ML24079A082

Draft for ACMUI Review - Yttrium-90 Microsphere Brachytherapy Sources and Device Eye90 Licensing Guidance

ML24079A082
Person / Time
Issue date:	03/19/2024
From:	Spence S NRC/NMSS/DMSST/MSEB
To:
Armstead L
References
Download: ML24079A082 (26)

Text

DRAFT FOR ACMUI REVIEW

DRAFT FOR ACMUI REVIEW Yttrium-90 Microsphere Brachytherapy Sources and Devices Eye90 Microspheres Licensing Guidance

[XXXX XX, 2023]

NRC Contact Sarah Spence MedicalQuestions.Resource@nrc.gov Table of Contents

1. Background............................................................................................................................ 1

2. 10 CFR 35.1000 Use............................................................................................................. 1

3. Licensing Guidance............................................................................................................... 2

4. General.................................................................................................................................. 2

4.1 Requirements not Specific to 10 CFR 35.1000 Use....................................................... 2

4.2 Radionuclides, Form, Possession Limits, and Purpose of Use...................................... 3

4.3 Facility Address and Description.................................................................................... 4

4.4 Leak Tests...................................................................................................................... 4

5. Training and Experience........................................................................................................ 4

5.1 Authorized Users............................................................................................................ 4

5.2 Radiation Safety Officer.................................................................................................. 9

5.3 Training and Experience Documentation....................................................................... 9

5.4 Team Approach.............................................................................................................. 9

5.5 Notification.................................................................................................................... 10

5.6 Grandfathering.............................................................................................................. 10

6. License Commitments......................................................................................................... 11

6.1 Procedures for Administration...................................................................................... 11

6.2 Written Directives......................................................................................................... 1 2

6.3 Medical Event Reporting.............................................................................................. 13

6.4 Sealed Source and Device Use.................................................................................... 14

6.5 Inventory....................................................................................................................... 15

6.6 Labeling........................................................................................................................ 15

6.7 Patient Release............................................................................................................ 1 5

6.8 Surveys......................................................................................................................... 15

i Draft for ACMUI Review 6.9 Radiation Protection Program Changes....................................................................... 17

7. Notes to Licensees.............................................................................................................. 18

7.1 Change in Physical Conditions of Use......................................................................... 18

7.2 Use of Other Y-90 Microspheres.................................................................................. 18

7.3 Waste Disposal Issues................................................................................................. 19

7.4 Autopsy and Cremation................................................................................................ 20

8. Notes to Regulators............................................................................................................. 21

8.1 Inspection Frequency................................................................................................... 21

8.2 Program Code.............................................................................................................. 21

9. Paperwork Reduction Act Statement................................................................................... 22

10. Public Protection Notification........................................................................................... 23

ii DRAFT FOR ACMUI REVIEW

1. Background This licensing guidance for yttrium-90 (Y-90) microsphere brach ytherapy is exclusively for the use of Eye90 microspheres. At the time of publication of this guidance, Eye90 microspher es is a new microsphere device approved by the Food and Drug Administration (FDA) under an Investigational Device Exemption (IDE) for clinical trial.

Eye90 microspheres are permanent implantable radiopaque glass Y-90 microspheres u sed for treatment of conditions of the liver. The microspheres are prov ided as a unit dose in 2.5 mL saline, contained in an acrylic shield. The microspheres are delivered to tumor vasculature via a catheter placed under fluoroscopy guidance using a proprietary delivery system comprised of a sterile, single-use delivery device and a re-useable, nonsterile system container. This product is unique to the existing FDA-approved Y-90 microsphere products at the t ime of publication, due to the radiopaque quality of the microspheres. The AU may choose to us e fluoroscopy to directly image the radiopaque microspheres in the tumor vasculature during adm inistration and via any x-ray imaging modality thereafter.

At the time of publication of this guidance, Eye90 microspheres does not have an SSDR safety certificate.

This document has been adapted from the existing guidance for o ther microsphere brachytherapy, Yttrium-90 Micros phere Brachytherapy Sources and Devices TheraSphere and SIR-Spheres Licensing Guidance (ML20080J208) revised in March 2020, to re flect necessary changes unique to Eye90 microspheres, in particular the ability to visualize the microspheres during administration via fluoroscopy. Because this product is new and still being investigated in early clinical trials at the time of publication, a separate gu idance was needed to facilitate any necessary future revisions as the NRC and medical communities g ain experience with Eye90 microspheres.

2. 10 CFR 35.1000 Use

Although Eye90 microspheres are manual brachytherapy sources used for permanent implantation therapy, Eye90 microspheres have many unique properties that merit radiation safety considerations other than those required by 10 CFR Part 35, Medical Use of Byproduct 1

DRAFT FOR ACMUI REVIEW Material, Subpart F, Manual Brachytherapy. These unique pro perties include the microspheres small size, the large number of microspheres used in a treatment, and the route of administration. As a result, Eye90 microspheres brachytherapy is regulated under 10 CFR 35.1000, Other medical uses of byproduct material or radiation from byproduct material1.

