Metabolic Solutions, Inc.; Receipt of Petition for Rulemaking

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.

cin 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

(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

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

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

he 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

ollected 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

olation

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

tains 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

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.

l 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]

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