[Federal Register: March 10, 2000 (Volume 65, Number 48)]
[Notices]
[Page 12999-13010]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10mr00-70]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-0553]


Positron Emission Tomography Drug Products; Safety and
Effectiveness of Certain PET Drugs for Specific Indications

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that the
Commissioner of Food and Drugs (the Commissioner) has concluded that
certain commonly used positron emission tomography (PET) drugs, when
produced under conditions specified in approved applications, can be
found to be safe and effective for certain indications specified in
this document. FDA announces the approval procedures for these PET
drugs and indications and invites manufacturers of these drugs to
submit applications for approval under this document. The agency is
taking this action in accordance with provisions of the Food and Drug
Administration Modernization Act of 1997 (the Modernization Act).
Elsewhere in this issue of the Federal

[[Page 13000]]

Register, FDA is issuing a draft guidance for industry entitled ``PET
Drug Applications--Content and Format for NDA's and ANDA's,'' which is
intended to assist manufacturers that submit applications for approval
as specified in this document.

ADDRESSES: Submit applications for approval to the Center for Drug
Evaluation and Research, Food and Drug Administration, 12229 Wilkins
Ave., Central Document Room, Rockville, MD 20852. Copies of the
published literature listed in the appendix to this document, FDA
reviews of the literature, product labeling referenced in section IV of
this document, and the transcript of the June 28 and 29, 1999, meeting
of the Medical Imaging Drugs Advisory Committee (the Advisory
Committee) will be on display at the Dockets Management Branch (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852. Electronic versions of these documents are
available on the Internet at http://www.fda.gov/cder/regulatory/pet/
default.htm.

FOR FURTHER INFORMATION CONTACT: John A. Friel, Center for Drug
Evaluation and Research (HFD-200), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-1651, FAX 301-827-3056, e-
mail: frielj@cder.fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

    PET is a medical imaging modality that uses a unique type of
radiopharmaceutical drug. PET drugs contain an atom that disintegrates
principally by emission of a positron, which provides dual photons that
are used for imaging, primarily for diagnostic purposes. Most PET drugs
are produced using cyclotrons at locations (sometimes called ``PET
centers'') that usually are in close proximity to the patients to whom
the drugs are administered (e.g., in hospitals or academic
institutions). Each PET drug ordinarily is produced under a physician's
prescription and, due to the short half-lives of PET drugs, is injected
intravenously into the patient within a few minutes or hours of
production.
    FDA has approved new drug applications (NDA's) for three PET drug
products: Sodium fluoride F 18 injection, rubidium chloride 82
injection, and fludeoxyglucose (FDG) F 18 injection. In 1972, FDA
approved NDA 17-042 for sodium fluoride F 18 injection as a bone
imaging agent to define areas of altered osteogenic activity. The NDA
holder ceased marketing this drug product in 1975. Rubidium chloride 82
injection (NDA 19-414), approved in 1989, is indicated for assessing
regional myocardial perfusion in the diagnosis and localization of
myocardial infarction. In 1994, FDA approved NDA 20-306, submitted by
The Methodist Medical Center of Illinois (Methodist Medical), for FDG F
18 injection for the identification of regions of abnormal glucose
metabolism associated with foci of epileptic seizures.
    On November 21, 1997, President Clinton signed into law the
Modernization Act (Public Law 105-115). Section 121(c)(1)(A) of the
Modernization Act directs FDA to establish appropriate procedures for
the approval of PET drugs in accordance with section 505 of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355) and to establish
current good manufacturing practice (CGMP) requirements for PET drugs.
Prior to establishing these procedures and requirements, FDA must
consult with patient advocacy groups, professional associations,
manufacturers, and persons licensed to make or use PET drugs.
    Under section 121(c)(2) of the Modernization Act, FDA cannot
require the submission of NDA's or abbreviated new drug applications
(ANDA's) for compounded PET drugs that are not adulterated under
section 501(a)(2)(C) of the act (21 U.S.C. 351(a)(2)(C)) (i.e., that
comply with United States Pharmacopeia (USP) PET compounding standards
and monographs) for a period of 4 years after the date of enactment or
2 years after the date that the agency adopts special approval
procedures and CGMP requirements for PET drugs, whichever is longer.
However, the act does not prohibit the voluntary submission and FDA
review of applications before these time periods expire.
    In accordance with the Modernization Act, FDA has conducted several
public meetings with a PET industry working group and other interested
persons to discuss proposals for PET drug approval procedures and CGMP
requirements. The industry working group, assembled by the Institute
for Clinical PET (ICP), an industry trade association, includes
representatives from academic centers, clinical sites, and
manufacturers, and it was supported by the Society for Nuclear
Medicine, the American College of Nuclear Physicians, and the Council
on Radionuclides and Radiopharmaceuticals. After consulting with this
working group and other interested persons, FDA decided to conduct its
own reviews of the published literature on the safety and effectiveness
of some of the most commonly used PET drugs for certain indications.
The agency believed that this would be the most efficient way to
develop new approval procedures for these drugs. Under current FDA
policy, the agency may rely on published literature alone to support
the approval of a new drug product under section 505 of the act (see
FDA's guidance for industry entitled ``Providing Clinical Evidence of
Effectiveness for Human Drugs and Biological Products'' (May 1998) and
its draft guidance entitled ``Applications Covered by Section
505(b)(2)'' (December 1999)).
    FDA reviewed the following PET drugs and indications for safety and
effectiveness: (1) FDG F 18 injection for use in oncology and for
assessment of myocardial hibernation, (2) ammonia N 13 injection for
evaluation of myocardial blood flow, and (3) water O 15 injection for
assessment of cerebral perfusion. FDA presented its preliminary
findings on the safety and effectiveness of these drugs for certain
indications to the ICP and others at public meetings. On June 28 and
29, 1999, FDA presented its findings on these drugs to the Advisory
Committee. The Advisory Committee concluded that FDG F 18 injection and
ammonia N 13 injection can be safe and effective for certain
indications, although it recommended some revisions to the indications
proposed by the agency. The Advisory Committee determined that, on the
basis of the literature presented for its review, it was unable to
conclude that water O 15 injection can be safe and effective for the
proposed use of measuring cerebral blood flow in patients with cerebral
vascular disorders associated with ischemia, hemodynamic abnormalities,
occlusion, and other vascular abnormalities. FDA stated that it would
conduct a more comprehensive review of the literature on the safety and
effectiveness of water O 15 injection for this use and then ask the
Advisory Committee to reconsider this drug at a subsequent meeting.

II. Highlights of This Document

    As discussed in section III of this document, FDA concludes that
FDG F 18 injection and ammonia N 13 injection, when produced under
conditions specified in approved applications, can be found to be safe
and effective for certain indications specified in that section and
invites manufacturers of these drugs to submit applications for
marketing approval \1\.

[[Page 13001]]

This document states the approval procedures for these PET drugs for
the particular indications identified. Depending on the circumstances
discussed below, applications for approval of these drugs and
indications may be either NDA's of the type described in section
505(b)(2) of the act or ANDA's submitted under section 505(j) of the
act.
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    \1\ Section 121(c)(1) of the Modernization Act directs FDA to
establish approval procedures and CGMP's for all PET drugs, without
any exclusion for compounded PET drugs. Consequently, references in
this document to PET drugs that are ``produced'' or ``manufactured''
include compounded PET drugs.
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    A 505(b)(2) application is an NDA for which at least one of the
investigations that the applicant relies on to demonstrate the drug's
safety and effectiveness was not conducted by or for the applicant, and
the applicant has not obtained a right of reference or use from the
person by or for whom the investigation was conducted.\2\ A 505(b)(2)
applicant can rely for approval on published literature or on FDA's
findings of safety and/or effectiveness for an approved drug.
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    \2\ A right of reference is the authority to rely upon an
investigation for approval of an application and includes the
ability to make the underlying raw data available for FDA audit, if
necessary (21 CFR 314.3(b)).
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    An ANDA is an application for approval of a ``generic'' version of
an approved drug. An ANDA must include information to show that the
drug has the same active ingredient(s), route of administration, dosage
form, strength, and conditions of use recommended in the labeling of an
approved drug. It must also contain information generally showing that
the labeling of the generic drug is the same as that of the approved
drug, that the generic drug is bioequivalent to the approved drug, and
that the composition, manufacturing, and controls of the generic drug
are sufficient to ensure its safety and effectiveness (section
505(j)(2)(A) of the act).
    To aid manufacturers in submitting 505(b)(2) applications or ANDA's
for FDG F 18 injection and ammonia N 13 injection for the indications
reviewed by FDA, the agency is making available a draft guidance
document, published elsewhere in this issue of the Federal Register,
that provides specific instructions for each drug.
    In addition, PET drug manufacturers may seek approval of
applications for FDG F 18 injection for epilepsy and sodium fluoride F
18 injection for bone imaging by relying on the findings of safety and
effectiveness made by the agency in approving the original NDA's for
these drugs. Again, such applications may be either NDA's or ANDA's,
depending on whether a manufacturer's proposed drug product is the same
as an approved drug product.
    If, after reviewing the relevant literature and consulting with the
Advisory Committee, FDA concludes that water O 15 injection is safe and
effective for a cerebral perfusion indication, the agency intends to
issue a Federal Register notice announcing this conclusion and inviting
manufacturers of this drug to submit applications for approval in
accordance with the procedures discussed in this document.
    In a future issue of the Federal Register, FDA intends to state its
approach to applications for approval of other PET drugs and new
indications for approved products in accordance with the Modernization
Act.

