ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

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1 Nuclear Regulatory Commission (NRC) 

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

3 Report on Training & Experience for Authorized Users of Alpha and Beta Emitters 

4 under 10 CFR 35.390

5

6 Sub-Committee Members: V. Dilsizian M.D., R. Ennis M.D., S. Langhorst Ph.D., 

7 C. Palestro, M.D. (chair), L. Weil, P. Zanzonico, Ph.D.

8

9 Introduction

10 The Sub-Committee on Training & Experience for Authorized Users was charged with the 

11 following tasks:

12 1. To determine if the current requirement of 700 hours for training and experience for 

13 authorized users (AU) of alpha and beta emitters, in 10CFR 35.390 (Training for use of 

14 unsealed byproduct material for which a written directive is required), places hardship 

15 on the patient community and to make recommendations for ACMUI action.

16

17 2. To establish a recommendation for the total number of hours of T&E for authorized 

18 users of such emitters that appropriately balances safety with reasonable patient access 

19 to these agents.

20

21
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

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22 Charge 1:

23 Background: Radiolabeled antibody treatment of lymphoma with beta emitters was approved

24 by the U. S. FDA approximately 14 years ago. Two agents initially were available: yittrium-90 

25 ibritumomab tiuexetan (Zevalin®) and iodine-131 tositumomab (Bexxar®). Use of both agents,

26 which peaked a few years after introduction, has, despite favorable clinical results, steadily 

27 declined since (Figure 1). Bexxar®, in fact, was withdrawn from the market in 2014, because of 

28 a lack of use (fewer than 75 patients treated in 2014).

29 FIGURE 1

30

31 (Adapted from Spectrum Pharmaceuticals, ACMUI meeting October 2015)

32 The subcommittee examined the factors that could possibly account for the decrease in 

33 use of these agents. 
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

3

34 Lack of knowledge: According to Dr. Cultrera’ s presentation at the Fall 205 ACMUI meeting, 

35 hematology/oncology fellows are not exposed to these agents during their training so they may 

36 not be aware that these agents are available and consequently do not prescribe them. This is 

37 an educational, not a regulatory issue.

38 Competition: Since these agents were introduced about 14 years ago, new, effective, therapies 

39 that do not involve radiation have been developed, and it likely that some of the decrease in 

40 use is related to the availability of these newer agents. This is not unique to radiolabeled 

41 antibodies; this is common to all drugs: as newer, equally or more effective, agents become

42 available, the use of older agents declines.

43 Shortage of Authorized Users: It has been suggested that the infrequent and declining use of 

44 these agents is a direct result of the requirement for 700 hours of training and experience to 

45 obtain Authorized User (AU) status that went into effect shortly after these agents were 

46 introduced. In his letter of 1/25/2016 to the ACMUI, Dr. Joseph Mace states that to his 

47 knowledge, “... no oncologist has been able to receive AU status under the alternate pathway, 

48 since the regulations went into effect...” Without knowledge of how many oncologists sought 

49 AU status prior to the rule change, it is not possible to assess the significance of this statement.

50 The only way to determine the impact on AU’s that the change in T&E requirements had, would 

51 be to have aggregate data on AU’s over time, data, which unfortunately, are not available. 
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

4

52 These considerations, it would appear, provide at least prima facie evidence that lack of clinical 

53 use of Bexxar® and Zevalin® is not due to a lack of AUs.

54 The assertion that a shortage of AUs is the cause of the decline in the use of these agents is 

55 undermined by the fact that even at many large medical centers with an abundance of 

56 clinicians and AUs who work closely together, these radiopharmaceuticals are used infrequently

57 (Figure 2). According to his January 2015 letter, Dr. Mace, who receives consultations from 

58 “across the state of Florida” has administered beta emitters, including Zevalin® to more than 40 

59 patients over the past decade, or only about 4 per year. 

60

61 FIGURE 2

62

63 (Adapted from Palestro, presented at the ACMUI meeting Oct 2015)
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

5

64 Safety: The exceptional safety record that has accompanied beta, and more recently alpha 

65 emitting radiopharmaceuticals, is indisputable. Therefore why not reduce the T&E

66 requirements anyway, regardless of whether or not there is a shortage of AU’s? It is important 

67 to note that the excellent safety records achieved with these agents have been attained, in the 

68 majority of cases, by or in conjunction with, AU’s who have successfully completed the rigorous 

69 T&E requirements. 

70

71 SUMMARY:

72 The ramifications of a change in T&E are potentially significant. In terms of safety, as already 

73 noted, the excellent safety records achieved with these agents have been attained, for the most 