3. Licensing Guidance

This guidance provides applicants with an acceptable means of s atisfying the requirements for a license for the use of Eye90 microspheres and is not intended to be the only means of satisfying the requirements for a license. The applicant must submit the information required to meet 10 CFR 30.33 and 35.12, as described below. The applicant should submit additional information and commitments requested below or may, unless the information is specifically required by regulation, submit alternative information and comm itments for review by the NRC to make a licensing determination. The commitments incorporate d into the license by license condition will be reviewed during routine inspections. If an a pplicant commits to the guidance provided below, the applicant is committing to follow commitmen ts described with the use of the word should.

4. General

4.1 Requirements not Specific to 10 CFR 35.1000 Use

Applicants must commit to meet the general requirements in 10 C FR Part 35, Subpart A, General Information; Subpart B, General Administrative Requirements; Subpart C, General Technical Requirements; Subpart L, Records; Subpart M, Reports; and Subpart N, Enforcement, except as specified in this guidance. Additionally, applicants must meet applicable requirements of 10 CFR Part 19, Notices, Instructions and Reports to Worker s: Inspection and Investigations; Part 20, Standards for Protection Against Radiation; 2 Part 30, Rules of General Applicability to

1 10 CFR 35.1000 is designated as Compatibility Category D. Agreement States are not required to adopt these

regulations for purposes of compatibility but are not prohibited from adopting Compatibility Category D regulations if they so choose. If Agreement States choose to adopt this licensing guidance, references to 10 CFR should be changed to the equivalent Agreement State regulations.

2 Refer to IN-21-02 for further information regarding compliance with Part 20.

2 DRAFT FOR ACMUI REVIEW Domestic Licensing of Byproduct Material; and Part 71, Packag ing and Transformation of Radioactive Material.

4.2 Radionuclides, Form, Possession Limits, and Purpose of Use

Pursuant to 10 CFR 35.12, the applicant shall identify the radi onuclide, chemical/physical form, requested maximum possession limit, and purpose of use. This i nformation may be submitted under a signed, dated letter or NRC Form 313, Application for Materials License. The following table provides the format for an acceptable request.

Eye90 Microspheres Radionuclides Yttrium-90 (NRC Form 313 Item 5a)

Chemical/Physical Form Glass For broad scope (NRC Form 313 Item 5b) microsphere licensees using the SSD (current exemption in 10 CFR manufacturer as 35.15(g):

listed in the Glass microsphere (current Sealed Source manufacturer as approved and Device for IDE by the FDA [e.g.,

Registry [e.g., ABK Biomedical, Inc.

ABK Biomedical, Model Eye90 Inc. Model Eye90 microspheres])

microspheres])

Maximum Possession Limit X* Ci total (NRC Form 313 Item 5c)

3 DRAFT FOR ACMUI REVIEW Purpose of Use Eye90 For broad scope (NRC Form 313 Item 6) microspheres for licensees using the permanent SSD exemption in 10 brachytherapy using CFR 35.15(g):

delivery system as Eye90 microspheres listed in the Sealed for permanent Source and Device brachytherapy using Registry delivery system as described in the FDA-approved IDE research protocol

• Based on the maximum amount the applicant anticipates having at one time (i.e., 3 Ci)

4.3 Facility Address and Description

Provide an address of use and description of the location where the Eye90 microspheres will be used and stored.

4.4 Leak Tests

Leak tests are not required for Eye90 microspheres. The small size and large number of Y-90 microspheres make leak testing, as required by 10 CFR 35.67(b), impractical. Further, leak testing is not required as the activity of each Y-90 microspher e is below the threshold in 10 CFR 35.67(f)(3).

5. Training and Experience

5.1 Authorized Users NRC has determined that individuals meeting the Authorized User (AU) training and experience (T&E) criteria A, B, and C provided below can be authorized for the use of Eye90 microspheres brachytherapy. Applicants may also submit alternative T&E crit eria to be reviewed on a case-by-case basis by NRC staff. The alternative T&E commitments sh ould include an explanation of

4 DRAFT FOR ACMUI REVIEW why the applicant believes the alternative T&E commitments demo nstrate that the individuals are qualified to be an AU.

A.