III. PET Drugs for Which FDA Has Reviewed Published Literature

    As discussed below, FDA generally agrees with and adopts the
Advisory Committee's conclusions on the safety and effectiveness of FDG
F 18 injection and ammonia N 13 injection, when produced under
conditions specified in approved applications, for the indications
stated in this document. In determining the safety and effectiveness of
these drugs, FDA relied on the published literature and, where
appropriate, previous agency determinations of safety or effectiveness.
FDA obtained relevant articles in the published literature from the PET
community and through the agency's own search of current, peer-reviewed
literature. In evaluating a drug's effectiveness, FDA reviewed only
those articles meeting the following criteria: (1) The studies involved
prospective, controlled trials with an appropriate standard of truth
(i.e., ``gold standard''); and (2) the article contained sufficient
information to evaluate the study protocol, endpoints, statistical plan
and methodology, sample size, accounting of enrolled patients, imaging
protocol, blinding procedures, and image handling methodology.
    FDA reviewed the literature to document the safety and
effectiveness of these PET drugs on the basis of clinical pharmacology
and biopharmaceutics, pharmacology and toxicology, and clinical and
statistical information. The agency sought evidence that the reviewed
drugs can provide useful clinical information related to their intended
indications for use. The appendix to this document contains a list of
published articles reviewed by FDA establishing that FDG F 18 injection
and ammonia N 13 injection can be found to be safe and effective for
specific indications when produced under conditions specified in
approved applications. Copies of FDA's reviews of the published
literature can be obtained in accordance with the ADDRESSES section of
this document.

A. FDG F 18 Injection for Use in Myocardial Hibernation and Oncology

1. Safety
    In evaluating the safety of FDG F 18 injection for both the
oncology and myocardial hibernation indications, FDA considered the
approximately two decades of clinical use of the drug and the
conclusions the agency reached in approving NDA 20-306 for this drug.
The currently labeled intravenous doses of FDG F 18 injection for
epilepsy are 5 to 10 millicuries (mCi) in adults and 2.6 mCi in
pediatrics. No significant adverse reactions have been reported for FDG
F 18 injection. In addition, FDA found no reports of adverse reactions
in the published literature on the effectiveness of FDG F 18 injection
or in a recent article by Silberstein and others (1996) reporting the
results of a 5-year prospective study on drugs used in nuclear medicine
at 18 collaborating institutions.
    The literature and FDA's finding on the safety of FDG F 18
injection in NDA 20-306 indicate that for an intravenous dose of 10 mCi
of the drug, the critical target organ (the bladder) absorbs only 6.29
rems based on a fixed bladder content over a 3-hour period. For higher
doses, the level and extent of radiation absorbed by the bladder walls
can be manipulated with hydration and shorter voiding intervals to
decrease radiation exposure. On the basis of this information, a 10-mCi
dose of FDG F 18 injection appears to pose a relatively low risk to
adult patients.
2. Safety and Effectiveness for Identifying Hibernating Myocardium
    FDA's search of the recent published literature on FDG F 18
injection yielded 632 articles, from which the agency identified 10
articles that: (1) Met the review criteria; (2) evaluated patients with
coronary artery disease (CAD) and left ventricular dysfunction; and (3)
considered whether FDG F 18 image findings before coronary
revascularization could predict the functional outcome of regions of
the left ventricle after revascularization. All of these articles
involved adequate and well-controlled clinical trials. FDA also
reviewed several other articles in support of the potential clinical
usefulness of FDG F 18 for such cardiac evaluations.

[[Page 13002]]

    The use of FDG F 18 injection for this purpose is based on the
premise that reversibly injured myocytes can metabolize glucose but
irreversibly injured myocytes cannot. Based on its review of the
literature, FDA concludes that a 10-mCi dose (for adults) of FDG F 18
injection produced under conditions specified in an approved
application can be found to be safe and effective in PET imaging of
patients with CAD and left ventricular dysfunction, when used together
with myocardial perfusion imaging, for the identification of left
ventricular myocardium with residual glucose metabolism and reversible
loss of systolic function.
3. Safety and Effectiveness for Evaluating Glucose Metabolism in
Oncology
    Published articles on the use of FDG F 18 for oncology imaging
first appeared in the 1980's. The use of FDG F 18 injection in oncology
is based on different rates of glucose metabolism that are expected to
occur in benign and malignant tissues.
    FDA's search of the published literature revealed about 150
articles involving clinical trials with FDG F 18 injection in oncology.
Of these, the agency identified 16 articles that met the review
criteria and had both a study population of greater than 50 and
histopathologic confirmation of the type of malignancy. Two of the
articles involved adequate and well-controlled trials. On the basis of
these and other supportive studies, FDA concludes that a 10-mCi dose
(for adults) of FDG F 18 injection produced under conditions specified
in an approved application can be found to be safe and effective in PET
imaging for assessing abnormal glucose metabolism to assist in
evaluating malignancy in patients with known or suspected abnormalities
found by other testing modalities or in patients with an existing
diagnosis of cancer.

B. Ammonia N 13 Injection for Assessing Myocardial Perfusion

    The published literature contains reports of clinical
investigations involving ammonia N 13 dating back to the 1970's. A
principal focus of these studies has been the use of ammonia N 13
injection to evaluate myocardial blood flow.
1. Safety
    Ammonia is a ubiquitous substance in the body, and its metabolism
and excretion are well understood. The maximum amount of ammonia in a
typical dose of ammonia N 13 injection is extremely small compared to
the amount of ammonia produced by the body. The reviewed published
literature does not identify any adverse events following the
administration of ammonia N 13 injection.
    The literature indicates that after a total intravenous dose of
approximately 25 mCi of ammonia N 13 injection, the critical target
organ (bladder wall) absorbs only 1.28 rems. Therefore, a 10-mCi dose
of ammonia N 13 injection appears to pose a relatively low risk to
adult patients.
2. Safety and Effectiveness for Assessing Myocardial Perfusion
    FDA's search of the published literature revealed 76 articles on
the use of ammonia N 13 injection for assessing myocardial perfusion.
Of these, 17 articles met the review criteria and provided a comparison
of myocardial perfusion results of ammonia N 13 injection to a
recognized standard of myocardial perfusion or to other appropriate
comparators. Two articles discussed the results of adequate and well-
controlled studies evaluating the effectiveness of ammonia N 13
injection in assessing myocardial perfusion. On the basis of these
studies, FDA concludes that a 10-mCi dose (for adults) of ammonia N 13
injection produced under conditions specified in an approved
application can be found to be safe and effective in PET imaging of the
myocardium under rest or pharmacological stress conditions to evaluate
myocardial perfusion in patients with suspected or existing CAD.

IV. Applications for Approval of Reviewed PET Drugs and Sodium
Fluoride F 18 Injection

A. Types of Applications Required for Reviewed PET Drugs

    Based on its review of the published literature and the
recommendations of the Advisory Committee, FDA has determined that FDG
F 18 injection and ammonia N 13 injection, when produced under
conditions specified in an approved application, can be found to be
safe and effective for the specified indications. Approved applications
are required because these drugs cannot be deemed generally recognized
as safe and effective under section 201(p)(1) and (p)(2) of the act (21
U.S.C. 321(p)(1) and (p)(2)), making them new drugs subject to
regulation under section 505 of the act. Congress recognized that PET
drugs are new drugs when it directed FDA, in section 121(c)(1)(A)(i) of
the Modernization Act, to establish appropriate approval procedures for
these drugs ``pursuant to section 505'' of the act.
    A principal reason why PET drugs are new drugs and not generally
recognized as safe and effective is that the approximately 70 PET
centers differ considerably in the way they formulate and manufacture
these drugs. Such variations in drug constituents and in manufacturing
procedures can significantly affect the identity, strength, quality,
and purity of the drugs in a manner that may well adversely affect
their safety and effectiveness. For example, these PET drugs are
injectable products that cannot be safe unless they are at least
sterile and pyrogen-free. Therefore, FDA must verify that appropriate
conditions and procedures regarding sterility and pyrogenicity exist at
each manufacturing site.
    Stability concerns are another example of why formulation and
manufacturing techniques must be considered in evaluating safety and
effectiveness. Without adequate controls, PET drugs may be unstable
when produced in high radioconcentrations (as occur at some PET
centers) due to radiolytic degradation of the drug substance. Such
degradation can result in a subpotent drug as well as administration of
radioactive moieties other than the intended drug substance. Depending
on their specific localization, such moieties can cause excessive
radiation of nontargeted tissues or interfere with imaging. This can
make a drug product unsafe in a susceptible population or result in
misdiagnosis.
    Another aspect of PET drug production that can adversely affect
safety is the potential for the development of impurities in the
finished product. Some of these impurities would pose a threat to the
health of patients.
    For these and other reasons, the agency cannot conclude that these
PET drugs are generally recognized as safe and effective for the above-
noted indications and therefore needs to review information on how each
drug product is formulated and produced at each manufacturing site.
Because these PET drugs are not generally recognized as safe and
effective, they are new drugs for which approved NDA's or ANDA's are
required for marketing under section 505(a) of the act and part 314 (21
CFR part 314).
    As previously noted, if a PET drug fully complies with all USP
standards and monographs pertaining to PET drugs, an application for
approval of such drug is not required until 2 years after FDA
establishes approval procedures and CGMP requirements for

[[Page 13003]]

