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Official Transcript of Proceedings NUCLEAR REGULATORY COMMISSION Title: Advisory Committee on the Medical Uses of

Isotopes Docket Number: N/A Location: Public Teleconference Date: June 16, 2015 Work Order No.: NRC-1664 Pages 1-123 NEAL R. GROSS AND CO., INC. Court Reporters and Transcribers 1323 Rhode Island Avenue, N.W. Washington, D.C. 20005 (202) 234-4433

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NEAL R. GROSS COURT REPORTERS AND TRANSCRIBERS 1323 RHODE ISLAND AVE., N.W. (202) 234-4433 WASHINGTON, D.C. 20005-3701 (202) 234-4433

UNITED STATES OF AMERICA

NUCLEAR REGULATORY COMMISSION

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ADVISORY COMMITTEE ON THE MEDICAL USES OF ISOTOPES

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PUBLIC TELECONFERENCE

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TUESDAY,

JUNE 16, 2015

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The meeting was convened at 2:00 p.m.

Eastern Daylight Time, Bruce R. Thomadsen, Ph.D., ACMUI

Chairman, presiding.

MEMBERS PRESENT:

BRUCE R. THOMADSEN, Ph.D., Chairman

PHILIP O. ALDERSON, M.D., Vice Chairman

FRANCIS M. COSTELLO, Agreement State

Representative

VASKEN DILSIZIAN, M.D., Nuclear Cardiologist

RONALD D. ENNIS, M.D., Radiation Oncologist

SUSAN M. LANGHORST, Ph.D., Radiation Safety

Officer

STEVEN R. MATTMULLER, Nuclear Pharmacist

MICHAEL O’HARA, Ph.D., FDA Representative

CHRISTOPHER J. PALESTRO, M.D., Nuclear Medicine

2


Physician

LAURA M. WEIL, Patients’ Rights Advocate

PAT B. ZANZONICO, Ph.D., Nuclear Medicine

Physicist

NRC STAFF PRESENT:

JOSEPHINE M. PICCONE, Ph.D., Director, Division

of Material Safety, State, Tribal and Rulemaking

Programs

PAMELA J. HENDERSON, Deputy Director, Division of

Material Safety, State, Tribal and Rulemaking

Programs

DOUGLAS BOLLOCK, Designated Federal Officer

SOPHIE HOLIDAY, Alternate Designated Federal

Officer, ACMUI Coordinator

MARYANN O. ABOGUNDE, NMSS/MSTR/MSEB

NEELAM BHALLA, NMSS/MSTR/RPMB

MARCIA CARPENTIER, OGC/GCHEA/AGCNRP

JACKIE COOK, RIV/DNMS/NMSB-B

GINA R. DAVIS, NMSS/DSFM/RMB

MICHAEL L. FULLER, NMSS/MSTR/MSEB

SANDRA GABRIEL, Ph.D., NMSS/MSTR/MSEB

ROBERT GALLAGHAR, RI/DNMS/MB

ESTHER HOUSEMAN, OGC/GCLR/RMR

DONNA-BETH HOWE, Ph.D., NMSS/MSTR/MSEB

PENNY LANZISERA, RI/DNMS/MB

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NRC STAFF PRESENT CONT’D

JOHARI MOORE, COMM/OCM

JAN NGUYEN, RI/DNMS/MB

DIANE RENDER, Ph.D., NMSS/MSTR/MSEB

GRETCHEN J. RIVERA-CAPELLA, NMSS/MSTR/MSEB

MICHELLE SMETHERS, NMSS/MSTR/SMPB

TARA WEIDNER, RI/DNMS/MB

ALSO PRESENT LEE ALLEN – Spectrum Pharmaceuticals, Inc.

ILHAM ALMAHAMID – New York State Department of

Health

KATHLEEN BRILL – Foley Hoag LLP

BRIAN CAREY – Foley Hoag LLP

CHARLES COLEMAN – Virginia Department of Health

JENNIFER CULTERA – Florida Cancer Specialists &

Research Institute

ROBERT DANSEREAU – New York State Department of

Health

AL DEJESUS – Spectrum Pharmaceuticals, Inc.

HUGH EVANS – Eckert & Ziegler Radiopharma, Inc.

NEBEYOU FEKADU – Cedar-Sinai Medical Center

ASFOU FENTA – Virginia Department of Health

KAREN FLANIGAN – New Jersey Department of

Environmental Protection

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ALSO PRESENT CONT’D

PHILIP GRIFFIN – Utah Division of Radiation

Control

MICHAEL GUASTELLA – Council on Radionuclides and

Radiopharmaceuticals (CORAR)

GEORGIA HEARN – American Society of Nuclear

Cardiology (ASNC)

AMANDA JOHNSEN – The Pennsylvania State

University

YUNGMI KIM – Spectrum Pharmaceuticals, Inc.

CAITLIN KUBLER – Society of Nuclear Medicine and

Molecular Imaging (SNMMI)

KAREN LANGLEY – University of Utah

ANGELIQUE LEE-ROWLEY – Spectrum Pharmaceuticals,

Inc.

ROBIN ROLAND LEVY – Lymphoma Research Foundation

RALPH LIETO – St. Joseph Mercy Health System

GARY LUNGER – Bayer

RICHARD MARTIN – American Association of

Physicists in Medicine (AAPM)

GENE MENENDEZ – Spectrum Pharmaceuticals, Inc.

MICHAEL PETERS – American College of Radiology

(ACR)

ANDREA RAVARD – Cedar Sinai Medical Center

CLARINE NARDI RIDDLE – Kasowitz

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ALSO PRESENT CONT’D

JOSEPH RODGERS – Theragenics Corporation

JAMES SCHUH – Council on Radionuclides and

Radiopharmaceuticals (CORAR)

KAREN SHEEHAN – Fox Chase Cancer Center

MICHAEL SHEETZ – University of Pittsburgh

CINDY TOMLINSON – American Society for Radiation

Oncology (ASTRO)

JEFFREY VACIRCA – Community Oncology Alliance

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T-A-B-L-E O-F C-O-N-T-E-N-T-S

Page

Opening Remarks 7

Training and Experience for Alpha and 14

Beta Emitters

Radioactive Seed Localization Subcommittee 53

Report

Comments Submitted by Members of the Public: 113

Community Oncology Alliance 113

The Council on Radionuclides and 115

Radiopharmaceuticals, Inc.

