[Federal Register: October 5, 2004 (Volume 69, Number 192)]
[Proposed Rules]
[Page 59569-59572]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05oc04-19]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 361
[Docket No. 2004N-0432]
Radioactive Drugs for Certain Research Uses; Public Meeting
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of public meeting; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is announcing a public
meeting to discuss the use of certain radioactive drugs for research
purposes without an investigational new drug application (IND) under
the conditions set forth in FDA regulations (typically, use of
radioactive drugs to determine drug disposition in the body). We are
seeking public input on the potential need to modify the conditions
under which these radioactive drugs are studied in light of the
scientific and technological developments since we adopted the
regulations in 1975.
DATES: The public meeting will be held on November 16, 2004, from 8
a.m. to 4 p.m. Submit electronic requests to speak plus a presentation
abstract by October 19, 2004, to Maria R. Walsh. Submit final
presentations and requests for special accommodations (due to
disability) by November 2, 2004, to Maria R. Walsh. Submit written or
electronic comments by January 16, 2005, to Division of Dockets
Management.
ADDRESSES: The public meeting will be held at the CDER Advisory
Committee Conference Room, rm. 1066, 5630 Fishers Lane, Rockville, MD
20857.
You may submit comments, identified by Docket No. 2004N-0432, by
any of the following methods:
Federal eRulemaking Portal: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov.
Follow the instructions for submitting comments.
Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments.
Follow the instructions for submitting comments on the agency Web site.
E-mail: fdadockets@oc.fda.gov. Include Docket No. 2004N-
0432 in the subject line of your e-mail message.
FAX: 301-827-6870.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions]: Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name
and Docket No. All comments received will be posted without change to
http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm, including any personal
information provided. For detailed instructions on submitting comments
and additional information on the rulemaking process, see the
``Comments'' heading in the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
and insert the docket number, found in brackets in the heading of this
document, into the ``Search'' box and follow the prompts, or go to the
Division of Dockets Management, Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852.
Transcripts of the public meeting will be available for review at
the Division of Dockets Management (see ADDRESSES) and on the Internet
at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets.
FOR FURTHER INFORMATION CONTACT: Maria R. Walsh, Center for Drug
Evaluation and Research (HFD-103), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-3139, FAX 301-480-3761, e-
mail: walsh@cder.fda.gov.
SUPPLEMENTARY INFORMATION:
I. Background
We are announcing a public meeting to discuss research on
radioactive drugs that is conducted under Sec. 361.1 (21 CFR 361.1).
We added this section to FDA regulations in 1975 (40 FR 31298 at 31308,
July 25, 1975). Under Sec. 361.1, certain radioactive drugs (drugs
that exhibit spontaneous disintegration of unstable nuclei with the
emission of nuclear particles or photons) are considered generally
recognized as safe and effective under specified conditions of use when
administered to human research subjects for certain basic research
uses. These uses include studies intended to obtain basic information
regarding the metabolism (including pharmacokinetics,
[[Page 59570]]
distribution, and localization) of a radioactive drug or regarding
human physiology, pathophysiology, or biochemistry, but not those
intended for immediate therapeutic, diagnostic, or similar purposes or
those intended to determine the safety and effectiveness of the drug.
When conducted in accordance with Sec. 361.1, clinical investigations
of radioactive drugs are not subject to the requirements for INDs
stated in part 312 (21 CFR part 312).
In general, to conduct studies using radioactive drugs under Sec.
361.1, an FDA-approved Radioactive Drug Research Committee (RDRC) must
first conclude the following:
1. The pharmacological dose is limited such that the amount of
active ingredient or ingredients administered is known not to cause any
clinically detectable pharmacological effect, based on data available
from published literature or from other valid human studies (Sec.
361.1(b)(2) and (d)(2)).