PET drugs. Although submission of applications is not required at this
time, FDA encourages the manufacturers of FDG F 18 injection and
ammonia N 13 injection to submit applications for approval under
section 505(b)(2) or (j) of the act, as discussed below in sections
IV.A.1 and IV.A.2, as soon as possible.
1. Applications for FDG F 18 Injection
    As noted above, there is already an approved application (NDA 20-
306, held by Methodist Medical) for FDG F 18 injection for the
identification of regions of abnormal glucose metabolism associated
with foci of epileptic seizures. To obtain approval to market their FDG
F 18 injection products for the new (myocardial and oncological)
indications discussed in section III.A of this document, initially all
applicants except Methodist Medical should submit 505(b)(2)
applications. FDA anticipates that such applicants will seek approval
for all three indications for FDG F 18 injection. In that case,
applicants should reference the safety and effectiveness data in the
published literature listed in the appendix to this document for the
myocardial and oncological indications for FDG F 18 injection and the
findings of safety and effectiveness regarding NDA 20-306 for the
epilepsy-related indication in accordance with Sec. 314.54. Methodist
Medical may, if it chooses, submit a supplemental NDA for each of the
two new indications in accordance with section 506A of the act (21
U.S.C. 356a) and this document. The supplemental applications need only
reference the information in the appendix to this document. Applicants
need not conduct their own clinical trials or submit copies of the
articles listed in the appendix.
    The drug product that is the subject of the first approved NDA for
FDG F 18 injection for the indications stated in section III.A of this
document (myocardial hibernation and oncology) most likely will be the
reference listed drug for these indications under section 505(j)(2)(A)
of the act and Sec. 314.3. FDA will continue to review as 505(b)(2)
applications those applications for FDG F 18 injection that have
already been filed at the time of approval of the first application.
After FDA approves the first application for FDG F 18 injection
submitted in response to this document, subsequent applications for
approval of the same drug for the same indications should generally be
submitted as ANDA's under section 505(j) of the act and
Sec. 314.92(a)(1), rather than as 505(b)(2) applications.\3\ FDA
anticipates that in many cases, NDA 20-306 will be the appropriate
reference listed drug for such ANDA's.\4\ However, as 505(b)(2)
applications are approved, the agency may identify additional products
as reference listed drugs.
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    \3\ Under Sec. 314.101(d)(9), FDA may refuse to file a 505(b)(2)
application for a drug that is a duplicate of a listed drug and is
eligible for approval under section 505(j) of the act.
    \4\ For the existing reference listed drug for FDG F 18
injection (NDA 20-306), the active ingredient is FDG F 18, the route
of administration is intravenous, the dosage form is injection, and
the strength is 4.0 to 40 mCi/milliliters (mL) at the end of
synthesis.
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    If a PET drug manufacturer's FDG F 18 injection product has an
active ingredient, route of administration, dosage form, or strength
that differs from that of a listed drug, the applicant would probably
submit a 505(b)(2) application. Alternatively, the applicant could
submit an ANDA after obtaining approval of a ``suitability petition''
for such a drug, although this would likely be a less efficient means
of obtaining marketing approval.\5\ (Because FDA has already approved a
suitability petition granting permission to submit an ANDA for FDG F 18
injection with a different strength (i.e., 1.6 to 58.4 mCi/mL at the
end of bombardment) than that of the reference listed drug, an ANDA
applicant could, if it desired, make reference in its own application
to the strength in the approved suitability petition.)
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    \5\ Under section 505(j)(2)(C) of the act, FDA will approve a
petition seeking permission to file an ANDA for a drug that has an
active ingredient, route of administration, dosage form, or strength
that differs from that of a listed drug unless the agency finds
that: (1) Investigations must be conducted to show the safety and
effectiveness of the drug or of any of its active ingredients, the
route of administration, the dosage from, or strength that differ
from the listed drug; or (2) a drug with a different active
ingredient may not be evaluated for approval as safe and effective
on the basis of the information required to be submitted in an ANDA.
If FDA approves a suitability petition for a drug product, the
applicant may then submit an ANDA. However, if FDA concludes that
additional studies are necessary to show the safety and/or
effectiveness of the drug proposed in the petition, the applicant
would need to submit a 505(b)(2) application to obtain marketing
approval.
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2. Applications for Ammonia N 13 Injection
    Because there is no approved ammonia N 13 injection product for any
indication, initially all manufacturers of this drug should submit
505(b)(2) applications. Applicants should reference the published
literature on the safety and effectiveness of ammonia N 13 injection
for assessment of myocardial perfusion listed in the appendix to this
document.
    After FDA approves the first application for ammonia N 13 injection
for assessing myocardial perfusion, subsequent applications for
approval of the same drug for the same indication could be submitted as
ANDA's. However, a 505(b)(2) application (or a suitability petition)
should be submitted if the active ingredient, route of administration,
dosage form, or strength of the applicant's ammonia N 13 injection
product differs from that of a listed drug.

B. Types of Applications Required for Sodium Fluoride F 18 for Bone
Imaging

    FDA approved sodium fluoride F 18 injection (NDA 17-042) in 1972 as
a bone imaging agent to define areas of altered osteogenic activity.
The current NDA holder, Nycomed Amersham, stopped marketing the drug in
March 1975.
    As an approved drug, sodium fluoride F 18 injection would normally
be listed in the ``Approved Drug Products with Therapeutic Equivalence
Evaluations'' (generally known as the ``Orange Book''), in accordance
with section 505(j)(7) of the act. However, certain drug products,
including sodium fluoride F 18 injection, that were approved for safety
and effectiveness but were no longer marketed on September 24, 1984,
are not included in the Orange Book. In implementing section 505(j)(7)
of the act, FDA decided not to retrospectively review products
withdrawn from the market prior to that date. Rather, the agency
determines on a case-by-case basis whether such drugs were withdrawn
from the market for safety or effectiveness reasons. FDA must make a
determination as to whether a listed drug was withdrawn from sale for
reasons of safety or effectiveness before it may approve an ANDA that
refers to the listed drug (Sec. 314.161(a)(1)).
    FDA reviewed its records and, under Sec. 314.161, determined that
sodium fluoride F 18 injection was not withdrawn from sale for reasons
of safety or effectiveness. Accordingly, the agency will list sodium
fluoride F 18 injection in the Orange Book's ``Discontinued Drug
Product List'' section, which delineates, among other items, drug
products that have been discontinued from marketing for reasons other
than safety or effectiveness. Because sodium fluoride F 18 injection
was not withdrawn from sale for reasons of safety or effectiveness, it
is still a listed drug, and FDA can approve ANDA's that refer to it.
FDA therefore invites those PET centers whose sodium fluoride F 18
injection product is the

[[Page 13004]]

same as the reference listed drug to submit ANDA's.\6\
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    \6\ For the reference listed drug, the active ingredient is
sodium fluoride F 18, the route of administration is intravenous,
the dosage form is injection, and the strength is 2.0 mCi/mL at the
time of calibration.
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    If a sponsor's sodium fluoride F 18 injection product is not the
same as the listed drug, the sponsor should submit a 505(b)(2)
application (or a suitability petition) rather than an ANDA. FDA
anticipates that this will be the case with most manufacturers of
sodium fluoride F 18 injection because the strength of their product is
likely to differ from that of the listed drug.

C. Additional Guidance on Submission of Applications and Labeling

    FDA is issuing a draft guidance document, published elsewhere in
this issue of the Federal Register, to assist PET drug manufacturers in
submitting NDA's and ANDA's for FDG F 18 injection, ammonia N 13
injection, and sodium fluoride F 18 injection in accordance with this
document. Among other things, the draft guidance addresses the
chemistry, manufacturing, and controls information that should be
provided in applications for these drugs.
    FDA has developed suggested labeling for FDG F 18 injection and
ammonia N 13 injection products for the indications discussed above.
The suggested labeling for FDG F 18 injection also includes the
previously approved indication of identification of regions of abnormal
glucose metabolism associated with foci of epileptic seizures. A
manufacturer seeking approval of FDG F 18 injection, ammonia N 13
injection, or sodium fluoride F 18 injection in accordance with this
document should submit product labeling that is consistent with the
recommended labeling. This labeling is available on the Internet at
http://www.fda.gov/cder/regulatory/pet and is on display in FDA's
Dockets Management Branch (address above). The labeling also will be
included in the forthcoming draft guidance document on the submission
of applications in accordance with this document.

D. Pediatric Assessments

    Under Sec. 314.55(a), each application for a new active ingredient
or new indication must contain data that are adequate to assess the
safety and effectiveness of the drug for the claimed indications in all
relevant pediatric subpopulations and to support specific dosing and
administration for the drug. When the course of a disease and the
effects of a drug are sufficiently similar in adults and pediatric
patients, FDA may conclude that pediatric effectiveness can be
extrapolated from adequate and well-controlled studies in adults,
usually supplemented with other information obtained in pediatric
patients. In addition, FDA may defer submission of some or all
pediatric assessments until after approval of a drug product for use in
adults, including when the agency determines that pediatric studies
should be delayed until additional safety or effectiveness data have
been collected (Sec. 314.55(b)).
    The original application for FDG F 18 injection (NDA 20-306) is
approved for epilepsy in pediatric patients. Based on available
radiation dosimetry data for different ages and information on the use
of glucose during pediatric development, FDA concludes that sufficient
data are available to support the statements on the pediatric use of
FDG F 18 injection found in the labeling referenced in section IV.C of
this document.
    Regarding ammonia N 13 injection, information exists on the known
effects of ammonia on the human body, the normal blood levels of
ammonia for different ages, the amount of ammonia N 13 injection
typically administered to patients, and the radiation dosimetry of the
drug for different ages. Therefore, FDA concludes that sufficient data
are available to support the statements on the pediatric use of ammonia
N 13 injection found in the labeling referenced in section IV.C of this
document.
    Limited data are available that are relevant to the pediatric use
of sodium fluoride F 18 injection for use in defining areas of altered
osteogenic activity. Therefore, FDA is deferring the pediatric
assessments required under Sec. 314.55(a) for sodium fluoride F 18
injection for this indication until 5 years after the date that the
agency adopts approval procedures and CGMP requirements for PET drugs.
This deferral will allow the agency to obtain additional safety and
effectiveness information on the use of sodium fluoride F 18 injection
before determining what pediatric studies may be necessary.

