
[Federal Register Volume 76, Number 228 (Monday, November 28, 2011)]
[Notices]
[Pages 72952-72953]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-30474]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2005-D-0086 (formerly Docket No. 2005D-0223)]


Guidance for Industry on Nonclinical Evaluation of Late Radiation 
Toxicity of Therapeutic Radiopharmaceuticals; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance for industry entitled ``Nonclinical 
Evaluation of Late Radiation Toxicity of Therapeutic 
Radiopharmaceuticals.'' The purpose of this guidance is to provide 
recommendations to industry for designing nonclinical toxicity studies 
to determine potential late radiation effects (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 trials of therapeutic 
radiopharmaceuticals. This guidance finalizes the draft guidance of the 
same name issued in June 2005.

DATES: Submit either electronic or written comments on Agency guidances 
at any time.

ADDRESSES: Submit written requests for single copies of this guidance 
to the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, rm. 2201, Silver Spring, MD 20993-0002. Send one self-addressed 
adhesive label to assist that office in processing your requests. See 
the SUPPLEMENTARY

[[Page 72953]]

INFORMATION section for electronic access to the guidance document.
    Submit electronic comments on the guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:  Adebayo Laniyonu, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 2350, Silver Spring, MD 20993-0002, (301) 
796-2050; or Siham Biade, Center for Drug Evaluation and Research, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 22, rm. 2311, 
Silver Spring, MD 20993-0002, (301) 796-2050.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing the availability of a 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 effects of 
therapeutic radiopharmaceutical agents. This guidance is not intended 
to address late radiation toxicity of radiobiologicals (e.g., 
radiolabeled monoclonal antibodies) or to apply to diagnostic 
radiopharmaceuticals whose low doses are not expected to elicit late 
radiation toxic effects.
    This 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.
    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 (exclusive of estimated risks of 
secondary malignancy) 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 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 
trials of therapeutic radiopharmaceuticals.
    This guidance finalizes the draft guidance of the same name issued 
in June 2005 and includes edits based on public comments to improve 
clarity.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents 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 requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. 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/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or http://www.regulations.gov.

    Dated: November 22, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-30474 Filed 11-25-11; 8:45 am]
BILLING CODE 4160-01-P


