ML20056A636

Request for OMB Review & Supporting Statement Re 10CFR35, Authorization to Prepare Radiopharm Reagent Kits & Elute Radiopharm Generators;Use of Radiopharm for Therapy. Estimated Respondent Burden Is 838 H

ML20056A636
Person / Time
Issue date:	07/30/1990
From:	Norry P NRC OFFICE OF INFORMATION RESOURCES MANAGEMENT (IRM)
To:
Shared Package
ML20055J356	List: ML20055J355 ML20056A636
References
OMB-3150-0010, OMB-3150-10, NUDOCS 9008080371
Download: ML20056A636 (15)

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SUPPORTING STATEMENT FOR THE IMMEDIATELY EFFECTIVE 10 CFR PARTS 30 AND 35 INTERIM FINAL RULE FOR " AUTHORIZATION TO PREPARE RAD 10 PHARMACEUTICAL REAGENT KITS AND ELUTE RAD:0 PHARMACEUTICAL GENERATORS; USE OF RAD 10 PHARMACEUTICALS FOR THERAPY" The NRC is requesting expedited Office of Management and Budget (OMB) processing because the interim final rule involves the elimination of restrictions which left in place would have an adverse impact on public health and safety, The NRC believes good cause exists for omitting the notice of proposed rule, making and the public procedures thereon and making the amendments in the interim final rule effective upon publication in the Federal Register without the customary thirty-day notice. The information collection requirements are an essential condition to permitting NRC's medical use and commercial nuclear pharmacy licensees to make departures from the manufacturers' preparation instructions and package inserts in accordance with 635.200(b),635.300,and commercial nuclear pharmacy license conditions similar to 535.200(b). OMB should approve or disapprove the collection of information within 5 days because it is essential to permit the departures authorized in the interim final rule as quickly as possible to assure proper patient care for certain patients adversely affected by the current regulations. The NRC consulted with the U.S. Food and Drug Administration (FDA) to assure the information collection requirements and burden were minimized while at the same time providing adequate protection of the public health and safety.

The Nuclear Regulatory Commission (NRC) is issuing an interim final rule to amend its regulations for a period of three years at 10 CFR Parts 30 and 35 relating to the preparation of diagnostic radiopharmaceuticals and uses'of therapeutic radiopharmaceuticals. The interim rule allows departures from the requirement that licensees who elute generators and prepare reagent kits do so only in accordance with the manufacturer's instructions for elution and preparation in the package insert (a prt of the FDA approved labeling) provided the licensees meet certain conditions and limitations. The interim rule also permits NRC licensees using byproduct material in a radiopharma-ceutical for a therapeutic use to depart from the package insert regarding indications for use and method of administration if certain requirements are met.

This action is being taken as an interim response to a petition for rulemaking submitted by the American College of Nuclear Physicians (ACNP) and the Society of Nuclear Medicine-(SNM) (54 FR 38239, September 15,1989).

The petition seeks relief, among other matters, from strict adherence to the manufacturer's preparation instructions and Jackage inserts in accordance with

$35.200(b), $35.300 and commercial nuclear piarmacy license conditions similar to535.200(b).

Information from the petition for rulemaking, public comments on the petition and subsequent discussions with licensees indicates that requirements in the nuclear pharmacy license conditions and 635.200(b) regarding preparation of radiopharmaceuticals and in 535.300 regarding indications and method of administration for therapy procedures may, in some cases, prevent authorized user physicians from providing proper care for certain patients.

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, In order to provide proper patient care for some uncommon disease states or patient conditions, it may be necessary to depart from the FDA-approved instructions to obtain diagnostic or therapeutic results not otherwise attainable or to reduce medical risk to particular patients.

The NRC has reevaluated these requirements and concluded this amendment is necessary to allow health professionals to provide diagnostic or therapeutic medical results not otherwise attainable or to reduce medical risks to particular patients because of their medical condition while continuing to protect public health and safety adequately.