Spectrum Pharmaceuticals, Inc. 117

Michael Sheetz and Jeffrey Brunette 120

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P R O C E E D I N G S 1

2:07 p.m. 2

MR. BOLLOCK: As the designated federal 3

officer for this meeting, I am pleased to welcome you 4

to this public meeting of the Advisory Committee today. 5

My name is Doug Bullock. I'm the Branch Chief of the 6

Medical Safety and Advanced Assessment Branch and I have 7

been designated as the federal officer for this Advisory 8

Committee in the course of 10 CFR Part 7.11. Present 9

today is the alternate designated federal officer, on 10

the phone, is Sophie Holiday, our ACMUI Coordinator. 11

This is an announced meeting of the 12

Committee and it's being held in the accordance of the 13

rules and regulations of the Federal Advisory Committee 14

Act and the Nuclear Regulatory Commission. This 15

meeting is being transcribed under the NRC and it may 16

also be transcribed or recorded by others. The meeting 17

was announced in the April 7, 2015 Edition of the Federal 18

Register, Volume 80, Page 18655. 19

The function of the Committee is to advise 20

the staff on issues and questions that arise in the 21

medical use of byproduct material. The Committee 22

provides counsel to staff, but does not determine or 23

direct the actual decisions of the staff or the 24

Commission. The NRC solicits the views of the Committee 25

8


and values their opinion. 1

I request that whenever possible, we try 2

to reach a consensus on the procedural issue that we'll 3

discuss today. There may be minority or dissenting 4

opinions. If you have such opinions, please allow them 5

to be read into the record. 6

At this point, would like to perform a roll 7

call of ACMUI members participating today. Starting 8

with Dr. Bruce Thomadsen, our therapy medical physicist 9

and Chairman. 10

CHAIRMAN THOMADSEN: Here. 11

MR. BOLLOCK: Okay. Next, Dr. Philip 12

Alderson, our health care administrator and 13

Vice-Chairman. Okay. Moving on. Mr. Frank Costello, 14

our agreement state representative. Okay. Moving on. 15

Dr. Vasken Dilsizian, our nuclear cardiologist. 16

MEMBER DILSIZIAN: Present. 17

MR. BOLLOCK: Okay. Thank you, Dr. 18

Dilsizian. Dr. Ronald Ennis, our radiation oncologist. 19

MEMBER ENNIS: Here. 20

MR. BOLLOCK: Thank you, Dr. Ennis. Dr. Sue 21

Langhorst, radiation safety officer. 22

MEMBER LANGHORST: Present. 23

MR. BOLLOCK: Mr. Steve Mattmuller, our 24

nuclear pharmacist. 25

9


MEMBER MATTMULLER: I'm here. 1

MR. BOLLOCK: Thank you. Dr. Michael 2

O'Hara, our FDA representative. Moving on. Dr. 3

Christopher Palestro, our nuclear medicine physician. 4

MEMBER PALESTRO: Present. 5

MR. BOLLOCK: Thank you, Dr. Palestro. Dr. 6

John Suh, radiation oncologist. 7

MS. HOLIDAY: He will not be joining us. 8

MR. BOLLOCK: Okay. And Ms. Laura Weil, our 9

patient's rights advocate. 10

MEMBER WEIL: I'm here. 11

MR. BOLLOCK: Thank you. And Dr. Pat 12

Zanzonico, our nuclear medicine physicist. Okay. 13

Well, we do have a quorum with at least seven members. 14

I now ask the NRC staff members who are present to 15

identify themselves. I'll start with the individuals 16

in the room here and we can go around the room. 17

MR. FULLER: This is Mike Fuller, medical 18

radiation safety team leader. 19

DR. HOWE: Donna-Beth Howe, medical team. 20

MS. DAVIS: Gina Davis, NMSS. 21

MS. HENDERSON: Pam Henderson, Deputy 22

Division Director, MSTR, NMSS. 23

MS. ABOGUNDE: Maryann Abogunde, medical 24

radiation team. 25

10


MR. BOLLOCK: Okay. Thank you. Now I'll 1

also go to the NRC Headquarters employees on the phone. 2

MS. RIVERA-CAPELLA: Gretchen 3

Rivera-Capella, medical team. 4

MR. BOLLOCK: Okay. I heard Gretchen. 5

Thank you. 6

MS. RIVERA-CAPELLA: You're welcome. 7

MS. HOLIDAY: I'm Sophie Holiday, ACMUI 8

Coordinator. 9

MR. BOLLOCK: Okay. Any other Headquarters 10

employees on the phone? All right. Thank you. And 11

next we'll go to our regional offices. Who do we have 12

on the call from Region I? I'm getting a little bit of 13

feedback, I couldn't hear anybody from Region I. Do we 14

have anyone from Region I? 15

MS. HOLIDAY: I'm sorry, I can hear a lot 16

of background discussion. If you could mute your phone, 17

please. Please mute your phone. 18

MR. BOLLOCK: Okay. We're still getting a 19

lot of background. Okay. All right. So no one from 20

Region I? Who do we have on the call from Region III? 21

All right. Hey, Sophie? 22

MS. HOLIDAY: Yes. 23

MR. BOLLOCK: Did you hear what Mike said? 24

MS. HOLIDAY: I did not. 25

11


MR. BOLLOCK: Just go ahead and mute 1

everybody. We'll get attendance at the end. 2

MS. HOLIDAY: Okay. 3

MR. BOLLOCK: We can't have it go on like 4

this. We've got to mute everyone but the ACMUI members 5

so we can continue on. 6

MS. HOLIDAY: Sure. 7

MR. BOLLOCK: Okay. All right. So we'll go 8

through the rest of the roll call. We do have a number 9

of members of the public who have emailed Sophie and 10

should be calling in. 11

We have a bridge line available, and that 12

phone number is 415-655-0059. The pass code to access 13

the bridge line is 944-664-243. 14

We are also using the GoToWebinar 15

application to view presentation handouts real time. 16

You can access this by going to www.gotomeeting.com and 17

searching for Meeting ID 126-126-243. You'll need to 18

register for the GoToMeeting to receive an audio PIN 19

to interact with any of the presenters. 20

The purpose of this meeting is to hear 21

presentations from representatives of Spectrum 22

Pharmaceuticals relating to the training experience for 23

authorized users of alpha and beta emitters, as well 24

as to discuss the Committee's comments on the existing 25

12


10 CFR 35.1000 licensing guide for iodine-125 1

palladium-103, low dose brachytherapy seeds used for 2

localization of non-palpable lesions. 3

Individuals who would like to ask a question 4

or make a comment regarding a specific issue the 5

Committee has discussed should request permission to 6

be recognized by the ACMUI Chairperson, Dr. Bruce 7

Thomadsen. Dr. Thomadsen at his option may entertain 8

comments or questions from the members of the public 9

who are participating with us today. 10

Comments and questions are usually 11

addressed by the Committee near the end of the meeting 12

after the Committee has fully discussed the topic. I'd 13

also like to add that handouts and agenda for this 14

meeting are available on the NRC's public website. 15

At this time, I would ask everyone on the 16

call who is not speaking to place their phones on mute. 17

If you do not have the capability to mute your phone, 18

please press Star 6 to utilize the conference line mute 19

and unmute function. I would ask everyone to exercise 20

extreme care to ensure that background noise is kept 21

at a minimum as any stray background noises can be very 22

disruptive on a conference call this large, as we've 23

already discovered. 24

At this point, I'd like to turn the meeting 25

13


over to Pamela Henderson, our Deputy Director Division 1

of Materials Safety State Travel and Rulemaking Programs 2

from the Office of Nuclear Material Safety and 3

Safeguards for some opening remarks. 4

MS. HENDERSON: Good afternoon, everyone. 5

I would like to welcome you to this meeting. Josephine 6

Piccone, who is our new Director will be joining us 7

sometime a little later. But could not be here for the 8

opening remarks. And with that, I would like to hand 9

it over to Dr. Thomadsen. Thank you. 10

CHAIRMAN THOMADSEN: Thank you very much. 11

And our first order of business is the request to address 12

the Committee by Spectrum Pharmaceuticals. Is a 13

representative there? 14

DR. CULTRERA: Yes, I'm here. Can you hear 15

me? 16

CHAIRMAN THOMADSEN: Barely. Can you speak 17

a little bit louder? 18

DR. CULTRERA: Yes. This is Dr. Jennifer 19

Cultrera. Is this a little bit better? 20

CHAIRMAN THOMADSEN: That's better, yes. 21

Thank you. And please proceed. 22

DR. CULTRERA: Okay. Thank you. I would 23

like to thank everybody on the conference call and with 24

ACMUI for hearing us today. And I'd like to present my 25

14


experiences. 1

My name is Jennifer Cultrera. I'm a 2

physician with Florida Cancer Specialists. And my 3

colleague's experience, Dr. Joe Mace, who was unable 4

to be here today due to a family emergency. Florida 5

Cancer Specialists is actually one of the largest 6

community oncology practices and we're centered here 7

in Florida with over 90 practices. 8

And I'd like to -- if you can maneuver the 9

slides a little bit to Slide Number 3 that would be great. 10

Thanks. And we'd like to talk to you today about 11

approving certain intravenous radiopharmaceuticals to 12

be administered by hematologists and medical 13

oncologists through an 80 hour course rather than the 14

700 hours of training which is currently necessary. 15

And this addresses the NRC rulemaking, 16

which states that its regulations discourage licenses 17

from using certain therapy options or otherwise 18

adversely impact clinical practice and if so, how. With 19

these slides today, I would hope that we're going to 20

educate you on the medical oncologist experience and 21

the patient care and how the restrictions placed on these 22

medications are now limiting the use of vitally 23

necessary cancer medications. And if you could proceed 24

to Slide 4? 25

15


So the clinical benefit of therapeutic 1

radiopharmaceuticals are that they produce a less 2

intensive treatment schedule, they're very 3

efficacious, as well as producing less constitutional 4

and somatic toxicity, such as chemotherapy, traditional 5

chemotherapy, and even some of the newer targeted agents 6

that are available both intravenous and PO. 7

And this is especially beneficial for 8

elderly cancer patients who have limited access. They 9

really don't have the capability of going to academic 10

centers that maybe 50 to 100 to even 150 miles away. 11

Slide 5 please. 12

So I'm going to use Zevalin as a 13

representative of this class of agents. And Zevalin is 14

used to treat follicular non-Hodgkins lymphoma 15

patients. And 80 percent of these patients are managed 16

by medical oncologists such as myself or hematologist 17

oncologists in the community. 18

Zevalin as a treatment is given 19

traditionally through authorized user, which are 20

traditionally radiation oncologists or nuclear 21

medicine physicians. And there has been a shortage of 22

AUs in the rural setting or settings that are outside 23

of academic institutions, which severally limit the use 24

of Zevalin and other radiopharmaceuticals for these 25

16


certain patient populations. 1

I'm going to present in subsequent slides 2

that beta emitter anti-cancer therapies have declined 3

since the imposition of the 700 hour training rule in 4

2002. And, actually, there is one RIT treatment at this 5

time which is unavailable due to lack of use, 6

specifically Bexxar. Next slide. 7

And this just points out that as a 8

hematologist oncologist, I'm responsible for basically 9

diagnosing my patients, treating them prior to getting 10

their radiopharmaceutical with traditional 11

chemotherapeutic agents or other targeted therapies. 12

We basically follow them on their cancer journey and 13

are side-by-side with them. 14

And it's very difficult sometimes to refer 15

them on to a secondary healthcare provider, which may 16

not be local to us and have the patients unable to really 17

have this continuity of care where we're able to order 18

the agent, administer the agent, and deal with the 19

follow-up and side effects. 20

And you can see here that outside of 21

actually administering the radiopharmaceutical, we are 22

responsible as the hematologist oncologist for the rest 23

of the patient's care. Next slide. 24

So, Dr. Mace is one of my colleagues. He's 25

17


also a practicing hematologist oncologist in Southern 1

Florida. And he's one of the few AUs that gained AU 2

status before the 700 training requirement was imposed. 3

I believe there's only five other AUs in his position 4

in the country. 5

He completed a radiation safety and 6

handling course that met this 80 hour requirement and 7

I would like to tell his quote here, "After my course 8

experience, I felt fully prepared to administer Zevalin, 9

with all of the attendant radiation safety and handling 10

issues." 11

He has administered Zevalin and Xofigo, the 12

other FDA approved radiopharmaceutical, for over ten 13

years with no safety incidents at our institution. And 14

I believe he has proven that these radiopharmaceuticals 15

can be given in the community oncology setting without 16

having the need to travel and providing the best patient 17

care close to home for them. Next slide. 18

This is a small diagram to show that the 19

radiation safety in alpha and beta emitters is 20

definitely feasible for use for a practicing medical 21

oncologist. As you can see here, gamma emission is 22

extremely dangerous. We're not asking to utilize that 23

type of radiation. We're asking for alpha emission, 24

which can be blocked by human skin, and beta emission, 25

18


which can be blocked by plastic. Next slide. 1

Alpha emitters, of which Xofigo is a 2

representative of, are listed here and some of the 3

properties of Xofigo. I am not going to belabor the 4

point to this very knowledgeable community. However, 5

these drugs are very safe and efficacious and limiting 6

their use will actually limit the development of drugs 7

and clinical trials. Next slide. 8

And beta emitters, of which we're going to 9

use Zevalin as a representative, you can notice here, 10

they have a very short half-life of 2.67 days and a short 11

pathlength of 5.3 millimeters. As well as a maximum 12

dose, which is given of Zevalin, of 30 millicuries. 13

The elimination of this agent in the body 14

is based on its parent molecule Rituxan, which also does 15

not remain in the body over 18 to 24 hours. So the actual 16

exposure that the patient is getting is very low. As 17

well as no exposure to their surroundings or their loved 18

ones. Next slide. 19

So there's a demonstrated safety record for 20

Zevalin. It's been approved since 2002. There's over 21

30 published studies with radiation safety with this 22

agent. And all of these studies have concluded that the 23

risks are minimal to negligible to both physician and 24

patient. 25

19


Over 10,000 administrations, only three 1

reports to the NRC for radiation safety issues. And all 2

of these three reports were during compounding. And I 3

want to stress that this drug is delivered as a 4

patient-ready dose, so there is no issues with exposure 5

for neither the patient nor the physician or their 6

families. 7

I would also like to stress that the FDA 8

removed a requirement for the indium-111 9

biodistribution scan based on its safety profile. And 10

despite these risks of Zevalin, now there's a 11

disproportionate burden for us to prescribe it because 12

of the restrictions that have been placed on the AUs. 13

Next slide please. 14

We're also concerned because of the impact 15

that may occur on new radiopharmaceuticals and, 16

unfortunately, if you're not exposed to an agent during 17

fellowship or a class of agents during fellowship and 18

training, it's very difficult to allow the new doctors 19

to begin to learn how to prescribe it and they won't 20

be using it. 21

And this is something that we're seeing with 22

radiopharmaceuticals at this time. The training and 23

experience requirements are discouraging current 24

clinicians from recommending Zevalin to patients. 25

20


There's a lack of exposure. I myself am seeing fellows 1

graduating right now and they have no idea what a 2

radiopharmaceutical is. 3

And as we have seen, the regulatory barriers 4

have contributed to the removal of one of these agents 5

from the market already. And there are several in 6

development which are threatened. Next slide. 7

So in my career, I actually was a lymphoma 8

specialist at Moffitt Cancer Center for several years. 9

And I was able to have access to radiopharmaceuticals 10

through our radiation oncology department. And I was 11

able to order these medications and have my radiation 12

oncologist prescribe them and have my patients benefit 13

greatly. 14

However, when I transitioned into the 15

community and moved about 100 miles away from my local 16

academic center, I find that I am unable to have access 17

to this agent to provide care for my patients. 18

Unfortunately, as a medical oncologist in a 80 hour work 19

week, I'm unable to undergo 700 hours of additional 20

training and experience to be able to become an AU so 21

that this could be provided to my community. Next 22

slide. 23

So I'd like to talk about the two pathways 24

which are available right now to become an AU. And the 25

21


first pathway is the certification pathway. And these 1

are available for physicians who are board certified 2

in radiology or nuclear medicine. And this would 3

traditionally be who we would contact in an academic 4

center to be able to provide the care for our patients. 5

I, myself, moving to a more rural community, 6

