[Federal Register Volume 91, Number 52 (Wednesday, March 18, 2026)]
[Proposed Rules]
[Pages 12951-12966]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2026-05320]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 892
[Docket No. FDA-2025-N-5996]
RIN 0910-AI93
Medical Devices; Radiology Devices; Classification of Blood
Irradiators
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to
classify blood irradiator devices (product code MOT), unclassified
preamendments devices, as follows: blood irradiator devices intended to
prevent transfusion-associated graft-versus-host disease into class II
(special controls) with premarket notification and blood irradiator
devices intended to prevent metastasis into class III (premarket
approval) to provide a reasonable assurance of safety and effectiveness
of these devices. Elsewhere in this issue of the Federal Register, FDA
is issuing a proposed order proposing to require the filing of a
premarket approval application for blood irradiator devices intended to
prevent metastasis.
DATES: Either electronic or written comments on the proposed rule must
be submitted by May 18, 2026.
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'').
[[Page 12952]]
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-5996 for ``Medical Devices; Radiology Devices;
Classification of Blood Irradiators.'' 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: http://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents, the
plain language summary of the proposed rule of not more than 100 words
as required by the ``Providing Accountability Through Transparency
Act,'' 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:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
A. Need for the Regulation
B. FDA's Current Regulatory Framework
C. History of This Rulemaking
IV. Legal Authority
V. Description of the Proposed Rule
A. Device Description
B. Risks to Health and Public Health Benefits
C. Proposed Classification and FDA's Findings
VI. Proposed Special Controls for Blood Irradiators Intended To
Prevent TA-GVHD
VII. Premarket Approval for Class III Devices
VIII. Proposed Effective/Compliance Dates
A. Devices That Are Proposed To Be Classified Into Class II
B. Devices That Are Proposed To Be Classified Into Class III
IX. Preliminary Economic Analysis of Impacts
X. Analysis of Environmental Impact
XI. Paperwork Reduction Act of 1995
XII. Federalism
XIII. Consultation and Coordination With Indian Tribal Governments
XIV. References
I. Executive Summary
A. Purpose of the Proposed Rule
FDA (Agency or we) is proposing to classify blood irradiator
devices, which are unclassified, preamendments devices, into two
classes based on intended use. FDA proposes to classify blood
irradiator devices 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, into class
II (special controls). Under this proposed rule, blood irradiators
intended to prevent TA-GVHD would be subject to premarket notification
to provide a reasonable assurance of safety and effectiveness of these
devices. FDA proposes to classify blood irradiator devices intended to
irradiate intraoperatively salvaged blood of cancer patients undergoing
surgery to prevent metastasis (blood irradiators intended to prevent
metastasis) into class III (premarket approval). A blood irradiator is
a prescription device used to deliver a controlled radiation dose to
blood or blood products. Blood and blood products in containers, such
as blood bags, are placed inside a canister(s) that is loaded into the
exposure chamber for irradiation. The radiation dose from blood
irradiators intended to prevent TA-GVHD is intended to inactivate
viable leukocytes, including lymphocytes, prior to transfusion to
prevent TA-GVHD. While TA-GVHD is a rare complication of transfusion,
in patients who develop TA-GVHD, it is fatal in the majority of
affected patients. The radiation dose from blood irradiators intended
to prevent metastasis is intended to result in damage of tumor cells.
Blood irradiators within the scope of this proposed rule include an x-
ray tube or a radionuclide sealed radiation source (e.g., Cobalt-60 or
Cesium-137). FDA currently regulates these unclassified devices as
devices that require premarket notification (510(k)), with product code
MOT.\1\ FDA intends to create a separate product code for blood
irradiators intended to prevent metastasis upon finalization of this
classification action.\2\
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\1\ FDA uses product codes to help categorize and assure
consistent regulation of medical devices. A product code consists of
three characters that are assigned at the time a product code is
generated and is unique to a product type. The three characters
carry no other significance and are not an abbreviation.
\2\ See ``Medical Device Classification Product Codes--Guidance
for Industry and FDA Staff,'' available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/medical-device-classification-product-codes-guidance-industry-and-food-and-drug-administration-staff.
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FDA initiated the classification of blood irradiators by consulting
the Radiological Devices Advisory Panel at a meeting held on April 12,
2012 (2012 Panel) (Ref. 1). The 2012 Panel recommended that blood
irradiators intended to prevent TA-GVHD be classified into class II,
because the 2012 Panel believed that general and special controls would
provide reasonable
[[Page 12953]]
assurance of the safety and effectiveness of these devices. The
materials considered by the 2012 Panel noted that one device had been
cleared at the time for the prevention of metastasis, but the 2012
Panel did not issue a recommendation as to the classification of blood
irradiators intended to prevent metastasis.
FDA initiated the classification of blood irradiators intended to
prevent metastasis by consulting the Radiological Devices Advisory
Panel at a meeting held on November 7, 2023 (2023 Panel) (Ref. 2). The
2023 Panel recommended that blood irradiators intended to prevent
metastasis be classified into class III. The 2023 Panel consensus was
that insufficient information exists to determine that general and
special controls are sufficient to provide reasonable assurance of
safety and effectiveness of these devices, and blood irradiators
intended to prevent metastasis present a potential unreasonable risk of
illness or injury.
FDA conducted its own analyses of information from the 2012 and
2023 Panels (Refs. 1 and 2), including risks identified in the Center
for Biologics Evaluation and Research (CBER) July 1993 memorandum
``Recommendations Regarding License Amendments and Procedures for Gamma
Irradiation of Blood Products'' (CBER Memorandum) (Ref. 3); postmarket
data regarding blood irradiators with product code MOT; adverse event
reports in FDA's Manufacturer and User Facility Device Experience
(MAUDE) database and Medical Device Report (MDR) database; information
in CDRH's Medical Device Recalls database, and published scientific
literature, as further described below. Based upon the analyses, FDA
agrees with the recommendations of the 2012 Panel and the 2023 Panel.
As such, FDA is proposing a split classification for blood irradiators.
FDA is proposing to classify blood irradiators intended to prevent
TA-GVHD, including those intended to inactivate leukocytes and/or
lymphocytes to prevent TA-GVHD, into class II (special controls). FDA
is proposing this action based on the determination that general
controls alone are not sufficient to provide reasonable assurance of
the safety and effectiveness of blood irradiators intended to prevent
TA-GVHD, and there is sufficient information to establish special
controls, in combination with general controls, to provide such
assurance. Under this proposal, premarket notification for blood
irradiators intended to prevent TA-GVHD would be required.
Additionally, manufacturers may wish to use predetermined change
control plans (PCCPs) as a way to implement future modifications to
their devices without needing to submit a new 510(k) for each
significant change or modification \3\ while continuing to provide a
reasonable assurance of device safety and effectiveness.\4\ FDA reviews
a PCCP as part of a marketing submission for a device to ensure the
continued safety and effectiveness of the device without necessitating
additional marketing submissions for implementing each modification
described in the PCCP.
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\3\ For the purpose of this proposed rule reference to
``modification'' means a significant change or modification that
would generally require a new premarket notification under 21 CFR
807.81(a)(3).
\4\ Section 3308 of the Food and Drug Omnibus Reform Act of
2022, Title III of Division FF of the Consolidated Appropriations
Act, 2023, Public Law 117-328 (``FDORA''), enacted on December 29,
2022, added section 515C ``Predetermined Change Control Plans for
Devices'' to the Federal Food, Drug, and Cosmetic Act (FD&C Act).
Section 515C has provisions regarding predetermined change control
plans (PCCPs) for devices requiring premarket approval or premarket
notification. Under section 515C, supplemental applications (section
515C(a)) and new premarket notifications (section 515C(b)) are not
required for a change to a device that would otherwise require a
premarket approval supplement or new premarket notification if the
change is consistent with a PCCP approved or cleared by FDA.
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FDA is proposing to classify blood irradiators intended to prevent
metastasis into class III (premarket approval). FDA is proposing this
classification as FDA believes that insufficient information exists to
determine that general controls and special controls would provide
reasonable assurance of safety and effectiveness for blood irradiators
intended to prevent metastasis, and that these devices present a
potential unreasonable risk of illness or injury. FDA is also
proposing, by proposed order published elsewhere in this issue of the
Federal Register, to require the filing of a premarket approval
application (PMA) for blood irradiators intended to prevent metastasis.
B. Summary of the Major Provisions of the Proposed Rule
This rule proposes to classify unclassified, preamendments blood
irradiators: blood irradiators intended to prevent TA-GVHD, including
those intended to inactivate leukocytes and/or lymphocytes to prevent
TA-GVHD, and blood irradiators intended to prevent metastasis. The
proposed rule, if finalized, would establish the identification and
classification for these blood irradiator devices. The proposed
classification action proposes to classify blood irradiators intended
to prevent TA-GVHD into class II as well as establish the special
controls necessary to provide reasonable assurance of the safety and
effectiveness of these devices. Under this proposed rule, premarket
notification would be required for blood irradiators intended to
prevent TA-GVHD. The proposed classification action proposes to
classify blood irradiators intended to prevent metastasis into class
III and require filing of a PMA. These proposed classification
regulations, if finalized, would identify these blood irradiator
devices as intended for prescription use.