The interim rule only applies to generators, reagent kits, and radiopharmaceuticals for which FDA has accepted a "New Drug Application" (NDA).

To determine the scope and nature of necessary departures from the manufacturer's instructions, as well as their safety significance, NRC will require licensees to retain the written directive for the tieparture and keep a record of the number of patient administrations under the departure.

During their safety inspections, NRC inspectors will collect copies of the writtet, directives for the departures and the record of the numher of patient administrations under each departure.

NRC will analyze the nature of, reasons for, and frequency of the departures. The information collected and results of the analysis will provide information necessary for NRC's resolution of the ACNP-SNM petition and decision whether to extend the interim period, make the rule permanent, or revise it.

The information is also needed because some departures may have drug safety and efficacy or other public health and safety implications that require alternative safety measures.

A.

JUSTIFICATION The NRC is amending three different sections of its regulations because pe of. material (diagnostic or safety requirements are imposed based on the ty(medical user or pharmacy).

therapeutic) in use, or the class of licensee No matter which case, each licensee will be required to retain a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radipharmaceutical and to keep a record of the number of patient administrations under each departure.

Section 30.34(i)(1)(i) requires radiopharmacies that tre licensed under 10 CFR Parts 30 and 32 to keep the written directive that authorizes departure from the manufacturer's instructions and a record of the number of prescriptions dispensed under the departure in auditable form and available for l

inspection for five years. The written directive tha must be retained would be created by a medical use licensee and transmitted to the radiopharmacy as 1'

part of the prescription. The record of the number of prescriptions dispensed l-under the departure would be created by the nuclear pharmacy.

I Section 30.34(i)(1)(ii) requires the licensee to keep records of written directives made by the authorized user physician that contain the emeroency notations and the information required by 930.34(1)(1)(i) in auditable form o

p and available for inspection for five years.

4 Section 35.200(c)(1) requires medical use licensees to keep the written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer's instructions would obtain medical results, not otherwise attainable, or to reduce medical risks to particular patients because of their medical condition. Section 35.200(c)(2) requires the written directive to be kept in an auditable form and available for inspection for five years.

Section 35.200(c)(2) reouires medical use licensees to keep the record of

-the number of patient administrations under the departure in an auditable form and available for inspection for five years.

Section 35.300(b)(2) requires medict, use licensees that administer therapy radiopharmaceuticals for indications and routes of administration not identified on the package insert to keep records of the departure, which include the specific nature of the departure and a brief statement of the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risk to particular patients because of their medical condition, and the record of the number of patient administrations under the departure in an auditable form and available for inspection for five years.

Regardless of which licensee creates or retains the written directive for the departure and the record of the number of patient administrations under the departure, the following justification is applicable.

1.

Keed for the Collection of Information. NRC's regulations in 10 CFR Part 35 concerning t'he madical use of byproduct material require NRC medical use licensees to prepare FDA approved products in accordance with the manufacturer's instructions. The interim final rule modifyir.g the requirement neither specifies types of changes that can be made, nor prohibits any changes to the manufacturer's instructions for tiDA products.

The NRC anticipates that the departures from the manufacturer's instructions may result in radiopharmaceuticals with increased or decreased specific activity, differences in biodistribution, and slight differences in solubility when compared to radiopharmaceuticals prepared and administered according to the manufacturer's instructions.

There may be alterations in the target to non-target ratio, the biological half-life of the radiopharmaceutical, the image acquisition time, or the sensitivity and specificity of the diagnostic examination.

The changes may also increase or decrease radiation exposure to the patient, physicians and technologists, medical care personnel,-and the general public.

HRC needs to collect information on the nature of, reason for, and frequency of departures made to analyze the potential health and safety impact of the departures.

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Agency Use of Information. The NRC will analyze the information on the nature of, reasons for, and the frequency of the departures made to verify NRC's current belief that the departures will not pose a significant public health and safety problem. Further, NRC will use its analysis to determine whether to make the interim rule permanent, L

remove the requirements to prepare radiopharmaceuticals in accordance with the package insert and the requirement to use therapy radiopharmaceuticals for listed indications and routes of administration, or let the interim rule expire. Some departures may i

require additional safety measures to provide adequate assurance of public health and safety.

l 3.