74 part, by or in conjunction with AU’s who have successfully completed the rigorous T&E 

75 requirements. Whether or not the safety records would be comparable in the hands of AU’s 

76 with considerably less T&E is a matter of conjecture. It has been suggested that 80 hours of 

77 T&E is sufficient for administration of these agents. This is based on the concept that if 80 hours 

78 of T&E is sufficient for radioactive iodine administration which, it has been asserted, is far more 

79 complex and hazardous, then a comparable amount of T&E is sufficient for administration of 

80 alpha & beta emitters. It is important to note that the field of Nuclear Medicine, including 

81 therapy, originated to a great extent in endocrinology, because of the role of radioactive iodine 

82 in the diagnosis and treatment of thyroid disease. Thus endocrinologists have a long history of 

83 familiarity with the use of radioactive materials. 
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

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84 Virtually all of the letters in support of a change in T&E support this change for oncologists. 

85 Surely there are other individuals, in other specialties, who are capable of administering these 

86 agents; should they also be included? Finally, should satisfactory completion of T&E allow an 

87 individual to administer all of these agents, or should use be restricted to specific 

radiopharmaceuticals as suggested in the February 9th 88 , 2016 letter of Hilliard et al. to the 

89 ACMUI?

90 Since it is not possible to conclude that the current T&E requirements are the only, or even the 

91 principal, cause of the decreased use of radiopharmaceuticals like Zevalin® and Bexxar®, and 

92 because of the potential issues raised by the proposed changes in T&E, the subcommittee 

93 recommends against the reduction in the number of hours of T&E required for 10 CFR 35.396 

94 use. 

95 Charge 2: 

96 Establish a recommendation for the total number of hours of T&E for authorized users of alpha 

97 and beta emitters to ensure safety.

98 While, for the reasons stated, the subcommittee opposes the reduction in the number of hours 

99 of T&E, we also recognize the need for a thorough review of the current T&E requirements. 

100 One important reason for this review is that is has been nearly 15 years since the current 

101 requirements were established. Since that time new radiopharmaceuticals have been 
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

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102 introduced and this is a trend that likely will continue. Appropriate T&E requirements for these 

103 agents need to be established. 

104 There is another important reason to undertake this review. The educational paradigm has 

105 changed over time. There has been a shift away from prescriptive curricula (i.e. specific number 

106 of classroom hours) to competency-based education. The time has come to reevaluate our 

107 educational approach to T&E, with an emphasis on competency, not just experience.

108 This undertaking is complicated and cannot be completed in weeks or even months. It requires 

109 input from many stakeholders, if it is to be successful. Once established, the T&E requirements 

110 need regular, periodic review, to ensure that they are current.

111 Therefore the subcommittee recommends that the ACMUI establish a standing subcommittee 

112 with the specific charge of periodically reviewing the T&E requirements currently in effect and

113 making recommendations for changes as warranted.

114

115 Endorsement

116 This report was unanimously approved by the subcommittee on February 24, 2016. However, a 

117 differing opinion with respect to the barriers to access follows:
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

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118 I support the Subcommittee’s assertion that the Training and Experience requirements 

119 need to be reviewed and re-evaluated. But I do not agree that the current requirements 

120 do not effectively create some barriers to access to care.

121 As the Subcommittee Report states, the 700 hour Training and Experience requirement 

122 for AUs of alpha and beta emitters is surely not the primary reason why these agents are 

123 not frequently used in many major medical centers. There is no shortage of clinicians 

124 available and authorized to administer these radiopharmaceuticals, and other factors 

125 must contribute to the lack of utilization. 

126 It is important to acknowledge that this condition may not hold true for the community 

127 setting, where NHL patients often receive treatment. NHL patients often live with the 

128 disease for many years, and require a varied armamentarium of therapies to address 

129 each subsequent recurrence. Many of these patients are elderly, unable to travel, have 

130 very limiting medical insurance networks, and may be too frail to tolerate the 

131 debilitating side effects of cytotoxic therapies. To assert that all patients have access to 

132 RIT is to ignore the logistical barriers that exist for those who are limited to receiving 

133 therapy in the rural or community setting. The 700 hour T&E requirement effectively 

134 limits AUs to those medical specialties that cover the requirements in residency training. 

135 Those specialists may simply not be available in the community setting, creating a real 
ACMUI Sub-Committee Draft Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390

Submitted on March 10, 2016

9

136 barrier to access for those patients who are unable to seek treatment in a larger medical 

137 center. 

138 Respectfully submitted,

139 Laura Weil, ACMUI Patients’ Rights Advocate