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{{#Wiki_filter:MEETING AGENDA ADVISORY COMMITTEE ON THE MEDICAL USES OF ISOTOPES September 21-22, 2020 WEBEX 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, September 21, 2020 OPEN SESSION
: 1. Opening Remarks                                                                        C. Einberg, NRC Mr. Einberg will formally open the meeting and provide opening remarks.
: 2. Old Business                                                                        K. Jamerson, NRC Ms. Jamerson will review past ACMUI actions and recommendations 10:00 - 11:30              and provide NRC responses.
: 3. Open Forum                                                                                        ACMUI The ACMUI will identify medical topics of interest for further discussion.
: 4. Medical Events Subcommittee Report                                                    R. Ennis, ACMUI Dr. Ennis will provide an analysis of FY19 medical events.
11:30 - 12:15                                            BREAK/LUNCH
: 5. Non-Medical Events                                                                  M. Sheetz, ACMUI Mr. Sheetz will provide an analysis of FY19 non-medical events reported by medical use facilities and commercial pharmacies.
: 6. New Drug Development and Labeling                                                    F. Lutterodt, FDA 12:15 - 2:00                Mr. Lutterodt will discuss the U.S. Food and Drug Administrations regulatory process for new drug development and labeling.
: 7. Dosimetry Methodology Update for Regulatory Guide 8.39,                                        D. Hamby, Phase 2 Revision                                                                        RCD Radiation Dr. Hamby will discuss the dosimetry methodology update for the                    Protection Assoc.
Regulatory Guide 8.39, Phase 2 revision.
2:00                                                  ADJOURN FOR THE DAY Tuesday, September 22, 2020 CLOSED SESSION
: 8. INFOSEC Training                                                                      R. Norman, NRC 10:00 - 12:00          9. Ethics Training                                                                          C. Safford, NRC
: 10. Allegations Training                                                                  S. Hawkins, NRC 1
 
12:00 - 12:15                                  BREAK Tuesday, September 22, 2020 OPEN SESSION
: 11. Medical Team Updates                                                      L. Dimmick, NRC Ms. Dimmick will provide an update on Medical Radiation Safety Team activities.
12:15 - 1:45  12. Open Forum                                                                        ACMUI The ACMUI will discuss medical topics of interest previously identified.
: 13. Administrative Closing                                                  K. Jamerson, NRC Ms. Jamerson will provide a meeting summary and propose dates for the spring 2021 meeting.
1:45                                          ADJOURN 2
 
2019 ACMUI RECOMMENDATIONS AND ACTION ITEMS Target Completion ITEM                                    DATE        STATUS Date for NRC Action The ACMUI endorsed the Appropriateness of Medical Event ACMUI 17 Reporting Subcommittee report and the recommendations              9/10/2019            Open      Spring 2021 Action provided therein.
The ACMUI endorsed the Evaluation of Extravasations Subcommittee Report, as amended, to note that under future ACMUI 18 revisions to Part 35 rulemakings, extravasations be captured as 9/10/2019                Open      Spring 2021 Action a type of passive patient intervention in the definition of patient intervention.
The ACMUI endorsed the Institutional Memory Subcommittee Report, as amended, to include the recommendation that a ACMUI 20 complete list of ACMUI members be updated and added to the          9/11/2019            Open*    09/14/2020 Action webpage. The Subcommittee membership was amended to add Dr. Wolkov.
  *Action completed via the September 14, 2020 NRC Response Memorandum (ADAMS Accession No. ML20254A179) -
pending formal closure by the ACMUI at the fall 2020 meeting.
1
 
2020 ACMUI RECOMMENDATIONS AND ACTION ITEMS Target Completion ITEM                              DATE          STATUS Date for NRC Action The ACMUI endorsed the Regulatory Guide (RG) 8.39, "Release of Patients Administered Radioactive Material" 1                                                                3/11/2020  Accepted    Open*    09/14/2020 Subcommittee report and the recommendations provided therein regarding the draft final RG 8.39, Revision 1, Phase 1.
Dr. Metter formed a subcommittee to review the impacts that COVID-19 could have or is having on the medical use community and determine if potential impacts could help the NRC prepare for any regulatory impacts. Subcommittee 2 membership includes: Dr. Vasken Dilsizian, Mr. Richard Green, 03/30/2020  Accepted    Open*    09/14/2020 Dr. Hossein Jadvar (chair), Ms. Melissa Martin, Ms. Megan Shober, and Dr. Harvey Wolkov. Non-voting subcommittee consultants include: Mr. Gary Bloom and Mr. Zoubir Ouhib.
NRC staff resource: Ms. Lisa Dimmick Dr. Metter amended the membership of the Training and Experience Requirements Subcommittee. Subcommittee membership now includes: Dr. Ronald Ennis, Dr. Hossein 3                                                                03/30/2020 Accepted    Open*    09/14/2020 Jadvar, Dr. Darlene Metter, Dr. Robert Schleipman (chair), Mr.
Michael Sheetz, and Ms. Megan Shober. Mr. Gary Bloom will serve as a non-voting subcommittee consultant.
The ACMUI endorsed the Patient Intervention subcommittee 4 report, as presented, and the recommendations provided          03/30/2020 Accepted    Open      Spring 2021 therein.
1
 
2020 ACMUI RECOMMENDATIONS AND ACTION ITEMS The ACMUI endorsed the Bylaws Subcommittee report, as 5                                                                    03/30/2020 Accepted Open*  09/14/2020 presented, and the recommendations provided therein.
Dr. Metter formed a subcommittee to review the abnormal occurrence criteria, with the following in mind: (1) define patient harm in AO; (2) reassess current AO criteria; (3) define goals of AO criteria and reporting; and (4) are current AO criteria 6 sufficient in regards to public health? Subcommittee                03/30/2020 Accepted Open*  09/14/2020 membership includes: Mr. Gary Bloom, Dr. Ronald Ennis, Dr.
Hossein Jadvar, Mr. Zoubir Ouhib, Mr. Michael Sheetz, and Ms. Megan Shober. NRC staff resource: Dr. Katie Tapp.
(subcommittee on hold until further notice from staff)
The ACMUI endorsed the Interventional Radiologist 7 Subcommitee report, as presented, and its recommendations          03/30/2020 Accepted Open*  09/14/2020 provided therein.
The ACMUI tentatively scheduled its fall 2020meeting for 8 September 21-22, 2020. The alternate date is September14-          03/30/2020 Accepted Open*  09/14/2020 15, 2020.
The ACMUI endorsed the COVID-19 Subcommittee report, as 9 presented, and its recommendations provided therein.                4/30/20  Accepted Open*  09/14/2020 (4/30/20)
  *Action completed via the September 14, 2020 NRC Response Memorandum (ADAMS Accession No. ML20254A179) - pending formal closure by the ACMUI at the fall 2020 meeting.
2
 
OPEN FORUM (No Handout)
 
Medical Events Subcommittee Report Ronald D. Ennis, M.D.
Advisory Committee on the Medical Uses of Isotopes September 21, 2020 1
1 Subcommittee Members
* Ronald D. Ennis, M.D. (Chair)
* Richard Green
* Darlene Metter, M.D.
* Michael OHara, Ph.D.
* Michael Sheetz
* Harvey Wolkov, M.D.
NRC Staff Resource: Donna-Beth Howe, Ph.D.
2 2
1
 
Process
* As begun in 2018, every two years the Medical Events Subcommittee will report on our review of events over the last 4 years to discern common themes within each section of 10 CFR Part 35 and across the sections, to inform a discussion of possible ways to decrease medical events (MEs).
* The Subcommittee reviewed the medical events for FYs 2016-2019.
3 3
Summary
* Two overarching themes remained
    - Performance of a time out 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 appears to be a contributing factor in a number of cases
* One new issue identified
    - Increase complexity of unsealed source administrations of newer agents may be leading to more equipment related MEs 4
4 2
 
35.200 Use of Unsealed Byproduct Material for Imaging and Localization Medical Events Summary 2016      2017    2018      2019      Total Cause Wrong drug              0        0      0          0          0 Wrong dosage            0        2      0          0          2 Wrong patient            0        1      0          0          1 Extravasation            0        1      0          0          1 Human error              0        0      0        1 (8        1 (8 patients)  patients)
Total                  0        4      0          1          5 3/5 possibly preventable by time out 5
5 35.300 Use of Unsealed Byproduct Material, Written Directive Required Medical Events Summary 2016      2017    2018      2019      Total WD not done or            1        2      1        2            6 incorrectly Error in delivery        1        1      0        1            3
(# capsules)
Wrong dose                1        0      0        0            1 Equipment                0        0      1        4            5 Human Error              1        0      0        1            2 Wrong patient            1        1      0        1            3 Total                    4        4      2        9          19 Time out could prevent 13/19 = 68%
Emerging increase in equipment issues 5/19 = 26% compared to 10% in last review 6
6 3
 
35.400 Manual Brachytherapy Medical Events Summary 2016    2017  2018 2019    Total Applicator issue (e.g. movement        1      0      0  0        1 during implant Wrong site implanted (e.g. penile      1      1      1  1        4 bulb)
Activity/prescription error (e.g. air  0      1      0  1        2 kerma vs mCi, enter wrong activity in planning software)
Prostate Dose                          18      5    11  3*      37 New device                            0      0      1  0        1 Total                                  20      7    13  5      45
  *Still using dose-based criteria 7
35.400 Manual Brachytherapy Medical Events Summary 2016        2017    2018    2019    Total Total MEs          20            7      13        5      45 Time out may have 0            1        0        1        2 prevented ME Lack of experience may have 1            1        1        1        4 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 possibly plays a role in the true MEs of this type, but hard to assess to what degree in each case.
* In approximately 13% (down from 25% in last review) of cases, a time-out or enhanced retraining prior to performance of an uncommon 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 Medical Events Summary 2016    2017    2018  2019      Total Cause Wrong position        1        2      3      4        10 Wrong reference      0        2      1      4        7 length Wrong plan            1        0      2      0        3 Wrong dose/source    0        0      1      0        1 strength Machine malfunction  3        2      3      1        9 Software failure      0    2 (9 pts)  0      1        3 Total                5    8 (14 pts)  10    10        33 10 10 5
 
35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit Medical Events Summary 2016      2017    2018    2019 Location Breast                0        0        1      0 Gynecological        2    7 (14 pts)    7      8 Skin                  1        0        1      0 Bronchus              0        0        0      0 Prostate              2        0        0      0 Brain                0        1        1      2 Total                5    8 (14 pts)  10      10 GYN tumors were 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 plans or dose)
* 2016        1/5 events
* 2017        0/8 events
* 2018        3/10 events
* 2019        3/10 events Total: 7/33 (21.2%) compared to 16% on last review 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 This is difficult to determine based on information in NMED. If assumption is made about wrong position as surrogate for infrequent user.
* 2016          1/5 events
* 2017          2/8 events
* 2018          1/10 events
* 2019          1/10 events Total: 5/33 (15.2%) compared to 32% on last review 13 13 35.1000 Radioactive Seed Localization Medical Events Summary 2016 2017 2018 2019 Total Medical Events                        1    0  1    0 Cause:
Delayed seed removal                1        1 (patient intervention)
Lost seed                                          0 Wrong implant site                                  0 14 14 7
 
35.1000 Intravenous Cardiac Brachytherapy Medical Events Summary 2016      2017        2018        2019        Total Did not follow          0          0          0          1            1 proper procedure Tortuous                0          0          1          1*          2 vessel anatomy Catheter issue          0          0          1          0            1 Total                  0          0          2          1            4
    *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 2016 2017 2018 2019 Total Medical Events                                      3      0      1    0 Cause:                                                    0      0      0    0 Back-up battery power source failure              0      0      1    0 Patient setup error                              2      0      0    0 Patient movement                                  1      0      0    2 Wrong site (treatment plan)                      0      0      0    0 16 16 8
 
35.1000 Y-90 Theraspheres Medical Events Summary 2016 2017 2018 2019 Total Total Medical Events                        13  15  14  15  57 Cause:
            > 20% residual activity remaining    9    7  11    9  36 in delivery device Delivery device setup error          1    2    2    1    6 Wrong dose (treatment plan          1    4    0    1    6 calculation error)
Wrong site (catheter placement      2    2    0    0    4 error)
Wrong dose vial selected                      1    4    5 17 17 35.1000 Y-90 SirSpheres Medical Events Summary 2016 2017 2018 2019 Total Total Medical Events                        13    8    7  11  39 Cause:
          > 20% residual activity remaining    9    7    2    8  26 in delivery device not due to stasis Wrong dose (treatment plan            2    0    2    0    4 calculation error)
Wrong site (catheter placement      2    1    2    2    7 error)
Wrong site (WD error)                0    0    1    1    2 18 9
 
Overview Y-90 Microsphere MEs FY2014 - 2017  N=91        FY2016 - 2019    N=96 Cause
                                                > 20% residual not due to stasis Wrong dose 7%          (treatment plan 6%
error) 12%              Wrong site (catheter placement error) 10%      62, 65%
Device setup error Wrong dose vial/WD error 19 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 20 10
 
