ML21272A165

Advisory Committee on the Medical Uses of Isotopes (ACMUI) October 4, 2021 Fall Meeting Handout

ML21272A165
Person / Time
Issue date:	10/04/2021
From:	Advisory Committee on the Medical Uses of Isotopes
To:
Celimar Valentin -Rodriguez, NMSS/MSST
References
Download: ML21272A165 (84)

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Advisory Committee on the Medical Uses of Isotopes Fall Meeting October 4, 2021 Meeting Handout

MEETING AGENDA ADVISORY COMMITTEE ON THE MEDICAL USES OF ISOTOPES October 4, 2021 Virtual Meeting NOTE: Sessions of the meeting may be closed pursuant to 5 U.S.C. 552(b) to discuss organizational and personnel matters that relate solely to internal personnel rules and practices of the ACMUI; information the release of which would constitute a clearly unwarranted invasion of personal privacy; information the premature disclosure of which would be likely to significantly frustrate implementation of a proposed agency action; and disclosure of information which would risk circumvention of an agency regulation or statute.

Monday, October 4, 2021 OPEN SESSION 10:00 - 10:15 1. Opening Remarks C. Einberg, NRC Mr. Einberg will formally open the meeting and Mr. Williams will K. Williams, NRC provide opening remarks.

10:15 - 10:30 2. Old Business D. DiMarco, NRC Mr. DiMarco will review past ACMUI recommendations and provide NRC responses.

10:30 - 11:00 3. Medical Events Subcommittee Report R. Ennis, ACMUI Dr. Ennis will provide an analysis of FY20 medical events.

11:00 - 11:45 4. Radionuclide Generator Knowledge and Practice R. Green, ACMUI Requirements Subcommittee Report Mr. Green will discuss the subcommittees recommendations on the knowledge and specialized practice requirements for eluting, measuring, and testing, and processing the eluate from radionuclide generator systems 11:45 - 12:00 5. Open Forum ACMUI, NRC The ACMUI will identify medical topics of interest for further discussion.

12:00 - 12:45 LUNCH 12:45 - 1:30 6. Emerging Radiopharmaceutical Therapy Knowledge H. Jadvar, ACMUI Requirements in Theranostics Subcommittee Dr. Jadvar will discuss the subcommittees recommendations on the knowledge and specialized practice requirements needed for the safe use and handling of emerging radionuclides in theranostics.

1:30 - 2:15 7. Future of Personalized Dosimetry R. Hobbs, AAPM Discuss the work of new AAPM task groups on this subject.

2:15 - 3:00 8. Production Challenges for Therapeutic Radiopharmaceuticals M. Shober, ACMUI Discuss production methods of emerging therapeutic radiopharmaceuticals and effects on radiation safety for end users, and the challenges of various production methods.

1

3:00 - 3:15 BREAK 3:15 - 3:30 9. Special Presentation to Mr. Michael Sheetz R. Lewis, NRC 3:30 - 3:45 10. Open Forum ACMUI, NRC The ACMUI will continue discussion on medical topics of interest.

3:45 - 4:00 11. Administrative Closing D. DiMarco, NRC Mr. DiMarco will provide a meeting summary and propose dates for the spring 2022 meeting.

ADJOURN 2

Open ACMUI Recommendations and Action Items Target Completion Item # Item Date Status Date for NRC Action 2019 The ACMUI endorsed the Appropriateness of 17 Medical Event Reporting Subcommittee report and 09/10/2019 Accepted Propose closure Fall 2021 the recommendations provided therein.

The ACMUI endorsed the Evaluation of Extravasations Subcommittee Report, as amended, to note that under future revisions to Part 35 18 09/10/2019 Accepted Open April 2022 rulemakings, extravasations be captured as a type of passive patient intervention in the definition of patient intervention.

2020 The ACMUI endorsed the Patient Intervention 4 subcommittee report, as presented, and the 03/30/2020 Accepted Open April 2022 recommendations provided therein.

As part of the Non-Medical Events report, the ACMUI recommended to the NRC staff and/or NMP to evaluate the issue of detection of short-lived 11 medical isotopes in municipal waste (waste from 09/21/2020 Accepted Propose closure Spring 2022 nuclear medicine patients that might be triggering the landfill alarms) and provide some level of guidance, best practices, or additional instructions.

1

Open ACMUI Recommendations and Action Items Target Completion Item # Item Date Status Date for NRC Action 2021 The ACMUI tentatively scheduled the fall meeting for October 4-5, 2021. The alternate meeting date is 1 03/16/2021 Accepted Propose closure Fall 2021 September 13-14, 2021. A virtual or in-person meeting for fall 2021 is to be determined.

The ACMUI endorsed the ACMUI Abnormal 2 Occurrence Subcommittee report, and the 05/27/2021 Accepted Propose closure Fall 2021 recommendations provided therein.

The ACMUI formed a new subcommittee on the Radionuclide Generator Knowledge and Practice 3 Requirements. The subcommittee is expected to 05/27/2021 Accepted Propose closure Fall 2021 provide a draft report and any recommendations at the fall 2021 ACMUI meeting.

The ACMUI formed a new subcommittee on Emerging Radiopharmaceutical Therapy Knowledge 4 Requirements in Theranostics. The subcommittee is 05/27/2021 Accepted Propose closure Fall 2021 expected to provide a draft report and any recommendations at the fall 2021 ACMUI meeting.

The ACMUI formed a new subcommittee on the Diffusing Alpha-emitter Radiation Therapy (DaRT)

Manual Brachytherapy Source. The subcommittee is 5 09/02/2021 Accepted Open Spring 2021 expected to provide a draft report and any recommendations at the spring 2022 ACMUI meeting.

2

Medical Events Subcommittee Report Ronald D. Ennis, M.D.

Advisory Committee on the Medical Uses of Isotopes October 4, 2021 1

1 Subcommittee Members

• Ronald D. Ennis, M.D. (Chair)

• Richard Green

• Darlene Metter, M.D.

• Zoubir Ouhib, M.S.

• Michael OHara, Ph.D.

• Michael Sheetz

• Harvey Wolkov, M.D.

2 2

1

Summary

• Two overarching themes remain

- Performance of a time out/use of a checklist immediately prior to administration of radioactive byproduct material, as is done in surgery and other settings, could have prevented some MEs

- Lack of recent or frequent performance of the specific administration or inattention during performance of the procedure/treatment appear to be contributing factor(s) in a number of cases

- NRC issued an Information Notice alerting the users to this issue in 2019.

https://www.nrc.gov/docs/ML1924/ML19240A450.pdf 3

3 Summary

• Specific issues

- Increase complexity of unsealed source administrations of newer agents may lead to more equipment related MEs in future

- MEs involving Y90 administration continue to be the most common MEs. We propose the creation of a subcommittee to evaluate this issue in more depth and, in conjunction with the vendors, propose solutions to decrease the frequency of MEs 4

4 2

35.200 Use of Unsealed Byproduct Material for Imaging and Localization Medical Events Summary 2017 2018 2019 2020 Total Cause Wrong drug 0 0 0 0 0 Wrong dosage 2 0 0 0 2 Wrong patient 1 0 0 0 1 Extravasation 1 0 0 0 1 Human error 0 0 1 (8 0 1 (8 patients) patients)

Total 4 0 1 0 5 3/5 possibly preventable by time out 5

5 35.300 Use of Unsealed Byproduct Material, Written Directive Required Medical Event Summary 2017 2018 2019 2020 Total WD not done or 2 1 2 0 5 incorrectly Error in delivery 1 0 1 0 2

(#capsules)

Wrong dose 0 0 0 0 0 Equipment 0 1 4 0 5 Human Error 0 0 1 2 3 Wrong patient 1 0 1 0 2 Total 4 2 9 2 17 6

6 3

35.400 Manual Brachytherapy Medical Event Summary 2017 2018 2019 2020 Total Applicator issue (e.g. 0 0 0 2 2 jam, eye plaque dislodged)

Wrong site implanted 1 1 1 2 5 (e.g. penile bulb, bladder)

Activity/prescription 1 0 1 0 2 error (e.g. air kerma vs mCi, enter wrong activity in planning software)

Prostate Dose 5 11 3 0 19 New device 0 1 0 0 1 dose-

• Still using based criteria Wrong source 0 0 0 1 1 Patient health 0 0 0 1 1

(?patient intervention) 7 35.400 Manual Brachytherapy Medical Event Summary 2017 2018 2019 2020 Total Total ME 7 13 5 6 31 Time out 1 0 1 1 3 may have prevented Lack of 1 1 1 1 4 experience/i nattention may have played a role 8

8 4

35.400 Manual Brachytherapy Many MEs in this category are no longer categorized as MEs due to change from dose to activity-based definition, although even in 2019 this definition continued to be used for some MEs.

