ML20202D412
| ML20202D412 | |
| Person / Time | |
|---|---|
| Issue date: | 02/01/1978 |
| From: | Minogue R NRC OFFICE OF STANDARDS DEVELOPMENT |
| To: | |
| References | |
| SECY-78-069, SECY-78-069-R, SECY-78-69, SECY-78-69-R, NUDOCS 9902010389 | |
| Download: ML20202D412 (15) | |
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ps Il UL I February 1, 1978 unino sans SECY-78-69 NUCLEAR REGilLATnRY COMMisslON POLICY SESSION ITEM For:
The Commissioners From:
Robert B. Minogue, Director, Offic:. of Standards Development k
Thru:
Executive Director for Operations
Subject:
PROPOSED AMEN 0MENTS TO 10 CFR PART 35 TO CHANGE CONDITIONS OF SPECIFIC LICENSES FOR CERTAIN GROUPS OF MEDICAL USES OF BYPRODUCT MATERIAL
Purpose:
To obtain Commission approval of a notice of proposed rulemaking that would delete the designation of specific diagnostic proce-
'dures for which certain radiopharmaceuticals may be used.
s Category:
This paper covers a minor policy question.
Issue:
Should NRC continur ^' restrict the physician's use of diagnostic radiopharmaceutica' N clinical procedures approved by FDA in the product labeling and designated in NRC regulations?
D^ cision Criteria:
1.
Need for physician freedom to choose what he believes to be the best available diagnostic procedure.
2.
Need to follow NRC's proposed policy statement and minimize intrusion into medical judgments affecting patients.
Alt rnatives:
1.
Continue present NRC restrictions on the physician's choice of clinical procedures.
2.
Delete NRC designation of both specific diagnostic proce-dures and specific therapeutic procedures.
3.
Delete NRC designation of specific diagnostic procedures.
Discussion:
In general, a distinction can be made between diagnostic and therapeutic procedures, with most diagnostic radioisotope proce-dures having a low radiation risk to patients.
Diagnostic radioisotope procedures ordinarily deliver no more than a few tenths of a rem ta the patient; on the other hand, therapeutic procedures can deliver many thousands of rems to localized areas of the patient.
Section 35.100 of 10 CFR Part 35 designates the chemical and physical form of radiopharmaceuticals in certain licensed 9902010389 780201
Contact:
PDR SECY 78-069 R PDR E. Podolak 443-6910
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9b The Commissioners 2
4 categories or.oups.
It also designates the diagnostic or therapeutic procedures for which each listed drug may be used.
The proposed amendments in Enclosure 1 would delete from 9 35.100 designation of the diagnostic procedures for which radiopharmaceu-ticals in Groups I, II, and III may be used.
The specific diagnostic procedures listed in 5 35.100 are essentially those approved by the Food and Drug Administration (FDA) in the prod-uct's labeling (package insert).
By listing only FDA-approved procedures, NRC regulations actually are more restrictive than FDA regulations.
FDA does not have the statutory authority to regulate a physi-cian's use of prescription drugs and, therefore, does not restrict their use of prescription drugs to FDA-approved procedures.
The logic behind FDA's policy regarding the physician's use of an approved drug for uses that have not been approved is described in Enclosure 1.
Essentially, FDA concludes that good medical practice requires that the physician be free to use drugs accord-ing to his best knowledge and judgment in the interest of the patient.
Due to the possibility of malpractice suits, physi-cians do not usually depart from the package insert unless the departure is a generally accepted medical practice.
When using any diagnostic radiopharmaceutical the physician may make the wrong diagnosis.
That is, he may not diagnose a condi-tion that exists (false negative); or he may incorrectly diagnose a condition as existing (false positive).
FDA requires a manufac-turer to submit substantial evidence of effectiveness for a diagnostic agent for a particular clinical procedure before it will approve that procedure for inclusion in the package insert.
When a physician decides to use a drug for a clinical procedure not approved in the package insert, his decision may be based on medical evidence found in the literature or his personal aRadioactive materials in 6 35.100 are divided into six groups, each group having similar requirements for user training and experience, facilities and equipment, and radiation safety procedures.