C. Legal Authority
The Agency is proposing this classification under the authority of
the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 301 et
seq.). Specifically, the relevant authority related to the proposed
classification includes section 513(a) through (d) of the FD&C Act (21
U.S.C. 360c(a) through (d)), regarding device classes, classification,
and panels and section 515 (21 U.S.C. 360e) regarding PMAs; and section
701(a) of the FD&C Act (21 U.S.C. 371(a)).
D. Costs and Benefits
The proposed rule, if finalized, would classify blood irradiators
(unclassified, preamendments devices) into two classes based on
intended use. It would classify blood irradiators intended to prevent
TA-GVHD into class II (special controls) and blood irradiators intended
to prevent metastasis into class III (premarket approval). Separately,
FDA also is issuing a proposed order requiring the filing of a PMA for
blood irradiators intended to prevent metastasis. Quantified benefits
of the proposed rule, if finalized, would consist of cost savings to
industry and FDA from a reduction in the quantity and time burden of
informal inquiries related to blood irradiators intended to prevent TA-
GVHD. We also estimate cost savings to industry and FDA from a
reduction in the number of 510(k) submissions necessitating requests
for additional information from FDA before and during review. Industry
and FDA could incur costs associated with premarket approval
applications for current and future blood irradiators intended to
prevent metastasis. We additionally quantify one-time costs to industry
to read and understand the proposed rule and the proposed order
requiring the filing of a PMA, as well as one-time costs to industry to
revise labeling. We estimate that the annualized benefits over 10 years
would range from $84 to $180,268 at a 7 percent discount rate, with a
primary
[[Page 12954]]
estimate of $90,176, and from $86 to $184,271 at a 3 percent discount
rate, with a primary estimate of $92,178. The annualized costs would
range from $0.68 million to $1.51 million at a 7 percent discount rate,
with a primary estimate of $1.07 million, and from $0.66 million to
$1.53 million at a 3 percent discount rate, with a primary estimate of
$1.07 million.
II. Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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510(k)................................. Premarket Notification.
ARO.................................... Accidental Radiation
Occurrence.
CBER................................... Center for Biologics Evaluation
and Research.
CDRH................................... Center for Devices and
Radiological Health.
CFR.................................... Code of Federal Regulations.
FDA.................................... Food and Drug Administration.
FD&C Act............................... Federal Food, Drug, and
Cosmetic Act.
Gy..................................... Gray.
MAUDE.................................. Manufacturer and User Facility
Device Experience database.
MDR.................................... Medical Device Report.
NRC.................................... Nuclear Regulatory Commission.
PCCP................................... Pre-Determined Change Control
Plan.
PMA.................................... Premarket Approval Application.
Ref.................................... Reference.
TA-GVHD................................ Transfusion-Associated Graft-
Versus-Host Disease.
U.S.C.................................. United States Code.
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III. Background
A. Need for the Regulation
After the enactment of the 1976 Medical Device Amendments, FDA
undertook an effort to identify and classify all preamendments devices
in accordance with section 513(d) of the FD&C Act (21 U.S.C. 360c(d)).
Section 513(b) of the FD&C Act (21 U.S.C. 360c(b)) requires FDA to
classify all preamendments devices into class I, II, or III. Currently,
blood irradiators, product code MOT, are unclassified devices subject
to premarket notification (510(k)) under section 510(k) of the FD&C Act
(21 U.S.C. 360(k)). Marketing of a new device within an unclassified
device type requires FDA clearance of a 510(k). As described below,
available records indicate FDA granted the first clearance of a blood
irradiator intended to prevent TA-GVHD (K837346) in 1983 based on
documentation that demonstrated that these devices are substantially
equivalent to device(s) of the same type that were in commercial
distribution prior to passage of the Medical Device Amendments on May
28, 1976. On May 26, 2005, FDA cleared the Raycell X-ray Blood
Irradiator device (K051065). The Raycell X-ray Blood Irradiator is the
first device to include, in addition to an intended use for the
prevention of TA-GVHD, a second intended use for the prevention of
metastasis.\5\ To date, FDA has cleared a total of 16 devices under
product code MOT. Two of the devices are cleared with dual intended
uses to prevent TA-GVHD and to prevent metastasis.
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\5\ The Raycell X-ray Blood Irradiator device was found to be
substantially equivalent to a previously cleared device that 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
NPRM, and for the reasons described in Sections V.B-C of this
preamble, FDA is proposing to separately classify these two device
types.
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FDA agrees with the 2012 Panel that general controls by themselves
are insufficient to provide reasonable assurance of the safety and
effectiveness of blood irradiators intended to prevent TA-GVHD, and
sufficient information exists to establish special controls to
adequately mitigate the risks to health and provide reasonable
assurance of safety and effectiveness of this device. FDA is proposing
to classify blood irradiators intended to prevent TA-GVHD into class
II. FDA agrees with the 2023 Panel that insufficient information exists
to determine that general and special controls are sufficient to
provide reasonable assurance of safety and effectiveness for blood
irradiators intended to prevent metastasis, and that the device
presents a potential unreasonable risk of illness or injury. FDA is
proposing to classify blood irradiators intended to prevent metastasis
into class III.
B. FDA's Current Regulatory Framework
The FD&C Act (21 U.S.C. 301 et seq.), as amended by the Medical
Device Amendments of 1976 (1976 amendments) (Pub. L. 94-295),
established 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: class I (general controls), class II (special controls),
and class III (premarket approval).
Section 513(a)(1) of the FD&C Act (21 U.S.C. 360c(a)(1)) defines
the three classes of devices. Class I devices are those devices for
which the general controls of the FD&C Act (controls authorized by or
under sections 501, 502, 510, 516, 518, 519, or 520 of the FD&C Act (21
U.S.C. 351, 352, 360, 360f, 360h, 360i, or 360j) or any combination of
such sections) are sufficient to provide reasonable assurance of safety
and effectiveness; or those devices for which insufficient information
exists to determine that general controls are sufficient to provide
reasonable assurance of safety and effectiveness or to establish
special controls to provide such assurance, but because the devices are
not purported or represented to be for a use in supporting or
sustaining human life or for a use which is of substantial importance
in preventing impairment of human health, and do not present a
potential unreasonable risk of illness or injury, are to be regulated
by general controls (section 513(a)(1)(A) of the FD&C Act.
Class II devices are those devices for which general controls by
themselves are insufficient to provide reasonable assurance of safety
and effectiveness, but for which there is sufficient information to
establish special controls to provide such assurance, including the
promulgation of performance standards, postmarket surveillance, patient
registries, development and dissemination of guidelines,
recommendations, and other appropriate actions the Agency deems
necessary to provide such assurance (section 513(a)(1)(B) of the FD&C
Act).
[[Page 12955]]
Class III devices are those devices for which insufficient
information exists to determine that general controls (controls
authorized by or under sections 501, 502, 510, 516, 518, 519, or 520 of
the FD&C Act or any combination of such sections) and special controls
would provide a reasonable assurance of safety and effectiveness, and
are purported or represented for a use in supporting or sustaining
human life or for a use which is of substantial importance in
preventing impairment of human health, or present a potential
unreasonable risk of illness or injury (section 513(a)(1)(C) of the
FD&C Act.
FDA refers to devices that were in commercial distribution before
the 1976 amendments as ``preamendments devices.'' The procedures for
classification of such devices are prescribed in sections 513(b)-(d) of
the FD&C Act (21 U.S.C. 360c(b)-(d)). FDA classifies these devices
after 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
(section 513(d)(1) of the FD&C Act. FDA has classified most
preamendments devices under these procedures.
A preamendments device that has been classified into class III only
requires premarket notification and not approval of a PMA until FDA
issues a final order under section 515(b) of the FD&C Act (21 U.S.C.
360e(b)) requiring premarket approval. FDA is also proposing, by
proposed order published elsewhere in this issue of the Federal
Register, to require the filing of a PMA for blood irradiators intended
to prevent metastasis.
Blood irradiators that include an x-ray source are radiation-
emitting electronic products and, accordingly, also are subject to the
Electronic Product Radiation Control requirements of the FD&C Act
(sections 531 through 542 (21 U.S.C. 360hh through 360ss)) (originally
enacted as the Radiation Control for Health and Safety Act of 1968),
and its implementing regulations. This includes compliance with certain
performance standards found in 21 CFR 1020.40 for cabinet x-ray
systems, pursuant to the authority found in section 534 of the FD&C Act
(21 U.S.C. 360kk). A blood irradiator that includes an x-ray source
meets the definition of a cabinet x-ray system found in 21 CFR
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.
Blood irradiators that include a radionuclide sealed radiation
source (sealed radiation source) may be subject to regulatory
requirements of the Nuclear Regulatory Commission (NRC) pursuant to its
authority under the Energy Reorganization Act of 1974 (42 U.S.C. 5801
et seq.).
C. History of This Rulemaking
As previously described, blood irradiator devices are unclassified,
preamendments devices. These devices have been subject to premarket
review through a 510(k) submission and have been cleared for marketing
if FDA found the device to be substantially equivalent to a legally
marketed predicate in accordance with section 513(i) of the FD&C Act
(21 U.S.C. 360c(i)). FDA has cleared a total of 16 devices within the
scope of this classification action. Consistent with the FD&C Act, FDA
convened the Radiological Devices Advisory Panel at two meetings
regarding the classification of blood irradiators.