35.1000 Medical Events That May Have Been Prevented by Time Out Y-90 RSL        Perfexion/Icon Microspheres 2016      0/1            2/3            3/26 2017      0                0            3/23 2018      0/1            0/1            4/21 2019      0              0/2            7/26 Total    0/2          2/6 (33%)    17/96 (18%)
21 35.1000 Medical Events That May Have Been Attributed to Lack of Experience or Infrequent User Y-90 RSL        Perfexion/Icon Microspheres 2016    0/1            2/3          1/26 2017      0              0            2/23 2018    0/1            0/1          2/21 2019      0              0/2          1/26 Total 0/2 (0%)      2/6 (33%)      6/96 (6%)
22 11
 
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 23 23 Possible Elements of a Time Out contd.
* 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) 24 24 12
 
Subcommittee Response to Findings
* The subcommittee recommended that the NRC staff issue an Information Notice alerting Authorized Users to the themes identified herein.
* IN-19-07, Methods to Prevent Medical Events, was published on August 26, 2019.
(ADAMS Accession No. ML19240A450) 25 25 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-90 26 26 13
 
U.S. Nuclear Regulatory Commission Advisory Committee on the Medical Uses of Isotopes Subcommittee on Medical Events Draft Report Submitted On: August 11, 2020 Subcommittee Members: Mr. Richard Green, Dr. Ronald D. Ennis (Chair), M.D., Dr. Darlene F.
Metter, Mr. Michael Sheetz, and Dr. Harvey Wolkov NRC Staff Resource: Dr. Donna-Beth Howe 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===
At the Fall 2018 ACMUI meeting this subcommittee initiated a new approach to reporting on MEs such that every 2 years the subcommittee will review medical events (MEs) occurring in the previous 4 years with the goal of identifying common themes within each section of 10 CFR Part 35 and discuss possible ways to prevent these MEs. The report herein is the second such in-depth 4-year review of MEs.
Findings The Subcommittee on Medical Events reviewed the Medical Events from FY 2016-19. Events from each section were reviewed in detail by a subcommittee member with expertise in the area. In the subcommittees review two years ago, we noted that a significant proportion of MEs might be prevented by the universal implementation of a time out prior to the procedure/treatment. In addition, we noted that a considerable number of events seemed to occur in situations in which the authorized user and team were performing a procedure/treatment with which they do not have much recent experience.
In the current review, the subcommittee found that the number of MEs, the types and the proportion possibly preventable by a time out and the proportion related to lack of experience, were about the same.
One new emerging trend was noted. In the delivery of unsealed byproduct material for which a written directive is required (10 CFR 35.300), there was an increase in the number of MEs related to equipment (e.g., catheter) issues. This is thought to be attributable to the increasing use of agents with more complex delivery (e.g., Lu-177 dotatate). The subcommittee anticipates this
 
trend will continue and warrants close observation. However, no specific intervention by NRC staff is recommended at this time.
A new Y-90 microsphere delivery device has been introduced by Sirtex. We will be watching for trends in MEs related to this problematic area with the introduction of this new device.
Concluding Remarks The subcommittee looks forward to performing an in-depth trend analysis in 2022 and next year will perform a focused one-year review of FY2020.
The subcommittee welcomes any comments and/or suggestions.
Respectfully Submitted, The Medical Event Subcommittee Ronald Ennis, MD, Chair
 
NonMedical Byproduct Material Events: FY18 and FY19 Michael Sheetz Advisory Committee on the Medical Uses of Isotopes September 21, 2020 1
1 NonMedical Events Reported by Medical Licensees
* NMED event reported by medical licensee
* Does not include medical events under 10 CFR 35.3045 or 35.3047
* Includes events reported under:
    - 10 CFR 35.3067 (leaking source)
    - 10 CFR 20.2201 (lost or stolen material)
    - 10 CFR 20.2202 (over exposures)
    - 10 CFR 30.50 (contamination)
    - 49 CFR 171.15 (transportation incidents) 2 2
1
 
NonMedical Event Categories Identified in FY18 and FY19 Category                FY18 FY19 Lost, Abandoned, or Stolen Sources        9      18 Leaking Sealed Source                    9      4 Transportation of Radioactive Material    5      3 Radiation Overexposure                    5      3 Radioactive Contamination                3      3 Equipment Malfunction                    1      4 Total  32      35 3
3 Total NMED Events (All Categories)
FY18 and FY19 67 805 NonMedical Events from Medical Licensees All Other Events 4
4 2
 
Lost, Abandoned, or Stolen Sources FY18 and FY19
* Lost I125 RSL seed - 9
* Lost RAM shipment - 6
* Missing I125/Pd103 brachy seeds - 3
* Temporary loss and recovery of RAM - 3
* Abandoned calibration sources - 2
* Lost Cs137 dose calibrator source - 1
* Patient removal of I125 brachy seeds - 1
* Ir192 source delivery to wrong location - 1
* Incomplete shipment of Lu177 - 1 5
5 Leaking Sealed Source FY18 and FY19
* Ir192 HDR source - 4
* Cs137 dose calibrator vial - 3
* I125 RSL seed - 2
* Co57 dose calibrator vial - 1
* Sr90 intravascular brachytherapy device - 1
* Co57 calibration rod - 1
* Ge68 phantom - 1 6
6 3
 
Transportation of Radioactive Material FY18 and FY19
* Contaminated package - 4
* Vehicle accident - 2
* Damaged package - 1
* High exposure rate - 1 7
7 Radiation Overexposure FY18 and FY19
* PET radiopharmaceutical production - 3
    - (50 mSv DDE, 690 mSv SDE, 600 mSv SDE)
* Nuclear medicine procedures - 2
    - (130 mSv DDE, 580 mSv SDE)
* Cyclotron repair - 1
    - (720 mSv SDE)
* C11 and F18 animal research - 1
    - (130 mSv DDE)
* Interventional radiology using Y90 microspheres - 1
    - (530 mSv SDE) 8 8
4
 
Radioactive Contamination FY18 and FY19
* Contamination of hospital room from patient receiving previous I131 therapy - 2
* Contamination of veterinary clinic from I131 treatment of cat - 2
* Patient contamination from administration of F18 - 1
* Contamination of hot lab following breakage of Tc99m vial - 1 9
9 Equipment Malfunction FY18 and FY19
* Sr90 IVB device source retraction failure - 2
* Defective HDR transfer guide tube - 1
* HDR device premature termination of treatment - 1
* Rb82 generator Sr82/85 breakthrough limits exceeded - 1 10 10 5
 
Other Events - Landfill Alarms
* Detection of shortlived medical isotopes in municipal waste
* No standard reporting requirement
* Declining number of events FY14    FY15    FY16  FY17  FY18    FY19 113    114    71    18    17        6
* Can result in significant response effort 11 11 Conclusions
* Relatively small number of NonMedical events
* Type of events occurring have minimal health and safety impact
* Declining number of landfill alarm responses reduces burden on both regulators and licensees 12 12 6
 
Acronyms
* C11 - carbon11
* CFR - Code of Federal Regulations
* Co57 - cobalt57
* Cs137 - cesium137
* DDE - Deep Dose Equivalent
* F18 - flourine18
* FY - Fiscal Year
* Ge68 - germanium68
* HDR - high dose rate 13 13 Acronyms
* I125/I131 - iodine125/131
* IR192 - iridium192
* IR - Interventional Radiology
* IVB - Intravascular Brachytherapy
* Lu177 - lutetium177
* mSv - milliSievert
* NMED - Nuclear Material Events Database
* Pd103 - palladium103
* PET - Positron Emission Tomography 14 14 7
 
Acronyms
* RAM - Radioactive Material
* Rb82 - rubidium82
* RSL - Radioactive Seed Localization
* SDE - Shallow Dose Equivalent
* Sr82/85/90 - strontium82/85/90
* Tc99m - technetium99 metastable
* Y90 - yittruim90 15 15 8
 
New Drug Development and Labeling Frank Lutterodt, M.S., MSDRA Division of Imaging and Radiation Medicine Division of Regulatory OperationsSpecialty Medicine Office of Regulatory Operations Center for Drug Evaluation and Research 1
Outline Overview Drug Development Process Regulating the Use of Radioactive Drugs in Basic Research PreClinical Phase Clinical Phase New Drug Application Review and Labeling 2
2 1
 
Drug Development Process 3
3 Regulating Radioactive Drugs in Basic Research Radioactive Drug Research Committee (RDRC)
(21 CFR 361.1)
For basic science research Not for use for immediate therapeutic, diagnostic or similar purpose No intent to determine safety or effectiveness for clinical use https://www.fda.gov/drugs/scienceandresearchdrugs/radioactivedrug researchcommitteerdrcprogram 4
4 2
 
New Drug Development Process PreClinical Research Synthesis and purification
* Target affinity
* Selectivity etc.
Animal Testing
* PK
* Proof of concept
* Toxicity
* Translation to humans Meetings with FDA https://www.fda.gov/media/109951/download 5
5 New Drug Development Process Clinical Phase Phase 1 Phase 1 approaches involve Investigational New Drug Application (IND) and may involve:
: 1. Exploratory IND
: 2. Traditional IND INDs are governed by 21 CFR 312.21 INDs are used to establish the safety or effectiveness of a drug to support the approval of a new use 6
6 3
 
New Drug Development Process Clinical Phase Phase 1 (Exploratory IND)
An exploratory IND study is a clinical trial that is conducted early in phase 1, involves very limited human exposure, and has no therapeutic or diagnostic intent.
The main purpose of this approach is to find promising drug candidates to enable the sponsor to proceed efficiently with the most promising drug.
https://www.fda.gov/media/72325/download 7
7 New Drug Development Process Clinical Phase Phase 1 (Traditional IND)
Traditional Phase 1 trials usually involve healthy volunteers to determine the drugs most frequent and serious adverse events, and often, how the drug is metabolized and excreted by the body Involve a small number of participants, generally in the range of 20 to 80 subjects https://clinicaltrials.gov/ct2/aboutstudies/glossary 21 CFR312.21 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.21 8
8 4
 
New Drug Development Process Clinical Phase Phase 2 Phase 2 clinical trial gathers more information about a drugs safety and effectiveness in the condition/disease being studied Larger group of subjects/participants are enrolled Subjects/participants receiving the drug may be compared with others receiving placebo Safety and shortterm adverse reactions continue to be evaluated 9
9 New Drug Development Process Clinical Phase Phase 3 During Phase 3, more information is gathered about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs Studies typically involve more participants and efficacy endpoints are assessed If safety and efficacy are adequately confirmed, clinical testing may end at this step and a New Drug Application (NDA) may be submitted 10 10 5
 
NDA Review Preclinical data (Pharmacology/Toxicology, Chemistry Manufacturing and Controls), and data from the clinical trials are reviewed to assist FDA in making a benefit/risk assessment A favorable benefit/risk assessment culminates in the review and approval of the drug labeling 11 11 New Drug Label and Labeling Label                            Labeling Any display of written,                All labels, as well as other printed, or graphic matter            written, printed, or graphic on the immediate container            matter accompanying the of any article, or any such            product.
matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity 21CFR1.3 (b) / FD&C Act section 201(k) 21CFR1.3 (a) /FD&C Act section 201(m) 12 12 6
 
Labeling Carton and Container Labels Prescribing Information (PI) Package Insert Patient Labeling Patient Instructions for Use, Patient Information, Medication Guide Operator Guide (User Manual) 13 13 Prescribing Information Physician Labeling Rule (PLR) Format was implemented in 2006 Contents of the Prescribing Information (PI)
Highlights Table of Contents Full Prescribing Information (FPI)
Pregnancy and Lactation Labeling Rule (PLLR) 21 CFR 201.56 and 201.57 Physicians Labeling Rule Requirements for Prescribing Information http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm 14 14 7
 
PLLR
* Label format change to reflect an integrated assessment of known risks relevant to pregnancy, lactation, and infertility based on available information/data Draft Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products  Content and Format http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan ces/ucm425398.pdf Pregnancy and Lactation Labeling Final Rule http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeli ng/ucm093307.htm 15 15 General Table of Contents in FPI BOXED WARNING 11 DESCRIPTION 1 INDICATIONS AND USAGE                    12 CLINICAL PHARMACOLOGY 2 DOSAGE AND ADMINISTRATION                12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS                12.2 Pharmacodynamics 4 CONTRAINDICATIONS                        12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS                  13 NONCLINICAL TOXICOLOGY 6 ADVERSE REACTIONS                        13.1 Carcinogenesis, Mutagenesis, 7 DRUG INTERACTIONS                        Impairment of Fertility 8 USE IN SPECIFIC POPULATIONS              13.2 Animal Toxicology and/or Pharmacology 8.1 Pregnancy                              14 CLINICAL STUDIES 8.2 Lactation                              15 REFERENCES 8.3 Females and Males of Reproductive      16 HOW SUPPLIED/STORAGE AND Potential                                  HANDLING 8.4 Pediatric Use                          17 PATIENT COUNSELING INFORMATION 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 16 16 8
 