1. Is identified as an AU for medical use in 10 CFR 35.1000 for Y-90 microspheres, 10 CFR 35.400, Use of sources for manual brachytherapy, or for medical use s in 10 CFR 35.300, Use of unsealed byproduct material for which a written direc tive is required, that includes the use described in 10 CFR 35.390(b) (1)(ii)(G)(3) on one of the following licenses or permits that authorizes the medical use o f byproduct material: A Commission or Agreement State license, a permit issued by a Com mission master materials licensee, a permit issued by a Commission or Agreemen t State licensee of broad scope, or a permit issued by a Commission master material s license broad scope permittee; or

2. Meets the training and experience requirements of 10 CFR 35.390 or 10 CFR 35.490; or

3. Meets the training and experience guidelines as follows:

i.

a. Experience in diagnostic radiology demonstrated by:

(a) Board certification in interventional radiology/diagnostic radiology by the American Board of Radiology (ABR) 2; or (b) Board certification in diagnostic radiology by the ABR 2; or (c) Board certification in diagnostic radiology by the American Osteopathic Board of Radiology (AOBR)3; or (d) Three years supervised clinical experience in diagnostic ra diology; and

b. Experience in interventional radiology demonstrated by:

(a) Board certification in interventional radiology/diagnostic radiology by the ABR2; or (b) Board subspecialty certification in interventional radiolog y by the AOBR2; or (c) One year of supervised clinical experience in interventiona l radiology; and

3 As noted on the NRC's Medical Uses Licensee Toolkit Web site, the NRC-approved ABR and AOBR certificates

contain the words "AU eligible" above the ABR or AOBR seal. For the purposes of this guidance, the NRC deems the certificates issued without AU Eligible to be adequate to meet the T&E guidelines in criteria A.3.i.a and A.3.i.b.

5 DRAFT FOR ACMUI REVIEW ii. Has 80 hours9.259259e-4 days <br />0.0222 hours <br />1.322751e-4 weeks <br />3.044e-5 months <br /> of classroom and laboratory training 4 for byproduct material requiring a written directive, applicable to Y-90 microspheres, which may b e concurrent with training received in accordance with criterion A.3.i in:

a. Radiation physics and instrumentation; and

b. Radiation protection; and

c. Mathematics pertaining to the use and measurement of radioac tivity; and

d. Radiation biology; iii. Has work experience under the supervision of an AU for Eye 90 microspheres brachytherapy or training provided by an Eye90 microspheres manufacturer representative involving:

a. Ordering, receiving, and unpacking radioactive materials saf ely and performing the related radiation surveys; and

b. Performing quality control procedures on instruments used to determine the activity of Eye90 microspheres and performing checks for proper operation of survey meters; and

c. Calculating and measuring the activity and safely preparing the Eye90 microspheres to be delivered to the patient or human research subject; and

d. Using procedures to control and to contain spilled byproduct material, including Eye90 microspheres, safely and using proper decontamination procedures. The procedures should address any special circumstances that may be encountered, such as the electrostatic charge of Eye90 microspheres and the proper survey instrument and survey technique for beta emitters 5; and iv. Has work experience or training under the supervision of an AU or manufacturer representative6 for Eye90 microspheres brachytherapy, including:

a. Preparing and administering patient dosage. The individual does not have to be the physician who places the micro-catheter or administers pati ent dosage, but it is necessary that the individual have training in the administr ation process,

4 For Board Certified physicians, if the Board Certification is recognized by the NRC on the NRC's Medical Uses

Licensee Toolkit Web site for 10 CFR 35.290, 35.390, 35.392, 35.394, and 35.396, the applicant or licensee need not submit detailed documentation of those AUs classroom and laboratory training to satisfy section A.3.ii. The applicant or licensee need only confirm that the individual has completed training on the use of Y-90 microspheres.

5 Appendix N, Model Emergency Procedures, NUREG-1556, Volume 9 provides additional guidance.

6 Because there were no licensees approved for Eye90 Microspheres at the time this licensing guidance was initially published in 2023, there are a limited number of AUs available to provide training. Therefore, training provided by a manufacturer representative will be accepted in lieu of training provided by an AU until [DATE].

6 DRAFT FOR ACMUI REVIEW including selection of activity of Eye90 microspheres to be administered to each treatment site and catheter positioning to ensure administratio n of the Eye90 microspheres is in accordance with the written directive; and

b. Using administrative controls to prevent a medical event inv olving the use of byproduct material7; and

c. Evaluation of patient or research subjects treatments to de termine whether the administered dosage was in accordance with the written directiv e or if a medical event has occurred.

B.

Has successfully completed training in the operation of the del ivery system, safety procedures, and clinical use for Eye90 microspheres. This requirement may be satisfied by completing a training program provided by the vendor for new us ers or by receiving training supervised by an AU8 who is authorized for Eye90 microspheres. Clinical use training to support unsupervised use should include at least three hands-on patient cases for Eye90 microspheres, conducted in the physical presence of an AU 6, 9 who is authorized for Eye90 microspheres.

Additionally, if the proposed AU is already trained on the use of another model of microspheres, they must be trained in the specific differences between Eye90 microspheres and the other model(s) of microspheres for which they are appr oved, including activity prescription, written directive preparation, microsphere administration, and spill procedures.