E. User Fees

    Under section 736(a)(1)(A)(ii) of the act (21 U.S.C.
379h(a)(1)(A)(ii)), FDA assesses an application fee for any human drug
application as defined in the statute. No application fee is required
for an ANDA or for a supplement for which clinical data are not
required.
    An application fee normally would be assessed for a 505(b)(2)
application for FDG F 18 injection, ammonia N 13 injection, and sodium
fluoride F 18 injection submitted in accordance with this document.
However, FDA intends to grant a waiver of application fees for these
drugs. Under section 736(d)(1) of the act, FDA can grant a waiver or
reduction in fees for several reasons, including when assessment of a
fee would present a significant barrier to innovation because of
limited resources available to the applicant or other circumstances
(section 736(d)(1)(B) of the act).
    FDA finds that, because of the unique circumstances surrounding the
regulation of PET drugs, assessment of an application fee on the PET
drugs noted above would present a significant barrier to innovation.
FDA is aware that Congress directed the agency to develop appropriate
approval procedures and CGMP requirements for PET drugs to ``take
account of the special characteristics of positron emission tomography
drugs and the special techniques and processes required to produce
these drugs'' (section 121(c)(1)(A) of the Modernization Act). One of
Congress' goals in enacting section 121 of the Modernization Act is to
promote the availability of FDA-approved PET drug products for the
patients who need them. As noted in the Senate report on the
Modernization Act, most of the approximately 70 PET centers in the
United States are part of academic medical centers (S. Rept. No. 43,
105th Cong., 1st Sess., at 53 (1997)). The report states that these
academic medical centers are facing unprecedented cost pressures,
suggesting that many PET centers would likely close without some kind
of regulatory relief. The report emphasizes that if PET centers close,
the benefits of PET would be unavailable to patients who need this
diagnostic technology.
    FDA finds that Congress intended for the agency to ease the
regulatory burden on PET centers, including by providing waivers of
user fees in appropriate circumstances. FDA further concludes that a
waiver of the application fees for applications seeking approval of FDG
F 18 injection, ammonia N 13 injection, and sodium fluoride F 18
injection products submitted in response to this document is consistent
with the congressional goal of promoting the availability of FDA-
approved PET drugs. Without a fee waiver, there may be a disincentive
for manufacturers of these PET drugs to submit NDA's under section
505(b)(2) of the act because an application fee normally would be
assessed on each application submitted only until FDA approves the
first NDA for a particular drug and indication. Once FDA approves such
a product, subsequently submitted 505(b)(2)

[[Page 13005]]

applications for the particular drug and indication will not be
assessed an application fee.
    On the other hand, if an applicant hoped to obtain market
exclusivity (as discussed in section IV.F of this document), it would
have an incentive to be the first to submit and obtain approval of an
NDA for one of these PET drugs. Therefore, for the reasons noted above,
FDA will waive the application fee for NDA's for FDG F 18 injection,
ammonia N 13 injection, and sodium fluoride F 18 injection products
submitted in accordance with this document, but only if the applicant
submits with its NDA a statement that it waives any right to market
exclusivity to which it may be entitled under the act.

F. Patent Protection and Market Exclusivity

    PET drug products approved by FDA may be protected from competition
by patents issued by the U.S. Patent and Trademark Office or by periods
of market exclusivity granted by FDA at the time of approval. Patent
and exclusivity protections may affect the approval of competing
505(b)(2) applications and ANDA's.
    Applicants submitting NDA's under section 505(b) of the act,
including 505(b)(2) applications, must file with the application, in
accordance with Sec. 314.53, a list of the patent numbers and
expiration dates for each patent that claims the drug substance, drug
product (formulation and composition), or method of using the drug that
is the subject of the application. No other patents may be submitted,
including process patents covering the manufacture of the drug.
Additional patent information must be submitted within 30 days of
approval of an application or, in the case of newly issued patents,
within 30 days of issuance of the patent. If an application is
approved, FDA will publish the patent information in the Orange Book.
    Certain PET drugs may also be eligible for patent term extensions
under 35 U.S.C. 156. Patent term extensions are issued by the U.S.
Patent and Trademark Office.
    Sponsors submitting NDA's for PET drug products may be eligible for
market exclusivity under the act. There are four types of exclusivity
available: (1) 5-year new chemical entity exclusivity, (2) 3-year
exclusivity for applications that require new clinical trials, (3) 6-
month pediatric exclusivity, and (4) 7-year exclusivity for drugs
intended to treat rare diseases or conditions (i.e., ``orphan drugs'').
Eligibility for exclusivity depends on, among other things, the
characteristics of the drug product and the type of studies conducted
by the applicant. A sponsor who believes its drug product is entitled
to exclusivity must submit supporting information in its NDA
(Sec. 314.50(j)). Applicants interested in determining whether a PET
drug product may be eligible for exclusivity are encouraged to discuss
the issue with the Center for Drug Evaluation and Research's Division
of Medical Imaging and Radiopharmaceutical Drug Products.
    A drug product that contains a new chemical entity may be eligible
for 5 years of market exclusivity under sections 505(c)(3)(D)(ii) and
(j)(5)(D)(ii) of the act and the regulations at Sec. 314.108. Whether a
drug qualifies for new chemical entity exclusivity depends on whether
the active moiety has been approved in another application submitted
under section 505(b) of the act. The ``active moiety'' is, in general
terms, ``the molecule or ion * * * responsible for the physiological or
pharmacological action of the drug substance'' (Sec. 314.108(a)). A
drug product containing a new chemical entity may be eligible for 5
years of exclusivity even if the drug product is submitted in a
505(b)(2) application that relies for approval on literature reviewed
by FDA supporting the safety and effectiveness of the drug. For new
chemical entity exclusivity, there is no requirement that the sponsor
conduct clinical trials to obtain the approval.
    New chemical entity exclusivity generally bars submission of any
505(b)(2) application or ANDA for a drug containing the same active
moiety for 5 years from the date the new chemical entity is
approved.\7\ If at the time the first NDA for an active moiety is
approved and given exclusivity, other applicants have already submitted
505(b)(2) applications for products with the same active moiety, the
agency may review and approve those applications, notwithstanding the
exclusivity the first drug product obtained at the time of approval (54
FR 28872 at 28901, July 10, 1989). The first drug product's exclusivity
will only bar submission of new 505(b)(2) applications or ANDA's.
Therefore, if applications are submitted relatively close in time, new
chemical entity exclusivity may not block approval of multiple
505(b)(2) applications for PET drugs with the same active moiety.
---------------------------------------------------------------------------

    \7\ An exception to this 5-year bar permits an applicant to
submit a 505(b)(2) application or ANDA after 4 years if it contains
a certification of invalidity or noninfringement for a patent listed
for the approved drug.
---------------------------------------------------------------------------

    Certain PET drug products may also be eligible for 3 years of
market exclusivity under section 505(c)(3)(D)(iii) and (c)(3)(D)(iv)
and (j)(5)(D)(iii) and (j)(5)(D)(iv) of the act and Sec. 314.108(b)(4).
Three-year exclusivity is granted when an NDA contains reports from new
clinical studies conducted or sponsored by the applicant and those
studies are essential to approval of the application. Bioequivalence
and bioavailability studies are not clinical studies that qualify for
exclusivity. A 505(b)(2) application may be eligible for 3-year
exclusivity if it relies in part on published literature or on FDA's
findings on the safety or effectiveness of a PET drug, but also
contains reports of new clinical studies conducted by the sponsor that
are essential to the approval of, for example, a new use for the drug.
    If a drug product is given 3 years of exclusivity, FDA is barred
from approving any 505(b)(2) application or ANDA for the same drug
product, or change to the product, as that for which the exclusivity
was granted. For example, if an applicant obtains 3 years of
exclusivity for a new indication for a PET drug, FDA may not approve an
ANDA for that indication for 3 years. However, the agency may approve
an ANDA for any previously approved indications not protected by the
exclusivity.
    Sponsors of PET drug products may also obtain pediatric exclusivity
in accordance with section 505A of the act (21 U.S.C. 355a). To be
eligible to obtain 6 months of pediatric exclusivity, a drug product
must have patent or exclusivity protection to which the pediatric
exclusivity period can attach. A drug product that has no patents
listed in the Orange Book or other market exclusivity will not be
eligible for pediatric exclusivity. To obtain pediatric exclusivity, a
sponsor must conduct studies as described in a written request issued
by FDA and must submit those studies within the timeframe described in
the written request and in accordance with the filing requirements.
Detailed information on qualifying for pediatric exclusivity is
available in FDA's guidance for industry entitled ``Qualifying for
Pediatric Exclusivity Under Section 505A of the Federal Food, Drug, and
Cosmetic Act'' (64 FR 54903, October 8, 1999).
    A PET drug product intended for the diagnosis of a rare disease or
condition (one that affects fewer than 200,000 people in the United
States) may be eligible for 7 years of orphan drug exclusivity under
sections 526 and 527 of the act (21 U.S.C. 360bb-360cc). Obtaining
orphan drug exclusivity is a two-step process. An applicant must

[[Page 13006]]

seek orphan drug designation for its drug prior to submitting an NDA.
If FDA designates the drug as an orphan drug and then approves it for
the designated indication, the drug will receive orphan drug
exclusivity. Orphan drug exclusivity bars FDA from approving another
application from a different sponsor for the same drug for the same
indication for a 7-year period.
    A sponsor who is entitled to any type of exclusivity for a PET drug
product may waive such exclusivity to allow one or more applicants to
submit applications for the product. For example, if the sponsor of a
505(b)(2) application for a PET drug were to obtain 5-year exclusivity,
a complete waiver of such exclusivity would enable other applicants to
immediately submit 505(b)(2) applications and ANDA's for a drug
containing the same active moiety.
    Information regarding patents and exclusivity periods for approved
drug products is published in the Orange Book. This information is
important for applicants considering submitting ANDA's or 505(b)(2)
applications for PET drugs. If a reference listed drug for an ANDA or a
listed drug for a 505(b)(2) application has listed patents, the ANDA or
505(b)(2) application will be required to contain certifications
regarding those patents (see Sec. 314.94(a)(12) for ANDA's,
Sec. 314.50(i) for 505(b)(2) applications).

