ML24162A086

Draft for ACMUI Review - Preliminary Extravasations Proposed Rule Federal Register Notice

ML24162A086
Person / Time
Issue date:	03/05/2024
From:	Carrie Safford NRC/SECY, NRC/NMSS/DREFS/MRPB
To:
L Armstead
References
RIN 3150-AK91, NRC-2022-0218
Download: ML24162A086 (44)

Text

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[7590-01-P]

NUCLEAR REGULATORY COMMISSION 10 CFR Part 35 NRC-2022-0218 RIN 3150-AK91 Reporting Nuclear Medicine Injection Extravasations as Medical Events AGENCY: Nuclear Regulatory Commission.

ACTION: Proposed rule.

SUMMARY

The U.S. Nuclear Regulatory Commission (NRC) is proposing to amend its regulations to require reporting of certain nuclear medicine injection extravasations as medical events and to require medical licensees to develop, implement, and maintain written procedures for evaluating and reporting extravasations. This proposed rule would affect medical licensees that administer intravenous radiopharmaceuticals for diagnostic and therapeutic purposes. The NRC plans to hold a public meeting to promote full understanding of this proposed rule and facilitate public comments.

DATES: Submit comments by [INSERT DATE 90 DAYS AFTER DATE OF PUBLICATION IN THE FEDERAL REGISTER]. Comments received after this date will be considered if it is practical to do so, but the NRC is able to ensure consideration only for comments received on or before this date.

2 ADDRESSES: You may submit comments by any of the following methods; however, the NRC encourages electronic comment submission through the Federal rulemaking website:

Federal Rulemaking website: Go to https://www.regulations.gov and search for Docket ID NRC-2022-0218. Address questions about NRC dockets to Dawn Forder; telephone: 301-415-3407; email: Dawn.Forder@nrc.gov. For technical questions contact the individuals listed in the FOR FURTHER INFORMATION CONTACT section of this document.

Email comments to: Rulemaking.Comments@nrc.gov. If you do not receive an automatic email reply confirming receipt, then contact us at 301-415-1677.

Fax comments to: Secretary, U.S. Nuclear Regulatory Commission at 301-415-1101.

Mail comments to: Secretary, U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001, ATTN: Rulemakings and Adjudications Staff.

Hand deliver comments to: 11555 Rockville Pike, Rockville, Maryland 20852, between 7:30 a.m. and 4:15 p.m. eastern time, Federal workdays; telephone:

301-415-1677.

You can read a plain language description of this proposed rule at https://www.regulations.gov/docket/NRC-2022-0218. For additional direction on obtaining information and submitting comments, see Obtaining Information and Submitting Comments in the SUPPLEMENTARY INFORMATION section of this document.

FOR FURTHER INFORMATION CONTACT: Irene Wu, Office of Nuclear Material Safety and Safeguards, telephone: 301-415-1951, email: Irene.Wu@nrc.gov and Daniel

3 DiMarco, Office of Nuclear Material Safety and Safeguards, telephone: 301-415-3303, email: Daniel.Dimarco@nrc.gov. Both are staff of the U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001.

SUPPLEMENTARY INFORMATION:

TABLE OF CONTENTS:

I.

Obtaining Information and Submitting Comments A. Obtaining Information B. Submitting Comments II.

Background

A. NRCs Medical Event Reporting Regulations B. Requests for and Consideration of Revisions to NRCs Regulations

1. NRCs Advisory Committee on the Medical Uses of Isotopes (ACMUI)

2. Lucerno Dynamics Petition

3. NRC Evaluation

4. NRC Rulemaking Plan and Commission Direction

5. Pre-rulemaking activities - Information Request III.

Discussion A. What Action is the NRC Taking?

B. Who Would this Action Affect?

C. Why Do the Requirements Need to be Revised?

D. Why Does the NRC Believe a Non-Dose-Based Criterion is Appropriate for Extravasations?

E. What is the Status of the Dosimetry Model?

F. Why Does the Reportable Threshold Require Reporting for an Extravasation that Results or Has the Potential to Result in a Radiation Injury from an Extravasation?

G. Why Does the Proposed Reporting Criterion Include a Determination by a Physician?

H. What Definitions Did the NRC Update?

I. Why is the NRC Requiring that Licensees Have Procedures to Detect and Report Extravasations?

IV.

Specific Requests for Comments V.

Section-by-Section Analysis VI.

Regulatory Flexibility Certification VII.

Regulatory Analysis VIII.

Backfitting and Issue Finality IX.

Cumulative Effects of Regulation X.

Plain Writing XI.

National Environmental Policy Act XII.

Paperwork Reduction Act Statement XIII.

Criminal Penalties XIV.

Coordination with NRC Agreement States

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Coordination with the Advisory Committee on the Medical Uses of Isotopes XVI.

Compatibility of Agreement State Regulations XVII.

Voluntary Consensus Standards XVIII. Availability of Guidance XIX.

Public Meeting XX.

Availability of Documents I. Obtaining Information and Submitting Comments A. Obtaining Information Please refer to Docket ID NRC-2022-0218 when contacting the NRC about the availability of information for this action. You may obtain publicly available information related to this action by any of the following methods:

Federal Rulemaking Website: Go to https://www.regulations.gov and search for Docket ID NRC-2022-0218.

NRCs Agencywide Documents Access and Management System (ADAMS): You may obtain publicly available documents online in the ADAMS Public Documents collection at https://www.nrc.gov/reading-rm/adams.html. To begin the search, select Begin Web-based ADAMS Search. For problems with ADAMS, please contact the NRCs Public Document Room (PDR) reference staff at 1-800-397-4209, at 301-415-4737, or by email to PDR.Resource@nrc.gov. For the convenience of the reader, instructions about obtaining materials referenced in this document are provided in the Availability of Documents section.

NRCs PDR: The PDR, where you may examine and order copies of publicly available documents, is open by appointment. To make an appointment to visit the PDR, please send an email to PDR.Resource@nrc.gov or call 1-800-397-4209 or 301-415-4737, between 8 a.m. and 4 p.m. eastern time, Monday through Friday, except Federal holidays.

B. Submitting Comments

5 The NRC encourages electronic comment submission through the Federal rulemaking website (https://www.regulations.gov). Please include Docket ID NRC-2022-0218 in your comment submission.

The NRC cautions you not to include identifying or contact information that you do not want to be publicly disclosed in your comment submission. The NRC will post all comment submissions at https://www.regulations.gov as well as enter the comment submissions into ADAMS. The NRC does not routinely edit comment submissions to remove identifying or contact information.

If you are requesting or aggregating comments from other persons for submission to the NRC, then you should inform those persons not to include identifying or contact information that they do not want to be publicly disclosed in their comment submission. Your request should state that the NRC does not routinely edit comment submissions to remove such information before making the comment submissions available to the public or entering the comment into ADAMS.

II. Background This section discusses the evolution of the existing regulatory framework for medical event reporting and the various requests for, and consideration of whether, certain extravasations should be included in medical event reporting to provide context for the proposed changes. As proposed in this rule, the NRC defines extravasation to mean the unintentional presence of a radiopharmaceutical in the tissue surrounding the blood vessel following an injection.

A.