1. 2012 Radiological Devices Advisory Panel
On April 12, 2012, FDA convened the 2012 Panel to secure
recommendations regarding risks and benefits presented by blood
irradiators as well as the appropriate classification and regulatory
controls that should apply to this device type (Ref. 1). At the
meeting, FDA requested that the 2012 Panel consider whether blood
irradiators intended to prevent TA-GVHD fit the statutory definition
for a class II device. The 2012 Panel considered the information about
this device type provided by FDA, including results and analysis from a
literature search and search of known adverse events (Ref. 1). The 2012
Panel considered both types of blood irradiators intended to prevent
TA-GVHD: the x-ray tube blood irradiators and the sealed radiation
source blood irradiators. The 2012 Panel did not issue a recommendation
as to the classification of blood irradiators intended to prevent
metastasis.
At the 2012 Panel meeting, FDA presented information on the
identified risks to health and proposed mitigation measures for blood
irradiators intended to prevent TA-GVHD. FDA-identified risks to health
included improper radiation dose to blood or blood products, radiation
exposure to the user, and electric shock. FDA proposed mitigation
measures for the identified risks to health, which included premarket
review of indications for use and design specifications, and compliance
with the CBER Memorandum (Ref. 3). The CBER Memorandum provides
recommendations to blood establishments on manufacturing, quality
control procedures, labeling and other aspects of manufacturing
irradiated blood and blood products. FDA also suggested in 2012 Panel
materials, as a mitigation for certain risks to health, compliance with
NRC regulations and certain regulations of states that have entered
into agreements with NRC that govern radioactive isotopes and their
safe use (collectively referred to in the remainder of this proposed
rule as ``NRC regulations''), which would apply to blood irradiators
that use a sealed radiation source. During the 2012 Panel meeting, FDA
presented the additional risk of damage to blood or blood components
from radiation. This risk is associated with a shorter shelf life for
irradiated blood and blood components, as noted in the CBER Memorandum
and discussed at the 2012 Panel.
The 2012 Panel agreed with the FDA-identified risks to health
associated with blood irradiators intended to prevent TA-GVHD. Several
of the 2012 Panel members suggested additional risks of mechanical or
crush injury from door closure and dose inhomogeneity. For dose
inhomogeneity, multiple Panel members expressed a concern that a large
dose inhomogeneity could result in the blood or blood product receiving
an ineffective dose of radiation. The main concern was the ability to
deliver 25 gray (Gy) of radiation targeted to the central portion of
the container and to achieve a 15 Gy minimum dose at any other point
within the container, as recommended in the CBER Memorandum, for all
contents in the irradiation exposure chamber for all possible fillings.
Several of the 2012 Panel members also expressed concern for safety and
security in terms of using the device and adequate training of
personnel. FDA has interpreted concerns about safety and security to be
about operator error and lack of safety controls on the device to
protect against exposure to the radiation source. There was some
disagreement among the 2012 Panel members as to whether manufacturer-
provided personnel training should be a special control because of the
challenge it puts on manufacturers and on facilities' ability to
perform their own training.
The 2012 Panel members suggested that the risks to health
associated with improper radiation dose, including not
[[Page 12956]]
achieving minimum dosing throughout the irradiated blood and blood
components due to dose inhomogeneity, could be mitigated by performance
standards and design controls (Ref. 1, 2012 Panel transcript at 187-
189). FDA interprets this discussion to mean performance testing to
demonstrate that the device performs as intended under anticipated
conditions of use, and certain labeling information. For dose
inhomogeneity, the 2012 Panel members also recommended periodic
demonstration of the dose uniformity and a recommended dosimetric
evaluation interval. Based upon the 2012 Panel discussion, FDA
interprets periodic demonstration of the dose uniformity at recommended
intervals to mean the inclusion of a recommended quality assurance
program by the manufacturer, that manufacturers provide information
about dosimetric distribution measured both in air and with the
canister or exposure chamber filled with water, and that manufacturers
provide information about decay and residual strength of the sealed
radiation source, where applicable. The 2012 Panel also suggested some
indication of dose rate and a manufacturer provided method for
identifying if the proper dose of radiation is delivered. To mitigate
against the risk of exposure to the sealed radiation source, which may
be caused by operator error or lack of safety controls on the device,
the 2012 Panel suggested adding a special control requiring safety and
security that limits who can operate the device. Some of the 2012
Panel-recommended mitigations were suggested by the CBER Memorandum.
The consensus of the 2012 Panel was that class I (general controls)
alone would not be adequate to provide a reasonable assurance of safety
and effectiveness for blood irradiators intended to prevent TA-GVHD and
that special controls could be identified. The 2012 Panel agreed that
the CBER Memorandum, although intended for blood establishments
manufacturing irradiated blood products, provided a good resource to
develop special controls for both sealed radiation source and x-ray
source devices. The 2012 Panel noted that blood irradiators are an
established technology to prevent TA-GVHD in transfused patients, and
that blood establishments' implementation of the recommendations in the
CBER Memorandum, together with the performance standards found in 21
CFR 1020.40 for cabinet x-ray systems, which would include x-ray source
blood irradiators, had resulted in few published problems and no
reported adverse events in literature over a long period of time when
the device was used at the CBER recommended dosage level. The 2012
Panel recommended that blood irradiators intended to prevent TA-GVHD be
classified into class II to provide reasonable assurance of safety and
effectiveness of these devices.
FDA tentatively agrees with the 2012 Panel's recommendation that
general controls and special controls are needed to provide reasonable
assurance of safety and effectiveness of blood irradiators intended to
prevent TA-GVHD and that this device be classified into class II.
General controls are insufficient to provide reasonable assurance of
safety and effectiveness of this device type based on the fatal nature
of TA-GVHD and risk of the disease if the radiation exposure does not
inactivate the lymphocytes present in the blood. Identification of the
dose of radiation necessary to inactivate lymphocytes, pre-market data
requirements showing that the blood irradiator is capable of delivering
this radiation dose to the blood and blood components, and labeling
requirements including required quality control processes are necessary
to mitigate the identified risks to health. Accordingly, FDA is
proposing to classify blood irradiators intended to prevent TA-GVHD
into class II (special controls).
2. 2023 Radiological Devices Panel of the Medical Devices Advisory
Committee
On November 7, 2023, FDA convened the 2023 Panel to make
recommendations regarding the risks and benefits presented by blood
irradiators intended to prevent metastasis as well as the appropriate
classification and regulatory controls that should apply to these
devices (Ref. 2). At the meeting, FDA requested that the 2023 Panel
consider whether blood irradiators intended to prevent metastasis fit
the statutory definition for a class III device. The 2023 Panel
considered the information provided by FDA about blood irradiators
intended to prevent metastasis, including results and analysis from a
literature search and search of known adverse events (Ref. 2).
During the 2023 Panel meeting, FDA presented information on the
identified risks to health for blood irradiators intended to prevent
metastasis as well as proposed mitigation measures. FDA identified
similar risks to health related to the device hardware and software as
blood irradiators intended to prevent TA-GVHD, which are similar in
design and function. Specifically, these risks to health included:
damage to blood components from radiation, unintended (non-therapeutic)
radiation exposure to the operator and public, electric shock or burn,
and mechanical or crush injury. FDA also identified unique risks to
health posed by the intended use of blood irradiators intended to
prevent metastasis, including 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, and delayed or lack of re-transfusion of irradiated blood or
blood component.
FDA's search of literature for blood irradiators intended to
prevent metastasis for the 2023 Panel returned a limited number of
articles (Ref. 2, FDA Executive Summary, Appendix D). None of the
articles identified as part of the systematic literature search
provided information on the safety assessment of the use of these
devices for prevention of metastasis. No articles provided definitive
information on the effect of salvaged blood irradiation on metastasis.
Moreover, the literature showed a lack of consensus on the specific
dose to use (reported doses were 25-50 Gy) to render tumor cells
nonviable, and for which cancer type and surgical procedure (Ref. 2,
Presentation (Classification of Blood Irradiators for the Prevention of
Metastasis)). Several articles observed that blood irradiation took
additional time to perform (Ref. 2, Presentation (Classification of
Blood Irradiators for the Prevention of Metastasis)). At the meeting,
FDA indicated that because long-term safety risks, such as the cancer
outcome, patient recovery, or survival, are unclear based upon the
available information, these risks to health may not be effectively
mitigated by special controls. Further, based on the available
information, there appears to be a lack of clinical data to demonstrate
a clear clinical benefit from use of the blood irradiators intended to
prevent metastasis.