even though I have access to a radiation oncologist, 7

actually several of them in the area, I am unable to 8

provide Zevalin for my patients because none of them 9

have chosen to become authorized users. 10

They feel that there is a burden to becoming 11

an AU where they need several proctored cases, three 12

proctored cases, from a current AU, as well as they 13

sometimes don't want to deal with the side effects of 14

these agents. The side effects are more hematologic in 15

response and the medical oncologist is a lot better 16

equipped to handle them. 17

The second pathway, the alternative 18

pathway, requires an additional 700 hours of training 19

and experience. And, again, this would be completely 20

-- I would be completely unable to do this as a practicing 21

medical oncologist or hematologist as it would entail 22

basically a second fellowship for me and limit my time 23

to be able to care for patients. Next slide. 24

So this is a map of the area of the current 25

22


authorized users just in Florida alone. And if you 1

notice, they're all basically lumped up in these large 2

cities, Tampa, Miami, Orlando, and Jacksonville, and 3

anybody in between is basically in a gap area where 4

they're unable to have access to radiopharmaceuticals. 5

And just in my area alone where I'm an hour 6

north of Orlando, that represents an 80 -- or, I'm sorry, 7

an hour and a half from Orlando, an 80 mile to 100 mile 8

drive for my frail, elderly patients in the villages 9

that they're unable to take. So they are not able to 10

obtain the benefits of this class of agents. Next 11

slide. 12

And this graph demonstrates how Zevalin 13

came to market in 2002 and then when the 700 hour training 14

restrictions were initiated in 2006, there was a 15

dramatic decline in the amount of Zevalin that was 16

prescribed. And, again, demonstrating that we're 17

losing a vital component of personalized medicine. 18

Next slide. 19

I'd like to talk a little bit to the 20

recommendation that we're asking for the rule making. 21

Next slide. 22

And our need is that patient access is 23

severely limited and it's declining outside of the 24

academic medical centers. And in the places where the 25

23


patients need the care, where the patients are 1

debilitated because of their disease, they're frail, 2

they are not mobile, we are unable to provide the 3

medications that they need. These are drugs that are 4

very safe and very efficacious. 5

I have had over ten years of experience also 6

following these patients and am very comfortable dealing 7

with the hematologic toxicities and other toxicities 8

that these agents may incur. They're low-risk alpha and 9

beta emitters and the 80 hours of training and relevant 10

work experience is appropriate for hematologist 11

oncologists who are seeking only to administer the 12

low-risk beta and alpha emitting radiopharmaceuticals. 13

And there is precedent in that there is an 14

80 hour training that was required of clinicians prior 15

to 2005, which is available to clinicians to administer 16

the oral I-131. Next slide. 17

Zevalin, in particular, is produced as a 18

patient-ready dose. It has a very low level of 19

radiation. And some states do require dose 20

verification, but this can be covered in the 80 hour 21

training requirement. It's delivered intravenously 22

and only universal radiation precautions are necessary, 23

which we all are familiar with who are working in a 24

healthcare setting and in a hospital setting. 25

24


The administration side effects I'd like 1

to point out are not related to the radiation exposure. 2

They're actually related to the parent compound, which 3

is rituximab, which is a monoclonal antibody that we 4

use every day in oncology. Next slide. 5

And the precedent for using the 80 hour 6

training is that in 2005, hematologists and oncologists 7

could become AUs, as Joe Mace is an example. And he's 8

been doing this for over ten years and he's been helping 9

our patients out. But one man for over 90 practices is 10

very difficult. And unfortunately, we can't get him out 11

to everywhere he's needed. So we do need that need for 12

increasing the authorized users. 13

The rulemaking created an alternative 14

pathway for 700 hours of training and experience. 15

However, it's all inclusive and what we'd like is for 16

a rule to be made for the alpha and beta emitters so 17

that medical oncologists and hematologists and other 18

clinicians could be allowed to administer these agents 19

when their patients are in need. Next slide. 20

And I'd like to talk a little bit about the 21

precedence for the oral administration of I-131, we are 22

asking for a similar requirement. The limited scope of 23

the license, it doesn't authorize the preparation of 24

radioactive drugs, but again, this comes as a 25

25


patient-ready dose. And it is a drug with a low 1

radiation and good safety record. So next slide. 2

And I'd just like to compare and contrast. 3

Right now the training requirements to administer 4

Zevalin require 700 hours. And according to the patient 5

release instructions, there is no need for a hospital 6

stay after receiving Zevalin. There is no need to limit 7

contact with your loved ones or others. 8

There's no effective radiation within your 9

body or bodily fluids. And after the first three days, 10

the only issues are universal precautions, which are 11

necessary for any type of either chemotherapy or 12

medications or any of day-to-day living. And of course, 13

wash your hands after using the toilet. 14

As well as -- then for iodine-131, that is 15

under the 80 hour training, you do have significant 16

restrictions where you need to be at least six feet away 17

from other people, you're avoiding crowds and places, 18

you're avoiding handling of any of your bodily fluids, 19

and you're not sharing a bed or bathroom with another 20

person. You're not sharing drinking glasses, plates, 21

or silverware. 22

So, as you can read here, there are several 23

more restrictions for an agent that has much less 24

training requirements at this time. Next slide. 25

26


So what we're asking in the recommendation 1

is to allow an 80 hour course for authorized users for 2

alpha and beta emitters. We are not asking -- in the 3

end, I don't think that all medical oncologists or 4

hematologists will want to be authorized users. But at 5

least those that are in gap areas may have the 6

opportunity to be able to offer these agents to their 7

patients. 8

Because right now in cancer medicine, any 9

personalized therapy is our goal to be able to keep these 10

patients living longer with a better quality of life. 11

And radiopharmaceuticals may help us get to that goal 12

quicker. And that's all I have for slides. I think if 13

you'd like to open it up for questions from Committee. 14

CHAIRMAN THOMADSEN: Yes. Thank you very 15

much. Do we have questions for the presenter? Can you 16

speak loudly and give your name? 17

MEMBER DILSIZIAN: Yes. Vasken Dilsizian. 18

Great presentation. Just to let you know, I'm a 19

cardiologist in training. And in nuclear cardiology by 20

doing additional fellowship in nuclear medicine. Very 21

similar to your training. 22

The reason there's a sub-specialty like 23

nuclear medicine that exists is specifically to 24

administer these registrations. I found it very 25

27


interesting in your discussions that you kept mentioning 1

radiation oncology, but not nuclear medicine. You also 2

know very well that every community hospital has to have 3

a nuclear medicine program for spec imagining and 4

nuclear medicine physician. 5

So I find it disingenuous, if you will, of 6

you not presenting the real fact that the Zevalin 7

decrease in the number of patients is not related to 8

lack of access. It's lack of referral of patients. As 9

you pointed out, Zevalin's only being used in very 10

limited number of patients. 11

DR. CULTRERA: I appreciate your comments 12

and, yes, I did mention radiation oncologists. 13

Unfortunately, in my community and from what I can see 14

from the authorized users, even in nuclear medicine, 15

I don't see that there are any nuclear medicine doctors 16

even in my community that will administer 17

radiopharmaceuticals. 18

I think that there are others on the line 19

that may be able to speak to that better in a little 20

bit. But in my experience, I have not had the capability 21

of referring to a nuclear medicine doctor that's an AU. 22

MEMBER DILSIZIAN: By definition, all 23

nuclear medicine physicians are AU and all nuclear 24

medicine physicians are trained and will welcome 25

28


additional therapeutics. It's just that there's no 1

referring physicians. So what I would like to suggest 2

is really not limit your discussion to radiation 3

oncology. 4

DR. CULTRERA: Okay. 5

MEMBER DILSIZIAN: All nuclear medicine 6

physicians will be happy to administer it. And they 7

will and they'll be happy to. It's just that the 8

opportunity hasn't been there because the referral 9

hasn't been there. 10


Other comments or questions? Hearing none, I think that 12

while there is a lot of potential discussion surrounding 13

the issues that have come up, I would like to establish 14

a subcommittee to evaluate if the 700 hour requirements 15

in the alternative pathway places a hardship on the 16

patient community. And I would ask Dr. Palestro to 17

chair that committee. Dr. Palestro, are you there? 18

MEMBER PALESTRO: Yes, I am. 19

CHAIRMAN THOMADSEN: Would you be willing 20

to chair that committee? 21

MEMBER PALESTRO: Yes, I will. 22

CHAIRMAN THOMADSEN: And I would like Dr. 23

Dilsizian, Dr. Ennis, Dr. Zanzonico, and Dr. Langhorst 24

to sit on that. I think that all of those are on the 25

29


line right now. Is that correct? 1

MEMBER DILSIZIAN: Yes. 2

MEMBER ZANZONICO: Yes. 3

MEMBER LANGHORST: Yes, I'm here. And might 4

I make a suggestion? This is Sue -- 5

CHAIRMAN THOMADSEN: Yes. 6

MEMBER LANGHORST: -- Langhorst. 7


MEMBER LANGHORST: Because of the patient 9

access question -- 10


MEMBER LANGHORST: -- would it be 12

appropriate to have Ms. Weil serve on this subcommittee? 13

CHAIRMAN THOMADSEN: I think it would be very 14

appropriate. Ms. Weil, would you be willing to sit on 15

that committee? The subcommittee? 16

MEMBER WEIL: Indeed, I would. 17

CHAIRMAN THOMADSEN: Very fine. 18

MS. HOLIDAY: Dr. Thomadsen, can you tell 19

me -- 20

CHAIRMAN THOMADSEN: Doctor -- 21

MS. HOLIDAY: -- this subcommittee -- 22

CHAIRMAN THOMADSEN: I'm sorry. Can you 23

speak a little bit louder, Ms. Holiday? 24

MS. HOLIDAY: Yes. Can you repeat what the 25

30


charge of this subcommittee is? 1

CHAIRMAN THOMADSEN: Yes. To evaluate if 2

the 700 hour training requirement places a hardship on 3

the patient community and to make recommendations for 4

potential changes if they feel that would be 5

appropriate. 6

MS. HOLIDAY: Excellent. And I have Dr. 7

Palestro as the chair, Dr. Dilsizian, Dr. Zanzonico, 8

Dr. Langhorst, and Ms. Weil? 9

CHAIRMAN THOMADSEN: And Dr. Ennis. 10

MS. HOLIDAY: And Dr. Ennis. Thank you. 11

MEMBER MATTMULLER: Dr. Thomadsen, can you 12

hear me? 13

CHAIRMAN THOMADSEN: I can barely hear you, 14

but I can. 15

MEMBER MATTMULLER: Yes. This is Steve 16

Mattmuller. And I'd like to ask a question if I may. 17

CHAIRMAN THOMADSEN: Please do. 18

MEMBER MATTMULLER: Yes. I'm the nuclear 19

pharmacist on the Committee. And we all agree that 20

these are terrific therapeutic radiopharmaceuticals 21

that are horribly underutilized. 22

And ourselves at Kettering Medical Center, 23

Kettering, Ohio and in caring for -- excuse me, Dayton. 24

We have in the metropolitan area a population of about 25

31


one million. Yet, for the past nine years, we've only 1

done three studies. 2

And so, I'm curious, I guess this follows 3

somewhat Dr. Dilsizian asked as to why there's a 4

reluctance on medical oncologists to refer patients to 5

us for these valuable drugs. And I also noticed, along 6

that same effort or question line, you showed on your 7

one slide that there was a lack of authorized users in 8

the Orlando area. 9

And we happen to be sponsored by the Seventh 10

Day Adventists and there's a large hospital in Orlando 11

called the Florida Hospital with well over 1,000 beds. 12

And they too are sponsored by the Seventh Day Adventists 13

and we share personnel at times. 14

So, when I spoke to them recently, they 15

mentioned that for the past nine years, with a much 16

larger metropolitan area, they too have only done three 17

patients. So, again, they're ready and willing as we 18

are to treat these patients, but we're not getting the 19

referrals from the medical oncologists. Would you be 20

able to explain why that is? 21

DR. CULTRERA: Yes. To answer your second 22

point first, about the Orlando area, actually I am about 23

an hour and a half north of the Orlando area. And I'm 24

very familiar with the Adventists system. We actually 25

32


have one that's about 45 minutes from my main practice 1

location in Tavares, Florida. 2

And they do not offer radiopharmaceuticals 3

there. They actually have to -- you have to travel to 4

Orlando. And my patients, many of them cannot. That's 5

the issue. Orlando does have AUs. Tampa does have AUs. 6

And Jacksonville, I believe, does have AUs. 7

But, outside of that, Florida ranges from 8

tip to tip about 400 miles and it's almost impossible 9

to get my 65 plus patient who may only have a golf cart 10

to be able to commute to and from his or her visits to 11

be able to get to these areas. So, yes, I mean, I would 12

love to be able to utilize those AUs in Orlando. And 13

I do for certain cases or patients that are able to get 14

out there. 15

Now, as to your first point as to why medical 16

oncologists are not referring, and this is, I of course 17

cannot speak for all medical oncologists, but what I 18

believe is -- number one, they may not have the 19

experience with using Zevalin. For many of them, they 20

left their fellowship and went straight into the 21

community and didn't have access to using the drug. 22

So they went to the next best agent that 23

they could use or not even, sometimes in the front line 24

setting, not even using any follow-up agents. I think 25

33


a lot of it is that they're just very unfamiliar with 1

the drugs and, hopefully, with Xofigo and other agents 2

that are hopefully going to be approved for other 3

malignancies in the solid tumor area, they're going to 4

start to be able to be utilized further and become more 5

knowledgeable. 6

And I think as well, when I was an 7

academician at Moffitt Cancer Center, I found that the 8

fellows weren't even being trained in the use of 9

radiopharmaceuticals. And we were actually using them 10

in a significant amount at Moffitt Cancer Center. So 11

I think if they don't learn it in their training, if 12

they don't see it being used by their colleagues, they're 13

just -- we're not going to know to refer the patients 14

out. 15

So that's my theory on why the medical 16

oncologists are not referring out. And, unfortunately, 17

sometimes even our local hospitals won't be able to use 18

these agents just because of cost and contracting. So 19

they might not have access through the hospital base 20

on the nuclear medicine side of things. 21

CHAIRMAN THOMADSEN: Thank you. Other 22

questions? 23

MEMBER DILSIZIAN: Yes. Vasken Dilsizian 24

again. 25

34



MEMBER DILSIZIAN: I guess it would be 2

similar to say that the oncologist may not have training 3

in MRI or CT, but they do understand what the role of 4

MRI and CT is in their patient management in their 5

training. 6

So, lack of training does not necessarily 7

mean that the technique is not available by other 8

sub-specialties that the oncologist should be treating 9

patients with radiation. That's why sub-specialties 10

exist. And so, to me, that's not a very good argument 11

that the teaching has to be incorporated just like any 12

other modality. 13

MEMBER WEIL: Dr. Thomadsen? 14


MEMBER WEIL: Laura Weil. 16

CHAIRMAN THOMADSEN: Who's speaking? Oh, 17

yes. 18

MEMBER WEIL: I'd like to -- 19

CHAIRMAN THOMADSEN: Ms. Weil. 20

MEMBER WEIL: I would just like a 21

clarification. Florida Cancer Specialists are 22

physician practices, non-hospital based. Correct? 23

DR. CULTRERA: Correct. 24

MEMBER WEIL: They're community based, 25

35


non-hospital. You must have affiliations with some 1

hospitals, but you're basically community practices? 2

DR. CULTRERA: Correct. 3

MEMBER WEIL: Thank you. 4

CHAIRMAN THOMADSEN: Other questions? 5

MEMBER MATTMULLER: Yes. I had a quick -- 6

this is Mattmuller again. 7

CHAIRMAN THOMADSEN: I'm hearing two here. 8

MEMBER MATTMULLER: Steve Mattmuller again. 9

CHAIRMAN THOMADSEN: Yes. Mr. Mattmuller. 10

MEMBER MATTMULLER: Just to point out, on 11

the Bexxar and quite possibly -- Bexxar compared to 12

Zevalin was much, much more difficult to use and to 13

prepare and much more complicated. And, in fact, most 14

people I believe would agree that its demise was 15

precipitated when Zevalin went from a two dose program 16

to a single dose program. And thus, was much, much 17

simpler to use versus the Bexxar. 18

