraph (b)(2)(i) to read as follows:
Sec. 892.7000 Blood irradiator devices.
* * * * *
(b) * * * * *
(2) * * * * *
(i) Date premarket approval application (PMA) or notice of
completion of product development protocol (PDP) is required. A PMA or
notice of completion of a PDP is required to be filed with the Food and
Drug Administration on or before [DATE OF THE LAST DAY OF THE 30TH FULL
CALENDAR MONTH AFTER EFFECTIVE DATE OF FINAL RULE], for any blood
irradiator as identified in paragraph (b)(2) of this section that was
in commercial distribution before May 28, 1976, or that has, on or
before [DATE OF THE LAST DAY OF THE 30TH FULL CALENDAR MONTH AFTER
EFFECTIVE DATE OF FINAL RULE], been found to be substantially
equivalent to any blood irradiator that was in commercial distribution
before May 28, 1976. Any other blood irradiator identified in paragraph
(b)(2) of this section shall have an approved PMA or declared completed
PDP in effect before being placed in commercial distribution.
Grace R. Graham,
Deputy Commissioner for Policy, Legislation, and International Affairs.
[FR Doc. 2026-05322 Filed 3-17-26; 8:45 am]
BILLING CODE 4164-01-P