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1 

2 

3 Nuclear Regulatory Commission (NRC) 

4 Advisory Committee on the Medical Uses of Isotopes (ACMUI)

Report on Licensing for Radium-223 (223 5 Ra) Dichloride 

6 November 20, 2012 

7 

8 

9 

10 Subcommittee Members 

11 Darice Bailey, Susan Langhorst, Steven Mattmuller, Christopher Palestro, Orhan Suleiman, Bruce 

12 Thomadsen, James Welsh, and Pat Zanzonico (Chair)

13 

14 Charge 

To provide recommendations on licensing of radium-223 (223Ra) dichloride (223 15 RaCl2). 

16 

17 Summary Statement and Recommendations 

223 18 RaCl2, currently a non-approved investigational agent undergoing clinical trials in the United 

19 States and elsewhere, represents a first-in-class, alpha particle-emitting therapeutic 

20 radiopharmaceutical. Based on relevant physical and biological considerations as well as clinical 

21 data to date, its intended indication is treatment of skeletal metastases in advanced, castrate22 resistant prostate cancer, delivering high biologically effective doses to malignant cells in bone with 

23 relative sparing of hematopoietic marrow and other normal tissues. The injection volume for the 

body weight-adjusted dose of 223 24 RaCl2 (50 kBq/kg (1.35 μCi/kg)) is determined based on the 

25 vendor-supplied activity concentration in a pre-calibrated solution. Nonetheless, to minimize the 

26 probability of a therapeutic misadministration, an appropriate radioassay system (e.g., a dose 

calibrator) for measurement of the 223 27 Ra activity prior to its administration and the residual activity 

28 following its administration is recommended, as with any therapeutic radiopharmaceutical. This 

29 would require calibration of the radioassay system using, for example, a National Institute of 

Standards and Technology (NIST)-traceable 223Ra standard. 223 30 RaCl2 does not differ significantly 

31 in terms of clinical use and management, radiation safety, and logistics from currently approved 

32 radiopharmaceuticals. Therefore, physicians already authorized to use therapeutic 

33 radiopharmaceuticals under § 35.390 or § 35.396 already have the requisite education, training, 

and experience to safely and effectively use 223 34 RaCl2. As such, licensing of authorized users of 

223 35 RaCl2 under § 35.390 (Category (G)(3) or (G)(4)), or § 35.396(d)(2), is therefore recommended. 

36 

37 Clinical Background 

38 Skeletal metastases commonly occur in many different malignancies, particularly advanced 

39 castrate-resistant prostate cancer, and are associated with severe morbidity and mortality (1). The 

40 resulting bone pain and possible fractures severely compromise the patient’s quality of life and 

41 thus require effective treatment. Various non-radiotherapeutic modalities are available such as 

42 analgesics, hormone therapy, orchiectomy, cytostatic and cytotoxic drugs, bisphosphonates, and 

43 surgery, but are not universally effective (2). External-beam radiotherapy is suitable only for well44 defined localized bone metastases, and extended-field radiation for more generalized skeletal 

45 disease is often accompanied by excessive toxicity (3). In the setting of widely disseminated 

46 skeletal metastases, systemic, bone-targeting radionuclide therapies have emerged as a safe, 

47 convenient, and reasonably effective palliative and therapeutic modality (4, 5). Current 

48 radiopharmaceuticals for palliation of painful skeletal metastases are exclusively beta particle 

emitters and include phosphorus-32 (32P) sodium phosphate, strontium-89 (89 49 Sr) strontium chloride 

(MetastronTM), yttrium-90 (90Y) yttrium citrate, tin-117m (117m 50 Sn) diethylenetriamine pentaacetic acid 

(DTPA), samarium-153 (153Sm) lexidronam (QuadrametTM), thulium-170 (170 51 Tm) ethylene diamine 
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tetramethylene phosphonate (EDTMP), lutecium-177 (177Lu) EDTMP, and rhenium-186 (186 52 Re) and 

rhenium-188 (188 53 Re) hydroxyethylidene diphosphonate (HEDP) (4,5). Currently approved 

radiopharmaceuticals for bone pain palliation include 32P sodium phosphate, 89 54 Sr strontium 

chloride, and 153 55 Sm lexidronam, while the others remain investigational. 