NRCs Medical Event Reporting Regulations

6 In 1980, the NRC amended the medical use regulations in part 35 of title 10 of the Code of Federal Regulations (10 CFR), Medical Use of Byproduct Material, to require the reporting of medical misadministrations (later renamed medical events) (45 FR 31701). The reporting and analysis of medical events helps to identify deficiencies in the safe use of radioactive material and to ensure that corrective actions are taken to prevent recurrence. In the 1980 rulemaking, the NRC stated in a comment response that it did not consider an extravasation to be a misadministration because extravasations frequently occur in otherwise normal intravenous or intraarterial injections and that extravasations are virtually impossible to avoid. After the 1980 rulemaking, the medical event reporting requirements were subsequently updated in final rules published in the Federal Register in July 1991, April 2002, and July 2018 (56 FR 34104, 67 FR 20250, and 83 FR 33046). In 2002, the term and criteria for misadministration were replaced with medical event and several updates were made to § 35.3045, Report and notification of a medical event. None of these updates addressed extravasations.

Consistent with the terminology currently used in 10 CFR part 35, the NRC will use the term medical event for the rest of this document.

B.

Requests for and Consideration of Revisions to NRCs Regulations

1. NRCs Advisory Committee on the Medical Uses of Isotopes (ACMUI)

In 2008 and 2009, ACMUI evaluated whether extravasations should continue to be excluded from medical event reporting after a licensee reported (and later retracted) an extravasation involving a common diagnostic radiopharmaceutical. During ACMUI public meetings in December 2008 and May 2009, the ACMUI discussed diagnostic and therapeutic extravasations and recommended all extravasations should continue to be excluded from the medical event reporting requirements, and the staff agreed with the recommendation.

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2. Lucerno Dynamics Petition On May 18, 2020, Lucerno Dynamics, LLC, submitted a petition for rulemaking (PRM)-35-22, that requested the NRC to amend 10 CFR part 35 to require medical event reporting of radiopharmaceutical extravasations that lead to an irradiation resulting in a localized dose equivalent exceeding 50 rem (0.5 sievert). On September 15, 2020, the NRC published a notice of docketing and request for public comment in the Federal Register (85 FR 57148). The comment period closed on November 30, 2020, and the NRC received 488 comment submissions from the medical community, Agreement States, congressional representatives, and members of the public. The NRC heard from medical professionals strongly opposed to regulating extravasations. Some representatives of the medical community commented that no technology can prevent extravasations, although monitoring for extravasations could allow clinicians to begin mitigation measures sooner. Multiple commenters stated that requiring extravasations to be reported as medical events would create a significant regulatory burden on licensees with no added safety benefit. One commenter stated that the NRC did not need to regulate extravasations because many institutions already have initiatives for injection quality monitoring and improvement, and multiple mechanisms exist to evaluate and promote the safe medical use of radioactive materials.

3. NRC Evaluation In a separate initiative, the NRC independently evaluated whether extravasations should be reported as medical events. To inform the independent evaluation, the NRC considered information from the petitioner, the ACMUI, Agreement States, and external stakeholders, as well as available published literature on extravasations. The NRCs preliminary evaluation of extravasations and medical event reporting resulted in the

8 consideration of several rulemaking options, all of which would require that certain extravasations be reported as medical events. The NRC provided its preliminary evaluation to the ACMUI extravasation subcommittee in April 2021. In September 2021, the subcommittees recommendations were presented to the full ACMUI during a public meeting. At that meeting, the ACMUI endorsed a non-dose-based rulemaking option for reporting extravasations that result in a radiation injury.

4. NRC Rulemaking Plan and Commission Direction On May 9, 2022, the NRC staff submitted to the Commission SECY-22-0043, Petition for Rulemaking and Rulemaking Plan on Reporting Nuclear Medicine Injection Extravasations as Medical Events (PRM-35-22; NRC-2020-0141), requesting approval to consider the issues raised in PRM-35-22 in the rulemaking process and to initiate rulemaking to require reporting of extravasations that require medical attention for a suspected radiation injury.

In staff requirements memorandum (SRM) to SECY-22-0043, dated December 12, 2022, the Commission approved the staffs recommendation to amend 10 CFR part 35 to include certain nuclear medicine injection extravasations as reportable medical events. Additionally, the Commission directed the staff to explore approaches to reduce reliance on patient reporting, develop regulatory guidance for all medical events, and look for opportunities to accelerate the rulemaking schedule without shortening public comment periods. On December 30, 2022, the NRC published a document in the Federal Register stating that the NRC would consider the issues raised in the petition in the rulemaking process and closed the petition docket (87 FR 80474).

5. Pre-rulemaking activities - Information Request

9 On April 19, 2023, the NRC staff published in the Federal Register an information request with preliminary proposed rule language and posed specific questions to obtain input from stakeholders (88 FR 24130). The questions were divided into three topics:

definitions, procedures, and healthcare inequities. The NRC staff provided a 90-day public comment period, which the NRC staff later extended by 45 days to allow members of the public more time to develop and submit their input (88 FR 45824; July 18, 2023). On May 24, 2023, the NRC staff held a public meeting to facilitate stakeholder feedback on the preliminary proposed rule language and questions included in the information request. During the meeting, the NRC staff presented background on development of the NRCs medical event reporting requirements, the NRCs current regulations on medical event reporting, the basis for the preliminary proposed rule language, and the basis for the questions in the April 19, 2023, information request.

Participants asked clarifying questions and were provided details on how to submit their feedback.

The NRC received over 200 submittals on the information request from members of the public, medical professionals, licensees, patient advocacy groups, nongovernmental organizations, and Agreement States. More than half of the submittals received were form letters that asked the NRC to reconsider the non-dose-based aspect of the extravasation rulemaking because it could put a burden on patients and stated the NRC should require providers to treat an extravasation like any other medical event (a threshold of 50 rem (0.5 sievert) localized dose). The NRC also received feedback that a rulemaking for extravasations was unnecessary because the NRC could instead clarify that the existing medical event regulations were inclusive of extravasations. (The NRC staff determined that extravasations do not fit under the current medical event criteria; therefore, 10 CFR Part 35 must be revised through the notice-and-comment rulemaking process in order to report them as medical events.) Copies of the submittals received on

10 the information request and preliminary proposed rule language may be viewed and downloaded from the Federal eRulemaking Website https://www.regulations.gov, under Docket ID NRC-2022-0218.

Since this comment period was outside the formal proposed rule notice-and-comment rulemaking process, formal responses to the submittals received on the information request were not prepared. However, the NRC considered these submittals in the development of this proposed rule and has made several modifications to the preliminary proposed rule language as a result of the public input. Those changes included:

Revising the definition for extravasation to mean the unintentional presence of a radiopharmaceutical in the tissue surrounding the blood vessel following an injection; Removing the definition for medical attention; Changing suspected radiation injury to radiation injury and revising the definition to mean a deterministic health effect to the area around an injection site that can be attributed to radiation; Revising § 35.3045 to require that licensees report the administration of byproduct material that results or has the potential to result in a radiation injury from an extravasation, as determined by a physician; and Revising the section on procedures for evaluating and reporting extravasations to clarify that licensees written procedures must provide high confidence that a reportable extravasation will be detected in a timely manner and reported in accordance with § 35.3045.

III. Discussion

11 A. What Action is the NRC Taking?

This NRC is proposing to amend 10 CFR part 35 to require that licensees report as a medical event an administration of byproduct material that results or has the potential to result in a radiation injury from an extravasation, as determined by a physician. The NRC is also proposing to amend 10 CFR part 35 to require that licensees have procedures in place for evaluating and reporting extravasations and that licensees retain a copy of those procedures for the duration of the license.