So, from our perspective, it wasn't the lack 19

of AUs, I mean, it was really the added complexity of 20

Bexxar versus Zevalin that really led to its downfall. 21

Thank you. 22

CHAIRMAN THOMADSEN: Thank you. Was there 23

somebody else that wanted to comment that was vying with 24

him? 25

36


MEMBER ENNIS: Yes. Ron Ennis. 1

CHAIRMAN THOMADSEN: Dr. Ennis. 2

MEMBER ENNIS: Yes. Just, again, it sounds 3

difficult for me to understand how if there is such a 4

demand and utility for these drugs that the nuclear 5

medicine physicians and the radiation oncology 6

physicians in the communities with whom you work, your 7

practices clearly work for a wide variety of care 8

patients, why there's a barrier to making that part of 9

that collaboration. 10

CHAIRMAN THOMADSEN: There seems to be a 11

conversation going on in the background. Can people 12

mute their phone please? Or microphone. Did the 13

speaker want to address the question? 14

DR. CULTRERA: Yes. So, of course, I can't 15

speak for why -- I can only speak for the radiation 16

oncologists and I personally have not spoken to nuclear 17

medicine physicians. But why they haven't become AUs 18

in my area, I was generally told that it was a very 19

cumbersome process to become an AU and it wouldn't 20

benefit them. 21

Even assured, because I had told them that 22

I would like to be able to refer patients, that they 23

would have that patient referral base. So I can't speak 24

as to why they're not becoming AUs. 25

37


I know my current affiliations with the 1

hospitals that are in my area, including Florida 2

Hospital, Waterman, The Villages Regional Hospital, and 3

Leesburg Regional Hospital, which cover probably about 4

a 60 to 70 mile radius, the nuclear medicine departments 5

in those three hospitals do not administer any of the 6

radiopharmaceuticals. Because we have discussed this 7

with them and there are no plans to in the future. 8

So that's -- and I know that there are other 9

oncologists in my practice that are in the rural setting 10

that don't have that -- their local hospitals as well, 11

they're not administering even some of the targeted 12

therapies that are intravenous that are not 13

radiopharmaceuticals. 14

MEMBER ENNIS: So is the problem that the 15

reimbursement is not commensurate with the work. And 16

if so -- 17

DR. CULTRERA: I think -- 18

MEMBER ENNIS: -- it's not a regulatory 19

question, but a CMS, financial insurance question. 20

DR. CULTRERA: I can't speak to that. I am 21

not knowledgeable on that front. There may be a 22

component of that happening in the hospital based 23

setting. I don't know about the community physicians 24

or the current community physicians that are able to 25

38


be AUs. 1

I do know as well that they also don't want 2

to have to deal with the follow-up of some of these 3

patients who do need to have regular hematologic 4

toxicity evaluations, basically a complete blood count 5

done every week for 10 to 12 weeks after they receive 6

the drug. And they don't want to have to deal with most 7

of the toxicity from the drug, which is basically 8

hematologic and not radiologic in nature. 9

CHAIRMAN THOMADSEN: I'll just ask the 10

question. That seems a bit strange because that is what 11

radiation oncologists generally have to deal with is 12

hematological complications of treatments. It seems 13

strange that this would be different from that. 14

DR. CULTRERA: I can only speak to what my 15

local radiation oncologists have discussed with me. 16

And those are my experiences. 17

CHAIRMAN THOMADSEN: Other questions from 18

the Committee? 19

MEMBER LANGHORST: Yes. Dr. Thomadsen, 20

this is Sue Langhorst. 21

CHAIRMAN THOMADSEN: Yes, Dr. Langhorst? 22

MEMBER LANGHORST: Dr. Cultrera, I wondered 23

if you have looked at this beyond Florida or are you 24

primarily looking at this strictly from your state 25

39


basis? 1

DR. CULTRERA: In my experience, I'm only 2

speaking based on Florida. However, there are other 3

members on the line that can speak after we're done to 4

better answer that question. And I know, basically, 5

other members from Spectrum, and I think CORAR, is here 6

that may be able to speak to the national issues that 7

are ongoing. 8

MEMBER LANGHORST: Okay. I just wondered if 9

there might be some special situations with the Florida 10

regulatory requirements. 11

DR. CULTRERA: From what I understand, no. 12

I think this is -- from what I see from the data that 13

Spectrum has presented to me, it's nationwide. 14

MEMBER LANGHORST: Okay. Thank you very 15

much. 16

CHAIRMAN THOMADSEN: Other questions from 17

the Committee? Otherwise -- 18

MEMBER ENNIS: Is Florida an agreement 19

state? 20

DR. CULTRERA: I'm sorry, can you repeat 21

that? 22

MEMBER ENNIS: Is Florida an agreement 23

state? 24

MS. HOLIDAY: Yes. This is Sophie. 25

40


Florida is an agreement state. 1

MEMBER ENNIS: Thank you. 2

CHAIRMAN THOMADSEN: Let me open up the floor 3

to others on the line if they have questions or comments 4

they would like to make. 5

DR. ALLEN: Yes. Lee Allen, Chief Medical 6

Officer at Spectrum Pharmaceuticals. Can I make a few 7

comments? 8

CHAIRMAN THOMADSEN: Dr. Allen. 9

DR. ALLEN: Yes. The questions that the NRC 10

raised was this question of are the regulations 11

discouraging the use of current therapeutic options and 12

adversely impacting clinical practice. And I think as 13

the subcommittee investigates the use of this product, 14

I think they will see that indeed it is. 15

And I think as Dr. Cultrera mentioned, these 16

patients are managed pretty much in totality in terms 17

of their clinical care and follow-up through the 18

hematologist oncologists. And in terms of -- the issue 19

that's being recommended here is the question of 20

allowing those physicians to manage the administration 21

of a relatively low risk beta emitter, alpha emitter 22

products to make them part of their clinical 23

armamentarium. 24

And we think that, that will certainly 25

41


enable the patients to have access to this more easily. 1

Again, I think there -- like everything else, there are 2

multiple reasons for the challenge in why patients 3

aren't referred. 4

But the reality is that this is a modality 5

that is very effective, particularly for elderly 6

patients. Because, again, unlike chemotherapy which 7

requires multiple rounds of treatment, this is a one 8

shot deal. One and done is the expression that's used. 9

So it would be very convenient for that 10

patient population who can't really handle the toxicity 11

of the repeated cycles of chemotherapy. So, again, I 12

think, back to the question on the table, I think the 13

current regulations do limit the use of this product 14

and do impact clinical care. 15

And I think that a reasonable solution is 16

to match the training requirement with the risk and 17

safety of managing alpha and beta emitters. And I think 18

the Committee has an opportunity to make a 19

recommendation on that and the subcommittee has an 20

opportunity to evaluate that more comprehensively. 21

Thank you. 22

CHAIRMAN THOMADSEN: Thank you, Dr. Allen. 23

Are there others on the line that -- 24

DR. VACIRCA: Yes. 25

42


CHAIRMAN THOMADSEN: -- would like to 1

comment? Who is that? 2

DR. VACIRCA: Hi, this is Jeffrey Vacirca. 3

I'm the CEO of North Shore Hematology Oncology in New 4

York. I'm a medical oncologist. But I'm also the Vice 5

President of Community Oncology Alliance. We prepared 6

a brief statement if that would okay to be read in? 7

CHAIRMAN THOMADSEN: Please. Yes. 8

DR. VACIRCA: So, Community Oncology 9

Alliance or COA is a non-profit organization. We're 10

dedicated to cancer patients and providers in the 11

community oncology setting. We currently represent 12

over 7,000 community oncologists and are deeply 13

concerned about any barriers to patients having access 14

to lifesaving treatments. 15

As part of this rulemaking, the NRC has 16

specifically requested comments on whether its 17

regulations discourage licensees from using certain 18

therapy options or otherwise adversely impact clinical 19

practice, and if so, how? Our members support the NRC's 20

efforts to update its regulations to reflect changes 21

in clinical practice, as well as advantages in medical 22

technology. 23

This rulemaking presents an opportunity 24

for the NRC to improve access to potentially lifesaving 25

43


anti-cancer treatments by addressing a shortage of 1

authorized users able to administer these treatments. 2

COA has been following the NRC's current rule making 3

process and has submitted a comment letter to the NRC 4

last fall. 5

In February, we attended and spoke at the 6

public meeting held by the NRC on alpha and beta emitters 7

training, as well as the experience requirements. COA 8

is pleased to share its thoughts with ACMUI on this topic 9

today. 10

The NRC's regulations create a shortage of 11

authorized users able to administer therapeutic 12

radiopharmaceuticals. Under current regulations, as a 13

drug administered parenterally and used primarily for 14

its beta radiation characteristics, therapeutic 15

radiopharmaceuticals can only be administered by an 16

authorized user who has met the training and experience 17

requirements set forth in 10 CFR 35.396. 18

These requirements involve either board 19

certification or 700 hours of training and experience 20

specifically in radionuclide handling. The 21

hematologists and oncologists who typically prescribe 22

therapeutic radiopharmaceuticals outside of the 23

hospital setting often do not have the training and 24

experience required to meet the AU requirements and do 25

44


not work at facilities that have such AUs. 1

They have extensive training and 2

experience and are frequently board certified, but in 3

different specialized field. The effect of the 4

regulation is to severely limit patient access to a very 5

safe and effective treatment. 6

Certain patient populations are 7

particularly negatively affected by a lack of AUs for 8

therapeutic radiopharmaceuticals. Access is 9

particularly difficult in rural geographies or in other 10

areas where patients must travel great distances to 11

their primary oncologist, and even further to a 12

specialized facility with an authorized user. 13

Standard treatment options that offer 14

excellent response rates should be available to all 15

patients, whether these patients live near an academic 16

medical center or in a more rural area of the country. 17

The experience of Doctors Mace and Cultrera, and many 18

other community oncologists, demonstrate the burden 19

that current regulations place on practitioners seeking 20

to provide patients with these treatment options. 21

Dr. Mace, with 80 hours of training and 22

experience in the safe handling of radionuclides 23

acquired before the current regulations went into 24

effect, has been safely administering these treatments 25

45


to patients in need for a decade. Dr. Cultrera has 1

worked with Dr. Mace and is unable to administer these 2

treatments because she cannot realistically complete 3

700 hours of additional training and experience with 4

the high demands of her practice. 5

Even though these treatments might be the 6

best option for some of her patients, she feels that 7

the burden placed on patients requiring them to travel 8

great distances to reach an authorized user is too high. 9

These patients are frequently frail and elderly and 10

traveling such distances can be taxing. 11

Doctors Mace and Cultrera have proposed a 12

change to the rules to permit a lesser training 13

requirement of 80 hours of classroom and laboratory 14

training, plus relevant work experience and case 15

administration, for a limited authorization to 16

administer alpha and beta emitters that are prepared 17

in a licensed specialty pharmacy and delivered 18

intravenously in a patient-ready dose. 19

COA would support this reasonable and 20

limited proposed change in the regulation. We do 21

recognize the difficulty of balancing safety 22

considerations with preserving patient access to 23

medical care and we encourage ACMUI to consider this 24

proposal that could significantly improve patient 25

46


access to lifesaving treatments in the community 1

oncology setting. Thank you. 2

CHAIRMAN THOMADSEN: Thank you, Dr. Allen. 3

Other comments? 4

MS. LEVY: This is Robin Levy calling from 5

the Lymphoma Research Foundation. May I -- 6


MS. LEVY: May I address the Committee now? 8

CHAIRMAN THOMADSEN: Yes. Please. 9

MS. LEVY: Thank you very much. Like I said, 10

my name is Robin Levy. I'm the Director of Public Policy 11

and Advocacy for the Lymphoma Research Foundation. The 12

Foundation has submitted a letter to the Committee and 13

I just wanted to speak today. 14

First, I'd like to say thank you for 15

addressing the issue and I appreciate the subcommittee 16

that you've just formed to evaluate the patient access 17

question. Because that is very important to the 18

Lymphoma Research Foundation and to our community. 19

The LRF is the nation's largest non-profit 20

organization devoted exclusively to funding innovative 21

lymphoma research and providing people with lymphoma 22

and healthcare professionals with up-to-date 23

information about this type of cancer. We appreciate 24

the opportunity to respond to this Commission and the 25

47


Foundation supports the NRC's efforts to update its 1

regulations and to reflect changes in the clinical 2

practice and advances in medical technology. 3

What we are concerned about is that we do 4

not want to see any changes that will affect -- any 5

regulation that will prove too burdensome for 6

practitioners and result in limited access to safe and 7

effective pharmaceuticals among the lymphoma 8

population. 9

We acknowledge the importance of training 10

and experience requirements when dealing with 11

therapeutic radiopharmaceuticals and we respectfully 12

request the NRC consider regulatory framework that 13

balances the importance of training and safety while 14

not creating undue hardship on hematologists and 15

oncologists who wish to administer these therapies. 16

A lymphoma patient faces a difficult and 17

complex process as it relates to their diagnosis and 18

treatment. And lymphoma is unique in that there are 19

more than 67 subtypes of the disease and each are 20

considered to be rare and complex diagnosis, which is 21

notorious for recurrence. And a lymphoma patient needs 22

access to every tool in the arsenal for the management 23

of their disease. 24

So we believe the Commission must find 25

48


balance between ensuring public safety during the 1

administration of radiopharmaceuticals, while not 2

hindering access to potentially lifesaving treatment. 3

And we thank you for the opportunity to address you. 4

CHAIRMAN THOMADSEN: Thank you for your 5

comment. Others on line? 6

MEMBER MATTMULLER: Yes. 7

CHAIRMAN THOMADSEN: Hearing none -- oh, 8

yes? 9

MEMBER MATTMULLER: Yes. Steve Mattmuller 10

again. 11

CHAIRMAN THOMADSEN: Mr. Mattmuller. 12

MEMBER MATTMULLER: Yes. I think Dr. 13

Cultrera has really mentioned a much simpler solution 14

to all of this. Because in the Dayton area, there is 15

ready access at our facility. And I know in the Orlando 16

area, while it may not be convenient to her patients, 17

but with -- and she's outside of the Orlando metropolitan 18

area, and they're ready. 19

And yet, both facilities between the two 20

of them, have done six patients in the past nine years. 21

Even though we're ready to go, we're just not getting 22

the referrals. 23

And she suggested that it was possibly that 24

the medical oncologists and the hematologists are 25

49


unaware of these radiopharmaceuticals and unaware that 1

they are available and ready to go. That through the 2

professional organizations, they need to educate their 3

members that, to use these valuable drugs to give the 4

best care to their patients, they need to refer them 5

to departments that are ready to go right now. Thank 6

you. 7

CHAIRMAN THOMADSEN: Thank you. 8

MEMBER DILSIZIAN: Vasken Dilsizian here. 9

CHAIRMAN THOMADSEN: Dr. Dilsizian. 10

MEMBER DILSIZIAN: Yes. I would like to 11

echo that the University of Maryland Medical Center is 12

an NCI sponsored oncology center and I've been here for 13

14 years. We have a great relationship with the 14

oncologists and radiation oncologists. And we've had 15

several meetings and dialogues about use of Zevalin by 16

the oncologists. 17

And I would like to report that we've 18

probably done only two patients over 14 years, despite 19

having 13 system hospitals in the Baltimore area. If 20

I could have one question, Dr. Allen, did you say you're 21

from North Shore, New York? Dr. Allen? Okay. That's 22

fine if he's not on -- 23

CHAIRMAN THOMADSEN: Ms. Holiday, is Dr. 24

Allen's microphone live? 25

50


MS. HOLIDAY: Yes. But I think he just 1

dropped off the call. 2

CHAIRMAN THOMADSEN: Oh, okay. 3

MEMBER DILSIZIAN: My question was actually 4

directed at Dr. Vacirca. Sorry. I just wanted to know 5

if Dr. Allen represents North Shore New York Oncology 6

Group, and I know Dr. Palestro is at North Shore 7

