MEDICAL PRELIMINARY REVIEW

NDA: n.a

DRUG: O-15 water (H~2~^15^O) For Injection

ROUTE: Intravenous

IMAGING: Positron Emission Tomography (PET)

INDICATION: Cerebral Vascular Blood Flow Assessment

CATEGORY: Preparation for Medical Imaging Advisory Committee

SPONSOR: n.a.

COMPLETED: June 7, 1999

PDUFA: n.a.

FDAMA: Section 121 Related Initiative

PREPARED BY: P. Love, M.D., M.B.A.

BACKGROUND:

Positron Emission Tomography (PET) is a rapidly evolving imaging
technology used to evaluate a variety of diseases on the basis of their
functional, metabolic, biochemical or physiologic processes. PET imaging
involves radioactive drugs (radiopharmaceuticals) that contain positron
emitting radionuclides that are detected by appropriately designed
imaging devices that display dual photon emissions. Frequently the
colloquial term "tracer" is applied to radioactive drugs with the
following characteristics[^1]: 1) "the behavior \[of the drug\] is
identical to that of the natural compound or process", 2) "the mass \[of
the drug is\] small compared to the endogenous compound" (e.g., \<1%),
and 3) "any difference between the \[drug\] and the natural compound
\[are\] negligible." Oxygen- 15-water has evolved as such a compound. It
is a natural constituent of the blood and, at the capillary level,
diffuses quickly into the tissue. The rate of clearance and diffusion is
a function of the regional blood flow. Therefore, in clinical practice
O-15 water PET has become a method of assessing cerebral blood flow.
Typically, O-15 water is administered by intravenous injection.
Occasionally, it is administered as O-15 carbon monoxide inhalation. The
carbon monoxide is converted to water in the lungs by carbonic
anhydrase. However, the available data did not address the
characterization of the inhaled pro-drug nor did it provide information
on the bioequivalence of the two drugs. Therefore, this review focuses
on O-15 water by injection. The computerized imaging methods use either
a clearance or an equilibrium method to calculate the measures of
cerebral blood flow. The clearance method uses relatively standard
volume and time functions that can be used to calculate the flow rates.
The equilibrium method uses a constant infusion and formulas that
consider the steady state level and the radioactive decay.

FDAMA (Food and Drug Modernization Act) of 1997, Section 121 requires
the Food and Drug Administration to develop approval procedures for PET
drugs (under subsections (b) or (j) of section 505 (21 USC 355)). As
part of the development process, the FDA is reviewing the available
published literature on several commonly used PET drugs including O-15
water. It is anticipated that such a review could lead to approval of
O-15 water under section 505(b)(2) of the act (21 CFR 355(b)(2)).

CHEMISTRY

O-15 water is produced by a cyclotron after bombarding nitrogen gas with
deuterons. This is followed by a palladium catalyzed reduction of the
O-15 gas by hydrogen to produce water. Typically, O-15 water is diluted
in normal saline for injection. The chemistry and manufacturing controls
section is currently under development and will not be addressed at this
time.

PHARMACOLOGY-TOXICOLOGY

Typically, O-15 water radioactive dose ranges between 0.21 mCi/kg to 0.4
mCi/kg (15-28 mCi) in humans. In some studies, doses as high as 60 mCi
were reported. In clinical practice, dosing appears to vary with the
complexity of the study.

Toxicology studies were not reported. The typical radiochemical
impurities produced during the manufacture of O-15 water appear to be
N-13 and F-18. Excipients from any solvents, seals, etc. were not
included in the available literature. It is anticipated that the
excipients will vary with the individual manufacturing process. The
final assessment is apt to be application specific. To the extent
possible this can be addressed in the development of the chemistry,
manufacturing and controls section of the application.

Concept information was reviewed by Dr. Nakissa Sadrieh and revealed
that blood flow in general is validated in a cardiac model in mongrel
dogs. In vivo assessments in ligated coronaries correlated with
radiolabeled microspheres at 0.95. Microsphere validation was used in
earlier approvals of radiopharmaceuticals to evaluate cerebral vascular
perfusion.