56 

223RaCl2 (half-life: 11.43 days) is a calcium-mimetic alpha-particle emitter1 57 which either avidly 

localizes in bone (particularly areas of active bone re-modeling typical of skeletal metastases)2 58 or is 

rapidly excreted (6). 223Ra has only short-lived radioactive progeny, radon-219 (219 59 Rn) (physical 

half-life: 3.96 seconds), polonium-215 (215Po) (0.00178 second), bismuth-211 (211 60 Bi) (2.17 

minutes), lead-211 (211Pb) (36.1 minutes) and thallium-207 (207 61 Tl) (4.77 minutes) (6). The alpha 

emissions of 223 62 Ra and its progeny are short-range, high-linear energy transfer (LET), and high63 relative biological effectiveness (RBE) radiations and should deliver highly localized, highly 

64 cytocidal radiation to metastatic cells in bone with relative sparing of the near-by bone marrow (6). 

In addition, 223 65 Ra and its progeny emit a number of externally countable and imageable x- and 

66 gamma-rays (81, 84, 154, and 269 keV) usable for pharmacokinetic studies, radiation dosimetry, 

and activity calibration (7). In principle, therefore, 223 67 RaCl2 potentially may provide more effective, 

68 less toxic palliation of skeletal metastases than current beta particle-emitting radiopharmaceuticals. 

69 Importantly, if approved by the US Food and Drug Administration (FDA), it would represent the 

70 very first alpha particle-emitting radiopharmaceutical in routine (i.e., non-investigational) clinical 

use3 71 in the United States. 

72 

223 73 RaCl2 has been extensively studied in patients in Europe as well as the United States (6, 8-13). 

74 Two open-label Phase-I trials (37 patients) and three double-blind Phase-II trials (255 patients) 

75 assessed radiation dosimetry, safety, and efficacy (decline in serum levels of prostate-specific 

76 antigen (PSA) and bone alkaline phosphatase (ALP) and prolongation of survival). Injected single 

77 doses varied from 5.2-252 kBq/kg (0.14-6.8 μCi/kg) body mass. Repeated treatment regimens 

78 varied in number of doses and time-dose schedule. A Phase-II clinical trial in patients with 

79 symptomatic, hormone-refractory prostate cancer showed improvement in survival, PSA levels, 

80 and ALP levels compared with placebo (i.e., no treatment), with no differences in hematologic 

81 toxicity. An international double-blind, placebo-controlled randomized trial (ALpharadin in 

SYMptomatic Prostate CAncer [ALSYMPCA]) was subsequently undertaken to compare 223 82 RaCl2

83 with placebo in patients with symptomatic, androgen-independent prostate cancer with skeletal 

84 metastases. The study was stratified based on ALP levels at registration, bisphosphonate use, 

85 and prior treatment with docetaxel. A total of 921 patients from 19 countries were enrolled, with 

86 overall survival being the primary endpoint. Importantly, the data demonstrated a statistically 

significant reduction in the risk of death for patients randomized to the 223 87 RaCl2 arm of the study 

88 (hazard ratio = 0.695; p = 0.00185), with a median overall survival of 14 months versus 11.2 

89 months in the placebo arm. The overall survival benefit was seen across all sub-groups. The time 

 

1

 Other potential clinical alpha particle-emitting, bone-seeking agents include thorium-227 (227Th) EDTMP, 227Th tetraazacyclododecane tetra(methylene) phosphonic acid (DOTMP), and 212Bi DOTMP (4,5) but these 

are not as advanced in terms of clinical use as 223Ra chloride. 

2

 The propensity for internalized radium to localize in bone has long been recognized. For example, radium 

watch dial painters in the 1920s and 30s subsequently developed bone cancers and leukemias as a result of 

ingesting the radium-266 (226Ra)-containing paint when “twirling” their paint brush tips to a fine point in their 

mouths. Importantly, 226Ra has a much longer half-life, 1,600 years, than 223Ra, a critically important factor 

related to its carcinogenecity in bone. 