The 2023 Panel agreed with the FDA-identified risks to health for
blood irradiators intended to prevent metastasis. The 2023 Panel
identified several additional risks to health related to the device's
intended use, including: risk of induction of a new cancer due to
irradiation of the blood or blood components, risk of induction of
mutations in cells irradiated more than once (i.e., if blood was
salvaged and re-transfused multiple times during the surgical
procedure), risks associated with the volume of blood that may need to
be irradiated and the additional operating procedure time, and risks
[[Page 12957]]
associated with usability including irradiating the salvaged blood
outside the operating room and the potential for blood to be
incorrectly labeled or misidentified. The 2023 Panel also 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 insufficient information exists
to determine that class I (general controls) and class II (special
controls) are sufficient to provide reasonable assurance of safety and
effectiveness for blood irradiators intended to prevent metastasis. The
2023 Panel members suggested that risks to health associated with the
device's hardware and software were similar to those for blood
irradiators intended to prevent TA-GVHD because device function and
design were the same. However, the risks to health associated with the
device's intended use--for the prevention of metastasis in cancer
patients receiving intraoperatively salvaged blood--could not fully be
identified or mitigated with general and special controls given the
very limited data available. In addition, there are uncertainties about
the effective radiation dose, including whether the dose would be the
same for all cancer types and all surgical procedures. Regarding the
benefit and risk assessment, the 2023 Panel consensus was there is no
definitive evidence showing that irradiation of intraoperatively
salvaged blood is effective to prevent metastasis in patients. As a
result, the risk of injury is unreasonable given the lack of probable
benefit. The 2023 Panel recommended that these devices be classified
into class III (premarket approval).
FDA agrees with the 2023 Panel that risks to health of blood
irradiators for the prevention of metastasis cannot fully be identified
or mitigated with special controls given the very limited data
available and that there is a potential unreasonable risk of illness or
injury for these devices given the lack of probable benefit. For the
reasons stated by the 2023 Panel, FDA has tentatively determined that
general controls and special controls are not sufficient to provide
reasonable assurance of safety and effectiveness of blood irradiators
intended to prevent metastasis. FDA is proposing that these devices be
classified into class III.
IV. Legal Authority
The Agency is proposing this classification under the authority of
the FD&C Act (21 U.S.C. 301 et seq.). Specifically, the relevant
authority related to the proposed classification includes sections
513(a) through (d) of the FD&C Act (21 U.S.C. 360c(a) through (d)),
regarding device classes, classification, and panels; and section 515
(21 U.S.C. 360e), regarding PMAs.
V. Description of the Proposed Rule
We are proposing to amend subpart G of 21 CFR part 892 by adding
Sec. 892.7000 to classify blood irradiators, currently categorized
under the product code MOT, with sub-sections for blood irradiators
intended to prevent TA-GVHD, including those intended to inactivate
leukocytes and/or lymphocytes to prevent TA-GVHD, and blood irradiators
intended to prevent metastasis, in accordance with section 513(d) of
the FD&C Act (21 U.S.C. 360c(d)) and section 701(a) of the FD&C Act (21
U.S.C. 371).
A. Device Description
A blood irradiator is a prescription device used to deliver a
controlled radiation dose to blood or blood products. Prescription
devices are exempt from the requirement for adequate directions for use
for the layperson under section 502(f)(1) of the FD&C Act (21 U.S.C.
352(f)(1)) and 21 CFR 801.5, as long as the conditions of 21 CFR
801.109 are met. This generic type of device may include an x-ray or a
sealed radiation source. Blood irradiators intended to prevent TA-GVHD
are used to deliver a controlled radiation dose to blood or blood
products prior to transfusion to prevent TA-GVHD. Blood irradiators
intended to prevent metastasis are used to irradiate intraoperatively
salvaged blood ex vivo for cancer patients undergoing surgery to assist
in the prevention of metastasis.
B. Risks to Health and Public Health Benefits
In evaluating the risks to health associated with use of blood
irradiators intended to prevent TA-GVHD and blood irradiators intended
to prevent metastasis, FDA considered information from the 2012 Panel
and 2023 Panel, respectively, including risks identified in the CBER
Memorandum (Ref. 3); postmarket data regarding blood irradiators with
product code MOT, including adverse event reports in the MAUDE
database; CDRH's Medical Device Recalls database, and the published
scientific literature, some of which is discussed in FDA's executive
summaries for the 2012 and 2023 Panel meetings (Refs. 1 and 2).
For blood irradiators intended to prevent TA-GVHD, in addition to
the literature analysis conducted for the 2012 Panel meeting, FDA
conducted literature searches on January 25, 2024, and September 23,
2024, for articles published since the 2012 Panel meeting about these
devices. These literature searches identified nine additional relevant
articles (Refs. 4-12). The information from the contemporary literature
analyses is consistent with the findings of the prior literature
analysis presented at the 2012 Panel meeting. For blood irradiators
intended to prevent metastasis, in addition to the literature analysis
conducted for the 2023 Panel meeting, FDA conducted a contemporary
literature search on September 23, 2024, for articles published since
the prior search for the 2023 Panel meeting. One new paper was
identified (Ref. 13). The information from the 2024 literature analysis
is consistent with the findings of the prior literature analysis
presented at the 2023 Panel meeting.
FDA's search of the MAUDE and MDR databases for the 2012 and 2023
Panel meetings for product code MOT, which includes blood irradiators
intended to prevent TA-GVHD and blood irradiators intended to prevent
metastasis, identified five MDRs related to blood irradiators reported
in MAUDE. Two MDRs contained no information, one was a suggestion for
devices to include an audible alarm, and two noted low x-ray tube
output that may have resulted in less than 15 Gy being delivered to all
locations within the irradiation canister. No direct adverse events to
patients were reported. Following these searches, FDA received one
additional report describing multiple adverse events on May 14, 2024.
The adverse events were related to high current safety interlock system
switch failures that were reported to result in superficial (first-
degree) burns. For blood irradiators intended to prevent TA-GVHD, the
proposed special controls covering demonstration of appropriate
functioning of safety systems, including interlocks, and electrical
safety testing are designed to mitigate this risk to health. During the
same time period, there were no accidental radiation occurrences (AROs)
reported under 21 CFR 1002.20 for devices with product code MOT
containing x-ray tubes. FDA conducted updated queries for MDRs on July
7, 2025, and for AROs on November 22, 2024 and August 4, 2025. No
additional reports were identified.
FDA also reviewed recalls reported under product code MOT from
November 2002 to June 22, 2025. There were two product recalls during
that time period. The first recall was a class 3 recall to complete a
cooling system
[[Page 12958]]
retrofit to preclude overheating and failure of the device. The recall
was terminated May 13, 2012.\6\ The second recall was a class 2 recall,
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).\7\ 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.
---------------------------------------------------------------------------
\6\ For details about termination of a recall see 21 CFR 7.55.
\7\ 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.
---------------------------------------------------------------------------
1. Risks to Health and Public Health Benefits for Blood Irradiators
Intended To Prevent TA-GVHD
As noted in Section III.C.1, for blood irradiators intended to
prevent TA-GVHD, the 2012 Panel members suggested additional risks to
health of mechanical crush and injury, dose inhomogeneity, and safety
and security in terms of using the device and adequate training of
personnel, which FDA has interpreted to be about operator error and a
lack of safety controls to protect against exposure to the radiation
source. FDA agrees that there is a risk to health of mechanical or
crush injury from door closure and has added it as a separate risk
category. The design of blood irradiators includes an amount of
shielding sufficient to prevent radiation exposure to the operator,
causing the door to be atypically heavy. FDA also agrees that dose
inhomogeneity may pose a risk that not all blood and blood products
placed in the device receive an effective dose of radiation. However,
FDA does not believe that dose inhomogeneity needs to be added as a
separate category of risk to health. Instead, FDA included this risk to
health within the description of the risk of improper radiation to
blood or blood products, with mitigations included in the proposed
special controls to address this concern. FDA included risks to health
posed by operator error and a lack of safety controls on the device
within ``Improper radiation dose to blood or blood products'' and
``Unintended radiation exposure to the operator and others,''
respectively. Safety controls include device access controls that may
be hardware or software controlled. FDA modified the risk category from
``Radiation exposure to the user'' to ``Unintended radiation exposure
to the operator and others'' to expressly capture risk to other persons
in the vicinity of the device in addition to the direct operator and to
clarify that the exposure is unintended (i.e., it is not part of the
limited degree of radiation exposure that is anticipated and accepted
when using a device that works via ionizing radiation).
Based upon the information described above, FDA identified the
following risks to health for blood irradiators intended to prevent TA-
GVHD:
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.
Improper radiation dose to blood or blood products:
Failure to deliver a proper radiation dose to the intended target can
result in immunologically active cells in transfused blood or blood
products, which may result in TA-GVHD, which is often fatal. Delivery
of an improper dose could result from multiple causes including:
inability of the device to deliver 25 Gy of radiation targeted to the
central portion of the container or a 15 Gy minimum dose at any other
point within the container; dose inhomogeneity; malfunction of the
device; lack of adequate maintenance, dosimetry or quality assurance
checks; electrical fault, electromagnetic interference, or mechanical
fault; or operator error causing improper dose delivery, including
improper loading of the sample canister and incorrect exposure time
entered into the user interface.
Unintended radiation exposure to the operator and others:
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. 14).
Insufficient presence of safety controls or interlocks within
irradiator design may result in unintended exposure.
Electrical shock: Electrical malfunction of the device or
operator contact with an energized portion may result in electrical
shock or burns. This can occur when there are insufficient or
malfunctioning safety controls or interlocks.
Mechanical crush or 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.