G. CGMP

    As noted in section I of this document, the Modernization Act
directs FDA to develop appropriate CGMP requirements for PET drugs. At
a public meeting held on February 19, 1999, FDA discussed its
preliminary approach to CGMP's for PET drugs with the PET industry
working group and other attendees. In response to comments from the PET
community, FDA revised its CGMP preliminary draft regulations. These
preliminary draft provisions were discussed at a public meeting held on
September 28, 1999. FDA intends to propose regulations on CGMP's for
PET drugs in a forthcoming issue of the Federal Register, after
obtaining additional public input.

H. Preapproval Inspections

    FDA is authorized under the act to inspect the facilities to be
used in the manufacture of a drug product prior to granting approval of
an application to ensure that the facilities and controls used to
manufacture the drug are adequate to preserve its identity, strength,
quality, and purity (sections 505(d)(3) and (k)(2) and 704(a)(1) of the
act (21 U.S.C. 374(a)(1)); see also Sec. 314.125(b)(12)). FDA will not
inspect PET drug manufacturing facilities for compliance with CGMP's
until 2 years after the date that the agency establishes CGMP
requirements for such drugs. However, until such time, if an
application for approval of a PET drug is submitted, FDA will conduct
an inspection to determine whether the facilities and controls used to
manufacture the proposed drug product conform to the USP's PET
compounding standards and monographs, in accordance with section
501(a)(2)(C) of the act (21 U.S.C. 351(a)(2)(C)),\8\ and to verify
other aspects of an NDA or ANDA submission.
---------------------------------------------------------------------------

    \8\ Section 501(a)(2)(C) of the act, established by the
Modernization Act, requires that PET drugs be produced in conformity
with the USP's PET drug compounding standards and monographs. This
provision will expire 2 years after the date on which FDA
establishes approval procedures and CGMP requirements for PET drugs.
---------------------------------------------------------------------------

V. Approval Procedures for Other PET Drugs and Indications

    FDA has not yet addressed the procedures for approval of other PET
drugs and of new indications for approved PET drugs. In FDA's proposed
rule on the evaluation and approval of in vivo radiopharmaceuticals
used for diagnosis and monitoring, published in the Federal Register of
May 22, 1998 (63 FR 28301 at 28303), the agency stated that it expected
the standards for determining safety and effectiveness set forth in the
proposed rule to apply to PET drugs, which are one type of
radiopharmaceutical.
    FDA published its final rule on diagnostic radiopharmaceuticals in
the Federal Register of May 17, 1999 (64 FR 26657). The final rule adds
part 315 (21 CFR part 315), which addresses how FDA will interpret and
apply certain provisions in part 314 to evaluate the safety and
effectiveness of diagnostic radiopharmaceuticals. The agency also
issued a draft guidance for industry entitled ``Developing Medical
Imaging Drugs and Biologics,'' which, when finalized, will provide
information on how the agency will interpret and apply the provisions
of the final rule. In a future issue of the Federal Register, FDA
intends to address whether and, if so, how new part 315 and the medical
imaging guidance should be modified in their application to PET drugs.

VI. Conclusions

    The Commissioner has concluded that FDG F 18 injection, when
produced under the conditions specified in an approved application, can
be found to be safe and effective in PET imaging in patients with CAD
and left ventricular dysfunction, when used together with myocardial
perfusion imaging, for the identification of left ventricular
myocardium with residual glucose metabolism and reversible loss of
systolic function, as discussed in section III.A.1 and III.A.2 of this
document. The Commissioner also has concluded that FDG F 18 injection,
when produced under the conditions specified in an approved
application, can be found to be safe and effective in PET imaging for
assessment of abnormal glucose metabolism to assist in the evaluation
of malignancy in patients with known or suspected abnormalities found
by other testing modalities or in patients with an existing diagnosis
of cancer, as discussed in section III.A.1 and III.A.3 of this
document. In addition, the Commissioner has concluded that ammonia N 13
injection, when produced under the conditions specified in an approved
application, can be found to be safe and effective in PET imaging of
the myocardium under rest or pharmacological stress conditions to
evaluate myocardial perfusion in patients with suspected or existing
CAD, as discussed in section III.B of this document. The Commissioner
bases these conclusions on FDA's review of the published literature on
these uses and on the recommendation by the agency's Medical Imaging
Drugs Advisory Committee that FDA find these drugs to be safe and
effective for these indications.
    In addition, manufacturers of FDG F 18 injection and sodium
fluoride F 18 injection may rely on prior agency determinations of the
safety and effectiveness of these drugs for certain epilepsy-related
and bone imaging indications, respectively, in submitting either
505(b)(2) applications or ANDA's for these drugs and indications.
    Applications for approval of these PET drug products should be
submitted in accordance with sections III and IV of this document as
well as the guidance documents and product labeling referenced in
section IV of this document.

VII. Assistance for Applicants

    If you have questions about this document or need help in preparing
an application for approval of one of the PET drugs discussed above,
contact John A. Friel (address above); also, application forms are
available from Friel's office. For further information and assistance
visit the Internet on PET drugs at http//www.fda.gov/cder/regulatory/
pet/default.htm.

[[Page 13007]]

VIII. Availability of Published Literature and Other Resources

    The published literature referenced in section III of this document
is listed in the appendix to this document. Copies of the published
literature, FDA reviews of the literature, product labeling referenced
in section IV of this document, and the transcript of the June 28 and
29, 1999, Advisory Committee meeting will be on display in the Dockets
Management Branch (address above) between 9 a.m. and 4 p.m., Monday
through Friday.

Appendix: Published Literature on the Safety and Effectiveness of
Reviewed PET Drugs