3

 The FDA’s revised policy on “Expanded Access to Investigational Drugs for Treatment Use” (21 CFR Parts 

312 and 316, Federal Register Vol 74, No 155 August 13, 2009) allows the use of agents such as 223RaCl2 to 

be expanded to a larger population beyond compassionate use in individual patients, but such “expandedaccess” use would still require compliance with the Investigational New Drug (IND) record-keeping, safety, 

ethical, and other requirements associated with human-subject experimentation.
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to a skeletal-related event was also significantly longer for patients in the 223 90 RaCl2 versus placebo 

91 arm, 13.6 versus 8.4 months (p = 0.00046). The time to disease progression based on PSA and 

ALP levels was also significantly longer in the 223RaCl2 arm. The patients randomized to 223 92 RaCl2

93 treatment tolerated it well. Both hematologic side-effects (grade-3 or -4 anemia, neutropenia, 

94 thrombocytopenia) and gastrointestinal side-effects (nausea, vomiting, diarrhea) did not occur with 

any greater frequency than with placebo. The former are related to localization of 223 95 RaCl2 in bone 

96 while the latter are related to its excretion through the intestines. It is noteworthy that the foregoing 

side-effects associated with therapeutic administration of 223 97 RaCl2 are hardly unique. For example, 

the dose-limiting toxicity associated with iodine-131 (131 98 I) iodide treatment of metastatic thyroid 

99 cancer and of radioimmunotherapy of cancer generally is most commonly myelosuppression. 

100 Nuclear Medicine physicians, Radiation Oncologists, and other physicians who administer 

101 radionuclide therapy are therefore already highly experienced in effectively managing such side102 effects. 

103 

104 To summarize the clinical findings to date (6, 8-13), more than 1,000 prostate cancer patients have 

been treated with 223 105 RaCl2 with single and repeated treatments with significant PSA declines and 

106 prolonged survival benefit, without therapy-limiting myelotoxicity, gastrointestinal toxicity or other 

107 significant normal-tissue toxicity compared to placebo. Although not yet approved by the FDA for 

108 routine clinical use, this investigational alpha particle-emitting agent appears to be a promising 

109 bone-targeted radionuclide therapy. 

110 

111 Radiation Safety and Logistical Considerations 

223 112 RaCl2 and its progeny emit 95%, 4%, and 1% of their total radiation energy in the form of alpha 

113 particles, beta particles, and x- and gamma-rays, respectively (6). Alpha particles have very short 

114 ranges (of the order of 10 m in bone and soft tissue) and thus present no external, or direct, 

radiation hazard. As long as standard universal precautions4 115 are observed and internalization is 

116 avoided, alpha particles pose no significant radiologic hazard overall - despite their high LET and 

117 high RBE. Importantly, this will likewise be the case for alpha particle-emitting 

118 radiopharmaceuticals in general. Universal precautions would also safeguard against the internal 

radiologic hazard of the small beta-particle component among the emissions of 223 119 Ra and its 

120 progeny. X- and gamma-rays are, of course, much more penetrating than alpha- and betaparticles but are emitted in very low abundance by 223 121 Ra and its progeny, with energies 

comparable to those of common diagnostic radionuclides such as a technetium-99m (99m 122 Tc) 

(gamma-ray energy: 140 keV) and fluorine-18 (18 123 F) (511 keV). At the same time, the single-dose 

administered activities of 223 124 RaCl2, 50 kBq/kg (1.35 μCi/kg) body mass or 3,500 kBq (95 μCi) total 

125 for a 70-kg Standard Man, are several orders of magnitude lower than that of routine diagnostic 

126 radiopharmaceuticals (for which the administered activities are of the order of 370 MBq = 370,000 

127 kBq (10 mCi = 10,000 μCi)). Thus, for such low-abundance x- and gamma-rays and such low 

activities, the external, or direct, radiation exposure and shielding requirements for 223 128 RaCl2 and its 

129 progeny are no greater than those for routinely used diagnostic radiopharmaceuticals - even 

though 223 130 RaCl2 is a therapeutic agent (14). Further, patients do not require medical confinement 

following 223 131 RaCl2 administration and may be treated on an outpatient basis. 

