[Federal Register Volume 65, Number 48 (Friday, March 10, 2000)]
[Notices]
[Pages 12999-13010]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-5865]


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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Register, FDA is issuing a draft guidance for industry entitled ``PET 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: [email protected].

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., ``18F-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 
[18F]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 [18F]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., ``[1-14C]-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 
13NH3 and 13N 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 13N-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