To support the implementation of these provisions, the NRC is proposing to add definitions of extravasation and radiation injury to the Definitions section of 10 CFR part 35. The NRC is also proposing changes that are corrective or of a minor or nonpolicy nature and do not substantially modify existing regulations in 10 CFR part 35 (e.g., inclusive language, plain language).

B. Who Would this Action Affect?

This proposed rule would affect all NRC and Agreement State medical licensees who administer intravenous radiopharmaceuticals for diagnostic and therapeutic purposes.

C. Why Do the Requirements Need to be Revised?

As noted in the Background section of this document, the NRC currently excludes radiopharmaceutical extravasations from its medical event reporting regulations in 10 CFR part 35. Therefore, extravasations that cause radiation injury, including those that meet the public health and safety significance criteria for an abnormal occurrence, are not required to be reported to the NRC for consideration in NRCs evaluation of medical events. If extravasations that result or have the potential to

12 result in a radiation injury are reported to the NRC, the NRC can track and trend these events and collect information on their occurrence, detection, mitigation, and possible preventive strategies that would be available for licensee and public use.

D. Why Does the NRC Believe a Non-Dose-Based Criterion is Appropriate for Extravasations?

The NRC supports a non-dose-based criterion for the reporting of certain extravasations in order to gain further understanding of the extravasations that have potential radiation safety concerns. The severity of the extravasation may depend on a multitude of factors, and an extravasation may result from a nuclear medicine injection that was correctly administered. Extravasation is a known risk in all medical injections because a vessel is being punctured and fluid may leak from the puncture site inadvertently. In response to the NRCs information request, commenters generally noted that extravasations may be prevalent, but extravasations tend to be of low volume and do not affect patient safety or care. Some commenters from the medical community agreed that extravasations that result in patient harm or compromise patient care are very rare and typically associated with therapeutic radiopharmaceuticals. However, as noted above, the NRC does not currently possess data on the extent to which extravasations may result in patient harm or compromise patient care because there is currently no reporting requirement for extravasations. The NRC expects that if finalized, the proposed reporting requirement would further the NRCs understanding of extravasations by providing information on radiation-safety-significant extravasations. As with all reporting requirements, such information could help the NRC understand the radiation safety risk posed by extravasations and collect and share information on extravasation trends, prevention, mitigation, and best practices. Because available information suggests that extravasations that result in patient harm or otherwise

13 compromise patient care are rare, the NRC does not see a need for a dose-based criterion at this time. Moreover, since an extravasation can occur during almost any radiopharmaceutical IV injection, imposing a dose-based criterion would require monitoring millions of administrations per year, which would result in significant regulatory burden for medical licensees for only a marginal increase in radiation safety.

In light of the above information on the risks posed by extravasations of radiopharmaceuticals, the NRC believes such a dose-based requirement would be inappropriate.

Further, a reporting requirement that does not include a dose-based threshold comports with the approach the NRC has taken for certain other reportable medical events. While medical reportable medical events under § 35.3045(a) include a dose-based threshold, other portions of § 34.3045 do not. The criteria in § 35.3045(a) are primarily based on human error (i.e., wrong radioactive drug or radionuclide, wrong route of administration, wrong individual, wrong mode of treatment); however, to be reportable, these errors must result in a dose that exceeds 0.05 Sv (5 rem) effective dose equivalent, 0.5 Sv (50 rem) to an organ or tissue, or 0.5 Sv (50 rem) shallow dose equivalent to the skin. The NRC also requires reporting of events where skin, organ, or tissues other than the treatment site receive doses that exceed by 0.5 Sv (50 rem) or more the expected dose to that site from the procedure and 50 percent or more the expected dose to that site from the procedure.

The NRC is proposing a criterion for reporting an extravasation in

§ 35.3045(a)(3) that is different from the other medical event reporting criteria in § 35.3045(a) because there is no method to assess whether the extravasation resulted from human error or from other factors outside the licensees control. Unintentional presence of radiopharmaceutical in the tissue surrounding a blood vessel may be observed even when the prescribed dosage of a radiopharmaceutical as indicated in the

14 written directive and intended by an authorized user (AU) is administered to a patient.

While there may be some delay time, normal biological processes will transport the dose to the intended target.

Although the proposed criterion in § 35.3045(a)(3) may differ from the other medical event criteria in § 35.3045(a), NRC does have provisions for medical event reporting criteria that are not based on human error or a dose threshold. For example, § 35.3045(b) requires reporting of medical events resulting from patient intervention. This reporting requirement is not predicated on a medical error having occurred or on a dose threshold being exceeded; rather, under § 35.3045(b) an event is reportable if due to intervention of a patient the administration or radiation from byproduct material results in unintended permanent functional damage to an organ or physiological system, as determined by a physician.

Additionally, there does not yet exist a standardized dosimetry model for extravasations. The NRC has determined that a reporting criterion for nuclear medicine injection extravasations that does not rely on a dose differential strikes the appropriate balance between the dosimetry required to properly characterize an extravasation and the potential for a radiation effect on a patient, regardless of whether the extravasation results from human error.

E. What is the Status of the Dosimetry Model?

Although the proposed reporting criterion for extravasations is not based on dose, licensees may want to perform a dose assessment of an extravasation because knowing the estimated dose to tissue could help licensees assess a suspected radiation injury. In SECY-22-0043, the staff indicated that it would develop a dosimetry model to assist licensees in characterizing reportable nuclear medicine injection extravasations.

The NRC is currently developing a dosimetry methodology as a module in the

15 VARSKIN+ computer code. VARSKIN+ is currently free to use and will allow interested stakeholders to use the code for dose assessments or research. This model is expected to be complete in early 2025.

F. Why Does the Reportable Threshold Require Reporting for an Extravasation that Results or Has the Potential to Result in a Radiation Injury from an Extravasation?

The reporting threshold in the proposed rule resulted from extensive interactions with ACMUI, medical professionals, and other members of the public. In its preliminary evaluation of nuclear medicine injection extravasations (July 30, 2021), the NRC assessed several options related to the potential reporting of extravasations as medical events. One of the options considered by the NRC was for licensees to report to the NRC as medical events extravasations that require medical attention due to radiation-induced tissue damage near the administration site. This reporting criterion would have captured extravasations from both diagnostic and therapeutic radiopharmaceuticals, while ensuring extravasations that pose a risk to the patient be reported and assessed.

In its preliminary evaluation, the NRC also stated that this criterion would not require monitoring of any radiopharmaceutical injection because only those extravasations significant enough to merit medical attention would need to be reported. Licensees could elect to perform dosimetry if they suspected that the extravasation would be significant enough to result in a radiation injury. The ACMUI, in the final report from the extravasation subcommittee, recommended that the NRC revise this option to report extravasations that require medical attention for a suspected radiation injury, in consideration of a comment from the American Society for Radiation Oncology. The ACMUI stated that this approach would provide the NRC with information related to the potential types of radiation injuries and frequency. The staff considered the ACMUIs recommendation, and also considered that the Organization of Agreement States and

16 several Agreement States also supported its recommendation that extravasations that require medical attention for a suspected radiation injury be reported as medical events because it would focus on the extravasations that pose the greatest risk to the patient while ensuring the National Materials Program is gathering and sharing data related to extravasation medical events. The Commission ultimately approved the staffs recommended option.