Hospital. 8

I was wondering how many patients has he 9

referred to North Shore Hospital given that Dr. Palestro 10

is a very competent authorized user, nuclear medicine 11

physician. That's what I thought. Thank you. 12

CHAIRMAN THOMADSEN: Okay. Thank you very 13

much. And with that, I think that we'll come to an end 14

of this part -- oh, am I hearing somebody? 15

MEMBER PALESTRO: Yes. Bruce, Chris 16

Palestro. Hello? 17

CHAIRMAN THOMADSEN: Dr. Palestro. 18

MEMBER PALESTRO: Yes. Can you hear me? 19


MEMBER PALESTRO: Couple of comments that 21

I'd like to make listening to the discourse. Number 22

one, to respond to the question that was just asked. 23

If I remember correctly, over the past year, we may have 24

done two Zevalin administrations. And I would say over 25

51


the past decade, we've averaged one to two per year. 1

In terms of unsealed source, if you will, 2

or intravenously administered, parenterally 3

administered radiopharmaceuticals, there doesn't seem 4

to be anything unique to me about Zevalin. They have 5

all, for whatever reason in the past, started out being 6

very popular with fairly large numbers of patients 7

receiving these treatments and then gradually it has 8

diminished over time for whatever reason. So it's not 9

unique to Zevalin. 10

In addition to that, in an area like the 11

New York metropolitan area where, if anything, we have 12

a surplus, an overabundance of authorized users who are 13

capable and willing to administer this sort of treatment 14

like Zevalin, the numbers just aren't there. So I think 15

it's more than just a barrier put up by regulations. 16

There are other reasons and I'm not sure what all they 17

are. 18

But if you look at the New York City area 19

and think about how many large academic institutions 20

there are with innumerable authorized users, all of whom 21

are experienced in radiopharmaceutical therapy of one 22

sort or another, it's more than regulations that account 23

for the lack of use. 24


52


Now I think we're ready to move on to the next agenda 1

item. Which is the report on the radionuclide 2

localization procedures. Dr. Ennis, are you ready to 3

present the Committee's report? 4

MEMBER ENNIS: I am, Mr. Chairman. Thank 5

you. 6

CHAIRMAN THOMADSEN: Then I will turn the 7

chair over to you. I have to step out for just about 8

a minute and a half. I'll be right back. But please 9

start, I've looked at the beginning of this. 10

MEMBER ENNIS: Okay. Very good. So thank 11

you, everyone. And behalf on Dr. Alderson, Mr. 12

Costello, and Dr. Zanzonico, I will be presenting the 13

results of the subcommittee's deliberations that we had 14

on the radioactive seed localization for mostly 15

non-palpable breast lesions. Next slide please. 16

So, as most on the call are probably aware, 17

the use of a radioactive seed to localize non-palpable 18

breast tumors began in the early 2000s. The NRC's first 19

guidance was issued in 2006. 20

This review on which I'm reporting now was 21

stimulated by a request from users to reanalyze the 22

guidelines and the ACMUI at large and the subcommittee 23

particularly thought this was an appropriate time given 24

the evolution in the procedure and the time elapsed since 25

53


the prior guidance. Next slide please. 1

The use of radioactive seed localization 2

has increased significantly since it started being used. 3

Oops, somehow my slide has jumped back to the first one. 4

Okay. So anyway. We reviewed the guidance again. 5

Next slide please. Okay, there we go. Please, back one 6

slide. All right. 7

So, it's interestingly and potentially has 8

already been started to be applied to other parts of 9

the body beyond the breast itself and particularly the 10

axilla. Which makes some sense given that the same 11

physicians are involved in that as part of the breast 12

treatment. But we can envision and some articles have 13

and the medical literature has, indeed, suggested the 14

possibility of using this for other similar procedures 15

in other parts of the body. So we bore that in mind. 16

The typical procedure's done with the I-125 17

seed with low activity of about 2.2 millicuries. And 18

this is low, but not that much lower than the low activity 19

seeds used in some brachytherapy procedures. And the 20

dose delivered with this to surrounding tissue, as the 21

whole idea of brachytherapy, is going to be very low, 22

particularly if the source is removed in a timely manner. 23

Of course, very close to the source there 24

are some significant doses, but that will in general 25

54


be a non-issue. Next slide please. 1

Getting into the specifics of the guidance 2

and the questions raised by the users. Our subcommittee 3

did not feel that a change in the authorized user 4

guidance would be appropriate in balancing the safety 5

concerns. We do agree that the work experience aspect 6

regarding removal of seeds is unnecessary, as that is 7

done by someone else. 8

And similarly, other radiation safety 9

training for the surgeon who is doing the lumpectomy 10

should not include preparing the sources for placement, 11

as that is something they are never going to be involved 12

in. Next slide please. 13

Regarding the Written Directive, the 14

subcommittee believes this continues to be an important 15

part of the safe use of these isotopes and the safe 16

execution of this procedure. We did agree to some 17

modifications that had been suggested as I will detail 18

in a moment. 19

Specifically, the Written Directive needs 20

to indicate the name of the patient and before the 21

procedure is done, the site of the body that's to be 22

implanted, left breast, right breast for example, the 23

isotope being used, iodine or palladium, and the 24

activity of the source that will be implanted. 25

55


And then after the procedure, but before 1

full completion of the procedure, documentation that, 2

that's what has happened, that the radionuclide has been 3

implanted, the site it was implanted, number of sources 4

used, the total activity of the sources, and the time 5

of exposure, i.e., time until surgery is planned. Next 6

slide. 7

Okay. And medical events would kind of 8

follow as a consequence of a Written Directive, if you 9

will, in a straightforward manner. A medical event 10

would have been considered to have occurred if the 11

radioactive source was placed into the wrong patient 12

or it was the wrong isotope or it was put into the wrong 13

part of the body, opposite breast for example, if the 14

activity placed was more than 20 percent longer than 15

anticipated, so the surgery did not happen in a timely 16

manner, or that it was 20 percent higher activity than 17

planned, these 20 percent numbers are consistent with 18

other regulatory guidelines in this space, if you will, 19

and obviously, a leaking source. 20

Exception of course is if this is due to 21

patient intervention, then this is not a medical event. 22

However, it is if it is expected that this would lead 23

to unintended permanent functional damage, as noted in 24

Part B. Next slide. 25

56


Regarding safety issues, there are a number 1

that were raised by our subcommittee or by the users. 2

And we will briefly review each of those. We do think 3

it continues to be important to have safety concerns 4

for ruptured seeds. And although they are rare events, 5

we know that there have been such events, so this is 6

not something that does not happen and, therefore, 7

concern for it needs to be continued. 8

We have felt that independent verification 9

of seed activity is an important part of quality and 10

safety. We agree that the preference stated in the 11

guidance for sodium iodide meters over Geiger meters 12

is really not necessary in this setting. 13

And we do advise -- specifically that 14

patients be advised not to breastfeed with the breast 15

into which a radioactive seed has been implanted until 16

that seed has been removed. Next slide. 17

In addition, we do believe written policies 18

need to be developed for a variety of scenarios where 19

things don't go as planned, such as loss of seed, 20

implantation of seed into the wrong location or wrong 21

patient, inability to locate a seed at the time of 22

surgery or at the time or pathological processing, and 23

if a patient who has had a radioactive seed implanted 24

does not show up. Next slide please. 25

57


Continuing on with some other points, we 1

do agree that all notions and comments about therapy 2

in the guidance are not relevant. And similarly dose 3

not relevant as we are not trying to deliver a dose in 4

the therapy. And recommend the guidance language be 5

modified to reflect these clarifications. 6

And also to clarify or to correct prior 7

guidance and allow seeds to be returned to the supplier 8

as being an acceptable form of taking care of the seeds 9

rather than needing to keep it to decay. Next slide. 10

In addition, we agreed that requiring staff 11

training to know how to deal with a patient who cannot 12

be discharged is unnecessary, as this would never occur 13

with this type of procedure being such low activity. 14

So that really is unnecessary. Reflect in the language 15

of the guidance that this could be used outside of the 16

breast, as is already occurring apparently. 17

And lastly, clarifying or changing the 18

language of the guidance in the ‘Change in Physical 19

Conditions of Use’ section to reflect the fact that the 20

sources are indeed now approved by FDA for this use, 21

which was not the case when the guidance was first put 22

into effect. Next slide. I think that may be the last 23

slide. 24

MS. HOLIDAY: That's the end of the slide 25

58


deck, Dr. Ennis. 1

MEMBER ENNIS: Okay. That's what I thought. 2

Okay. Thank you. 3

CHAIRMAN THOMADSEN: And Dr. Ennis, would 4

you now want to take comments from the Committee on the 5

report itself? Which is -- 6

MEMBER ENNIS: Sure. I'd be happy -- 7

CHAIRMAN THOMADSEN: -- extensive. 8

MEMBER ENNIS: -- to do that. 9

CHAIRMAN THOMADSEN: I'll let you chair that 10

discussion too. 11

MEMBER ENNIS: Okay. Great. Are there any 12

members of the Committee that would like to bring up 13

any issues before we open up the floor to outside? 14

MEMBER WEIL: Dr. Ennis, this is Laura Weil. 15

MEMBER ENNIS: Hi Laura. Go ahead. 16

MEMBER WEIL: In the text of your detailed 17

report, you provide figures for the anticipated low 18

risks of exposure to any members of the public from 19

patients with implanted seeds. But you provide the 20

figures only for a single implanted seed. 21

And, yet, earlier in the report, you 22

mentioned that from one to four seeds may be used. For 23

clarity's sake, I would suggest that the report be 24

amended to include that range of exposures. Which are 25

59


certainly nothing to be concerned about. But just for 1

accuracy's sake. 2

MEMBER ENNIS: Sure. That's a good point. 3

Absolutely. Thank you. Okay. I'll make a note of 4

that. 5

CHAIRMAN THOMADSEN: This is Bruce 6

Thomadsen again. Sophie? I'm sorry, Ms. Holiday? 7

MS. HOLIDAY: Yes. 8

CHAIRMAN THOMADSEN: Would we be able to get 9

that report up on the screen so we could go to places 10

people might talk about? 11


CHAIRMAN THOMADSEN: There we go. Thank 13

you. Now I had -- Dr. Ennis? 14

MEMBER ENNIS: Yes, please. 15

CHAIRMAN THOMADSEN: I have some comments. 16


CHAIRMAN THOMADSEN: If you go to Page 2, 18

where it discusses OLINDA, which is -- let me get there 19

on mine. It's the second paragraph at the top of -- 20

MEMBER ENNIS: Okay. 21

CHAIRMAN THOMADSEN: -- Page 2. It talks 22

about how the dose could be calculated with OLINDA, but 23

in this case, the doses would be overestimates due to 24

the lack of backscatter from a breast in the algorithm 25

60


used. And it just might be -- the statement that we could 1

use OLINDA to calculate it may be qualified, just 2

recognizing it'll be an overestimate. 3

MEMBER ENNIS: All right. I think we could 4

certainly do that. Do you feel strongly that we should 5

use some other software to model the dose rather than 6

OLINDA? 7

CHAIRMAN THOMADSEN: No. No, just, I think, 8

just recognizing that the doses calculated are 9

overestimates is quite sufficient. 10

MEMBER ENNIS: Okay. That's quite 11

reasonable. We'll have to modify the report 12

accordingly. 13

CHAIRMAN THOMADSEN: And then, later in that 14

paragraph, when it talks about the dose to the breast 15

from the seed, if the seed were removed seven days 16

post-implantation and you're talking about the mean dose 17

to the breast, does that account for the volume of the 18

breast that surrounds the seed that is removed? 19

MEMBER ENNIS: So you're saying, is the dose, 20

when we say that are we saying the dose that remains 21

in the breast? Or does that mean the dose to the breast, 22

which includes some dose absorbed into the tissue that's 23

been removed? 24

CHAIRMAN THOMADSEN: That's -- 25

61


MEMBER ENNIS: Is that your questions? 1

CHAIRMAN THOMADSEN: The question is, if 2

you're calculating the mean dose to the breast, is the 3

breast that's included in that mean also include the 4

tissue around the source which is being removed? If so 5

-- 6

MEMBER ENNIS: Right. Yes. 7

CHAIRMAN THOMADSEN: -- then it actually -- 8

MEMBER ENNIS: I do. 9

CHAIRMAN THOMADSEN: What's that? 10

MEMBER ENNIS: I'm sorry. Continue. 11

CHAIRMAN THOMADSEN: If that's the case, 12

then the mean dose to the breast is going to be 13

considerably lower than the dose if you calculate it 14

with the tylectomy sample in situ. 15

MEMBER ENNIS: Right. Correct. I 16

understand. So, is Dr. Zanzonico on the call? 17

CHAIRMAN THOMADSEN: He was not earlier. 18

MS. HOLIDAY: Can you all hear him? 19

CHAIRMAN THOMADSEN: No. Is he there? 20

MEMBER ZANZONICO: Yes. Hello? 21

MEMBER ENNIS: Hi. Speak a little louder 22

please. 23

MEMBER ZANZONICO: Yes. Hello? 24

CHAIRMAN THOMADSEN: Hello. 25

62


MEMBER ZANZONICO: Hello? 1

MEMBER ENNIS: Hi. 2

MEMBER ZANZONICO: Can you hear me? 3

MEMBER ENNIS: Yes. 4

MEMBER ZANZONICO: I've been on the call 5

since the beginning. For some reason, I haven't been 6

heard, though I didn't take it personally when my 7

questions and comments were removed. 8

(Laughter.) 9

MEMBER ZANZONICO: Is there a question 10

coming my way? 11


CHAIRMAN THOMADSEN: Yes. Can you hear us? 13


CHAIRMAN THOMADSEN: The question is on Page 15

2 of the report. And it deals with the calculation of 16

the mean breast dose from the seed that's in place for 17

seven days. 18


CHAIRMAN THOMADSEN: And the question is, 20

does that mean dose include the dose to the breast tissue 21

that will be removed during the tylectomy? 22

MEMBER ZANZONICO: Yes. But it is the mean 23

dose, so it doesn't account for the fact that there will 24

be a much higher dose to the local tissue and a lower 25

63


dose to the more distal tissue. But it does incorporate 1

in the mean the tissue that will be removed. 2

CHAIRMAN THOMADSEN: So the effect of mean 3

dose would, again, be much lower? Since -- 4


CHAIRMAN THOMADSEN: -- the tissue would be 6

removed? 7

MEMBER ZANZONICO: Are you talking about the 8

effective dose now? 9

CHAIRMAN THOMADSEN: No. No, the effective 10

dose isn't going to change much. But the mean dose to 11

the breast, effectively, would be a lot less -- 12

MEMBER ZANZONICO: You're correct. 13

CHAIRMAN THOMADSEN: -- because the high -- 14

MEMBER ZANZONICO: That's correct. 15

CHAIRMAN THOMADSEN: -- highest doses will 16

be gone? 17

MEMBER ZANZONICO: Yes. That's correct. 18

CHAIRMAN THOMADSEN: There might be some 19

note to that in the report. Just to recognize that. 20

MEMBER ZANZONICO: Understood. That sounds 21

reasonable. 22

CHAIRMAN THOMADSEN: The next comment is on 23

Page 3, under Changes to Guidance Considered by the 24

Subcommittee in Its Recommendations. In the first 25

64


paragraph there, it mentions palladium-103 and says the 1

subcommittee sees no reason to exclude this isotope and, 2

therefore, recommends retaining the reference to it in 3

the title. 4

But by doing so, you're not recognizing the 5

possibility of other radionuclides, such as cesium-131, 6

which would give a much lower dose to the patient for 7

similar activity implanted at the beginning. 8

MEMBER ENNIS: So I suppose, although the 9

short half-life, I think, would make that source an 10

unlikely candidate. 11

CHAIRMAN THOMADSEN: Well, the short 12

half-life is nine days. 13

MEMBER ENNIS: Right. 14

CHAIRMAN THOMADSEN: If you talk about the 15

source being implanted for, at the most, seven days, 16

you still have a considerable activity at the end of 17

the seven days. 18

MEMBER ENNIS: Right. So are you -- 19

CHAIRMAN THOMADSEN: Definitely - 20

MEMBER ENNIS: -- suggesting that we remove 21

-- 22

CHAIRMAN THOMADSEN: That would weakly -- 23

MEMBER ENNIS: Are you suggesting that the 24

title ought not mention any particular isotope? 25

65


CHAIRMAN THOMADSEN: Correct. 1

MEMBER ENNIS: I see. 2

CHAIRMAN THOMADSEN: That would -- 3

MEMBER ENNIS: We can certainly -- 4

CHAIRMAN THOMADSEN: -- be my suggestion. 5

MEMBER ENNIS: -- consider that. 6

CHAIRMAN THOMADSEN: Just refer to them as 7

brachytherapy sources. 8


CHAIRMAN THOMADSEN: And next one is on Page 10