PostMarket Activity Supplemental applications INDs Drug Advertising Manufacturer Inspections Active Surveillance Safety Reports 17 17 Examples of Radiological Drugs Regulated at CDER Positron Emission Tomography Generators Scintigraphic Agents Magnetic Resonance Imaging Media Ultrasound Contrast Media Ionic Iodinated Contrast Media NonIonic Iodinated Contrast Media Noniodinated Contrast Media 18 18 9
 
Conclusion The discovery and development of new drugs can be long and complicated From conception to the marketing of a drug, FDA encourages sponsors/applicants to meet early in development Radiopharmaceutical and PET drugs are regulated by both NDA and labeling regulations (21 CFR 314, 21 CFR 201.56 and 201.57) 19 19 20 10
 
Backup Slides 21 21 New Drug Development Process Links
* https://www.fda.gov/patients/learnabout druganddeviceapprovals/drugdevelopment process 22 22 11
 
Labeling for Radiopharmaceuticals and PET Products Imaging instructions are placed in the Dosage and Administration sections IMAGING INSTRUCTIONS Image Acquisition Guidelines Timing and Duration Location (head, body)
Patient Instructions (voiding)
Device Parameters (e.g. 2D or 3D PET, software reconstruction)
Image Display Orientation Coloring Display Image Interpretation Positive vs. Negative 23 23 12
 
DOSIMETRY METHODOLOGY UPDATE FOR REGULATORY GUIDE 8.39, PHASE 2 SEPTEMBER 21, 2020 1
OVERVIEW Phase 2 revisions to Regulatory Guide (RG) 8.39 are intended to update the dosimetry methodology Proposed direction will provide a versatile, realistically-conservative threshold for dosimetry The ease of basic thresholds and, if necessary, the ability to create patient-specific thresholds Thresholds are based on maximum bystander equivalent dose of 5 mSv and 1 mSv Breastfeeding infants are protected to the same level and the method is simplified Emerging technologies are easily supported with the new methodology RCD RADIATION PROTECTION ASSOCIATES                                                      2 2
1
 
BASIC THRESHOLD PHILOSOPHY 10 CFR 35.75: release is authorized if bystander TEDE < 5 mSv written instructions required if bystander TEDE > 1 mSv Instruction                      Release Threshold                      Threshold Dose to Bystander                                                                    ALARA No Regulatory Action                                                      Hold Patient Instructions 1 mSv to                        5 mSv to Bystander                      Bystander Release Authorized                                      No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                                                    3 3
NO RELEASE Start                                                    Calculate patient hold time Determine interruption time                              Is A0 < 5 mSv        NO                                  Calculate 5 mSv patient basic threshold?                                              specific threshold YES YES                Determine Is breastfeeding                                                      FO, FG, and FB interruption                                                  NO                        YES          Is A0 < 5 mSv      NO Is A0 < 1 mSv NO                warranted?                                                                                          patient specific basic threshold?
threshold?
YES                                      YES Is A0 > 1 mSv          YES              Is the patient                                            Calculate 1 mSv patient infant                                                                                          specific threshold breastfeeding?
threshold?
NO                                        NO YES            Is A0 < 1 mSv Provide patient                                                                                                                      patient specific instructions                                                                                                                          threshold?
Provide patient                      NO Preserve record                        instructions if required RCD RADIATION PROTECTION ASSOCIATES                                                                                                                    4 4
2
 
Patient-Specific      Breastfeeding Dose-Rate                    Basic Activity Activity              Activity            Examples Constant                      Threshold Threshold              Threshold Basic                                Breastfeeding Measurement                                Interruption Threshold                                    Time THE DOSE-RATE CONSTANT RCD RADIATION PROTECTION ASSOCIATES                                                                              5 5
THE CURRENT METHOD (SIMPLISTIC AND CONSERVATIVE WITH ONLY MINOR PATIENT-SPECIFIC INPUTS)
The estimated external time-integrated                effective dose equivalent is:
k  conversion constant exposure rate constant 1.44                    A0  administered activity Tr  radiological half-life E  occupancy factor r  point/point distance In RG 8.39 Rev 0, gamma exposure constants come from several different sources without a consistent method of calculation. Additionally, point geometry is mandated, occupancy is overly simplistic, and pharmacokinetics can be applied if biological studies are available (but theres quite a bit of question here).
RCD RADIATION PROTECTION ASSOCIATES                                                                              6 6
3
 
STANDARDIZED DOSE-RATE CONSTANT, pr The purpose of standardizing the gamma constant is:
to provide a consistent method of calculation, specifically for patient release; to develop a tissue dose constant (point kernel) as opposed to an exposure constant; to use the ICRP 107 nuclear decay database with an energy threshold of 10 keV; to include primary photons, as well as bremsstrahlung from conversion & Auger electrons and beta emission; to surround the source in a 2 cm tissue sphere (attenuation/buildup); and to encapsulate implants in 50 m of titanium.
RCD RADIATION PROTECTION ASSOCIATES                                                                          7 7
COMPARISON OF DOSE-RATE CONSTANTS all values in units of [mSv m2 GBq-1 h-1]
pr          Smith &            Peplow Nuclide  Rev 0        (ICRP 107)        Stabin 2012            2020 67Ga  0.0203          0.0234            0.0217            0.0225 90Y      -        0.000798                -          0.000000362 99mTc  0.0204          0.0196            0.0215            0.0184 111In 0.0867          0.0736            0.0934            0.0615 123I 0.0435          0.0394            0.0481            0.0285 125I 0.0383          0.0301            0.0473            0.0125 131I 0.0594          0.0582            0.0594            0.0548 177Lu      -          0.00548            0.00489            0.00518 192Ir*  0.124a          0.122b            0.124c            0.117c
                                              *Encapsulation: a200 m steel; b50 m titanium; cnone RCD RADIATION PROTECTION ASSOCIATES                                                                          8 8
4
 
Patient-Specific            Breastfeeding Dose-Rate                    Basic Activity Activity                    Activity              Examples Constant                      Threshold Threshold                  Threshold Basic                                          Breastfeeding Measurement                                        Interruption Threshold                                              Time THE BASIC ACTIVITY & MEASUREMENT THRESHOLDS RCD RADIATION PROTECTION ASSOCIATES                                                                                          9 9
CALCULATION OF THE BASIC ACTIVITY THRESHOLD, Q0 integrated dose limitation
* r  distance between patient and bystander pr  dose-rate constant point kernel
* 1.44
* Tr  physical radiological half-life Therefore, the basic activity threshold for release at 1 meter (point-to-point) for 99mTc is:
5
* 1 5                                              29 0.0196
* 1.44
* 6.02 1    5.8 RCD RADIATION PROTECTION ASSOCIATES                                                                                        10 10 5
 
CALCULATION OF THE BASIC MEASUREMENT THRESHOLD, M0 Q0    basic activity threshold
* pr    dose-rate constant point kernel r    distance from source to instrumentation Therefore, the basic measurement threshold for release at 1 meter (point-to-point) for 99mTc is:
29
* 0.0196 5                                                  0.58 1
RCD RADIATION PROTECTION ASSOCIATES                                                                                        11 11 Assume a given radionuclide has the basic instruction and release thresholds as shown and suppose 1 GBq of that nuclide has been administered. The activity is less than the basic thresholds for release and for instruction.
(1)                            (5) 1 GBq            1.5 GBq                          7.5 GBq Activity Threshold                Activity Threshold for Instruction                    for Release Dose to Bystander                                                        ALARA No Regulatory Action                                                    Hold Patient Instructions 1 mSv to                          5 mSv to Bystander                        Bystander Release Authorized                                    No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                        12 12 6
 
Now suppose 10 GBq of that same nuclide has been administered to a different patient. This time the administered activity exceeds the basic threshold for instruction and for release.
(1)                            (5) 1.5 GBq                          7.5 GBq      10 GBq Activity Threshold                Activity Threshold for Instruction                    for Release Dose to Bystander                                                              ALARA No Regulatory Action                                                    Hold Patient Instructions 1 mSv to                          5 mSv to Bystander                        Bystander Release Authorized                                    No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                                    13 13 Patient-Specific            Breastfeeding Dose-Rate                        Basic Activity Activity                      Activity                Examples Constant                          Threshold Threshold                    Threshold Basic                                                Breastfeeding Measurement                                                  Interruption Threshold                                                      Time THE PATIENT-SPECIFIC ACTIVITY THRESHOLD PATIENT-SPECIFIC MODIFYING FACTORS APPLIED TO THE BASIC THRESHOLD RCD RADIATION PROTECTION ASSOCIATES                                                                                                    14 14 7
 
NO RELEASE Start                                              Calculate patient hold time Determine interruption time                  Is A0 < 5 mSv    NO                                Calculate 5 mSv patient basic threshold?                                          specific threshold YES YES                Determine Is breastfeeding                                          FO, FG, and FB interruption                                  NO                            YES      Is A0 < 5 mSv        NO Is A0 < 1 mSv NO                warranted?                                                                          patient specific basic threshold?
threshold?
YES                          YES Is A0 > 1 mSv      YES      Is the patient                                      Calculate 1 mSv patient infant                                                                          specific threshold breastfeeding?
threshold?
NO                            NO YES      Is A0 < 1 mSv Provide patient                                                                                                    patient specific instructions                                                                                                          threshold?
Provide patient                  NO Preserve record                        instructions if required RCD RADIATION PROTECTION ASSOCIATES                                                                                                    15 15 THE PATIENT-SPECIFIC ACTIVITY THRESHOLD, QM Q0 basic activity threshold FO occupancy factor FG
                                                    *
* geometry factor FB biokinetic factor To provide realism, the licensee justifies that the patient-specific occupancy factor is 0.80, the geometry factor is 0.94, and the biokinetic factor is 0.84. Therefore, with a basic release threshold of 7.5 GBq, the patient-specific threshold for release, QM(5), is:
7.5 5                          12 0.80
* 0.94
* 0.84 RCD RADIATION PROTECTION ASSOCIATES                                                                                                    16 16 8
 
Using the patient-specific thresholds, and still considering the 10 GBq administered activity, the patient can be released with instruction.
(1)                          (5) 2.4 GBq            10 GBq      12 GBq Activity Threshold              Activity Threshold for Instruction                  for Release Dose to Bystander                                                            ALARA No Regulatory Action                                                    Hold Patient Instructions 1 mSv to                        5 mSv to Bystander                      Bystander Release Authorized                                    No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                                      17 17 THE OCCUPANCY FACTOR, FO The licensee draws from a comprehensive patient survey to determine occupancy factor, FO.
Sample questions Do you have children?                                                            Yes                                            No Are you breastfeeding?                                                          Yes                                            No Youll return home using which form of transportation?                          Plane        Bus        Train      Subway  Private Will family members travel with you?                                            Yes                                            No How many others live in your home?                                                4          3            2          1        0 Do you normally sleep with someone in the same bed?                              Yes                                            No What is the total time (hours) of your return trip?                              >10          8            6          4      <2 Will your return trip require a hotel stay?                                      Yes                                            No RCD RADIATION PROTECTION ASSOCIATES                                                                                                      18 18 9
 
DEVELOPMENT OF THE OCCUPANCY FACTOR Radiopharmaceutical Total Dose is Divided into Thirds The patient survey indicates that two individuals are candidates for the maximum bystander:
5 days (1) the patients driver (8-hour trip)
(2) the patients co-worker (half-time;                          13 days starting day 10)
RCD RADIATION PROTECTION ASSOCIATES                                                          19 19 5 days 13 days Driver                              8 Coworker                          20 x x = 0.02 x  x  +    x1x = 0.05 RCD RADIATION PROTECTION ASSOCIATES                                                          20 20 10
 
Fraction of time in the vicinity of X days Y days patient Cotravelers Caregivers Family members Cohabitants Roommates Coworkers RCD RADIATION PROTECTION ASSOCIATES                                        21 21 THE GEOMETRY FACTOR, FG The geometry factor accounts for more realistic (less conservative) photon flux originating in the patient and impacting the bystander.
The assumption of a point source with a point receptor is no longer required.
FG is a function of both source/receptor geometry and distance between the two.
RCD RADIATION PROTECTION ASSOCIATES                                        22 22 11
 
THE BIOKINETIC FACTOR, FB A unitless surrogate for the residence time of a radionuclide in the body Retention functions are specific to the chemical form of an administered agent and, therefore, FB is different for each pharmaceutical (and likely, each person)
We define FB as the ratio of integrated activity considering effective loss to that considering only radiological loss:
RCD RADIATION PROTECTION ASSOCIATES                                                                        23 23 CALCULATION OF THE BIOKINETIC FACTOR Single-exponential retention function:              Double-exponential retention function:
RCD RADIATION PROTECTION ASSOCIATES                                                                        24 24 12
 