In Section II.e of the information request, the NRC issued preliminary proposed rule language and sought public comment on this specific reporting criterion. Responses were generally mixed on the definition of medical attention. Some commenters pointed to the definitions provided by the Common Terminology Criteria for Adverse Events (CTCAE) or deferred to the expertise of the medical community. Other commenters stated that the definition of medical attention was too ambiguous, as it was unclear who is providing the attention, what attention is being provided, and whether the care is preventative or reactive. Commenters also stated that some types of non-invasive or minor medical attention should not be included in the definition. The NRC has decided to revise the reporting requirements to remove medical attention due to the ambiguity of the term. Additionally, healthcare providers may already have mitigative measures for when a patient experiences an extravasation. Regardless of the severity of the extravasation, the NRC has determined that the application of medical care should not itself be a trigger for medical event reporting.

Some commenters suggested that the NRC require the reporting of an extravasation that results in an observable radiation injury. The commenters stated that only objective criteria can be used for uniform and fair implementation of the regulations.

However, the NRC decided to keep the reporting criterion based on the potential for radiation injury in § 35.3045(a)(3) because deterministic effects of radiation to the skin often manifest days to weeks after exposure to radiation, depending on the dose. By

17 focusing on the potential for radiation injury, the licensee does not need to wait for deterministic effects to manifest to ensure appropriate assessment and reporting of an extravasation that could result in risk to the patient. This places the responsibility of reporting on the licensee and reduces reliance on patient involvement in the identification of a reportable extravasation. Additionally, focusing on the potential for harm ensures that licensees have adequate procedures to detect and assess extravasations while the patient is still in the care of the licensee.

Many commenters stated that the NRC should only require reporting of extravasations of therapeutic radiopharmaceuticals because extravasations from diagnostic radioactive drugs rarely result in harm to patients. There have been cases reported in scientific literature that show that certain radiopharmaceutical extravasations may have significant health effects for patients, including those from diagnostic administrations. For example, extravasations from I-131-iodocholesterol resulting in an erythematous plaque and Thallium-201 resulting in a radiation ulcer have been reported in the literature. Because radiation damage from all types of radiopharmaceutical administrations, although rare, continues to be documented in the literature, the NRC determined that including diagnostic radiopharmaceutical administrations in extravasation medical event reporting is consistent with the NRCs Medical Use of Byproduct Material policy statement (65 FR 47654; August 3, 2000), which states that the NRC will regulate the radiation safety of patients primarily to assure the use of radionuclides is in accordance with the physicians directions, when justified by the risk to the patients. The ACMUI, in their final report, agreed that the NRC may be interested in all radiopharmaceutical extravasations that can cause radiation damage from a public health and safety perspective. Therefore, the NRC is not limiting the reporting criterion to only therapeutic administrations of radioactive drugs to ensure that the NRC captures risk to the patient from any radiopharmaceutical administration.

18 Several commenters recommended that the NRC align its reporting criterion with the CTCAE1 developed by the National Cancer Institute. Specifically, commenters suggested that reporting be required if the extravasation results in a CTCAE Grade 3 or 4 event that can be attributed to radiation. The NRCs proposed reporting criterion is analogous to a potential for a CTCAE Grade 2 event. The NRC determined that the reportable level of potential radiation injury is appropriate because radiation injury to the injection site is not a typical risk in radiopharmaceutical injections like it is in other medical applications of radiation. The relative risk is well understood in machine produced radiation and the link between dose and tissue injury is well defined. In radiopharmaceutical extravasation, the amount of material extravasated, the time the material dwells in the area, and a multitude of other physical and patient-related factors complicate the potential for radiation injury.

In the proposed reporting criterion for extravasations, the NRC replaced suspected radiation injury with an extravasation that results or has the potential to result in a radiation injury and removed the requirement for medical attention. The NRC determined that the definition of radiation injury should not be ambiguous since the deterministic effects of radiation to tissue are well defined. Similarly, removing the more ambiguous term medical attention would provide more clarity and not impose additional burden to a licensee that is responding to an extravasation appropriately.

G. Why Does the Proposed Reporting Criterion Include a Determination by a Physician?

The proposed criterion in § 35.3045(a)(3) requires that the potential for radiation injury be determined by a physician. The NRC received input from a number of stakeholders, and the ACMUI recommended in their final report, that determination of a 1 https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm

19 suspected radiation injury should be made by an AU. The NRC agrees that a complex issue such as a determination of a radiation injury from an extravasation should be made by a physician, but the NRC considers all physicians, not just those that are AUs, to have the expertise to make this determination. The expertise and experience required to make a determination of a radiation injury is not exclusive to AUs; some guidelines, such as the American College of Radiologys Manual on Contrast Media, recommend a surgical consult for severe extravasation injuries. Some commenters also stated that patients may not have regular access to a licensees physician or an AU, such as patients who travel for medical treatments. The NRC recognizes that the complexity of diagnosing and treating a radiation injury is a matter of medical practice. The NRC considered whether other healthcare professionals (e.g., nurses, nuclear medicine technologists, physicists) could assess and determine whether an extravasation results or has the potential to result in a radiation injury. However, the NRC concluded that physicians are best suited to make this determination based on their training and experience, as well as their knowledge of a patients condition, medical history, and plan of care.

H. What Definitions Did the NRC Update?

As discussed in the background section of this document, the NRC initially proposed defining extravasation as the leakage of a radiopharmaceutical from the blood vessel into the surrounding tissue. In response to the NRCs request for information and comment on preliminary proposed rule language, the NRC received feedback on this definition of extravasation, including as to whether the NRC should (1) use the term extravasation or infiltration, (2) limit the definition to therapeutic radiopharmaceuticals, and (3) use the term leakage in the definition. Commenters noted that the definition of extravasation implied tissue damage from a vesicant, and that

20 radioisotopes could be considered as a type of vesicant. Some commenters noted that infiltration may also mean the leakage of pharmaceutical around the injection site, but that this leakage does not result in tissue damage. Comments from the public stated that the NRCs preliminary proposed definition did not take into account extravasations that miss the blood vessel entirely and inject the radiopharmaceutical into the interstitial volume directly.

Upon consideration of this feedback, in this proposed rule the NRC defines the term extravasation in § 35.2 as the unintentional presence of a radiopharmaceutical in the tissue surrounding the blood vessel following an injection. The NRC has replaced the text leakage with the phrase, presence of radiopharmaceutical surrounding the blood vessel. Unintentional presence captures injections that miss the blood vessel entirely in addition to injections that result in extravasations. As discussed in section III F. of this proposed rule, the NRC does not believe that the definition of extravasation should be limited to therapeutic radiopharmaceuticals. While the risk of deterministic effects from extravasations of diagnostic and therapeutic radiopharmaceuticals is different, diagnostic radiopharmaceutical extravasations have been shown in scientific literature to have caused radiation injury. Therefore, the NRC has determined that limiting the definition of extravasations to therapeutic uses of radiopharmaceuticals is not appropriate. The NRC also considered but has excluded from the definition of extravasation unsealed byproduct materials that are not radiopharmaceuticals, such as microspheres. The NRC determined that because a treatment site must be specified in the written directive for these administrations, any events would be captured under the wrong treatment site criteria.

In the preliminary proposed rule language, the NRC defined suspected radiation injury as a potential or observable deterministic health effect to the area around an injection site that can be attributed to radiation. As part of its information request, the

21 NRC received feedback on this definition of suspected radiation injury. Commenters questioned the utility of the qualifiers potential and suspected and requested clarification of the term deterministic health effect. There were also comments stating that the suspected radiation injury determination should be made by some medical authority.