Number 5. And it's -- the comment is on the Medical Event 11

Reporting B. And the question I would have is the 12

question of whether you need in the event reporting a 13

paragraph talking about unintended permanent 14

functional damage. This sounds more like an OA than a 15

medical event. 16

MEMBER ENNIS: And OA is a -- 17

MS. HOLIDAY: AO? 18

CHAIRMAN THOMADSEN: AO. Sorry, yes. AO. 19

Abnormal occurrence. 20

MEMBER ENNIS: I see. 21

CHAIRMAN THOMADSEN: Which are 22

automatically reported. Is that right? Ms. Holiday? 23

MS. HOLIDAY: I'm sorry. What did you say, 24

Dr. Thomadsen? 25

66


CHAIRMAN THOMADSEN: In that paragraph, 1

which is the B in here, that would fall into the category 2

of an abnormal occurrence, would it not? 3

MS. HOLIDAY: I think that was proposed 4

language for the abnormal occurrence criteria. 5

CHAIRMAN THOMADSEN: At one point, yes. 6

DR. HOWE: Dr. Thomadsen? This particular 7

-- 8


DR. HOWE: This particular -- this is -- 10

CHAIRMAN THOMADSEN: Who is speaking right 11

now? 12

DR. HOWE: -- Dr. Howe. This is Dr. Howe at 13

the NRC. This particular language in Section B 14

parallels the language in medical event reporting if 15

there's patient intervention. It has nothing to do with 16

the abnormal occurrence. 17

It has to do with if there's patient 18

intervention, it would only be reported -- and it was 19

a medical event, then you would only report it if you 20

have permanent functional damage. So that's where that 21

particular language comes from. 22

CHAIRMAN THOMADSEN: Very fine. Thank you. 23

And the next one is in the last line of that page. The 24

verification of source activity and the question I have 25

67


is -- 1

MEMBER ENNIS: Do we have a question? I 2

think there's a question. 3

MEMBER ZANZONICO: Yes. While we're on -- 4

this is Pat Zanzonico. While we're on that section, if 5

you look at the second line of Item A, it appears that 6

there's some text missing, doesn't there? At the very 7

end of the line? 8

MEMBER ENNIS: That's just how the slides 9

are projecting. It's cut off. The end of the lines are 10

cut off on my screen as well, but I think that is just 11

how the text is projecting on our webinar. 12

CHAIRMAN THOMADSEN: Actually, I'm looking 13

at the Acrobat, the PDF, and indeed, that line does end 14

exactly like on the screen. 15

VICE CHAIRMAN ALDERSON: Yes. This is Phil 16

Alderson. Can you hear me? 17


MEMBER ENNIS: Phil. Go ahead. 19

VICE CHAIRMAN ALDERSON: Yes. Good. 20

That's great. Because like Pat Zanzonico, I've been on 21

listen-only most of the time, ever since it began. I'm 22

looking at a piece of paper, I hate to be so out of touch 23

with reality of the current day. But it's the full 24

sentence is there. It's as it's appropriately written 25

68


and material results in dash and then it goes through 1

all the subsets. So, it's a computer problem. 2

CHAIRMAN THOMADSEN: Okay. 3

MEMBER LANGHORST: Hi. This is Sue 4

Langhorst. May I offer something in this section? 5

MEMBER ENNIS: Sure, Sue. Go ahead. 6

MEMBER LANGHORST: I just -- Dr. Ennis is 7

there anything different here than is in medical event 8

reporting? And might it be easier to just reference 9

medical event reporting and any differences that you 10

may be recommending? And I couldn't tell that there 11

were any differences that you all were recommending. 12

MEMBER ENNIS: I'd have to bring up those 13

--- it parallels it. All dose issues are removed and 14

I think that's probably the main difference. 15

MS. HOLIDAY: Dr. Ennis, this is Sophie. 16

MEMBER ENNIS: Yes, Sophie. 17

MS. HOLIDAY: I just wanted to point out that 18

one of the biggest differences in this section is that 19

the subcommittee put language in there about 20

administration of radioactive byproduct material for 21

more than 20 percent longer than planned. 22

MEMBER ENNIS: Correct. 23

MS. HOLIDAY: And administration of the 24

radioactive byproduct material activity of more than 25

69


20 percent of the intended activity. 1

MEMBER ENNIS: Correct. Thank you. 2

MEMBER LANGHORST: This is Sue Langhorst 3

again. I think it might be better if you, just my 4

personal opinion, if you only discuss what the 5

differences are rather than trying to figure out are 6

you saying something different for all these other items 7

that are exactly the same as in the regulations. 8


MEMBER LANGHORST: That's just my thought. 10

MEMBER ENNIS: Right. I guess the 11

alternative thought is to put the whole thing in one 12

place so that users have one place to look to know rather 13

than, oh God, I've got to look here for part of the 14

regulation and here for another part. 15

MEMBER LANGHORST: This is Sue. Okay, I 16

understand. 17

MEMBER ENNIS: I think, Dr. Thomadsen -- 18


MEMBER ENNIS: -- you had more comments. 20

CHAIRMAN THOMADSEN: Yes. On the last line 21

on that page, Verification of Source Activity, since 22

these all come sterile, what is the recommendation of 23

the subcommittee to perform that verification? 24

MEMBER ENNIS: So this may be something we 25

70


have to reconsider actually, based on Mr. Sheetz's 1

follow-up comments. 2

VICE CHAIRMAN ALDERSON: I'm sorry, Bruce, 3

could you --- this is Phil. Would you restate your 4

question? I didn't understand your question in 5

relation to this sentence. 6

CHAIRMAN THOMADSEN: The current practice 7

in brachytherapy to evaluate source activity or source 8

strength rather than activity is to measure seeds in 9

a well chamber. If the seeds are sterile, that makes 10

it very difficult to do. 11

Some places have come up with procedures, 12

but they aren't universally accepted. So the question 13

here is, since these sources come loaded and sterile, 14

how is the committee expecting the users to make this 15

determination of activity? 16

VICE CHAIRMAN ALDERSON: Thank you. 17

MEMBER ZANZONICO: Dr. Thomadsen? This is 18

Pat Zanzonico. 19


MEMBER ZANZONICO: When you're referring to 21

a well chamber in the context of assaying seeds for 22

brachytherapy, are you referring to something other than 23

a dose calibrator? 24

CHAIRMAN THOMADSEN: A well chamber used for 25

71


brachytherapy usually is designed slightly differently 1

than the typical nuclear medicine well chamber, although 2

they have many features in common. But, yes, you could 3

potentially use a nuclear medicine well chamber if it 4

were calibrated. 5

MEMBER ZANZONICO: Right. This is Pat 6

Zanzonico again. I think as Dr. Ennis said, there's 7

probably something we need to reconsider. But I would 8

think a standard nuclear medicine dose calibrator could 9

easily be calibrated with the source from the 10

manufacturer initially to calibrate the dose calibrator 11

to allow it to give an accurate reading of the seed in 12

the whole assembly, in the whole sterile assembly. 13

CHAIRMAN THOMADSEN: And that's a question 14

too. Some people have suggested that the varying 15

thickness in a needle can markedly affect the reading 16

in a brachytherapy seed of that energy. 17

MEMBER ZANZONICO: Agreed. That's why 18

there would have to be some initial calibration to 19

account for that and that calibration would subsequently 20

be used for actual patient seeds after that. 21

CHAIRMAN THOMADSEN: The variation was 22

needle-to-needle as opposed to 23

manufacturer-to-manufacturer. 24

MEMBER ZANZONICO: Understood. 25

72


MEMBER LANGHORST: Dr. Ennis, this is Sue 1

Langhorst. 2

MEMBER ENNIS: Yes, Sue? 3

MEMBER LANGHORST: I would recommend that 4

you drop that recommendation. Because in 10 CFR 35.432 5

in Paragraph D, that allows licensees to use instead 6

of their own measurement, measurements provided by the 7

source manufacturer or a calibration laboratory that's 8

accredited. And so, the recommendation that the 9

subcommittee has put forward on measuring the seed 10

strength, it goes beyond what the current regulations 11

have for regular brachytherapy seeds. 12

MEMBER ENNIS: Yes. I agree. We will 13

definitely reconsider this particular point. 14

MEMBER ZANZONICO: This is Pat Zanzonico 15

again. While I initially thought it was good idea to 16

retain the end-user calibration, just based on this 17

discussion and given the low energies of the I-125 18

emissions, it may actually be more problematic. As Dr. 19

Langhorst is suggesting, it may be more problematic to 20

retain that requirement. It brings more problems than 21

it potentially solves. But we should reconsider it. 22

VICE CHAIRMAN ALDERSON: Yes. This is 23

Alderson. I agree. 24

MEMBER ENNIS: Very good. 25

73


CHAIRMAN THOMADSEN: Okay. I only have two 1

more. 2

MEMBER ENNIS: Go ahead, please. 3

CHAIRMAN THOMADSEN: On the next page, under 4

Training. The first three words are "the subcommittee 5

agrees" and it's not clear with whom it's agreeing. 6

MEMBER ENNIS: With the user presentation. 7

CHAIRMAN THOMADSEN: Yes. But I don't think 8

the report is in response to any -- 9

MEMBER ENNIS: Fair enough. 10

CHAIRMAN THOMADSEN: -- user presentation. 11

MEMBER ENNIS: We will change that language. 12

Correct. Thank you. 13

CHAIRMAN THOMADSEN: And I think it's also 14

used down under Procedures also. 15


CHAIRMAN THOMADSEN: And my -- 17

MEMBER ENNIS: Thank you. 18

CHAIRMAN THOMADSEN: My last point is on the 19

next paragraph, Survey Instruments and Radiation Survey 20

Requirements. I do not see why you need to designate 21

either sodium iodide or Geiger-Mueller counters, rather 22

than just saying detector with demonstrated capability 23

to detect the radiation from the sources at the radiation 24

levels anticipated. There are diode detectors that can 25

74


do just as well, along with other scintillator detectors 1

and it just seems that you don't need to restrict it 2

to those detectors. 3

VICE CHAIRMAN ALDERSON: If you don't want 4

to restrict it to those, I think you should just show 5

on a sentence or a phrase that says, or other detectors 6

that provide acceptable readings. I think that many 7

people who read this will actually be guided by the fact 8

that some of these detectors are named rather than just 9

talking about ones that are only acceptable. 10

They'll say, well what are they and how do 11

we find out? So I accept your recommendation, but think 12

this should be an addendum to what's already here. 13

MEMBER ENNIS: Are there specifics that we 14

would need to stipulate in what is considered an 15

acceptable? 16

CHAIRMAN THOMADSEN: Well, and that's a good 17

question for both of those detectors too. Because you 18

can have a sodium iodide meter that has a thick enough 19

shield around the detector that it won't measure the 20

radiation from the iodine. And likewise, the GM 21

counter. 22

So even with those, you would need to 23

specify that the detectors have demonstrated the 24

capability to detect the radiation from the sources at 25

75


the radiation level. Which is usually probably with 1

that same source. 2

MEMBER ENNIS: So are we going to be 3

requiring people to demonstrate ex vivo and how are we 4

going to -- are we going to now have a whole kind of 5

requirement and documentation before using whatever 6

detector -- is that what we're talking about? 7

CHAIRMAN THOMADSEN: Well, it doesn't sound 8

like a bad idea. If you're going to parallel, for 9

example, with a prostate implant, for looking for lost 10

seeds in the operating room, you have to check that the 11

radiation detector is capable of detecting the seeds. 12

MEMBER LANGHORST: This is Sue Langhorst. 13


MEMBER LANGHORST: When a licensee requests 15

approval to do such things, that's part of what the 16

regulators review is whether they have adequate 17

equipment to perform surveys and so on. So I think -- 18

I agree with Dr. Thomadsen that we should probably just 19

say that it's a survey meter capable of detecting the 20

seed activity. And you might say, for example, and you 21

may list a few of these things. 22

But I think it doesn't have to go beyond 23

that. We may want to include in there caution about 24

being able to see the seeds in light of other nuclear 25

76


medicine procedures that may be impacting a given 1

patient. Mr. Sheetz has that in one of his comments -- 2


MEMBER LANGHORST: -- on the report. Thank 4

you. 5

MEMBER ENNIS: Thank you, Sue. 6

MEMBER ZANZONICO: This is Pat Zanzonico. 7

Yes. I think we could easily revise this paragraph to 8

incorporate all these concerns. But we may not be able 9

to do the word-smithing in real time. 10

CHAIRMAN THOMADSEN: Oh, I wouldn't think 11

you'd want to. 12


MEMBER ZANZONICO: Okay. 14

CHAIRMAN THOMADSEN: That would be 15

difficult, yes. 16

MEMBER ENNIS: Very well. Any other 17

comments on this topic? Dr. Thomadsen, do you have any 18

more? 19

CHAIRMAN THOMADSEN: No. I'm done. Thank 20

you. 21

MEMBER ENNIS: Thank you very much. Any 22

other Committee members have any other questions or 23

comments? 24


77


Langhorst again. 1


MEMBER LANGHORST: I wanted to ask about 3

whether the subcommittee might want to consider 4

including -- and I've lost my place as to exactly where 5

that should be. But as far as patient intervention 6

goes, defining if the patient is not able to have surgery 7

when scheduled, would that be -- like the patient doesn't 8

come back or something to that effect, would that be 9

considered patient intervention? 10

MEMBER ENNIS: That was our thinking and 11

understanding in our committee discussions, yes. 12

MEMBER LANGHORST: This is Sue again. We 13

may want to specify that a little bit more clearly. 14

Because I didn't get that out of what I read. 15

MEMBER ENNIS: Thoughts from any other 16

Committee members on that particular issue? Okay. We 17

will consider that as well. Any other comments or 18

questions? 19

MEMBER PALESTRO: Yes. Chris Palestro. I 20

have one question. On your presentation, Slide Number 21

7, addressing breast-feeding and a recommendation that 22

it be deferred until such time as the seed or seeds are 23

removed. What happens in the case of a ruptured or 24

transected seed? 25

78


MEMBER ENNIS: Well, I guess this would come 1

under the recommendation that guidelines be put into 2

place -- I don't know that we are going to mandate those 3

guidelines. We talked elsewhere about putting into 4

place guidelines should a seed rupture, and I guess this 5

would fall under that. 6

I don't know that we would as a guidance 7

go beyond that. I'm certainly interested in what other 8

people have to say. Wearing my medical hat, I would say 9

that the patient would be advised not to breast-feed 10

until X number of half-lives have passed. Probably 11

many. 12

MEMBER PALESTRO: Thank you. 13

MEMBER ZANZONICO: This is Pat Zanzonico. 14

Yes. I mean, it would obviously be unfortunate and 15

hopefully very rare, but I think to be internally 16

consistent, if the seed were ruptured and the activity 17

were not retrievable, the only logical course of action 18

would be to have the patient discontinue breast-feeding 19

until physical decay has effectively eliminated the 20

activity. 21

MEMBER ENNIS: Well, I guess the question 22

on the table though is, is this something that ought 23

to be written into guidance language? 24


79


Thomadsen. It actually sounds reasonable to have it in 1

there. I hadn't thought of it. 2

MEMBER WEIL: This is Laura Weil. May I 3

suggest something? 4

MEMBER ENNIS: Please. 5

MEMBER WEIL: In that bullet point, perhaps 6

what needs to be communicated is that the patient should 7

be advised not to breast-feed with the breast into which 8

an intact seed has been implanted and successfully 9

removed. And all those other unfortunately situations 10

would then default to a different set of precautions. 11

VICE CHAIRMAN ALDERSON: This is Phil 12

Alderson. I was thinking of an example of how could this 13

possibly happen. And the one thing I could come up with 14

is that the person who has the seed implanted and also 15

is breast-feeding, which is, again, probably unlikely, 16

but in any case, is in a modest automobile accident where 17

they are pushed forward into a steering wheel or 18

something. And that blunt impact on the anterior chest 19

wall ruptures the seed while it's actually in their 20

breast and before they have everything done and the 21

seed's removed. 22

So this could happen. And in that sense, 23

I would agree with whoever it was that stated that 24

perhaps we should include some language that the public 25

80


would easily understand in that regard. 1

MEMBER ENNIS: Okay. Then we should come up 2

with some language accordingly. And I guess the key 3

thing really would be how many half-lives. 4

VICE CHAIRMAN ALDERSON: Ten. 5

MEMBER ENNIS: Very good. 6

MEMBER LANGHORST: Hi, this is -- Dr. Ennis, 7

this is Sue Langhorst again. 8


MEMBER LANGHORST: I had a question on 10

training for authorized users. Because the 11

subcommittee's not suggesting any changes in the 12

training requirements, does that mean that an authorized 13

user who is not a 490 authorized user, they cannot train 14

anyone else? 15

MEMBER ENNIS: So, are you asking that 16

someone who is a 290 who has already been trained, can 17

he or she subsequently train someone else? 18

MEMBER LANGHORST: Yes. Because I think 19