CLINICAL PHARMACOLOGY

The physical half-life of O-15 is approximately 2.1 minutes. The dose of
water is substantially less than the total body water and it is expected
to behave as water in the body. Given the rapid physical decay, the
radioactivity diminishes in 15 minutes. Therefore, the radioactivity
risk is primarily to rapidly dividing tissues. The literature provides
radiation dosimetry information in newborns and infants. As per Dr.
Alfredo Sancho's Clinical Pharmacokinetics review, some information on
adult data was obtained from the International Commission on
Radiological Protection. More detailed data on adult dosimetry would be
useful for labeling.

CLINICAL - EFFICACY

The basis for the efficacy determination is derived from an assessment
of the published literature. These studies were not conducted with the
intent of seeking drug approval. A recent FDA publication on [Guidance
for Industry: Providing Clinical Evidence of Effectiveness for Human
Drug and Biologic Products]{.underline}, May 1998, page 19 describes
several principles on the use of published literature in establishing
efficacy. These principles include: 1) multiple studies conducted by
different investigators where each of the studies clearly has an
adequate design and where the findings across studies are consistent, 2)
the use of a prospective statistical plan, full accounting of the study
subjects; 3) a high level of detail in the published reports, including
clear and adequate descriptions of statistical plans, analytic methods
(prospectively determined), and study endpoints; 4) clearly appropriate
end points that can be objectively assessed, and are not dependent on
investigator judgement; and 5) robust results achieved by
protocol-specified analyses that yield a consistent conclusion of
efficacy and do not require selected post hoc analyses such as covariate
adjustment, subsetting or reduced data sets (e.g., analysis of only
responders or compliant patients, or of an "eligible" or "evaluable"
subset).

The literature for this review was obtained from USP listings and from a
reference list provided by the Institute for Clinical PET (ICP). The ICP
reference list is based on a Medline search of English language articles
published between 1966 and 1999.

The USP and ICP references identified a total of 82 articles that
appeared to involve O-15 water by injection. The articles were
subdivided into 6 neurologic areas: aneurysm, AV malformations,
epilepsy, meningiomas, presurgical localization, and stroke. Also, the
USP list contained two articles on cardiac imaging.

During the review, the articles were screened for inclusion as
potentially key studies that were apt to establish efficacy. An adequate
protocol design was considered to have at least the following
characteristics: 1) prospective development, 2) blinded image
interpretation, 3) adequate standard of truth, 4) clinically appropriate
control groups/imaging modalities, 5) described statistical plan, 6)
sample size of approximately 50 patients or more, or 7) more than 40
patients in a clinical outcomes study or special population study (e.g.,
pediatrics). The comparison to prospectively assessed long term clinical
outcomes and the study of special populations (e.g., pediatrics, disease
subpopulations) was also important. Other reviewed articles were
considered to support the functional, physiologic concept of cerebral
blood flow imaging.

On consideration of the 82 literature articles, 14 articles were not
directly relevant to the clinical review (7 did not study O-15 water by
injection, 1 discussed chemistry and manufacturing, 1 discussed
pharmacokinetics, and 5 discussed pharmacology studies). These articles
were considered by the respective disciplines. Also, 1 article was
available from the FDA library in abstract only. As shown in the
following table, of the remaining 75 clinical articles identified, the
majority were review articles, case/series reports, descriptive
methodology-feasibility reports, or research articles. These were
considered as supportive of the concept of O-15 water PET imaging. As
reflected in an earlier paragraph, for articles to be reviewed for
possible substantial support, the number of patients was greater than
50, or the articles involved \>40 patients in a clinical outcomes study
or in a difficult to study population. Two articles that studied 87 and
117 patients, and 2 articles that studied special population (e.g.,
pediatrics, rare disorder) were identified that provide either
substantial evidence or strongly supportive evidence for efficacy. These
articles along with a few representative conceptual supporting articles
are discussed in this review. A list of all references is attached to
the appendix of this review.

