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M240409B: Slides - Meeting with Advisory Committee on the Medical Uses of Isotopes
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Issue date:	04/09/2024
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Overview of ACMUI Activities Hossein Jadvar, M.D., Ph.D.

ACMUI Chair/Nuclear Medicine Physician April 9, 2024

Todays Agenda

Hossein Jadvar, M.D., Ph.D., ACMUI Chair

- Overview of ACMUI activities

Richard Harvey, DrPH, ACMUI Radiation Safety Officer Representative

- ACMUIs Review and Analysis of Reported Medical Events from Fiscal Years 2021-2023 2

Todays Agenda (contd)

Megan Shober, ACMUI Agreement State Representative

- ACMUI Comments on Revisions to Regulatory Guide 8.39, Release of Patients Administered Radioactive Material

Josh Mailman, ACMUI Patients' Rights Advocate

- Patients Rights Advocates Perspectives on

Regulatory Guide 8.39, Release of Patients Administered Radioactive Material

Reporting of Nuclear Medicine Injection Extravasations 3

Overview of the ACMUI

ACMUI Role

Membership

2022-2024 Topics

Current Subcommittees

Future 4

Role of the ACMUI

Advise the U.S. Nuclear Regulatory Commission (NRC) staff on policy & technical issues that arise in the regulation of the medical use of radioactive material in diagnosis & therapy.

Comment on changes to NRC regulations & guidance.

Evaluate certain non-routine uses of radioactive material.

Provide technical assistance in licensing, inspection &

enforcement cases.

Bring key issues to the attention of the Commission for appropriate action.

5

ACMUI Membership (13 members)

Nuclear Medicine Physician, Chair (Dr. Hossein Jadvar)

Nuclear Pharmacist, Vice Chair (Mr. Richard Green)

Nuclear Cardiologist (Dr. Andrew Einstein)

2 Radiation Oncologists (Drs. Michael Folkert & Harvey Wolkov)

Diagnostic Radiologist (Vacant)

FDA Representative (Dr. Michael OHara) 6 6

ACMUI Membership (13 members)

2 Medical Physicists: Nuclear Medicine (Ms. Melissa Martin) & Radiation Therapy (Mr. Zoubir Ouhib)

Patients Rights Advocate (Mr. Josh Mailman)

Agreement State Representative (Ms. Megan Shober)

Healthcare Administrator (Ms. Rebecca Allen)

Radiation Safety Officer (Dr. Richard Harvey) 7 7

ACMUI Consultant

Interventional Radiologist (Dr. John Angle) 8 8

ACMUI Topics December 2022 - April 2024

Decommissioning financial assurance for sealed and unsealed radioactive materials

Impact of ABRs termination request and review of NRCs process for recognition of specialty boards

Medical events

A review of prescription error reduction methods 9

9

ACMUI Topics December 2022 - April 2024 (contd)

Akesis Galaxy RTi Unit licensing guidance

Eye90 Microsphere Device licensing guidance

Liberty Vision Y-90 episcleral brachytherapy source licensing guidance 10 1

0

ACMUI Topics in 2023 by Non-NRC Entities

Overview of ICRP Publication 153, Radiological Protection in Veterinary Practice 11 1

1

Staff Presentations to the ACMUI (2022-2024) 12 1

2

Medical events

Limited revisions to the NRCs abnormal occurrence criteria

Reporting of nuclear medicine injection extravasations

Overview of NRC requirements and guidance for release of animals administered radioactive material

Financial Assurance for Disposition of Category 1 and 2 Byproduct Material Radioactive Sealed Sources

Staff Presentations to the ACMUI (2022-2024)

(contd)

