[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]



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.


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 

ADDRESSES: The public meeting will be held at the CDER Advisory 
Committee Conference Room, rm. 1066, 5630 Fishers Lane, Rockville, MD 
    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 
    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.

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.


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.  
    8. The study is based on a sound rationale and is of sound design 
such that information of scientific value may result (Sec.  
    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

[[Page 59571]]

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 
    The request to participate should contain the following 
    (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, 
    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]