  -----------------------------------------------------------------------
  **Table 1: Results of Literature Search**

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

+-----------------------------------------------------------------+----+
| **Total Identified**                                            | ** |
|                                                                 | 82 |
|                                                                 | ** |
+-----------------------------------------------------------------+----+
| Did not use O-15 water                                          | 7  |
+-----------------------------------------------------------------+----+
| Chemistry, Manufacturing                                        | 1  |
+-----------------------------------------------------------------+----+
| Pharmacokinetics                                                | 1  |
+-----------------------------------------------------------------+----+
| Animal                                                          | 5  |
+-----------------------------------------------------------------+----+
| Abstracts (article pending from library)                        | 1  |
+-----------------------------------------------------------------+----+
| Duplicate articles                                              | 2  |
+-----------------------------------------------------------------+----+
| Review/summary articles[^2]                                     | 5  |
+-----------------------------------------------------------------+----+
| Case Reports                                                    | 18 |
+-----------------------------------------------------------------+----+
| Cardiac methodology / feasibility (33 patients)                 | 1  |
+-----------------------------------------------------------------+----+
| Cerebral Methodology / feasibility (\< 10 patients)             | 14 |
+-----------------------------------------------------------------+----+
| Cerebral Methodology / feasibility (11 - 29 patients)           | 19 |
+-----------------------------------------------------------------+----+
| Cerebral Usage feasibility / research into disease mechanisms;  | 3  |
|                                                                 |    |
| 30-39 patients                                                  |    |
+-----------------------------------------------------------------+----+
| **Cerebral Pediatric population (15; 49 patients)**             | *  |
|                                                                 | *2 |
|                                                                 | ** |
+-----------------------------------------------------------------+----+
| **Cerebral Clinical outcomes (40 - 50 patients)**               | *  |
|                                                                 | *1 |
|                                                                 | ** |
+-----------------------------------------------------------------+----+
| **Cerebral Clinical Outcomes (87; 117 patients)**               | *  |
|                                                                 | *2 |
|                                                                 | ** |
+-----------------------------------------------------------------+----+

Of the two cardiac imaging articles, one (Bergmann 1989, #A2) was a
pharmacologic study that evaluated dogs and 11 human subjects. (This is
included under the animal studies). The second article (Walsh 1988, \#
A14) evaluated 33 patients with coronary artery disease documented on
angiography. The article concluded that while O-15 water is freely
diffusible and should easily reflect blood flow, "severe limitations
must be considered" and the O-15 water results are "noisier than those
with ^13^NH~3~ or ^82^ Rb." They recommend further study to determine
the "sensitivity and specificity." Since other data are not available,
this review is limited to the neurologic indications.

REVIEWED ARTICLES:

Cerebral blood flow is considered to be a functional, physiologic
indication. As such it is consistent with the approaches discussed in
the agency's [Draft Guidance for Industry: Developing Medical Imaging
Drugs and Biologics]{.underline}, October, 1998, page 5. The principle
of assessing cerebral blood flow with radiopharmaceutical drug products
was established with in vivo comparisons to radiolabeled polystyrene
microspheres. Several radiopharmaceuticals are approved for the
evaluation of cerebral perfusion. The labeling, however, does not use
the term measurement. The O-15 water PET imaging techniques involve the
calculated measurement of cerebral perfusion. For this review, the
submitted articles typically presented information on the clinical
utility of measuring cerebral blood flow in several clinical disorders.
Most of these were ischemic disorders that arose from cerebral vascular
events. These will be discussed in section A below. Additionally,
several articles discussed the potential of O-15 water to enhance
existing diagnostic/disease monitoring modalities or to identify
functioning areas of the brain. These will be discussed in section B.
Within each section, the articles are listed by author, article
identifying information, and the reference list code in the parenthesis.