COMPARISON OF FB USING DIFFERENT MODELS demonstrating the variability in FB for Na131I retention.
[h]      *E 1
                                                          *E 2        f1        Te1 [h]      f2      Te2 [h]  FB Single exponential                    -        -        -          -          -        1.0      100    0.52 Hyperthyroidism                  -        -        -        0.20        7.68      0.80      125    0.53
                                        -        -        -        0.20        7.68      0.80      106    0.45
                                        -        -        -        0.165        6.73      0.835      191    0.84 1        0.25    0.75      0.20        7.68      0.80      125    0.40 8        0.75    0.25      0.20        7.68      0.80      125    0.15 Thyroid cancer                  -        -        -        0.95        7.68      0.05      175    0.084 1        0.25    0.75      0.95        7.68      0.05      175    0.063 8        0.75    0.25      0.95        7.68      0.05      175    0.037 RCD RADIATION PROTECTION ASSOCIATES                                                                                  25 25 Patient-Specific        Breastfeeding Dose-Rate                        Basic Activity Activity                Activity          Examples Constant                          Threshold Threshold                Threshold Basic                                    Breastfeeding Measurement                                    Interruption Threshold                                        Time THE BREASTFEEDING ACTIVITY THRESHOLD RCD RADIATION PROTECTION ASSOCIATES                                                                                  26 26 13
 
NO RELEASE Start                                                  Calculate patient hold time Determine interruption time                            Is A0 < 5 mSv      NO                                  Calculate 5 mSv patient basic threshold?                                              specific threshold YES YES                    Determine Is breastfeeding                                                        FO, FG, and FB interruption                                              NO                              YES      Is A0 < 5 mSv        NO Is A0 < 1 mSv NO                warranted?                                                                                        patient specific basic threshold?
threshold?
YES                                    YES Is A0 > 1 mSv        YES              Is the patient                                          Calculate 1 mSv patient infant                                                                                        specific threshold breastfeeding?
threshold?
NO                                      NO YES      Is A0 < 1 mSv Provide patient                                                                                                                  patient specific instructions                                                                                                                        threshold?
Provide patient                  NO Preserve record                            instructions if required RCD RADIATION PROTECTION ASSOCIATES                                                                                                                  27 27 PROPOSED METHOD AND ASSUMPTIONS Infant dose from external exposure (to body and to breast) and internal exposure from breastmilk consumption two geometry factors (FG) with associated distance (r) for the external exposures Pharmaceutical retention, R(t), describes activity over time in the mothers body and the derived concentration in breastmilk Biokinetic factor:
Occupancy factor for breastfeeding: FO = 0.17 e.g., 30-minute duration every 3 hours Maximum breastmilk concentration assumed at tmax hours after administration unless there is interruption, the time of first feeding is assumed at tmax (currently 3 hours)
Breastmilk consumption rate: 40 mL/hr Infant absorption fraction: f1 = 1 Infant dose coefficients taken from ICRP 128, RADAR, literature, etc.
RCD RADIATION PROTECTION ASSOCIATES                                                                                                                  28 28 14
 
COMPARISON OF BREASTFEEDING INTERRUPTION TIMES RG                NUREG        ICRP    ICRP      Stabin &    Sloan 8.39    ACMUI      1556          106    128        Breitz  Kettering Radiopharmaceutical            Rev 0    2019        Rev 3      2007    2015        2000      2017 67Ga    citrate        28 d      31 d      1 mo        > 3 wk  > 3 wk      cessation  21 d 99mTc    DTPA aerosol        none      24 h      none        none      -        none      24 h 99mTc    RBC in vivo      24 h      24 h        6h          12 h    12 h        12 h      24 h 111In  WBC            6d      5.7 d      7d          none    none        none      7d 123I  NaI            3d      2.7 d      none        > 3 wk  > 3 wk      cessation    7d 123I  MIBG          24 h      none      24 h        > 3 wk  > 3 wk        48 h      7d 131I  NaI        cessation    32 d    cessation    > 3 wk  > 3 wk      cessation cessation RCD RADIATION PROTECTION ASSOCIATES                                                                                29 29 Patient-Specific        Breastfeeding Dose-Rate                    Basic Activity Activity                Activity            Examples Constant                      Threshold Threshold              Threshold Basic                                      Breastfeeding Measurement                                    Interruption Threshold                                        Time EXAMPLES DEMONSTRATING THE METHODOLOGY RCD RADIATION PROTECTION ASSOCIATES                                                                                30 30 15
 
Y-90 MICROSPHERES 56 yo female administered 1.3 GBq 90Y resin microspheres For the treatment of hepatocellular carcinoma 1.3 GBq            14 GBq                        68 GBq Basic Threshold                Basic Threshold for Instruction                for Release Dose to Bystander                                                            ALARA No Regulatory Action                                              Hold Patient Instructions 1 mSv to                      5 mSv to Bystander                    Bystander Release Authorized                              No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                  31 31 I-131 FOR THYROID CANCER 40 yo male administered 7.4 GBq 131I as NaI For the treatment of thyroid remnants and metastases 0.062 GBq                      0.31 GBq            7.4 GBq Basic Threshold                Basic Threshold for Instruction                for Release Dose to Bystander                                                            ALARA No Regulatory Action                                              Hold Patient Instructions 1 mSv to                      5 mSv to Bystander                    Bystander Release Authorized                              No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                  32 32 16
 
0.31 5                    13 I-131 FOR THYROID CANCER                                                                                  0.40 0.72 0.084 40 yo male administered 7.4 GBq 131I as NaI                                                                    0.062 1                    2.6 For the treatment of thyroid remnants and metastases                                                    0.40 0.72 0.084 2.6 GBq        7.4 GBq          13 GBq Patient Threshold              Patient Threshold for Instruction                  for Release Dose to Bystander                                                            ALARA No Regulatory Action                                                Hold Patient Instructions 1 mSv to                      5 mSv to Bystander                      Bystander Release Authorized                                No Release RCD RADIATION PROTECTION ASSOCIATES                                                                                          33 33 QUESTIONS?
RCD RADIATION PROTECTION ASSOCIATES                                                                                          34 34 17
 
Updates from the Medical Radiation Safety Team September 22, 2020 Lisa Dimmick, Team Leader, Medical Radiation Safety Medical Safety and Events Assessment Branch Division of Materials Safety, Security, State, and Tribal Programs Office of Nuclear Material Safety and Safeguards 1
COVID19
* NRC Preparation for Temporary Regulatory Relief Requests
    - Developed guide and a template to quickly process anticipated exemption requests.
* Public meetings
    - April 22, 2020 meeting to gather stakeholder input (meeting summary available at ML20122A253)
    - April 30, 2020 ACMUI COVID19 Subcommittee meeting (subcommittee report available at ML20125A148)
    - May 13, 2020 SNMMI Town Hall
* May 5, 2020 Letter to NRC Medical Licensees
    - Enclosure contains a table of 10 CFR Parts 19, 20, 30, and 35 requirements for which the NRC may consider expedited requests for temporary exemption.
    - ML20126G385 and https://www.nrc.gov/materials/miau/medusetoolkit.html 2
2 1
 
COVID19
* Updated the table for expedited exemptions during COVID19, August 2020 (ML20233B145)
      - Continually reviewing information received from medical professional societies and medical licensees regarding the impact of the COVID19 emergency.
* Virtual training/training modification requests
      -  CBNC
      -  ASNC, SNMMI, ACR, ASTRO
      -  Elekta
      -  NorthStar 3
3 Authorized User Training and Experience
* SECY200005, Rulemaking Plan for Training and Experience Requirements for Unsealed Byproduct Material, January 13, 2020 (ML19217A318)
* Recommended rulemaking: (1) remove prescriptive training and experience (T&E) requirements, (2) NRC and Agreement States no longer review and approve T&E, (3) authorized users must be credentialed by a recognized medical specialty board, and (4) maintain highlevel board recognition criteria.
* Recent letters to the Commission from urologists supporting the recommended rulemaking.
* SECY200005 is still being reviewed by the Commission.
4 4
2
 
Patient Release
* SECY180015, Staff Evaluation of the U.S. Nuclear Regulatory Commission's Program Regulating Patient Release After Radioisotope Therapy, January 29, 2018 (ML17279B139)
* Brochure - What You Should Know About Treatments With Radioactive Drugs, May 2019 (ML19121A242)
* Phase 1 update of Regulatory Guide 8.39 Rev 1, Release of Patients Administered Radioactive Material, April 2020 (ML19232A081) 5 5
Patient Release
* Notice of Docketing for the Peter Crane petition was published in the Federal Register on April 13, 2020 and subsequently withdrawn by the petitioner on July 10, 2020
* Whats next?
    - Patient Release videotarget release: November 2020
    - Phase 2 update Regulatory Guide 8.39target release:
spring 2022 6
6 3
 
New Process for Reviewing Emerging Medical Technologies
* The Medical Team is transforming its process for reviewing emerging medical technologies (EMTs). The benefits of this new process are that it:
        - Streamlines the review process and license guidance development
        - Provides a cost savings in both time and staff resources;
        - Remains inclusive of NRC regional, Agreement State, and ACMUI contribution to license guidance development; and
        - Ensures consistency and a more uniform approach to license guidance development.
7 7
New Process for Reviewing Emerging Medical Technologies Medical Team            Standing individual with        Committee,                  Concur and issue Resolve support develops            ACMUI,                        licensing comments licensing        Agreement States,                  guidance guidance          Regions review Total time  8 months (6 months savings) 8 8
4
 
Rulemaking Plan:
Emerging Medical Technologies
* Rulemaking plan will provide options to codify licensing requirements for EMTs and address calibration and dose measurement issues for Rb82 generators.
      - Rulemaking options range from only addressing Rb82 generators, codifying requirements for only certain EMTs, or codifying more performancebased licensing requirements for EMTs across most of 10 CFR Part 35
* Rulemaking plan will go to the Commission in December 2020.
* ACMUI will receive a courtesy copy of the draft rulemaking plan in October 2020.
9 9
Extravasation
* House and Senate FY20 appropriation bills required a report on updates to injection quality monitoring, classification, and reporting requirements regarding extravasations.
      - Congressional report submitted on March 17, 2020 (ML20050W302) 10 10 5
 
Extravasation
* Petition for rulemaking PRM3522, Reporting Nuclear Medicine Injection Extravasations as Medical Events, was submitted to the NRC on May 18, 2020
      - Find more information on the petition on the Federal rulemaking website, https://www.regulations.gov, by searching Docket ID NRC20200141
      - Public comment period on the petition will run from September through November 2020 11 11 Extravasation
* Medical Team staff is coordinating their evaluation of whether extravasations should be reported as medical events with the petition review working group.
* Medical Team will hold a public meeting for medical community input on extravasations and medical event reporting. (Tentatively scheduled for December 8, 2020)
* Medical Team will seek ACMUI review of their preliminary recommendations in early March 2021.
* A decision on whether to accept the petition for rulemaking will be made by June 2021.
12 12 6
 
Veterinary Release
* Medical Team is evaluating a request to release dogs following treatment of osteoarthritis using a Sn117m colloid.
* Veterinary release is subject to 10 CFR Part 20 limits for members of the general public, which are:
      - 100 mrem per year
      - 2 mrem in any one hour
* The proposed release procedure contains a pre screening questionnaire to determine the need to modify or stop any typical interactions (e.g., co sleeping) for a duration of time after release.
* Staff is still reviewing this request.
13 13 Upcoming Meetings
* FDANRC Workshop Enhancing Development of Emerging Technologies: Radiopharmaceuticals and Radiological Devices, October 14, 2020, 8am5pm. https://www.fda.gov/drugs/news eventshumandrugs/fdanrcworkshopenhancingdevelopment emergingtechnologiesradiopharmaceuticalsandradiological
* AAHP and Medical Health Physics Section Special Session Therapy Patient Release Issues, October 15, 2020, 25 pm.
* International Conference on Radiation Safety: Improving Radiation Protection in Practice. IAEA, November 920, 2020.
https://www.iaea.org/newscenter/news/comingupfullyvirtual iaearadiationsafetyconference
* Commission Meeting with the Advisory Committee on the Medical Uses of Isotopes (ACMUI), November 18, 2020, 10am - 12pm
* Extravasation public meeting, December 8, 2020. Meeting details to be provided at a later date.
14 14 7
 
Acronyms
* AAHPAmerican Academy of Health Physics
* ACMUIAdvisory Committee on Medical Uses of Isotopes
* ACRAmerican College of Radiology
* ASNCAmerican Society of Nuclear Cardiology
* ASTROAmerican Society for Radiation Oncology
* CBNCCertification Board of Nuclear Cardiology
* EMTEmerging Medical Technology
* FDAU.S. Food and Drug Administration
* FYFiscal Year
* IAEAInternational Atomic Energy Agency 15 15 Acronyms
* Mrem  millirem
* Rb82rubidium82
* Sn117mtin117m
* SNMMISociety of Nuclear Medicine and Molecular Imaging
* T&E - training and experience 16 16 8
 