2. The radiation dose is limited such that the amount of
radioactive material administered is the smallest radiation dose
practical to perform the study without jeopardizing the benefits
obtained from the study, and the dose, for adult subjects, does not
exceed the following:
Table 1.--Limits of Radiation Dose for Adults
------------------------------------------------------------------------
Annual and Total
Organ or System Single Dose Dose Sieverts
Sieverts (Rems) (Rems)
------------------------------------------------------------------------
Whole body 0.03 (3) 0.05 (5)
------------------------------------------------------------------------
Active blood-forming organs 0.03 (3) 0.05 (5)
------------------------------------------------------------------------
Lens of the eye 0.03 (3) 0.05 (5)
------------------------------------------------------------------------
Gonads 0.03 (3) 0.05 (5)
------------------------------------------------------------------------
Other organs 0.05 (5) 0.15 (15)
------------------------------------------------------------------------
For subjects under 18 years of age, the radiation dose must not exceed
10 percent of the adult dose (Sec. 361.1(b)(3)).
3. The design and quality of the study and the importance of the
information it seeks to obtain justify the exposure of research
subjects to radiation (Sec. 361.1(b)(1)(iii)).
4. The investigator has appropriate qualifications for the conduct
of a study involving radioactive drugs (Sec. 361.1(d)(3)).
5. The investigator has the appropriate licensure for handling
radioactive materials (Sec. 361.1(d)(4)).
6. The mechanisms for selecting research subjects and obtaining
informed consent are appropriate (Sec. 361.1(d)(5)).
7. The radioactive drug to be administered meets appropriate
chemical, pharmaceutical, radiochemical, and radionuclidic standards
for identity, strength, quality, and purity; and radioactive drugs for
parenteral use are prepared in sterile and pyrogen-free form (Sec.
361.1(d)(6)).
8. The study is based on a sound rationale and is of sound design
such that information of scientific value may result (Sec.
361.1(d)(7)).
9. There are mechanisms in place for identifying and reporting
adverse reactions (Sec. 361.1(d)(8)).
10. The study has been reviewed and approved by an institutional
review board (IRB) (Sec. 361.1(d)(9)).
Since we added Sec. 361.1 in 1975, there have been numerous
developments in imaging technology, pharmacology, toxicology, and
dosimetry that have had a significant impact on the use of radioactive
drugs. In light of these changes, we are considering whether issuance
of guidance on, or even revision of, Sec. 361.1 would be appropriate.
To that end, we are holding a public meeting to obtain input on what
actions we should take, if any, concerning the regulation of basic
research involving radioactive drugs. To facilitate discussion at the
public meeting and assist us in our review of this matter, we have the
following questions concerning the application of Sec. 361.1:
1. Pharmacology Issues: Section 361.1(b)(2) requires that the
amount of radioactive drug to be administered be known not to cause any
clinically detectable pharmacological effect in humans. According to
Sec. 361.1(d)(2), investigators must provide pharmacological dose
calculations based on published literature or other human data to
demonstrate an absence of a clinically detectable pharmacological
effect (thus, no radioactive drug may be studied ``first in humans''
under current Sec. 361.1).
a. For an active ingredient chemically manufactured in the
laboratory that is also a body constituent (an endogenous substance),
what percentage of estimated daily endogenous production could be
considered to have no pharmacological effect? (Because heterogeneous
biological products (e.g., monoclonal antibodies and therapeutic
proteins such as interferon, interleukin, other cytokines, and enzymes)
are foreign proteins and are assumed to have the potential to produce
an antigenic response, they should be excluded from consideration
unless they have been shown to have no immunologic response.)
b. For an active ingredient that is not endogenous, what animal, in
vitro, and/or in vivo data would be needed to demonstrate that there is
no human pharmacological effect? Is there an absolute dose that would
ensure no pharmacological effect? If so, what data would be needed to
support that dose?
c. How may an investigator confirm that a radioactive drug causes
no clinically detectable pharmacological effect in humans in accordance
with Sec. 361.1(b)(2)? What parameters should be measured, how
frequently, and what criteria should be used to determine if a
pharmacologic effect has occurred?