Overall, two studies are key to the efficacy assessment (Grubb et. al.,
1998 and D Powars. et. al., 1999). These are discussed respectively in
section A.1 and B.1 below. Three studies are supportive (Derdeyn, et.
al. 1998; Kuwabara, et. al. 1997, and Briere, et. al 1997). These are
presented respectively in sections A.2, A.3, and B.2 below. Also,
examples of 4 conceptually supportive articles are discussed. These are
W. Powers, et. al, 1989; Marchal et. al., 1993; and Viñas et. al., 1997;
and Duncan et. al., 1997. Each is discussed respectively in section A4,
A5, B3 and B4.

A. **CEREBRAL BLOOD FLOW MEASUREMENT: ISCHEMIC DISEASE**

**MODELS**

Approximately 55 articles discussed the use of O-15 water measurements
of cerebral blood flow in stroke, aneurysm, AVM or rare disorders such
as Moyamoya disease. Of these, two articles in stroke evaluated \> 50
patients.

**1. GRUBB, et. al. [Importance of Hemodynamic Factors in the Prognosis
of Symptomatic Carotid Occlusion,]{.underline} JAMA, 1998; 280 (12),
1055-60 \[Reference E1\]**

This study was a prospective, blinded assessment of the oxygen
extraction fraction measured by O-15 water PET imaging. The oxygen
extraction fraction is considered to be a risk factor for the occurrence
of a repeat stroke. Clinical outcomes were monitored for a mean of 31.5
months. Eligible patients were recruited from 15 local hospitals that
contributed 419 subjects for possible inclusion; 87 were enrolled. (The
remainder either refused or were not eligible). Also, 18 normal
volunteers were recruited from public advertisement. Gender or racial
demographics were not presented. Eligible patients had 1) contrast
angiographic evidence of occlusion of one or both common or internal
carotid arteries, or 2) "transient ischemic neurologic deficits" or
"mild to moderate permanent ischemic neurologic deficits in the
appropriate carotid artery territory." Initially, all inclusion criteria
had to be met within 120 days of PET imaging. The protocol was modified
to eliminate the time frame, and MR angiography or ultrasound were added
as other methods to demonstrate arterial occlusion. The exclusion
criteria eliminated patients with "non-atherosclerotic" causes of the
neurologic deficits and eliminated patients with pending cerebrovascular
surgery that might "alter the cerebral hemodynamics." After enrollment,
the presenting neurologic deficits were grouped as "cerebral transient
ischemic attacks (\< 24 hr duration), cerebral infarct (\> 24 hours),
retinal event (any duration), and as single or recurrent episodes."

Enrolled patients received a contrast CT to define infarct zones. Normal
volunteers received a MRI scan of the brain and ultrasound of the
carotid arteries. Normal was considered to be \< 50% occlusion by
angiography, MRA or ultrasound.

According to the Grubb article, the procedures used to measure the
oxygen extraction fraction were described by Mintun[^3]; however, only
the ratio of H~2~^15^O to O^15^O was reported in the results of the
Grubb article. PET images were obtained on the Siemens models 953B and
961 with attenuation with gallium 68 or germanium-68 rod sources. The
water/oxygen ratios were normalized to 0.40. Reportedly, the error in
the ratio is \< 5%. Supporting information was not included in the
article. PET abnormal areas that corresponded to infarct on CT or MRI
were excluded from the analysis.

OEF (oxygen extraction fraction) mean values for the middle cerebral
artery (MCA) region were calculated. The normal range was based on the
maximum and minimum values of the 18 normal volunteers. Blinded
categorization of the hemodynamic function was made based on the
following definitions: stage 0- normal CBF and normal OEF; stage 1 -
constant cerebral blood flow with increased cerebral blood volume
because of compensatory vasodilation and a normal left to right OEF
ratio; stage II - an increased OEF with left to right OEF ratio outside
the normal range. For analytic purposes, patients were divided into
those with or without stage II hemodynamic function.

