[Federal Register: June 20, 2005 (Volume 70, Number 117)]
[Notices]
[Page 35448-35449]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20jn05-56]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 2005D-0223]
Draft Guidance for Industry on Nonclinical Evaluation of Late
Radiation Toxicity of Therapeutic Radiopharmaceuticals; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Nonclinical
Evaluation of Late Radiation Toxicity of Therapeutic
Radiopharmaceuticals.'' The purpose of this draft guidance is to
provide recommendations to industry for designing nonclinical toxicity
studies to determine potential late radiation toxicities (radiation-
induced injuries occurring after a latency period of several months to
years) of therapeutic radiopharmaceuticals administered systemically.
The purpose of such studies is to help minimize the risk of late-
occurring irreversible radiation toxicities in clinical studies of
therapeutic radiopharmaceuticals.
DATES: Submit written or electronic comments on the draft guidance by
September 19, 2005. General comments on agency guidance documents are
welcome at any time.
ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information (HFD-240), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857. Send one self-addressed adhesive label to
assist that office in processing your requests. Submit written comments
on the draft guidance to the Division of Dockets Management (HFA-305),
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville,
MD 20852. Submit electronic comments to http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/dockets/ecomments.
See the SUPPLEMENTARY INFORMATION section for electronic
access to the draft guidance document.
FOR FURTHER INFORMATION CONTACT: Adebayo Laniyonu or Renee Tyson,
Center for Drug Evaluation and Research (HFD-160), Food and Drug
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-7510.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry
entitled ``Nonclinical Evaluation of Late Radiation Toxicity of
Therapeutic Radiopharmaceuticals.'' The objective of this guidance is
to provide recommendations to industry for designing nonclinical
toxicity studies to determine potential late radiation toxicities of
therapeutic radiopharmaceutical agents. This guidance is not intended
for diagnostic radiopharmaceuticals or for radiobiologicals (e.g.,
radiolabeled monoclonal antibodies).
Late radiation toxicity differs from early or acute radiation
toxicity. Acute radiation toxicity (e.g., bone marrow failure, nausea,
vomiting, diarrhea, and oral mucositis) occurs within days to weeks of
an acute dose of radiation and is often self-limiting and reversible.
In contrast, late radiation toxicity (e.g., renal failure, pulmonary
fibrosis, and chord transection) occurs after a latency period of
several months to years, during which relatively normal organ function
continues. Late radiation toxicity is usually progressive and
irreversible.
Therapeutic radiopharmaceuticals are typically administered
systemically to treat cancer. The radiation absorbed doses delivered by
therapeutic radiopharmaceuticals may be comparable to those delivered
with external beam radiotherapy (XRT). At therapeutic doses of
radiation, the late radiation toxicities commonly associated with XRT
(e.g., brain necrosis, paralysis, pulmonary fibrosis, liver or kidney
failure, and hemorrhagic cystitis) can also be seen with therapeutic
radiopharmaceuticals. With XRT, if the total dose given to an organ is
less than its tolerance dose, the probability of symptomatic late
radiation toxicity to that organ will be minimal. The tolerance doses
of most human organs for conventional fractionated XRT are known, and
are routinely used to direct the safe administration of XRT. In FDA's
experience, however, there are few clinical data from which to estimate
organ tolerance doses for therapeutic radiopharmaceuticals.
Furthermore, late radiation toxicity has been observed when Medical
Internal Radiation Dose (MIRDOSE) estimates of radiation absorbed doses
delivered by therapeutic radiopharmaceuticals to target organs were
substantially below the published XRT organ tolerance doses.
Therefore, there is a need to gain additional knowledge in this
area to support the safe administration of therapeutic
radiopharmaceuticals to humans. Because studies in humans would be
unethical, the best means to gain insight into this issue is by
conducting nonclinical late radiation toxicity studies. These studies
will aid in identifying organs at risk and establish a margin of safety
for late radiation toxicity. As a result, these studies will help to
minimize the risk of late-occurring radiation toxicities in clinical
studies of therapeutic radiopharmaceuticals.
This draft guidance focuses solely on late radiation safety
concerns that are unique to therapeutic radiopharmaceuticals, and
provides recommendations for late radiation toxicity nonclinical study
designs including issues regarding good laboratory practices, species
selection, dose selection, timing of study, and study parameters.
This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance, when
finalized, will represent the agency's current thinking on nonclinical
evaluation of late radiation toxicity of therapeutic
radiopharmaceuticals. It does not create or confer any rights for or on
any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
[[Page 35449]]
requirements of the applicable statutes and regulations.
II. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) written or electronic comments regarding this document.
Submit a single copy of electronic comments or two paper copies of any
mailed comments, except that individuals may submit one paper copy.
Comments are to be identified with the docket number found in brackets
in the heading of this document. The draft guidance and received
comments may be seen in the Division of Dockets Management between 9
a.m. and 4 p.m., Monday through Friday.
III. Electronic Access
Persons with access to the Internet may obtain the document at
either http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cder/guidance/index.htm or http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm.
Dated: June 9, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-12040 Filed 6-17-05; 8:45 am]
BILLING CODE 4160-01-S