Information Notice 2000-19, Implementation of Human Use Research Protocols Involving U.S. Nuclear Regulatory Commission Regulated Materials
| ML003773013 | |
| Person / Time | |
|---|---|
| Issue date: | 12/05/2000 |
| From: | Cool D Office of Nuclear Material Safety and Safeguards |
| To: | |
| Howe D, NRC/NMSS, 415-7848 | |
| References | |
| IN-00-019 | |
| Download: ML003773013 (15) | |
UNITED STATES
NUCLEAR REGULATORY COMMISSION
OFFICE OF NUCLEAR MATERIAL SAFETY AND SAFEGUARDS
WASHINGTON, D.C. 20555 December 5, 2000
NRC INFORMATION NOTICE 2000-19: IMPLEMENTATION OF HUMAN USE RESEARCH
PROTOCOLS INVOLVING U.S. NUCLEAR
REGULATORY COMMISSION REGULATED
MATERIALS
Addressees
All medical use licensees.
Purpose
This information notice is intended to remind medical use licensees of their responsibility to
ensure compliance with U.S. Nuclear Regulatory Commission (NRC) requirements and all their
license conditions, when participating in the research involving human subjects using NRC
regulated materials. It is also intended to remind licensees that Title10 of the Code of Federal
Regulations (CFR) Section 35.6, Provisions for research involving human subjects, is not a
blanket authority to conduct research involving human subjects.
Licensees should review this information for applicability to their own procedures and consider
actions, if appropriate, to preclude violations similar to those described in this notice. However, information contained in this notice does not constitute any new NRC requirements, and no
written response to this information notice is required.
Background:
The participation of four NRC licensees in research studies involving human subjects is
discussed in Attachment 1. The first three licensees were participating in a U. S. Food and
Drug Administration (FDA)-accepted investigational new drug (IND) trial and the fourth licensee
was participating in an FDA-accepted investigative device exemption (IDE) trial. These trials
involved the use of byproduct material in radioactive drugs, or sealed sources and devices for
radiation therapy using blind research protocols.
In three of the four cited cases, the licensees participating in the research studies were found to
be conducting research using byproduct material in violation of NRC requirements. Although all
of these licensees were in compliance with the requirements of 10 CFR 35.6, they overlooked
other applicable NRC requirements. Additionally, one licensee (the fourth) incorrectly believed
10 CFR 35.6 provided blanket authorization to conduct research involving human subjects
regardless of whether the licensee complied with the conditions of its license or other NRC
requirements.
December 5, 2000
Discussion:
Some research involving human subjects and especially blinded research studies pose unique
radiation safety challenges and issues. These issues are summarized below and discussed in
more detail in a question and answer format in Attachment 2.
In order to conduct research involving human subjects NRC licensees need to:
ÿ have a medical use license;
ÿ be licensed for the specific medical use included in the research;
ÿ be licensed to use the regulated material specifically for the medical use included in
the research;
ÿ comply with 10 CFR 35.6;
ÿ comply with all applicable NRC requirements in 10 CFR, including those in 10 CFR
Part 35, not just the requirements of 10 CFR 35.6; and
ÿ comply with all license conditions.
When participating in research studies regulated by FDA, the licensee needs to be aware that:
ÿ FDA review of the device1, drug, or biologic may not be substituted for NRCs
licensing review; and
ÿ following the FDA-accepted protocol does not assure compliance with NRC
requirements
In general, when conflicts occur between protocols (or radiation safety information within
protocols) and NRC requirements, it is the licensees responsibility to resolve the conflicts and
be in compliance with the NRC requirements. This may involve contacting NRC, the protocol
sponsor, or both.
Licensees also need to be aware that participation in a blind study does not relieve the
licensee from meeting the:
ÿ labeling requirements in 10 CFR Part 35;
ÿ written directive requirements;
ÿ research subject release and the instruction requirements of § 35.75;
ÿ hospitalization requirements in 10 CFR Part 35; and
ÿ misadministration notification and reporting requirements.
Medical broad scope licensees have a broader licensing authorization and can participate in
research studies that may not be authorized for medical limited scope licensees because of the
restrictions in § 35.49.
One of the cited cases involved a limited specific medical use licensee attempting to participate
in an intravascular research study using sealed sources and a device that had not been
1 FDA classifies a source as a device. December 5, 2000
evaluated and registered by NRC or an Agreement State. Attachment 3 addresses the
approach NRC uses to review a limited specific scope licensees request to participate in
intravascular brachytherapy research studies on human subjects.
Summary:
Any licensee with questions concerning compliance with NRC or Agreement State requirements
or license amendments related to research involving human research subjects and regulated
materials, should contact either NRC regional licensing personnel or its corresponding
Agreement State for advice. Licensees may also want to distribute this notice to researchers
using NRC-regulated materials to conduct human research, as well as individuals responsible
for radiation safety and quality management programs. This could save licensees considerable
time and resources, and avoid violations of regulatory requirements.