In evaluating benefits associated with the use of blood irradiators
intended to prevent TA-GVHD, FDA considered information from the 2012
Panel regarding the classification of blood irradiators intended to
prevent TA-GVHD and the published scientific literature. The
information indicated that blood irradiation is an accepted method to
prevent TA-GVHD by inactivation of T-lymphocytes to prevent post-
transfusional proliferation and has been widely used for this purpose
since the 1970s (Ref. 1, Executive Summary, Appendix A, Section III.A).
2. Risks to Health and Benefits to Public Health for Blood Irradiators
Intended To Prevent Metastasis
As noted in Section III.C.2, in addition to the risks to health
that FDA presented at the 2023 Panel for blood irradiators intended to
prevent metastasis, Panel members suggested additional risks to health:
risk of induction of a new cancer due to irradiation of the blood or
blood components, risk of induction of mutations in cells irradiated
more than once (i.e., if blood was salvaged and re-transfused multiple
times during the surgical procedure), risks associated with the volume
of blood that may need to be irradiated and the additional operating
procedure time, 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 additional risks to health identified by the 2023
Panel. However, FDA does not believe that induction of mutations in
cells irradiated more than once needs to be added as a separate
category of risk to health. FDA views this risk as a subset of the risk
of induction of a new cancer due to the irradiation of the blood or
blood components. Multiple irradiations may lead to a greater chance of
a cell being damaged. Should this damage result in negative changes in
the cell, the risk to the patient would be induction of a new cancer if
cells are malignantly transformed. Accordingly,
[[Page 12959]]
we have included the risk of induction of mutations in cells within the
description of the risk ``Induction of a new cancer due to irradiation
of the blood or blood components.''
We have included the risk associated with the volume of blood that
may need to be irradiated with the description of the risk to health
``Delayed or lack of re-transfusion of irradiated blood or blood
components.'' Irradiation of the blood adds time to the intraoperative
procedure, after salvage and filtration have occurred. Depending how
much blood is removed for re-transfusion and when it is re-transfused
during the procedure, irradiation may need to occur multiple times. In
addition, FDA has updated the wording of the risk to health ``Damage to
blood components from radiation'' to ``Damage to blood or blood
components from radiation'' to better reflect the variety in the
product re-transfused (e.g., blood with plasma proteins and clotting
factors, washed red blood cells). The term blood component was
originally used to specify that it was a blood component (i.e.,
lymphocyte or red blood cell) that was damaged by irradiation. FDA also
updated the wording of the risk to health ``Unintended radiation
exposure to the operator and public'' to ``Unintended radiation
exposure to the operator and others'' to clearly reflect other persons
who may be at risk of such exposure (e.g., patients, bystanders).
Based on the information described in this Section V.B., FDA has
identified the following risks to health associated with 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:
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. 13).
Insufficient presence of safety controls or interlocks within
irradiator design may result in unintended exposure.
Electrical shock: \8\ 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.
---------------------------------------------------------------------------
\8\ 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 earlier
in this proposed rule for blood irradiators intended to prevent TA-
GVHD; the description of this risk to health is identical to what
was included in the 2023 Panel materials.
---------------------------------------------------------------------------
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.
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. 15). 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.
In evaluating benefits associated with the use of blood irradiators
intended to prevent metastasis, FDA considered information from the
2023 Panel regarding the classification of blood irradiators intended
to prevent metastasis and the results of published scientific
literature searches performed on April 20, 2023 and September 23, 2024.
The information indicated that there appears to be a lack of clinical
data to demonstrate that irradiating intraoperatively salvaged blood is
able to prevent metastasis in patients and therefore there is no clear
clinical benefit from use of the blood irradiators intended to prevent
metastasis.
C. Proposed Classification and FDA's Findings
Based on FDA's experience with blood irradiators intended to
prevent TA-GVHD, including those intended to inactivate leukocytes and/
or lymphocytes to prevent TA-GVHD, the 2012 Panel's recommendations,
and other available information, FDA is proposing to classify blood
irradiators
[[Page 12960]]
intended to prevent TA-GVHD into class II. FDA is proposing to classify
blood irradiators intended to prevent TA-GVHD into class II because
general controls alone are insufficient to provide reasonable assurance
of the safety and effectiveness of these devices (see Section III.C.1)
as presented and discussed during the 2012 Panel meeting (Ref. 1). FDA
also believes there is sufficient information to establish special
controls to mitigate the risks to health of the device. FDA has
tentatively determined that the special controls, in addition to
general controls, will provide reasonable assurance of the safety and
effectiveness of blood irradiators intended to prevent TA-GVHD. Blood
irradiators intended to prevent TA-GVHD would be subject to 510(k)
requirements under section 510(k) of the FD&C Act (21 U.S.C. 360(k)).
Based on FDA's experience with blood irradiators intended to
prevent metastasis, the 2023 Panel's recommendations, and other
available information, FDA is proposing to classify blood irradiators
intended for use in irradiating intraoperatively salvaged blood of
cancer patients undergoing surgery to prevent metastasis into class
III. FDA is proposing this classification because FDA believes that
insufficient information exists to determine that general controls and
special controls would provide reasonable assurance of safety and
effectiveness for these devices and, based upon assessment of benefits
and risks, 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, as described in section V.B.2, 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. Elsewhere in this issue of
the Federal Register, FDA is proposing through a proposed order to
require the filing of a PMA under section 515(b) of the FD&C Act. The
proposed order will only be finalized if and when FDA finalizes this
proposed rule classifying blood irradiators intended to prevent
metastasis in class III.
VI. Proposed Special Controls for Blood Irradiators Intended To Prevent
TA-GVHD
FDA is proposing the special controls identified in this section
for blood irradiators intended to prevent TA-GVHD. FDA believes that
these special controls, in addition to general controls, are necessary
to provide a reasonable assurance of safety and effectiveness of these
devices. Special controls for blood irradiators intended to prevent TA-
GVHD were discussed at the 2012 Panel (Ref. 1, Executive Summary Table
III). The consensus of the 2012 Panel was that the CBER Memorandum was
a good resource for establishing special controls for these devices,
including blood irradiators for TA-GVHD that use an x-ray source. The
2012 Panel concurred that the recommendations described in the CBER
Memorandum provided sufficient guidance for a reasonable assurance of
safety and effectiveness for this device type with some additional risk
mitigations suggested by the 2012 Panel (Ref. 1, Transcript at 196).
The proposed special controls listed below for blood irradiators
intended to prevent TA-GVHD include some risk mitigations and special
controls proposed and recommended at the 2012 Panel meeting. FDA agrees
with the 2012 Panel that certain recommendations suggested by the CBER
Memorandum would support reasonable assurance of safety and
effectiveness of blood irradiators to prevent TA-GVHD. As a result, the
proposed risk mitigations and special controls for blood irradiators
intended to prevent TA-GVHD include controls that are recommended in
the CBER Memorandum for blood banks that FDA has determined are
appropriate for and adaptable to devices to mitigate the identified
risks. The proposed special controls include items suggested by the
CBER Memorandum that were specifically discussed by the 2012 Panel
members as well as those that were not specifically discussed but that
FDA has determined to be relevant to this classification action. The
proposed special controls include performance testing; labeling
information including a device description, specifying that the device
is intended to prevent TA-GVHD, and a warning that elevated levels of
potassium have been reported in irradiated blood; software
verification, validation, and hazard analysis; and electrical and
electromagnetic compatibility testing.
FDA agrees with those 2012 Panel members who suggested a special
control to require manufacturer training of operators on device use is
not necessary for reasonable assurance of safety and effectiveness for
the device. FDA believes that the warnings and detailed procedures and
information required by the proposed special controls in the labeling,
including clear identification of intended operators, along with
adequate warnings, are sufficient, together with other special
controls, to mitigate against risks caused by operator error such as
improper radiation dose to blood or blood products. FDA also notes 21
CFR 606.20, which among other things requires personnel responsible for
the collection, processing, compatibility testing, storage or
distribution of blood or blood components to have adequate training and
experience, including professional training as necessary, or
combination thereof, to assure competent performance of their assigned
functions. There have been limited adverse events reported in the MAUDE
database, including no reports that were a result of operator error. At
this time, FDA believes a special control requiring separate operator
safety training given by the manufacturer is unnecessary for reasonable
assurance of safety and effectiveness of this device type.
FDA also disagrees with the 2012 Panel suggestion that a special
control requiring a minimum dose homogeneity percentage and
specification of a particular dose rate to be used when irradiating the
blood or blood products is necessary for reasonable assurance of safety
and effectiveness. FDA does not believe a minimum dose homogeneity
percentage and specification of dose rate ensure that all blood within
the container receive a minimum dose of 15 Gy of radiation, nor would
they account for mechanisms implemented in device design to address
dose inhomogeneity. Instead, to address risks from dose inhomogeneity,
FDA is proposing special controls to ensure delivery of at least 25 Gy
of radiation targeted to the central portion of the container and a
minimum dose of at least 15 Gy at any other point within the container,
and performance testing demonstrating conformance with the 25 Gy to the
central portion of the container and 15 Gy minimum dose at any other
point. FDA does agree with the Panel's suggestion that the manufacturer
should provide information on the decay of the source and the residual
strength of the source so that dose rate can be assessed. FDA also
agrees with the Panel that the manufacturer should provide the
dosimetric distribution. This information can be used by the operator
[[Page 12961]]
to make decisions on how to ensure requirements at individual blood
irradiation facilities are met. FDA has included in the proposed
special controls labeling controls that include information about the
specifications of the device including: dose rate, dosimetric
distributions including dose uniformity within each irradiation
canister provided with the device, and a detailed procedure for
identifying the proper loading configuration of blood and blood
products in the canister.