I. Published Literature on FDG F 18 Injection:

A. Pharmacology, Toxicology, and Biopharmaceutics

    1. Altehoefer, C., ``LBBB: Challenging Our Concept of Metabolic
Heart Imaging With Fluorine-18-FDG and PET,'' Journal of Nuclear
Medicine, 39:263-265, 1998.
    2. Baer, F. M. et al., ``Predictive Value of Low Dose Dobutamine
Transesophageal Echocardiography and Fluorine-18 Fluorodeoxyglucose
Positron Emission Tomography for Recovery of Regional Left
Ventricular Function After Successful Revascularization,'' Journal
of the American College of Cardiology, 28:60-69, 1996.
    3. Bessell, E. M., A. B. Foster, and J. H. Westwood, ``The Use
of Deoxyfluoro-D-glucopyranoses and Related Compounds in a Study of
Yeast Hexokinase Specificity,'' Biochemical Journal, 128:199-204,
1972.
    4. Bessell, E. M. et al., ``Some In Vivo and In Vitro Antitumour
Effects of the Deoxyfluoro-D-glucopyranoses,'' European Journal of
Cancer, 9:463-470, 1973.
    5. Camici, P. et al., ``Increased Uptake of F-18 Fluoro-
deoxyglucose in Post-Ischemic Myocardium of Patients With Exercise-
Induced Angina,'' Circulation, 74:281-282, 1986.
    6. Camici, P., E. Ferrannini, and L. H. Opie, ``Myocardial
Metabolism in Ischemic Heart Disease: Basic Principles and
Application to Imaging by Positron Emission Tomography,'' Progress
in Cardiovascular Diseases, 32:217-238, 1989.
    7. Carr, R. et al., ``Detection of Lymphoma in Bone Marrow by
Whole-Body Positron Emission Tomography,'' Blood, 91:3340-3346,
1998.
    8. Clarke, K., and R. L. Veech, ``Metabolic Complexities in
Cardiac Imaging,'' Circulation, 91:2299-2301, 1995.
    9. Crane, P. D. et al., ``Kinetics of Transport and
Phosphorylation of 2-fluor-2-deoxy-D-glucose in Rat Brain,'' Journal
of Neurochemistry, 40:160-167, 1993.
    10. Dowd, M. T. et al., ``Radiation Dose to the Bladder Wall
From 2-[18F] Fluoro-2-deoxy-D-glucose in Adult Humans,'' Journal of
Nuclear Medicine, 32:707-712, 1991.
    11. Fuglsang, A., M. Lomholt, and A. Gjedde, ``Blood-Brain
Transfer of Glucose and Glucose Analogs in Newborn Rats,'' Journal
of Neurochemistry, 46:1417-1428, 1986.
    12. Gallagher, B. M. et al., ``<SUP>18</SUP>F-labeled 2-deoxy-2-
fluoro-D-glucose as a Radiopharmaceutical for Measuring Regional
Myocardial Glucose Metabolism In Vivo: Tissue Distribution and
Imaging Studies in Animals,'' Journal of Nuclear Medicine, 18:990-
996, 1977.
    13. Gallagher, B. M. et al., ``Metabolic Trapping as a Principle
of Radiopharmaceutical Design: Some Factors Responsible for the
Biodistribution of (18F) 2-Deoxyglucose,'' Journal of Nuclear
Medicine, 19:1154-1161, 1978.
    14. Gerber, B. L. et al., ``Myocardial Blood Flow, Glucose
Uptake, and Recruitment of Inotropic Reserve in Chronic Left
Ventricular Ischemic Dysfunction: Implications for the
Pathophysiology of Chronic Myocardial Hibernation,'' Circulation,
94:651-659, 1996.
    15. Gjedde, A., ``Glucose Metabolism,'' in Principles of Nuclear
Medicine (edited by H. Wagner, Z. Szabo, and J. W. Buchanan, 2d
ed.), W. B. Saunders Co., Philadelphia, 1995.
    16. Gough, A. L., and N. C. Keddie, ``An Assessment of the
Reproducibility and Safety of 2-deoxy-D-glucose as a Gastric Acid
Stimulant in Duodenal Ulcer Patients,'' Gut, 16:171-176, 1975.
    17. Gould, K. L. et al., ``Myocardial Metabolism of
Fluorodeoxyglucose Compared to Cell Membrane Integrity for the
Potassium Analogue Rubidium-82 for Assessing Infarct Size in Man by
PET,'' Science, 12:306-314, 1956.
    18. Gould, K. L., ``PET Perfusion Imaging and Nuclear
Cardiology,'' Journal of Nuclear Medicine, 32:579-606, 1991.
    19. Gropler, R. J., and S. R. Bergman, ``Myocardial Viability--
What Is the Definition?,'' Journal of Nuclear Medicine, 32:10-12,
1991.
    20. Hariharan, R. et al., ``Fundamental Limitations of
[<SUP>18</SUP>F]2-deoxy-2-fluoro-D-glucose for Assessing Myocardial
Glucose Uptake,'' Circulation, 91:2435-2444, 1995.
    21. International Commission on Radiological Protection, ICRP
Publication 53: Radiation Dose to Patients From
Radiopharmaceuticals, Pergamon Press, Oxford, England, 1988, pp. 75-
76.
    22. Jones, S. D. et al., ``The Radiation Dosimetry of 2-F-18
Fluoro-2-deoxy-D-glucose in Man,'' Journal of Nuclear Medicine,
23:613-617, 1982.
    23. Kanazawa, Y. et al., ``Metabolic Pathway of 2-Deoxy-2-
fluoro-D-glucose Studied by F-19 NMR,'' Life Sciences, 39:737-742,
1986.
    24. Kuwabara, H., A. C. Evans, and A. Gjedde, ``Michaelis-Menten
Constraints Improved Cerebral Glucose Metabolism and Regional Lumped
Constant Measurements With [18F]fluoro-deoxyglucose,'' Journal of
Cerebral Blood Flow Metabolism, 10:180-189, 1990.
    25. Kuwabara, H., and A. Gjedde, ``Measurements of Glucose
Phosphorylation With FDG and PET Are Not Reduced by
Dephosphorylation of FDG-6-phosphate,'' Journal of Nuclear Medicine,
32:692-698, 1991.
    26. Lowe, V. J. et al., ``Prospective Investigation of Positron
Emission Tomography in Lung Nodules,'' Journal of Clinical Oncology,
16:1075-1084, 1998.
    27. Mejia, A. A. et al., ``Absorbed Dose Estimates in Positron
Emission Tomography Studies Based on the Administration of 18F-
Labeled Radiopharmaceuticals,'' Journal of Radiation Research,
32:243-261, 1991.
    28. Phelp, M. E. et al., ``Tomographic Measurement of Local
Cerebral Glucose Metabolic Rate in Humans With (F-18)2-fluoro-2-
deoxy-D-glucose: Validation of Method,'' Annals of Neurology, 6:371-
388, 1979.
    29. Reivich, M. et al., ``The [<SUP>18</SUP>F]Fluorodeoxyglucose
Method for the Measurement of Local Cerebral Glucose Utilization in
Man,'' Circulation Research, 44:127-137, 1979.
    30. Schwaiger, M., and R. Hicks, ``The Clinical Role of
Metabolic Imaging of the Heart by Positron Emission Tomography,''
Journal of Nuclear Medicine, 32:565-578, 1991.
    31. Silverman, M., and J. Black, ``High Affinity Phlorizin,
Receptor Sites and Their Relation to the Glucose Transport Mechanism
in the Proximal Tubule of Dog Kidney,'' Biochim Biophys Acta,
394:10-30, 1975.
    32. Smith, T. A. D., ``FDG Uptake, Tumor Characteristics and
Response to Therapy,'' Nuclear Medicine Communication, 19:97-105,
1998.
    33. Sokoloff, L., ``[1-<SUP>14</SUP>C]-2-deoxy-D-glucose Method
for Measuring Local Cerebral Glucose Utilization: Mathematical
Analysis and Determination of the `Lumped' Constants,'' Neuroscience
Research Program Bulletin, 14:466-468, 1976.
    34. Sokoloff, L. et al., ``The [1-14C]-deoxyglucose Method for
the Measurement of Local Cerebral Glucose Utilization: Theory,
Procedure, and Normal Values in the Conscious and Anesthetized
Albino Rat,'' Journal of Neurochemistry, 28:897-916, 1977.
    35. Sols, A., and R. K. Crane, ``Substrate Specificity of Brain
Hexokinase,'' Journal of Biological Chemistry, 210:581-595, 1954.
    36. Suolinna, E. M. et al., ``Metabolism of 2-[18F]fluoro-2-
deoxyglucose in Tumor-Bearing Rats: Chromatographic and Enzymatic
Studies,'' International Journal of Radiation Applications and
Instrumentation, 5:577-581, 1986.
    37. Tewson, T. J., and K. A. Krohn, ``PET Radiopharmaceuticals:
State of the Art and Future Prospects,'' Seminars in Nuclear
Medicine, 3:221-234, 1998.
    38. The Methodist Medical Center of Illinois, Fludeoxyglucose
F18 Injection [18F] FDG Diagnostic--For Intravenous Administration,
NDA 61-636, Peoria, Illinois, 1991.
    39. Thomas, D. G., and H. L. Duthie, ``Use of 2 Deoxy-D-glucose
to Test for the Completeness of Surgical Vagotomy,'' Gut, 9:125-129,
1968.
    40. Van Holde, M., Biochemistry, Benjamin Publishing Co.,
Redwood City, California, 1990.

B. FDG F 18 Injection for Myocardial Hibernation

    41. Baer, F. M. et al., ``Predictive Value of Low Dose
Dobutamine Transesophageal Echocardiography and Fluorine-18
Fluorodeoxyglucose Positron Emission Tomography for Recovery of
Regional Left Ventricular Function After Successful

[[Page 13008]]

