[Federal Register Volume 64, Number 85 (Tuesday, May 4, 1999)]
[Proposed Rules]
[Pages 23796-23798]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-11110]


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NUCLEAR REGULATORY COMMISSION

10 CFR Part 32

[Docket No. PRM-32-5]


Metabolic Solutions, Inc.; Receipt of Petition for Rulemaking

AGENCY: Nuclear Regulatory Commission.

ACTION: Petition for rulemaking; Notice of receipt.

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SUMMARY: The Nuclear Regulatory Commission (NRC) has received and 
requests public comment on a petition for rulemaking dated March 5, 
1999, filed by Metabolic Solutions, Inc. (petitioner). The petition has 
been docketed by the Commission and has been assigned Docket No. PRM-
32-5. The petitioner is requesting that the NRC regulations be amended 
to extend a regulatory distribution exemption to the petitioner's 
product, an ``Erythromycin Breath Test.'' That test uses a three-
microcurie dose of carbon-14 (C14)-erythromycin to measure the rate of 
drug metabolism in the human liver. Current NRC regulations permit 
distribution of radioactive drug capsules that contain one microcurie 
of C14-urea to persons exempt from licensing. Dose regulations also 
permit any person exempt from the requirements of a license to use the 
capsules for diagnostic tests in humans. The petitioner believes that 
exempting the C14-erythromycin from regulatory control would make the 
breath test more widely available and reduce the costs of clinical 
trials without increasing the radiation risk to the public.

DATES: Submit comments by July 20, 1999. Comments received after this 
date will be considered if it is practical to do so, but assurance of 
consideration cannot be given except as to comments received on or 
before this date.

ADDRESSES: Submit comments to: Secretary, U.S. Nuclear Regulatory 
Commission, Washington, DC 20555. Attention: Rulemakings and 
Adjudications Staff.
    Deliver comments to 11555 Rockville Pike, Rockville, Maryland, 
between 7:30 am and 4:15 pm on Federal workdays.
    For a copy of the petition, write: David L. Meyer, Chief, Rules and 
Directives Branch, Division of Administrative Services, Office of 
Administration, U.S. Nuclear Regulatory Commission, Washington, DC 
20555-0001.
    You may also provide comments via the NRC's interactive rulemaking 
website through the NRC home page (http://www.nrc.gov). This site 
provides the availability to upload comments as files (any format), if 
your web browser supports that function. For information about the 
interactive rulemaking website, contact Ms. Carol Gallagher, (301) 415-
5905 (e-mail: [email protected]).

FOR FURTHER INFORMATION CONTACT: David L. Meyer, Office of 
Administration, U.S. Nuclear Regulatory Commission, Washington, DC 
20555. Telephone: 301-415-7162 or Toll Free: 1-800-368-5642 or E-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

Background

    On December 2, 1997 (62 FR 63634), the NRC published a final rule 
in the Federal Register that permitted the

[[Page 23797]]

distribution of radioactive drug capsules that contain one microcurie 
of carbon-14 (C14)-urea to persons exempt from licensing. The rule 
added 10 CFR 30.21 entitled, ``Radioactive drug: Capsules containing 
carbon-14 urea for ``in vivo'' diagnostic use for humans,'' and 10 CFR 
32.21 entitled, ``Radioactive drug: Manufacture, preparation, or 
transfer for commercial distribution of capsules containing carbon-14 
urea each for ``in vivo'' diagnostic use for humans to persons exempt 
from licensing; Requirements for a license.'' The rule became effective 
on January 2, 1998.
    On March 12, 1999, the Nuclear Regulatory Commission received a 
petition for rulemaking submitted by the petitioner, Metabolic 
Solutions, Inc., a biomedical firm located in Nashua, New Hampshire. 
The petitioner requests that the NRC extend the regulatory distribution 
exemption for one microcurie of C14 urea to include an ``Erythromycin 
Breath Test'' being developed by the petitioner that contains a three-
microcurie dose of C14-erythromycin. To do this, NRC would have to 
amend its regulations pertaining to the manufacture, distribution, and 
use of radioactive drugs in 10 CFR Parts 30 and 32.
    The breath test is a tool used by researchers and physicians in the 
clinical study phases of drug research studies. The petitioner states 
that the erythromycin breath test measures the in vivo activity of a 
liver microsomal cytochrome P450 enzyme, CYP3A4, that metabolizes about 
40 to 50% of all drugs in the body. This test is currently used in 
clinical research studies to help determine the safety of new drugs. 
Specifically, the test measures the effect that drugs have on the 
CYP3A4 enzyme system, potential interactions with other co-administered 
drugs on the enzyme system, and the range of safe drug tolerance within 
a population. The petitioner believes that dosimetry information for 
the exempted C14-urea will be very similar to the results for the C14-
erythromycin.
    According to the petitioner, exempting the C14-erythromycin from 
``regulatory control'' would make the breath test more widely available 
and lower the costs of clinical trials. Also, the petitioner has 
concluded that the exemption would not present a radiation risk to the 
general public any higher than the risk associated with the 
distribution exemption for drug capsules that contain one microcurie of 
C14-urea. (Note: The Commission has not exempted the C14-urea 
radioactive drug from ``regulatory control.'' NRC requires the 
manufacturer and distributor to have an NRC license that authorizes the 
manufacture or distribution of the product to ``persons exempt'' from 
licensing under 10 CFR 30.21 or an equivalent regulation of an 
Agreement State.) The NRC has determined that the petition meets the 
threshold sufficiency requirements for a petition for rulemaking under 
10 CFR 2.802. The petition has been docketed as PRM-32-5. The NRC is 
soliciting public comment on the petition for rulemaking.