Recent medical events related to radiopharmaceutical administrations

ACMUI Reporting Structure

Medical Team Updates

INFOSEC, Ethics, and Allegations Training 13 1

3

Current ACMUI Subcommittees 14 1

4

Eye90 Microspheres

Akesis Galaxy RTi unit

Liberty Vision Y-90 brachytherapy source

Training and Experience for All Modalities Subcommittee

Extravasations and Medical Event Reporting

Future

ACMUI will continue to

-Provide advice and technical assistance

-Comment on NRC regulations and guidance

-Evaluate uses of radioactive material

-Bring key issues to the attention of the Commission 1

5

Acronyms

ABR - American Board of Radiology

ACMUI - Advisory Committee on Medical Uses of Isotopes

EMT - Emerging Medical Technologies

FDA - U.S. Food & Drug Administration

ICRP - International Commission on Radiological Protection

INFOSEC - Information Security

ME - Medical Event

NRC - U.S. Nuclear Regulatory Commission

T&E - Training and Experience

Y yttrium-90 1

6

17 ACMUIs Review and Analysis of Reported Medical Events from Fiscal Years 2021-2023 Richard P. Harvey, DrPH Advisory Committee on the Medical Uses of Isotopes April 9, 2024

Subcommittee Members

Richard Harvey, DrPH (Chair)

Michael Folkert, M.D.

Richard Green, B.S.

Darlene Metter, M.D.

Zoubir Ouhib, M.S.

Harvey Wolkov, M.D.

Consultant: John Angle, M.D.

NRC Staff Resource: Daniel DiMarco, M.S.

18

Subcommittee Charge

Review Medical Events (MEs) to advise the Advisory Committee on the Medical Use of Isotopes (ACMUI) and United States Nuclear Regulatory Commission (NRC) about emerging trends that may need regulatory attention.

19

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Background===

The NRC and ACMUI review MEs that occur throughout the country.

MEs occur when radioactive material use in healthcare results in unexpected radiation dose to patients. (Please refer to 10 CFR 35 Subpart M - Reports and more specifically 10 CFR 35.3045 - Report and Notification of a Medical Event for more information.)

The Medical Events Subcommittee of the ACMUI reviews the data to analyze the nature of medical events, identify emerging trends and provide recommendations to the ACMUI and NRC.

20

Medical Event Review

FY21 - October 1, 2020 to September 30, 2021

FY22 - October 1, 2021 to September 30, 2022

FY23 - October 1, 2022 to September 30, 2023 21

Summary

Two overarching themes remain

- Human Error

Communication/feedback

Failure to work in teams

- Inexperience

Rapidly evolving use of radiopharmaceuticals

Dissemination of use to smaller institutions with lower frequency of procedures performed 22

Specific Issues

Increasing MEs: new and increasing use of current therapeutic radiopharmaceuticals 90Y microsphere procedures remain the most common MEs.

ACMUI Action: Added 2 specialty-specific subcommittee members

ACMUI recommendation: AU adhere to manufacturer recommendations (i.e. avoid aggregation: use recommended catheter size and needle gauge) 23

35.200 Use of Unsealed Byproduct Material for Imaging and Localization 24 5/5 (100%) possibly preventable by time out in 2021 & 2023 (Wrong Drug, Wrong Dosage & Wrong Patient)

Medical Events Summary 2017 2018 2019 2020 2021 2022 2023 Total Cause Wrong Drug 0

0 0

0 1

2 Wrong Dosage 2

0 0

0 1

0 0

3 Wrong Patient 1

0 0

0 2

0 0

3 Extravasation*

1 0

0 0

0 1

Human Error 0

0 1 (8 patients) 0 0

0 0

1 (8 patients)

Total 4

0 1

0 4

0 1

10

NRC does not have reporting requirement for extravasations

25 35.300 Use of Unsealed Byproduct Material, Written Directive Required Medical Event Summary 2017 2018 2019 2020 2021 2022 2023 Total WD not done or incorrectly 2

1 2

0 0

1 1

7 Error in delivery

(# capsules) 1 0

1 0

0 1

0 3

Wrong Dose 0

0 0

0 4

3 8

15 Equipment 0

1 4

0 2

1 0

8 Human Error 0

0 1

2 3

4 0

10 Wrong Patient 1

0 1

0 0

2 Wrong Drug 0

0 0

0 1

0 2

3 Total 4

2 9

2 10 10 11 48 Time out: 2021-5/10 (50%), 2022-3/10 (30%), 2023-10/11 (91%)

