Information Notice 2016-03, Revision to the National Institute of Standards and Technology Standard for Radium-223
| ML15264B095 | |
| Person / Time | |
|---|---|
| Issue date: | 01/12/2016 |
| From: | Dan Collins Division of Materials Safety, Security, State, and Tribal Programs |
| To: | |
| Cockerham A | |
| References | |
| IN-16-003 | |
| Download: ML15264B095 (4) | |
ML15264B095 UNITED STATES
NUCLEAR REGULATORY COMMISSION
OFFICE OF NUCLEAR MATERIALS SAFETY AND SAFEGUARDS
WASHINGTON, D.C. 20555-0001
January 12, 2016
NRC INFORMATION NOTICE 2016-03:
REVISION TO THE NATIONAL INSTITUTE OF
STANDARDS AND TECHNOLOGY STANDARD
FOR RADIUM-223 AND IMPACT ON DOSE
CALIBRATION FOR THE MEDICAL USE OF
RADIUM-223 DICHLORIDE
ADDRESSEES
All U.S. Nuclear Regulatory Commission (NRC) medical licensees, NRC Master Materials
Licensees, Agreement State Radiation Control Program Directors, and State Liaison Officers.
PURPOSE
The NRC is issuing this Information Notice (IN) to alert addressees that the National Institute of
Standards and Technology (NIST) revised its primary standard for radium-223 (Ra-223) and to
convey the impact this revision will have on the calibration of patient doses of Ra-223 dichloride
(trade name Xofigo). Recipients should review the information contained in this notice for
applicability to their facilities and consider taking appropriate action, if necessary. However, the
information conveyed in this notice is not a new NRC requirement; therefore, no specific action
or written response to this notice is required.
The NRC is providing this notice to the Agreement States for information and distribution to
medical use licensees, as appropriate.
BACKGROUND
Ra-223 dichloride is an injectable radiopharmaceutical used to treat skeletal metastases in
advanced, castration-resistant prostate cancer. Ra-223 emits alpha particles and has a half-life
of 11.4 days. Once in the body, Ra-223 dichloride mimics calcium and forms complexes in
areas of increased bone turnover, such as sites of bone metastases. Ra-223 dichloride kills
tumor cells through highly localized, short-range alpha irradiation. Although Ra-223 is primarily
an alpha-emitter, the activity of Ra-223 can be measured in a radioisotope dose calibrator that
has been calibrated with NIST-traceable Ra-223 reference material. Following U.S. Food and Drug Administration approval in May 2013, Bayer Pharma AG (Bayer),
began commercial distribution of Xofigo domestically. Bayer provided Xofigo customers with a
NIST-traceable Ra-223 standard syringe and an appropriate dial setting for dose calibrators
based on NIST data published in 2010.1
DESCRIPTION OF CIRCUMSTANCES
In 2013, NIST was made aware of studies performed by the National Physical Laboratory (NPL)
(the National Measurement Institute of the United Kingdom) in which an approximately 10
percent difference was found between NPLs activities obtained using several primary methods
and those obtained with the calibration factors published by NIST from 2010. Subsequently, NIST performed additional testing using more robust methods than previously available to verify
NPLs results and confirmed that activity readings were lower than expected. On March 11,
2015, NIST published information2 regarding the revised primary standard for Ra-223 resulting
in a numerical increase of 10.5 percent for the new primary standard. This change was only to
the numerical value of the quantity of Ra-223, as the actual amount of Ra-223 in the primary
standard did not change.
Bayer notified Xofigo customers of the NIST standardization change and future labeling and
calibration impacts in a letter dated March 18, 2015. See Bayer Letter to Healthcare
Professionals for Ra-223 NIST Standardization Issue, available in ADAMS under Accession
No. ML15264B158. In the letter, Bayer stated that they will provide customers with a new NIST-
traceable Ra-223 standard syringe and dose calibration dial setting based on the NIST revised
primary standard. Bayer also stated that they will increase the numerical values listed on the
package label by approximately 10 percent. For example, the labeling of the patient dosage will
be updated from 50kBq/kg of body weight to 55kBq/kg of body weight. Additionally, Bayer
stated that the manufacturing and product documentation will be updated and labeled as 1100
kBq/mL (previously 1000 kBq/mL) and 6.6 MBq/vial (previously 6.0 MBq/vial).
The NRCs licensees are typically authorized for the possession and medical use of Ra-223 dichloride in the millicurie range. Xofigo doses are administered in the microcurie range, so
the NRC does not anticipate the need to update licenses as a result of the new primary NIST
standard. Furthermore, Bayer stated in its March 18, 2015, letter that the revised NIST standard
for Ra-223 does not change the actual amount of Ra-223 dichloride being administered to
patients and will not impact the safety and efficacy of Xofigo.
