[Federal Register Volume 70, Number 117 (Monday, June 20, 2005)]
[Notices]
[Pages 35448-35449]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-12040]


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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Draft Guidance for Industry on Nonclinical Evaluation of Late 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availability of a draft guidance for industry entitled ``Nonclinical 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 The purpose of this draft guidance is to 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DATES:  Submit written or electronic comments on the draft guidance by 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ADDRESSES:  Submit written requests for single copies of the draft 
guidance to the Division of Drug Information (HFD-240), Center for Drug 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on the draft guidance to the Division of Dockets Management (HFA-305), 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://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access to the draft guidance document.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    FDA is announcing the availability of a draft guidance for industry 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://www.fda.gov/cder/guidance/index.htm or 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