ML20245F077
| ML20245F077 | |
| Person / Time | |
|---|---|
| Issue date: | 06/30/1989 |
| From: | Harriet Karagiannis NRC OFFICE FOR ANALYSIS & EVALUATION OF OPERATIONAL DATA (AEOD) |
| To: | |
| Shared Package | |
| ML20245F032 | List: |
| References | |
| TASK-AE, TASK-N901 AEOD-N901, NUDOCS 8906280030 | |
| Download: ML20245F077 (7) | |
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l AE0D ENGINEERING EVALUATION EE REPORT N0: AE00/N901 !
DATE: JUNE 1989 EVALUATOR / CONTACT: HARRIET KARAGIANNIS
SUBJECT:
USE OF RADI0 ACTIVE IODINE FOR INFREQUENT MEDICAL STUDIES AND {
THOSE PERFORMED UNDER AN FDA INVESTIGATIONAL EXEMPTION FOR A l NEW DRUG (IND)
INTRODUCTION
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1 In 1980, the U.S. Nuclear Regulatory Commission (NRC) promulgated a regulation requiring its licensees to report misadministration of radiopharmaceuticals used for diagnostic or therapeutic purposes. Other events may also be reported to the NRC as required under 10 CFR 20.405(a) by license condition, or may be included in an inspection report.
The Division of Safety Programs (DSP) in the Office for Analysis and Evaluation of Operational Data (AE0D) regularly reviews these reported misadministration and events. During this review, the staff noted that because of the inadequacy of the quality assurance (QA) procedures followed by licensee personnel involved in the preparation and administration of radioactive iodine for diagnostic and therapeutic procedures, patients received unintended thyroid doses. Some of these misadministration occurred during studies performed under a Food and Drug Administration (FDA) investigational exemption for a new drug (IND)* and infrequent medical studies.** The others were routine clinical studies.
BACKGROUND IND and infrequent medical studies are usually performed by NRC medical broad-scope materials licensees. A medical broad-scope byproduct materials license requires that licensees have a radiation safety committee to conduct safety evaluations of the proposed uses of byproduct material (including a review of facilities and equipment, operating and handling procedures, and training and experience of users) and to approve uses of the materials. For broad-scope licensees, IND and infrequent medical studies have to be approved by the licensee's radiation safety committee but not by the NRC. Thus, the NRC may not be aware of the number and type of IND studies that are performed nor the extent of radiation hazards associated with them. It is only during an NRC inspection that these studies are identified and reviewed for compliance.
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- NRC materials licensees pursuant to 10 CFR 35.200 may use any byproduct j material in a diagnostic radiopharmaceutical or any generator or reagent l kit for preparation and diagnostic use of a radiopharmaceutical containing I byproduct material fcr which the FCA has accepted a " Notice of Claimed Investigational Exemption for a New Drug" (IND) or approved a "New Drug {
Application"(NDA), 1
- Infrequent medical studies involve nonroutinely used NDA materials and i
procedures using licensed sealed source devices, {
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Medical limited-scope licensees under 10 CFR Part 35 are authorized to use
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byproduct material listed in their licenses and any changes in their program (if l not ministerial *) must be approved by the NRC. However, these licensees are required to follow the manufacturer's instructions that accompany the radio- l j
pharmaceutical for the various studies. Therefore, the NRC will not be informed 1 of any IND studies performed by such licensees, if not listed in their license (s),
until an inspection is conducted. !
IND and infrequent medical studies are usually performed in the nuclear medicine or the radiation therapy department of the applicable medical institution.
These studies, however, are sometimes performed in one of the research depart-ments of such institutions (e.g., Case 1, page 3) whose personnel may not have up-to-date knowledge of the radiation safety handling procedures.
An IND application must be filed with the FDA in order to conduct a " clinical investigation," which means "any experiment in which a drug (radioactive or nonradioactive) is administered or dispensed to, or used involving one or more human subjects." The FDA regulations define the person or persons who apply for the IND as the sponsor and the professional who conducts the clinical investigation as the investigator. The investigator may also file the IND application and would then be called the sponsor-investigator.
Usually the large medical institutions that perform IND studies form a Radio-active Drug Research Committee (RDRC) intended to obtain basic research informa~-
tion and approve medical research studies (not all medical institutions necessarily have an RDRC, although they may be performing IND studies). The FDA periodically monitors each RDRC through a review of annual reports, as well as by onsite inspections. There are RDRC regulations that pertain to radiation dose to subjects, pharmacological dosage, and qualifications of investigators, as well as the requirement to obtain a license for possession and use of radioactive materials. Therefore, in regard to the use of radioactive material, the responsible investigator or institutions must be licensed by the NRC or the appropriate Agreement State.