The purpose of this grouping is to reduce adminis-trative costs by eliminating the need for licensees to seek an amendment to their license each time they wish to use an additional radiopharmaceutical in a group for which they are licensed.
Under the grouping procedure, an application for a specific license for the use of any one radiopharmaceutical in a particular group is treated by NRC as an application for all radiopharmaceuticals in that group.
Th7 Commissioners 3
experience with a particular product.
The physician's decision may be based on a threshold that is lower than FDA's criteria of
" substantial evidence." Therefore, the physician may be more likely to make an incorrect diagnosis when he ' departs from the package insert than when he follows it.
The use of diagnostic radiopharmaceuticals in Groups I, II and III for clinical procedures that have not been approved by FDA entails low risk to the patient, provided the physician follows 1
the product labeling with regard to (1) chemical and physical l
form, (2) route of administration, and (3) recommended dosage range.* Enclosure 1 proposes to amend 6 35.14 to ensure that, when a physician chooses to depart from the labeling regarding diagnostic clinical procedure, he follows the labeling regarding the above three items.
For therapeutic uses of radiopharmaceuticals, the risk to the patient is not low; therefore, Groups IV and V (authorizing theracy procedures) are not included in the proposal to delete I
clinical procedures from 6 35.100.
Because FDA has not fully implemented its authority under the Medical Device Amendments of 1976, Group VI radioactive medical devices also have not been included in the proposal.
In addition to removing an NRC restriction on physicians' medical judgment, the proposed amendments will have the advan-tage of minimizing the necessity for NRC to routinely update the l
radiopharmaceuticals listed in Groups I, II and III of 6 35.100.
l Under the current system, it is necessary for NRC to amend these regulations each time FDA approves a new diagnostic procedure for the radiopharmaceuticals already listed in these groups.
As an item of minor importance, the staff also proposes to l
update the lists in Groups I, II and III, by deleting certain chemical l
nUnder current NRC regulations the physician is not required to follow the package t
insert regarding the recommended dosage range.
Dosage is dependent on pertinent characteristics of the patient, available instrumentation and the judgment of the physician.
Under the proposed amendment, the physician still will not be restricted regarding dosage range if he follows the package insert with respect to the clinical procedure, i
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fhe Commissioners 4
forms for which there is no current FDA approval.
These chemical forms, such as iodopyracet, sodium diatrizoate and diatrizoate methylglucamine, were originally placed in the Groups when the Atomic Energy Commission regulated the safety and efficacy of radiopharmaceuticals incorporating byproduct material.
Since that time, these chemical forms have been replaced by other products and, when the FDA took over the safety and efficacy regulatory function, the radiopharmaceutical manufacturers did not request FDA approval for these chemical forms.
Alternative 1.
Continue present NRC restrictions on the physician's choice of clinical procedures.
Pro:
Maximum patient protection from the risks associated with the use of radiopharmaceuticals for clinical procedures other than those approved by FDA in the product's labeling.
Con: (1) Patient will be denied benefit of advances in diag-nostic and therapeutic nuclear medicine that precede approval by FDA and labeling revision by the manu-facturer.
(2) Physicians will continue to be under a restriction in their own use of radioactive drugs that is inconsistent with the way FDA regulates drugs generally.
Alternative 2.
Delete NRC designation of both specific diag-nostic and specific therapeutic clinical procedures.
Pro: (1)
Patients benefit from advances in diagnostic and therapeutic nuclear medicine that precede approval by FDA and labeling revision by the manufacturer.
(2) Allows a physician freedom to use radiopharmaceuticals as he would other drugs in generally accepted medical practice.
Con:
Patient risk from the use of therapeutic radiopharmaceu-ticals for clinical procedures other than those approved by FDA in the product's labeling is not low.
Alternative 3.
Delete NRC designation of the specific diagnostic procedures.
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l The Commissioners 5
Pro: (1) Patients benefit from advances in diagno". nuclear medicine that precede approval by FDA
..a labeling revision by the manufacturer.
(2) Allows a physician freedom to use diagnostic radio-pharmaceuticals as he would other drugs in good medical practice.
(3) Patient remains protected from the risks associated with the use of therapeutic radiopharmaceuticals for clinical procedures other than those approved by FDA in the product's labeling.