No specific written response to this information notice is required. If you have any questions
about this matter, please contact the technical contacts listed below or the appropriate regional
office.
Donald A. Cool, Director
Division of Industrial and
Medical Nuclear Safety
Office of Nuclear Material Safety
and Safeguards
Technical Contacts: Robert L. Ayres, Ph.D., NMSS Donna-Beth Howe, Ph.D., NMSS
(301) 415-5746 (301) 415-7848 E-mail: rxa1@nrc.gov E-mail: dbh@nrc.gov
Attachments:
1. Licensee Case Histories
2. Questions and Answers
3. Criteria for a Limited Specific Scope Licensee
to Participate in Intravascular Brachytherapy
Research Studies on Human Subjects
4. List of Recently Issued NMSS Information Notices
5. List of Recently Issued NRC Information Notices December 5, 2000
evaluated and registered by NRC or an Agreement State. Attachment 3 addresses the
approach NRC uses to review a limited specific scope licensees request to participate in
intravascular brachytherapy research studies on human subjects.
Summary:
Any licensee with questions concerning compliance with NRC or Agreement State requirements
or license amendments related to research involving human research subjects and regulated
materials, should contact either NRC regional licensing personnel or its corresponding
Agreement State for advice. Licensees may also want to distribute this notice to researchers
using NRC-regulated materials to conduct human research, as well as individuals responsible
for radiation safety and quality management programs. This could save licensees considerable
time and resources, and avoid violations of regulatory requirements.
No specific written response to this information notice is required. If you have any questions
about this matter, please contact the technical contacts listed below or the appropriate regional
office.
/RA/
Donald A. Cool, Director
Division of Industrial and
Medical Nuclear Safety
Office of Nuclear Material Safety
and Safeguards
Technical Contacts: Robert L. Ayres, Ph.D., NMSS Donna-Beth Howe, Ph.D., NMSS
(301) 415-5746 (301) 415-7848 E-mail: rxa1@nrc.gov E-mail: dbh@nrc.gov
Attachments:
1. Licensee Case Histories
2. Questions and Answers
3. Criteria for a Limited Specific Scope Licensee
to Participate in Intravascular Brachytherapy
Research Studies on Human Subjects
4. List of Recently Issued NMSS Information Notices
5. List of Recently Issued NRC Information Notices
Accession No. ML003773013 DOCUMENT NAME: A & G(I:\):IN_99hum8.WPD (IMNS-7311) *see previous concurrence
OFC MSIB MSIB MSIB TechED OGC MSIB D/IMNS
NAME RAyres/ll* DBHowe* FSturz* EKraus* STreby* LWCamper* DACool
DATE 6/ 03 /99 6/03/99 6/03 /99 6/06 /99 3/ 24 /00 7 / 29 /99 11/29/00
OFFICIAL RECORD COPY
ATTACHMENT 1 IN-2000-19 December 5, 2000
LICENSEE CASE HISTORIES
Investigational New Drug Trial Cases:
Three NRC licensees were participating in a therapeutic radioactive drug research study. The
drug manufacturer was conducting Phase II clinical trials accepted by the US Food and Drug
Administration (FDA) pursuant to an Investigational New Drug (IND) application. The protocol
called for blind studies to compare the effectiveness of several dosage levels of the
investigational drug against both the commercially available therapeutic radiopharmaceutical
Metastron (containing strontium-89 chloride) and a placebo. Because the studies were
blind, neither the individual administering the dosage nor the human research subject was
informed of the drug/placebo or the dosage administered. To keep the identity of the drug or
placebo delivered secret, the delivery administration procedures were identical.
The investigational drug was primarily a photon emitter, unlike Metastron which is primarily a
beta emitter. Research subjects administered Metastron, which contains strontium-89, do not
pose an external radiation hazard to other individuals. The photon emitter in the investigational
drug could, however, pose an external radiation hazard to others. The proposed human
research subject instructions in the protocol were similar to those suggested for Metastron, and therefore did not address steps to minimize exposure to other individuals from a photon
emitter. Additionally, the dosage levels under investigation included a dosage of the
investigational drug that, if administered, might have required hospitalization of the human
research subjects, in accordance with 10 CFR 35.75(a). Human research subject-specific
information (such as biological clearance or personal behavior) needed to be considered to
determine whether the total effective dose equivalent to other individuals from exposure to the
released research subject could exceed 0.5 millisievert (0.5 rem).
NRC inspectors determined that two licensees participating in this protocol failed to recognize
that the sponsors suggested instructions to the research subjects were inappropriate for the
investigational drug and that one dosage level could require hospitalization of the research
subject, unless other criteria were considered. In both cases, the medical broad scope
radiation safety committees did not review or approve the 10 CFR Part 33 required safety
evaluations addressing radiation safety issues for proposed uses of byproduct material
associated with these research studies.