132 

As noted, 223Ra has a physical half-life of 11.43 days; its radioactive progeny, 219Rn, 215Po, 211 133 Bi, 

211Pb, and 207Tl, have much shorter half-lives, ranging from 0.00178 second to 36.1 minutes. 223 134 Ra 

135 and its progeny thus have sufficiently short half-lives for on-site decay-in-storage of radioactively 

136 contaminated waste followed by disposal as non-radioactive waste. At the same time, the x- and 

gamma-rays emitted by 223 137 Ra and its progeny, although low in abundance, are sufficient for assay 

 

4

 Universal precautions (e.g., wearing of disposable gloves) constitute a method of infection control in which 

all human fluids, tissue etc are handled as if they are know to be infected with transmissible pathogens. 
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138 of any such waste. This can be done using conventional survey meters such as Geiger (G-M) 

139 counters - in order to verify that the exposure (or count) rates from contaminated or possibly 

140 contaminated waste are at or below background levels. Likewise, surveys of ambient exposure 

141 rates and of removable radioactive contamination (i.e., “wipes tests”) associated with the use of 

223 142 RaCl2 may be performed with instrumentation (surveys meters and well counters, respectively) 

143 already routinely available in Nuclear Medicine facilities. 

144 

223 145 RaCl2 is a simple salt of radium, and not a radiolabeled molecule. It therefore requires no 

146 synthesis or other preparation by the clinical site and does not undergo any sort of chemical 

147 decomposition. Quality control procedures for determination of radiochemical purity and special 

storage conditions (e.g., refrigeration) are therefore not required for 223 148 RaCl2. As distributed by 

149 Bayer Healthcare (Pittsburgh, PA), it is provided in a crimped glass vial as an injectable isotonic 

150 solution with an activity concentration of 1,000 kBq/ml (27 μCi/ml) at calibration (15). The 

151 recommended administered activity is 50 kBq/kg (1.35 μCi/kg) body mass (15). A patient-specific 

152 volume of injectate, calculated using the following formula, is drawn directly from the vendorprovided 223 153 RaCl2 solution (15): 

154 

 Volume to inject (ml) = Body mass (kg) x 50 kBq/kg

 Decay factor x 1000 kBq/ml 155 

156 

157 where the decay factor is the fractional decay factor (as derived from a vendor-provided “decay 

factor table,” for example) for the time interval from the date and time of calibration of the 223 158 RaCl2

159 to the planned date and time of administration. 

160 

161 Implicit in the foregoing dose-prescription algorithm is that the user is not required to assay the 

223 162 Ra activity prior to its administration or the residual activity following its administration, as is 

163 typically done in Nuclear Medicine (especially for therapeutic administrations). Bayer Healthcare 

has asserted that measurement of the 223 164 Ra activities is not necessary, as the patient-specific dose 

165 corresponds to a calculated volume of the vendor-supplied solution with the vendor-specified pre166 calibrated activity concentration (15). Bayer Healthcare has further asserted that such activity 

measurements would be potentially unreliable because (a) a setting for 223 167 Ra is not provided on 

168 currently available dose calibrators and (b) the pre-administration activity and, in particular, the 

residual activity would be too low (in the tens of kBq (μCi) range) to measure reliably (15). 223 169 Ra 

170 does, however, emit measurable x- and gamma-rays (7), and dose calibrators can thus be 

calibrated by the end user for 223 171 Ra using a National Institute of Standards and Technology (NIST)-

traceable 223Ra standard (16). In addition, assay of the pre-administration and residual 223 172 Ra 

173 activities, even if inexact, would help avoid potentially “catastrophic” misadministrations. By 

174 verifying that the actual pre-administration activity is consistent with the prescribed activity and that 

175 the residual activity is insignificant, clinically important over-dosing and/or under-dosing of the 

patient (e.g., due to mis-calibration of the vendor-supplied 223 176 RaCl2 solution or inaccurate drawing 

177 of the patient-specific injectate) as well as administration of an incorrect radionuclide could likely be 

178 avoided. Such activity assays would thus provide an additional level of safety at the treatment site 

179 independent of the vendor’s manufacturing and calibration procedures. In a therapy setting, such 

180 redundancy, or cross-checking, is certainly prudent and is standard in Nuclear Medicine, especially 

181 in therapeutic applications. An appropriate radioassay system (e.g., a dose calibrator) for 

measurement of the 223 182 Ra activity prior to its administration or the residual activity following its 

administration is therefore recommended for the therapeutic use of 223 183 RaCl2. 