Upon consideration of this feedback, the NRC is proposing to define the term radiation injury in § 35.2 as a deterministic health effect to the area around an injection site that can be attributed to radiation. The potential for radiation injury is more appropriate in the reporting requirement, rather than the Definitions section. This proposed rule would require licensees to assess the risk to the patient in a prompt manner. This provision will ensure that the patient has sufficient information in the event that a radiation injury manifests after the patient has been released from the licensee's care. Licensees will also be able to glean additional and more accurate information from an early assessment of an extravasation, such as the specific timing of symptoms, any patient or clinician actions during the extravasation, and estimates of the volume of radiopharmaceutical extravasated. This information could be less accurate or unavailable if time is given to allow an observable effect to manifest.

Several commenters stated that deterministic effects of radiation injury should be well defined in the regulation. The NRC, however, determined that a specific deterministic effect should not be included in the definition for radiation injury. While the deterministic effects to the skin and tissues are well understood, these effects do not manifest consistently in patient populations. Therefore, the NRC determined that the potential for these effects is best determined on a case-by-case basis by a physician as proposed in § 35.3045(a)(3).

22 I. Why is the NRC Requiring that Licensees Have Procedures to Detect and Report Extravasations?

In SRM-SECY-22-0043, the Commission directed the staff to evaluate whether the NRC should require licensees to develop, implement, and maintain written procedures to provide high confidence that radiation-safety-significant extravasations will be detected and reported. As part of the preliminary proposed rule language, the NRC included a requirement for licensees to have procedures that address extravasations. In the information request, the NRC asked questions regarding what steps licensees can take to minimize, detect, assess, and characterize radiopharmaceutical extravasations.

Many commenters agreed that licensees should be required to have procedures to address extravasations and that licensees should be provided the flexibility to institute their own policies for detecting and monitoring radiopharmaceutical extravasations.

The proposed requirements in new § 35.42 ensure that extravasations are being properly evaluated and managed during patient care. The proposed requirements in § 35.42 concerning written procedures would also ensure that licensees detect and report reportable extravasations as they happen, and the model procedures referenced in the implementation guidance provide information that licensees can give to patients so that patients can identify symptoms or signs of a radiation injury that manifests after being released from the licensees care. The NRC determined that licensees should handle minimizing extravasations as part of their quality management and injection quality programs. The proposed procedures would also require that licensees take steps to document how licensees implement these procedures in their evaluation of extravasations that may meet the proposed reporting criteria in § 35.3045(a)(3). The NRC has determined that documentation of the assessment of these incidents will ensure that licensees are evaluating potentially reportable extravasations in accordance with their written procedures and that regulators have the information necessary to

23 determine if further inquiry of incidents involving potential radiation injury from an extravasation is needed.

IV. Specific Requests for Comments The NRC is seeking advice and recommendations from the public on this proposed rule.

The NRC is seeking feedback on the term high confidence, as used in

§ 35.41 and proposed § 35.42 with respect to procedures for written directives and for detecting and reporting extravasation medical events. Specifically, the NRC is seeking input on whether the NRC should include a definition of high confidence in § 35.2.

Please provide the rationale for your response.

The NRC is seeking feedback related to the procedures for detecting and reporting extravasation medical events. Currently, the proposed § 35.42(b) would require a licensees written procedures to address how the licensee will determine that a reportable extravasation has occurred and how the licensee documents this determination. The NRC is seeking feedback on what elements should be included as part of these procedures. Additionally, the NRC is seeking feedback on whether licensees should be required to document and keep records of their assessments, including the process and determination of whether an extravasation is reportable. We are also seeking feedback on what steps the NRC can take to ensure that licensees are implementing these procedures. Please provide the rationale for your responses.

The NRC is seeking feedback on whether the proposed procedures in § 35.42 should also include monitoring of patients, rather than only requiring monitoring of injections, to ensure licensees are detecting extravasations as defined in § 35.3045 in a timely manner.

24 The NRC is seeking feedback on the assumptions used in developing the cost-benefit estimates in the regulatory analysis. Specifically, the NRC is seeking feedback related to the assumptions regarding extravasation rates and the costs licensees would incur to obtain additional methodologies or equipment or both to comply with this proposed rule. Please provide the rationale or specific numerical support for your response.

V. Section-by-Section Analysis The following paragraphs describe the specific changes proposed by this rulemaking.

Section 35.2 Definitions This proposed rule would add definitions for Extravasation and Radiation injury.

Section 35.8 Information collection requirements: OMB approval This proposed rule would add new §§ 35.42 and 35.2042 to the approved information collection requirements contained in § 35.8(b) for Office of Management and Budget (OMB) control number 3150-0010.

Section 35.42 Procedures for evaluating and reporting extravasations This proposed rule would add new § 35.42 to require written procedures for evaluating and reporting extravasations.

Section 35.2042 Records for procedures for evaluating and reporting extravasations This proposed rule would add new § 35.2042 to require a copy of the procedures required by § 35.42(a) for the duration of the license.

Section 35.3045 Report and notification of a medical event

25 This proposed rule would add new paragraph (a)(3) to require the report and notification of a medical event that results or has the potential to result in a radiation injury from an extravasation, as determined by a physician.

In addition, this proposed rule would replace shall with must in § 35.3045 and make minor editorial and conforming changes to include gender-inclusive language.

VI. Regulatory Flexibility Certification The NRC has prepared a draft regulatory analysis of the impact of this proposed rule on small entities. This proposed rule would affect 5,933 medical licensees that administer radiopharmaceuticals, some of which may qualify as small business entities as defined by § 2.810, NRC size standards. On the basis of the draft regulatory analysis conducted for this action, the estimated costs of this proposed rule for affected licensees are one-time implementation costs of $2,393 per licensee and annual costs of

$26 per licensee. The NRC determined that the selected alternative reflected in the proposed rule is the least burdensome and most flexible alternative that would accomplish the NRC's regulatory objective. The draft regulatory flexibility analysis is included as a section in the draft regulatory analysis.

The NRC is seeking public comment on the potential impact of this proposed rule on small entities. The NRC particularly desires comments from licensees who qualify as small businesses, specifically as to how the proposed regulation will affect them and how the regulation may be tiered or otherwise modified to impose less stringent requirements on small entities while still adequately protecting the public health and safety and common defense and security. Comments on how the regulation could be modified to take into account the differing needs of small entities should specifically discuss:

26 (a) The size of the business and how the proposed regulation would result in a significant economic burden upon it as compared to a larger organization in the same business community; (b) How the proposed regulation could be further modified to take into account the business's differing needs or capabilities; (c) The benefits that would accrue, or the detriments that would be avoided, if the proposed regulation was modified as suggested by the commenter; (d) How the proposed regulation, as modified, would more closely equalize the impact of NRC regulations as opposed to providing special advantages to any individuals or groups; and (e) How the proposed regulation, as modified, would still adequately protect the public health and safety and common defense and security.

Comments should be submitted as indicated under the ADDRESSES caption.

VII. Regulatory Analysis The NRC has prepared a draft regulatory analysis on this proposed regulation.

The analysis examines the costs and benefits of the alternatives considered by the NRC.

The conclusion from the analysis is that this proposed rule and associated guidance would result in a cost to the industry (NRC and Agreement State medical licensees that administer intravenous radiopharmaceuticals for diagnostic and therapeutic purposes),

the NRC, and Agreement States of $29,357,000 using a 7-percent discount rate and

$35,889,000 using a 3-percent discount rate. Though the regulatory analysis indicates the proposed rule would not be quantitatively beneficial, the NRC plans to proceed with the proposed rule because it concluded that these costs would be outweighed by the qualitative public health benefits of the rulemaking, as discussed in the regulatory

27 analysis. The NRC requests public comment on the draft regulatory analysis. The regulatory analysis is available as indicated in the Availability of Documents section of this document. Comments on the draft regulatory analysis may be submitted to the NRC as indicated under the ADDRESSES caption of this document.