(Wrong Drug, Wrong Dosage & Wrong Patient)

35.400 Manual Brachytherapy Medical Event Summary

Still using dose-based criteria 2017 2018 2019 2020 2021 2022 2023 Total Applicator issue (e.g.

jam, eye plaque dislodged) 0 0

0 2

0 1

1 4

Wrong site implanted (e.g. penile bulb, bladder) 1 1

1 2

2 0

0 7

Activity/prescription error (e.g. air kerma vs mCi, enter wrong activity in planning software) 1 0

1 0

0 3

Wrong Dose 5

11 3

0 0

0 2

21 New Device 0

1 0

0 0

1 26

27 35.400 Manual Brachytherapy Medical Event Summary 2017 2018 2019 2020 2021 2022 2023 Total Wrong Source 0

0 0

1 0

0 0

1 Patient Health

(?patient intervention) 0 0

0 1

0 0

0 1

Wrong Patient 0

0 0

0 1

0 0

1 Total 7

13 5

6 4

1 3

39 "Time Out" may have prevented 1

0 5

1 2

0 0

9

Potentially ~23% (9/39) of ME from 2017 to 2023 may have been prevented with the use of a Time Out (wrong site, wrong source and wrong patient):

- Time Out or checklist for 2021 may have prevented: 3/4 (75%)

- No benefit in 2022 or 2023 28 35.400 Manual Brachytherapy

29 35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit Medical Event Summary 2017 2018 2019 2020 2021 2022 2023 Total Wrong position 2

3 4

7 0

1 3

20 Wrong reference length 2

1 4

2 2

2 0

13 Wrong plan 0

2 0

0 0

4 Wrong dose/source strength 0

1 0

0 0

0 2

1 Machine/applicator malfunction 2

3 1

1 1

2 2

12 Software/hardware failure 2 (9 patients) 0 1

1 0

0 0

4 Treatment planning 0

0 0

2 1

2 0

5 Human Error 0

0 0

0 1

4 1

6 Total 8

10 10 13 5

11 8

65

30 GYN tumors most common site of ME 35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit Medical Event Summary 2017 2018 2019 2020 2021 2022 2023 Total Location Breast 0

1 0

0 0

2 Gynecological 7

7 8

10 4

2 5

43 Skin/neck 0

1 0

2 1

5 1

10 Bronchus 0

0 0

0 Prostate 0

0 0

0 1

1 Brain 1

1 2

0 0

4 Unknown 0

0 0

4 1

5 Total 8

10 10 13 5

11 8

65

MEs that may have been prevented by timeout (wrong plan or dose)

2017 0/8 events

2018 3/10 events

2019 0/10 events

2020 0/13 events

2021 0/5 events

2022 0/11 events

2023 2/8 events Total 5/65 (8%)

31 35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit

MEs caused by infrequent user/inattention This is difficult to determine based on information in NMED. For this assessment, assumed wrong position is a surrogate for infrequent user/inattention - improved training may be beneficial 2017 2/8 events 2018 3/10 events 2019 4/10 events 2020 7/13 events 2021 0/5 events 2022 1/11 events 2023 3/8 events 32 35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit Total 20/65 (31%)

35.1000 Radioactive Seed Localization Medical Events Summary 2018 2019 2020 2021 2022 2023 Total Medical Events 0

1 0

1 Cause:

Delayed seed removal (patient intervention) 0 1

0 0

0 1

Lost seed 0

0 0

0 Wrong implant site 0

0 0

0 Seed migration 0

0 0

1 0

0 33

35.1000 Intravenous Cardiac Brachytherapy Medical Events Summary 2017 2018 2019 2020 2021 2022 2023 Total Did not follow proper procedure 0

0 1

0 0

1 Tortuous vessel anatomy 0

1 1*

0 0

2 Catheter issue 0

1 0

0 0

2 Wrong Site 0

0 0

0 1

1 Total 0

2 2

1 0

0 1

6 34

AU felt this is patient intervention No time out issues

35.1000 Gamma Knife Perfexion,

Icon and Esprit Medical Events Summary 2017 2018 2019 2020 2021 2022 2023 Total Total Medical Events 0