Clinical follow-up of the patients was made by telephone every 6 months
to document such things as the onset of new symptoms (neurologic or
other medical), or a new functional condition. Monthly medical treatment
was recorded. If indicated, follow-up physical exams were done.

The primary endpoint was a "subsequent ischemic stroke with symptoms \>
24 hours in any cerebrovascular territory." The secondary endpoint was
"ipsilateral ischemic stroke and death."

Statistical analyses were completed with the Cox proportional hazards
model. Twenty variables[^4] were analyzed in a "univariate analysis."
All variables with p\<0.20 were included in a multivariate analysis,
those with \<0.05 were included in the final analysis. Only treatment
was considered as time dependent.

Results:

Of the 419 screened patients, 87 (21%) were enrolled and 81 (19%) (58
men, 23 women) completed the initial evaluation. The mean age of the
patients was approximately 65. The number of screened volunteers was not
reported; 18 volunteers (10 men, 8 women; mean age 45 years) were
recruited. This provided a total study population of 105 enrolled, 99
evaluated. The racial or ethnic demographics were not provided. The
disease demographics of the patients and the normal volunteers had
statistically significant differences in their history of neurologic
symptoms, the high density lipoprotein cholesterol level, and ongoing
medical treatment*. (Such differences are expected in a population of
patients and normal subjects).* Overall, 6 PET image sets were excluded:
4 because of poor technical quality and 2 because of large infarct size.
The presence of carotid occlusion was established by contrast
angiography in 75 patients, MRI in 6, and ultrasound in 2. The
proportion of patients who had PET imaging within the original protocol
time frame of 120 days was 60 (75%) patients, and 72 (90%) within 1 year
(i.e., an additional 12 patients had PET imaging between 120 and 365
days). None of the patients had a bilateral occlusion and 12 patients
had an endarterectomy before PET.

Of the 81 enrolled patients, 39 (48%) were defined as having stage II
hemodynamic abnormalities on the basis of the PET OEF values; 42 (52%)
with normal OEF were defined as hemodynamically normal. After 31.5
months (mean) follow-up 12/39 (31%) with abnormal OEF had a stroke, and
3/42 (7%) patients with normal OEF had a stroke (all strokes p = 0.005,
ipsilateral 0.004). Differences were similar regardless of hemisphere. A
subgroup analysis was reported for those patients who met the original
protocol inclusion criteria of PET imaging within 120 days. In these
patients the difference of stroke events was consistent at an increased
risk of all stroke (p=0.008) and ipsilateral stroke (p=-0.02) in
patients with stage II hemodynamic abnormalities.

In the univariate analysis (odds ratio), age and stage II hemodynamic
failure conferred independent risk. In an age adjusted relative risk
analysis, the result was 6 \[1.7 - 21.6\] for all; 7.3 \[1.6 - 33.4 \]
ispilateral stroke. Overall, during the follow-up period in each
subgroup, 6 patients died and 2 patients were censored apparently
because of large infarcts that invalidated the PET images. There were 16
patients that had retinal symptoms. (Because of the small number of
these patients, the clinical relevance of a subanalysis on this group
can not be determined.) Other demographic characteristics were described
in the report. While these are of interest for future studies of stroke
patients, they are less relevant to the efficacy assessment of O-15
water and will not be further discussed in this review.

*Assessment: This is a strong study that comprehensively presents the
results of a prospective, blinded read study of patients with documented
stroke. The protocol and its amendments are identified. All patients and
their disposition are identified. The prospective statistical analysis
is presented and appropriate subsets that reflect amendments are
presented. Dr. Mahbob Sobhan's (statistician) assessment is that the
method of analysis is "adequate to quantify the relative risk of stroke
associated with increased OEF measurements." However, the "validity and
generalization of normal range used to classify stage II patients were
not supported by other evidence." Additionally, the imaging point
results and clinical interpretations are correlated with long term
blinded follow up of the clinical outcomes. The study weaknesses are the
absence of an analysis of the racial or ethnic demographics and the
absence of a description of the adverse events monitoring during O-15
water imaging. Although racial or ethnic factors are not expected to
change the actual blood flow or oxygen extraction measurements, these
differences might affect the clinical outcome results. There is nothing
in the narrative to suggest an enrollment bias on the basis of race or
ethnicity.*