VIII. Backfitting and Issue Finality The NRC's backfitting provisions (which are found in the regulations at

§§ 50.109, 70.76, 72.62, and 76.76) and issue finality provisions of 10 CFR part 52 do not apply to this rule. Part 35 of 10 CFR does not contain a backfitting provision, and this rulemaking will not impact activities authorized by parts 50, 52, 70, 72, or 76. As a result, this rulemaking cannot constitute "backfitting" as defined in 10 CFR Chapter I or otherwise affect the issue finality of a 10 CFR part 52 approval.

IX. Cumulative Effects of Regulation The NRC seeks to minimize any potential negative consequences resulting from the cumulative effects of regulation (CER). The CER describes the challenges that licensees, or other impacted entities such as State partners, may face while implementing new regulatory positions, programs, or requirements (e.g., rules, generic letters, backfits, inspections). The CER is an organizational effectiveness challenge that may result from a licensee or impacted entity implementing a number of complex regulatory actions, programs, or requirements within limited available resources.

The NRC is following its CER process by engaging with external stakeholders throughout this proposed rule and related regulatory activities. Public involvement has included a public meeting to facilitate feedback on the April 19, 2023, information

28 request and publication of preliminary proposed rule language. The NRC is considering holding additional public meetings during the remainder of the rulemaking process.

To better understand the potential CER implications incurred due to this proposed rule, the NRC is requesting comment on the following questions. Responding to these questions is voluntary, and the NRC will respond to any comments received in the final rule.

1. In light of any current or projected CER challenges, does the proposed rules effective date provide sufficient time to implement the new proposed requirements, including changes to programs, procedures, and the facility?

2. If CER challenges currently exist or are expected, what should be done to address them? For example, if more time is required for implementation of the new requirements, what period of time is sufficient?

3. Do other (NRC or other agency) regulatory actions (e.g., orders, generic communications, license amendment requests, inspection findings of a generic nature) influence the implementation of the proposed rules requirements?

4. Are there unintended consequences? Does the proposed rule create conditions that would be contrary to the proposed rules purpose and objectives? If so, what are the unintended consequences, and how should they be addressed?

5. Please comment on the NRCs cost and benefit estimates in the regulatory analysis that supports the proposed rule.

X. Plain Writing The Plain Writing Act of 2010 (Pub. L. 111-274) requires Federal agencies to write documents in a clear, concise, and well-organized manner. The NRC has written this document to be consistent with the Plain Writing Act as well as the Presidential

29 Memorandum, Plain Language in Government Writing, published June 10, 1998 (63 FR 31885). The NRC requests comment on this document with respect to the clarity and effectiveness of the language used.

XI. National Environmental Policy Act The NRC has determined that this proposed rule is the type of action described in § 51.22(c)(3)(iii). Therefore, neither an environmental impact statement nor environmental assessment has been prepared for this proposed rule.

XII. Paperwork Reduction Act This proposed rule contains (a) new or amended collection(s) of information subject to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq). This proposed rule has been submitted to the OMB for review and approval of the information collection(s).

Type of submission, new or revision: Revision.

The title of the information collection: Reporting Nuclear Medicine Injection Extravasations as Medical Events, Proposed Rule.

The form number if applicable: N/A.

How often the collection is required or requested: On occasion.

30 Who will be required or asked to respond: NRC and Agreement State licensees who administer intravenous radiopharmaceuticals for diagnostic and therapeutic purposes.

An estimate of the number of annual responses: 6,650 (489 reporting responses

+ 5,933 recordkeepers + 228 third-party disclosure responses).

The estimated number of annual respondents: 5,933 (547 NRC licensees +

5,386 Agreement State licensees).

An estimate of the total number of hours needed annually to comply with the information collection requirement or request: 20,193.15 hours1.736111e-4 days <br />0.00417 hours <br />2.480159e-5 weeks <br />5.7075e-6 months <br /> (652 reporting +

19,085.15 recordkeeping + 456 third-party disclosure).

Abstract: The NRC is proposing to amend 10 CFR part 35 to require reporting of certain nuclear medicine injection extravasations as medical events. The proposed changes would help staff track and trend extravasation medical events and collect information on their occurrence, detection, mitigation, and possible preventive strategies that would be available for licensee and public use. The proposed rule would also require licensees to develop, implement, and maintain written procedures for evaluating and reporting extravasations. These procedures are necessary to provide high confidence that these extravasations will be detected in a timely manner and reported to the NRC.

The NRC is seeking public comment on the potential impact of the information collection(s) contained in this proposed rule and on the following issues:

31

1.

Is the proposed information collection necessary for the proper performance of the functions of the NRC, including whether the information will have practical utility?

2.

Is the estimate of the burden of the proposed information collection accurate?

3.

Is there a way to enhance the quality, utility, and clarity of the information to be collected?

4.

How can the burden of the proposed information collection on respondents be minimized, including the use of automated collection techniques or other forms of information technology?

A copy of the OMB supporting statement is available in ADAMS under Accession No. ML24017A137 or can be obtained free of charge by contacting the NRCs PDR reference staff at 1-800-397-4209, at 301-415-4737, or by email to PDR.resource@nrc.gov. You may obtain information and comment submissions related to the OMB clearance package by searching on https://www.regulations.gov under Docket ID NRC-2022-0218.

You may submit comments on any aspect of these proposed information collection(s), including suggestions for reducing the burden and on the above issues, by the following methods:

Federal rulemaking website: Go to https://www.regulations.gov and search for Docket ID NRC-2022-0218.

Mail comments to: FOIA, Library, and Information Collections Branch, Office of Information Services, Mail Stop: T6-A10M, U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001 or to the OMB reviewer at: Office of Information and Regulatory Affairs (3150-0010), Attn: Desk Officer for the Nuclear Regulatory

32 Commission, 725 17th Street, NW, Washington, DC 20503; telephone: 202-395-1741, email: oira_submission@omb.eop.gov.

Submit comments by [INSERT DATE 30 DAYS AFTER PUBLICATION IN THE FEDERAL REGISTER]. Comments received after this date will be considered if it is practical to do so, but the NRC staff is able to ensure consideration only for comments received on or before this date.

Public Protection Notification The NRC may not conduct or sponsor, and a person is not required to respond to, a collection of information unless the document requesting or requiring the collection displays a currently valid OMB control number.

XIII. Criminal Penalties For the purposes of Section 223 of the Atomic Energy Act of 1954, as amended (AEA), the NRC is issuing this proposed rule that would amend part 35 under one or more of Sections 161b, 161i, or 161o of the AEA, except as noted in § 35.4002(b).

Willful violations of the part 35 regulations not listed in § 35.4002(b) would be subject to criminal enforcement. Criminal penalties as they apply to regulations in part 35 are discussed in § 35.4002.

XIV. Coordination with NRC Agreement States The working group that prepared this proposed rule included a representative from the Organization of Agreement States. A draft of the proposed rule was provided to

33 the Agreement States for review. Comments from Agreement States were taken into consideration during the development of this proposed rule.

XV. Coordination with the Advisory Committee on the Medical Uses of Isotopes On [DATE], a draft of the proposed rule was provided to the ACMUI for a 90-day review. The draft was made public to facilitate the ACMUIs review in a public forum. The ACMUI established a subcommittee to review and comment on the draft proposed rule.