The FDA retains oversight responsibility or authority over an investigation carried out under an IND. If the FDA finds that the investigator is not following the IND regulations, then that particular IND application is put on hold for an enforcement action.**
- Under 10 CFR 35.2, " ministerial change" means a change that is made, after ascertaining the applicable requirements, by persons in cuthority in conformance with the requirements, and without making a discretionary judgment about l whether those requirements should apply in the case at hand. i
- Presentation by A. E. Jones, M.D. (FDA), at the NRC/FDA interagency meeting on January 22, 1988.
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ANALYSIS OF CASES i j
i Case 1
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Iodine-123 thiouracil (I-TU) procedure '
North Shore University Hospital (an Agreement State licensee)
Manhasset, New York March 1988 The Brookhaven National Laboratory (BNL) has been collaborating with a physician at the nearby North Shore University Hospital (NSUH) on the use of iodothiouracil.*
Iodothiouracil is used for diagnostic studies of patients who have ocular melanomas; the studies are performed under an IND.
On March 8, 1988, a scientist at BNL prepared iodine-123 TV in equipment previously used to prepare iodine-125 TU. The equipment, a Sephadex column, was used to separate untreated radiciodide from radioiodinated thiouracil. This column had been used the previous week to purify 25 millicuries of iodine-125 TV, which was stored for future use. The scientist had washed the column with acetic acid before using it to purify the iodine-123 TV, and believing that it was suitable for reuse, made no assay to determine if the column still contained iodine-125. The product activity was checked after purification using a Capintec dose calibrator ** and assuming that all activity was iodine-123 no analysis for radionuclidic purity *** was made. Thus, the presence of iodine-125 was not detected.
The physician, the IND sponsor, injected the patient with the solution without assaying it. The physician also inadvertently neglected to administer potassium iodine to the patient, as required by the FDA protocol. Tumor and blood samples taken during surgery indicated iodine-125 contamination. A radioactive count of the patient's thyroid showed that the absorbed thyroid dose was 130 rads.
However, if potassium iodine had been administered as stipulated in the protocol for this study, the thyroid dose would have been insignificant.
An internal investigation revealed the following:****
o Administrative oversight of investigators performing procedures under an IND was lacking, o The procedure for preparing radioactive iodine thiouracil was changed, 1 but the IND was not amended. l
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- Iodoth1ouracil-thiouracil and sodium iodide containing either of two iodine isotopes, iodine-123 or iodine-125 (designated as iodine-123 TV or iodine- {
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- An assa; device designed to measure radioactivity in radionuclides and radiopharmaceuticals and not designed to assay radionuclidic purity. An ionization chamber is used to dettet radiaticn.
- The fraction of the total radioactive material that is present in the form of the stated radionuclides.
- C. W. Flood, Jr., " Report of the Committee Investigating the Preparation and Shipment of Iodine-123 as a Radiopharmaceutical at Brookhaven National Laboratcry," March 8,1988.
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o The training and experience of personnel involved in the preparation of iodine-thiouracil were inadequate.
o No radionuclidic analysis was performed after the preparation of iodine thiouracil.
o The dose calibrator was not routinely calibrated with standard sources.
o The radiopharmaceutical was not assayed before it was administered to the patient.
o Potassium iodide was not administered to the patient to block the thyroid as stipulated in the protocol for this study, o Proper equipment was not dedicated to this project.
Case 2 Iodine-131 meta-iodobenzylguanidine (MIBG) adrenal procedure The Fairfax Hospital (NRC licensee)
Falls Church, Virginia August 1988 The Fairfax Hospital reported a misadministration to a patient undergoing a nuclear medicine adrenal procedure under an IND. The patient received 2.7 millicuries of iodine-131 MIBG instead of the prescribed 500 ricrocuries.
As a result, the patient's adrenal medullae received a dose of 268 rad instead of the prescribed 50 rad. The thyroid burden was negligible, since the patient's thyroid was blocked with a Lugol's solution as prescribed in the protocol.
The licensee concluded that the causes of this misadministration were the following:
o Personnel performing the iodine-131 MIBG procedure were not familiar with the proper dosage required for such procedures.
o The iodine-131 MIBG procedure was relatively new and was used infrequently.
Case 3 Iodine-131 MIBG adrenal procedure Henry Ford Hospital (HRC licensee)
Detroit, Michigan August 1988 Henry Ford Hospital reported a misadministration to a patient undergoing a nuclear medicine iodine-131 MIBG adrenal procedure. The patient received a dosage of 2 millicuries instead of the prescribed dosage of 500 microcuries.
As a result, the estimated dose to the patient's adrenal medullae was 220 rad '
instead of the prescribed 50 rad. The patient': thyroid received negligible exposure, since it was blocked before the administration of the radiopharma-ceutical. The licensee concluded that this misadministration was due to the following:
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o The iodine-131 MIBG procedure was a relatively new and uncommon procedure.
o Personnel performing the procedure misunderstood the dosage order.