OPEN FORUM (No Handout)
 
March 2021 Sunday              Monday              Tuesday              Wednesday                  Thursday                  Friday              Saturday 28                    1                    2                        3                      4                          5                  6 7                  8                    9                      10                      11                        12                13 NRC RIC                NRC RIC                  NRC RIC          APhA Annual Meeting    APhA Annual Meeting 14                  15                  16                        17                      18                        19                20 APhA Annual Meeting APhA Annual Meeting 21                  22                  23                        24                      25                        26                27 28                  29                  30                        31                      1                          2                  3 PESASH              PESACH 4                  5  Notes NRC's Regulatory Information Conference - March 9-11 American Pharmacists Association (APhA) Annual Mtg. - March 12-15 Passover (Pesach) begins March 28 - April 4 (work permitted March 30-April 2 with restrictions)
 
April 2021 Sunday          Monday              Tuesday                Wednesday                Thursday                    Friday        Saturday 28              29                  30                      31                        1                      2                3 PESACH 4                5                    6                        7                        8                      9              10 EASTER PESACH 11              12                  13                      14                      15                      16              17 AAPM Clinical 18              19                  20                      21                      22                      23              24 AAPM Clinical      AAPM Clinical AAPM Clinical                                                    CIRMS                  CIRMS                    CIRMS NCRP                NCRP 25              26                  27                      28                      29                      30                1 2                3 Notes American Association of Physicists in Medicine (AAPM) Spring Clinical Meeting - April 17-20 National Council on Radiation Protection & Measurements (NCRP) Annual Meeting - April 19-20 Council on Ionizing Radiation Measurements & Standards (CIRMS) Annual Meeting - April 21-23}}

Latest revision as of 00:33, 25 September 2020

Advisory Committee on the Medical Uses of Isotopes (ACMUI) September 21-22, 2020 Meeting Ebinder
ML20258A209
Person / Time
Issue date: 09/14/2020
From:
Office of Nuclear Material Safety and Safeguards
To:
Jamerson K
References
Download: ML20258A209 (69)
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MEETING AGENDA ADVISORY COMMITTEE ON THE MEDICAL USES OF ISOTOPES September 21-22, 2020 WEBEX 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, September 21, 2020 OPEN SESSION

1. Opening Remarks C. Einberg, NRC Mr. Einberg will formally open the meeting and provide opening remarks.
2. Old Business K. Jamerson, NRC Ms. Jamerson will review past ACMUI actions and recommendations 10:00 - 11:30 and provide NRC responses.
3. Open Forum ACMUI The ACMUI will identify medical topics of interest for further discussion.
4. Medical Events Subcommittee Report R. Ennis, ACMUI Dr. Ennis will provide an analysis of FY19 medical events.

11:30 - 12:15 BREAK/LUNCH

5. Non-Medical Events M. Sheetz, ACMUI Mr. Sheetz will provide an analysis of FY19 non-medical events reported by medical use facilities and commercial pharmacies.
6. New Drug Development and Labeling F. Lutterodt, FDA 12:15 - 2:00 Mr. Lutterodt will discuss the U.S. Food and Drug Administrations regulatory process for new drug development and labeling.
7. Dosimetry Methodology Update for Regulatory Guide 8.39, D. Hamby, Phase 2 Revision RCD Radiation Dr. Hamby will discuss the dosimetry methodology update for the Protection Assoc.

Regulatory Guide 8.39, Phase 2 revision.

2:00 ADJOURN FOR THE DAY Tuesday, September 22, 2020 CLOSED SESSION

8. INFOSEC Training R. Norman, NRC 10:00 - 12:00 9. Ethics Training C. Safford, NRC
10. Allegations Training S. Hawkins, NRC 1

12:00 - 12:15 BREAK Tuesday, September 22, 2020 OPEN SESSION

11. Medical Team Updates L. Dimmick, NRC Ms. Dimmick will provide an update on Medical Radiation Safety Team activities.

12:15 - 1:45 12. Open Forum ACMUI The ACMUI will discuss medical topics of interest previously identified.

13. Administrative Closing K. Jamerson, NRC Ms. Jamerson will provide a meeting summary and propose dates for the spring 2021 meeting.

1:45 ADJOURN 2

2019 ACMUI RECOMMENDATIONS AND ACTION ITEMS Target Completion ITEM DATE STATUS Date for NRC Action The ACMUI endorsed the Appropriateness of Medical Event ACMUI 17 Reporting Subcommittee report and the recommendations 9/10/2019 Open Spring 2021 Action provided therein.

The ACMUI endorsed the Evaluation of Extravasations Subcommittee Report, as amended, to note that under future ACMUI 18 revisions to Part 35 rulemakings, extravasations be captured as 9/10/2019 Open Spring 2021 Action a type of passive patient intervention in the definition of patient intervention.

The ACMUI endorsed the Institutional Memory Subcommittee Report, as amended, to include the recommendation that a ACMUI 20 complete list of ACMUI members be updated and added to the 9/11/2019 Open* 09/14/2020 Action webpage. The Subcommittee membership was amended to add Dr. Wolkov.

  • Action completed via the September 14, 2020 NRC Response Memorandum (ADAMS Accession No. ML20254A179) -

pending formal closure by the ACMUI at the fall 2020 meeting.

1

2020 ACMUI RECOMMENDATIONS AND ACTION ITEMS Target Completion ITEM DATE STATUS Date for NRC Action The ACMUI endorsed the Regulatory Guide (RG) 8.39, "Release of Patients Administered Radioactive Material" 1 3/11/2020 Accepted Open* 09/14/2020 Subcommittee report and the recommendations provided therein regarding the draft final RG 8.39, Revision 1, Phase 1.

Dr. Metter formed a subcommittee to review the impacts that COVID-19 could have or is having on the medical use community and determine if potential impacts could help the NRC prepare for any regulatory impacts. Subcommittee 2 membership includes: Dr. Vasken Dilsizian, Mr. Richard Green, 03/30/2020 Accepted Open* 09/14/2020 Dr. Hossein Jadvar (chair), Ms. Melissa Martin, Ms. Megan Shober, and Dr. Harvey Wolkov. Non-voting subcommittee consultants include: Mr. Gary Bloom and Mr. Zoubir Ouhib.

NRC staff resource: Ms. Lisa Dimmick Dr. Metter amended the membership of the Training and Experience Requirements Subcommittee. Subcommittee membership now includes: Dr. Ronald Ennis, Dr. Hossein 3 03/30/2020 Accepted Open* 09/14/2020 Jadvar, Dr. Darlene Metter, Dr. Robert Schleipman (chair), Mr.

Michael Sheetz, and Ms. Megan Shober. Mr. Gary Bloom will serve as a non-voting subcommittee consultant.

The ACMUI endorsed the Patient Intervention subcommittee 4 report, as presented, and the recommendations provided 03/30/2020 Accepted Open Spring 2021 therein.

1

2020 ACMUI RECOMMENDATIONS AND ACTION ITEMS The ACMUI endorsed the Bylaws Subcommittee report, as 5 03/30/2020 Accepted Open* 09/14/2020 presented, and the recommendations provided therein.

Dr. Metter formed a subcommittee to review the abnormal occurrence criteria, with the following in mind: (1) define patient harm in AO; (2) reassess current AO criteria; (3) define goals of AO criteria and reporting; and (4) are current AO criteria 6 sufficient in regards to public health? Subcommittee 03/30/2020 Accepted Open* 09/14/2020 membership includes: Mr. Gary Bloom, Dr. Ronald Ennis, Dr.

Hossein Jadvar, Mr. Zoubir Ouhib, Mr. Michael Sheetz, and Ms. Megan Shober. NRC staff resource: Dr. Katie Tapp.

(subcommittee on hold until further notice from staff)

The ACMUI endorsed the Interventional Radiologist 7 Subcommitee report, as presented, and its recommendations 03/30/2020 Accepted Open* 09/14/2020 provided therein.

The ACMUI tentatively scheduled its fall 2020meeting for 8 September 21-22, 2020. The alternate date is September14- 03/30/2020 Accepted Open* 09/14/2020 15, 2020.

The ACMUI endorsed the COVID-19 Subcommittee report, as 9 presented, and its recommendations provided therein. 4/30/20 Accepted Open* 09/14/2020 (4/30/20)

  • Action completed via the September 14, 2020 NRC Response Memorandum (ADAMS Accession No. ML20254A179) - pending formal closure by the ACMUI at the fall 2020 meeting.

2

OPEN FORUM (No Handout)

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

Advisory Committee on the Medical Uses of Isotopes September 21, 2020 1

1 Subcommittee Members

  • Ronald D. Ennis, M.D. (Chair)
  • Richard Green
  • Darlene Metter, M.D.
  • Michael OHara, Ph.D.
  • Michael Sheetz
  • Harvey Wolkov, M.D.

NRC Staff Resource: Donna-Beth Howe, Ph.D.

2 2

1

Process

  • As begun in 2018, every two years the Medical Events Subcommittee will report on our review of events over the last 4 years to discern common themes within each section of 10 CFR Part 35 and across the sections, to inform a discussion of possible ways to decrease medical events (MEs).
  • The Subcommittee reviewed the medical events for FYs 2016-2019.

3 3

Summary

  • Two overarching themes remained

- Performance of a time out 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 appears to be a contributing factor in a number of cases

  • One new issue identified

- Increase complexity of unsealed source administrations of newer agents may be leading to more equipment related MEs 4

4 2

35.200 Use of Unsealed Byproduct Material for Imaging and Localization Medical Events Summary 2016 2017 2018 2019 Total Cause Wrong drug 0 0 0 0 0 Wrong dosage 0 2 0 0 2 Wrong patient 0 1 0 0 1 Extravasation 0 1 0 0 1 Human error 0 0 0 1 (8 1 (8 patients) patients)

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

5 35.300 Use of Unsealed Byproduct Material, Written Directive Required Medical Events Summary 2016 2017 2018 2019 Total WD not done or 1 2 1 2 6 incorrectly Error in delivery 1 1 0 1 3

(# capsules)

Wrong dose 1 0 0 0 1 Equipment 0 0 1 4 5 Human Error 1 0 0 1 2 Wrong patient 1 1 0 1 3 Total 4 4 2 9 19 Time out could prevent 13/19 = 68%

Emerging increase in equipment issues 5/19 = 26% compared to 10% in last review 6

6 3

35.400 Manual Brachytherapy Medical Events Summary 2016 2017 2018 2019 Total Applicator issue (e.g. movement 1 0 0 0 1 during implant Wrong site implanted (e.g. penile 1 1 1 1 4 bulb)

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

Prostate Dose 18 5 11 3* 37 New device 0 0 1 0 1 Total 20 7 13 5 45

  • Still using dose-based criteria 7

35.400 Manual Brachytherapy Medical Events Summary 2016 2017 2018 2019 Total Total MEs 20 7 13 5 45 Time out may have 0 1 0 1 2 prevented ME Lack of experience may have 1 1 1 1 4 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 possibly plays a role in the true MEs of this type, but hard to assess to what degree in each case.
  • In approximately 13% (down from 25% in last review) of cases, a time-out or enhanced retraining prior to performance of an uncommon 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 Medical Events Summary 2016 2017 2018 2019 Total Cause Wrong position 1 2 3 4 10 Wrong reference 0 2 1 4 7 length Wrong plan 1 0 2 0 3 Wrong dose/source 0 0 1 0 1 strength Machine malfunction 3 2 3 1 9 Software failure 0 2 (9 pts) 0 1 3 Total 5 8 (14 pts) 10 10 33 10 10 5

35.600 Use of a sealed source in a remote afterloader unit, teletherapy unit, or gamma stereotactic unit Medical Events Summary 2016 2017 2018 2019 Location Breast 0 0 1 0 Gynecological 2 7 (14 pts) 7 8 Skin 1 0 1 0 Bronchus 0 0 0 0 Prostate 2 0 0 0 Brain 0 1 1 2 Total 5 8 (14 pts) 10 10 GYN tumors were 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 plans or dose)

  • 2016 1/5 events
  • 2017 0/8 events
  • 2018 3/10 events
  • 2019 3/10 events Total: 7/33 (21.2%) compared to 16% on last review 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 This is difficult to determine based on information in NMED. If assumption is made about wrong position as surrogate for infrequent user.