184 

185 Licensing Considerations 

As noted, 223 186 RaCl2 represents a first-in-class - that is, an alpha particle-emitting - 

187 radiopharmaceutical. As such, it raises the issue of the appropriate NRC licensure for authorized 
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users of this agent. 223 188 RaCl2 should be licensed under § 35.300 of the Code of Federal 

189 Regulations (CFR) (Appendix 1). Within the NRC’s regulatory framework, there would appear to 

be several different licensing options for 223 190 RaCl2, namely, authorized users who meet training and 

191 experience requirements under § 35.390 (Appendix 2), § 35.396 (Appendix 3), or § 35.1000 A 

(Appendix 4). Despite its alpha-particle emissions, 223 192 RaCl2 does not differ fundamentally from 

193 current routinely used therapeutic radiopharmaceuticals. Given the similarities in clinical use and 

radiation safety considerations (as detailed above) between 223 194 RaCl2 and current therapeutic 

195 radiopharmaceuticals, the use of which is authorized under § 35.390 (Appendix 2), the use of 

223 196 RaCl2 should likewise be authorized under § 35.390. It would appear that either Category (3) or 

(4) in § 35.390 would be appropriate for 223 197 RaCl2. Category (3) applies to, “Parenteral 

198 administration of any beta emitter, or a photon- emitting radionuclide with a photon energy less 

199 than 150 keV, for which a written directive is required”; it does not explicitly include or exclude 

alpha-particle emitters, however. Since 223 200 Ra progeny emit beta particles as well as alpha 

particles, 223 201 RaCl2 technically might be considered a “Category (3)” radiopharmaceutical. However, 

even if “Category (3)” were interpreted as not applying to 223 202 RaCl2, Category (4), which applies to, 

203 “Parenteral administration of any other radionuclide, for which a written directive is required,” would 

certainly apply. This same conclusion applies to § 35.396 (Appendix 3). Licensing of 223 204 RaCl2

205 under § 35.1000 (Appendix 4) is not an appropriate option as that would imply it differs significantly 

206 in terms of clinical use and management, radiation safety, and logistics from current therapeutic 

207 radiopharmaceuticals, and this is not the case. Physicians already authorized to use such 

208 radiopharmaceuticals under § 35.390 or § 35.396 already have the requisite education, training, 

and experience to safely and effectively use 223 209 RaCl2, and should not be required to provide 

210 additional training-and-experience documentation to be licensed for its use. 

211 

212 References 

213 1. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin 

214 Cancer Res 12(Suppl): 6243s-6249s, 2006. 

215 2. Coleman RE. Management of bone metastases. The Oncologist 5: 463-470, 2000. 

216 3. Chow E, Harris K, Fan G, Tsao M, and Sze WM. Palliative radiotherapy trials for bone 

217 metastases: A systematic review. J Clin Oncol 25: 1423-1436. 

218 4. Tomblyn M. The role of bone-seeking radionuclides in the palliative treatment of patients with 

219 painful osteoblastic skeletal metastases. Cancer Control 19: 137-144, 2012. 

220 5. Ogawa K and Washiyama K. Bone target radiotracers for palliative therapy of bone 

221 metastases. Curr Med Chem, 2012 [Epub ahead of print]. 

222 6. Bruland OS, Nilsson S, Fisher DR, and Larsen RH. High-linear energy transfer irradiation 

targeted to skeletal metastases by the -emitter 223 223 Ra: Adjuvant or alternative to conventional 

224 modalities? Clin Cancer Res 12 (Suppl): 6250s-6257s, 2006. 

225 7. Hindorf C, Chittenden S, Aksnes AK, Chris Parker C, and Glenn D. Flux GD. Quantitative 

226 imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of 

227 bone metastases. Nucl Med Commun 33: 726-732, 2012. 

8. Nilsson S, Balteskard L, Fossa SD et al. Phase I study of Alpharadin2 (223 228 Ra), and -emitting 

229 bone-seeking agent in cancer patients with skeletal metastases. Eur J Nucl Med Mol Imaging 

230 31: S290 [abstract], 2004. 
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231 9. Nilsson S, Balteskard L, Fossa SD, et al. First clinical experiences with  emitter radium-223 in 

232 the treatment skeletal metastases from breast and prostate cancer. Clin Cancer Res 11:4451-

233 4459, 2005. 