*Overall, this is considered an adequate and well controlled literature
study to describe a clinical setting in which O-15 water PET imaging has
benefit. Specifically, the benefit is in the assessment of flow and
metabolism in the objective determination of an oxygen extraction
fraction. Cerebral perfusion pressure (CPP), if normal, reflects a
balance between flow and metabolism. This balance is defined as stage 0.
In stage 1, with moderately decreased blood flow, the arteries dilate to
increase blood volume and compensate (autoregulation). In stage II,
there is a severe decrease in CPP and vasodilatation cannot compensate.
The CBF decreases and the OEF increases to maintain oxygenation. The
authors suggest that without the ability to compare the CBF and
metabolic measurements, differences in stage 0, 1 or 2 can not be
detected. PET studies of O-15 water and a metabolic marker would allow
such comparisons.*

*Additional hypotheses offered by the authors are that the
identification of hemodynamic changes is helpful in predicting the risk
for subsequent stroke. This suggestion needs further study.*

**2. DERDEYN, et al. [Increased Oxygen Extraction Fraction is Associated
with Prior Ischemic Events in Patients with Carotid
Occlusion,]{.underline} Stroke, 1998; 29, 754-758. \[Reference E2\]**

This article is from the same investigational group as the preceding
Grubb article. The basic protocol used similar methodology, PET imaging
cameras, and the same reference group of 18 normal subjects. Therefore,
the protocol will not be described again. For this study, the eligible
patients were prospectively enrolled from a population with symptomatic
and asymptotic carotid artery occlusions. The objective was to determine
if "baseline clinical, epidemiological or angiographic risk factors were
associated with the most severe category of hemodynamic compromise,
increased OEF." Eligible patients were part of a prospective
longitudinal blinded study. Whether this population included patients
enrolled in the Grubb article is not stated.

Results: A total of 117 patients were enrolled (86 men, 31 women, mean
age of 65 \" 8.8 years ). Of these 108 had carotid angiography that
revealed bilateral lesions in 3 patients, unilateral in 105.
Angiographic lesions were scored according to the most severe site and
recorded as \< or ≥50%. The PET imaging occurred on the day of
enrollment and within a mean of 66 days from the stroke event. The range
of time from the onset of the first stroke event to PET imaging was 0 to
4,745 days (13 years). The results of the outliers were not identified
clearly.

PET used O-15 water for CBF, O-15 oxygen inhalation for OEF, O-15 carbon
monoxide for cerebral blood volume measurements. The O-15 oxygen and
O-15 carbon monoxide will not be discussed in this review. The data
results were presented as a risk factor analysis that revealed the
asymptomatic history and cholesterol HDL levels as independent risk
factors. In addition, of the patients with abnormal (high) OEF, 39 (89%)
had a previous stroke (especially ispilateral); of the patients with a
normal OEF, 42 (57%) had previous stroke. The authors conclude that
future studies of stroke risk should consider that "asymptomatic
patients are less likely to have increased OEF" (i.e., stage II
hemodynamic changes).

*Assessment: This article used the same protocol as that in the Grubb
article; however, less detail is presented. The description is
acceptable because of the link to the Grubb article. Overall, the
article presents the results of academic research to identify subsets of
stroke patients with different risks. O-15 water (along with other PET
drugs) is used to detect functional and metabolic differences in blood
flow and oxygen extraction. While this study*

*does not present a clinical setting from which a patient will derive
immediate benefit, it does further document the ability of O-15 water to
measure cerebral blood flow. This article is considered supportive of
efficacy.*