  • 2016 1/5 events
  • 2017 2/8 events
  • 2018 1/10 events
  • 2019 1/10 events Total: 5/33 (15.2%) compared to 32% on last review 13 13 35.1000 Radioactive Seed Localization Medical Events Summary 2016 2017 2018 2019 Total Medical Events 1 0 1 0 Cause:

Delayed seed removal 1 1 (patient intervention)

Lost seed 0 Wrong implant site 0 14 14 7

35.1000 Intravenous Cardiac Brachytherapy Medical Events Summary 2016 2017 2018 2019 Total Did not follow 0 0 0 1 1 proper procedure Tortuous 0 0 1 1* 2 vessel anatomy Catheter issue 0 0 1 0 1 Total 0 0 2 1 4

  • 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 2016 2017 2018 2019 Total Medical Events 3 0 1 0 Cause: 0 0 0 0 Back-up battery power source failure 0 0 1 0 Patient setup error 2 0 0 0 Patient movement 1 0 0 2 Wrong site (treatment plan) 0 0 0 0 16 16 8

35.1000 Y-90 Theraspheres Medical Events Summary 2016 2017 2018 2019 Total Total Medical Events 13 15 14 15 57 Cause:

> 20% residual activity remaining 9 7 11 9 36 in delivery device Delivery device setup error 1 2 2 1 6 Wrong dose (treatment plan 1 4 0 1 6 calculation error)

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

Wrong dose vial selected 1 4 5 17 17 35.1000 Y-90 SirSpheres Medical Events Summary 2016 2017 2018 2019 Total Total Medical Events 13 8 7 11 39 Cause:

> 20% residual activity remaining 9 7 2 8 26 in delivery device not due to stasis Wrong dose (treatment plan 2 0 2 0 4 calculation error)

Wrong site (catheter placement 2 1 2 2 7 error)

Wrong site (WD error) 0 0 1 1 2 18 9

Overview Y-90 Microsphere MEs FY2014 - 2017 N=91 FY2016 - 2019 N=96 Cause

> 20% residual not due to stasis Wrong dose 7% (treatment plan 6%

error) 12% Wrong site (catheter placement error) 10% 62, 65%

Device setup error Wrong dose vial/WD error 19 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 20 10

35.1000 Medical Events That May Have Been Prevented by Time Out Y-90 RSL Perfexion/Icon Microspheres 2016 0/1 2/3 3/26 2017 0 0 3/23 2018 0/1 0/1 4/21 2019 0 0/2 7/26 Total 0/2 2/6 (33%) 17/96 (18%)

21 35.1000 Medical Events That May Have Been Attributed to Lack of Experience or Infrequent User Y-90 RSL Perfexion/Icon Microspheres 2016 0/1 2/3 1/26 2017 0 0 2/23 2018 0/1 0/1 2/21 2019 0 0/2 1/26 Total 0/2 (0%) 2/6 (33%) 6/96 (6%)

22 11

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 23 23 Possible Elements of a Time Out contd.
  • 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) 24 24 12

Subcommittee Response to Findings

  • The subcommittee recommended that the NRC staff issue an Information Notice alerting Authorized Users to the themes identified herein.
  • IN-19-07, Methods to Prevent Medical Events, was published on August 26, 2019.

(ADAMS Accession No. ML19240A450) 25 25 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

U.S. Nuclear Regulatory Commission Advisory Committee on the Medical Uses of Isotopes Subcommittee on Medical Events Draft Report Submitted On: August 11, 2020 Subcommittee Members: Mr. Richard Green, Dr. Ronald D. Ennis (Chair), M.D., Dr. Darlene F.

Metter, Mr. Michael Sheetz, and Dr. Harvey Wolkov NRC Staff Resource: Dr. Donna-Beth Howe 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

At the Fall 2018 ACMUI meeting this subcommittee initiated a new approach to reporting on MEs such that every 2 years the subcommittee will review medical events (MEs) occurring in the previous 4 years with the goal of identifying common themes within each section of 10 CFR Part 35 and discuss possible ways to prevent these MEs. The report herein is the second such in-depth 4-year review of MEs.

Findings The Subcommittee on Medical Events reviewed the Medical Events from FY 2016-19. Events from each section were reviewed in detail by a subcommittee member with expertise in the area. In the subcommittees review two years ago, we noted that a significant proportion of MEs might be prevented by the universal implementation of a time out prior to the procedure/treatment. In addition, we noted that a considerable number of events seemed to occur in situations in which the authorized user and team were performing a procedure/treatment with which they do not have much recent experience.

In the current review, the subcommittee found that the number of MEs, the types and the proportion possibly preventable by a time out and the proportion related to lack of experience, were about the same.

One new emerging trend was noted. In the delivery of unsealed byproduct material for which a written directive is required (10 CFR 35.300), there was an increase in the number of MEs related to equipment (e.g., catheter) issues. This is thought to be attributable to the increasing use of agents with more complex delivery (e.g., Lu-177 dotatate). The subcommittee anticipates this

trend will continue and warrants close observation. However, no specific intervention by NRC staff is recommended at this time.

A new Y-90 microsphere delivery device has been introduced by Sirtex. We will be watching for trends in MEs related to this problematic area with the introduction of this new device.

Concluding Remarks The subcommittee looks forward to performing an in-depth trend analysis in 2022 and next year will perform a focused one-year review of FY2020.

The subcommittee welcomes any comments and/or suggestions.

Respectfully Submitted, The Medical Event Subcommittee Ronald Ennis, MD, Chair

NonMedical Byproduct Material Events: FY18 and FY19 Michael Sheetz Advisory Committee on the Medical Uses of Isotopes September 21, 2020 1

1 NonMedical Events Reported by Medical Licensees

  • NMED event reported by medical licensee
  • Includes events reported under:

- 10 CFR 35.3067 (leaking source)

- 10 CFR 20.2201 (lost or stolen material)

- 10 CFR 20.2202 (over exposures)

- 10 CFR 30.50 (contamination)

- 49 CFR 171.15 (transportation incidents) 2 2

1

NonMedical Event Categories Identified in FY18 and FY19 Category FY18 FY19 Lost, Abandoned, or Stolen Sources 9 18 Leaking Sealed Source 9 4 Transportation of Radioactive Material 5 3 Radiation Overexposure 5 3 Radioactive Contamination 3 3 Equipment Malfunction 1 4 Total 32 35 3

3 Total NMED Events (All Categories)

FY18 and FY19 67 805 NonMedical Events from Medical Licensees All Other Events 4

4 2

Lost, Abandoned, or Stolen Sources FY18 and FY19

  • Lost I125 RSL seed - 9
  • Lost RAM shipment - 6
  • Missing I125/Pd103 brachy seeds - 3
  • Temporary loss and recovery of RAM - 3
  • Abandoned calibration sources - 2
  • Lost Cs137 dose calibrator source - 1
  • Patient removal of I125 brachy seeds - 1
  • Ir192 source delivery to wrong location - 1
  • Incomplete shipment of Lu177 - 1 5

5 Leaking Sealed Source FY18 and FY19

  • Ir192 HDR source - 4
  • Cs137 dose calibrator vial - 3
  • I125 RSL seed - 2
  • Co57 dose calibrator vial - 1
  • Co57 calibration rod - 1
  • Ge68 phantom - 1 6

6 3

Transportation of Radioactive Material FY18 and FY19

  • Contaminated package - 4
  • Vehicle accident - 2
  • Damaged package - 1
  • High exposure rate - 1 7

7 Radiation Overexposure FY18 and FY19

  • PET radiopharmaceutical production - 3

- (50 mSv DDE, 690 mSv SDE, 600 mSv SDE)

  • Nuclear medicine procedures - 2

- (130 mSv DDE, 580 mSv SDE)

  • Cyclotron repair - 1

- (720 mSv SDE)

  • C11 and F18 animal research - 1

- (130 mSv DDE)

  • Interventional radiology using Y90 microspheres - 1

- (530 mSv SDE) 8 8

4

Radioactive Contamination FY18 and FY19

  • Contamination of hospital room from patient receiving previous I131 therapy - 2
  • Contamination of veterinary clinic from I131 treatment of cat - 2
  • Patient contamination from administration of F18 - 1
  • Contamination of hot lab following breakage of Tc99m vial - 1 9

9 Equipment Malfunction FY18 and FY19

  • Sr90 IVB device source retraction failure - 2
  • Defective HDR transfer guide tube - 1
  • HDR device premature termination of treatment - 1
  • Rb82 generator Sr82/85 breakthrough limits exceeded - 1 10 10 5

Other Events - Landfill Alarms

  • Detection of shortlived medical isotopes in municipal waste
  • No standard reporting requirement
  • Declining number of events FY14 FY15 FY16 FY17 FY18 FY19 113 114 71 18 17 6
  • Can result in significant response effort 11 11 Conclusions
  • Relatively small number of NonMedical events
  • Type of events occurring have minimal health and safety impact
  • Declining number of landfill alarm responses reduces burden on both regulators and licensees 12 12 6

Acronyms

  • C11 - carbon11
  • CFR - Code of Federal Regulations
  • Co57 - cobalt57
  • Cs137 - cesium137
  • F18 - flourine18
  • FY - Fiscal Year
  • Ge68 - germanium68
  • I125/I131 - iodine125/131
  • IR192 - iridium192
  • IR - Interventional Radiology
  • Lu177 - lutetium177
  • mSv - milliSievert
  • NMED - Nuclear Material Events Database
  • Pd103 - palladium103
  • PET - Positron Emission Tomography 14 14 7

Acronyms

  • RAM - Radioactive Material
  • Rb82 - rubidium82
  • RSL - Radioactive Seed Localization
  • SDE - Shallow Dose Equivalent
  • Sr82/85/90 - strontium82/85/90
  • Tc99m - technetium99 metastable
  • Y90 - yittruim90 15 15 8

New Drug Development and Labeling Frank Lutterodt, M.S., MSDRA Division of Imaging and Radiation Medicine Division of Regulatory OperationsSpecialty Medicine Office of Regulatory Operations Center for Drug Evaluation and Research 1

Outline Overview Drug Development Process Regulating the Use of Radioactive Drugs in Basic Research PreClinical Phase Clinical Phase New Drug Application Review and Labeling 2

2 1

Drug Development Process 3

3 Regulating Radioactive Drugs in Basic Research Radioactive Drug Research Committee (RDRC)

(21 CFR 361.1)

For basic science research Not for use for immediate therapeutic, diagnostic or similar purpose No intent to determine safety or effectiveness for clinical use https://www.fda.gov/drugs/scienceandresearchdrugs/radioactivedrug researchcommitteerdrcprogram 4

4 2

New Drug Development Process PreClinical Research Synthesis and purification

  • Target affinity
  • Selectivity etc.

Animal Testing

  • PK
  • Proof of concept
  • Toxicity

5 New Drug Development Process Clinical Phase Phase 1 Phase 1 approaches involve Investigational New Drug Application (IND) and may involve:

1. Exploratory IND
2. Traditional IND INDs are governed by 21 CFR 312.21 INDs are used to establish the safety or effectiveness of a drug to support the approval of a new use 6

6 3

New Drug Development Process Clinical Phase Phase 1 (Exploratory IND)

An exploratory IND study is a clinical trial that is conducted early in phase 1, involves very limited human exposure, and has no therapeutic or diagnostic intent.

The main purpose of this approach is to find promising drug candidates to enable the sponsor to proceed efficiently with the most promising drug.

https://www.fda.gov/media/72325/download 7

7 New Drug Development Process Clinical Phase Phase 1 (Traditional IND)

Traditional Phase 1 trials usually involve healthy volunteers to determine the drugs most frequent and serious adverse events, and often, how the drug is metabolized and excreted by the body Involve a small number of participants, generally in the range of 20 to 80 subjects https://clinicaltrials.gov/ct2/aboutstudies/glossary 21 CFR312.21 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.21 8

8 4

New Drug Development Process Clinical Phase Phase 2 Phase 2 clinical trial gathers more information about a drugs safety and effectiveness in the condition/disease being studied Larger group of subjects/participants are enrolled Subjects/participants receiving the drug may be compared with others receiving placebo Safety and shortterm adverse reactions continue to be evaluated 9

9 New Drug Development Process Clinical Phase Phase 3 During Phase 3, more information is gathered about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs Studies typically involve more participants and efficacy endpoints are assessed If safety and efficacy are adequately confirmed, clinical testing may end at this step and a New Drug Application (NDA) may be submitted 10 10 5

NDA Review Preclinical data (Pharmacology/Toxicology, Chemistry Manufacturing and Controls), and data from the clinical trials are reviewed to assist FDA in making a benefit/risk assessment A favorable benefit/risk assessment culminates in the review and approval of the drug labeling 11 11 New Drug Label and Labeling Label Labeling Any display of written, All labels, as well as other printed, or graphic matter written, printed, or graphic on the immediate container matter accompanying the of any article, or any such product.

matter affixed to any consumer commodity or affixed to or appearing upon a package containing any consumer commodity 21CFR1.3 (b) / FD&C Act section 201(k) 21CFR1.3 (a) /FD&C Act section 201(m) 12 12 6

Labeling Carton and Container Labels Prescribing Information (PI) Package Insert Patient Labeling Patient Instructions for Use, Patient Information, Medication Guide Operator Guide (User Manual) 13 13 Prescribing Information Physician Labeling Rule (PLR) Format was implemented in 2006 Contents of the Prescribing Information (PI)