2. Radiation Dose Limits for Adult Subjects: The radiation dose
limits for adult subjects specified in Sec. 361.1(b)(3)(i) are based
on the basic occupational radiation protection criteria established by
the Nuclear Regulatory Commission under 10 CFR 20.101. FDA's thinking
in 1975 was that these criteria would enable a potential research
subject to make an informed decision regarding participation in a study
under Sec. 361.1 because the subject would, in effect, be deciding
whether he or she was willing to assume the same risk as a radiation
worker for the duration of the study. Considering the advances in
scientific knowledge and regulatory changes that have occurred
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since 1975, including new data on radiation effects (Ref. 1) and new
recommendations on radiation dose limits (Refs. 2, 3, and 4), are the
current dose limits for adults still appropriate for research conducted
under Sec. 361.1? If not, what dose limits are appropriate? Should
there be different dose limits for different adult age groups?
3. Assurance of Safety for Pediatric Subjects: Currently, Sec.
361.1 allows for the study of radioactive drugs in subjects less than
18 years of age without an IND if:
The study presents a unique opportunity to gain
information not currently available, requires the use of research
subjects less than 18 years of age, is without significant risk to
subjects, and is supported with review by qualified pediatric
consultants to the RDRC;
The radiation dose does not exceed 10 percent of the adult
radiation dose specified in Sec. 361.1(b)(3)(i); and
As with adult subjects, the following requirements, among
others, are met: (1) The study is approved by an institutional review
board (IRB) that conforms to 21 CFR part 56, (2) informed consent of
the subjects' legal representative is obtained in accordance with 21
CFR part 50, and (3) the study is approved by the RDRC that assures all
other requirements of Sec. 361.1 are met.
Alternatively, when a study is conducted under an IND in accordance
with part 312, the sponsor must submit to FDA the study protocol,
protocol changes and information amendments, pharmacology/toxicology
and chemistry information, and information regarding prior human
experience with the same or similar drugs (see Sec. Sec. 312.22,
312.23, 312.30, and 312.31). Additionally, Sec. 312.32 requires that
sponsors promptly review all information relevant to the safety of the
drug obtained or otherwise received by the sponsor from any source,
foreign or domestic. This includes information derived from any
clinical or epidemiological investigations, animal investigations,
commercial marketing experience, reports in the scientific literature,
and unpublished scientific papers, as well as reports from foreign
regulatory authorities. Section 312.32 also requires that sponsors
submit IND safety reports to FDA.
a. Does Sec. 361.1 provide adequate safeguards for pediatric
subjects during the course of a research project intended to obtain
basic information about a radioactive drug, or should these studies
only be conducted under an IND?
b. If we assume that Sec. 361.1 provides adequate safeguards for
pediatric subjects during such studies, given our present knowledge
about radiation and its effects, can we conclude that the current dose
limits for pediatric subjects do not pose a significant risk? If not,
what dose limits would be appropriate to ensure no significant risk for
pediatric subjects? Should there be different dose limits for different
pediatric age groups?
4. Quality and Purity: What standards for quality and purity should
apply to radioactive drugs administered under Sec. 361.1 to ensure the
safety of research subjects?
5. Exclusion of Pregnant Women: Section 361.1(d)(5) requires that
each female research subject of childbearing potential state in writing
that she is not pregnant or, on the basis of a pregnancy test, be
confirmed as not pregnant before she may participate in any research
study involving a radioactive drug under Sec. 361.1. Is written
attestation adequate assurance that female research subjects are not
pregnant? If not, what other assurance should be provided?
6. RDRC Membership:
a. Under Sec. 361.1(c)(1), an RDRC must include the following
expertise: (1) A physician recognized as a specialist in nuclear
medicine, (2) a person qualified to formulate radioactive drugs, and
(3) a person with special competence in radiation safety and radiation
dosimetry. Would an RDRC benefit from any additional expertise, such as
a pharmacologist or toxicologist? Should such memberships be required?
b. Under Sec. 361.1(c)(4), changes in the membership of an RDRC
must be submitted to FDA as soon as, or before, vacancies occur on the
committee. However, the regulations do not require approval of new
members by FDA before a new member assumes committee responsibilities.