As noted in Section III.C.1, at the 2012 Panel FDA suggested in the
2012 Panel materials compliance with NRC regulations as a mitigation
for risks to health from improper radiation dose to blood and blood
products, and radiation exposure to the user. We are not including
compliance with NRC regulations as a special control in this proposed
rule. FDA recognizes that devices containing sealed radiation sources
and use of such devices by blood establishments may be subject to NRC
regulations and that such regulations may have an effect on the safe
use of the device. However, FDA believes that the proposed special
controls for blood irradiators intended to prevent TA-GVHD,
specifically, non-clinical performance testing demonstrating that the
device performs as intended under anticipated conditions of use, which
includes documentation demonstrating that safety features, including
interlocks, access controls, and shielding perform as intended,
labeling, and software verification, validation, together with general
controls, are sufficient to provide reasonable assurance of safety and
effectiveness of this device type.
Table 1 summarizes how each identified risk to health described in
section V.B.1 would be mitigated by the proposed special controls. The
mitigation measures in the table have been modified from those
presented in Table III of the 2012 Panel Executive Summary during the
2012 Panel meeting (Ref. 1, Executive Summary). The language in Table 1
is more general and identifies the type of mitigation measure (e.g.,
labeling) rather than the specific method (e.g., ensure preventative
maintenance program). The mitigation measures have also been modified
to include the types of mitigation measures presented and identified at
the 2012 Panel meeting (e.g., compliance with the 1993 CBER Memorandum)
with more clarity and specificity regarding the special controls needed
to provide reasonable assurance of safety and effectiveness of the
device.
Irradiation of blood and blood products to prevent TA-GVHD has been
in routine use for decades. TA-GVHD occurs when viable T-lymphocytes in
transfused blood or blood products engraft, multiply, and react against
the tissues of the recipient. Gamma and x-ray radiation can abrogate
the ability of lymphocytes to proliferate in vitro, and studies show
that irradiation of at least 15 Gy (gamma irradiation) reduces
lymphocyte response to mitogens by 90% (Refs. 3 and 16). The 1993 CBER
Memorandum recommended that the dose of radiation delivered to the
blood or blood product should be 25 Gy targeted to the central portion
of the container and 15 Gy as the minimum dose delivered at any other
point. To mitigate the risk of TA-GVHD in patients receiving a
transfusion of blood or blood products due to the improper radiation
dose being given to the blood or blood products, FDA believes that
performance testing is needed to show that the device is capable of
delivering the 25 Gy dose targeted to the central portion of the
container and minimum 15 Gy dose at any other point within the
container. To further mitigate against an improper dose of radiation
being delivered to the blood or blood component, either due to operator
error or device malfunction, the device function that allows the
operator to identify if exposure was prematurely terminated must be
validated, and any software functions must undergo software
verification, validation, and hazard analysis. To further mitigate this
risk, the device labeling must also include information that is needed
by the operator to irradiate all contents of the container to the
desired dose. This includes:
A summary of the performance testing conducted that
demonstrates that the device can deliver 25 Gy of radiation targeted to
the central portion of the container and a minimum of at least 15 Gy of
radiation at any other point within the container;
A detailed procedure that allows the device operator to
verify the minimum dose delivered during each use, the dose rate and
dose delivered by the device to the container, and if the exposure has
been prematurely terminated;
A detailed procedure identifying the proper loading
configuration of the blood or blood component within the canister and
exposure chamber and isodose curves for each loading configuration;
Information about the specifications of the device--the
dosimetric distributions within each canister provided with the
irradiator measured both in air and loaded with water equivalent
material, including dose homogeneity; and
Instructions for device maintenance.
To mitigate the risk of damage to the blood or blood components
from radiation, FDA believes that the labeling must include appropriate
warnings and limitations needed for safe use, including statements that
irradiation reduces the shelf stability of blood and that elevated
potassium levels have been reported in irradiated red blood cell
products.
To mitigate the risk of radiation exposure to the operator from the
device, FDA believes that documentation is needed to demonstrate that
the device performs as intended under anticipated conditions of use,
including safety features of the device, which include its interlocks,
access controls, and radiation shielding. For any safety features
controlled by software, software verification, validation and hazard
analysis of the features must be performed to ensure that these
features perform as intended under anticipated conditions of use.
Finally, to further mitigate this risk, FDA believes that labeling must
include an identification of the safety features that enable operators
to protect themselves and other nearby persons from unnecessary
radiation exposure and the details of their specifications.
To mitigate against electrical shock or burns, FDA believes that
adequate performance testing must demonstrate the electrical safety,
mechanical safety, thermal safety, and electromagnetic compatibility of
any electrical components of the device.
Finally, to mitigate against the risk of mechanical crush injury,
FDA believes that labeling must include adequate warnings indicating
that improper placement of hands or limbs could result in a mechanical
crush injury.
Further, FDA believes that the special controls proposed for blood
irradiators intended to prevent TA-GVHD, in addition to the general
controls, mitigate the risks to health and are necessary to provide
reasonable assurance of safety and effectiveness.
[[Page 12962]]
Table 1--Identified Risks to Health and Proposed Mitigation Measures for
Blood Irradiators Intended To Prevent TA-GVHD
------------------------------------------------------------------------
Identified risks to health Mitigation measures
------------------------------------------------------------------------
Damage to blood or blood components Labeling.
from radiation.
Improper radiation dose to blood or Performance testing
blood products. and descriptive information.
Software verification,
validation, and hazard
analysis.
Labeling.
Unintended radiation exposure to the Performance testing
operator and others. and descriptive information.
Software verification,
validation, and hazard
analysis.
Labeling.
Electrical shock....................... Electrical safety,
mechanical safety, and thermal
safety testing.
Electromagnetic compatibility
testing.
Mechanical crush or injury............. Labeling.
------------------------------------------------------------------------
VII. Premarket Approval for Class III Devices
FDA has determined that insufficient information exists to
determine that general controls and special controls would provide a
reasonable assurance of safety and effectiveness for blood irradiators
intended to prevent metastasis and that these devices present a
potential unreasonable risk of illness or injury based on the limited
clinical information that is available. FDA found no evidence that the
physical aspects (hardware and software) of blood irradiators intended
to prevent metastasis pose a potential unreasonable risk of illness or
injury. However, we found no available information about the short- and
long-term safety risks presented by the intended use of blood
irradiators intended to prevent metastasis, including cancer outcome,
patient recovery, or survival. Given the limited reported clinical use
of blood irradiators for the irradiation of intraoperative blood
salvaged from cancer patients to assist in the prevention of metastasis
in the published literature, the list of risks to health currently
identified in this proposed classification action may not be
exhaustive. For effectiveness, FDA found no definitive available
evidence showing that irradiation of intraoperatively salvaged blood is
able to prevent metastasis in patients or that it does not trigger an
immunological response that could worsen patient prognosis (promote
recurrence or invasiveness, or surgical recovery). In addition, the
dose of radiation necessary to remove proliferative tumor cells is
unclear, and the effects on the blood and blood products are unknown.
Given the uncertainty about the extent of risks posed by the device,
the lack of evidence supporting effectiveness, and a large amount of
uncertainty surrounding the patient benefit from the device, FDA is
proposing to classify blood irradiators intended to prevent metastasis
into class III.
As required by section 515(b) of the FD&C Act, FDA is publishing
elsewhere in this issue of the Federal Register a proposed order to
require the filing of a PMA, which will be finalized if this
classification action is finalized and these devices for this intended
use are classified into class III. The proposed order also contains
FDA's proposed findings regarding: the degree of risk of illness or
injury designed to be eliminated or reduced by requiring that blood
irradiators intended to prevent metastasis have an approved PMA when
intended for use that includes delivering a controlled radiation dose
to irradiate intraoperatively salvaged blood of cancer patients
undergoing surgery to prevent metastasis and the benefit to the public
from use of the device.
These findings are based on the reports and recommendations of the
advisory committees (panels) for the classification of these devices
along with information submitted to the public docket, postmarket data,
adverse event reports in the MAUDE and MDR databases, information in
CDRH's Medical Device Recalls database, and published scientific
literature.
VIII. Proposed Effective/Compliance Dates
FDA proposes that any final rule based on this proposed rule become
effective 30 days after its date of publication in the Federal
Register. If this classification action is finalized, FDA proposes the
implementation strategy set forth below.
A. Devices That Are Proposed To Be Classified Into Class II
Blood irradiators intended to prevent TA-GVHD proposed to
be classified into class II that have not been legally marketed prior
to the effective date of any final rule, or blood irradiators intended
to prevent TA-GVHD that have been legally marketed, but are required to
submit a new 510(k) under 21 CFR 807.81(a)(3) because the device is
about to be significantly changed or modified and have not submitted
such 510(k) by the effective date of any final rule: FDA is proposing
that manufacturers would have to obtain 510(k) clearance before
marketing the new or modified device and would be required to comply
with the applicable special controls as of the effective date. We
believe that 30 days is a reasonable effective date given that FDA
would not have received updated submissions regarding, and therefore
would not have familiarity with, the noncompliant devices in this
category, and given the concern about the probable consequences of
device failure, including TA-GVHD, which can result in patient death.