The dosages administered by the third licensee were below levels that required the research
subject to be released with instructions. This licensee also complied with all NRC requirements
and will not be discussed further.
First IND Licensee
The first licensee administered a dosage without recognizing that the dosage could have
required hospitalization, for compliance with 10 CFR 35.75. The human research subject
was released with written instructions, but the instructions were inappropriate for the
radionuclide administered. After learning of the apparent unauthorized release, the
licensee, using subject-specific elimination rates, determined that exposures to other
individuals were not likely to exceed 5 millisievert (0.5 rem). However, this determination
ATTACHMENT 1 IN-2000-19 December 5, 2000
should have been made before releasing the human research subject and appropriate
instructions provided to the research subject.
Second IND Licensee
The second licensee administered dosages of the investigational drug to two human
research subjects. In the first of these administrations, the dosage to the subject was such
that, if the subject were to be released, other individuals were likely to receive a total
effective dose equivalent in excess of 5 millisievert (0.5 rem). This subject was
hospitalized, but for reasons unrelated to the radiopharmaceutical dosage administration.
Licensee personnel did not recognize that the subject was required to be hospitalized for
compliance with 10 CFR 35.75. In addition, the licensee neither provided instruction to
personnel providing care to the human research subject in accordance with 10 CFR
35.310, nor followed the applicable safety precautions in 10 CFR 35.315.
When the research subject was released from the hospital, other individuals were likely to
receive a total effective dose equivalent between 5 millisievert (0.5 rem) and 1 millisieverts
(0.1 rem). Thus, before this subject was released, the licensee was required to provide
instructions on actions recommended to maintain doses to other individuals as low as
reasonably achievable. However, the required instructions were not provided to the
research subject. The dosage for the second research subject was high enough that this
subject also needed to be provided with instructions. Instructions were not provided for
this research subject either.
After identifying the first incident, NRC contacted the IND sponsor and discussed the sections
of the protocol that contributed to the licensees being in noncompliance with NRC regulations.
The sponsor amended its FDA IND application to revise the protocols suggested human
research subject instructions. The revised instructions now include precautions to minimize
exposure to other individuals. The sponsor also alerted the protocol participants that one
dosage level of the investigational drug may require hospitalization of the human research
subject to meet the requirements of 10 CFR 35.75.
Investigational Device Exemption Trial Case:
A fourth licensee received an intravascular brachytherapy device, containing multiple sealed
sources of strontium-90, from the device manufacturer, to participate in its Investigational
Device Exemption (IDE) clinical trial. The purpose of the trial was to establish the efficacy of
using intravascular brachytherapy to prevent restenosis in coronary arteries after balloon
angioplasty. Although this licensee was authorized to possess this device and sources under
its broad-scope research and development license, it was not authorized to use the device on
humans under its medical use license of limited scope.
In this specific intravascular brachytherapy research case, NRC inspectors identified the
following two failures to comply with NRC requirements:
ATTACHMENT 1 IN-2000-19 .
December 5, 2000
The Sr-90 sealed sources are not listed in 10 CFR 35.400 for the application (intravascular
brachytherapy) for which they were used. Under 10 CFR 35.400, the only authorized use
for strontium-90 sealed sources is for treatment of superficial eye conditions. Therefore, the
licensee needed to apply for, and receive, an exemption from the requirements of 10 CFR
35.400; and,
2. Neither the Sr-90 sealed sources nor the device had been reviewed by NRC or an
Agreement State for distribution authorized by a license issued pursuant to 10 CFR
32.74 as required by 10 CFR 35.49(a) nor had an exemption from this requirement been
granted. Section 35.49(a) requires sealed sources or devices for medical use to be
manufactured, labeled, packaged, and distributed in accordance with a license issued
pursuant to 10 CFR Part 30 and 10 CFR 32.74, or the equivalent requirements of an
Agreement State. Since this device (and its sources) did not meet these requirements, it could not be used on humans by a NRC limited-scope medical use licensee.
Thus, this licensee did not meet the requirements of 10 CFR 35.49(a) and 10 CFR 35.400,
respectively. Had the licensee applied to NRC for the appropriate exemptions and approval to
participate in this human research intravascular brachytherapy trial, these violations could have
been avoided. The underlying cause of the violations are addressed in the six specific licensing
review factors (Attachment 3) that NRC considers before authorizing a limited scope medical
use licensee to participate in such clinical trials.
Once the cited violations related to the human use of this device were discovered, the licensee
voluntarily discontinued its participation in the ongoing clinical trial. The device(s) and sources
were returned to the trials sponsor while the licensee pursued an amendment request for an
alternative pathway, as described in the answer to question 13 in Attachment 2 of this
Information Notice.
