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

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

1 

1 Nuclear Regulatory Commission (NRC) 

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

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

4 Emitters 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 Introduction 

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

10 following tasks: 

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

12 (T&E) for authorized users (AU) of alpha and beta emitters, in 10 CFR 35.390 (Training 

13 for use of unsealed byproduct material for which a written directive is required), places 

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

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

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

17 to these agents. 

18 Charge 1: 

19 

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

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

22 ibritumomab tiuexetan (Zevalin®) and iodine-131 tositumomab (Bexxar®). Use of both agents, 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

2 

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

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 Bexxar®, in fact, was withdrawn from the market in 2014, because of 

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

26 FIGURE 1 – Number of Zevalin Patients from 2002-2014 

27 

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

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

30 use of these agents. 

31 Lack of knowledge: According to Dr. Cultrera’ s presentation at the Fall 2015 ACMUI meeting, 

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

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

34 an educational, not a regulatory issue. 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

3 

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

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

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

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

39 available, the use of older agents declines. 

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

41 these agents is a direct result of the requirement for 700 hours of T&E to obtain AU status that 

42 went into effect shortly after these agents were introduced. In his letter of 1/25/2016 to the 

43 ACMUI, Dr. Joseph Mace states that to his knowledge, “... no oncologist has been able to 

44 receive AU status under the alternate pathway, since the regulations went into effect...” 

45 Without knowledge of how many oncologists sought AU status prior to the rule change, it is not 

46 possible to assess the significance of this statement. The only way to determine the impact on 

47 AUs that the change in T&E requirements had, would be to have aggregate data on AUs over 

48 time, data, which unfortunately, are not available. These considerations, it would appear, 

49 provide at least prima facie evidence that lack of clinical use of Bexxar® and Zevalin® is not due 

50 to a lack of AUs. 

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

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

53 clinicians and AUs who work closely together, these radiopharmaceuticals are used infrequently 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

4 

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

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

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

57 FIGURE 2 – Zevalin Administrations at Various Institutions 

58 

59 (Adapted from Palestro, presented at the ACMUI meeting Oct 2015) 

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

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

62 requirements anyway, regardless of whether or not there is a shortage of AUs? It is important 

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

64 majority of cases, by or in conjunction with, AUs who have successfully completed the rigorous 

65 T&E requirements. 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

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66 SUMMARY: 

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

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

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

70 requirements. Whether or not the safety records would be comparable in the hands of AUs 

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

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

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

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

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

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

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

78 familiarity with the use of radioactive materials. 

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

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

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

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

radiopharmaceuticals as suggested in the February 9th 83 , 2016 letter of Hilliard et al. to the 

84 ACMUI? 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

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

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

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

88 recommends against the reduction in the number of hours of T&E required for 10 CFR 35.390 

89 use. 

90 Charge 2: 

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

92 and beta emitters to ensure safety. 

93 While, for the reasons stated, the subcommittee at this time opposes the reduction in the 

94 number of hours of T&E, we also recognize the need for a thorough review of the current T&E 

95 requirements. One important reason for this review is that is has been nearly 15 years since the 

96 current requirements were established. Since that time new radiopharmaceuticals have been 

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

98 agents need to be established. 

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

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

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

102 educational approach to T&E, with an emphasis on competency, not just experience. 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

7 

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

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

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

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

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

108 making recommendations for changes as warranted. 

109 Endorsement 

110 The report was unanimously approved by the subcommittee on February 24, 2016. However, a 

111 differing opinion with respect to the barriers to access follows: 

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

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

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

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

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

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

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

119 must contribute to the lack of utilization. 
ACMUI Sub-Committee Final Report on Training & Experience For Authorized Users of Alpha 

and Beta Emitters under 10 CFR 35.390 

Submitted on March 16, 2016

8 

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

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

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

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

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

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

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

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

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

129 Those specialists may simply not be available in the community setting, creating a real 

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

131 center. 

132 Respectfully submitted, 

133 Laura Weil, ACMUI Patients’ Rights Advocate 

134 The report was unanimously approved by the Committee at its public meeting on March 10, 

135 2016.