Reduction of Burden Throuch Information Technolocy. There are no i

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legal obstacles to reducing the burden associatec, with this information collection-through information technology. However, because of the types of information sought, the assessment does not lend.itself readily to the use of automated information technology for transfer.

4.

Effort To Identify Duplication. The Information Requ'irements I

Control Automateo System (IRCAS) was searched to identify duplication.

None was found.

5.

Effort To Use Similar Information. There is no similar information j

available to NRC. NRC's medical use licensees are required in 535.200(b)and535.300 to follow package insert instructions when i

preparing NDA products and providing radiopharmaceutical therapy.

6.

Effort To Reduce Small Business Burden. Some licensees who provide l

nuclear medicine and radiopharmacy services are small entities, i.e.,

small businesses. NRC needs to determine the scope and depth of departures at all medical licensees' facilities.

It is not possible to reduce the burden on small entities by less frequent or less complete collection of information because information is needed on all kinds of and sizes of -licensees.

7.-

Consequences of Less Frequent Collection. The written directive for a specific departure is only' collected upon initial occurrence for a e

_particular patient or radiopharmaceutical.

Subsequent treatments for the patient or other patients needing the same departure may be by

'i reference-to the written directive for that departure. The record of the number of patient administrations under the departure is made upon occurrence. Less frequent collection; i.e., not at all, would

. impair the ability of the NRC to evaluate the need for future rule-making on this. issue.

8.

Circumstances Which Justify Variation From OMB Guidelines.

NRC wil1~

require licensees to retain records of departures from written directives for five years to ensure NRC has sufficient time to assess the data to determine if there is a need for additional safety measures to provide adequate assurance of public health and safety.

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Consultations Outside the NRC.

The NRC staff has consulted with i

staff members of both the FDK Center for Drug Evaluation and l

Research and the FDA Center for Biologics Evaluation and Research on W rule and supporting recordkeeping requirements.

10.

Confidentiality of Information.

NRC provides no pledge of confidentiality l

for the collection of information, except for information that might i

identify a patient.

Responses and results obtained, except for information.

j that might identify a patient, may be released to the public.

11.

Justification for Sensitive Ouestions.

None. The information collection requirement does not contain any sensitive questions.

Estimate of Burden._

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s There are seven million nuclear medicine diagnositic clinical procedures and 30,000 clinical therapeutic radiopharmaceutical procedures performed nationwide each year. Thirty percent of these procedures are performed by NRC licensees and it is estimated that

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one percent of these procedures will need departures to manufacturer's instructions.

The NRC estimates that half of the medical use licensees will prepare their radiopharmaceuticals from generator elutions and reagent kits and half will order them from commercial nuclear pharmacies.

Further, NRC estimates 10 percent o' the requested depatures will involve preparing an original wir ten directive'and 90 percent will involve referencing the origina' ;ritten directive.

Table 1.

Estimate of Licensees' Compliance Burden.

Regulation No. of records Total of annual-section annually Hrs./ record burden (in hrs.).

3 11,500-0.02 230 530.34(i)(1) 635.200(c) 2,300 0.08 184 20,700 0.02 414 535.200(c)(2) 11,500 0.02 230

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100 0.1 10 1

TOTAL:

46,100 1,068 For departures permitted in 935.200(c), the estimated information i

collection burden for the authorized user physician is approxiruately 0.08 hour9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> for each original written directive for a specific departure, 0.02 hour2.314815e-5 days <br />5.555556e-4 hours <br />3.306878e-6 weeks <br />7.61e-7 months <br /> for each subsequent directive referencing the original written directive, and 0.02 hour2.314815e-5 days <br />5.555556e-4 hours <br />3.306878e-6 weeks <br />7.61e-7 months <br /> for recording each patient administration.