We review the qualifications of new members when we receive them and
contact the RDRC when we identify new members we consider to be
unqualified, but we do not always receive notifications of changes in
membership in a timely manner. At times, this has resulted in
unqualified members serving on RDRCs for extended periods. Should the
regulations specifically require that FDA approve RDRC membership
changes before new members assume committee responsibilities? For
example, would it be appropriate for the regulations to allow FDA 15
days to review the qualifications of a proposed new member before the
member could assume committee responsibilities?
II. Registration and Presentations
No registration is required to attend the meeting. Seating is
limited to 120 and will be on a first-come, first-served basis. If you
need special accommodations due to a disability, please inform Maria R.
Walsh by November 2, 2004.
If you wish to present information at the public meeting, submit
your electronic request and an abstract of your presentation by the
close of business on October 19, 2004, to Maria Walsh (see FOR FURTHER
INFORMATION CONTACT).
The request to participate should contain the following
information:
(1) Presenter's name; (2) address; (3) telephone number; (4) e-mail
address; (5) affiliation, if any; (6) abstract of the presentation; and
(7) approximate amount of time requested for the presentation.
We request that persons and groups having similar interests
consolidate their comments and present them through a single
representative. We will allocate the time available for the meeting
among the persons who request to present. Because of limited time, we
will accept only one presenter per organization. We reserve the right
to deny requests if the proposed topic is not germane. After reviewing
the requests to present and abstracts, we will schedule each appearance
and notify each participant by e-mail or telephone of the time allotted
to the person and the approximate time the person's presentation is
scheduled to begin. Presenters planning to use electronic presentations
in Microsoft PowerPoint, Microsoft Word, or Adobe Acrobat PDF must send
them to us by the close of business on November 2, 2004. Presenters who
do not meet this deadline may provide handouts of their presentations
at the meeting.
The meeting schedule will be available on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/meeting/clinicalResearch/default.htm
and at the
meeting. After the meeting, the schedule and presentations will be
placed on file in the Division of Dockets Management under the docket
number listed in the heading of this notice.
III. Comments
Interested persons may submit written or electronic comments on or
before January 16, 2005, to the Division of Dockets Management (see
ADDRESSES). You must submit two copies of comments identified with the
docket number found in brackets in the heading of this document. The
received comments may be seen at the Division of Dockets Management,
Monday through Friday between 9 a.m. and 4 p.m.
[[Page 59572]]
IV. Transcripts
Approximately 30 days after the public meeting, you can examine a
transcript of the meeting on the Internet at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm
or at the Division of Dockets Management (see
ADDRESSES), Monday through Friday between 9 a.m. and 4 p.m. You may
also request a copy of the transcript from the Freedom of Information
Office (HFI-35), Food and Drug Administration, 5600 Fishers Lane, rm.
12A-16, Rockville, MD 20857, at a cost of 10 cents per page or on CD at
a cost of $14.25 each.
V. References
The following references have been placed on display in the
Division of Dockets Management and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Preston, D.L., Y. Shimizu, D.A. Pierce, A. Suyama, and K.
Mabuchi, ``Studies of mortality of atomic bomb survivors, Report 13:
Solid cancer and noncancer disease mortality: 1950-1997,'' Vol. 160,
No. 4, pp. 381-407, Radiation Research, 2003.
2. International Commission on Radiological Protection, ``1990
Recommendations of the International Commission on Radiological
Protection,'' Annals of the International Commission on Radiological
Protection (ICRP), ICRP Publication 60, vol. 21, No. 1-3, pp. 1-201,
1991.
3. National Council on Radiation Protection Measurements (NCRP),
``Limitation of Exposure to Ionizing Radiation,'' NCRP Report no.
116, Bethesda, MD, 1993.
4. National Council on Radiation Protection and Measurements,
``Principles and Application of Collective Dose in Radiation
Protection,'' NCRP Report No. 121, Bethesda, MD, 1995.
Dated: September 24, 2004.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 04-22354 Filed 10-4-04; 8:45 am]
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