234 10. Nilsson S, Franzen L, Tyrrell C et al. Bone-seeking radium-223 adjuvant to external beam 

235 radiotherapy demonstrates significant decline in bone-alkaline phosphatase and PSA in 

236 patients with hormone refractory prostate cancer [abstract]. ASCO Prostate Cancer 

237 Symposium 2006. 

238 11. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, 

239 Johannessen DC, Sokal M, Katharine Pigott K, Yachnin JR, Garkavij M, Strang P, Harmenberg 

240 J, Bolstad B, and Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory 

241 prostate cancer: A randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 8: 

242 587-594, 2007. 

243 12. Parker C, Heinrich D, O’Sullivan JM et al. Overall survival benefit of radium-223 chloride 

244 (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration245 resistant prostate cancer (CRPC): A phase III randomised trial (ALSYMPCA) [Abstract]. 

246 European Multidisciplinary Cancer Congress 2011. 

247 13. Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, Staffurth J, Vasanthan S, 

248 Andersson C, and Bruland ØS. A randomized, dose–response, multicenter phase II study of 

249 radium-223 chloride for the palliation of painful bone metastases in patients with castration250 resistant prostate cancer. Eur J Cancer 48: 678–686, 2012. 

251 14. Cheetham PJ and Petrylak DP. Alpha particles as radiopharmaceuticals in the treatment of 

252 bone metastases: mechanism of action of radium-223 chloride (Alpharadin) and radiation 

253 protection. Oncology 26: 330-337, 2012. 

254 15. Bayer Healthcare. Medical uses of radium-223 chloride. Presentation to the NRC Advisory 

Committee on Medical uses of Isotopes (ACMUI), Rockville, MD, April 17th 255 , 2012.

256 16. Bergeron DE, Zimmerman BE, and Cessna JT. Development of secondary standards for 

223 257 Ra. Appl Radiat Isot 68:1367-1370, 2010. 

258 

259 
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260 Appendix 1

261 § 35.300 Use of unsealed byproduct material for which a written directive is required. 

262 A licensee may use any unsealed byproduct material prepared for medical use and for which a 

263 written directive is required that is264 (a) Obtained from: 

265 (1) A manufacturer or preparer licensed under § 32.72 of this chapter or equivalent Agreement 

266 State requirements; or 

267 (2) A PET radioactive drug producer licensed under § 30.32(j) of this chapter or equivalent 

268 Agreement State requirements; or 

269 (b) Excluding production of PET radionuclides, prepared by: 

270 (1) An authorized nuclear pharmacist; 

271 (2) A physician who is an authorized user and who meets the requirements specified in §§ 35.290, 

272 35.390, or 

273 (3) An individual under the supervision, as specified in § 35.27, of the authorized nuclear 

274 pharmacist in paragraph (b)(1) of this section or the physician who is an authorized user in 

275 paragraph (b)(2) of this section; or 

276 (c) Obtained from and prepared by an NRC or Agreement State licensee for use in research in 

277 accordance with an Investigational New Drug (IND) protocol accepted by FDA; or 

278 (d) Prepared by the licensee for use in research in accordance with an Investigational New Drug 

279 (IND) protocol accepted by FDA. 

280 [67 FR 20370, Apr. 24, 2002, as amended at 68 FR 19324, Apr. 21, 2003; 69 FR 55738, Sep. 16, 

281 2004; 71 FR 15009, Mar. 27, 2006; 72 FR 55932 Oct. 1, 2007] 

282 
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283 Appendix 2

284 § 35.390 Training for use of unsealed byproduct material for which a written directive is 

285 required. 

286 Except as provided in § 35.57, the licensee shall require an authorized user of unsealed byproduct 

287 material for the uses authorized under § 35.300 to be a physician who288 (a) Is certified by a medical specialty board whose certification process has been recognized by the 

289 Commission or an Agreement State and who meets the requirements in paragraphs (b)(1)(ii)(G) 

290 and (b)(2) of this section. (Specialty boards whose certification processes have been recognized 

291 by the Commission or an Agreement State will be posted on the NRC's Web page.) To be 

292 recognized, a specialty board shall require all candidates for certification to: 

293 (1) Successfully complete residency training in a radiation therapy or nuclear medicine training 

294 program or a program in a related medical specialty. These residency training programs must 