ATTACHMENT 2 IN-2000-19 December 5, 2000
QUESTIONS AND ANSWERS
NRC staff developed the following questions and answers to assist licensees who are planning
to conduct research involving human subjects. Closely related questions and answers will be
referenced to avoid significant redundancy. However, you may find some repetition in the
answers because each is, for the most part, expected to stand alone.
1. What kind of NRC license do I need to conduct research involving human research
subjects using byproduct material?
You must have a medical use license (or a medical use authorization) because 10 CFR Part
35, Medical Use of Byproduct Material, is the only part in NRC regulations that permits the
intentional internal or external administration of byproduct material or the radiation
therefrom to human research subjects. Depending on the experience, size and complexity
of the medical use program, either a broad scope or limited scope medical use license may
be issued.
2. I have an NRC medical use license. What other NRC regulatory requirements do I
have to comply with to conduct research involving NRC regulated materials and
human research subjects?
Licensees conducting human research using radioactive drugs, sealed sources, and/or
devices are responsible for ensuring that, in addition to 10 CFR 35.6, they comply with all
other applicable NRC requirements and license conditions. Radioactive drug, sealed
source, and device manufacturers and other research protocol sponsors may not always be
cognizant of NRC and Agreement State requirements and the radiation safety implications
of their proposed research. Therefore, it is the licensees responsibility to ensure that: (1) it
is authorized to possess the materials and devices needed to participate in the research
studies; (2) the materials and devices to be used in the research are included in the specific
medical uses authorized in the license; (3) the procedures in the research protocols do not
conflict with NRC regulatory and license requirements; and (4) it is in compliance with 10
CFR 35.6, its license, and any other NRC regulatory requirements.
When conflicts occur between the protocols and NRC requirements, it is the licensees
responsibility to seek resolution of such conflicts with the protocol sponsor or the NRC. In
addition, the research to be conducted may include uses, radionuclides, or quantities which
are not authorized by the license, in which case the NRC must be contacted. For example, licensees may need to apply for and obtain a license amendment to authorize the
possession and use of radionuclides not authorized in the license and/or to increase the
possession limit(s) for one or more radionuclides. Also, the broad scope medical use
licensees radiation safety committee should be diligent in its review of new procedures, to
assure compliance with all NRC requirements.
In the intravascular brachytherapy device case, the licensee believed that compliance with
the requirements of 10 CFR 35.6 provided sufficient authorization to conduct human
research with the device, notwithstanding any other applicable requirements of NRC
regulations. The licensee was authorized to possess and use the material on the research
and development (non-medical use) part of the license but was not authorized to posses or
ATTACHMENT 2 IN-2000-19 December 5, 2000
use it on the medical use part of the license. A licensee conducting research with
byproduct material involving human subjects must use only material authorized by the
medical use license and in accordance with all applicable provisions of the license (e. g., the
quantities, a particular medical use, use by individuals identified on the license for the
particular medical use, etc.) and NRC regulations (e.g. the requirements in 10 CFR 19, 20,
30, 33, 35, etc.).
3. I intend to participate in a clinical trial that has been reviewed by FDA. As long as I
have a medical use license and the device1, drug, or biologic has been reviewed by
FDA, I can use it, right?
Not necessarily. As discussed in the previous response, before you can participate in a
clinical trial, you must, among other things, be authorized to possess the materials and
devices needed to participate in the research studies and you must only use the materials
and devices for the specific medical uses as authorized in the license. Although the device, drug, or biologic may have been reviewed by FDA, it is not necessarily included in the
authorization in your NRC license. Generally, a sealed source and /or device will require a
radiation safety review and registration by NRC or an Agreement State before its use can be
authorized by NRC or an Agreement State. If you have any questions, you should contact
NRC.
Problems occur when a licensee mistakenly assumes the FDA IDE application review and
acceptance processes2 are equivalent to, and can be substituted for, NRC or Agreement
State radiation safety review and registration of the source/device. The focus of FDAs IND
and IDE application reviews is on informed consent, institutional review board approval, and
medical safety and effectiveness issues as related to the protection of the patient. The FDA
reviews do not specifically address non-FDA compliance issues.
The NRC review and approval process is broader in terms of radiation safety. In particular, the NRC review evaluates not only the radiation safety of the patient or human research
subject, but radiation protection of workers and the general public from unintentional
radiation exposures from such devices. Thus, FDAs IDE review is not the equivalent to the
NRC radiation safety review and cannot be substituted for it. The same is true of the FDA
review and acceptance of IND applications for radioactive drugs and biologics.
4. If I have a medical use license and will follow an FDA reviewed protocol, can I be
assured of meeting NRC requirements?
Not necessarily. There is no assurance the research sponsor and FDA are aware of all the
NRC requirements, your license authorizations, and all the radiation safety implications of
the sponsors protocol. You need to review the protocol and ensure the radiation safety
1 FDA classifies a source as a device.
2 Because FDA designated intravascular brachytherapy devices as significant risk
devices, FDA regulations mandate that FDA review and accept IDE submissions for
all clinical trials using intravascular brachytherapy devices.