Case 4 Brachytherapy procedure
- The University of Cincinnati Medical Center (NRC licensee)
Cincinnati, Ohio August 1984 The University of Cincinnati Medical Center reported the rupture of an iodine-125 seed (nominal activity of 40 millicuries). The seed was one of eight seeds !
being used as a temporary implant in the brachytherapy treatment of a brain tumor.
Because of the initial high activity of the seeds, they could be used as removable brachytherapy implants (according to the 3M Company specification sheet for the 1
seeds). The same set of seeds had been used at the medical center to treat several patients. This reuse of the seeds involved removing the seeds from catheters and loading them into new catheters before each insertion.
4 It was during the removal and loading of the seeds that one of the seeds ruptured. The leaking seed was implanted and, as a result, the patient received a thyroid exposure of 2087 rad. In addition, numerous personnel involved in the control and cleanup of the contamination received iodine-125 uptakes.
AEOD enalysed this event
- and concluded that certain quality assurance procedures, although they were not included in the manufacturers specifications, could have prevented the rupture of the seed if they had been followed. Such procedures are as follows:
a removal of the seeds from catheters under a fume hood a comprehensive wipe surveys of tools and the area used for the removal and reloading of the seeds, and/or o leak testing of the seeds following the removal / unloading operation Also, if a thyroid-blockina agent had been administered in this case, the thyroid exposure would have been insignificant.
1 Case 5 Brachytherapy prccedures**
NRC licensees reported six brachytherapy events following iodine-125 seed implantation, during which the seeds leaked and resulted in patient thyroid exposures. These exposures varied from 120 millirad to 22 rad, l
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- AE00 Case Stuoy C601, " Rupture of an Iodine-125 Brachytherapy Source at the University of Cincinnati Medical Center," August 1986.
- IE Information Notice 80-3E, " Leaking and Dislodged Iodine-125 Implant Seeds,"
and Supplement 1 to IE Information Notice 80-35, and AE0D report, " Review
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of Iodine-125 Sealed Source Leakage Incidents 1980-1982." j
The conclusions of an evaluation of these events at that time by an NRC medical physics consultant, Dr. Peter Almond of M.D. Anderson Hospital and Tumor Institute, were the following:
o Personnel performing the brachytherapy procedures were not familiar with the use of the brachytherapy treatment equipment.
o Licensees should review the possibility of performing bioassays when difficulties are encountered during seed implantation.
FINDINGS AND CONCLUSIONS As a result of the analysis and evaluation of the above cases, we have concluded that management oversight of the performance of IND and infrequent medical studies is not adequate. Also, personnel involved in these studies lack know-ledge of and experience with the appropriate radiation safety quality assurance steps that should be followed and which are required by the FDA or the NRC.
Although the subject cases involve small amounts of radioactive iodine, it is our understanding that in the future medical institutions may be widely using much larger amounts of radioactive iodine for the performance of monoclonal l
antibody IND studies. As a result, the impact of any misadministration on the health and safety of the patients and the licensee employees could be much greater.
Specific suggestions for NRC materials inspections are as follows:
L o Revise NRC Inspection Procedure 87100 to include (1) identification of licensee procedures performed in the nuclear medicine or the radiation therapy department under an IND and during infrequent medical studies in order to verify that personnel performing such procedures have adequate training, experience, and equipment and (2) identification of the research l departments where radioactive materials are prepared and administered for such studies to ascertain the researchers' initial and refresher training, the frequency of surveys at the research departments, and the use of appropriate equipment for these studies.
I o Verify that the committees (e.g., radiation safety committee) adequately supervise the use of radioactive material for IND and infrequent medical studies to ensure compliance with NRC regulations.
l 0 Verify that investigators are following the radiation safety quality assurance procedures specified in the FDA sponsor's application for IND and as required by the RDRC.
NMSS/INMS should also consider the following:
o Require patient bioassay and thyroid blocking (1) when radioactive iodine is used for human research under an IND, (2) when difficulties are encountered in % plants, and (3) when surgery it performed in the implant area shortly after the seeds are implanted.
o In collaboration with the FDA, evaluate the overlap between the two agencies of the radiation safety requirements imposed on NRC licensees for the subject studies.
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-7. .l o' Obtain'from the FDA a list of NRC licensees whose FDA/IND application was
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put on hold because of violations of the procedures specified in the !
sponsor's application, and determine if any NRC radiation safety requirements {
have been violated. This should be a continuing activity.
- o. Require NRC licensees that perform IND and infrequent medical studies to .{
establish quality assurance procedures regarding radiation safety handling i techniques used for these studies.
o Update NMSS Policy and Guidance Directive FC 86-5, " Authorizing Participation in IND Studies," in regards to regional licensing _and inspection guidance.
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