For departures permitted in 535.300(b),theestimatedburdenis 0.1 hour1.157407e-5 days <br />2.777778e-4 hours <br />1.653439e-6 weeks <br />3.805e-7 months <br /> for recording each patient administration.

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Estimated Annualized Cost tc the Federal Government.

The NRC estimates about 2000 medical license" will be subject to the requirement (seeTable2). The number of me; al licensees has remained fairly constant over time.

Table 2.

Licensees affected by the interim final rule.

Program code Type of licensee Number of licensees 2110 Medical Inst. Broad 118 2120 Medical Inst. Limited 1409 2121 Medical Inst. Custom 14 2200 Private Practice Limited 293 2201 Private Practice Custom 181 2220 Mobile Service 22 2500 Nuclear Pharmacies 50 TOTAL:

2087

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Records will be collected during the medical licensee's regularly scheduled inspections.

Each departure record the NRC collects will consist of both the written directive and its corresponding number of patient administration. Although inspection frequencies vary among the different types of licensees, the majority of licensees are inspected every three years. Thus about one third, or 7700, of the records of deviation and the corresponding nuinber of patient administrations will be collected each year.

Collecting the Information Photocopying-7700 one-page records S 770 Analyzing the Information Based on cases examined to date, the staff estimates an

$70,840 average 0.1 hour1.157407e-5 days <br />2.777778e-4 hours <br />1.653439e-6 weeks <br />3.805e-7 months <br /> is needed to analyze each record. Most, which have been discussed extensively in the scientific literature or studied in depth the first time reported, will require virtually no analysis. A few may require discussions among the staff. The NRC uses a technical labor rate of $92 per hour; this results in a cost of $70,840 (7700 records x 0.1 hour1.157407e-5 days <br />2.777778e-4 hours <br />1.653439e-6 weeks <br />3.805e-7 months <br /> / record x $92/ hour). Analysis results will be used to determine whether future rulemaking is needed.

Total estimated cost

$71,610 14.

Publication for S tatistical Use.

None.

Publication of the collected responses and analysis is not intended.

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[7590-01]

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l List of Subjects 10 CFR Part 30 I

l Byproduct material, Criminal Pena'ty, Government contracts, Intergovernmental relationr, Isotopes, Nuclear materials, Radiation protection, Reporting and recordkeeping requirements, i

10 CFR Part 35 Byproduct material, Criminal Penalty, Drugs, Health f acilities, Health professions, Incorporation by reference, Medical devices, Nuclear materials, Occupational safety and health, Radiation protecticn, Reporting and recordkeeping requirements.

For the reasons set out in the preanbie and under the autnority of the Atomic Energy Act of 1954, cs amended, the Energy Reorganization Act

' 1974, as amended, and 5 U.S.C. 552 ana 553, the NRC is proposing to adopt the followino amendments to 10 CFR Parts 30 and 35.

PART 30 - RULES OF GENERAL APPLICABILITY TO DOMESTIC LICENSING OF SYPRODUCT MATERIAL 1.

The authority citation for Part 30 is revisec to reac as follows:

Authority:

Secs. 81, 82, 161, 182, 183, 186, 68 Stat. 935, 948, 953, 954, 955 as amendec, sec. 234, 83 Stat. 444, as amended (A2 U.S.C.

2112, 2201, 2232, 2233, 2236, 2282); secs. 201, as amended, 202, 206, 88 Stat. 1242, as amenceo, 12aa, 1246 (42 'J.S.C. 5841, 5842, 5846).

Sections 30.7 also issuto....eer Pub. L.95-601, sec. 10, 92 Stat.

2951 (42 U.S.C. 5851).

Section 30.34(b) also issued under sec. 184, 68 Stat. 954, as amended (42 U.S.C. 2234). Section 30.61 also issued under secs.187, 68 Stat. 955 (42 U.S.C. 2237).

For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C.