However, if a proposed AU cannot complete patient cases prior t o authorization; the licensee may request conditional approval with the proposed AU s completion of at least

7 Appendix S, Model Procedures for Developing, Maintaining, and Implementing Written Directives, NUREG-1556,

Volume 9 provides additional guidance.

8 A physician who is not an AU but who meets the T&E criteria for Eye90 microspheres may be approved to supervise

another physicians training or first hands-on patient cases on a case-by-case basis.

9 Because there were no licensees approved for Eye90 microspheres at the time this licensing guidance was initially published in [YEAR], there are a limited number of preceptors available to provide training and sign attestations.

Therefore, the NRC is postponing requiring a written attestation until [DATE HERE]. At that time, attestations will be required for individuals who are not already authorized for use of Eye90 microspheres. The NRC will continue to review the availability of preceptors and may revise this guidance if it determines that sufficient preceptors have not become available. In addition, all individuals seeking authorization for use of Eye90 microspheres must submit documentation of successful completion of required training as provided by the manufacturer.

7 DRAFT FOR ACMUI REVIEW three mock simulated cases. Mock simulated cases should demons trate issues that are encountered during Eye90 microspheres administration procedures and should be completed by the individual in the physical presence of a manuf acturer representative or an AU6 who is authorized Eye90 microspheres. Following conditional approval, the individual should complete the clinical casework described above, includin g case work, within a year following the license issuance or amendment that names the indi vidual as an AU for Eye90 microspheres use. The licensee may submit documentation to the NRC request ing an extension of this timeframe. The supporting documentation shou ld include a commitment to perform continuing T&E (e.g., one additional mock case prior to performing patient cases) in Eye90 microspheres until the first three patient cases are completed, and

C.

Has obtained written attestation that the individual has satisf actorily completed the requirements in criteria A and B of this section and is able to independently fulfill the radiation safety-related duties as an AU for Eye90 microspheres. The attestation must be obtained from either:

1. An AU6, 7 who is authorized forEye90 microspheres ; or

2. A residency program director who affirms in writing that the attestation represents the consensus of the residency program faculty where at least one f aculty member is a physician who is an AU6 for Eye90 microspheres brachytherapy and concurs with the attestation provided by the residency program director. The res idency training program must be approved by the Residency Review Committee of the Accreditation Council for Graduate Medical Education or the Royal College of Physicians a nd Surgeons of Canada or the Council on Postdoctoral Training of the American Osteopa thic Association and must include T&E specified in criteria A and B of this section.

In accordance with 10 CFR 35.59, the T&E specified above must h ave been obtained within the seven years preceding the date of application or the individual must have had related continuing education and experience since the required T&E was completed. Recent training provided under Section B may be sufficient to show recentness of training. Th is recentness of training requirement applies to all individuals, including those who are board certified or listed as an AU on an NRC or Agreement State license.

8 DRAFT FOR ACMUI REVIEW 5.2 Radiation Safety Officer The Radiation Safety Officer (RSO) must have training as specif ied in 10 CFR 35.50, including training in radiation safety, regulatory issues, and emergency procedures for Y-90 microsphere use. An RSO already listed on a license that includes one type of Y-90 microsphere device does not require additional approval for another type of Y-90 m icrosphere device but should be familiar with all radiation safety aspects, including cleaning up spills, associated with all devices used at the facility.

5.3 Training and Experience Documentation

The applicant must submit documentation of the above T&E for al l physicians requesting authorization to use Eye90 microspheres. This documentation shall include the clinical use cases and written attestation and supervising physician T&E, if necessary. For individuals completing the patient cases following the license amendment, t his documentation shall include documentation from the manufacturer representative or supervisi ng physician of the three mock simulated cases and a commitment that each individual will comp lete at least the first three hands-on patient cases supervised in the physical presence of a n AU7, 8 who is authorized for the Eye90 microspheres. The documentation should commit to requiring the individual to perform a mock simulated case if six months or more have passed since last performing a hands-on or mock simulated case. Additionally, for applicants that have individuals completing the patient cases following the license amendment, the applican ts commitment will include submitting documentation from the manufacturer to the appropria te NRC Regional Office within 60 days of when these three patient cases have been satisfactor ily completed.

5.4 Team Approach

Microsphere brachytherapy treatment is usually conducted using a multi-disciplinary team approach. The AU should consult with individuals, as necessary, with expertise in:

• cancer management (e.g., radiation or medical oncology);

• catheter placement;

• radiation dosimetry; and

• safe handling of unsealed byproduct material.

9 DRAFT FOR ACMUI REVIEW One individual may satisfy more than one of the listed areas of expertise. The applicant shall commit to provide training in the licensees procedures to all individuals involved in Eye90 microspheres use, commensurate with the individuals duties to be performed. This training must be provided to all individuals preparing, measuring, perfo rming dosimetry calculations, or administering Eye90 microspheres.