ATTACHMENT 2 IN-2000-19 December 5, 2000
aspects are in compliance with NRCs requirements. As discussed in the response to
question 2, licensees need to resolve any conflicts between the protocols and NRC
requirements.
If the research sponsor is unaware of NRC requirements, following the sponsors protocols
(or the radiation safety information contained in the protocol) may create dilemmas for
licensees. The sponsor expects the licensee to follow the protocol to maintain the scientific
integrity of the study, and the NRC expects the licensee to be in compliance with its license
and other NRC requirements. Sometimes these two expectations are in conflict. For
example, if the licensee follows the sponsors protocol that contains incorrect radiation safety
information, the licensee may be in a position of noncompliance with NRC requirements.
Conversely, if the licensee complies with NRC requirements, the licensee may deviate from
the protocol in a manner that could invalidate the scientific integrity of the study. Before this
happens, licensees should make both the NRC and the research sponsor aware of any
conflicts between the sponsors protocols and NRC regulatory requirements. It may take
coordination between all three to resolve the conflicts.
5. I intend to participate in a blind clinical trial. Are there any special concerns I
should be aware of in terms of compliance with NRC requirements?
Many medical research protocols call for comparison treatments in which groups of human
research subjects receive different treatments. Some of these studies are blind, i.e., only
the research sponsor (or the sponsors agent) knows which treatment group a particular
research subject is in. In a blind clinical trial, the treatment protocols are standardized so
that all research subjects are handled the same way and neither the human research subject
nor the physician monitoring that research subject knows which treatment is given.
Research sponsors use blind studies because they are an important means of obtaining
unbiased scientific data. However, if the research sponsor is unaware of NRC requirements, the blind aspect of the study may cause additional dilemmas for licensees. The sponsor
expects the licensee to keep certain information from the research subject and the physician
following the research subject. However, the licensee may have labeling, measurement, posting, and notification requirements that may reveal this information which could affect the
blind nature of the study and thus possibly invalidate its scientific integrity. Before this
happens, the licensee needs to make both the NRC and the research sponsor aware of any
conflicts between the sponsors protocols and NRC regulatory requirements, so that such
conflicts may be resolved.
Regulatory compliance may present problems in following blind protocols when subjects
receive placebos, approved products, or investigational products that are governed by
significantly different radiation safety precautions. In order to maintain the blind nature of
the study, a licensee may elect to treat all human research subjects, even those
administered placebos, as if they had received the byproduct material requiring the most
stringent radiation safety instructions and precautions. The intent of this approach would be
to ensure licensee compliance with NRC requirements for those human research subjects
that need the most stringent radiation safety instructions and precautions. However, as will
be discussed later, such an approach may not be practical for research subjects that do not
need such instructions and precautions.
ATTACHMENT 2 IN-2000-19 December 5, 2000
Examples of NRC medical use requirements that should be considered when reviewing
blind protocols include, but are not limited to, those related to syringe labeling (§ 35.60),
written directives (§ 35.2), release of individuals receiving certain therapeutic treatments
(§35.75), misadministration reporting (§ 35.33), and providing appropriate safety instructions
and safety precautions (§§ 35.75, 35.310, 35.315, 35.410, and 35.415).
6. Does NRC require me to perform radiation surveys, provide radiation instructions to
the human research subject, and/or hospitalize the research subject, post rooms as
radioactive, etc., even if the research subject received no byproduct material?
No, whether you, as a medical use licensee, are required to take such actions as performing
radiation surveys, providing radiation instructions to human research subjects, hospitalizing
research subjects, and posting rooms as radioactive depends upon the type and dose or
dosages of byproduct material administered. However, the research sponsor will expect you
to treat all research subjects the same, to the extent necessary to maintain the blind nature
of the study.
For example, NRC would require hospitalization for those human research subjects that
could not be released in accordance with 10 CFR 35.75, Release of individuals containing
radiopharmaceuticals or permanent implants. Differentiation between these human
research subjects and others could reveal to the subjects and their physicians which
treatment they received, and jeopardize the scientific integrity of the study. On the other
hand, not hospitalizing the research subject when required by 10 CFR 35.75 would violate
NRC requirements. Resolving the conflicts as discussed below could ensure the integrity of
the study and compliance with NRC requirements.
In the specific IND cases discussed in this Information Notice, the licensees overlooked
applicable NRC requirements. When the conflict was first identified, NRC contacted the IND
sponsor to identify other licensees conducting the research with similar problems and
discussed the protocol sections that put both licensees in noncompliance with NRC
regulations. The sponsor amended its FDA IND application to revise the protocols
suggested human research subject instructions. The sponsor also alerted the protocol
participants that one dosage level of the investigational drug may require hospitalization to
meet the requirements of 10 CFR 35.75.