that was one of the questions of whether a new person 20

being trained -- they couldn't be trained by a 290 21

authorized user who's been approved for this procedure, 22

because that person is not a 490 trained authorized user. 23

MEMBER ENNIS: Right. Yes, that was raised 24

by the comments from the users. Other members of the 25

81


Committee can obviously speak as well. Becoming an 1

authorized user for RSL, I don't know, is there a way 2

in regulatory space that, that person has a designation 3

of some type? That can -- I don't know. This is more 4

of a regulatory language and process question, I think, 5

that I'm a little less familiar on being new to the 6

Committee. 7

MEMBER LANGHORST: I think the regulatory 8

language, and NRC staff can help me on this, is on the 9

-- when it talks about getting training from an 10

individual, it talks about someone who's approved in 11

that procedure. I don't have that pulled up in front 12

of me. But I think -- 13

MS. HOLIDAY: It's on the screen, Dr. 14

Langhorst. 15

MEMBER LANGHORST: This is from the report 16

or this is the regulations? 17

MS. HOLIDAY: This is from the current 18

35.1000 guidance. 19

MEMBER LANGHORST: Okay. Sorry, I'm going 20

to have to read it. I can't speak and read at the same 21

time. 22


MEMBER LANGHORST: I take it back. 24

DR. HOWE: This is Dr. Howe. In partial 25

82


response to, I believe, your question or statement. 1

When someone is authorized for a 35.1000 use, at least 2

on an NRC license, then they are authorized for that 3

particular NRC 35.1000 use. And so that authorized user 4

would be listed for radioseed localization. 5

One of the concerns for having training from 6

the 35.490 is that many of the requirements for keeping 7

an inventory and accounting for seeds are significantly 8

different from what an authorized user is normally doing 9

in 35.200 uses. 10

MEMBER ENNIS: Right. That is -- 11

CHAIRMAN THOMADSEN: It seems like -- 12

MEMBER ENNIS: -- the advantage -- 13

CHAIRMAN THOMADSEN: -- the question might 14

be, though, that if somebody has trained under Part 1000 15

for this procedure, could they then act as a preceptor 16

and trainer for somebody else for this procedure? 17

MEMBER ENNIS: Right. That is exactly the 18

question on the table right now. 19


again. I think they would be the best ones to be giving 21

that training specific for this 35.1000 use. 22

VICE CHAIRMAN ALDERSON: This is Alderson. 23

I think they would be good trainers also. 24

CHAIRMAN THOMADSEN: And this is Bruce. I 25

83


agree. 1

MEMBER LANGHORST: So this is Sue again. I 2

would recommend that the subcommittee maybe work on that 3

wording just to make sure to clarify that, that's what 4

they're meaning. That a person who may have originally 5

the 290 training, that once they become an authorized 6

user for this seed localization under 35.1000, that they 7

may act as a trainer and preceptor for other authorized 8

users or other 290 users who want to become seed 9

localization authorized users. 10

MEMBER ENNIS: Right. And again, this would 11

not be a generalizable thing. This can be made to be 12

a specific that they're trained in this specific one 13

and they can precept in this specific one. Dr. Howe, 14

am I understanding that correct? 15

DR. HOWE: Could you repeat? 16

MEMBER ENNIS: Just clarifying your 17

comments. I think I understood it correctly, but we 18

could stipulate that a 290 who is specifically approved 19

in the 35.1000 RSL, very specifically could then be a 20

preceptor and that would not be generalizable to other 21

35.1000 or other things. It could be made that 22

specific. 23

DR. HOWE: Yes. It would not extend to any 24

other 35.1000 use. 25

84


MEMBER ENNIS: Thank you. All right. The 1

subcommittee will consider this as well. 2


again, Dr. Ennis. And one thing I just want to say is, 4

I really appreciate the subcommittee's work on all this. 5

I think you guys did a marvelous job on this and 6

appreciate all your thoughts and discussions in this 7

request to update a very old guidance document that was 8

much needed. 9

MEMBER ENNIS: On behalf of the committee, 10

we accept your compliments. 11

(Laughter.) 12

MEMBER ENNIS: Any other questions or 13

comments from the Committee? Okay. I guess we will now 14

open the floor for comments or questions from the public. 15

MR. LIETO: Question. 16

MEMBER ENNIS: Yes. Is there a question? 17

MR. LIETO: This is Ralph Lieto from St. 18

Joseph Mercy Hospital in Ann Arbor. Can you hear me? 19

MEMBER ENNIS: Yes, we can. Please go 20

ahead. 21

MR. LIETO: I had just a couple questions. 22

On your Written Directive recommendations, your subpart 23

II for after implantation. The very last criteria there 24

where it says total activity implanted and exposure 25

85


time/time planned before surgery. Is the exposure time 1

and the time planned before surgery supposed to be both 2

a criteria of the Written Directive? Or is it one -- 3

MEMBER ENNIS: So -- 4

MR. LIETO: -- or the other? 5

MEMBER ENNIS: I suppose we should clarify 6

that language. Exposure time seems to be an older 7

phrase from more of a therapeutic type of concept. And 8

what we really meant was time from the implantation until 9

it's supposed to be removed at surgery. Perhaps we 10

should take out the exposure time phrase completely. 11

MR. LIETO: I take it that the intent was 12

sort of like the old cesium implant sources that were 13

-- 14

MEMBER ENNIS: Correct. 15

MR. LIETO: -- specified by you were going 16

to take it out at a certain time. 17

MEMBER ENNIS: Yes. Correct. It's coming 18

from that language base. That's correct. 19

MR. LIETO: Okay. Related to that is the -- 20

in terms of activity implanted, did the subcommittee 21

give any consideration to the activity being a range 22

with the seeds? I think -- 23

MEMBER ENNIS: Make a case -- 24

MR. LIETO: I just think that things are 25

86


being - 1

MEMBER ENNIS: Make a case why that would 2

be -- 3

MR. LIETO: Well, I -- 4

MEMBER ENNIS: -- a situation. 5

MR. LIETO: Well, I'm just thinking that a 6

Written Directive would allow -- if it was more than 7

one seed, rather than specifying the activity per seed, 8

you would say X seeds, say 3 seeds between 0.2 and 0.3 9

millicuries. Because the sense of the report is that 10

it's written as if you're doing a -- that dose is the 11

priority here. Absorbed dose is the priority in 12

consideration of these implants, when really whether 13

you're using 0.2 or 0.3 millicurie seed is really 14

immaterial for, at least, the purposes of the study. 15

And I think you might want to consider some 16

flexibility to permit a range or so forth, a range of 17

activity of seeds that could be used and not get into 18

where you could potentially then fall into a Written 19

Directive -- or excuse me, a medical event, from the 20

way the Written Directive is done. 21

MEMBER ENNIS: It seems that, other 22

Committee members can certainly speak, but it seems to 23

me that when you're putting a particular seed in a 24

particular patient, you know which seed it is and you 25

87


ought to know which seed it is and not just be fishing 1

them out from a bucket. I don't really quite get how 2

this is really, from a practical point of view, a 3

concern. 4

MR. LIETO: Well, all right. Well, just 5

like I said, I just thought it might be a consideration 6

for how these seeds are, how the prescription is written 7

for the Written Directive. Because I could see that 8

there could be a facility that would be using spent 9

brachytherapy seeds where they would have a range of 10

seeds of availability for this type of purpose. And 11

just give that type of flexibility rather than overly 12

prescriptive nature for what's being prescribed. My 13

next question had to do -- 14

CHAIRMAN THOMADSEN: Could I just make a 15

suggestion on that though? 16

MEMBER ENNIS: Please. 17

CHAIRMAN THOMADSEN: In that type of 18

situation --- this is Bruce Thomadsen. In that type of 19

a situation, if they have a brachytherapy program, they 20

should be able to measure the activity and know the 21

actual activity of that given seed, no? 22

MR. LIETO: Agreed. 23


CHAIRMAN THOMADSEN: It's still good to hear 25

88


from you, Ralph. 1

MR. LIETO: Thank you. It's good to 2

participate. My next question had to do with the 3

medical event recommendations. I wasn't sure, are you 4

recommending that this be the changes to the Part 35 5

definition? 6

MEMBER ENNIS: No. This is for this 7

particular guidance only. 8

MR. LIETO: Well, I guess, might not be able 9

to be answered now, but I'd like to understand from NRC 10

staff how you can change an ME definition in guidance 11

space. I could understand that there might be 12

designations that you would want maybe some follow-up 13

action on, such as if the source had to be in there, 14

say, 20 percent longer in time, which might be due to 15

some event that's beyond the licensee's control. 16

But I guess I'd be really concerned about 17

the precedent that would be set in changing an ME 18

definition in guidance space. Because I could see a 19

number of other applications where there might be the 20

interest to do this for other Part 1000 uses -- 21

CHAIRMAN THOMADSEN: This is -- 22

MR. LIETO: -- which -- 23

CHAIRMAN THOMADSEN: This is Bruce. And you 24

already have that going on with the microspheres. 25

89


DR. HOWE: Correct. Dr. Thomadsen, if I 1

could answer that? This is Dr. Howe. When we look at 2

35.1000 guidance, we are looking at the unique 3

characteristics of the particular device or use and if 4

it has a unique characteristic that would prevent it 5

from meeting part of the requirement, we can modify the 6

guidance so that it meets kind of the standard of what 7

the guidance is looking for, but may be particular to 8

this use. 9

And as you stated, in the yttrium-90 10

microspheres, we recognize that stasis would always lead 11

to a medical event. And so we said that you could write 12

stasis in the Written Directive and if you reach stasis, 13

that would not be a medical event. And we have other 14

35.1000 guidance where we've manipulated the medical 15

event reporting requirements to fit the unique 16

properties of that particular medical use. So this not 17

a precedent. 18

MR. LIETO: But this is not a unique source, 19

unlike the Y-90 brachytherapy. Okay. This is a low 20

dose sealed source used in brachytherapy applications. 21

I mean, I guess I'm trying to understand why this unique 22

for this type of application, yet iodine, palladium, 23

whatever that's applied to prostate or lung or so forth, 24

would not have the potential for having these same types 25

90


of applications. 1


Thomadsen again. You could also look at capsules with 3

iodine-131, sodium iodide used for imaging and for 4

therapy, the same capsule with the same radionuclide, 5

just with different activities, would be used for each. 6

That's the procedure that's defining whether you would 7

fall under medical event reporting in one way or another 8

that way. 9

MR. LIETO: I'm sorry, Bruce. I'm not sure 10

if I'm following your -- the capsules are not considered 11

sealed sources. 12

CHAIRMAN THOMADSEN: No. I'm just saying, 13

we have an analogous situation where we have the same 14

radionuclide delivered in the same way, but used in one 15

case for diagnosis and for another case for therapy. 16

And yet if we have a difference of 20 percent in dose 17

in one case, with the therapy, it's an event. Whereas, 18

if it's a 20 percent difference in the imaging, it's 19

not an event. 20

So, the procedure itself can be demarcating 21

the rules for medical event reporting. And in this 22

case, you have the same source and in the same form, 23

yet the procedure itself is very different. In this 24

case, it's much more like an imaging study. Whereas, 25

91


in brachytherapy, it's therapy. 1

MR. LIETO: No. I guess I would disagree. 2

The analogy you're using with I-131 would not -- I mean, 3

they're both capsules given orally, it's just the 4

difference in activity that's administered. That's the 5

only criteria difference. And the physical form 6

difference is the same. I mean, physical form is the 7

same. There's not a difference. 8

I mean, you're adding a medical event 9

definition for a diagnostic procedure based on time that 10

the source is left in the patient. I mean, you're 11

creating some unique medical event definitions for a 12

diagnostic procedure. I just think that there's going 13

to be some real difficulty with these added restrictions 14

or prescriptive definition of a medical event. Because 15

I'm assuming these do encompass the current definition, 16

you're adding other specific criteria. 17

MEMBER ENNIS: Anyone have any comments? 18

MEMBER ZANZONICO: Well, this is Pat. I 19

mean, I appreciate the importance of precedence, but 20

apparently, even though this is an existing source, it 21

is a distinct application. And as was pointed out, 22

there is a precedence for defining medical events in 23

guidance space. So I think given that it's specific for 24

this application, I think the potential for abuse of 25

92


this practice is avoided. And I personally -- 1

MR. LIETO: What is -- 2

MEMBER ZANZONICO: -- don't have any real 3

concern with defining a medical event for the 4

radioactive seed localization as it's been recommended 5

in the subcommittee's report. 6

MR. LIETO: Dr. Ennis, what is the problem 7

that you're trying to solve that the current definition 8

does not address? 9

MEMBER ENNIS: The main issue has to do with 10

removing any issues of dose, since dose is not really 11

relevant. But keeping the spirit of making sure the 12

source is safely implanted and explanted and the 13

exposure to patient's surrounding tissues is aligned, 14

is what was intended. 15

MR. LIETO: So the current definition is an 16

activity-based, and that's what you're trying to 17

demonstrate here, correct? 18

MEMBER ENNIS: This is an activity-based 19

definition, correct. 20

MR. LIETO: Well, I guess why then the time 21

issue being entered into the definition? If the right 22

activity is put in and so forth, it still seems like 23

you've got this dose characteristic associated with it 24

indirectly. 25

93


MEMBER ENNIS: Right. Well, I guess there 1

-- I mean, there certainly is an exposure element here. 2

There's no doubt that the reason this can be regulated 3

this way as opposed to like a permanent seed implant 4

is because, one of the elements is because of the short 5

time it's expected to be in the breast. There is no doubt 6

that's part of why regulations can be a little different. 7

And this is a way of assuring that, that's happening. 8

MR. LIETO: I appreciate that and I guess 9

I respectfully will just, I guess, have to agree to 10

disagree on that issue. 11

MR. FULLER: Dr. Ennis, this is Mike Fuller 12

with the NRC. If I may? 13

MEMBER ENNIS: Sure. Please, Mike. 14

MR. FULLER: Mr. Lieto, this is Mike Fuller, 15

as I said. To allow this to go ahead and proceed, I think 16

there's a lot of information that we could provide you 17

offline. 18

If you wanted to contact me after this 19

meeting, I'd be happy to walk you through a lot of the 20

things that are in the existing 35.1000 guidance right 21

after seed localization studies. And then, maybe help 22

that way. But rather than take the time in this meeting, 23

maybe I could help you offline. 24

MR. LIETO: Fair enough. Thank you. 25

94


MEMBER ENNIS: Are there any other comments 1

from the public? 2

MEMBER MATTMULLER: Yes. Well, actually 3

from the Committee. This is Steve Mattmuller. And I 4

just noticed in our package, there was a letter from 5

Michael Sheetz and Jeffrey Brunette, both health 6

physicists, in regards to this topic. And it seems they 7

have some differing opinions to what the Committee came 8

up with. So I guess my real question is, had you had 9

a chance to read this and to evaluate their comments 10

in formulating your -- 11

MEMBER ENNIS: So we had their presentation 12

that they made to our Committee a couple months ago. 13

We only recently received their response. As a 14

subcommittee, we have not met or decided whether to meet 15

to discuss their response to our posted guidance. Most 16

of what's in there has either been addressed, actually, 17

in this conversation or is just, frankly, a repeat of 18

a position they had already presented once that we may 19

have not agreed with. 20

MEMBER MATTMULLER: Okay. That's fine. I 21

just thought as a public meeting, since their comments 22

had been submitted, we should acknowledge that. So, 23

thank you. 24

MEMBER ENNIS: Sure. Thank you. 25

95


MR. SHEETZ: This is Mike Sheetz. I guess 1

I would like to make comments. 2

MEMBER ENNIS: Sure. Please go ahead. 3

MR. SHEETZ: -- Appropriate time. We have 4

submitted written comments. Both Jeff Brunette and I 5

have active programs. Ms. Holiday, I'm not sure if it's 6

possible to bring up our document? It may be easier if 7

somebody can see the responses or our comments. 8

MS. HOLIDAY: Sure. Let me pull them up. 9

MR. SHEETZ: Okay. And I wish to thank the 10

ACMUI for establishing a subcommittee to review the 11