5.5 Notification

The NRC recognizes that, if an AU satisfies the T&E listed in N RCs licensing guidance for Eye90 microspheres and is currently listed on a Commission or Agreement State med ical use license or permit for Eye90 microspheres, the AU should be allowed to work under a different license for the medical use of Eye90 microspheres. A limited specific medical use applicant initially applying for authorization for the medical use of Eye 90 microspheres or an existing licensee applying for an amendment may request authorization to notify the NRC in the future that it has permitted an AU to work at its facility without req uesting an additional license amendment, provided the following conditions are met:

1. the AU satisfies the T&E listed in this licensing guidance f or Eye90microspheres; and

2. the AU is currently listed for Eye90 microspheres use on a Commission or Agreement State license, a permit issued by a Commission master materials licensee, a permit issued by a Commission or Agreement State licensee of a broad s cope, or a permit issued by a Commission master materials license broad scope per mittee; and

3. the licensee provides the NRC a copy of the license or permi t on which the AU is listed for Eye90 microspheres use; and

4. the licensee provides the NRC documentation of the completio n of three patient cases if previously not submitted to the NRC; and

5. the licensee provides documentation of the above listed cond itions to NRC for each AU no later than 30 days after the date that the licensee allows t he AU to work as an AU for the Eye90 microspheres.

If this authorization is approved, these notification condition s will be incorporated as license conditions on the license.

5.6 Grandfathering

10 DRAFT FOR ACMUI REVIEW If a licensee adopts this licensing guidance revision, physicia ns who are currently authorized for the medical use of Eye90 microspheres under T&E criteria listed in previous revisions do not have to meet the revised criteria in this revision for Eye90 mi crospheres.

6. License Commitments

The applicant shall commit to follow all the requirements in 10 CFR Part 35 for brachytherapy sources and manual brachytherapy use, except where replaced by the following licensing commitments:

6.1 Procedures for Administration

The licensee must have procedures f or administration requiring a written directive as specified in 10 CFR 35.41, specifically to ensure high confidence that the patients or human research subjects identity is verified before each administration and e ach administration is in accordance with the written directive. As Eye90 microspheres are too small to be calibrated in accordance with 10 CFR 35.432, the licensee shall determine and record the activity of each dosage before medical use in accordance with 10 CFR 35.63 and 10 CFR 35.60 even though Eye90 microspheres are not considered to be unsealed byproduct material. The lic ensee shall commit to following the manufacturers procedures or submit alt ernative methods for calculating and documenting the dose or activity to the treatment site; pre paring the dose for administration; determining shunting to non-treatment sites; and determining if a medical event has occurred (e.g., performing pre-and post-vial dose measurements with app ropriate instrumentation, evaluating post-treatment imaging). For the purpose of this gu idance, shunting is defined as blood flow through pathway or bypass due to patient vasculature causing the Eye90 microspheres to flow to an unwanted location. Unexpected dose or activity to an organ or tissue other than the treatment site that is caused by catheter placement during delivery of the Eye90 microspheres is not considered shunting and should be evaluated as a possib le medical event.

Administration of Eye90 microspheres must be performed in accordance with the written directive. The licensee shall record the dose or activity deli vered to the treatment site. The record shall be prepared within 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> after the completion o r termination of the

11 DRAFT FOR ACMUI REVIEW administration and must include the name of the individual who determined the dose or administered activity and the date the record is completed.

6.2 Written Directives

The licensee must complete a written directive, which must be d ated and signed by an AU before the administration in accordance with 10 CFR 35.40(a) and 10 CFR 35.40(c) unless a delay in order to provide a written directive would jeopardize the patient's health, as allowed under 10 CFR 35.40(c)(1). The licensee shall retain a copy of the written directive in accordance with 10 CFR 35.2040.

Due to the unique properties of Eye90 microspheres brachytherapy, the following written directive condition should be used instead of 10 CFR 35.40(b).

The written directive shall include the patient or human resear ch subjects name; the treatment site; the radionuclide (including the physical form [ Y-90 microspheres]); the model of spheres (e.g. Eye90 microspheres ) or manufacturer; the prescribed dose or activity; and, if appropriate for the type of microsphere used, the statement or dose or activity delivered at stasis.

For the purpose of written directive and medical event reportin g requirements in the Eye90 microspheres guidance, prescribed dose means the total dose (rad or Gy). Alternatively, prescribed activity (mCi or GBq) may be used in lieu of prescri bed dose. If prescribed activity is used in lieu of prescribed dose, the activity shall be used for all documentation and evaluations.

As described in 10 CFR 35.2, treatment site means the anatomi cal description of the tissue intended to receive a radiation dose, as described in a written directive. For instance, the treatment site may be described as the lobe or segment that is intended to receive the Eye90 microspheres and the tissue that is expected to receive Eye90 microspheres due to shunting.

For the purpose of this guidance, stasis is defined as a stoppage or slowdown in the flow of blood. The inability to complete administration due to clogging or kinking of the catheter is not considered stasis.