Lack of experience or inattention possibly plays a role in the true MEs of this type, but hard to assess to what degree in each case.

In approximately 15% of cases, a time out/checklist, enhanced retraining prior to performance of an uncommon procedure or increase attention during the procedure might have prevented the ME. 9 9

35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit 2017 2018 2019 2020 Total Wrong 2 3 4 7 16 position Wrong 2 1 4 2 9 reference length Wrong plan 0 2 0 0 2 Wrong Medical Event Summary dose/source 0 1 0 0 1 strength Machin/applic 2 3 1 1 7 ator malfunction Software/har 2 (9 pts) 0 1 1 4 dware failure Treatment 0 0 0 2 2 planning Total 8 (14 pts) 10 10 13 41 10 10 5

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 Location Breast 0 1 0 1 Gynecological 7 (14 7 8 10 pts)

Skin/neck 0 1 0 2 Bronchus 0 0 0 0 Prostate 0 0 0 0 Brain 1 1 2 0 Total 8 (14 10 10 13 pts)

GYN tumors most common site of ME 11 11 35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit MEs that may have been prevented by timeout (wrong plan or dose)

• 2017 0/8 events

• 2018 3/10 events

• 2019 3/10 events

• 2020 10/13 events Total 16/41 (39%)

12 12 6

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 2017 2/8 events

• 2018 1/10 events

• 2019 1/10 events

• 2020 9/13 events Total 13/41 (32%)

13 13 35.1000 Radioactive Seed Localization Medical Events Summary 2018 2019 2020 2021 Total Medical 0 1 0 1 Events Cause:

Delayed seed 0 1 0 0 removal (patient intervention)

Lost seed 0 0 0 0 Wrong implant site 0 0 0 0 Seed migration 0 0 0 1 14 7

35.1000 Intravenous Cardiac Brachytherapy

• Medical Events Summary 2017 2018 2019 2020 Total Did not follow 0 0 1 0 1 proper procedure Tortuous 0 1 1* 0 2 vessel anatomy Catheter issue 0 1 0 1 2 Total 0 2 2 1 5

• AU felt this is patient intervention No time out issues Difficult to assess the unfamiliarity issue, but possibly played a role in some 15 15 35.1000 Gamma Knife Perfexion' and Icon' Medical Events Summary 2017 2018 2019 2020 Total Medical Events 0 1 2 2 Cause: 0 0 0 0 Back-up battery power source 0 1 0 0 failure Patient setup error 0 0 0 1 Patient movement 0 0 2 0 Wrong site (treatment plan) 0 0 0 0 Pt motion management system 0 0 0 1 failure 16 8

35.1000 Y-90 Theraspheres Medical Events Summary 2017 2018 2019 2020 Total Total Medical Events 15 14 15 15 59 Cause:

> 20% residual activity remaining 7 11 9 12 39 in delivery device Delivery device setup error 2 2 1 1 6 Wrong dose (treatment plan 4 0 1 0 5 calculation error)

Wrong site (catheter placement 2 0 0 2 4 error)

Wrong dose vial selected 0 1 4 0 5 For 2020: Time out 3/15 (20%),

Infrequent/inattention 12/15 (80%)

17 35.1000 Y-90 SirSpheres Medical Events Summary 2017 2018 2019 2020 Total Total Medical Events 8 7 11 8 34 Cause:

> 20% residual activity remaining 7 2 8 8 25 in delivery device not due to stasis Wrong dose (treatment plan 0 2 0 0 2 calculation error)

Wrong site (catheter placement 1 2 2 0 5 error)

Wrong site (WD error) 0 1 1 0 2 2020: Time out: 0 Infrequent/inattention: 8/8 (100%)

18 9

Actions to Prevent 35.1000 Y-90 Microsphere Medical Events

• Review mechanics of Y-90 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 19 Possible Elements of a Time Out

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

• Procedure to be performed

• Isotope

• 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) 20 20 10

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

• Y - Yttrium 21 21 11

Nuclear Regulatory Commission (NRC)

Advisory Committee on the Medical Uses of Isotopes (ACMUI)

Subcommittee on Medical Events Subcommittee Final Report Submitted On: October 4, 2021 Subcommittee Members: Mr. Richard Green, Dr. Ronald D. Ennis (Chair), M.D., Dr. Darlene F. Metter, Mr.

Zoubir Ouhib, Mr. Michael Sheetz, Dr. Harvey Wolkov Charge The specific charge of this subcommittee is to annually review the medical events (MEs) with an eye to advising the ACMUI and NRC about emerging trends needing regulatory attention.

Background

The subcommittee reviewed medical events from the Fiscal year 2020 as part of its ongoing annual or biennial review.

Findings The Medical Events during 2020 were similarly low as in years past. This issue regarding time outs and checklists as a method to minimize MEs was again noted. In the committees discussion regarding the category that it had previously called infrequent/inexperience use the point was made that some of these events may be due to inattention at the time of the procedure rather than infrequent or inexperience use.

So, this category has been renamed to highlight this ambiguity. The NRC has issued an Information Notice in 2019 advising the user community about these issues.

https://www.nrc.gov/docs/ML1924/ML19240A450.pdf The concern raised by this subcommittee last year that emerging, more complex, radiopharmaceuticals may lead to an increase in MEs was not seen. There was only one such event in 2020.

MEs involving Y-90 microspheres continue to be the most common, although as a proportion of all such procedures an ME is very rare. The MEs occur with both Therasphere and Sirsphere, although more commonly with Therasphere, despite reportedly equal market share of the two products. Because of this, the subcommittee recommends the appointment of a subcommittee specifically focused on investigating the MEs associated with this therapy and to propose, in consultation with the vendors, methods to decrease these MEs.

Concluding Remarks The subcommittee looks forward to performing an in-depth trend analysis in 2022.

The subcommittee welcomes any comments and/or suggestions.

Respectfully Submitted, The Medical Event Subcommittee

Radionuclide Generator Knowledge and Practice Requirements Subcommittee Report Richard L. Green Advisory Committee on the Medical Uses of Isotopes October 4, 2021 1

Subcommittee Members

• Vasken Dilsizian, M.D.

• Richard Green (Chair)

• Melissa Martin

• Megan Shober

• Harvey Wolkov, M.D.

• NRC Staff Resource: Maryann Ayoade 2

1

Subcommittee Charge

• To review and evaluate the knowledge and practice requirements for eluting, measuring and testing, and processing the eluate from radionuclide generator systems based on the evolution of radionuclide generator distribution.

• To evaluate and determine the appropriateness of the requirements and how best to obtain the required knowledge and practice.

3 Subcommittee Charge (contd.)

• To evaluate whether and how additional knowledge and practice should be obtained as necessary to supervise the use of ANY radionuclide generator system.

• Provide considerations and recommendations to staff.

4 2

Introduction In 1994, the NRC amended its commercial distribution of radioactive drugs and medical use regulations in 10 CFR Parts 32 and 35, in part, to allow properly qualified nuclear pharmacists and authorized users who are physicians with greater discretion in preparing radioactive drugs containing byproduct material for medical use.

5 Introduction (contd.)

The rule, Preparation, Transfer for Commercial Distribution, and Use of Byproduct Material for Medical Use, resulted in the language presently found in 10 CFR 35.290, Training for imaging and localization studies. Specifically, 10 CFR 35.290(c)(1)(ii)(G) relative to generators reads:

- (G) Eluting generator systems appropriate for preparation of radioactive drugs for imaging and localization studies, measuring and testing the eluate for radionuclidic purity, and processing the eluate with reagent kits to prepare labeled radioactive drugs; 6

3

Background

Over the last 27 years there has been significant change in:

- Types of radionuclide generators used in clinical nuclear medicine practice

- Location where generators are housed and used

- Individuals who handle generators 7

Molybdenum99/Technetium99m (99Mo/99mTc) generators

• Prior to 1972, 99Mo/99mTc generators were ubiquitous and were found in every clinical nuclear medicine facility.

• First CRP opened in 1972 and today there are approximately 300 CRPs in the United States.