Revascularization,'' Journal of the American College of Cardiology,
28:60-69, 1996.
    42. Bax, J. J. et al., ``Accuracy of Currently Available
Techniques for Prediction of Functional Recovery After
Revascularization in Patients With Left Ventricular Dysfunction Due
to Chronic Coronary Artery Disease: Comparison of Pooled Data,''
Journal of the American College of Cardiology, 30:1451-1460, 1997.
    43. Bonow, R. O. et al., ``AHA Medical/Scientific Statement,
Special Report, Cardiac Positron Emission Tomography: A Report for
Health Professionals From the Committee on Advanced Cardiac Imaging
and Technology of the Council on Clinical Cardiology, American Heart
Association,'' Circulation, 84:447-454, 1991.
    44. Carrel, T. et al., ``Improvement of Severely Reduced Left
Ventricular Function After Surgical Revascularization in Patients
With Preoperative Myocardial Infarction,'' European Journal of
Cardio-Thoracic Surgery, 6:479-484, 1992.
    45. DepreAE1, C. et al., ``Correlation of Functional Recovery
With Myocardial Blood Flow, Glucose Uptake, and Morphologic Features
in Patients With Chronic Left Ventricular Ischemic Dysfunction
Undergoing Coronary Artery Bypass Grafting,'' Journal of Thoracic
Cardiovascular Surgery, 113:371-378, 1997.
    46. Di Carli, M. F. et al., ``Value of Metabolic Imaging With
Positron Emission Tomography for Evaluating Prognosis in Patients
With Coronary Artery Disease and Left Ventricular Dysfunction,''
American Journal of Cardiology, 73:527-533, 1994.
    47. Di Carli, M. F. et al., ``Quantitative Relation Between
Myocardial Viability and Improvement in Heart Failure Symptoms After
Revascularization in Patients With Ischemic Cardiomyopathy,''
Circulation, 92:3436-3444, 1995.
    48. Eitzman, D. et al., ``Clinical Outcome of Patients With
Advanced Coronary Artery Disease After Viability Studies With
Positron Emission Tomography,'' Journal of American College of
Cardiology, 20:559-565, 1992.
    49. Gerber, B. L. et al., ``Myocardial Blood Flow, Glucose
Uptake, and Recruitment of Inotropic Reserve in Chronic Left
Ventricular Ischemic Dysfunction: Implications for the
Pathophysiology of Chronic Myocardial Hibernation,'' Circulation,
94:651-659, 1996.
    50. Gropler, R. J. et al., ``Comparison of Carbon-11-Acetate
With Fluorine-18-Fludeoxyglucose for Delineating Viable Myocardium
by Positron Emission Tomography,'' Journal of the American College
of Cardiology, 22:1587-1597, 1993.
    51. International Commission on Radiological Protection,
``Radiation Dose to Patients From Radiopharmaceuticals,'' in ICRP
Publication 53, vol. 18, No. 1-4, Oxford Pergamon Press, New York,
1988.
    52. Jones, S. D. et al., ``The Radiation Dosimetry of 2-F-18
Fluoro-2-deoxy-D-glucose in Man,'' Journal of Nuclear Medicine,
23:613-617, 1982.
    53. Knuuti, M. J. et al., ``Myocardial Viability: Fluorine-18-
deoxyglucose Positron Emission Tomography in Prediction of Wall
Motion Recovery After Revascularization,'' American Heart Journal,
127:785-796, 1994.
    54. Louvain, B. et al., ``Predictive Value of FDG Imaging in 502
Patients With Chronic Ischaemic Left Ventricular Dysfunction
Enrolled in a Prospective European Multicentre Viability Study,''
Heart, 75(Supp. 1):P68, 1996.
    55. Lucignani, G. et al., ``Presurgical Identification of
Hibernating Myocardium by Combined Use of Technetium-99m Hexakis 2-
Methoxyisobutylisonitrile Single Photon Emission Tomography and
Fluorine-18 Fluoro-2-deoxy-D-glucose Positron Emission Tomography in
Patients With Coronary Artery Disease,'' European Journal of Nuclear
Medicine, 19:874-881, 1992.
    56. Maes, A. F. et al., ``Assessment of Myocardial Viability in
Chronic Coronary Artery Disease Using Technetium-99m Sestamibi
SPECT: Correlation With Histologic and Positron Emission Tomographic
Studies and Functional Follow-Up,'' Journal of the American College
of Cardiology, 29:62-68, 1997.
    57. Marwick, T. H. et al., ``Metabolic Responses of Hibernating
and Infarcted Myocardium to Revascularization: A Follow-Up Study of
Regional Perfusion, Function, and Metabolism,'' Circulation,
85:1347-1353, 1992.
    58. Marwick, T. H. et al., ``Prediction by Postexercise Fluoro-
18-deoxyglucose Positron Emission Tomography of Improvement in
Exercise Capacity After Revascularization,'' American Journal of
Cardiology, 69:854-859, 1992.
    59. O'Rourke, R. A. et al., ``Special Report: Guidelines for
Clinical Use of Cardiac Radionuclide Imaging: A Report of the
American College of Cardiology/American Heart Association Task Force
on Assessment of Cardiovascular Procedures (Subcommittee on Nuclear
Imaging),'' Journal of the American College of Cardiology, 8:1471-
1483, 1986.
    60. Schelbert, H. et al., ``Position Paper of the Cardiovascular
Council of the Society of Nuclear Medicine: Clinical Use of Cardiac
Positron Emission Tomography,'' Journal of Nuclear Medicine,
34:1385-1388, 1993.
    61. Silberstein, E. B., and the Pharmacopeia Committee of the
Society of Nuclear Medicine, ``Prevalence of Adverse Reactions to
Positron Emitting Radiopharmaceuticals in Nuclear Medicine,''
Journal of Nuclear Medicine, 39:2190-2192, 1998.
    62. Tamaki, N. et al., ``Positron Emission Tomography Using
Fluorine-18 Deoxyglucose in Evaluation of Coronary Artery Bypass
Grafting,'' American Journal of Cardiology, 64:860-865, 1989.
    63. Tamaki, N. et al., ``Prediction of Reversible Ischemia After
Revascularization: Perfusion and Metabolic Studies With Positron
Emission Tomography,'' Circulation, 91:1697-1705, 1995.
    64. Tielisch, J. et al., ``Reversibility of Cardiac Wall-Motion
Abnormalities Predicted by Positron Tomography,'' New England
Journal of Medicine, 314:884-888, 1986.
    65. Wijns, W. et al., ``Hibernating Myocardium,'' New England
Journal of Medicine, 339:173-181, 1998.

C. FDG F 18 Injection in Oncology

    66. Avril, N. et al., ``Metabolic Characterization of Breast
Tumors With Positron Emission Tomography Using F 18
Fluorodeoxyglucose,'' Journal of Clinical Oncology, 14:1848-1857,
1996.
    67. Bury, T. et al., ``Whole-Body 18-FDG Positron Emission
Tomography Staging of Non-Small Cell Lung Cancer,'' European
Respiratory Journal , 10:2529-2534, 1997.
    68. Carr, R. et al., ``Detection of Lymphoma in Bone Marrow by
Whole-Body Positron Emission Tomography,'' Blood, 91:3340-3346,
1998.
    69. Delbeke, D. et al., ``Evaluation of Benign vs. Malignant
Hepatic Lesions With Positron Emission Tomography,'' Archives of
Surgery, 133:510-516, 1998.
    70. Dietlein, M. et al., ``Fluorine-18 Fluorodeoxyglucose
Positron Emission Tomography and Iodine-131 Whole-Body Scintigraphy
in the Follow-Up of Differentiated Thyroid Cancer,'' European
Journal of Nuclear Medicine, 24:1342-1348, 1997.
    71. Friess, H. et al., ``Diagnosis of Pancreatic Cancer by 2[18-
F]-Fluoro-2-deoxy-D-glucose Positron Emission Tomography,'' Gut,
36:771-777, 1995.
    72. Gupta, N. C., J. Maloof, and E. Gunel, ``Probability of
Malignancy in Solitary Pulmonary Nodules Using Fluorine-18-FDG and
PET,'' Journal of Nuclear Medicine, 37:943-948, 1996.
    73. Holder, Jr., W. et al., ``Effectiveness of Positron Emission
Tomography for the Detection of Melanoma Metastases,'' Annals of
Surgery, 227:764-771, 1998.
    74. Lowe, V. J. et al., ``Semiquantitative and Visual Analysis
of FDG-PET Images in Pulmonary Abnormalities,'' Journal of Nuclear
Medicine, 35:1771-1776, 1994.
    75. Lowe, V. J. et al., ``Prospective Investigation of Positron
Emission Tomography in Lung Nodules,'' Journal of Clinical Oncology,
16:1075-1084, 1998.
    76. Meyer, G. J. et al., ``PET Radiopharmaceuticals in Europe:
Current Use and Data Relevant for the Formulation of Summaries of
Product Characteristics (SPCs),'' European Journal of Nuclear
Medicine, 22:1420-1432, 1995.
    77. Moog, F. et al., ``18-F-Fluorodeoxyglucose-Positron Emission
Tomography as a New Approach to Detect Lymphomatous Bone Marrow,''
Journal of Clinical Oncology, 16:603-609, 1998.
    78. Sazon, D. A. et al., ``Fluorodeoxyglucose-Positron Emission
Tomography in the Detection and Staging of Lung Cancer,'' American
Journal of Respiratory Critical Care Medicine, 153:417-421, 1996.
    79. Schiepers, C. et al., ``Contribution of PET in the Diagnosis
of Recurrent Colorectal Cancer: Comparison With Conventional
Imaging,'' European Journal of Surgical Oncology, 21:517-522, 1995.
    80. Silberstein, E. B., and the Pharmacopeia Committee of the
Society of Nuclear Medicine, ``Prevalence of Adverse Reactions to
Positron Emitting Radiopharmaceuticals in Nuclear Medicine,''
Journal of Nuclear Medicine, 39:2190-2192, 1998.
    81. Silberstein, E. B., J. Ryan, and the Pharmacopeia Committee
of the Society of Nuclear Medicine, ``Prevalence of Adverse
Reactions in Nuclear Medicine,'' Journal of Nuclear Medicine,
37:185-192, 1996.

[[Page 13009]]

    82. Utech, C., C. S. Young, and P. F. Winter, ``Prospective
Evaluation of Fluorine-18 Fluorodeoxyglucose Positron Emission
Tomography in Breast Cancer for Staging of the Axilla Related to
Surgery and Immunocytochemistry,'' European Journal of Nuclear
Medicine, 23:1588-1593, 1996.
    83. Valk, P. E. et al., ``Staging Non-Small Cell Lung Cancer by
Whole-Body Positron Emission Tomographic Imaging,'' Annals of
Thoracic Surgery, 60:1573-1582, 1995.
    84. Vansteenkiste, J. F. et al., ``Lymph Node Staging in Non-
Small Cell Lung Cancer With FDG-PET Scan: A Prospective Study of 690
Lymph Node Stations From 68 Patients,'' Journal of Clinical
Oncology, 16:2142-2149, 1998.