6.2.1 Termination of Treatment Due to Stasis

12 DRAFT FOR ACMUI REVIEW If the administration was terminated because of stasis, then th e total dose or activity to the treatment site is the value of the total dose or activity admin istered when stasis occurred and the administration was terminated. The record shall be prepare d within 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> after the completion or termination of the administration and must includ e the name of the individual who determined the administered dose or activity, the signature of an AU for Eye90 microspheres,

and the date signed.

6.2.2 Emergent Patient Conditions

If the procedure must be modified due to emergent patient condi tions that prevent administration in accordance with the written directive (e.g., artery spasm or sudden change in blood pressure), the AU shall document such changes in the writ ten directive within 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> after the completion or termination of the administration. The modification to the written directive shall include the reason for not administering the in tended dose or activity, the signature of an AU for Eye90 microspheres, and the date signed.

6.2.3 Termination of Treatment Due to Observed Deposition

If the AU decides to terminate administration due to observatio n of undesired radiopaque microsphere deposition, the AU may make an oral revision to a w ritten directive to modify the prescribed dose or activity. The oral revision must be document ed as soon as possible in the patient's record. A revised written directive must be signed by an AU within 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> of the oral revision and shall include a reason for the termination, the do se or activity delivered, the signature of an AU for Eye90 microspheres, and the date signed. If the dose delivered to the unintended target exceeds the thresholds for medical event reporting as ou tlined in Section 6.3, then the licensee shall comply with the medical event reporting and noti fication requirements as described in 10 CFR 35.3045(b)-(g).

6.3 Medical Event Reporting

In place of 10 CFR 35.3045(a), the licensee shall commit to rep ort any event, except for an event that is caused by shunting as described in the criteria b elow, or as a result of patient intervention, as defined in 10 CFR 35.2 as an actions by the pa tient or human research subject,

13 DRAFT FOR ACMUI REVIEW whether intentional or unintentional, such as dislodging or rem oving treatment devices or prematurely terminating the administration. The criteria for ev ent reporting is:

• the administration of byproduct material results in a dose tha t exceeds 0.05 Sv (5 rem) effective dose equivalent or 0.5 Sv (50 rem) to an organ or tis sue; and o an administration of the wrong radionuclide or type of microsp here; or o an administration to the wrong individual or human research su bject; or o an administration by the wrong route of administration; or o an administration by the wrong mode of treatment; or

• the total dose or activity delivered differs from the prescrib ed dose or activity, as documented in the written directive, by 20 percent or more, exc ept when stasis or emergent patient conditions are documented and resulted in a to tal dose or activity administered that was less than that prescribed; or

• A dose to the skin or an organ or tissue other than the treatm ent site that exceeds by 0.5 Sv (50 rem) to an organ or tissue and 50 percent or more of the dose expected from the administration defined in the written directive (excluding shun ting as defined in Section 6.1 when shunting was evaluated prior to the treatment in accordanc e with the manufacturers procedures.)

Additionally, the licensee shall comply with the medical event reporting and notification requirements as described in 10 CFR 35.3045(b)-(g).

6.4 Sealed Source and Device Use

The licensee should commit to only use Eye90 microspheres for therapeutic medical uses as approved in the SSD registration certificate for Eye90 microsph eres, including maximum activity per vial limit.10

10 At the time of publication of this guidance, Eye90 Microspheres does not have a Sealed Source and Device (SSD)

registration certificate. Note that 10 CFR 35.15(g) exempts licensees possessing a Type A specific license of broad scope from the SSD manufacturer requirement in 10 CFR 35.49(a). Broad scope licensees instead must perform their own internal safety evaluation as mentioned in Section 7.1.

14 DRAFT FOR ACMUI REVIEW 6.5 Inventory

Due to the short half-life of Y-90 (64 hours7.407407e-4 days <br />0.0178 hours <br />1.058201e-4 weeks <br />2.4352e-5 months <br />) and the fact that microspheres are not managed as individual discrete sources, the requirements in 10 CFR 35.67 for semi-annual physical inventory of brachytherapy sources and recordkeeping in 10 CFR 35.2406 are not applicable to microspheres. Rather, the requirements for brachytherapy sourc e accountability (10 CFR 35.406), receipt (10 CFR 20.1906), labeling (10 CFR 20.1904 and 10 CFR 35.69), storage (10 CFR 20.1801 and 10 CFR 35.92), and disposal (see the Waste Disposal Issues section of this guidance document) are sufficient to ensure accountability of Y-90 in the form of microspheres possessed by a licensee.

6.6 Labeling

The licensee should commit to the following when the Eye90 micr ospheres are placed in vials, syringes, or radiation shields that are not labeled by the manu facturer:

• Label vials and vial radiation shields with the radioactive de vice (i.e. Eye90 microspheres); and

• Label syringes and syringe radiation shields with the radioact ive device.