8 4

Molybdenum99/Technetium99m (99Mo/99mTc) generators (contd.)

• The locations of most 99Mo/99mTc generators migrated from hospital nuclear medicine departments to CRPs as nuclear medicine facilities converted to patient ready unit doses and utilized the services of CRPs for the provision of radiopharmaceuticals.

9 Molybdenum99/Technetium99m (99Mo/99mTc) generators (contd.)

• Today approximately 95% of all radiopharmaceuticals used in the United States originate from a CRP.

• As a result of the consolidation of activities, there are fewer 99Mo/99mTc generators in use today than were used in the past.

10 5

Molybdenum99/Technetium99m (99Mo/99mTc) generators (contd.)

• It is estimated that the United States utilizes approximately 720 new 99Mo/99mTc generators weekly, with 90% of them (~660) delivered to CRPs for use under the direction of an ANP and 10% of them (~60) delivered to hospital facilities for use under the direction of an AU physician or local ANP.

11 Strontium82/Rubidium82 (82Sr/82Rb) generators

• Because of the 75 second halflife of 82RbCl2 used for PET myocardial perfusion imaging, all 82Rb generators are in clinical nuclear medicine facilities for use under the direction of an AU physician.

12 6

Germanium68/Gallium68 (68Ge/68Ga) generators

• It is estimated that currently in the United States, approximately 70% of 68Ge/68Ga generators are delivered to CRPs for use under the direction of an ANP and 30% are delivered to hospital facilities for use under the direction of an AU physician.

13 Background (contd.)

• The evolution of where radionuclide generators are located has presented challenges for fellows intraining in residency programs.

• Many residency programs made arrangements with commercial radiopharmacies for their fellowsintraining to attend generator training but due to COVID19 these radiopharmacies have restricted access to their facilities.

14 7

Background (contd.)

• This increased the knowledge and practice burden affecting fellowsintraining who were unable to attend commercial radiopharmacies to receive generator training due to COVID19 closures of these facilities.

15 Background (contd.)

• In June 2020, several professional societies (ASNC, SNMMI, ACR, and ASTRO) united to request that the U.S. NRC consider Title 10 of the Code of Federal Regulations (10 CFR) 35.290(c)(1)(ii)(G), Training for Imaging and Localization Studies, as a potential area for regulatory relief during the Coronavirus Disease 2019 (COVID19) PHE.

16 8

Background (contd.)

• This letter states that most of the commercial radiopharmacies that supply portions of this training are closed to visiting trainees because of the COVID19 PHE and may not reopen for the foreseeable future.

17 Background contd.

• This letter further states that they believe that this experience requirement can be satisfied virtually, via demonstrative educational webinars during the duration of the PHE. ([ADAMS]

Accession No. ML20231A931).

18 9

Discussion The Subcommittee deliberated the intent of the existing Rule language, including:

The knowledge elements necessary for AU physicians to possess with regard to generator systems Various methods of acquiring knowledge of these element 19 Discussion (contd.)

• The Subcommittee recognizes the AU physicians role, as described in 10 CFR 35.27, in supervising nuclear medicine technologists who may be operating generator systems at clinical sites.

• The Subcommittee believes that AUs, whether or not they personally use radionuclide generators:

must be familiar with how generators work how breakthrough is tested how reagent kits are used to label radioactive drugs 20 10

Discussion (contd.)

• The Subcommittee also believes that it is not necessary for AU physicians to have direct hands on work experience with the generators, although the Subcommittee recognizes that direct work experience is an excellent way to fulfill the training requirements.

21 Discussion (contd.)

• In order to facilitate learning, and to provide training programs flexibility to deliver training, the Subcommittee discussed the strengths and limitations of inperson, prerecorded, or live virtual training opportunities.

22 11

Discussion (contd.)

• The Subcommittee believes that training can incorporate any combination of these methods, but the Subcommittee believes it is essential for the training to include an opportunity for physicians to ask questions about the subject material and receive answers in real time.

23 Discussion (contd.)

• In addition, it is important for the trainer to be able to assess physician learning as the training is progressing. If prerecorded material is used to deliver a portion of the training, there should also be a live component (whether inperson or via virtual meeting) where trainees and trainers can directly interact.

24 12

Discussion (contd.)

• Consistent with existing regulation, the Subcommittee further believes that it is not necessary to mandate training on every radionuclide generator system. Training programs should have the flexibility to modify the training curriculum as the use of generator systems evolves.

25 Conclusion - Subcommittee Recommendation

• Current rule language in 10 CFR 35.290(c)(1)(ii)(G):

- (G) Eluting generator systems appropriate for preparation of radioactive drugs for imaging and localization studies, measuring and testing the eluate for radionuclidic purity, and processing the eluate with reagent kits to prepare labeled radioactive drugs; and

• Subcommittee proposed revision:

- (G) Participating in educational sessions to gain knowledge and provide supervision of - (1) radionuclide generator systems and their operation;(2) the measurement of radionuclidic impurities and acceptable limits; and (3) the use of reagent kits with radionuclide eluate to prepare radioactive drugs.

26 13

Acronyms

• ACMUI - Advisory Committee on the Medical Uses of Isotopes

• ACR - American College of Radiology

• ADAMS Agencywide Documents Access and Management System

• ANP - Authorized Nuclear Pharmacist

• ASNC - American Society of Nuclear Cardiology

• ASTRO - American Society for Radiation Oncology

• AU - Authorized User

• CFR - Code of Federal Regulations 27 Acronyms

• CRP - Centralized Radiopharmacy

• 68Ge/68Ga - Germanium68/Gallium68

• 99Mo/99mTc - Molybdenum99/Technetium99m

• NRC - U.S. Nuclear Regulatory Commission

• PET - Positron Emission Tomography

• PHE - Public Health Emergency

• SNMMI - Society of Nuclear Medicine and Molecular Imaging

• 82Sr/82Rb - Strontium82/Rubidium82 28 14

U.S Nuclear Regulatory Commission Advisory Committee on the Medical Uses of Isotopes Subcommittee on Radionuclide Generator Knowledge and Practice Requirements Draft Report Submitted on September 8, 2021 Subcommittee Members:

Vasken Dilsizian, M.D.

Richard Green (Chair)

Melissa Martin Megan Shober Harvey Wolkov, M.D.

NRC Staff Resource: Maryann Ayoade Subcommittee Charge:

• To review and evaluate the knowledge and practice requirements for eluting, measuring and testing, and processing the eluate from radionuclide generator systems based on the evolution of radionuclide generator distribution.

• To evaluate and determine the appropriateness of the requirements and how best to obtain the required knowledge and practice.

• To evaluate whether and how additional knowledge and practice should be obtained as necessary to supervise the use of any radionuclide generator system.

• Provide considerations and recommendations to staff.

Background:

In 1994, the NRC amended its commercial distribution of radioactive drugs and medical use regulations in 10 CFR Parts 32 and 35, in part, to allow properly qualified nuclear pharmacists and authorized users who are physicians with greater discretion in preparing radioactive drugs containing byproduct material for medical use. The rule, Preparation, Transfer for Commercial Distribution, and Use of Byproduct Material for Medical Use, resulted in the language presently found in 10 CFR 35.290, Training for imaging and localization studies. Specifically, 10 CFR 35.290(c)(1)(ii)(G) relative to generators reads:

(G) Eluting generator systems appropriate for preparation of radioactive drugs for imaging and localization studies, measuring and testing the eluate for radionuclidic purity, and processing the eluate with reagent kits to prepare labeled radioactive drugs; Over the last 27 years, the types of radionuclide generators used in clinical nuclear medicine practice, the location where they are housed and used, and the individuals who handle them have all significantly changed.

Molybdenum-99/Technetium-99m (99Mo/99mTc) generators Prior to 1972, 99Mo/99mTc generators were ubiquitous and were found in every clinical nuclear medicine facility. The first centralized radiopharmacy (CRP) opened in 1972 and today there are approximately 300 centralized radiopharmacies in the United States. Over the course of time, the locations of most 99Mo/99mTc generators migrated from hospital nuclear medicine departments to CRPs as nuclear medicine facilities converted to patient ready unit doses and utilized the services of CRPs for the provision of radiopharmaceuticals. Today approximately 95% of all radiopharmaceuticals used in the United States originate from a CRP. As a result of the consolidation of activities, there are fewer 99Mo/99mTc generators in use today than were used in the past. It is estimated that the United States utilizes approximately 720 new 99Mo/99mTc generators weekly, with 90% of them (~660) delivered to CRPs for use under the direction of an authorized nuclear pharmacist (ANP) and 10% of them (~60) delivered to hospital facilities for use under the direction of an authorized user (AU) physician or local ANP.