7. I intend to participate in a blind clinical trial that compares a nonradioactive
treatment with a byproduct material therapy treatment. The authorized user will know
when the written directive is dated and signed that the subject is receiving the
byproduct material treatment and the trial will no longer be blind. How do I comply
with NRCs requirement and the blind protocol?
All administrations of byproduct material, or the radiation therefrom, identified in 10 CFR
35.32, Quality management program, must have a written directive signed and dated by an
authorized user prior to the administration. Licensees participating in blind research
studies using therapeutic radioactive drugs and devices are not relieved from this
requirement.
ATTACHMENT 2 IN-2000-19 December 5, 2000
Both the IDE and IND studies discussed in this Information Notice were blind studies and
included placebo treatments, i.e., dummy sources or saline injections. Three of the
licensees complied with the written directive requirement; one did not. The two methods
described below have been used to meet NRCs written directive requirements and maintain
the blind nature of the research. Licensees may develop other alternatives that meet the
same objectives.
One method is to prepare a specific written directive containing required information, i.e., the
isotope and the dose or dosage to be given to individually identified human research
subjects. No written directive is needed or prepared for the placebo recipients. In this
method, the authorized user who signs and dates the written directive is not the physician
monitoring the human research subject. The licensee maintains the blind nature of the
study by ensuring the research subject and the physician monitoring the human research
subject do not have access to, or knowledge of, the written directive.
In another method, the authorized user signs and dates a written directive for each human
research subject regardless of whether a written directive is required. All directives include
identical information and instructions addressing all possible administrations covered in the
research. In this case, because all the instructions are identical, the authorized user is not
aware of (blind to) the specific administration to a particular human research subject. NRC
has accepted the use of written directives containing such identical instructions listing all the
possible administrations to be delivered and indicating that the one delivered will be in
accordance with the protocol. The protocol provides a methodology to match individual
research subjects with specific administrations.
8. What happens if there is a misadministration during a blind clinical trial?
If a misadministration occurs, the licensee must comply with the misadministration
notification, reporting, and record keeping requirements in 10 CFR 35.33, even if this affects
the blind nature of the study. Depending on the research and the nature of the error, compliance with the notification and reporting requirements for misadministrations may not
necessarily compromise the blind nature of the study.
9. The clinical protocol calls for a therapy procedure to be conducted as an outpatient
treatment. Are there any special concerns I should be aware of?
When considering protocols involving radiopharmaceuticals, sealed sources, and devices for
therapeutic purposes, licensees must be especially vigilant to ensure that the human
research subjects and patients administered the investigational drugs or permanent implants
are released in accordance with 10 CFR 35.75. The research sponsor may not be aware of
this regulation.
NRCs Regulatory Guide 8.39, Release of Patients Administered Radioactive Materials, aids licensees in determining, in part: (1) when the licensee may authorize the release of an
individual who has been administered radiopharmaceuticals or permanent implants
containing radioactive material; (2) when instructions to the individual are required by 10
CFR 35.75(b); and (3) when records required by 10 CFR 35.75(c) and (d) are to be
generated and maintained. The guide lists default values for administered activities of
ATTACHMENT 2 IN-2000-19 December 5, 2000
commonly used radionuclides and corresponding dose rates that can be used to determine if
patients and human research subjects may be released in compliance with the dose limits in
The guide also provides suggested procedures, based on patient-specific factors, that
licensees may use to calculate doses to other individuals from exposure to patients who
have been administered activities higher than the default values listed in the guide.
Regardless of the instructions in the protocol, if you are unable to determine, based on the
default values or calculations or measurements, that the individual can be released in
accordance with 10 CFR 35.75, then the individual human research subject must be
hospitalized to comply with 10 CFR 35.75. If an individual is hospitalized for compliance with
10 CFR 35.75, then you must also comply with the safety instruction and safety precautions
in §§ 35.310, 35.315, 35.410 and 35.415, as appropriate. As discussed earlier, if this
affects the blind nature of the study, the research sponsor needs to be made aware of the
situation.
10. I have a limited scope medical use license and intend to participate in a clinical
trial for a new sealed source or medical device. Are there any special concerns I
should be aware of?
A number of regulatory issues may arise when a limited scope medical use licensee needs
to use a new sealed source or device in a clinical trial. Intravascular brachytherapy was
selected for discussion to illustrate some of these issues because it is presently the most
active area of human research using sealed sources and devices.
Intravascular brachytherapy currently involves a very diverse set of devices, sources, and
procedures. NRC noted a number of common deficiencies in reviewing applications and
responding to inquires from limited specific medical use licensee seeking to use intravascular
brachytherapy devices to participate in intravascular brachytherapy human trials. The six
licensing review factors, in Attachment 3 of this Information Notice, were developed from this
practical experience and represent the minimum information necessary for review of an
intravascular brachytherapy application. As stated earlier, licensees conducting human
research using sealed sources and/or devices are responsible for insuring that, in addition to
10 CFR 35.6, they comply with all other applicable NRC requirements and license conditions
(e.g., 10 CFR 35.49 and 10 CFR Part 35, Subpart G).