Blood irradiators intended to prevent TA-GVHD proposed to
be classified into class II that have been legally marketed prior to
the effective date of any final rule and are not about to be
significantly changed or modified in a manner that requires a 510(k),
and blood irradiators intended to prevent TA-GVHD for which 510(k)
submissions have been submitted before the effective date of any final
rule: FDA generally does not intend to enforce compliance with the
special control requirements, including the labeling requirements, for
a period of 12 months following the effective date of the final rule,
although FDA intends to carefully assess the application of this policy
to any devices for which submissions are made between the date of
publication of the final rule and the effective date. If a manufacturer
were to market such a device after 12 months following the effective
date of the final rule, and that device did not comply with the special
controls, the enforcement discretion policy described above would no
longer apply, meaning FDA would evaluate enforcement action against
such a manufacturer under its usual approach. FDA believes that a
period of one year from the effective date of this final rule would be
appropriate for manufacturers
[[Page 12963]]
to come into compliance with such requirements, as we are generally
familiar with these devices and we believe changes for existing devices
to come into compliance are generally limited to minor labeling
changes. We also believe this compliance period is appropriate to
accommodate the reliance interests of manufacturers who have developed
products and submitted premarket notifications based on the previous
regulatory status quo, under which blood irradiators are subject to
510(k) requirements but not special controls. FDA believes this
approach would help ensure the efficient and effective implementation
of the classification action, if finalized as currently proposed.
B. Devices That Are Proposed To Be Classified Into Class III
If this proposal to classify blood irradiators intended to
prevent metastasis in class III and the related proposed order to
require the approval of a PMA are finalized, blood irradiators intended
to prevent metastasis by delivering a controlled radiation dose to
irradiate intraoperatively salvaged blood of cancer patients undergoing
surgery to prevent metastasis would be considered adulterated if either
a PMA is not filed with FDA prior to the last day of the 30th calendar
month beginning after the month in which the classification of the
device into class III becomes effective or a PMA is filed but approval
is denied, suspended, or withdrawn (see section 501(f)(1)(A) and
501(f)(2)(B) of the FD&C Act (21 U.S.C. 351(f)(1)(A) and (2)(B))).
In this event, the device can no longer be introduced into
interstate commerce (see, e.g., section 301(a) of the FD&C Act (21
U.S.C. 331(a))) unless it meets a relevant exemption, such as the
exemption for investigational use devices. The requirements of the
investigational device exemption regulations are set forth in 21 CFR
part 812.
IX. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 14192, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4).
Executive Orders 12866 and 13563 direct us to assess all benefits
and costs of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits.
Rules are economically significant under Executive Order 12866 if they
have an annual effect on the economy of $100 million or more; or
adversely affect in a material way the economy, a sector of the
economy, productivity, competition, jobs, the environment, public
health or safety, or State, local, or tribal governments or
communities. The Office of Information and Regulatory Affairs has
determined that this proposed rule is not a significant regulatory
action under Executive Order 12866.
Executive Order 14192 requires that any new incremental costs
associated with certain significant regulatory actions ``shall, to the
extent permitted by law, be offset by the elimination of existing costs
associated with at least 10 prior regulations.'' This proposed rule, if
finalized as proposed, is not expected to be an Executive Order 14192
regulatory action because this rule is not significant under Executive
Order 12866.
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because net annualized compliance costs of the proposed rule
are more than 1 percent of average annual revenues and unquantified
effects are uncertain, we find that the proposed rule will have a
significant economic impact on a substantial number of small entities.
The Unfunded Mandates Reform Act of 1995 (Section 202(a)) requires
us to prepare a written statement, which includes estimates of
anticipated impacts, before proposing ``any rule that includes any
Federal mandate that may result in the expenditure by State, local, and
tribal governments, in the aggregate, or by the private sector, of
$100,000,000 or more (adjusted annually for inflation) in any 1 year.''
The current threshold after adjustment for inflation is $187 million,
using the most current (2024) Implicit Price Deflator for the Gross
Domestic Product. This proposed rule would not result in an expenditure
in any year that meets or exceeds this amount.
The proposed rule, if finalized, would classify blood irradiators
(unclassified, preamendments devices) into two classes based on
intended use. It would classify blood irradiators intended to prevent
TA-GVHD into class II (special controls) and blood irradiators intended
to prevent metastasis into class III (premarket approval application).
The proposed special controls for blood irradiators intended to prevent
TA-GVHD are already generally practiced by manufacturers of currently
cleared devices, with the primary change consisting of the labeling
special controls. FDA believes that the proposed special controls,
together with the general controls in the FD&C Act, would provide
reasonable assurance of the safety and effectiveness of these devices
and help ensure that all new devices meet the same standards as the
currently marketed devices. FDA has determined that general controls
and special controls together are insufficient to provide reasonable
assurance of safety and effectiveness for blood irradiators intended to
prevent metastasis, and that these devices present a potential
unreasonable risk of illness or injury. Separately, FDA also is issuing
a proposed order requiring the filing of a PMA for blood irradiators
intended to prevent metastasis.
Quantified benefits of the proposed rule, if finalized, would
consist of cost savings to industry and FDA from a reduction in the
quantity and time burden of informal inquiries related to blood
irradiators intended to prevent TA-GVHD. We also estimate cost savings
to industry and FDA from a reduction in the number of 510(k)
submissions necessitating requests for additional information from FDA
before and during review. Industry and FDA could incur costs associated
with premarket approval for current and future blood irradiators
intended to prevent metastasis. Industry would incur costs to prepare
and submit PMAs and annual and supplemental reports and costs to
undergo facility inspections. In turn, FDA would incur costs to review
and respond to PMAs and annual and supplemental reports, and costs to
inspect facilities. We quantify the associated user fees for these PMAs
and annual and supplemental reports as transfers from industry to FDA.
We additionally quantify one-time costs to industry to read and
understand the proposed rule and the proposed order requiring the
filing of a PMA, as well as one-time costs to industry to revise
labeling.
We summarize the quantified benefits and costs of the proposed
rule, if finalized, in Table 2. We estimate that the annualized
benefits over 10 years would range from $84 to $180,268 at a 7 percent
discount rate, with a primary estimate of $90,176, and from $86 to
$184,271 at a 3 percent discount rate, with a primary estimate of
$92,178. The annualized costs would range from $0.68 million to $1.51
million at a 7 percent discount rate, with a primary estimate of $1.07
million, and from $0.66 million to $1.53 million at a 3 percent
discount rate, with a primary estimate of $1.07 million.
[[Page 12964]]
Table 2--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
[Millions of 2024 dollars]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized ($m/year)............ $0.09 $0.0001 $0.18 2024 7 10 Estimated benefits are cost
0.09 0.0001 0.18 2024 3 10 savings.
Annualized Quantified..................... .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------
Qualitative...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized ($m/year)............ 1.07 0.68 1.51 2024 7 10
1.07 0.66 1.53 2024 3 10
Annualized Quantified..................... .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
------------------------------------------------------------------------
Qualitative...............................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized ($m/year).... 0.05 0.03 0.07 2024 7 10 User fee payments associated
0.05 0.03 0.07 2024 3 10 with premarket approval for
class III blood irradiator
devices.
---------------------------------------------------------------------------------------------------------
From: Blood irradiator device
industry
To: FDA
---------------------------------------------------------------------------------------------------------
Other Annualized Monetized ($m/year)...... .......... .......... .......... .......... .......... ..........
.......... .......... .......... .......... .......... ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local, or Tribal Government: None............................................................................................................
Small Business: Quantified effects of more than 1 percent of average annual revenues and uncertain unquantified effects.............................
Wages: None.........................................................................................................................................
Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
We estimate that the present value of total benefits over 10 years
would range from $0.001 million to $1.35 million at a 7 percent
discount rate, with a primary estimate of $0.68 million, and from
$0.001 million to $1.62 million at a 3 percent discount rate, with a
primary estimate of $0.81 million. The present value of total costs
would range from $5.09 million to $11.38 million at a 7 percent
discount rate, with a primary estimate of $8.06 million, and from $5.80
million to $13.41 million at a 3 percent discount rate, with a primary
estimate of $9.39 million.
In line with Executive Order 14192, in Table 3 we estimate present
and annualized values of costs, cost savings, and net costs over a
perpetual time horizon. We estimate that this proposed rule would
generate $570,338 in annualized net costs at a 7 percent discount rate,
discounted relative to year 2024, over a perpetual time horizon.