Con: (1) Physicians will continue to be under a restriction in their use of therapeutic radiopharmaceuticals.
(2) Patients may be denied benefit of advances in therapeutic procedures that precede FDA approval.
Recommendation:
The Commission:
1.
Approve a notice of proposed rulemaking (Enclosure 1) that would delete NRC designation of the specific diagnostic procedures in 6 35.100 (Alternative 3).
2.
Note:
a.
The proposed rule would be published in the Federal Register for 60-day public comment.
(The proposed medical policy statement and the proposed misadministra-tion reporting requirement would be published in the same edition of the Federal Register for 60-day public comment.
A single Congressional Letter and public announcement will cover the three notices);
b.
If, after expiration of the comment period, no significan adverse comments or significant questions have been received and no substantial changes in the text of the rule are indicated, the Executive Director for Operations will arrange for publication of the amendment in final form.
If significant questions have been received or substantial changes in the text of the rule are ir.dicated the revised amendment will be submitted to the Commission for approval.
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The Commissioners 6
I Coordination:
The Offices of Nuclear Mate
.is Safety and Safeguards, Inspection and Enforcement, State Pr grams, and the Division of Rules and
)
Records concur in the recommendation of this paper.
The Offices of Policy Evaluation and General Counsel have no comment at this time.
The Office of the Executive Legal Director has no legal objection.
Anticipated Consideration at an open meeting during the Week of February 27, Scheduling:
1978.
M Robert B. Minogue, irector Office of Standards Development
Enclosure:
FEDERAL REGISTER Notice of Proposed Rulemaking 1
DISTRIBUTION Commissioners Comission Staff Offices Exec Dir for Operations Secretariat l
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NUCLEAR REGULATORY. COMMISSION
_[10_CFR Part 35]
HUMAN USES OF BYPRODUCT MATERIAL 1
. Change in License Conditions for Certain Medical Licenses AGENCY:
U.S. Nuclear Regulatory Commission ACTION':
Proposed rule.
SUMMARY
The Nuclear' Regulatory Commission is considering amending its regulations (a)"to' permit physicians greater latitude, when they use certain low risk diagnostic radiopharmaceuticals, by no longer designating-authorized clinical procedures and (b) by deleting from several licensing groups certain chemical forms not approved by FDA.
DATES:
Comment period expires 4
-ADDRESSES:
Written comments or suggestions for consideration ir, connection with the proposed anendment should be submitted to the Secretary of the Commission, U.S. Nuclear Regulatory Commission, M Washington,' D.C. 20555, Attention:
Docketing and Service Branch.
Copies of comments received may be examined at the Commission's
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Public Document Room at 1717 H Street, NW., Washington, D.C.
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Insert'date 60 days from publication in Federal Register.
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Enclosure l' i
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d FOR FURTHER'INFORMATION. CONTACT:
Edward Podolak, Office of Standards Development, U.S.' Nuclear Regulatory Commission, Washington, D.C.
' 20555 (Phone:
301.443-6910).
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SUPPLEMENTARY INFORMATION: :In the most common type of license for the l
medical use of byproduct material, NRC restricts the physician's use of'radiopharmaceuticals essentially to those clinical procedures approved-
- by the Food and Drug Administration (FDA) in the product's labeling.
The package insert, a part of the product labeling, has scientific, i
medical, legal and administrative significance.
The purpose of the package insert-is to ' provide the physician with specific information
- about the use of the radiopharmaceutical.
This information, which is l
reviewed and approved by FDA, includes:
1.
The chemical and physical form of the drug; 2.
Recommended usual dose and usual dose range; 3.
Indications and usage (clinical procedures);
4.
Route of administration to which the labeling applies; l
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Contraindications; and 6.
Warnings.
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Under the so-called Group
- medical licenses, NRC restricts the physician's choice of clinical procedures to FDA approved procedures.
This is accomplished by listing in 10 CFR S 35.100 each radioisotope the chemical and physical form of the radiopharmaceutical and the authorized clinical procedures.
Each time FDA approves a new clinical procedure for a radiopharmaceutical listed in 5 35.100, NRC must consider amending 9 35.100 to include the new procedure.