Strontium-82/Rubidium-82 (82Sr/82Rb) generators Because of the 75 second half-life of 82RbCl2 used for PET myocardial perfusion imaging, all 82Rb generators are in clinical nuclear medicine facilities for use under the direction of an AU physician.

Germanium-68/Gallium-68 (68Ge/68Ga) generators It is estimated that currently in the United States, approximately 70% of 68Ge/68Ga generators are delivered to CRPs for use under the direction of an ANP and 30% are delivered to hospital facilities for use under the direction of an AU physician.

The evolution of where radionuclide generators are located has presented challenges for fellows-in-training in residency programs. Many residency programs had made arrangements with commercial radiopharmacies for their fellows-in-training to attend generator training but due to COVID-19 these radiopharmacies have restricted access to their facilities. This increased the knowledge and practice burden affecting fellows-in-training who were unable to attend commercial radiopharmacies to receive generator training due to COVID-19 closures of these facilities.

In June 2020, several professional societies (American Society of Nuclear Cardiology, Society of Nuclear Medicine and Molecular Imaging, American College of Radiology, and the American Society for Radiation Oncology) united to request that the U.S. Nuclear Regulatory Commission (NRC) consider Title 10 of the Code of Federal Regulations (10 CFR) 35.290(c)(1)(ii)(G), Training for Imaging and Localization Studies, as a potential area for regulatory relief during the Coronavirus Disease 2019 (COVID-19) Public Health Emergency (PHE). This letter states that most of the commercial radiopharmacies that supply portions of this training are closed to visiting trainees because of the COVID-19 PHE and may not reopen for the foreseeable future. This letter further states that they believe that this experience requirement can be satisfied virtually, via demonstrative educational webinars during the duration of the public health emergency. (Agencywide Documents Access and Management System [ADAMS] Accession No. ML20231A931).

Discussion:

The Subcommittee deliberated the intent of the existing Rule language, the knowledge elements necessary for authorized user physicians to possess with regard to generator systems, and various methods of acquiring knowledge of these elements. The Subcommittee recognizes the authorized user physicians role, as described in 10 CFR 35.27, supervising nuclear medicine technologists who may be operating generator systems at clinical sites. Consequently, the Subcommittee believes that authorized users, whether or not they personally use radionuclide generators, must be familiar with how generators work, how breakthrough is tested, and how reagent kits are used to label radioactive drugs. The Subcommittee also believes that it is not necessary for authorized user physicians to have direct hands-on work experience with the generators, although the Subcommittee recognizes that direct work experience is an excellent way to fulfill the training requirements.

In order to facilitate learning, and to provide training programs flexibility to deliver training, the Subcommittee discussed the strengths and limitations of in-person, pre-recorded, or live virtual training opportunities. The Subcommittee believes that training can incorporate any combination of these methods, but the Subcommittee believes it is essential for the training to include an opportunity for physicians to ask questions about the subject material and receive answers in real time. In addition, it is important for the trainer to be able to assess physician learning as the training is progressing. If pre-recorded material is used to deliver a portion of the training, there should also be a live component (whether in-person or via virtual meeting) where trainees and trainers can directly interact.

Consistent with existing regulation, the Subcommittee further believes that it is not necessary to mandate training on every radionuclide generator system. Training programs should have the flexibility to modify the training curriculum as the use of generator systems evolves.

Conclusion - Subcommittee Recommendation:

Current rule language in 10 CFR 35.290(c)(1)(ii)(G):

(G) Eluting generator systems appropriate for preparation of radioactive drugs for imaging and localization studies, measuring and testing the eluate for radionuclidic purity, and processing the eluate with reagent kits to prepare labeled radioactive drugs; Subcommittee proposed revision:

(G) Participating in educational sessions to gain knowledge and provide supervision of -

(1) radionuclide generator systems and their operation; (2) the measurement of radionuclidic impurities and acceptable limits; and (3) the use of reagent kits with radionuclide eluate to prepare radioactive drugs.

Respectfully Submitted on September 8, 2021 Radionuclide Generator Knowledge and Practice Requirements Subcommittee Advisory Committee on the Medical Uses of Isotopes (ACMUI)

U.S. Nuclear Regulatory Commission (NRC)

OPEN FORUM (No Handout)

Emerging Radiopharmaceutical Therapy Knowledge Requirements in Theranostics Hossein Jadvar, MD, PhD, MPH, MBA Advisory Committee on the Medical Uses of Isotopes October 4, 2021 1

Agenda

• ACMUI Subcommittee Membership

• ACMUI Subcommittee Charge

• Theranostics (Background)

• Theranostics (Emerging Agents)

• Theranostics (Challenges)

• Knowledge Requirements

• Theranostics Room Setup 2

2 1

Emerging RPT Knowledge Requirements in Theranostics - ACMUI Subcommittee Membership

• Hossein Jadvar, MD, PhD (Nuclear Medicine Physician; Chair)

• Vasken Dilsizian, MD (Nuclear Cardiologist)

• Ronald Ennis, MD (Radiation Oncologist)

• Michael OHara, PhD (FDA Representative)

• Zoubir Ouhib (Therapy Medical Physicist)

• Josh Mailman (Patients Rights Advocate)

• Maryann Ayoade (NRC Staff Resource) 3 3

ACMUI Subcommittee Charge

• To outline the knowledge and specific or specialized practice or policy requirements needed for the safe use and handling of emerging radiopharmaceuticals in theranostics.

• Provide considerations and recommendations to staff.

4 4

2

Background

• Definition: Systemic integration of diagnostic tools (e.g.,

nuclear imaging) and therapeutic agents (e.g.,

radiopharmaceuticals) related to the same (or similar*)

biomolecular target (or parameter*)

• Precision / Personalized Medicine

• History: 1941 with treatment of a hyperthyroid patient with radioiodine by Saul Hertz, MD, at Massachusetts General Hospital 5

5 Background (contd.)

• Current oncologic theranostic agents

• 123I/131I (NaI symporter; thyroid)

• 111In/90Y-ibritumomab (anti-CD20; lymphoma)

• 18F-NaF/99mTc-MDP; 223RaCl2 (osteoblastic mets; mCRPC)*

• 99mTc-MAA; 90Y-microspheres (hyperperfusion; liver tumors)*

• 123I/131I-MIBG (norepinephrine transporter; pheochromocytoma, paraganglioma)

• 68Ga/64Cu-DOTATATE, 68Ga-DOTATOC; 177Lu-DOTATATE (SSTR+ neuroendocrine tumors) 6 6

3

Theranostics (Emerging Agents)

• Within near future

• 68Ga*/18F-PSMA*; 177Lu-PSMA** (mCRPC)

(*FDA approved; ** FDA approval anticipated)

• In the horizon

• 225Ac/227Th-PSMA (alpha RLT; mCRPC)

• 68Ga-pentixafor/177Lu-, 90Y-pentixather (chemokine receptor 4; multiple myeloma)

• 68Ga/177Lu-NeoB (GRPR; solid tumors)

• 68Ga/177Lu-FAPI (fibroblast activation protein; multiple cancers) 7 7

Theranostics (Emerging Agents) (contd.)

• In the horizon (contd.)

• 89Zr/177Lu-girentuximab (carbonic anhydrase IX; clear cell RCC)

• Ga/177Lu-FF58 (integrin 35; GBM) 68

• 18F/131I-PARPi (DNA repair enzyme Poly-(ADP ribose) polymerase 1; multiple cancers) 8 8

4

Theranostics (Challenges)

• Technical

• Interdisciplinary teams

• Standardized protocols

• Radionuclide pipeline / supply chain

• Economic

• Comparative cost; cost-utility

• Reimbursement

• R&D funding 9

9 Theranostics (Challenges) (contd.)

• Biomedical

• Basic science, pre-clinical, first-in-human, and large prospective clinical trials

• Single, tandem, combination therapies

• New applications 10 10 5

Emerging RPT Knowledge Requirements in Theranostics

• Make up of the healthcare team at the time of administration

• Depending upon the therapy, the team administering the dose may consist of - AU with appropriate training in theranostics, CNMT, RSO, Registered Nurse, and Medical Physicist (if available/applicable)

• AU must be present at the time of dose administration 11 11 Emerging RPT Knowledge Requirements in Theranostics (contd.)