11. What is the regulatory basis for the licensing review factors in Attachment 3 to this
Information Notice?
The licensing review factors in Attachment 3 are specific to intravascular brachytherapy, a
medical use that is not specifically listed in 10 CFR 35. The regulatory basis for each review
factor is provided for clarification. In licensing review factor 2, for example, participation in
ATTACHMENT 2 IN-2000-19 December 5, 2000
the FDA-accepted IDE satisfies the requirements of 35.6.1 The licensee must, however, provide the IDE number and copy of the IDE to meet the requirements in 10 CFR 30.33.
Other research studies involving medical uses specifically included in 10 CFR Part 35 may
not involve all or any of these review factors because the basic radiation safety programs are
already reflected in the regulations. In fact, depending on your license (i.e., the license
authorizes the byproduct material for the same medical uses as the research) and the nature
of the research (i.e., it is conducted, funded, supported, or regulated by a Federal agency
that has implemented the Federal Policy for the Protection of Human Subjects), you may
already be authorized to conduct research involving human subjects without applying for and
obtaining a license amendment from NRC.
12. I have a broad scope medical use license and intend to participate in a clinical trial
for an unregistered sealed source or medical device. Are there any special
concerns I should be aware of?
A medical use licensee of broad scope is exempt from the requirements of 10 CFR 35.49(a)
and 10 CFR 35.400 by a standard license conditions and generally does not need to seek a
license amendment to participate in these studies. However, problems have been reported
with broad-scope licensees radiation safety committee reviews and approvals of these
unregistered sources and/or devices used in these trials. This issue is addressed separately
in NRC Information Notice 99-24 Broad-Scope Licensees Responsibilities for Reviewing
and Approving Unregistered Sealed Sources and Devices. The Internet address is
http://www.nrc.gov/NRC/GENACT/GC/IN/1999/in99024.txt for this Information Notice.
13. I have a limited scope medical use license. How can I participate in medical device
clinical trials normally open only to broad scope medical use licensees?
Frequently, a limited scope medical use licensee applies for authorization to participate in
clinical trials using a source or device that has not been reviewed and approved by the NRC
or an Agreement State.
Such a licensee may consider one of the following approaches to assuring compliance with
NRC requirements:
1. Ask the trial sponsor to have its source or device evaluated and registered by NRC
or an Agreement State, and submit their application to participate in the trials after
the source or device is registered;
2. Submit an application that requests a custom review of the source or device from
NRC. This provides NRC with all the necessary information for this review, but
delays authorization to participate in the trial(s) until the source or device review is
successfully completed;
1 The research is regulated by FDA, a Federal Agency that has implemented The
Federal Policy for the Protection of Human Subjects.
ATTACHMENT 2 IN-2000-19 December 5, 2000
3. Submit an application that requests authorization for the limited scope medical use
Radiation Safety Committee to perform the requisite radiation safety and
engineering review of the source and/or device in-house, following the criteria set
forth in 10 CFR 32.210. The in-house expertise available may need to be
augmented to perform this review and there can be no prior assurance that the
results of the review would be acceptable to NRC or an Agreement State; or,
4. Submit an application to become a broad-scope medical use licensee, if the medical
use program meets the criteria in 10 CFR Part 33.
ATTACHMENT 3 IN-2000-19 December 5, 2000
LICENSING REVIEW FACTORS USED FOR REVIEWING A LIMITED-SCOPE MEDICAL USE
LICENSEES REQUEST TO PARTICIPATE IN INTRAVASCULAR BRACHYTHERAPY
RESEARCH STUDIES
Each of the following six licensing review factors are specifically used by NRC to approve
participation by a limited specific scope licensee in intravascular brachytherapy research studies
on humans using sealed sources of byproduct materials and/or devices. The regulatory basis
for each review factor is either clearly stated within the factor or placed at the end of the factor.
Compliance with all other applicable Nuclear Regulatory Commission (NRC) requirements is
presumed.
1. The radiation sources and/or devices used in the research must have undergone an
appropriate sealed source and/or device safety evaluation and been issued a certificate of
registration by NRC, or by an Agreement State, for intravascular brachytherapy applications.
(10 CFR 30.32 and 10 CFR 35.49)
2. The provisions for protecting human research subjects, pursuant to 10 CFR 35.6, Provisions for Research Involving Human Subjects, must be satisfied. For significant-risk
procedures, such as intravascular brachytherapy, this may be satisfied through participation
in an U.S. Food and Drug Administration (FDA) approved Investigational Device Exemption
(IDE) trial.2 The FDA-assigned IDE number should be identified in the licensing request and
a copy of the IDE application provided. (10 CFR 30.33)
3. Only those physicians already authorized to use 10 CFR 35.400 byproduct materials or who
meet the training and experience requirements in 10 CFR 35.940 can be designated as
authorized users for the procedure. In the later case, an NRC amendment and approval is
required before use.