The purpose of this proposed rule change is to delete the speci-fication of the diagnostic clinical procedures from the lists of radiopharmaceuticals in Groups I, II and III of 9 35.100.
This would permit a physician to use these diagnostic radiopharmaceuticals for 1
clinical procedures not included in the product labeling.
The use of an approved drug for indications that have not been approved in the product labeling has been discussed by FDA in a FEDERAL REGISTER announcement (40 FR 15392) concerning the " Labeling for Prescription Drugs Used in Man":
... the labeling is not intended either to preclude the physician's use of his best judgment in the interest of the patient or to impose liability if he xThe most common types of NRC specific licenses for the medical uses of byproduct material are the Group medical licenses under S 35.14 that apply to those radioactive materials listed in S 35.100.
The radio-active materials listed in 6 35.100 are divided into six groups, each group having similar requirements for user training and experience, l
facilities and equipment, and radiation safety procedures.
Groups I, II and III are lists of radiopharmaceuticals for diagnostic procedures; l
Groups IV and V are lists of radiopharmaceuticals for therapeutic procedures; and Group VI is a list of radioactive medical devices for both diagnostic and therapeutic procedures.
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does not follow the' package insert.
The (FDA)
Commissioner clearly recognizes that-the labe, of a marketed drug does not always contain e
.,a most current. information available to physi. s relating
.i to the proper use of the drug in goe inedical practice.
Advances in medical knowledge and practice inevitably
. precede' labeling: revision by the manufacturer and formal label approval by the Food and Drug Administration.
Good medical practice and patient interests thus require that physicians be free to use drugs according to their best knowledge and judgment.
Certainly, where a physician uses a drug for a use not in the approved labeling, he has the responsibility to be well informed about the drug and to base such use on a firm scientific rationale or on sound medical evidence, and to maintain adequate medical. records of the drugs use and effects, but such usage in the practice of medicine is not in violation of the Federal Food, Drug and Cosmetic Act.
4 The Commission believes that the use of radiopharmaceuticals listed in Groups' I, II and II'for diagnestic clinical procedures not
. yet approved by FDA entails low risk to the patient, provided the chemical and physical form, route of administration and the dosage range remain the same as specified in the radiopharmaceutical labeling.
Therefore, the Co0 mission is also proposing to amend 6 35.14 to require the physician to comply with the product labeling with respect to these three items, when he uses Groups I, II and III radiopharmaceuti-cals for clinical procedures not specified in the product labeling.
Because of the higher patient risk, the Commission will continue to restrict the uses of therapeutic radioactive drugs in Groups IV and V to clinical. procedures approved by FDA in the product labeling.
The 1
uses of radioactive medical devices in Group VI will continue to be restricted to clinical procedures determined to be safe and effective 4
l by NRC in consultation wit"
. advisory Committee on the Medical Uses of Isotopes.
The Commi.nion is also proposing to update the lists in Groups I, II and III by deleting certain chemical forms not approved by FDA.
j These chemical forms, such as iodopyracet, sodium diatrizoate and diatrizoate methylglucamine, were originally placed in the groups when
'the Atomic Energy Commission regulated the safety and efficacy of radiopharmaceuticals incorporating byproduct material.
Since then, these chemical forms have been replaced by other products and, when I
the FDA took over the safety and efficacy function, the radiopharmaceuti-cal manufacturers did not request FDA approval.
Under the Atomic Energy Act of 1954, as amended, the Energy Reorganization Act of 1974, as amended, and Section 553 of Title 5 of the United States Code, notice is hereby given that adoption of the following amendments to 10 CFR Part 35 is contemplated.
1.
In 6 35.14(b), add a new paragraph (6) to read as follows:
6 35.14 Specific licenses for certain groups of medical uses of byproduct material.
(b) * * *
(6) For Groups I, II and III any licensee using byproduct material for clinical procedures other than those specified in the product labeling (package insert) shall comply with the product labeling regarding:
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chemical' and physical form; y
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'(ii). route of administration; and i
(iii) dosage range.
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2.