1 2

2 0

2 1

8 Cause:

Back-up battery power source failure 0

1 0

0 0

1 Patient set-up error 0

0 0

1 0

0 0

1 Patient movement 0

0 2

0 0

2 Wrong site (treatment plan) 0 0

0 0

Wrong site (human error-shifting of co-registration images) 0 0

0 1

0 2

Patient motion management system failure 0

0 0

1 0

1 Device Malfunction 0

0 0

0 1

1 35

35.1000 90Y Theraspheres Medical Events Summary For 2021 - 2023: Time out 4/23 (17%), 2/23 (9%), 1/22 (5%) - Wrong Dose*

Infrequent/inattention 10/23 (43%), 2/23 (9%), 11/22 (50%) - > 20% Residual 2017 2018 2019 2020 2021 2022 2023 Total Total Medical Events 15 14 15 15 23 23 22 127 Cause:

> 20% residual activity remaining in delivery device/leakage 7

11 9

12 10 2

11 62 Delivery device set-up error 2

2 1

1 1

0 2

9 Wrong dose (treatment plan calculation error) 4 0

1 0

0 3

1 9

Wrong site (catheter placement error & size) 2 0

0 2

1 7

3 15 Wrong dose vial selected*

0 1

4 0

1 1

1 8

Wrong dose (calibration error)*

0 0

3 1

0 4

Aggregation of microspheres 0

0 0

0 7

9 4

20 36

35.1000 90Y SirSpheres Medical Events Summary 2021 - 2023: Time out: 1/18(6%), 1/9(11%), 2/9(22%) - Wrong Site (WD)

Infrequent/inattention: 2/18(11%), 1/9(11%), 6/9(67%) - >20% Residual 2017 2018 2019 2020 2021 2022 2023 Total Total Medical Events 8

7 11 8

18 9

9 70 Cause:

> 20% residual activity remaining in delivery device/leakage 7

2 8

8 2

1 6

34 Wrong dose (treatment plan calculation error) 0 2

0 0

2 1

0 5

Wrong site (catheter placement error & defective catheter) 1 2

2 0

4 0

1 10 Wrong site (WD error) 0 1

1 0

1 1

2 6

Aggregation of microspheres 0

0 0

0 9

6 0

15 37

Actions to Prevent 35.1000 90Y Microsphere Medical Events

Ensure familiarity with the mechanics of 90Y microsphere delivery device and setup procedures

Confirm all data and calculations in treatment plan

Perform Time Out to assure all elements of treatment are in accordance with Written Directive 38

Identity of patient via two identifiers (e.g. name and DOB)

Procedure to be performed Radiopharmaceutical Activity Dosage -second check of dosage calculation and that the WD and dosage to be delivered are identical Others as applicable

- units of activity (LDR prostate)

- anatomic location

- patient name on treatment plan

- treatment plan independent second check has been performed

- reference length (HDR)

- Implant site location (RSL) 39 Possible Elements of a Time Out

Acronyms 10 CFR - Title 10 of the Code of Federal Regulations AUs - authorized users FY - fiscal year GYN - gynecological HDR - high dose-rate LDR - low dose rate mCi - milliCurie ME - medical event RSL - radioactive seed localization WD - written directive Y - Yttrium 40

ACMUI COMMENTS ON REVISIONS TO REGULATORY GUIDE 8.39 Commission Briefing l April 9, 2024 l Megan Shober

SUBCOMMITTEE MEMBERS 4

2 Hossein Jadvar Josh Mailman Melissa Martin Megan Shober NRC staff resource: Katie Tapp

PREVIOUS COMMISSION ENGAGEMENT 4

3 2011: Identify gaps in release data 2012: Revisit release calculations 2014: Revise Regulatory Guide 8.39 2018: Received staff evaluation of patient release program

TIMELINE Regulatory Guide 8.39 Release of Patients Administered Radioactive Material 4