4. Radiation safety commitments (which are part of the radiation safety program required by 10
CFR 20.1101) must be contained in a document suitable for public release. Important
radiation safety commitments, which are not proprietary, are often contained in the FDA IDE
application, which is a proprietary document. These commitments must be in a separate
document that can be incorporated in the license by reference and available to the public.
5. The NRC must have access to proprietary information pertaining to medical use, device
performance, and radiation safety concerns with the device, for use during licensing and
inspection activities. (10 CFR 30.33 and 10 CFR 30.52)
6. An exemption from the requirements of 10 CFR 35.400 must be applied for and granted to
use any sealed source and/or device for intravascular brachytherapy.
2 The research is regulated by FDA, a Federal agency that has implemented The
Federal Policy for the protection of Human Subjects.
Attachment 4 December 5, 2000
LIST OF RECENTLY ISSUED
NMSS INFORMATION NOTICES
_____________________________________________________________________________________
Information Date of
Notice No. Subject Issuance Issued to
_____________________________________________________________________________________
2000-18 Substandard Material Supplied 11/29/2000 All 10 CFR1 Part 50 licensees and
by Chicago Bullet Proof applicants
Systems All category 1 fuel facilities
All 10 CFR1 Part 72 licensees and
applicants
2000-16 Potential Hazards Due to 10/5/2000 All Licensees that process
Volatilization of Radionuclides unsealed byproduct material
2000-15 Recent Events Resulting in 9/29/2000 All radiography licensees
Whole Body Exposures
Exceeding Regulatory Limits
2000-12 Potential Degradation of 9/21/2000 All holders of licenses for nuclear
Firefighter Primary Protective power, research, and test
Garments reactors and fuel cycle facilities
2000-11 Licensee Responsibility for 8/7/2000 All U.S. NRC 10 CFR Part 50 and
Quality Assurance Oversight of Part 72 licensees, and Part 72 Contractor Activities Regarding Certificate of Compliance holders
Fabrication and Use of Spent
Fuel Storage Cask Systems
2000-10 Recent Events Resulting in 7/18/2000 All material licensees who
Extremity Exposures prepare or use unsealed
Exceeding Regulatory Limits radioactive materials, radio- pharmaceuticals, or sealed
sources for medical use or for
research and development
2000-07 National Institute for 4/10/2000 All holders of operating licenses
Occupational Safety and for nuclear power reactors, non- Health Respirator User Notice: power reactors, and all fuel cycle
Special Precautions for Using and material licensees required to
Certain Self-Contained have an NRC approved
Breathing Apparatus Air emergency plan
Cylinders
2000-05 Recent Medical 3/06/2000 All medical licensees
Misadministrations Resulting
from Inattention to Detail
Attachment 5 December 5, 2000
LIST OF RECENTLY ISSUED
NRC INFORMATION NOTICES
_____________________________________________________________________________________
Information Date of
Notice No. Subject Issuance Issued to
______________________________________________________________________________________
2000-18 Substandard Material Supplied 11/29/2000 All 10 CFR1 Part 50 licensees and
by Chicago Bullet Proof applicants
Systems All category 1 fuel facilities
All 10 CFR1 Part 72 licensees and
applicants
2000-17 S1 Crack In Weld Area of Reactor 11/16/2000 All holders of OL for nuclear
Coolant System Hot Leg Piping power reactors except those who
At V.C. Summer have ceased operations and have
certified that fuel has been
permanently removed from the
reactor vessel
Crack In Weld Area of Reactor 10/18/2000 All holders of OL for nuclear
2000-17 Coolant System Hot Leg Piping power reactors except those who
At V.C. Summer have ceased operations and have
certified that fuel has been
permanently removed from the
reactor vessel
2000-16 Potential Hazards Due to 10/5/2000 All NRC licensees that process
Volatilization of Radionuclides unsealed byproduct material
2000-15 Recent Events Resulting in 9/29/2000 All radiography licensees
Whole Body Exposures
Exceeding Regulatory Limits
2000-14 Non-Vital Bus Fault Leads to 9/27/2000 All holders of OL for nuclear
Fire and Loss of Offsite Power power reactors
2000-13 Review of Refueling Outage 9/27/2000 All holders of OL for nuclear
Risk power reactors
2000-12 Potential Degradation of 9/21/2000 All holders of licenses for nuclear
Firefighter Primary Protective power, research, and test
Garments reactors and fuel cycle facilities
______________________________________________________________________________________
OL = Operating License
CP = Construction Permit