295 include 700 hours of training and experience as described in paragraphs (b)(1)(i) through 

296 (b)(1)(ii)(E) of this section. Eligible training programs must be approved by the Residency Review 

297 Committee of the Accreditation Council for Graduate Medical Education, the Royal College of 

298 Physicians and Surgeons of Canada, or the Committee on Post-Graduate Training of the American 

299 Osteopathic Association; and 

300 (2) Pass an examination, administered by diplomates of the specialty board, which tests 

301 knowledge and competence in radiation safety, radionuclide handling, quality assurance, and 

302 clinical use of unsealed byproduct material for which a written directive is required; or 

303 (b)(1) Has completed 700 hours of training and experience, including a minimum of 200 hours of 

304 classroom and laboratory training, in basic radionuclide handling techniques applicable to the 

305 medical use of unsealed byproduct material requiring a written directive. The training and 

306 experience must include307 (i) Classroom and laboratory training in the following areas308 (A) Radiation physics and instrumentation; 

309 (B) Radiation protection; 

310 (C) Mathematics pertaining to the use and measurement of radioactivity; 

311 (D) Chemistry of byproduct material for medical use; and 

312 (E) Radiation biology; and 

313 (ii) Work experience, under the supervision of an authorized user who meets the requirements in 

314 §§ 35.57, 35.390, or equivalent Agreement State requirements. A supervising authorized user, who 

315 meets the requirements in § 35.390(b), must also have experience in administering dosages in the 

316 same dosage category or categories (i.e., § 35.390(b)(1)(ii)(G)) as the individual requesting 

317 authorized user status. The work experience must involve- 
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318 (A) Ordering, receiving, and unpacking radioactive materials safely and performing the related 

319 radiation surveys; 

320 (B) Performing quality control procedures on instruments used to determine the activity of dosages, 

321 and performing checks for proper operation of survey meters; 

322 (C) Calculating, measuring, and safely preparing patient or human research subject dosages; 

323 (D) Using administrative controls to prevent a medical event involving the use of unsealed 

324 byproduct material; 

325 (E) Using procedures to contain spilled byproduct material safely and using proper 

326 decontamination procedures; 

327 (F) [Reserved] 

328 (G) Administering dosages of radioactive drugs to patients or human research subjects involving a 

329 minimum of three cases in each of the following categories for which the individual is requesting 

330 authorized user status331 (1) Oral administration of less than or equal to 1.22 gigabecquerels (33 millicuries) of sodium 

332 iodide I-131, for which a written directive is required; 

(2) Oral administration of greater than 1.22 gigabecquerels (33 millicuries) of sodium iodide I-1312 333 ; 

334 (3) Parenteral administration of any beta emitter, or a photon- emitting radionuclide with a photon 

335 energy less than 150 keV, for which a written directive is required; and/or 

336 (4) Parenteral administration of any other radionuclide, for which a written directive is required; and 

337 (2) Has obtained written attestation that the individual has satisfactorily completed the 

338 requirements in paragraphs (a)(1) and (b)(1)(ii)(G) or (b)(1) of this section, and has achieved a 

339 level of competency sufficient to function independently as an authorized user for the medical uses 

340 authorized under § 35.300. The written attestation must be signed by a preceptor authorized user 

341 who meets the requirements in §§ 35.57, 35.390, or equivalent Agreement State requirements. 

342 The preceptor authorized user, who meets the requirements in § 35.390(b) must have experience 

343 in administering dosages in the same dosage category or categories (i.e., § 35.390(b)(1)(ii)(G)) as 

344 the individual requesting authorized user status. 

345 [67 FR 20370, Apr. 24, 2002, as amended at 68 FR 19325, Apr. 21, 2003; 68 FR 75389, Dec. 31, 

346 2003; 69 FR 55738, Sep. 16, 2004; 70 FR 16364, Mar. 30, 2005; 71 FR 15009, Mar. 27, 2006; 74 

347 FR 33905, Jul. 14, 2009] 

2 348 Experience with at least 3 cases in Category (G)(2) also satisfies the requirement in Category 

349 (G)(1) 

350 
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351 Appendix 3

352 § 35.396 Training for the parenteral administration of unsealed byproduct material requiring 

353 a written directive. 

