View source for Information Notice 2000-19, Implementation of Human Use Research Protocols Involving U.S. Nuclear Regulatory Commission Regulated Materials

{{Adams
| number = ML003773013
| issue date = 12/05/2000
| title = Implementation of Human Use Research Protocols Involving U.S. Nuclear Regulatory Commission Regulated Materials
| author name = Cool D
| author affiliation = NRC/NMSS
| addressee name = 
| addressee affiliation = 
| docket = 
| license number = 
| contact person = Howe D,   NRC/NMSS, 415-7848
| document report number = IN-00-019
| document type = NRC Information Notice
| page count = 15
}}
{{#Wiki_filter: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:
      &#xff;    have a medical use license;
      &#xff;    be licensed for the specific medical use included in the research;
      &#xff;    be licensed to use the regulated material specifically for the medical use included in

the research;
      &#xff;    comply with 10 CFR 35.6;
      &#xff;    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

&#xff;    comply with all license conditions.

When participating in research studies regulated by FDA, the licensee needs to be aware that:
      &#xff;    FDA review of the device1, drug, or biologic may not be substituted for NRCs

licensing review; and

&#xff;    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:
      &#xff;    labeling requirements in 10 CFR Part 35;
      &#xff;    written directive requirements;
      &#xff;    research subject release and the instruction requirements of &sect; 35.75;
      &#xff;    hospitalization requirements in 10 CFR Part 35; and

&#xff;    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 &sect; 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 (&sect; 35.60),
   written directives (&sect; 35.2), release of individuals receiving certain therapeutic treatments

(&sect;35.75), misadministration reporting (&sect; 35.33), and providing appropriate safety instructions

and safety precautions (&sect;&sect; 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

10 CFR 35.75.

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 &sect;&sect; 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.

(10 CFR 2.790)
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}}

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