Highlights Table of Contents Full Prescribing Information (FPI)

Pregnancy and Lactation Labeling Rule (PLLR) 21 CFR 201.56 and 201.57 Physicians Labeling Rule Requirements for Prescribing Information http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm084159.htm 14 14 7

PLLR

  • Label format change to reflect an integrated assessment of known risks relevant to pregnancy, lactation, and infertility based on available information/data Draft Guidance for Industry: Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products Content and Format http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan ces/ucm425398.pdf Pregnancy and Lactation Labeling Final Rule http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeli ng/ucm093307.htm 15 15 General Table of Contents in FPI BOXED WARNING 11 DESCRIPTION 1 INDICATIONS AND USAGE 12 CLINICAL PHARMACOLOGY 2 DOSAGE AND ADMINISTRATION 12.1 Mechanism of Action 3 DOSAGE FORMS AND STRENGTHS 12.2 Pharmacodynamics 4 CONTRAINDICATIONS 12.3 Pharmacokinetics 5 WARNINGS AND PRECAUTIONS 13 NONCLINICAL TOXICOLOGY 6 ADVERSE REACTIONS 13.1 Carcinogenesis, Mutagenesis, 7 DRUG INTERACTIONS Impairment of Fertility 8 USE IN SPECIFIC POPULATIONS 13.2 Animal Toxicology and/or Pharmacology 8.1 Pregnancy 14 CLINICAL STUDIES 8.2 Lactation 15 REFERENCES 8.3 Females and Males of Reproductive 16 HOW SUPPLIED/STORAGE AND Potential HANDLING 8.4 Pediatric Use 17 PATIENT COUNSELING INFORMATION 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 10 OVERDOSAGE 16 16 8

PostMarket Activity Supplemental applications INDs Drug Advertising Manufacturer Inspections Active Surveillance Safety Reports 17 17 Examples of Radiological Drugs Regulated at CDER Positron Emission Tomography Generators Scintigraphic Agents Magnetic Resonance Imaging Media Ultrasound Contrast Media Ionic Iodinated Contrast Media NonIonic Iodinated Contrast Media Noniodinated Contrast Media 18 18 9

Conclusion The discovery and development of new drugs can be long and complicated From conception to the marketing of a drug, FDA encourages sponsors/applicants to meet early in development Radiopharmaceutical and PET drugs are regulated by both NDA and labeling regulations (21 CFR 314, 21 CFR 201.56 and 201.57) 19 19 20 10

Backup Slides 21 21 New Drug Development Process Links

Labeling for Radiopharmaceuticals and PET Products Imaging instructions are placed in the Dosage and Administration sections IMAGING INSTRUCTIONS Image Acquisition Guidelines Timing and Duration Location (head, body)

Patient Instructions (voiding)

Device Parameters (e.g. 2D or 3D PET, software reconstruction)

Image Display Orientation Coloring Display Image Interpretation Positive vs. Negative 23 23 12

DOSIMETRY METHODOLOGY UPDATE FOR REGULATORY GUIDE 8.39, PHASE 2 SEPTEMBER 21, 2020 1

OVERVIEW Phase 2 revisions to Regulatory Guide (RG) 8.39 are intended to update the dosimetry methodology Proposed direction will provide a versatile, realistically-conservative threshold for dosimetry The ease of basic thresholds and, if necessary, the ability to create patient-specific thresholds Thresholds are based on maximum bystander equivalent dose of 5 mSv and 1 mSv Breastfeeding infants are protected to the same level and the method is simplified Emerging technologies are easily supported with the new methodology RCD RADIATION PROTECTION ASSOCIATES 2 2

1

BASIC THRESHOLD PHILOSOPHY 10 CFR 35.75: release is authorized if bystander TEDE < 5 mSv written instructions required if bystander TEDE > 1 mSv Instruction Release Threshold Threshold Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 3 3

NO RELEASE Start Calculate patient hold time Determine interruption time Is A0 < 5 mSv NO Calculate 5 mSv patient basic threshold? specific threshold YES YES Determine Is breastfeeding FO, FG, and FB interruption NO YES Is A0 < 5 mSv NO Is A0 < 1 mSv NO warranted? patient specific basic threshold?

threshold?

YES YES Is A0 > 1 mSv YES Is the patient Calculate 1 mSv patient infant specific threshold breastfeeding?

threshold?

NO NO YES Is A0 < 1 mSv Provide patient patient specific instructions threshold?

Provide patient NO Preserve record instructions if required RCD RADIATION PROTECTION ASSOCIATES 4 4

2

Patient-Specific Breastfeeding Dose-Rate Basic Activity Activity Activity Examples Constant Threshold Threshold Threshold Basic Breastfeeding Measurement Interruption Threshold Time THE DOSE-RATE CONSTANT RCD RADIATION PROTECTION ASSOCIATES 5 5

THE CURRENT METHOD (SIMPLISTIC AND CONSERVATIVE WITH ONLY MINOR PATIENT-SPECIFIC INPUTS)

The estimated external time-integrated effective dose equivalent is:

k conversion constant exposure rate constant 1.44 A0 administered activity Tr radiological half-life E occupancy factor r point/point distance In RG 8.39 Rev 0, gamma exposure constants come from several different sources without a consistent method of calculation. Additionally, point geometry is mandated, occupancy is overly simplistic, and pharmacokinetics can be applied if biological studies are available (but theres quite a bit of question here).

RCD RADIATION PROTECTION ASSOCIATES 6 6

3

STANDARDIZED DOSE-RATE CONSTANT, pr The purpose of standardizing the gamma constant is:

to provide a consistent method of calculation, specifically for patient release; to develop a tissue dose constant (point kernel) as opposed to an exposure constant; to use the ICRP 107 nuclear decay database with an energy threshold of 10 keV; to include primary photons, as well as bremsstrahlung from conversion & Auger electrons and beta emission; to surround the source in a 2 cm tissue sphere (attenuation/buildup); and to encapsulate implants in 50 m of titanium.

RCD RADIATION PROTECTION ASSOCIATES 7 7

COMPARISON OF DOSE-RATE CONSTANTS all values in units of [mSv m2 GBq-1 h-1]

pr Smith & Peplow Nuclide Rev 0 (ICRP 107) Stabin 2012 2020 67Ga 0.0203 0.0234 0.0217 0.0225 90Y - 0.000798 - 0.000000362 99mTc 0.0204 0.0196 0.0215 0.0184 111In 0.0867 0.0736 0.0934 0.0615 123I 0.0435 0.0394 0.0481 0.0285 125I 0.0383 0.0301 0.0473 0.0125 131I 0.0594 0.0582 0.0594 0.0548 177Lu - 0.00548 0.00489 0.00518 192Ir* 0.124a 0.122b 0.124c 0.117c

  • Encapsulation: a200 m steel; b50 m titanium; cnone RCD RADIATION PROTECTION ASSOCIATES 8 8

4

Patient-Specific Breastfeeding Dose-Rate Basic Activity Activity Activity Examples Constant Threshold Threshold Threshold Basic Breastfeeding Measurement Interruption Threshold Time THE BASIC ACTIVITY & MEASUREMENT THRESHOLDS RCD RADIATION PROTECTION ASSOCIATES 9 9

CALCULATION OF THE BASIC ACTIVITY THRESHOLD, Q0 integrated dose limitation

  • r distance between patient and bystander pr dose-rate constant point kernel
  • 1.44
  • Tr physical radiological half-life Therefore, the basic activity threshold for release at 1 meter (point-to-point) for 99mTc is:

5

  • 1 5 29 0.0196
  • 1.44
  • 6.02 1 5.8 RCD RADIATION PROTECTION ASSOCIATES 10 10 5

CALCULATION OF THE BASIC MEASUREMENT THRESHOLD, M0 Q0 basic activity threshold

  • pr dose-rate constant point kernel r distance from source to instrumentation Therefore, the basic measurement threshold for release at 1 meter (point-to-point) for 99mTc is:

29

  • 0.0196 5 0.58 1

RCD RADIATION PROTECTION ASSOCIATES 11 11 Assume a given radionuclide has the basic instruction and release thresholds as shown and suppose 1 GBq of that nuclide has been administered. The activity is less than the basic thresholds for release and for instruction.

(1) (5) 1 GBq 1.5 GBq 7.5 GBq Activity Threshold Activity Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 12 12 6

Now suppose 10 GBq of that same nuclide has been administered to a different patient. This time the administered activity exceeds the basic threshold for instruction and for release.

(1) (5) 1.5 GBq 7.5 GBq 10 GBq Activity Threshold Activity Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 13 13 Patient-Specific Breastfeeding Dose-Rate Basic Activity Activity Activity Examples Constant Threshold Threshold Threshold Basic Breastfeeding Measurement Interruption Threshold Time THE PATIENT-SPECIFIC ACTIVITY THRESHOLD PATIENT-SPECIFIC MODIFYING FACTORS APPLIED TO THE BASIC THRESHOLD RCD RADIATION PROTECTION ASSOCIATES 14 14 7

NO RELEASE Start Calculate patient hold time Determine interruption time Is A0 < 5 mSv NO Calculate 5 mSv patient basic threshold? specific threshold YES YES Determine Is breastfeeding FO, FG, and FB interruption NO YES Is A0 < 5 mSv NO Is A0 < 1 mSv NO warranted? patient specific basic threshold?

threshold?

YES YES Is A0 > 1 mSv YES Is the patient Calculate 1 mSv patient infant specific threshold breastfeeding?

threshold?

NO NO YES Is A0 < 1 mSv Provide patient patient specific instructions threshold?

Provide patient NO Preserve record instructions if required RCD RADIATION PROTECTION ASSOCIATES 15 15 THE PATIENT-SPECIFIC ACTIVITY THRESHOLD, QM Q0 basic activity threshold FO occupancy factor FG

  • geometry factor FB biokinetic factor To provide realism, the licensee justifies that the patient-specific occupancy factor is 0.80, the geometry factor is 0.94, and the biokinetic factor is 0.84. Therefore, with a basic release threshold of 7.5 GBq, the patient-specific threshold for release, QM(5), is:

7.5 5 12 0.80

  • 0.94
  • 0.84 RCD RADIATION PROTECTION ASSOCIATES 16 16 8

Using the patient-specific thresholds, and still considering the 10 GBq administered activity, the patient can be released with instruction.

(1) (5) 2.4 GBq 10 GBq 12 GBq Activity Threshold Activity Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 17 17 THE OCCUPANCY FACTOR, FO The licensee draws from a comprehensive patient survey to determine occupancy factor, FO.

Sample questions Do you have children? Yes No Are you breastfeeding? Yes No Youll return home using which form of transportation? Plane Bus Train Subway Private Will family members travel with you? Yes No How many others live in your home? 4 3 2 1 0 Do you normally sleep with someone in the same bed? Yes No What is the total time (hours) of your return trip? >10 8 6 4 <2 Will your return trip require a hotel stay? Yes No RCD RADIATION PROTECTION ASSOCIATES 18 18 9

DEVELOPMENT OF THE OCCUPANCY FACTOR Radiopharmaceutical Total Dose is Divided into Thirds The patient survey indicates that two individuals are candidates for the maximum bystander:

5 days (1) the patients driver (8-hour trip)

(2) the patients co-worker (half-time; 13 days starting day 10)

RCD RADIATION PROTECTION ASSOCIATES 19 19 5 days 13 days Driver 8 Coworker 20 x x = 0.02 x x + x1x = 0.05 RCD RADIATION PROTECTION ASSOCIATES 20 20 10

Fraction of time in the vicinity of X days Y days patient Cotravelers Caregivers Family members Cohabitants Roommates Coworkers RCD RADIATION PROTECTION ASSOCIATES 21 21 THE GEOMETRY FACTOR, FG The geometry factor accounts for more realistic (less conservative) photon flux originating in the patient and impacting the bystander.

The assumption of a point source with a point receptor is no longer required.

FG is a function of both source/receptor geometry and distance between the two.

RCD RADIATION PROTECTION ASSOCIATES 22 22 11

THE BIOKINETIC FACTOR, FB A unitless surrogate for the residence time of a radionuclide in the body Retention functions are specific to the chemical form of an administered agent and, therefore, FB is different for each pharmaceutical (and likely, each person)

We define FB as the ratio of integrated activity considering effective loss to that considering only radiological loss:

RCD RADIATION PROTECTION ASSOCIATES 23 23 CALCULATION OF THE BIOKINETIC FACTOR Single-exponential retention function: Double-exponential retention function:

RCD RADIATION PROTECTION ASSOCIATES 24 24 12

COMPARISON OF FB USING DIFFERENT MODELS demonstrating the variability in FB for Na131I retention.