• Therapy should be done in a dedicated and regulatory-approved room appropriate for radioisotope administrations

• Non-radiation workers (e.g., oncology nurse) participating in the procedure may need to wear a radiation badge as determined by the RSO 12 12 6

Emerging RPT Knowledge Requirements in Theranostics (contd.)

• Extravasation; patient release criteria (addressed by other ACMUI subcommittees)

• Radioactive waste management (refer to the facility established guidelines and regulations)

• The AU is responsible for patient concerns related to RPT, including radiation induced injuries

• Ensure that emerging theranostics are within the regulatory guidelines 13 13 Emerging RPT Knowledge Requirements in Theranostics (contd.)

• AU is encouraged to avail themselves of all the newest training information for each new theranostics as they emerge

• Patient specific dosimetry may play an important role; as relevant data becomes mature, AUs should stay abreast of developments

• Outreach to promote accurate information about safety and efficacy of theranostics 14 14 7

Theranostics Room Setup 15 15 Acronyms

• ACMUI: Advisory Committee on the Medical Uses of Isotopes

• AU: Authorized User

• CNMT: Certified Nuclear Medicine Technologist

• FDA: Food and Drug Administration

• R&D: Research and Development

• RPT: Radiopharmaceutical Therapy

• RSO: Radiation Safety Officer 16 16 8

U.S. Nuclear Regulatory Commission Advisory Committee on the Medical Uses of Isotopes Subcommittee on Emerging Radiopharmaceutical Therapy Knowledge Requirements in Theranostics Draft Report Submitted on September 20, 2021 Subcommittee Members:

Vasken Dilsizian, M.D.

Ronald Ennis, M.D.

Hossein Jadvar, M.D., PhD (Chair)

Josh Mailman Michael OHara, PhD Zoubir Ouhib NRC Staff Resource: Maryann Ayoade Subcommittee Charge:

The Subcommittee was formed in May 2021, by Dr. Darlene Metter, Chair of the Advisory Committee on the Medical Uses of Isotopes (ACMUI) to:

• To outline the knowledge and specific or specialized practice or policy requirements needed for the safe use and handling of emerging radiopharmaceuticals in theranostics.

• Provide considerations and recommendations to staff.

The Subcommittee reviewed the relevant literature (see reference section) and met virtually four times in July and August 2021 to discuss the charge and propose several considerations in consultation with the NRC staff.

==

Introduction:==

Theranostics is the systemic integration of diagnostic tools (e.g., nuclear imaging) and therapeutic agents (e.g., radiopharmaceuticals) targeted to the same (or similar*) biomolecule (or physiologic parameter*). This concept is the fundamental foundation for precision medicine that has advanced considerably in view of our enhanced understanding of biology, developments in diagnostic technologies, and expansion of therapeutic options. Precision (or personalized) medicine is hoped to improve patient outcome. While theranostics may be applied to a variety of diseases, cancer has been the primary focus in this field (1-4).

Theranostics is a recent term, but it has long been a major player in the history of nuclear medicine, and the list and interest in use of theranostics have been increasing. Early example of theranostics dates back to 1941 when Dr. Saul Hertz from Massachusetts General Hospital, in Boston, MA, treated a patient with Graves disease realizing that radioiodine can target the thyroid tissue based on the basic knowledge that thyroid gland concentrates iodine.

The list below are the currently clinically available theranostics imaging-therapy companion agents, with the biological and disease targets shown in the parenthesis:

• I/

123 131 I (NaI symporter; thyroid)

• 111 In-/90Y-ibritumomab (anti-CD20; lymphoma)

• 18 F-NaF/99mTc-MDP; 223RaCl2 (osteoblastic metastasis; mCRPC)*

• 99m Tc-MAA; 90Y-microspheres (hyperperfusion; liver tumors)*

• 123 I-/131I-MIBG (norepinephrine transporter; pheochromocytoma, paraganglioma)

• 68 Ga-/64Cu-DOTATATE, 68Ga-DOTATOC; 177Lu-DOTATATE (SSTR+

neuroendocrine tumors NaI=sodium iodide, CD20=cluster of differentiate 20, mCRPC=metastatic castration-resistant prostate cancer, NaF=sodium fluoride, MAA=macroaggregated albumin, MDP=methyl diphosphonate, MIBG=meta-iodobenzylguanidine, DOTA= 1,4,7,10-tetraazacyclododecane-N,N,N,N-tetraacetic acid, DOTATOC=DOTA-d-Phe1-Tyr3-octreotide, DOTATATE= DOTA-DPhe1,Tyr3-octreotate In the near future, theranostics based on prostate specific membrane antigen (PSMA) will be available clinically for the imaging evaluation of prostate cancer (initial staging, biochemical recurrence) and radioligand therapy of metastatic castration-resistant prostate cancer. The imaging agents 68Ga-PSMA-11 and 18F-DCFPyL (PylarifyTM) were approved by the FDA in December 2020 and May 2021, respectively. The favorable results of the randomized phase III VISION clinical trial on the therapy companion - 177Lu-PSMA-617 - has recently been published in the New England Journal of Medicine facilitating an anticipated FDA approval within Q1 of 2022 (5).

Additional theranostics pairs are in the horizon within the next 7 years. These include the following companion agents with the biological and disease targets shown in the parenthesis:

• 225 Ac-/227Th-PSMA (alpha RLT; mCRPC)

• 68 Ga-pentixafor/177Lu-, 90Y-pentixather (chemokine receptor 4; multiple myeloma)

• 68 Ga-/177Lu-NeoB (GRPR; solid tumors)

• 68 Ga-/177Lu-FAPI (fibroblast activation protein; multiple cancers)

• 89 Zr-/177Lu-girentuximab (carbonic anhydrase IX; clear cell RCC)

• 68 Ga-/177Lu-FF58 (integrin a3b5; GBM)

• 18 F-/131I-PARPi (DNA repair enzyme Poly-(ADP ribose) polymerase 1; multiple cancers)

RLT=radioligand therapy, GRPR=gastrin-releasing peptide receptor, FAPI=fibroblast activated protein inhibitor, RCC=renal cell carcinoma, GBM=glioblastoma multiforme Challenges:

Despite being a rapidly developing field, theranostics faces several challenges that will need to be addressed adequately in order for it to be fully integrated into clinical medicine (3).

• Technical Challenges:

Need for standardized and efficient protocols; formation of interdisciplinary teams; incorporation into clinical guidelines; education and training.

• Economic challenges:

Investment into supporting the supply chain for a steady pipeline of radioisotopes relevant to theranostics; sufficient reimbursement; comparative cost-utility analysis; Research and Development funding.

• Biomedical Challenges:

Additional basic science, pre-clinical, first-in-human, and large prospective clinical trials; evaluation of single, tandem, and combination therapies; development of new applications in oncology and non-oncology arenas.

Subcommittee Specific Comments:

1) Radiopharmaceutical (RPT) Healthcare Team:

Depending upon the therapy, the healthcare team administrating the RPT dose may consist of the Authorized User (AU) with appropriate training in theranostics, Certified Nuclear Medicine Technologist (CNMT), Registered Nurse, Radiation Safety Officer (RSO), and Medical Physicist (if available/applicable).

2) Authorized User responsibilities:

AU must be present at the time of dose administration; AU is responsible for patient concerns related to RPT, including radiation induced injuries; AU is encouraged to avail themselves of all the latest training information for each new theranostics as they emerge.

3) Radiation safety issues:

Non-radiation workers of the healthcare team (e.g. oncology nurse) participating in the procedure may need to wear radiation badges for monitoring as determined by the RSO; therapy should be done in a dedicated and regulatory-approved room appropriate for radioisotope administrations (see Fig. 1); extravasation; patient release criteria (these issues are addressed by other ACMUI subcommittees).

4) Regulatory issues:

Radioactive waste management (refer to the facility established guidelines and regulations); ensure that emerging theranostics are performed within the regulatory guidelines.

5) Dosimetry:

Dosimetry-based (as opposed to fixed-activity) may play an increasingly important role (6-10); dosimetry-based approach may optimize patient outcome while minimizing

radiation toxicity; no randomized controlled trials to provide level 1 evidence for benefits of dosimetry-based approach; research is needed on impact of combined other nonradioactive therapy agents on RPT biodistribution and radiosensitivity, standardization across clinics, software and medical physicists, development of robust methodology for challenges of surrogate-imaging, microscale radiation effect and daughter distribution (relevant for alpha particles), and research on potential patient benefit versus cost and complexity of logistics; as relevant data becomes mature, AUs should stay abreast of developments in dosimetry.