6.7 Patient Release The licensee should commit to develop procedures that describe measures taken to ensure that radiation emissions, which may include bremsstrahlung, from eac h patient or human research subject permits his or her release in accordance with 10 CFR 35.75. Guidance for release of patients or human research subjects following administration of radioactive materials may be found in Regulatory Guide 8.39, Release of Patients Administered Radioactive Materials.

6.8 Surveys

As the Eye90 microspheres are too small to be seen, licensees should survey, with an appropriate radiation detection survey instrument, all areas th at the Eye90 microspheres are prepared for use or administered. The survey should be conduct ed immediately following each preparation and administration in unrestricted areas and by the end of the day for restricted areas.

A licensee should retain a record of each survey for three year s and the record should include the date of the survey, the results of the survey, the instrume nt used to perform the survey, and 15 DRAFT FOR ACMUI REVIEW the name of the individual who performed the survey. Licensees do not need to perform surveys in an area(s) where patients or human research subjects are con fined when they cannot be released under 10 CFR 35.75.

16 DRAFT FOR ACMUI REVIEW 6.9 Radiation Protection Program Changes

This guidance may be revised as additional experience is gained regarding the medical use of Eye90 microspheres. A licensee currently authorized to use these products that i s committed by license condition to following provisions in a previous revi sion of this guidance may request a license amendment to commit to following this revision of the g uidance instead. The licensee must apply for and receive this license amendment in order to m ake program changes to conform to this revision of the guidance.

An applicant initially applying for authorization for the medic al use of Eye90 microspheres, or a licensee applying for an amendment to conform with this revisio n of the guidance may request to incorporate into its license a change process similar to 10 CFR 35.26. Such a change process can allow some future changes to radiation safety progr ams without a license amendment provided that the change process requires the followi ng conditions to be met for revisions to the radiation safety program:

1. the revision is in compliance with the regulations; and

2. the revision is based upon NRCs current guidance for Eye90 microspheres Y-90 microspheres 35.1000 use posted on the NRCs Medical Uses Licensee Toolkit Web site; and

3. the revision has been reviewed and approved by the licensee s RSO and licensees management; and

4. the affected individuals are instructed on the revised progr am before the change is implemented; and

5. the licensee will retain a record of each change for five ye ars; and

6. the record will include a copy of the appropriate website gu idance, the old procedure, the new procedure, the effective date of the change, and the signat ure of the licensee management that reviewed and approved the change.

If approved, these conditions for use of the updated guidance w ill be incorporated as license conditions in the license.

17 DRAFT FOR ACMUI REVIEW

7. Notes to Licensees

7.1 Change in Physical Conditions of Use

At the time of publication of this guidance, Eye90 microspheres is does not have an SSD registration certificate. Upon issuance of an SSD registration certificate for Eye90 microspheres, the following guidance applies:

If the physical conditions of use exceed those reported in the SSD registration certificate, the limited specific medical use licensee shall request an amendmen t for the new conditions, and a broad scope licensee shall perform its own engineering and radi ation safety evaluation addressing those differences.

7.2 Use of Other Y-90 Microspheres

At the time of publication of this guidance, Eye90 microspheres is pending an SSD safety evaluation. Upon issuance of an SSD registration certificate fo r Eye90 microspheres, the following guidance applies:

The SSD safety evaluation for a specific manufacturers Y-90 mi crosphere does not cover the use of any other Y-90 microspheres in its device for administra tion. The medical use of such a source will require a new SSD registration certificate (or safe ty evaluation by the broad scope medical use licensee) that addresses the conditions of use, saf ety of the new Y-90 microspheres, and compatibility of the new microspheres with th e microsphere delivery system(s).

The SSD safety evaluation for a given manufacturers Y-90 micro sphere delivery system does not cover the use of that manufacturers Y-90 microspheres with another manufacturers delivery system or the use of another manufacturers Y-90 micro spheres with the given manufacturers delivery system. Before authorization, the medi cal use of such a delivery system will require a new SSD registration certificate (or safe ty evaluation by the broad scope medical use licensee) that addresses the conditions of use, saf ety of the microsphere delivery system, and compatibility of the new delivery system with the Y-90 microspheres.

18 DRAFT FOR ACMUI REVIEW 7.3 Waste Disposal Issues

Y-90 microspheres are known to potentially contain radioactive impurities, some of which are long-lived (i.e., half-lives of greater than 120 days) (Refer t o Information Notice (IN) 2007-10, Yttrium-90 Therasphere and Sirspheres Impurities). Due to different manufacturing processes, the activity and radionuclides of the impurities var y for different Y-90 microsphere products. Impurities that have been recently found in reactor-activated microspheres include small amounts of long-lived radionuclides such as europium-152, europium-154, and cobalt-60.11 Impurities that have been recent ly found from microspheres with generator-produced Y-90 include trace amounts of strontium-90. 12 While this IN was generated in response to other products, licensees should be prepared to follow similar precau tions and procedures when handling waste generated by Eye90 Microspheres.