1 J. T. Cessna and B. E. Zimmerman, Standardization of radium-223 by liquid scintillation counting, Appl. Radiat. Isot.
68, 1523-1528 (2010) and D. E. Bergeron, B. E. Zimmerman, and J. T. Cessna, Development of secondary
standards for 223Ra, Appl. Radiat. Isot. 68, 1367-1370 (2010).
2 B. E. Zimmerman, D. E. Bergeron, J. T. Cessna, R. Fitzgerald, and L. Pibida, Revision of the NIST Standard for
223Ra: New Measurements and Review of 2008 Data, Journal of Research of NIST, 120, 37-57 (2015). As stated in the purpose section of this IN, this notice does not convey any new NRC
requirements. Therefore, licensees are not required to take any action based on this notice. As
stated in its March 18, 2015 letter, Bayer is contacting healthcare providers to provide
information on how to obtain an updated NIST-traceable standard and to prepare for future
changes in the dose calibrator dial setting. The new dial setting should not be used for verifying
the activity in patient dosages until Bayer implements label changes in 2016. Bayer will notify
Xofigo customers of the label change via letter a few weeks before the implementation date.
When the label change occurs and the new dial setting is to be implemented, licensees may
update internal procedures, as needed (e.g., to reflect the new dial setting on the dose
calibrator).
CONCLUSION
Bayer's March 18, 2015, letter emphasizes that no immediate action on the part of its customers
is necessary for meeting the new calibration standard. NRC advises affected licensees to
continue to use the existing NIST-traceable Ra-223 standard syringe and calibration dial setting
until notified otherwise by Bayer.
CONTACT
This notice requires no specific action or written response. Licensees may contact Bayer at
(888) 842-2937 or visit www.xofigo.us.com for additional information on how to obtain an
updated NIST-traceable Ra-223 standard syringe and to prepare for future changes in the dose
calibrator dial setting. For regulatory questions, please contact the technical contact below.
/RA Pamela Henderson for/
Daniel S. Collins, Director
Division of Material Safety, State, Tribal
and Rulemaking Programs
Office of Nuclear Material Safety
and Safeguards
Technical Contact:
Michael Fuller, NMSS
Phone: (301) 415-0520
Email: Michael.Fuller@nrc.gov
Note: NRC generic communications may be found on the NRC public Web site, http://www.nrc.gov, under NRC Library > Document Collections As stated in the purpose section of this IN, this notice does not convey any new NRC
requirements. Therefore, licensees are not required to take any action based on this notice. As
stated in their March 18, 2015 letter, Bayer is contacting healthcare providers to provide
information on how to obtain an updated NIST-traceable standard and to prepare for future
changes in the dose calibrator dial setting. The new dial setting should not be used for verifying
the activity in patient dosages until Bayer implements label changes in 2016. Bayer will notify
Xofigo customers via letter a few weeks before the implementation date of the label change.
When the label change occurs and the new dial setting is to be implemented, licensees may
update internal procedures, as needed (e.g. to reflect the new dial setting on the dose
calibrator).
CONCLUSION
Bayer's March 18, 2015, letter emphasizes that no immediate action on the part of its customers
is necessary for meeting the new calibration standard. NRC advises affected licensees to
continue to use the existing NIST-traceable Ra-223 standard syringe and calibration dial setting
until notified otherwise by Bayer.
CONTACT
This notice requires no specific action or written response. Licensees may contact Bayer at
(888) 842-2937 or visit www.xofigo.us.com for additional information on how to obtain an
updated NIST-traceable Ra-223 standard syringe and to prepare for future changes in the dose
calibrator dial setting. For regulatory questions, please contact the technical contact below.
/RA Pamela Henderson for/
Daniel S. Collins, Director
Division of Material Safety, State, Tribal
and Rulemaking Programs
Office of Nuclear Material Safety
and Safeguards
Technical Contact:
Michael Fuller, NMSS
Phone: (301) 415-0520
Email: Michael.Fuller@nrc.gov
Note: NRC generic communications may be found on the NRC public Web site, http://www.nrc.gov, under NRC Library > Document Collections
ADAMS Accession No. ML15264B095
- via email
OFFICE
MSTR/MSEB
MSTR/MSEB
MSTR/MSEB
NAME
- ACockerham
AMcIntosh
DBollock
- NLO
PHenderson for
DCollins
DATE
9/25/15
10/14/15
10/1/15
1/7/16
1/12/16 OFFICIAL RECORD DOCUMENT