354 Except as provided in § 35.57, the licensee shall require an authorized user for the parenteral 

355 administration requiring a written directive, to be a physician who356 (a) Is an authorized user under § 35.390 for uses listed in §§ 35.390(b)(1)(ii)(G)(3) or 

357 35.390(b)(1)(ii)(G)(4), or equivalent Agreement State requirements; or 

358 (b) Is an authorized user under §§ 35.490, 35.690, or equivalent Agreement State requirements 

359 and who meets the requirements in paragraph (d) of this section; or 

360 (c) Is certified by a medical specialty board whose certification process has been recognized by the 

361 Commission or an Agreement State under §§ 35.490 or 35.690, and who meets the requirements 

362 in paragraph (d) of this section. 

363 (d)(1) Has successfully completed 80 hours of classroom and laboratory training, applicable to 

364 parenteral administrations, for which a written directive is required, of any beta emitter, or any 

365 photon-emitting radionuclide with a photon energy less than 150 keV, and/or parenteral 

366 administration of any other radionuclide for which a written directive is required. The training must 

367 include— 

368 (i) Radiation physics and instrumentation; 

369 (ii) Radiation protection; 

370 (iii) Mathematics pertaining to the use and measurement of radioactivity; 

371 (iv) Chemistry of byproduct material for medical use; and 

372 (v) Radiation biology; and 

373 (2) Has work experience, under the supervision of an authorized user who meets the requirements 

374 in §§ 35.57, 35.390, 35.396, or equivalent Agreement State requirements, in the parenteral 

375 administration, for which a written directive is required, of any beta emitter, or any photon-emitting 

376 radionuclide with a photon energy less than 150 keV, and/or parenteral administration of any other 

377 radionuclide for which a written directive is required. A supervising authorized user who meets the 

378 requirements in § 35.390 must have experience in administering dosages as specified in §§ 

379 35.390(b)(1)(ii)(G)(3) and/or 35.390(b)(1)(ii)(G)(4). The work experience must involve— 

380 (i) Ordering, receiving, and unpacking radioactive materials safely, and performing the related 

381 radiation surveys; 

382 (ii) Performing quality control procedures on instruments used to determine the activity of dosages, 

383 and performing checks for proper operation of survey meters; 

384 (iii) Calculating, measuring, and safely preparing patient or human research subject dosages; 
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385 (iv) Using administrative controls to prevent a medical event involving the use of unsealed 

386 byproduct material; 

387 (v) Using procedures to contain spilled byproduct material safely, and using proper 

388 decontamination procedures; and 

389 (vi) Administering dosages to patients or human research subjects, that include at least 3 cases 

390 involving the parenteral administration, for which a written directive is required, of any beta emitter, 

391 or any photon-emitting radionuclide with a photon energy less than 150 keV and/or at least 3 cases 

392 involving the parenteral administration of any other radionuclide, for which a written directive is 

393 required; and 

394 (3) Has obtained written attestation that the individual has satisfactorily completed the 

395 requirements in paragraph (b) or (c) of this section, and has achieved a level of competency 

396 sufficient to function independently as an authorized user for the parenteral administration of 

397 unsealed byproduct material requiring a written directive. The written attestation must be signed by 

398 a preceptor authorized user who meets the requirements in §§ 35.57, 35.390, 35.396, or 

399 equivalent Agreement State requirements. A preceptor authorized user, who meets the 

400 requirements in § 35.390, must have experience in administering dosages as specified in §§ 

401 35.390(b)(1)(ii)(G)(3) and/or 35.390(b)(1)(ii)(G)(4). 

402 [70 FR 16365, Mar. 30, 2005; 71 FR 15010. Mar. 27, 2006; 74 FR 33906, Jul. 14, 2009] 

403 
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404 Appendix 4

405 § 35.1000 Other medical uses of byproduct material or radiation from byproduct material. 

406 A licensee may use byproduct material or a radiation source approved for medical use which is not 

407 specifically addressed in subparts D through H of this part if-- 

408 (a) The applicant or licensee has submitted the information required by § 35.12(b) through (d); and 

409 (b) The applicant or licensee has received written approval from the Commission in a license or 

410 license amendment and uses the material in accordance with the regulations and specific 

411 conditions the Commission considers necessary for the medical use of the material.