Licensees should be aware that t he activity and type of impurit ies can change and be different from that described above. The NRC does not limit manufacturer s to specific manufacturing processes, and it is therefore possible for the activity and ty pes of radionuclide impurities to change for all Y-90 microsphere products. Additionally, unused or partially used vials are likely to contain higher activities of impurities.

Although impurities need not be listed on an NRC license; licen sees are responsible to ensure the microspheres are handled and disposed of in accordance with 10 CFR Part 20 and Part 35 requirements. Specifically, 10 CFR 35.92 requires that licensees monitor byproduct material with a physical half-life of less than or equal to 120 days at the s urface before disposal and determine that its radioactivity cannot be distinguished from the backgro und radiation level with an appropriate radiation detection survey meter before disposal. Therefore, regardless of the length of time they have been allowed to decay, licensees are not perm itted to dispose of Y-90

11 J. Metyko, J. Williford, W. Erwin, J. Poston, S. Jiminez. Long-lived Impurities of 90Y-labeled microspheres,

TheraSphere and SIR-Spheres, and the impact on patient dose and waste management. Health Phys. 103(3), S204-S208 (2012).

12 J. Metyko, W. Erwin, J. Poston, and S. Jimenez. 90Sr Content in 90Y-labeled SIR-Spheres and Zevalin. Health Phys.

107(5), S177-S180 (2014) 19 DRAFT FOR ACMUI REVIEW microspheres if radioactivity can be distinguished from the bac kground radiation level with an appropriate radiation detection survey meter.

If waste is determined to contain impurities with a physical ha lf-life of greater than 120 days that can be distinguished from the background radiation level with a n appropriate radiation detection survey meter, the licensee may need to use one or more of the f ollowing means to dispose of waste associated with the Eye90 microspheres :

• return the Eye90 microspheres to the manufacturer, if the manufacturer is authorized to receive Y-90 microspheres; or

• transfer the Eye90 microspheres to an authorized recipient pursuant to requirements in 10 CFR Part 20 and Part 30.

See Regulatory Issue Summary 2004-17, Revision 1, Revised Decay-in-Storage Provisions for the Storage of Radioactive Waste Containing Byproduct Material, for more information regarding requirements for holding waste for decay-in-storage.

7.4 Autopsy and Cremation

Eye90 microspheres are permanent implants that are not removed from the body by biological methods. Because Y-90 has a 64-hour half-life, Y-90 will likel y have significantly decayed before a patients death. Patients treated with Eye90 microspheres will not usually represent an external radiation hazard to persons handling the body. Howeve r, in the case of autopsy or cremation, the radiation hazard increases due to the need for i ndividuals to handle tissues that may contain radioactive material, especially if the death occur s soon after treatment with Eye90 microspheres. The National Council on Radiation Protection and Measurement s (NCRP) Report No. 155, Management of Radionuclide Therapy Patients, December 2006, may contain helpful information for radiation safety considerations associated with autopsy or cremation of patients with permanent implants. Additionally, NUREG-1556, Volume 9, Appendix N, Model Emergency Procedures, contains additional guidance regarding autopsy and cremation of patients who have received therapeutic amounts of radionuclides.

7.5 Radiation Safety Committee

20 DRAFT FOR ACMUI REVIEW If a licensee is required to have an RSC in accordance with 10 CFR 35.24(f), then the committee must include an AU for the use of Y-90 microspheres.

8. Notes to Regulators

8.1 Inspection Frequency

Licenses authorizing Eye90 microspheres brachytherapy should be inspected every two years.

Per Enclosure 1 to Inspection Manual Chapter 2800, licenses authorizing emerging technology under 10 CFR 35.1000 are assigned a Priority 2 inspection code.

8.2 Program Code

The NRC regions should use program code 02240.

21 DRAFT FOR ACMUI REVIEW

9. Paperwork Reduction Act Statement

This Licensing Guidance provides voluntary guidance for impleme nting the mandatory information collections in 10 CFR Parts 30 and 35 that are subj ect to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et. seq.). These information collec tion were approved by the Office of Management and Budget (OMB), approval numbers 3150-0017 and 3150-0010. Send comments regarding this information collection to the Informati on Services Branch (T6-A10M),

U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001, or by e-mail to Infocollects.Resource@nrc.gov, and to the OMB reviewer at: OMB Office of Information and Regulatory Affairs (3150-0017, 3150-0010), Attn: Desk Officer f or the Nuclear Regulatory Commission, 725 17th Street, NW Washington, DC 20503; e-mail: oira_submission@omb.eop.gov.

22 DRAFT FOR ACMUI REVIEW

10. Public Protection Notification

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

23 DRAFT FOR ACMUI REVIEW