6) Other relevant issues:

Outreach to AUs, healthcare providers, and patients to promote accurate information about safety and efficacy of theranostics (11).

Fig. 1. An illustrative example of a Radiopharmaceutical Therapy clinic room; an attached bathroom is to the left of the picture (not shown).

References:

(1) Jadvar H, et al. Radiotheranostics in Cancer Diagnosis and Management. Radiology 2018; 286:388-400.

(2) Turner JH, et al. An Introduction to the Clinical Practice of Theranostics in Oncology.

Br J Radiol 2018; 91:20180440.

(3) Herrmann K, et al. Radiotheranostics: A Roadmap for Future Development. Lancet Oncol 2020; 21:e146-e156.

(4) Gomes Marin JF, et al. Theranostics in nuclear medicine: Emerging and Re-emerging Integrated Imaging and Therapies in the Era of Precision Oncology. Radiographics 2020; 40:1715-1740.

(5) Sartor O, et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; 385:1091-1103.

(6) Sgouros G, et al. Dosimetry for Radiopharmaceutical Therapy. Semin Nucl Med 2014; 44:172-178.

(7) Lassmann M, et al. The Relevance of Dosimetry in Precision Medicine. J Nucl Med 2018; 59:1494-1499.

(8) Divgi C, et al. Overcoming Barriers to Radiopharmaceutical Therapy (RPT): and Overview from the NRG-NCI Working Group on Dosimetry of Radiopharmaceutical Therapy. Int J Radiat Biol 2021; 109:905-912.

(9) Roncali E et al. Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy. J Nucl Med 2021; 62:1133-1139.

(10) SNMMI 177Lu Dosimetry Challenge 2021. J Nucl Med 2021; 62:10N.

(11) SNMMI Theranostics Video: https://www.youtube.com/watch?v=Bb8Ts5HWS40 Respectfully Submitted on September 20, 2021 Emerging RPT Knowledge Requirements in Theranostics Subcommittee Advisory Committee on the Medical Uses of Isotopes (ACMUI)

U.S. Nuclear Regulatory Commission (NRC)

FUTURE OF PERSONALIZED DOSIMETRY: AAPM PERSPECTIVE Robert F Hobbs, Johns Hopkins ACMUI, October 4th 2021 1

OUTLINE

1. Principles of Prospective Personalized Treatment Planning for RPT

2. Examples

3. Roadblocks

4. Bio-effect Modeling

5. Combination Therapies

6. alpha-particle RPT 2

1

1. RPT STANDARD TREATMENTS

• 100 mCi radioiodine for thyroid ablation

• 200 mCi radioiodine for thyroid therapy

• 200 mCi I-131 mIBG for neuroendocrine tumours

• 200 mCi x 4 for Y-90 DOTATATE of neuroendocrine tumours

• 200 mCi x 4 for Lu-177 DOTATATE for neuroendocrine tumours

• 200 mCi x 4 for Lu-177 PSMA for bone metastases

• 50 kBq/kg x 6 for Ra-223 for bone metastases Credit: G. Flux Royal Marsden. EANM 18 J. Capala NCI Theranostics 18 3

NORMAL ORGAN AD-BASED TREATMENT PLANNING FOR RPT Standard is the chemotherapy paradigm of dose escalation Patient 1 Patient 2 AA limit is set by patients with 4 AD=ADDLT 4

AD<<ADDLT maximum retention DLO Activity DLO Activity 3 3 BUT great inter-patient 2 AADLT 2 AADLT variability - Xbeam is limited 1 AD ADDLT 1 1 2 by NO toxicity 1 2 3 4 1 2 3 4 RPT is radiation just as Xbeam Time Time 4

2

Admin Activity (AA) vs Abs Dose Example of patient 131I-anti-CD20 Ab; NHL patients Wahl, RL Semin Oncol 03 variability Previously demonstrated that 75 cGy to WB increases RM toxicity Increasing database shows consistent large disparities in NO dose up to an order of magnitude -

current state of dosimetry 5

2. PEDIATRIC THYROID CANCER PATIENT:

REAL-TIME TREATMENT PLANNING Real time (1 week) 131I treatment planning for an 11 year-old girl with metastatic differentiated papillary thyroid cancer using 3D-RD.

Heavy lung involvement meant concern about pulmonary toxicity and concern for overdosing Used 124I and PET/CT for dosimetric assessment - Whole body PET/CT scans were performed at 1, 24, 48, 72, and 96 h Hobbs et al. JNM 09 6

3

124I PET/CT IMAGE (24 H) 7 3D-RD ESTIMATION Activity converted to I-131 Monte Carlo for each time point Plot dose rate in lungs Functional Fit Integrate for absorbed dose Scale to 27 Gy a AA: 5.1 GBq a Press et al. N Eng J Med 93 8

4

2. CONCLUSIONS Feasibility of real time treatment planning using 3D-RD, patient-specific dosimetry.

A higher recommended AA (60 % more) than by an S-value based method (with a highly favorable clinical outcome) was obtained.

Re-visitation of methods led to convergence -

QA: do both methods (much misunderstanding about relative merits of MIRD (absorbed fraction) versus voxelized dosimetry 9

MICROSPHERES Increased survival in Y-90 microspheres treated using combination of Normal Organ toxicity threshold (120 Gy) and lesion dosimetry objectives (min 205 Gy, max 250 Gy) using pre-therapeutic Tc99m-MAA dosimetry AAA (Lu-177-DOTATATE) will not sell Garin et al, Lancet Gastroenterol Hepatol 2020 doses of greater than 200 mCi 10 5

3. ROADBLOCKS

- Huge interest of companies, Nuke Med physicians, but still reluctant to use dosimetry.

- A large fraction of nuclear medicine physicians, med oncs do not understand the point of dosimetry

- Standardization and QA

- Lack of qualified physicians and physicists

- Reimbursement

- lack of understanding of importance of RPT historically. New Grant for 90Y-microspheres using Tc99m-MAA as surrogate - first submitted in 2011!

Mantra is that the onus is on dosimetry to prove it is necessary for each and every modality 11 REASONS FOR HOPE Interest by Radiation Oncology, who understand dosimetry, therapy, uncertainty analysis, dose reporting and QA SNMMI have engaged in a number of projects: Challenge, Registry, Education..

NCI proposes many RPT-based initiatives (often led by Med Oncs..)

Imaging software companies providing software to make dosimetry more accessible NCI, ICRU, IAEA, ASTRO, MIRD, SNMMI advocate dosimetry-based treatment planning Education of physicians and physicists Standardization and QA -

AAPM, NIST, IROC 12 6

Education Expertise Distribution and Overlap of Specialty Professional Society Certified Medical Physicists AND Actually Home for Physicists Qualified TRT Dosimetry Physicists Truly Qualified Truly Qualified Targeted Radionuclide Therapy AAPM SNMMI Targeted Radionuclide Therapy Dosimetry Dosimetry Experts Experts Certified Certified Nuclear Certified Nuclear Medicine Radiation Medicine Certified Radiation Physicists Therapy Physicists

1. MANY more RT physicists than Physicists Therapy Physicists NM physicists.

2. RT Physicists are engaged daily in clinical workflow, NM primarily engaged in care 1. AAPM is primary home to RT and feeding of imaging and Physicists NM measurement equipment

2. SNMMI is primary home to NM

3. RT physicist work reimbursed as part of routine clinical Physicists.

workflow. 3. TRT Dosimetry physicists

4. TRT experienced physicists primarily (not exclusively) are are currently operating in a SNMMI members (MIRD, niche specialty. RADAR).

Credit: J. Sunderland U Iowa. SNMMI/NCI Theranostics 18 13 COLLABORATION/COOPERATION ?

ASTRO/SNMMI met several times at leadership level to propose collaboration and recognized complementary expertise Pathway of Care document was breaking point, has become more of a turf war AAPM oversees all Medical physicists, both Nuclear Medicine and Radiation Oncology (ABR Nuclear Medicine and Radiation Therapy). Neither are ideally suited for RPT, given current training requirements. Further education for retrospective training is needed in both fields and Integrating RPT-specific training in current curricula is necessary for prospective MPs. (SNMMI also has ABNM certification).