Table 3--Executive Order 14192 Summary Table
[Millions of 2024 dollars, discounted over a perpetual time horizon relative to year at a 7 percent discount
rate]
----------------------------------------------------------------------------------------------------------------
Primary
estimate Low estimate High estimate
----------------------------------------------------------------------------------------------------------------
Present Value of Costs.......................................... $9.21 $4.59 $14.54
Present Value of Cost Savings................................... 1.06 0.001 2.12
Present Value of Net Costs...................................... 8.15 4.59 12.42
Annualized Costs................................................ 0.64 0.32 1.02
Annualized Cost Savings......................................... 0.07 0.0001 0.15
Annualized Net Costs............................................ 0.57 0.32 0.87
----------------------------------------------------------------------------------------------------------------
Note: Due to uncertainty regarding future impacts of the proposed rule, if finalized, we assume that
undiscounted costs and cost savings in years 10 through infinity would equal costs and cost savings in year 9.
We assume that costs and cost savings would begin to accrue in 2028 (year 0).
We have developed a Preliminary Economic Analysis of Impacts that
assesses the impacts of the proposed rule. The full preliminary
analysis of economic impacts is available in the docket for this
proposed rule (Ref. 17) and at https://www.fda.gov/about-fda/economics-staff/regulatory-impact-analyses-ria.
X. 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.
XI. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed rule contains no new
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.
[[Page 12965]]
XII. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
this proposed rule does not contain policies that have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. Accordingly,
we conclude that the proposed rule does not contain policies that have
federalism implications as defined in the Executive Order and,
consequently, a federalism summary impact statement is not required.
XIII. Consultation and Coordination with Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.
XIV. 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 also are 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. ``Recommendations Regarding License Amendments and Procedures
for Gamma Irradiation of Blood Products,'' issued July 22, 1993.
Available at http://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/otherrecommendationsformanufacturers/memorandumtobloodestablishments/ucm062815.pdf.
4. Ozdogu H, Boga C, Asma S, et al. ``Organ damage mitigation with
the Baskent Sickle Cell Medical Care Development Program
(BASCARE).'' Medicine Feb. 2018;97(6):e9844. doi:10.1097/
MD.0000000000009844. Available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944669/.
5. Nodeh FK, Hosseini E, Ghasemzadeh M. ``The effect of gamma
irradiation on platelet redox state during storage.'' Transfusion.
Feb 2021;61(2):579-593. doi:10.1111/trf.16207. Available at https://onlinelibrary.wiley.com/doi/full/10.1111/trf.16207.
6. Patidar GK, Joshi A, Marwaha N, et al. ``Serial assessment of
biochemical changes in irradiated red blood cells.'' Transfusion and
apheresis science: official journal of the World Apheresis
Association: official journal of the European Society for
Haemapheresis. Jun 2014;50(3):479-87. doi:10.1016/
j.transci.2014.02.002. Available at https://www.sciencedirect.com/science/article/abs/pii/S1473050214000305?via%3Dihub.
7. Hauck-Dlimi, B., Schiffer, K., Eckstein, R., et al. ``Influence
of Irradiation on Leukodepleted Small Unit Red Blood Cell (RBC) Bags
for Infant Transfusion in Additive Solution SAG-M.'' Clinical
laboratory, 2016;62(7), 1295-1301. doi:10.7754/Clin.Lab.2015.151127.
Available at https://www.clin-lab-publications.com/article/2182.
8. Castro G, Merkel PA, Giclas HE, et al. ``Amotosalen/UVA treatment
inactivates T cells more effectively than the recommended gamma dose
for prevention of transfusion-associated graft-versus-host
disease.'' Transfusion. Jun 2018;58(6):1506-1515. doi:10.1111/
trf.14589. Available at https://onlinelibrary.wiley.com/doi/10.1111/trf.14589.
9. Nollet KE, Ngoma AM, Ohto H. ``Transfusion-associated graft-
versus-host disease, transfusion-associated hyperkalemia, and
potassium filtration: advancing safety and sufficiency of the blood
supply.'' Transfusion and Apheresis Science. 2022;61(2).
doi:10.1016/j.transci.2022.103408. Available at https://www.sciencedirect.com/science/article/abs/pii/S1473050222000702?via%3Dihub.
10. Kleinman S, Stassinopoulos A. ``Transfusion-associated graft-
versus-host disease reexamined: potential for improved prevention
using a universally applied intervention.'' Transfusion. Nov
2018;58(11):2545-2563. doi:10.1111/trf.14930. Available at https://onlinelibrary.wiley.com/doi/10.1111/trf.14930.
11. Mantuano A, Salata C, Mota CL, et al. ``Technical Note: Fricke
dosimetry for blood irradiators.'' Medical Physics. 2021;48(1):500-
504. doi:10.1002/mp.14487. Available at https://aapm.onlinelibrary.wiley.com/doi/10.1002/mp.14487.
12. Peng D, Bai W, Zhang C, et al. ``X-ray irradiation effectively
inactivated lymphocytes in transfusion in vivo monitored by the
bioluminescence transfusion-associated graft-versus-host disease
model.'' Vox sanguinis. 2024;119(3):181-192. doi: 10.1111/vox.13559.
Epub 2024 Jan 16. PMID: 38226529. Available at https://onlinelibrary.wiley.com/doi/10.1111/vox.13559.
13. Merolle L, Schiroli D, Farioli D, et al. ``Reduction of EpCAM-
Positive cells from a cell salvage product is achieved by leucocyte
depletion filters alone.'' Journal of Clinical Medicine. Jun
2023;12(12). doi:10.3390/jcm12124088. Available at https://pmc.ncbi.nlm.nih.gov/articles/PMC10299373/.
*14. 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).
15. 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.
16. Valerius NH, Johansen KS, Nielson OS. ``Effect of in vitro x-
irradiation on lymphocyte and granulocyte function.'' Scandinavian
journal of haematology.1981; 27:9-18.
*17. FDA, ``Preliminary Regulatory Impact Analysis, Initial
Regulatory Flexibility Analysis, and Unfunded Mandates Reform Act
Analysis: Radiology Devices; Classification of Blood Irradiators''
Available at https://www.fda.gov/economics-staff/regulatory-impact-analyses-ria.
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:
[[Page 12966]]
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Add Sec. 892.7000 to subpart G to read as follows:
Sec. 892.7000; Blood irradiator devices.
(a) Identification. A blood irradiator device is a prescription
device used to deliver a controlled radiation dose to blood or blood
products to prevent transfusion-associated graft-versus-host disease
through delivery of a radiation dose to blood or blood products prior
to transfusion or to irradiate intraoperatively salvaged blood in
cancer patients undergoing surgery to assist in the prevention of
metastasis. This generic type of device includes an x-ray or a sealed
radionuclide radiation source.
(b) Classification.
(1) Class II (special controls) when intended to prevent
transfusion-associated graft-versus-host disease through delivery of a
radiation dose to blood or blood products prior to transfusion. The
special controls for this device are:
(i) Non-clinical performance testing must demonstrate that the
device performs as intended under anticipated conditions of use and
must include:
(A) Documentation demonstrating that the device delivers a dose of
at least 25 Gy of radiation targeted to the central portion of the
container.
(B) Documentation demonstrating that the device delivers a minimum
dose of at least 15 Gy of radiation at any other point within the
container.
(C) Documentation demonstrating that safety features, including
interlocks, access controls, and shielding, perform as intended.
(D) Validation of the method that allows the operator to identify
if the exposure has been prematurely terminated.
(ii) Software verification, validation, and hazard analysis must be
performed.
(iii) Performance testing must demonstrate the electrical safety,
mechanical safety, thermal safety, and electromagnetic compatibility of
any of the electrical components of the device.
(iv) Labeling must include:
(A) The intended use statement must specify that the device is
intended to prevent transfusion-associated graft-versus-host disease.
(B) A summary of the performance testing conducted demonstrating
that the device can deliver 25 Gy of radiation targeted to the central
portion of the container and a minimum of at least 15 Gy at any other
point within the container.
(C) A detailed procedure allowing the device operator to verify:
(1) The minimum dose delivered during each use;
(2) The dose rate and dose delivered by the device to the
container; and
(3) If the exposure has been prematurely terminated.
(D) Identification of the safety features that enable operators to
protect themselves and other nearby persons from unnecessary radiation
exposure and details of their specifications.
(E) A detailed procedure for identifying the proper loading
configuration of the blood or blood products within the canister and
exposure chamber and isodose curves for each loading configuration.
(F) Information about the specifications of the device including:
(1) Dosimetric distributions, including dose uniformity, within
each irradiation canister provided with the irradiator measured both in
air and loaded with water equivalent material;
(2) Dose rate; and
(3) For radionuclide sealed radiation source irradiators, the
strength of the source and the dose correction factor.
(G) Instructions for device maintenance, including:
(1) A recommended schedule of maintenance; and
(2) A recommended quality assurance program to ensure that the
device continues to meet its specifications.
(H) A warning statement indicating that irradiation reduces the
shelf stability of blood and blood products.
(I) A warning statement indicating that elevated potassium levels
have been reported in irradiated red blood cell products.
(J) A warning statement indicating that improper placement of hands
or limbs could result in a mechanical crush injury.
(2) Class III (premarket approval) when intended to irradiate
intraoperatively salvaged blood in cancer patients undergoing surgery
to assist in the prevention of metastasis.
(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 THE
EFFECTIVE DATE OF THE 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.
Robert F. Kennedy, Jr.,
Secretary, Department of Health and Human Services.
[FR Doc. 2026-05320 Filed 3-17-26; 8:45 am]
BILLING CODE 4164-01-P