E2/3); 55 30.3, 30.34(t,),lc), (f), (9), and (i), 30.41(a), and (c), and 1~. 53 are 1ssued uncer cec.161b, 68 Stat. 9a8, as amended

[7590-01]

(42U.S.C.'2201(b));andil 30.6,30.9,30.34(g),30.36,30.51,30.52, 30.55, and 30.56(b) and (c), are issued under sec.161o, 68 Stat. 950, as amended (42 U.S.C. 2201(o)).

s t-L Ini30.34, paragraph (i)isaddedtoreadasfollows:

4.

i 30.34 Terms and conditions of licenses.

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(i)(1)From[insertdateofpublication]to[in, t date 3 years from the date of publication], each licensee eluting generators and processing radioactive material with diagnostic reagent kits for which f

the Food and Drug Administration (FDA) has approved a "New Drug Applicati'on" (NDA) may depart from the manufacturer's elution and L

preparation instructions (tor radiopharmaceuticals authorized for use pursuant to i 35.200) provided that:

(1) The licensee has a written cirective made by an authorized user physician that airects a specific departure for 4 particular patient, or patients, or for a radiopharmaceutical, and +hich includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manuf acturer's instructions N preparing the radiopharmaceutical would obtain medical X

results not'otherwise attainable or would reduce medical risks to particular patients because of their medical condition.. The licensee shall keep the written directive and a record of the number of prescriptions dispensed under the departure in an auditable form and available for inspection for f years; ur (ii) An author _ized user physician determines, in accordance with i 35.200(c), that a delay in preparing the radiopharmaceutical in order to make a written directive would, jeopardize the patient's health because of In this case, the emergent nature of the patient's medical condition.

the' licensee shall obtain the written directive made by the authorized user physician which contains the notation regarding the emergency and all the information specified in (i) above within 3 working days after w4.

pu

.w The license sh; 1 keep these records in an p c.th:

auditableformanoavailableforinspectionforfyears.

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[7590-01]

(2) Theactionsauthorizedinparagraph(i)(1)arepermitted notwithstanding more restrictive language in license conditions unless those license conditions specifically reference i 30.34(1).

(3) Nothing in this section relieves the licensee from complying with other applicable NRC, FDA and other Federal, or State regulations governing the elution of generators and preparation of reagent kits.

PART 35 - MEDICAL USE OF BYPRODUCT MATERIAL 3.

The authority citation for Part 35 is revised to read as follows:

1 Authority:

Secs. 81, 161, 182, 183, 68 Stat.

935, 948, 953, 954, as amended, (42 U.S.C. 2111, 2201, 1132, 2233); sec.,201, 88 Stat.

1242, as amencea (42 U.S.C. 5841).

For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C.

2273); 55 35.11, 35.13, 35.20(a) and (b), 35.22, 35.23, 35.25, 35.2/ (a),

(c)and(d),35.31(a),35.49,35.50(a)-(d),35.51(a)-(c),35.53 (a)-(b), 35.59 (a)-(c), (e)(1), (g) and (h), 35.60, 35.61, 35.70(a)-(f),

35.7d, 35.80 (a)-(e), 35.90, 35.92 (a), 35.120, 35.200 (b) and (c),

35.204, (a) ar.c (b), 35.205, 35.220, 35.300, 35.310 (a), 35.315, 35.320, 35.400, 35.404, (a), 35.406 (a) and (c), 35.410 (a), 35.415, 35.420, 35.500, 35.520, 35.605, 35.606, 35.610 (a) and (b), 35.615, 35.620, 35.630, (a) anc (b), 35.632 (a)-(t), 35.634 (a)-(e), 35.636 (a) and (b),

35.641 (a) and (b), 35.645 (a) and (b), 35.900, 35.910, 35.920, 35.930, 35.932, 35.934, 35.940, 35.941, 35.950, 35.960, 35.961, 35.670, and 35.971, are issued under sec.161b, 68 Stat. 948, as amended (42 U.S.C.