II. Published Literature on Ammonia N-13 Injection in Myocardial
Perfusion

    85. Beanlands, R. S. et al., ``Can Nitrogen-13 Ammonia Modelling
Define Myocardial Viability Independent of Fluorine-18
Fluorodeoxyglucose?'' Journal of American College of Cardiology,
29:537-43, 1997.
    86. Beanlands, R. S. et al., ``Noninvasive quantification of
regional myocardial flow reserve in patients with coronary
atherosclerosis using N-13 ammonia positron emission tomography,''
Journal of American College of Cardiology, 26:1465-75, 1995.
    87. Bormans, G. et al., ``Metabolism of Nitrogen-13 Labeled
Ammonia in Different Conditions on Dogs, Human Volunteers and
Transplant Patients,'' European Journal of Nuclear Medicine, 22:116-
121, 1995.
    88. Czernin, J. et al., ``Effects of Short-Term Cardiovascular
Conditioning and Low-Fat Diet on Myocardial Blood Flow and Flow
Reserve,'' Circulation, 92:197-204, 1995.
    89. De Jong, R. M. et al., ``Posterolateral Defect of the Normal
Human Heart Investigated With Nitrogen-13-Ammonia and Dynamic PET,''
Journal of Nuclear Medicine, 36:581-585, 1995.
    90. Demer, L. L. et al., ``Assessment of Coronary Artery Disease
Severity by PET: Comparison With Quantitative Arteriography in 193
Patients,'' Circulation, 79:825-35, 1989.
    91. Di Carli, M. F. et al., ``Myocardial Viability in Asynergic
Regions Subtended by Occluded-Coronary Arteries: Relation to the
Status of Collateral Flow in Patients With Chronic Coronary Artery
Disease,'' Journal of American College of Cardiology, 23:860-868,
1994.
    92. Di Carli, M. F. et al., ``Value of Metabolic Imaging With
Positron Emission Tomography for Evaluating Prognosis in Patients
With Coronary Artery Disease and Left Ventricular Dysfunction,''
American Journal of Cardiology, 73:527-33, 1994.
    93. Flannery, D. B., Y. E. Hsia, and B. Wolf, ``Current Status
of Hyperammonemic Syndrome,'' Hepatology, 2:495-506, 1982.
    94. Fudo, T. et al., ``F 18 Deoxyglucose and Stress N 13 Ammonia
Positron Emission Tomography in Anterior Wall Healed Myocardial
Infarction,'' American Journal of Cardiology, 61:1191-1197, 1988.
    95. Gelbard, A. S. et al., ``Imaging of the Human Heart After
Administration of L-(N 13) Glutamate,'' Journal of Nuclear Medicine,
21:988-991, 1980.
    96. Gewirtz, H. et al., ``Positron Emission Tomographic
Measurements of Absolute Regional Myocardial Blood Flow Permits
Identification of Nonviable Myocardium in Patients With Chronic
Myocardial Infarction,'' Journal of American College of Cardiology,
23:851-859, 1994.
    97. Gewirtz, H. et al., ``Quantitative PET Measurements of
Regional Myocardial Blood Flow: Observations in Humans With Ischemic
Heart Disease,'' Cardiology, 88:62-70, 1997.
    98. Gould, K. L. et al., ``A Noninvasive Assessment of Coronary
Stenoses by Myocardial Perfusion Imaging During Pharmacologic
Coronary Vasodilation: Clinical Feasibility of Positron Cardiac
Imaging Without a Cyclotron Using Generator-Produced Rubidium-82,''
Journal of American College of Cardiology, 7:775-789, 1986.
    99. Gould, K. L. et al., ``Short-Term Cholesterol Lowering
Decreases Size and Severity of Perfusion Abnormalities by Positron
Emission Tomography After Dipyridamole in Patients With Coronary
Artery Disease: A Potential Noninvasive Marker for Healing Coronary
Endothelium,'' Circulation, 89:1530-1538, 1994.
    100. Gould, K. L. et al., ``Changes in Myocardial Perfusion
Abnormalities by PET After Long-Term, Intense Risk Factor
Modification,'' Journal of American Medical Association, 274:894-
901, 1995.
    101. Grover-McKay, M. et al., ``Regional Myocardial Blood Flow
and Metabolism at Rest in Mildly Symptomatic Patients With
Hypertrophic Cardiomyopathy,'' Journal of American College of
Cardiology, 13:317-324, 1989.
    102. Haas, F. et al., ``Preoperative Positron Emission
Tomographic Viability Assessment and Perioperative and Postoperative
Risk in Patients With Advanced Ischemic Heart Disease,'' Journal of
American College of Cardiology, 30:1693-1700, 1997.
    103. Hutchins, G. D. et al., ``Noninvasive Quantification of
Regional Blood Flow in the Human Heart Using N 13 Ammonia and
Dynamic Positron Emission Tomographic Imaging,'' Journal of American
College of Cardiology, 15:1032-1042, 1990.
    104. International Commission on Radiological Protection, ICRP
Publication 53: Radiation Dose to Patients From
Radiopharmaceuticals, Pergamon Press, Oxford, England, 1988, pp. 61-
62.
    105. Konishi, Y. et al., ``Myocardial Positron Tomography With N
13 Ammonia in Assessment of Aortocoronary Bypass Surgery,'' Japanese
Circulation Journal, 52:411-416, 1988.
    106. Krivokapich, J. et al., ``Kinetic Characterization of
<SUP>13</SUP>NH<INF>3</INF> and <SUP>13</SUP>N Glutamine Metabolism
in Rabbit Heart,'' American Journal of Physiology, 246:H267-H273,
1984.
    107. Krivokapich, J. et al., ``13-N Ammonia Myocardial Imaging
at Rest and With Exercise in Normal Volunteers: Quantification of
Absolute Myocardial Perfusion With Dynamic Positron Emission
Tomography,'' Circulation, 80:1328-1337, 1989.
    108. Laubenbacher, C. et al., ``An Automated Analysis Program
for the Evaluation of Cardiac PET Studies: Initial Results in the
Detection and Localization of Coronary Artery Disease Using Nitrogen
13-Ammonia,'' Journal of Nuclear Medicine, 34:968-978, 1993.
    109. Lockwood, A. H. et al., ``The Dynamic Effects of Ammonia
Metabolism in Man,'' Journal of Clinical Investigation, 63:449-460,
1979.
    110. Lockwood, A. H., L. Bolomey, and F. Napoleon, ``Blood-Brain
Barrier to Ammonia in Humans,'' Journal of Cerebral Blood Flow
Metabolism, 4:516-522, 1984.
    111. Marshall, R. C. et al., ``Identification and
Differentiation of Resting Myocardial Ischemia and Infarction in Man
With Positron Computed Tomography, 18 F-Labeled Fluorodeoxyglucose
and N 13 Ammonia,'' Circulation, 67:766-778, 1983.
    112. The Merck Index (edited by S. Budavari, 11th ed.), Merck &
Co., Rahway, New Jersey, 1989.
    113. Meyer, G. J. et al., ``PET Radiopharmaceuticals in Europe:
Current Use and Data Relevant for the Formulation of Summaries of
Product Characteristics (SPCs),'' European Journal of Nuclear
Medicine, 22:1420-1432, 1995.
    114. Mody, F. V. et al., ``Differentiating Cardiomyopathy of
Coronary Artery Disease From Non-Ischemic Dilated Cardiomyopathy
Utilizing Positron Emission Tomography,'' Journal of American
College of Cardiology, 17:373-383, 1991.
    115. Muzik, O. et al., ``Validation of Nitrogen 13-Ammonia
Tracer Kinetic Model for Quantification of Myocardial Blood Flow
Using PET,'' Journal of Nuclear Medicine, 34:83-91, 1993.
    116. Muzik, O. et al., ``Assessment of Diagnostic Performance of
Quantitative Flow Measurements in Normal Subjects and Patients With
Angiographically Documented Coronary Artery Disease by Means of
Nitrogen 13 Ammonia and Positron Emission Tomography,'' Journal of
American College of Cardiology, 31:534-540, 1998.
    117. Niemeyer, M. G. et al., ``Nitrogen 13 Ammonia Perfusion
Imaging: Relation to Metabolic Imaging,'' American Heart Journal,
125:848-854, 1993.
    118. Nitzsche, E. U. et al., ``Quantification and Parametric
Imaging of Renal Cortical Blood Flow In Vivo Based on Patlack
Graphical Analysis,'' Kidney International, 44:985-996, 1993.
    119. Oxford Textbook of Clinical Hepatology (edited by N.
McIntyre et al.), Oxford University Press, Oxford, England, 1991.
    120. Rauch, B. et al., ``Kinetics of <SUP>13</SUP>N-Ammonia
Uptake in Myocardial Single Cells Indicating Potential Limitations
in Its Applicability as a Marker of Myocardial Blood Flow,''
Circulation, 71:387-393, 1985.
    121. Rosenspire, K. C. et al., ``Metabolic Fate of N 13 Ammonia
in Human and Canine Blood,'' Journal of Nuclear Medicine, 31:163-
167, 1990.
    122. Sambuceti, G. et al., ``Microvascular Dysfunction in
Collateral-Dependent Myocardium,'' Journal of American College of
Cardiology, 26:615-623, 1995.
    123. Schelbert, H. R. et al., ``N 13 Ammonia as an Indicator of
Myocardial Blood Flow,'' Circulation, 63:1259-1272, 1981.
    124. Schelbert, H. R. et al., ``Noninvasive Assessment of
Coronary Stenoses by Myocardial Imaging During Pharmacologic

[[Page 13010]]

Coronary Vasodilation,'' American Journal of Cardiology, 49:1197-
1207, 1982.
    125. Schwaiger, M., and O. Muzik, ``Assessment of Myocardial
Perfusion by Positron Emission Tomography,'' American Journal of
Cardiology, 67:35D-43D, 1991.
    126. Shah, A. et al., ``Measurement of Regional Myocardial Blood
Flow With N 13 Ammonia and Positron Emission Tomography in Intact
Dogs,'' Journal of American College of Cardiology, 5:92-100, 1985.
    127. Silberstein, E. B., J. Ryan, and the Pharmacopeia Committee
of the Society of Nuclear Medicine, ``Prevalence of Adverse
Reactions in Nuclear Medicine,'' Journal of Nuclear Medicine,
37:185-192, 1996.
    128. Silberstein, E. B., and the Pharmacopeia Committee of the
Society of Nuclear Medicine, ``Prevalence of Adverse Reactions to
Positron Emitting Radiopharmaceuticals in Nuclear Medicine,''
Journal of Nuclear Medicine, 39:2190-2192, 1998.
    129. Soufer, R. et al., ``Relationship Between Reverse
Redistribution on Planar Thallium Scintigraphy and Regional
Myocardial Viability: A Correlative PET Study,'' Journal of Nuclear
Medicine, 36:180-187, 1995.
    130. Storch-Becker, A., K. Kaiser, and L. E. Feinendegen,
``Cardiac Nuclear Medicine: Positron Emission Tomography in Clinical
Medicine,'' European Journal of Nuclear Medicine, 13:648-652, 1988.
    131. Tamaki, N. et al., ``Dynamic Positron Computed Tomography
of the Heart With a High Sensitivity Positron Camera and Nitrogen N
13 Ammonia,'' Journal of Nuclear Medicine, 26:567-575, 1985.

    Dated: March 6, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-5865 Filed 3-7-00; 11:42 am]
BILLING CODE 4160-01-F