The subcommittee discussed their report on the draft proposed rule at a publicly held teleconference on [DATE], and the report was unanimously approved by the full committee. The ACMUI provided its final report on [DATE].

XVI. Compatibility of Agreement State Regulations On the basis of the Agreement State Program Policy Statement approved by the Commission on October 2, 2017, and published in the Federal Register (82 FR 48535; October 18, 2017), NRC program elements can be placed into six categories (A, B, C, D, NRC, or health and safety (H&S)) to form the basis for evaluating and classifying the program elements. Under the Policy Statement, a program element means any component or function of a radiation control regulatory program, including regulations and other legally binding requirements imposed on regulated persons, which contributes to implementation of that program.

Compatibility Category A are those program elements that include basic radiation protection standards and scientific terms and definitions that are necessary to understand radiation protection concepts. Compatibility Category A program elements

34 adopted by an Agreement State should be essentially identical to those of the NRC to provide uniformity in the regulation of agreement material on a nationwide basis.

Compatibility Category B pertains to a limited number of program elements that cross jurisdictional boundaries and should be addressed to ensure uniformity of regulation on a nationwide basis. For Compatibility Category B, the Agreement State program element shall be essentially identical to that of NRC. Program elements in Compatibility Category C include those program elements that are important for an Agreement State to have in order to avoid conflict, duplication, gaps, or other conditions that would jeopardize an orderly pattern in the regulation of agreement material on a national basis. An Agreement State program shall embody the essential objectives of the Category C program elements.

Under Category C, Agreement State program elements may be more restrictive than NRC program elements; however, they should not be so restrictive as to prohibit a practice authorized by the Atomic Energy Act of 1954 (AEA), as amended, and in the national interest without an adequate public health and safety or environmental basis related to radiation protection.

Compatibility Category D are those program elements that do not meet any of the criteria of Category A, B, or C, above, and are not required to be adopted by Agreement States for purposes of compatibility. An Agreement State has the flexibility to adopt and implement program elements within the States jurisdiction that are not addressed by the NRC or that are not required for compatibility (i.e., Compatibility Category D). However, such program elements of an Agreement State relating to agreement material shall (1) not create conflicts, duplications, gaps, or other conditions that would jeopardize an orderly pattern in the regulation of agreement material on a nationwide basis; (2) not preclude a practice authorized by the AEA and in the national interest; and (3) not

35 preclude the ability of the NRC to evaluate the effectiveness of Agreement State programs for agreement material with respect to protection of public health and safety.

Compatibility Category NRC are those program elements that address areas of regulation that cannot be relinquished to the Agreement States under the AEA, or provisions of Title 10 of the of the Code of Federal Regulations. The NRC maintains regulatory authority over these program elements and the Agreement States must not adopt these NRC program elements. However, an Agreement State may inform its licensees of these NRC requirements through a mechanism under the States administrative procedure laws, as long as the State adopts these provisions solely for the purposes of notification and does not exercise any regulatory authority as a result.

Category H&S program elements embody the basic health and safety aspects of the NRCs program elements. Although H&S program elements are not required for purposes of compatibility, they do have particular health and safety significance. The Agreement State must adopt the essential objectives of such program elements to maintain an adequate program.

The proposed new definition for extravasation in § 35.2 would be designated as Compatibility Category B. The NRC has determined that this definition needs to be adopted to ensure a consistent regulatory approach across the National Materials Program and inconsistent definitions of this term would have direct and significant transboundary implications.

The proposed new definition for radiation injury in § 35.2 would be designated as Compatibility Category H&S because the essential objectives of this provision have health and safety significance and need to be adopted by the Agreement States.

Proposed new requirements related to procedures for evaluating and reporting extravasations in § 35.42(a) and (b) would be designated as Compatibility Category H&S

36 because the essential objectives of these provisions have health and safety significance and need to be adopted by the Agreement States.

Proposed new requirements related to procedures for evaluating and reporting extravasations in § 35.42(c) would be designated as Compatibility Category D.

Compatibility Category D are those program elements that do not meet any of the criteria of Category A, B, or C, above, and, therefore, do not need to be adopted by Agreement States for purposes of compatibility. The proposed Compatibility Category D designation for this provision would provide the flexibility for Agreement States insofar as requiring licensees to retain the copy of the procedures for a time period other than the duration of the license as specified in proposed § 35.2042. Proposed new requirements for maintaining records for procedures for evaluating and reporting extravasations in

§ 35.2042 would be designated as Compatibility Category D. Compatibility Category D are those program elements that do not meet any of the criteria of Category A, B, or C, above, and, therefore, do not need to be adopted by Agreement States for purposes of compatibility. The proposed Compatibility Category D designation for this provision would provide the flexibility for Agreement States insofar as requiring licensees to retain the copy of the procedures for a time period other than the duration of the license as specified in the proposed regulations.

Proposed new requirements for report and notification of a medical event in

§ 35.3045(a)(3) would be designated as Compatibility Category C because the NRC has determined that the essential objectives of these provisions need to be adopted by the Agreement States. The proposed compatibility category of this provision is to maintain consistency with the compatibility category designation for the current § 35.3045, which is Compatibility Category C.

Compatibility categories for other provisions that are subject to amendment would remain unchanged.

37 The final rule would be a matter of compatibility between the NRC and the Agreement States, thereby providing consistency among Agreement State and NRC requirements. The compatibility (A, B, C, D, and NRC) and adequacy (H&S) categories are designated in the following table:

Compatibility Table Section Change Subject Compatibility Existing New 10 CFR 35.2 New Definition: Extravasation B

10 CFR 35.2 New Definition: Radiation injury H&S 10 CFR 35.8(b)

Amend Information collection requirements: OMB approval D

D 10 CFR 35.42(a)

New Procedures for evaluating and reporting extravasations H&S 10 CFR 35.42(b)

New Procedures for evaluating and reporting extravasations H&S 10 CFR 35.42(c)

New Procedures for evaluating and reporting extravasations D

10 CFR 35.2042 New Records for procedures for evaluating and reporting extravasations D

10 CFR 35.3045(a)

Amend Report and notification of a medical event C

C 10 CFR 35.3045(a)(3)

New Report and notification of a medical event C

10 CFR 35.3045(b)

Amend Report and notification of a medical event C

C 10 CFR 35.3045(c)

Amend Report and notification of a medical event C

C 10 CFR 35.3045(d)

Amend Report and notification of a medical event C

C 10 CFR 35.3045(e)

Amend Report and notification of a medical event C

C 10 CFR 35.3045(g)

Amend Report and notification of a medical event C

C XVII. Voluntary Consensus Standards

38 The National Technology Transfer and Advancement Act of 1995, Pub. L. 104-113, requires that Federal agencies use technical standards that are developed or adopted by voluntary consensus standards bodies unless the use of such a standard is inconsistent with applicable law or otherwise impractical. In this proposed rule, the NRC will revise the regulations to require reporting of certain nuclear medicine injection extravasations as medical events. This action does not constitute the establishment of a standard that contains generally applicable requirements.

XVIII. Availability of Guidance The NRC is issuing new draft guidance, Draft Regulatory Guide DG-8062, Medical Event Evaluation and Reporting, for the implementation of the proposed requirements in this rulemaking. The guidance is available in ADAMS under Accession No. ML24016A109. You may obtain information and comment submissions related to the draft guidance by searching on https://www.regulations.gov under Docket ID NRC-2022-0218.