[h] *E 1

  • E 2 f1 Te1 [h] f2 Te2 [h] FB Single exponential - - - - - 1.0 100 0.52 Hyperthyroidism - - - 0.20 7.68 0.80 125 0.53

- - - 0.20 7.68 0.80 106 0.45

- - - 0.165 6.73 0.835 191 0.84 1 0.25 0.75 0.20 7.68 0.80 125 0.40 8 0.75 0.25 0.20 7.68 0.80 125 0.15 Thyroid cancer - - - 0.95 7.68 0.05 175 0.084 1 0.25 0.75 0.95 7.68 0.05 175 0.063 8 0.75 0.25 0.95 7.68 0.05 175 0.037 RCD RADIATION PROTECTION ASSOCIATES 25 25 Patient-Specific Breastfeeding Dose-Rate Basic Activity Activity Activity Examples Constant Threshold Threshold Threshold Basic Breastfeeding Measurement Interruption Threshold Time THE BREASTFEEDING ACTIVITY THRESHOLD RCD RADIATION PROTECTION ASSOCIATES 26 26 13

NO RELEASE Start Calculate patient hold time Determine interruption time Is A0 < 5 mSv NO Calculate 5 mSv patient basic threshold? specific threshold YES YES Determine Is breastfeeding FO, FG, and FB interruption NO YES Is A0 < 5 mSv NO Is A0 < 1 mSv NO warranted? patient specific basic threshold?

threshold?

YES YES Is A0 > 1 mSv YES Is the patient Calculate 1 mSv patient infant specific threshold breastfeeding?

threshold?

NO NO YES Is A0 < 1 mSv Provide patient patient specific instructions threshold?

Provide patient NO Preserve record instructions if required RCD RADIATION PROTECTION ASSOCIATES 27 27 PROPOSED METHOD AND ASSUMPTIONS Infant dose from external exposure (to body and to breast) and internal exposure from breastmilk consumption two geometry factors (FG) with associated distance (r) for the external exposures Pharmaceutical retention, R(t), describes activity over time in the mothers body and the derived concentration in breastmilk Biokinetic factor:

Occupancy factor for breastfeeding: FO = 0.17 e.g., 30-minute duration every 3 hours3.472222e-5 days <br />8.333333e-4 hours <br />4.960317e-6 weeks <br />1.1415e-6 months <br /> Maximum breastmilk concentration assumed at tmax hours after administration unless there is interruption, the time of first feeding is assumed at tmax (currently 3 hours3.472222e-5 days <br />8.333333e-4 hours <br />4.960317e-6 weeks <br />1.1415e-6 months <br />)

Breastmilk consumption rate: 40 mL/hr Infant absorption fraction: f1 = 1 Infant dose coefficients taken from ICRP 128, RADAR, literature, etc.

RCD RADIATION PROTECTION ASSOCIATES 28 28 14

COMPARISON OF BREASTFEEDING INTERRUPTION TIMES RG NUREG ICRP ICRP Stabin & Sloan 8.39 ACMUI 1556 106 128 Breitz Kettering Radiopharmaceutical Rev 0 2019 Rev 3 2007 2015 2000 2017 67Ga citrate 28 d 31 d 1 mo > 3 wk > 3 wk cessation 21 d 99mTc DTPA aerosol none 24 h none none - none 24 h 99mTc RBC in vivo 24 h 24 h 6h 12 h 12 h 12 h 24 h 111In WBC 6d 5.7 d 7d none none none 7d 123I NaI 3d 2.7 d none > 3 wk > 3 wk cessation 7d 123I MIBG 24 h none 24 h > 3 wk > 3 wk 48 h 7d 131I NaI cessation 32 d cessation > 3 wk > 3 wk cessation cessation RCD RADIATION PROTECTION ASSOCIATES 29 29 Patient-Specific Breastfeeding Dose-Rate Basic Activity Activity Activity Examples Constant Threshold Threshold Threshold Basic Breastfeeding Measurement Interruption Threshold Time EXAMPLES DEMONSTRATING THE METHODOLOGY RCD RADIATION PROTECTION ASSOCIATES 30 30 15

Y-90 MICROSPHERES 56 yo female administered 1.3 GBq 90Y resin microspheres For the treatment of hepatocellular carcinoma 1.3 GBq 14 GBq 68 GBq Basic Threshold Basic Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 31 31 I-131 FOR THYROID CANCER 40 yo male administered 7.4 GBq 131I as NaI For the treatment of thyroid remnants and metastases 0.062 GBq 0.31 GBq 7.4 GBq Basic Threshold Basic Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 32 32 16

0.31 5 13 I-131 FOR THYROID CANCER 0.40 0.72 0.084 40 yo male administered 7.4 GBq 131I as NaI 0.062 1 2.6 For the treatment of thyroid remnants and metastases 0.40 0.72 0.084 2.6 GBq 7.4 GBq 13 GBq Patient Threshold Patient Threshold for Instruction for Release Dose to Bystander ALARA No Regulatory Action Hold Patient Instructions 1 mSv to 5 mSv to Bystander Bystander Release Authorized No Release RCD RADIATION PROTECTION ASSOCIATES 33 33 QUESTIONS?

RCD RADIATION PROTECTION ASSOCIATES 34 34 17

Updates from the Medical Radiation Safety Team September 22, 2020 Lisa Dimmick, Team Leader, Medical Radiation Safety Medical Safety and Events Assessment Branch Division of Materials Safety, Security, State, and Tribal Programs Office of Nuclear Material Safety and Safeguards 1

COVID19

  • NRC Preparation for Temporary Regulatory Relief Requests

- Developed guide and a template to quickly process anticipated exemption requests.

  • Public meetings

- April 22, 2020 meeting to gather stakeholder input (meeting summary available at ML20122A253)

- April 30, 2020 ACMUI COVID19 Subcommittee meeting (subcommittee report available at ML20125A148)

- May 13, 2020 SNMMI Town Hall

  • May 5, 2020 Letter to NRC Medical Licensees

- Enclosure contains a table of 10 CFR Parts 19, 20, 30, and 35 requirements for which the NRC may consider expedited requests for temporary exemption.

- ML20126G385 and https://www.nrc.gov/materials/miau/medusetoolkit.html 2

2 1

COVID19

- Continually reviewing information received from medical professional societies and medical licensees regarding the impact of the COVID19 emergency.

  • Virtual training/training modification requests

- CBNC

- ASNC, SNMMI, ACR, ASTRO

- Elekta

- NorthStar 3

3 Authorized User Training and Experience

  • SECY200005, Rulemaking Plan for Training and Experience Requirements for Unsealed Byproduct Material, January 13, 2020 (ML19217A318)
  • Recommended rulemaking: (1) remove prescriptive training and experience (T&E) requirements, (2) NRC and Agreement States no longer review and approve T&E, (3) authorized users must be credentialed by a recognized medical specialty board, and (4) maintain highlevel board recognition criteria.
  • Recent letters to the Commission from urologists supporting the recommended rulemaking.
  • SECY200005 is still being reviewed by the Commission.

4 4

2

Patient Release

  • SECY180015, Staff Evaluation of the U.S. Nuclear Regulatory Commission's Program Regulating Patient Release After Radioisotope Therapy, January 29, 2018 (ML17279B139)
  • Brochure - What You Should Know About Treatments With Radioactive Drugs, May 2019 (ML19121A242)

Patient Release

  • Notice of Docketing for the Peter Crane petition was published in the Federal Register on April 13, 2020 and subsequently withdrawn by the petitioner on July 10, 2020
  • Whats next?

- Patient Release videotarget release: November 2020

- Phase 2 update Regulatory Guide 8.39target release:

spring 2022 6

6 3

New Process for Reviewing Emerging Medical Technologies

  • The Medical Team is transforming its process for reviewing emerging medical technologies (EMTs). The benefits of this new process are that it:

- Streamlines the review process and license guidance development

- Provides a cost savings in both time and staff resources;

- Remains inclusive of NRC regional, Agreement State, and ACMUI contribution to license guidance development; and

- Ensures consistency and a more uniform approach to license guidance development.

7 7

New Process for Reviewing Emerging Medical Technologies Medical Team Standing individual with Committee, Concur and issue Resolve support develops ACMUI, licensing comments licensing Agreement States, guidance guidance Regions review Total time 8 months (6 months savings) 8 8

4

Rulemaking Plan:

Emerging Medical Technologies

  • Rulemaking plan will provide options to codify licensing requirements for EMTs and address calibration and dose measurement issues for Rb82 generators.

- Rulemaking options range from only addressing Rb82 generators, codifying requirements for only certain EMTs, or codifying more performancebased licensing requirements for EMTs across most of 10 CFR Part 35

  • Rulemaking plan will go to the Commission in December 2020.
  • ACMUI will receive a courtesy copy of the draft rulemaking plan in October 2020.

9 9

Extravasation

  • House and Senate FY20 appropriation bills required a report on updates to injection quality monitoring, classification, and reporting requirements regarding extravasations.

- Congressional report submitted on March 17, 2020 (ML20050W302) 10 10 5

Extravasation

  • Petition for rulemaking PRM3522, Reporting Nuclear Medicine Injection Extravasations as Medical Events, was submitted to the NRC on May 18, 2020

- Find more information on the petition on the Federal rulemaking website, https://www.regulations.gov, by searching Docket ID NRC20200141

- Public comment period on the petition will run from September through November 2020 11 11 Extravasation

  • Medical Team staff is coordinating their evaluation of whether extravasations should be reported as medical events with the petition review working group.
  • Medical Team will hold a public meeting for medical community input on extravasations and medical event reporting. (Tentatively scheduled for December 8, 2020)
  • Medical Team will seek ACMUI review of their preliminary recommendations in early March 2021.
  • A decision on whether to accept the petition for rulemaking will be made by June 2021.

12 12 6

Veterinary Release

  • Medical Team is evaluating a request to release dogs following treatment of osteoarthritis using a Sn117m colloid.
  • Veterinary release is subject to 10 CFR Part 20 limits for members of the general public, which are:

- 100 mrem per year

- 2 mrem in any one hour

  • The proposed release procedure contains a pre screening questionnaire to determine the need to modify or stop any typical interactions (e.g., co sleeping) for a duration of time after release.
  • Staff is still reviewing this request.

13 13 Upcoming Meetings

  • FDANRC Workshop Enhancing Development of Emerging Technologies: Radiopharmaceuticals and Radiological Devices, October 14, 2020, 8am5pm. https://www.fda.gov/drugs/news eventshumandrugs/fdanrcworkshopenhancingdevelopment emergingtechnologiesradiopharmaceuticalsandradiological
  • AAHP and Medical Health Physics Section Special Session Therapy Patient Release Issues, October 15, 2020, 25 pm.
  • International Conference on Radiation Safety: Improving Radiation Protection in Practice. IAEA, November 920, 2020.

https://www.iaea.org/newscenter/news/comingupfullyvirtual iaearadiationsafetyconference

  • Extravasation public meeting, December 8, 2020. Meeting details to be provided at a later date.

14 14 7

Acronyms

  • AAHPAmerican Academy of Health Physics
  • ACMUIAdvisory Committee on Medical Uses of Isotopes
  • ACRAmerican College of Radiology
  • ASNCAmerican Society of Nuclear Cardiology
  • ASTROAmerican Society for Radiation Oncology
  • CBNCCertification Board of Nuclear Cardiology
  • EMTEmerging Medical Technology
  • FDAU.S. Food and Drug Administration
  • FYFiscal Year
  • IAEAInternational Atomic Energy Agency 15 15 Acronyms
  • Mrem millirem
  • Rb82rubidium82
  • Sn117mtin117m
  • SNMMISociety of Nuclear Medicine and Molecular Imaging
  • T&E - training and experience 16 16 8

OPEN FORUM (No Handout)

March 2021 Sunday Monday Tuesday Wednesday Thursday Friday Saturday 28 1 2 3 4 5 6 7 8 9 10 11 12 13 NRC RIC NRC RIC NRC RIC APhA Annual Meeting APhA Annual Meeting 14 15 16 17 18 19 20 APhA Annual Meeting APhA Annual Meeting 21 22 23 24 25 26 27 28 29 30 31 1 2 3 PESASH PESACH 4 5 Notes NRC's Regulatory Information Conference - March 9-11 American Pharmacists Association (APhA) Annual Mtg. - March 12-15 Passover (Pesach) begins March 28 - April 4 (work permitted March 30-April 2 with restrictions)

April 2021 Sunday Monday Tuesday Wednesday Thursday Friday Saturday 28 29 30 31 1 2 3 PESACH 4 5 6 7 8 9 10 EASTER PESACH 11 12 13 14 15 16 17 AAPM Clinical 18 19 20 21 22 23 24 AAPM Clinical AAPM Clinical AAPM Clinical CIRMS CIRMS CIRMS NCRP NCRP 25 26 27 28 29 30 1 2 3 Notes American Association of Physicists in Medicine (AAPM) Spring Clinical Meeting - April 17-20 National Council on Radiation Protection & Measurements (NCRP) Annual Meeting - April 19-20 Council on Ionizing Radiation Measurements & Standards (CIRMS) Annual Meeting - April 21-23

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