2201(b)); and si 35.14, 35.21, (b) 35.22 (b) 35.2', (b) 35.27, (a) and (c), 35.29 (b), 35.33 (a)-(e), 35.36 (b), 35.50 (e), 35.51 (d), 35.53 (c), 35.59 (d) and (e)(2), 35.59 (g) and (1), 35.73 (g) 35.80 (f), 35.92 7

(b), 35.200 (c) 35.204, (c), 35.300 (b), 35.310 (b), 35.315 (b), 35.404 (b),35.406(b)and(d)35.410(b),35.415(b),35.610,(c),35.615

. d)(4), 35.630(c), 35.632 (g), 35.634 (f), 35.636 (c), 35.641 (c), 35.643 l

(

(c), 35.645, and 35.647 (c) are issued under sec. 1610., 68 Stat. 950, as amenced (42 U.S.C. 2201(o)).

L7590-01)

~

i 35.8 Information Collection Requirements: OMB approval.

(b) The approved information collection requirements contained in this part appear in il 35.12, 35.13, 35.14, 35.21, 35.22, 35.23, 35.27, 35.29, 35.31, 35.33, 35.50, 35.51, 35.53, 35.59, 35.60, 35.61, 35.70, 35.80, 35.92, 35.200, 35.204, 35.205, 35.300, 35.310, 35.315, 35.404, 35.406, 35.410, 35.415, 35.606, 35.610, 35.615, 35.630, 35.632, 35.634, 35.636, 35.641, 35.643, 35.645, and 35.647.

5.

In i 35.200, paragraph (c), is added to read as follows:

i 35.200 Use of radiopharmaceuticals, generators, and reagent kits for imaging and localization studies.

(c) (1)-From [ insert date of publicationj to Linser,t date 3 years the date of publicationj, a licensee may depart f rom the f

from manufacturer's instructions for eluting. generators and preparing reagent,

kits for wnich FDA has approved an NDA, provided that the licensee has a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radio-pharmaceutical, and which includes the specific nature of the departure, a' precise description of the departure, and a brief statement of the l

reasons why the departure from the manufacturer's instruccions Jer p y

preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular 1,

If the authorized user patients because of their medical condition.

physician determines. that a delay in preparing the radiopharmaceutical in order to make a written directive would jeopardize the patient's health because of the emergent. nature of the patient's medical condition, the radiopharmaceutical may be prepared without first making a written The authorized user physician shall make notation of this directive.

determination in the written directive within 3 working days after the X

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19

[7590-01)

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(2) The licensee shall keep the written directive and a record of the number of patient administrations under the departure in an auditable tormandavailableforinspectionforaperiodoffyears.

(3) Nothing in this section relieves'the licensee trom complying with other applicable NRC, FDA ano other Federal, or State regulations governing the elution of generators and preparation of reagent kits.

6.

In 6 35.300, theexistingtextisdesignatedasparagraph(a) and a new paragraph (b) 15 added to read as tollows:

6 35.300 Use of radiopharmaceuticals for therapy.

w (b) (1) From Linsert date of publication) to [ insert cate 3 years from the date of publication], a licensee may depart from the package insert instructions regarding indications or methoc of administration for a radiopharcaceutical for wnich FDA has approved an NOA, proviced that the authorized user physician makes a record of the departure which includes the specific nature of the departure and a brief statement of the reascns why the departure would obtain medical results not otherwise attainable or would recuce medical risks to particular patients wd

&.+ < = -_j_- % m) cercition. L e u because of their medica n~.

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(2) The licensee shall w this record within 3 working days of the administration and keep this record and a record of the number of patient administrations under the departure in an auditable form and available for inspection for f years.

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.i (7590-01]

(3) Nothing in this section relieves the licensee from complying with other applicable NRC, FDA (including requirements governing the submission ot' an IND) and other Federal, or State regulations governing the use of radiopharmaceuticals for therapy.

Dateo at Rockville, Maryland, this day of 1990.

For t*

'!uclear Regulatory Commission.

~

Samuel J. Chilk, i

Secretary of the Commission

.