Discussion of the Petition

    The petitioner believes that the NRC regulations codified at 10 CFR 
parts 30 and 32 extend a regulatory exemption for drug capsules that 
contain one microcurie of C-14 urea. According to the petitioner, this 
exemption should be extended to its erythromycin breath test (ERMBT). 
In support of this request, the petitioner contends that the dosimetry 
information for the exempted C14-urea capsules will be very similar to 
that for the ERMBT. The petitioner has provided supporting 
documentation for its position (Exhibit A) entitled, ``Dosimetry of 
C14-Erythromycin.'' Additional supporting documentation (Exhibit B), 
includes: information related to the trademark, chemical ingredients, 
pharmacology, clinical safety, contraindications, adverse reactions, 
dosimetry, drug storage and stability, manufacturing procedures, 
analysis methodology and quality assurance procedures associated with 
the ERMBT.
    The petitioner explains that ERMBT dosimetry data has not been 
collected in humans because it predates FDA regulations that govern 
disposition and metabolism data. In the study cited by the petitioner, 
dosimetry calculations were based on data collected from intravenous 
administration of C14-erythromycin in 10 male rats. The study found 
that in male rats the C14-erythromycin rapidly metabolized in the liver 
and that the resulting metabolite was excreted in bile. The petitioner 
indicates that the study also found that most radioactivity resulting 
from administration of the C14-erythromycin in male rats was either 
exhaled or excreted. The study also indicated a general distribution of 
radioactivity in various tissues of male rats after C14-erythromycin 
administration. The highest concentrations were present in the liver, 
spleen, pancreas, kidney, adrenal and submaxillary glands, lungs, and 
intestinal tract. Lower amounts of radioactivity were found in the 
skin, fat, and brain.
    The rat intracellular distribution studies concluded, petitioner 
states, that erythromycin and its metabolites were capable of entering 
various cellular components of the liver. The studies also indicated 
that the C14-erythromycin dose emits beta radiation to exposed 
individuals. The Oak Ridge Institute for Science and Education, 
Radiation Dose Information Center Radiation calculated dose estimates 
for humans administered C14-erythromycin. These estimates are based on 
data gathered in rats and are described in Appendix 1 of Exhibit A 
attached to the petition for rulemaking. The petitioner indicates that 
data was extrapolated to humans using a weight-based extrapolation 
method where possible.
    The petitioner believes that the information presented in Appendix 
2 of Exhibit A indicates that the effective dose equivalent from the 
ERMBT dose (i.e. 2.1 millirem) is comparable to about one-fourth of a 
chest X-ray and is significantly lower than other nuclear medicine 
tests. Estimated human organ radiation exposures are presented in 
Appendix 3 of Exhibit A. The highest calculated organ doses to humans 
from a three microcurie dosage of C14-erythromycin are 2.8 millirem to 
the ovaries, 2.3 millirem to the gallbladder, 1.47 millirem to the 
small intestine, and 0.6 millirem to the urinary bladder wall.
    In Exhibit B, the petitioner notes that the ERMBT dose has been 
administered to patients since 1988 at the University of Michigan 
Medical Center. Although a few individuals reported a metallic taste in 
their mouths immediately after ingestion, no adverse reactions have 
been experienced or reported.
    Because the product is used as a research tool, users of the test 
must receive approval from Investigational Review Boards to administer 
the ERMBT dose in clinical research studies. The petitioner states that 
these studies have found that allergic reactions to erythromycin are 
very rare. The studies also found that gastrointestinal side effects 
due to the erythromycin, such as abdominal pain, cramping, and mild 
nausea are the most common adverse reactions and are erythromycin dose 
related. According to the studies, adverse effects are relatively 
infrequent in erythromycin doses that contain less than one gram of 
erythromycin. The petitioner notes that the ERMBT dose contains less 
than 0.05 milligrams and that no adverse effects have occurred with 
this dose amount.
    According to the petitioner, the ERMBT is currently used only by 
researchers and physicians who can access a site that has obtained an 
NRC license to handle radio pharmaceuticals. The petitioner states that 
it is often inconvenient to use a C14 product. As stated by the 
petitioner, many clinical

[[Page 23798]]

drug studies occur in physicians' offices where there is either a total 
ban on radioactivity or the facilities do not possess a license to use 
radioactive substances. The petitioner contends that the market size 
for the ERMBT is much smaller than that of the exempted urea test. 
Estimates by the petitioner are that less than 10,000 patients would 
receive the ERMBT between two to five times in clinical studies each 
year (less than 100,000 tests). The petitioner states that the C14-urea 
test encompassed 600,000 people who could be tested two or three times 
including diagnosis and follow-up testing. Without a regulatory 
exemption, the petitioner believes that the market size would be too 
small to be economically feasible to pursue FDA approval for the use of 
the ERMBT.

The Petitioner's Conclusions

    The petitioner concludes that dosimetry information of the C14-
erythromycin will be very similar to that of the exempted C14-urea. 
Also, the petitioner concludes that exempting the C14-erythromycin from 
regulatory control will make the ERMBT more widely available and reduce 
clinical trial expenses. Lastly, the petitioner concludes that the 
exemption would not present a radiation risk to the general public any 
higher than the risk associated with the distribution exemption for 
drug capsules that contain one microcurie of C14-urea.
    The petitioner requests that the NRC grant a regulatory 
distribution exemption for the ERMBT similar to the current exemption 
for C14-urea capsules. This would require amending the regulations 
pertaining to use of radioactive drugs in 10 CFR Parts 30 and 32.

    Dated at Rockville, Maryland, this 28th day of April, 1999.

    For the Nuclear Regulatory Commission.
Annette L. Vietti-Cook,
Secretary of the Commission.
[FR Doc. 99-11110 Filed 5-3-99; 8:45 am]
BILLING CODE 7590-01-P