ACR_AAPM_SNMMI Technical Standards document is case in point Nuke Med uses technologists for administrations, concern over lack of physicists and push to ue technologist/physician combo for dosimetry as well 14 7

AAPM EFFORTS AAPM has RPT sub-committee under Therapy Physics (since March) and a Nuclear Medicine sub-committee under Imaging Physics.

Collaboration as been mediocre. Decision was to form a separate committee given the large interest in the field. Grid strategy.

TG proposals: Y-90 microsphere dosimetry update to TG144, Lu-177 dosimetry (with SNMMI, EANM, NCI), dose calibrator standardization and traceability of standards (EPC, NIST).

WG proposals: I-131 therapies (TGs to follow), Alpha-RPT, radioactive microspheres.

MPPG: Y-90 microsphere utilization, (RPT to follow)

Education: proposal of Summer School 2023, RPT Track at annual meeting, collaborations with SNMMI and ASTRO annual meetings 15 MPPG/TG ON Y-90 MICROSPHERES Non-standardization of dosimetry - modality has evolved separately from RPT, such that nomenclature, formalism are modality-specific, very confused and confusing.

Activity specification is not very precise - within 10 %, pushing for 5 %.

Lung shunt fraction is non-uniform and generally not very precise; Tc99m site not necessarily correlating with microsphere administration .

Thresholds for toxicity really not known.

Segmentectomy prescription uses lobar dosimetry as workaround.

Relative dosimetry is used, but rarely validated - pushing for post-therapy imaging for QA check a la brachytherapy Precision of voxelized dosimetry poorly understood 16 8

4. RADIOBIOLOGY OR BIO-EFFECT MODELING Many modifiers of Biological Response:

- Repair - single/double strand DNA breaks, different types of repair. Different types of damage direct vs. indirect damage. Affected by dose rate.

- Reassortment - sensitivity depending on the life cycle of the cell. Different types of cell death.

- Reoxygenation - more oxygen has potential for free radicals. Hypoxic versus normoxic cells,

- Repopulation - tumor cell proliferation 17 BIOLOGICAL EFFECTIVE DOSE (BED)

Nomenclature from shape of surviving fraction of cells from single bolus of radiation on a log-linear plot (blue line)

Different dose rates give different responses -

standardize/normalize dose (account for/eliminate dose rate effect) - green line Equivalent linear dose compared to the linear-quadratic absorbed dose with a repair term a G Effectively Accounts for dose rate variations BED D1 D For exponential decay, G is given by: G ( )

18 9

BED for Normal Organ Correlation with Toxicity Correlation between kidney dose (Gy) and creatinine clearance loss/year (% baseline) N=18 Standard kidney volumes 60 60 Creatinine clearance loss/year Creatinine clearance loss/year R=0.93 p<0.0001 40 40

(% baseline) (% baseline) 20 20 0 0 20 30 40 0 10 20 30 40 50 60 Dose Standard volume (Gy) Biologic Effective Dose (Gy)

Barone et al, JNM 2005 MIRD Pamphlet 20, Wessels et al. J Nucl Med 08 19

5. COMBINED 153SM-EDTMP RPT WITH EBRT Chelate is bone seeking calcium mimetic -

treat pediatric metastatic osteosarcoma

- EBRT can deliver precise amounts of radiation dose to tumors but limited by adjacent normal tissues (e.g. spinal cord)

- RPT delivers radiation dose to all tumor sites including micro-metastases very conformal but can not escalate radiation dose to tumor limit and treats systemic disease, limited by uptake in normal organs 20 10

RPT-EBRT AD EQUIVALENCE RPT Di BEDi Di 1 Gi ( )

AD from EBRT fractionated i / i AD from RPT over time d

EBRT BEDi Di 1 What about biological i / i equivalence?

Use BED as a bridge DRPT DRPT Gi ()

Equivalence depends on EQD 2 2

dose per fraction, d Bodey et al. Cancer Biother Radiopharm 03 Bodey et al. IJROBP 04 21 PROCEDURE (2013-2016)

a. Stem cell collection for autologous transplant

b. CTsim used for both EBRT and RPT treatment planning

c. Low dose 153Sm-EDTMP (1 mCi/kg)

d. SPECT/CT imaging at 4, 24 and 48 h, image reconstruction and combined EBRT-RPT treatment plan.

e. High dose 153Sm-EDTMP determined from plan (max 20 mCi/kg)

f. High dose imaging at 4, 24 and 48 h (dead-time correction),

image reconstruction and EBRT plan adjustments

g. IMRT (SBRT) treatment

h. Autologous stem cell transplant when permissible from bone marrow absorbed dose (recovery) 22 11

EBRT - Treatment plan Pelvic Tumor Spinal cord 50.9 Gy (EBRT) 46 Gy (EBRT) 19.9 Gy (RPT) 2.4 Gy (RPT) 23 EBRT-RPT CONCLUSIONS

- The created treatment planning protocol combining RPT and EBRT for metastatic osteosarcoma in pediatric patients showed potential. Targeted tumors received a prescribed tumoricidal absorbed dose (> 70 Gy) due to the RPT boost

- Not a clinical success. Only 4 patients treated, diseases were not stayed.

Choice of tumors and location, cant treat the tumors around the trachea/heart/major vessels, which were life threatening and were the cause of death. In future be more selective of the patients and tumor location and burden. Need to combine with chemotherapy.

- Importance of standardized dose from bio-effect modeling general poorly understood in RPT. Often EBRT MTDs are used without converting, AD is cumulated over fractions regardless of kinetics, non-standard bio-effect modeling even less understood (Y-90 microsphere BED, e.g.)

24 12

5. COMBINATION 131I-TOSITUMOMAB AND 90Y-IBRITUMOMAB TIUXETAN Different isotopes have different emission characteristics, idealized for different range of metastatic tumor sizes Normal organ toxicities may be orthogonal - increase activity and dose. Application to myeloablative Bexxar and Zevalin therapy of lymphoma Hobbs et al. JNM 13 25 COMBINING NORMAL ORGAN MTDS At myeloablative regimes, 131I-tositumomab is limited by lung toxicity, 90Y is limited by liver. a Measure kinetics in patient and establish di,j, solve for AB.

MTD lu AZ d Z ,lu AB d B ,lu Madsen et al. J Nucl Med 06 MTD li AZ d Z ,li AB d B ,li a Song et al. J Nucl Med 07 a Wiseman et al. Eur J Nucl Med 00 26 13

OPTIMIZE TO NO/TUMOR BED Intersection is MTBED to both organs (30 Gy for lungs, 35 Gy for liver)

Kinetics from patient data BUT target is tumor, not Normal Organs. Tumor BED as a function of AB Company withdrew support because of dosimetry 27 CONSIDERATIONS FOR RPT ?

Where are Bexxar and Zevalin now ? Dosimetry is often blamed (Bexxar had basic dosimetry, but Zevalin did not). Territorialism (oncologists vs. nuclear medicine), lack of support by drug companies for personalized quantitative medicine Is this relevant to current situation ? Fixed activity at fractionated regimens for class-based therapies from chemo are still the norm. Dosimetry is being forced to adapt to this paradigm (single/reduced time point dosimetry) rather than leading changed to personalized reduced fraction/single fraction therapy.

Compromise on precision of dosimetry leads to poor correlations, cannot be used for personalized dosimetry-based treatment planning - consider ATA recommendations in 2006 based on non-standardized dosimetry.

28 14

SINGLE TIME POINT DOSIMETRY Driven by a desire to reduce cost and patient inconvenience Chemo paradigm: Dosimetry is primarily retrospective and toxicity is determined empirically.

Driven by multi-fraction paradigm.

Studies are optimized for a single organ. Best results assume mono-exponential fits.

For single modality compromise between organs/tumor best times. Uncertainty is given as 10 %, but that is mean uncertainty, individual uncertainty is 2-3 times higher.

Compromise is to have no information on kinetics, so uncertainty on BED is ??? Cumulative AD is typically used instead of cumulated BED. What would Barone result look like ?

Decades of EBRT show the need and benefits for high precision in radiation therapy. Cost and inconvenience should be measured against EBRT (5-8 weeks of daily therapy) rather than nuclear medicine diagnostic procedures.

Highly precise multi-time point pre-therapeutic dosimetry could lead to reduction in number of fraction for safer, more effective, less inconvenient and less expensive therapies.