The draft regulatory guide describes an approach acceptable to NRC staff to meet the requirements for evaluating and reporting all medical events, including extravasation events as described in this proposed rule. The draft regulatory guide provides licensees with guidance on when medical event reports are required, how reports should be made, and what is required to be in the report. In addition, the draft regulatory guide provides guidance for procedures for administrations requiring a written directive and for evaluating and reporting extravasation events as described in this proposed rule.

39 You may submit comments on this draft regulatory guidance by the method outlined in the ADDRESSES section of this document.

XIX. Public Meeting The NRC will conduct a public meeting on this proposed rule to promote full understanding of the proposed rule and associated guidance document.

The NRC will publish a notice of the location, time, and agenda of the meeting on the NRCs public meeting website within at least 10 calendar days before the meeting.

Stakeholders should monitor the NRCs public meeting website for information about the public meeting at: https://www.nrc.gov/public-involve/public-meetings/index.cfm.

XX. Availability of Documents The documents identified in the following table are available to interested persons through one or more of the following methods, as indicated.

DOCUMENT ADAMS ACCESSION NO. / WEB LINK /

FEDERAL REGISTER CITATION Proposed Rule and Draft Guidance Documents Draft Regulatory Analysis for the Reporting Nuclear Medicine Injection Extravasations as Medical Events Proposed Rule ML24016A293 Draft Supporting Statement for Information Collections Contained in the Reporting Nuclear Medicine Injection Extravasations as Medical Events Proposed Rule ML24017A137 Draft Regulatory Guide DG-8062, Medical Event Evaluation and Reporting ML24016A109 SECY-24-0XXX, Proposed Rule:

Reporting Nuclear Medicine Injection Extravasations as Medical Events (RIN 3150-AK91; NRC-2022-0218), [DATE]

ML24016A294

40 Related Documents ACMUI Meeting Transcript, December 18, 2008 ML090340745 ACMUI Meeting Transcript, May 7, 2009 ML092090034 ACMUI Meeting Summary, September 2, 2021 ML21267A021 ACMUI Extravasation Subcommittee, Final Report, [DATE]

[MLXXXXXXXXX]

Final Rule: Misadministration Reporting Requirements, May 14, 1980 45 FR 31701 Final Rule: Quality Management Program and Misadministrations, July 25, 1991 56 FR 34104 Final Rule: Medical Use of Byproduct Material, April 24, 2002 67 FR 20250 Final Rule: Medical Use of Byproduct Material - Medical Event Definitions, Training and Experience, and Clarifying Amendments, July 16, 2018 83 FR 33046 Preliminary Evaluation of Radiopharmaceutical Extravasation and Medical Event Reporting for ACMUI Review, July 30, 2021 ML21223A085 PRM-35-22, Petition for Rulemaking, Reporting Nuclear Medicine Injection Extravasations as Medical Events, May 18, 2020 ML20157A266 PRM-35-22, Reporting Nuclear Medicine Injection Extravasations as Medical Events, Petition for Rulemaking, Notification of Docketing and Request for Comment, September 15, 2020 85 FR 57148 PRM-35-22, Reporting Nuclear Medicine Injection Extravasations as Medical Events, Petition for Rulemaking, Consideration in the Rulemaking Process, December 30, 2022 87 FR 80474 Reporting Nuclear Medicine Injection Extravasations as Medical Events, Preliminary Proposed Rule Language, Notice of Availability and Public Meeting, April 19, 2023 88 FR 24130 Reporting Nuclear Medicine Injection Extravasations as Medical Events, Preliminary Proposed Rule Language, Extension of Comment Period, July 18, 2023 88 FR 45824 SECY-22-0043, Petition for Rulemaking and Rulemaking Plan on Reporting ML21268A005 (package)

41 Nuclear Medicine Injection Extravasations as Medical Events (PRM-35-22; NRC-2020-0141), May 9, 2022 SRM-SECY-22-0043, Staff Requirements - SECY-22-0043 - Petition for Rulemaking and Rulemaking Plan on Reporting Nuclear Medicine Injection Extravasations as Medical Events (PRM-35-22; NRC-2020-0141), December 12, 2022 ML22346A112 (package)

Plain Language in Government Writing, June 10, 1998 63 FR 31885 Agreement State Program Policy Statement, October 18, 2017 82 FR 48535 The NRC may post materials related to this document, including public comments, on the Federal rulemaking website at https://www.regulations.gov under Docket ID NRC-2022-0218. In addition, the Federal rulemaking website allows members of the public to receive alerts when changes or additions occur in a docket folder. To subscribe: 1) navigate to the docket folder (NRC-2022-0218); 2) click the Subscribe link; and 3) enter an email address and click on the Subscribe link.

List of Subjects in 10 CFR Part 35 Biologics, Byproduct material, Criminal penalties, Drugs, Health facilities, Health professions, Labeling, Medical devices, Nuclear energy, Nuclear materials, Occupational safety and health, Penalties, Radiation protection, Reporting and recordkeeping requirements.

For the reasons set out in the preamble and under the authority of the Atomic Energy Act of 1954, as amended; the Energy Reorganization Act of 1974, as amended; and 5 U.S.C. 552 and 553, the NRC is proposing to amend 10 CFR part 35 as follows:

42 PART 35-MEDICAL USE OF BYPRODUCT MATERIAL

1. The authority citation for part 35 continues to read as follows:

Authority: Atomic Energy Act of 1954, secs. 81, 161, 181, 182, 183, 223, 234, 274 (42 U.S.C. 2111, 2201, 2231, 2232, 2233, 2273, 2282, 2021); Energy Reorganization Act of 1974, secs. 201, 206 (42 U.S.C. 5841, 5846); 44 U.S.C. 3504 note.

2. In § 35.2, add definitions for Extravasation and Radiation injury in alphabetical order to read as follows:

§ 35.2 Definitions.

Extravasation means the unintentional presence of a radiopharmaceutical in the tissue surrounding the blood vessel following an injection.

Radiation injury means a deterministic health effect to the area around an injection site that can be attributed to radiation.

§ 35.8 [Amended]

3. In § 35.8(b), add in numerical order, 35.42 and 35.2042.

4. Add §35.42 to read as follows:

§ 35.42 Procedures for evaluating and reporting extravasations.

(a) For any administration in which an extravasation can occur, the licensee must develop, implement, and maintain written procedures to provide high confidence that an extravasation that results or has the potential to result in a radiation injury, as determined by a physician, will be detected in a timely manner and reported in accordance with § 35.3045.

43 (b) The written procedures required by paragraph (a) of this section must address how the licensee determines that an extravasation meets the criteria in

§ 35.3045(a)(3) for a medical event and how the licensee documents this determination.

(c) A licensee must retain a copy of the procedures required under paragraph (a) of this section in accordance with § 35.2042.

5. Add §35.2042 to read as follows:

§ 35.2042 Records for procedures for evaluating and reporting extravasations.

A licensee must retain a copy of the procedures required by § 35.42(a) for the duration of the license.

6. In § 35.3045:

a. Remove the word shall wherever it may appear, and add in its place, the word must;

b. Add paragraph (a)(3); and

c. In paragraph (e) remove the phrase he or she and add in its place the phrase the referring physician.

The addition to read as follows:

§ 35.3045 Report and notification of a medical event.

(a) *

(1) *

(3) The administration of byproduct material that results or has the potential to result in a radiation injury from an extravasation, as determined by a physician.

Dated: <Month XX, 2024>.

For the Nuclear Regulatory Commission.

44 Carrie M. Safford, Secretary of the Commission.