4 Revision 0 Issued 1997 Revision 1 Draft 2019 Draft Final 2019 Issued 2020 Revision 2 Draft 2021

REVISION 2 SCOPE 4

5 Overhauled methodology to calculate dose to bystanders Updated release thresholds based on administered activity and dose rate Updated breastfeeding interruption times

TIMELINE-REVISION 2 4

6 8/11/2021 To ACMUI for review 12/15/2021 ACMUI approved comments 7/14/2023 NRC response to ACMUI comments 4/21/2023 Public comment

REVISION 2 COMMENTS Focused on external dose contribution Significantly reduced threshold for patient-specific release calculations No example for most common release scenario (i.e., I-131 patient going home) 4 7

REVISION 2 ISSUES Overly complex model requires unrealistic knowledge of patient behavior.

ACMUI did not support:

Release of Patient after a Hold Time

Material Separated from Patient 4

8

NEXT STEPS 4

9 When requested by NRC staff, review draft final Revision 2 and provide recommendations.

ABBREVIATIONS 5

0 ACMUI: Advisory Committee on the Medical Uses of Isotopes I-131: iodine-131

Patients Rights Advocate Perspectives on Regulatory Guide 8.39, Release of Patients Administered Radioactive Material Reporting of Nuclear Medicine Injection Extravasations Josh Mailman

AGENDA Extravasations Reg Guide 8.39 52

EXTRAVASATIONS

WHAT HAS CHANGED SINCE OUR LAST PUBLIC MEETING IN FALL 2023

There has been no update since our last meeting

Current recommendation has patients being part of the reporting process

In general patients dont know what an extravasation means

Education will need to be done

How often does this happen and how does this impact safety and efficacy

Can we use other data to help us determine this 54

ARE PATIENTS DISCUSSING THIS Clearly there are some patient organizations that are.

In the NET Community which has been using Dota Imaging since 2017 and Dota Therapy - this topic has rarely if ever been discussed without me initiating conversation on the topic. I have talked to 100s if not 1,000s of NET patients and this issue is rarely if ever raised.

Top topics Will / how does this imaging work?

How long do I need to be off long-acting therapy?

How do I deal with some of the side effects that are presented on the label (extravasations and injection site issue did not make the label)?

How do I travel safely home?

What precaution do I take around loved ones (partners, children and animals)?

55

IS THERE OTHER DATA THAT CAN GUIDE OUR GUIDANCE We have seen data that significant Extravasations can occur in 1 out of 30 or 1 out of 300.000.

If it was 1 out of 30 and had a patient impact, I would assume we should have seen it in FDA Phase 3 reporting for NETTER-1, NETTER-2, or Vision Trials.

If it impacted the efficacy of treatment, the manufacturer would have an incentive to require this during the trial, as it would improve efficacy and potentially the guideline placement.

Many centers are performing post-therapy SPECT scans. Some at 3 to 4 hours4.62963e-5 days 0.00111 hours 6.613757e-6 weeks 1.522e-6 months post treatment and others at 24 hours2.777778e-4 days 0.00667 hours 3.968254e-5 weeks 9.132e-6 months . We may be able to capture data from those centers that can help us better understand the real-world impact of this.

56

REGULATORY GUIDE 8.39 RELEASE OF PATIENTS ADMINISTERED RADIOACTIVE MATERIAL

WHAT HAS CHANGED SINCE OUR LAST PUBLIC MEETING IN FALL 2023

There has been no update since our last meeting

ACUMI Committee is awaiting staff update for new rounds of comments

In general, I have not been able to engage the patient community to get feedback.

58

ARE PATIENTS DISCUSSING THIS For the most part, patients and referring oncologists have very little any insight into Reg 8.39, yet many of their conversations revolve around the topic Top topic For NET Patients as pertains to Patient Release Criteria How do I travel safely home?

What precautions do I take around loved ones (partners, children, and animals)?

Why does one centers instructions differ from another Do the examples take into account different ligands, chelators, and isotopes?

Is a PSMA Alpha patient sweat radioactive?

59

THANK YOU Josh Mailman Josh@norcalcarcinet.org 60

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