29 Bragg peak

-PARTICLE THERAPY Massive particles, He nuclei (~

8000 times electron),

deposit greater energy -

high Linear Energy Transfer (LET) and RBE Very short range 100 microns for 5 -10 MeV alphas ideal for micrometastases 30 15

Which -particles for RPT ?

Currently only Ra-223 is FDA-approved Clinical trials and pre-clinical studies with:

- Pb-212

- At-211

- Ac-225 (has been used with peptides and PSMA)

- Th-227

- Bi-213 31 RPT used in NET Remarkable results with Ac-225-peptide sometimes after unsuccessful Lu-177-peptide (N.B. Bi-213 peptides also used)

Kratochwil et al. Curr Radiopharm 18 2 questions: Kratochwil et al. EJNMMI 15

- why is this not ubiquitous ?

- why is this working at all ?

Ballal et al. EJNMMI 20 32 16

CAN WE USE RPT DOSIMETRY FOR ALPHAS ?

225Ac-7.16.4 treatment of pulmonary metastases from breast cancer Murine tail vein injection, 105 NT2 cells, lung metastasis, 5 wks, 100%. a Therapy: effective BUT renal toxicity despite low dose b Calculated 2+ Gy to kidneys (typical toxicity thresholds ~40 Gy BED) a Song et al. Clin Cancer Res 08 b Song et al. Cancer Res 09 33 ALPHA-PARTICLE DOSIMETRY Can we apply RPT dosimetry paradigms to RPT?

4 Challenges:

1. RBE (standardization, variability of parametrization) value of ~5, but could vary

2. sub-organ localization of activity - short range means higher dose concentration

3. re-localization of daughters (225Ac chain has 4

-emissions, with 213Bi 45 min HL)

4. low count rate for imaging (typical therapeutic activity is 100 Ci - few mCi)

Carrasquillo et al. EJNMMI13 34 17

RBE RBE definition: RBE DL DH SF EQD2 reference dose a L LdL EQDX DL L L X Ratio is now called RBE2 b:

RBE 2 L 2 L a Bentzen et al. Radiother Oncol 12 b Hobbs et al. Radiation Res 14 35 APPLICATION 2 different cell lines:

- murine breast cancer: NT2.5 (RBE

= 2.4 -9.0, RBE2 = 5.9)

- human breast cancer: MDA-MB-231 (RBE = 2.4 - 6.0, RBE2 = 4.5)

Report raw data as well as derived quantities !

Remaining variability reflect true biological effect Hobbs et al. Radiation Res 14 36 18

MIRD MODEL AT SMALL SCALE - NEPHRON MODEL Use simple geometrical shapes (spheres, toroids cylinders) for S-values

1. Fold tubules to simulate proximity

2. Discriminate between tubule cells (simple cuboidal epithelials) and lumina

3. Consider range of s and ratios of proximal/distal neighbors

4. Parameterize from ex vivo data/cadavers Hobbs et al. Phys Med Biol 12 37 MACRO TO MICRO CONVERSION Measure (isotope) activity conc aij(t) in compartments AND whole organ

• Multiply by fraction of occupancy fi to apportion fraction of activity gi to compartments Free 213Bi Human translation Hobbs et al. Phys Med Biol 12 38 19

ACTIVITY QUANTIFICATION ORGAN Measure in - counter Only 213Bi emits photons Fit to double exponential to quantify activities at time sacrifice Daughters in tumors tend to stay in tumors Daughters in normal organs tend to be voided (often caught in kidneys) 39 APPLICATION - 213BI IMAGING Kidneys collected from her2-neu mice at 5, 15, 60 min p.i. of 213Bi Frozen and cryo-sectioned in 8

µm thin slices for staining and imaging with Alpha-Camera.

Imaging time between 30 and 60 min.

Focalized Activity Uptake RPT - specific Translate to Human 40 20

MICRODOSIMETRY Non - uniform dose distribution at the No of cells cellular level from statistics Consideration of nuclear/DNA target

- cross-section, cellular localization of decay, cord length of potential No hits interaction Alpha-particles have fewer hits per cell kill on average, but low average hits means potential for Poisson Distribution - probabilistic.

X Can there be other mechanisms of Nucleus radiation induced cell death ?

41 BYSTANDER EFFECT - IMMUNE RESPONSE Relates to RPT effectiveness:

- bystander effect(s): cells release chemicals that Chouin et al. Radiat Res 09 Howell et al. Int J Radiat Biol 12 cause death in neighboring cells

- immune response (likely linked to abscopal effect):

a. cells die a more dramatic death than by low LET radiation and dead cells are presented to immune system that generate reaction.

b. short range and high conformality means tumor microenvironment is much less irradiated than by standard RPT or EBRT 42 21

6. CONCLUSIONS RPT dosimetry much more complex than traditional RPT - not ready for general use Currently underdosing by a far greater ratio than RPT Small scale dosimetry (MIRD/AF method) fundamental for understanding and quantifying dosimetry More site/cell type-specific RBE, RPT apportionment factors needed Bio-effect modeling at cellular level/TME still in infancy need to converge approaches 43 GENERAL CONCLUSIONS Dosimetry-based Treatment Planning is catching on.

(Only in microspheres for now)

Chemo paradigm still dominates - territorialism and big pharma are obstacles Standardization, Education, Guidelines still needed (AAPM plays a role here)

Radiobiology and Bio-effect Modeling will drive further developments - extend common language to other non-radiation modalities AlphaRPT will play an increasing role 44 22

THANK YOU FOR YOUR ATTENTION!

45 23

Production Challenges for Novel Therapy Radionuclides Megan Shober Advisory Committee on the Medical Uses of Isotopes October 4, 2021 1

Overview

• Production methods

• Physics challenges

• Chemistry challenges

• Radiation safety challenges 2

2 1

Copper67

• ~2.5 day halflife, beta decays to stable zinc67

• Acceleratorproduced from stable target:

68Zn(,p)67Cu

• Known target separation chemistry

• Paired with copper64 diagnostic agent 3

3 Copper67

• Chelators have not held the copper in place.

Increased radiation dose to liver

• Production is adequate to meet current demand.

4 4

2

Lutetium177

• 6.6 day halflife, beta decays to stable hafnium177

• Two production methods 5

5 Lutetium177 Direct https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463871/, accessed 1/20/2021 6

6 3

Lutetium177 Direct Indirect https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463871/, accessed 1/20/2021 7

7 Lutetium177

• Radiation safety challenges (direct method)

- Impurity is not eligible for disposal via decayin storage.

• Chemical challenges (indirect method)

- Ytterbium and lutetium are very difficult to chemically separate.

- Ytterbium is difficult to source.

8 8

4

Actinium225

• 10 day halflife, decay chain of four alphas and two betas to bismuth209

• Extremely limited supply cannot support research demand.

9 9

Actinium225 National Isotope Development Center

• Producing 4050 mCi every six weeks from thorium229 stock.

• Providing ~100 mCi every other month from accelerator produced Ac225.

10 10 5

Accelerator Produced Actinium225

• Thorium target irradiation produces actinium 227 as a trace contaminant.

- Minimal effect on patient dosimetry

- Huge radiation safety challenges for facility

• Actinium227

- 22 year halflife

- Extremely difficult to detect, 44 keV beta 11 11 Accelerator Produced Ac225 Safety area Ac225 Ac227 Annual limit on 3E1 microcuries 4E4 microcuries intake Reportable spill 1.5 microcuries 0.002 microcuries (5 x ALI)

Financial assurance Not required 10 microcuries 12 12 6

Accelerator Produced Actinium225

• To avoid coproducing actinium227, use a radium226 target.

- Highly radioactive target, which must be recovered and reused

- Radon gas production

- Must limit accelerator beam strength to reduce production of impurities

- Maintenance concerns 13 13 Thorium227

• 18.7 day half life, decay chain of five alphas and two betas to stable lead207

• Produced by beta decay from actinium227

• Supply chain already in place to support production of radium223 14 14 7

Thorium227

• Waste management

- Cant use ten halflife rule of thumb due to ingrowth of daughter products.

• Concerns about migration of daughter products within body 15 15 Conclusions

• There is rising interest in production via accelerators and generators.

• Reducing impurities is paramount.

• Radiation safety concerns are driving decision making for both producers and end users.

16 16 8

Questions?

17 17 Abbreviations

• Ac: actinium

• ALI: annual limit on intake

• Cu: copper

• keV: kiloelectron volts

• Lu: lutetium

• mCi: millicuries

• Zn: zinc 18 18 9

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