NRC's guidance document on RSL and presenting 12

recommendations and the draft report. And while we 13

support most of the recommendations from the 14

subcommittee, there are a couple areas where we think 15

there could be some alternatives made to make the 16

guidance more relevant to the way the procedure's 17

performed. And to be able to increase patient access 18

and still maintain a high level of safety. 19

MEMBER ENNIS: Mr. Sheetz, I would just ask 20

you if you would in this conversation, to make clear 21

how this is different than what you presented already. 22

Since we certainly have heard your previous presentation 23

and taken that into consideration. 24

MR. SHEETZ: Okay. The one comment was 25

96


already, with respect to the qualifications for the 1

authorized user has already been discussed. With 2

respect to an authorized user being approved for RSL 3

through the 290 pathway, that they be allowed to be the 4

preceptor for another 290 authorized user in the process 5

to become approved. And so once -- 6

MEMBER ENNIS: Yes. We discussed -- 7

MR. SHEETZ: -- an authorized user is 8

approved -- we discussed that. The main point on the 9

authorized user is that both the current NRC guidance 10

document and the ACMUI's subcommittee report states or 11

implies that only an authorized user may implant a seed 12

for RSL. 13

In 10 CFR 35.27, use of radioactive 14

materials by individuals working under the supervision 15

of an AU is permitted under certain conditions. And so 16

obviously, the RSL procedure involves implanting a seed, 17

removing a seed, and extracting the seed from the 18

specimen, where the last two procedures are performed 19

by individuals working under the supervision of the AU. 20

And so, I don't see why a radiologist 21

trained in the procedure cannot implant a seed under 22

the supervision of an AU. There's no other precedent 23

in the current regulations or in Part 35 that requires 24

the use of the radioactive material to only be performed 25

97


by the AU. So it's unprecedented. 1

And this is not a therapeutic procedure. 2

It's very similar to radiologists administering, 3

injecting technetium sulfur colloid for sentinel node 4

biopsy procedures. They're not authorized users. 5

They're not nuclear medicine physicians. They're 6

radiologists. And so this is a very similar situation. 7

And radiologists by training -- 8

MEMBER ENNIS: Well, again, the first -- if 9

you just clarify how this is different than what you 10

discussed at the prior presentation. 11

MR. SHEETZ: Well, I guess I'm trying to 12

clarify and make sure that it was understood on -- 13


MR. SHEETZ: -- how this procedure was 15

performed. That this procedure is performed by 16

radiologists who routinely implant clips to mark biopsy 17

sites and wires to localize lesions. And so implanting 18

the seed is a very equivalent procedure. But the 19

radiologist may not qualify as an authorized user under 20

290, due to when their training occurred and so forth. 21

MEMBER ENNIS: There are pathways to deal 22

with that. 23

MEMBER LANGHORST: Hi, this is Sue 24

Langhorst. 25

98


MEMBER ENNIS: Yes, Sue. 1

MEMBER LANGHORST: May I ask a quick question 2

on that? So, the subcommittee believes that the 3

authorized user is the only individual who can implant 4

the seed? No radiation worker or other worker can work 5

under their supervision to do so? Is that your intent? 6


MEMBER LANGHORST: Okay. I disagree with 8

that. I agree with Mr. Sheetz on -- we have other 9

individuals who work under the supervision of the 10

authorized user and I think that could happen in this 11

case. Thank you. 12

CHAIRMAN THOMADSEN: Yes. A common example 13

is, once again, the microspheres. Where the 14

microspheres are usually administered by an 15

interventional radiologist while the authorized user 16

may be the radiation oncologist or a nuclear medicine 17

physician. 18

MR. LIETO: Comment please? Not from the 19

Committee. 20


MR. LIETO: This is Ralph Lieto again. I 22

would endorse both Sue and Mr. Sheetz also. I mean, your 23

nuclear medicine technologists are not AUs and they're 24

administering activities orders of magnitude greater 25

99


than this per patient multiple times a day. And they're 1

not an AU. 2

And at our institution, actually the 3

technologists are the ones that do inject activity for 4

sentinel lymph node studies. They've been trained and 5

they do it under the supervision of an AU, but the AU 6

is not standing next to them when they do it. I think 7

this is just almost a total analogy to those types of 8

situations. 9

MEMBER ENNIS: I guess the subcommittee will 10

reconsider this issue. 11

MR. SHEETZ: This is Mike Sheetz again. 12

With respect to the Written Directive, a couple of 13

comments. That I think that the Written Directive 14

should be able to be signed by the individual working 15

under the supervision of the AU. Should that come to 16

be. I also think that it should be the prescribed 17

activity or activity range per source that's identified 18

under I. 19

MEMBER ENNIS: Prescribed activity -- 20

MR. SHEETZ: And on top of what -- 21

MEMBER ENNIS: -- as opposed to what? 22

MR. SHEETZ: As opposed to just activity. 23

MEMBER ENNIS: And what's the difference? 24

MR. SHEETZ: Because there are protocols for 25

100


diagnostic studies that state that this is the activity 1

or this is the activity range that is intended to be 2

administered for the procedure. Again, this is not 3

therapy. And I would contend that the activity range 4

should be allowed as is done in other diagnostic studies. 5

And the reason for that is we order many 6

seeds and store them for use. And so we don't know what 7

the exact activity is going to be on that day. Well, 8

we can look it up and that's not necessarily what was 9

prescribed. And as stated earlier, we would accept any 10

activity from 50 microcuries to 200 microcuries. 11

So the exact activity is really irrelevant. 12

And so from a procedural standpoint, it would be more 13

convenient to be able to prescribe this activity range 14

as is permitted elsewhere. 15

And then with respect to after 16

implantation, instead of exposure time and time planned 17

for surgery, I would simply say the scheduled surgery 18

date. Since, again, exposure time is not pertinent. 19

It's really when the surgery is scheduled. 20

MEMBER ENNIS: Any comments for Mr. Sheetz? 21

MEMBER ZANZONICO: This is Pat Zanzonico, 22

a member of the subcommittee. I think there have been 23

a lot of good points raised in Mr. Sheetz's document 24

and being discussed here. And I think as Dr. Ennis said, 25

101


they need to be considered carefully and perhaps that 1

best would be done offline rather than trying to make 2

any sort of decision at this time. 3

VICE CHAIRMAN ALDERSON: Yes. This is 4

Alderson, also a member of the subcommittee. I agree 5

with Dr. Zanzonico. 6

MEMBER ENNIS: Very good then. Our 7

subcommittee will schedule a follow-up meeting to 8

discuss the issues raised. 9

CHAIRMAN THOMADSEN: I have -- this is Bruce 10

Thomadsen. And I have one more that I forgot about, but 11

it came out just with what's on the screen right now. 12

And that is, since these are brachytherapy sources, 13

rather than activity, it should be source [strength]. 14

MEMBER ENNIS: I'm sorry. Bruce? 15

CHAIRMAN THOMADSEN: Rather than activity 16

or activity range or whatever you end up with that, it 17

should be source strength. 18

MR. SHEETZ: Well, again, these are not used 19

for therapy and so we're going to use the manufacturer's 20

rated activity. 21

CHAIRMAN THOMADSEN: I understand that and 22

the professional organizations are trying to move the 23

manufacturers away from activity altogether and it seems 24

counterproductive to have that written into regulatory 25

102


guidance here when the activity itself can't really be 1

specified for these sources meaningfully. Just like in 2

the brachytherapy Written Directive, it's not activity, 3

it's source strength actually. 4

MEMBER ENNIS: That is good. Are there any 5

other comments for discussion? 6

MR. SHEETZ: I'm not sure if you wanted me 7

to continue through for the other items in the document 8

or you were going to look at them and then evaluate. 9

MEMBER ENNIS: I mean, if there's something 10

new, I'm happy for you to discuss it please. 11

MR. SHEETZ: Well, there is in the medical 12

event since you included some sieverts criteria. I 13

would recommend that under A, IV, and V, or Four and 14

Five, that the medical event definition for RSL included 15

a dose threshold of 0.5 sieverts to tissue at one 16

centimeter so that we bring this back to a dose threshold 17

base, which all other medical events are conditional 18

on. 19

So this goes back to the previous discussion 20

on modifying the definition of a medical event, which 21

I think is certainly appropriate. Because it's a 22

different procedure and it's covered under 35.1000. 23

But I think -- 24

MEMBER ENNIS: It strikes me as a little -- 25

103


MR. SHEETZ: -- those criteria -- 1

MEMBER ENNIS: Go ahead. 2

MR. SHEETZ: But I think the criteria under 3

IV and IV(1) is the administration of the byproduct 4

materials more than 20 percent longer than planned or 5

administration of the byproduct material of more than 6

20 percent of what's intended. 7

I think there should be a dose threshold 8

tied to that, i.e. greater than 0.5 sieverts, 20 percent 9

longer than planned if the surgery is scheduled that 10

same day and it goes for more than five hours from what 11

the time was scheduled, it becomes a medical event. So 12

20 percent is approximately five hours per day. 13

MEMBER ENNIS: Right. So, but the whole 14

point of this, of course, is not have to do it the same 15

day because it's more convenient. So I don't know that 16

it's a realistic scenario and I do find it a little ironic 17

that we spent a lot of time talking about how there's 18

very little dose and it's not a dose, we're not 19

delivering dose, and yet we want to yet include those 20

now. 21

MR. SHEETZ: I want to include a dose 22

threshold. I have no problem with the criteria where 23

surgery was delayed or scheduled or the activity 24

implanted was outside of what was prescribed range or 25

104


outside of plus/minus 20 percent prescribed. But there 1

should be a dose threshold tied to it as there is with 2

any other procedure under medical event. 3

MEMBER ZANZONICO: This Pat Zanzonico. I 4

just think a dose threshold as a criteria for medical 5

event, not matter how it's parsed, just becomes very 6

problematic in practice. And I think the criteria for 7

medical event are designed to identify where something, 8

for lack of a better term, incorrect was done on the 9

part of the caregiver. Like the seed was left in place 10

longer than intended, other than patient intervention. 11

And it just strikes me that a dose threshold just becomes 12

very problematic in practice. 13


Langhorst. 15


MEMBER LANGHORST: In 10 CFR 35.3045, that's 17

report and notification of medical event, I think what 18

Mr. Sheetz is asking for is that the subcommittee include 19

that first statement that all medical events there is 20

a dose threshold that has to be met before it's a medical 21

event. And so it's in the regulations right now and I 22

think that's all Mr. Sheetz is asking is if you're going 23

to include the whole medical event, that you include 24

that part also. 25

105


MEMBER ENNIS: Yes. No, I understand that. 1

Although there is, as you, I think, well know, a move 2

to move away from dose when it comes to the definition 3

of medical events in permanent brachytherapy. So I 4

don't know that it's true going forward that all medical 5

events are defined by dose. 6

As Pat was alluding to, it sounds to me it 7

would be challenging for the team, who doesn't think 8

in dose and has argued so strongly that they don't need 9

to or want to think in dose, to then have to think in 10

dose to decide whether or not something was a medical 11

event and not having the tools to estimate dose 12

potentially. It seems like it's creating problems that 13

is much cleaner if we avoid. 14

MR. SHEETZ: But the dose threshold is 15

already there for, say, diagnostic procedures. And so 16

if the dose left in the seed, the 0.5 sieverts or effect 17

dose equivalent dose threshold, then it doesn't rise 18

to the level of a medical event, does not need to be 19

reported. 20

And so that's all I'm asking for here is 21

that if a certain dose threshold, i.e. 0.5 sieverts to 22

tissue at one centimeter, which is a look-up table. So 23

there's no calculation really on the part of the 24

licensee. It depends on the seed activity and the 25

106


length of time implanted. So it's a very simply look-up 1

table type of calculation. 2

MR. LIETO: Comment, please? 3

MEMBER ENNIS: Yes, please comment. 4

MR. LIETO: This is Ralph Lieto. I think the 5

problematic part of the medical event definition is IV 6

there which -- because all the other ones are pretty 7

much, I think, very prescriptive in terms of it either 8

happened or it didn't or the activity is what it is or 9

it isn't. It's that time factor that gets into that 20 10

percent longer. 11

Is there something that maybe could be done 12

by the subcommittee in addressing maybe events that 13

might cause delays, therefore the dose would be higher 14

than that 20 percent? Mr. Sheetz alluded to the fact 15

that a surgical schedule delay could put things back 16

several hours or maybe even until the next morning. 17

Is there some way to maybe address that 18

specific issue? Which gets to, I think, the only part 19

of that definition that gets to a dose issue where you'd 20

need to be concerned about a threshold. 21

MEMBER ENNIS: In the subcommittee's future 22

meeting, we will certainly discuss this issue. Does 23

anyone have any comments for the moment? 24

MR. SHEETZ: If I can also state with respect 25

107


to the source activity verification previously 1

discussed. It's really impractical. Most everybody 2

is using the pre-loaded seeds and needles, coming in 3

a sterile package. 4

It is impractical to assay this in a dose 5

calibrator or any other type of equipment without 6

breaking sterility. There's always a stainless steel 7

or lead sleeve shielding it, so you'd have to take that 8

off to put it into the dose calibrator or other 9

instrument. 10

Again, would compromise sterility. Again, 11

in 35.4323B for brachytherapy sources, you're allowed 12

to reference the manufacturer's source strength or 13

activity. So, why not for RSL? 14

MEMBER ENNIS: Yes. And of course, then you 15

have a very specific activity, not an activity range. 16

MR. SHEETZ: Right. I previously presented 17

as far as imagining being able to substitute for the 18

survey. I see the Committee feels strong that the 19

survey be performed and the imaging should not be able 20

to substitute for that. 21

I would still contend that there's not going 22

to be confusion in interpreting the image with respect 23

to a seed or a clip. Radiologists are trained and very 24

adept at identifying a seed and can certainly 25

108


differentiate between the two. 1

And in fact, if you use a sodium iodide or 2

GM meter in the OR environment, where there is 3

technetium, you would be confused because you couldn't 4

tell whether it was activity coming from technetium or 5

from the iodine-125 seed. So I would ask you reconsider 6

also that the imaging may be satisfactory to replace 7

the survey. 8

And then also with respect to the 9

instrumentation, the instrument that is used in the 10

operating environment by the surgeon is a gamma probe. 11

Which does have the capability to window and 12

discriminate between different energies and different 13

isotopes. And that's the instrument really of choice 14

for doing the survey in the OR environment as far as 15

identifying the seed and make sure it's in the tissue 16

specimen and not in the cavity. 17

And then this instrument that does not fit 18

the standard annual calibration procedures. And so in 19

my previous presentation, it was the gamma probe that 20

I was looking to have exempt from an annual calibration 21

because it really doesn't get calibrated. It has its 22

own self-check every time you turn it on. I think the 23

sodium iodide or GM detector should still be subject 24

to annual calibration requirements. And that concludes 25

109


my comments. 1

MEMBER ENNIS: Thank you, Mr. Sheetz. Any 2

comments from anyone else? Okay. Hearing none, 3

Chairman Thomadsen? 4

CHAIRMAN THOMADSEN: Yes. Right 5

MEMBER ENNIS: Our subcommittee report 6

appears to be done. 7


And I would hope that your committee could report back 9

at the fall meeting. Does that seem reasonable? 10


CHAIRMAN THOMADSEN: Very good. Do we have 12

other items of business that anybody wishes to bring 13

up? Hearing none, thank you very much for your report. 14

Thank you very much for everybody's participation. And 15

we will see you in the fall. 16

(Whereupon, the above-entitled matter went 17

off the record at 4:37 p.m.) 18

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