In i 35.100, paragraphs (a), (b) and (c) are revised to read
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9 35.100 Schedule A - Groups of medical uses of byproduct
. material.
(a) Group I.-
Use of prepared radiopharmaceuticals for certain diagnostic studies involving _ measurements of uptake, dilution and excretion.
This group does not include imaging or localization studies.
(1) Iodine-131 as sodium iodide, iodinated human serum albumin, labeled rose bengal, triolein, sodium iodohippurate or sodium iothalamate; (2) Iodine-125 as sodium iodide, iodinated human serum albumin, oleic acid or sodium iothalamate; e
(3) Cobalt-58 as labeled cyanocobalamin; (4) Cobalt-60 as labeled cyanocobalamin; 1
(5) Chromium-51 as sodium chromate or labeled human serum albumin; p
(6) Iron-59 as citrate; 1
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.(7) Technetium-99m as pertechnetate; and
. (8) Any byproduct material in a radiopharmaceutical and for a l
diagnostic use involving measurements of uptake', dilution or
. excretion for which a." Notice of. Claimed Investigational Exemption
- for a New Drug" (IND) has been accepted by the Food and Drug Administration (FDA).
(b) ' Group II.
Use of prepared radiopharmaceuticals for diagnostic l
imaging and localization' studies.
(1)
Iodine-131'as. sodium iodide, iodinated human serum albumin, macroaggregated fodinated human serum albumin, colloidal (micro-aggregated)'iodinated human serum albumin, rose bengal or sodium iodohippurate; (2)
Iodine-125 as sodium iodide or fibrinogen; (3)' Chromium-51 as human serum albumin; (4) Gold-198 in colloidal form; (5) Mercury-197 as chlormerodrin; (6). Mercury-203 as chlormerodrin; (7) Selenium-75 as selenomethionine; i.
(8) Strontium-85 as nitrate;
'(9) Technetium-99m as pertechnetate, labeled sulfur colloid or macroaggregated human serum albumin;
'(10) Ytterbium-169 as diethylenetriaminepentaacetic acid (Sn);
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(11) Indium-113m as chloride; i
(12) Any byproduct material in a radiopharmaceutical prepe-rrom a reagent kit listed in paragraph (c)(4) of this sectic..i; and (13) Any byproduct material in a radiopharmaceutical and for a diagnostic use involving imaging or localizing for which a " Notice of Claimed Investigational Exemption for a New Drug" (IND) has been accepted by the Food and Drug Administrroion (FDA).
(c) Group III.
Use of generators and reagent kits for the prepara-
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tion and tse of radiopharmaceuticals containing byproduct material for certain diagnostic studies.
)
(1) Molybdenum-99/ technetium-99m generators for the elution of technetium-99m as pertechnetate; (2) Technetium-99m as pertechnetate for use with reagent kits for preparation and use of radiopharmaceuticals contain technetium-99m as provided in paragraphs (c)(4) and (5) of this section; (3) Tin-113/ indium-113m generators for the elution of the indium-113m i
as chloride; (4) Reagent kits for preparation of technetium-99m labeled:
(i) Sulfur colloid; (ii) Iron-ascorbate-diethylenetriaminepentaacetic acid complex; (iii) Diethylenetriaminepentaacetic acid (Sn);
(iv) Human serum albumin microspheres; 8
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(v)-
Polyphosphates; I.
l (vi)
Macroaggregated humer. cum albumin; (vii) Distannous etidrsnate complex; i
l (viii) Stannous pyrophosphate; (ix)
Human serum albumin; and l.
(5) Any generator or reagent kit for preparation and diagnostic use L
of a radiopharmaceutical containing byproduct material for which
-generator or reagent kit a " Notice of Claimed Investigational Exemp-tion of a New Drug" (IND) has been accepted by the Food and Drug Administration (FDA).
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i (Secs. 81, 161, Pub. Law 83-703, 68' Stat. 935, 948 (42 U.S.C. 2111, i
2201); Sec. 201, Pub. Law 93-438, 88 Stat. 1242 (42 U.S.C. 5841).)
r Dated at this day of 1978.
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For the Nuclear Regulatory Commission.
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l Samuel J. Chilk l
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Secretary of the Commission L
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