**3. Kuwabara Y., [Response to Hypercapnia in Moyamoya Disease:
Cerebrovascular Response to Hypercapnia in Pediatric and Adult Patients
with Moyamoya Disease]{.underline}, Stroke, 1997; 28, 701-707.
\[Reference E5\]**

Moyamoya disease is a rare disorder of unknown etiology that is
associated with cerebral ischemic events[^5]. The authors state that
there are some differences in the clinical events in adult and pediatric
patients (i.e., adults have more cerebral hemorrhage, pediatric patients
have transient ischemic attacks). This article presented the results of
prospectively studied pre-operative evaluations with O-15 water PET
imaging measurements of the hemodynamics in 20 patients (13 adult and 7
pediatric) and 7 normal controls. Eligible patients were selected from
an earlier study of 52 subjects. In these 20 patients, both the adult
and pediatric patients had TIA like events and bilateral carotid artery
occlusion or stenosis on angiography. Whether these were the only
patients in the larger study with these characteristics was not stated.
PET images were obtained after O-15 water at 740 MBq bolus injection.
(Also, O-15 carbon monoxide was given by inhalation). The oxygen
extraction fraction was measured at steady state. Whether the images
were read blindly is not stated in the article.

Results: This research suggests that the hemodynamic reserve is
diminished in both age groups. The authors offer suggestions for
additional treatment studies.

*Assessment: This article describes the use of O-15 water to measure
cerebral blood flow. The study population is small; however, to some
extent this offset by the fact that this is an uncommon disorder. An
image interpretation bias and patient selection bias cannot be excluded.
Also, a clear clinical utility in this setting is not defined. This
article is considered supportive of the type of clinical research study
that can be accomplished by O-15 water (e.g., a study to elucidate
physiologic processes and possibly develop treatment regimens)*

4\. **POWERS W. et. al. [Influence of Cerebral Hemodynamics on Stroke
Risk: One Year Follow-up of 30 Medically Treated Patients]{.underline},
Ann Neurology 1989; 25, 325-330. \[Reference G14\]**

This is an early article that evaluated the potential relevance of the
hemodynamic responses to long term outcomes in stroke. Like the Grubb
and Derdeyn articles it assessed the results of O-15 water images in
patients with either 1) \> 75% carotid occlusions on angiography, or 2)
a transient ischemic attack or completed stroke. The study appears to be
a prospectively designed retrospective study of 30 patients who happened
to have PET images and had at least one year of follow-up information
from medical records, patient and family. Regions of abnormality were
based upon previous images from 17 abnormal control subjects.

Repeat PET imaging methods were similar to those of the Grubb and
Derdeyn articles; however, the patient's eyes and ears were not covered.
(The difference in ear or eye coverage might affect brain activity.)
Whether the repeat PET images were evaluated blindly was not stated in
the article. The primary outcome measure was the comparison of stroke
rates in patients with and without stage I and II hemodynamic
abnormalities. The control group was historical and was derived from the
EC/IC (extracranial/intracranial) Bypass Trial study (n=714). The null
hypothesis was that any stroke rate in patients with hemodynamic
abnormalities would be greater than that in the EC/IC bypass trial. This
study did not reject the null, and the authors concluded that they
"failed to demonstrate that medically treated patients with symptomatic
carotid artery disease who have evidence of cerebral hemodynamic
compromise are at higher risk for early stroke." Therefore, they
recommend against using O-15 water PET results for "prognostic forecasts
or therapeutic decisions in symptomatic" patients.

As*sessment: This is an early, retrospective study of 47 subjects. The
details of the data from the historic control trial were not described
in sufficient detail to allow a comprehensive assessment. Image
interpretation bias and patient selection bias cannot be excluded. The
article describes the use of O-15 water to measure cerebral blood flow.
As such, it is considered supportive of the concept, but it does not
define utility in a clinical setting. It is superseded by subsequent
studies.*

5\. **MARCHAL, G. et. al., [PET Imaging of Cerebral Perfusion and Oxygen
Consumption in Acute Ischaemic Stroke: Relation to Outcome]{.underline},
Lancet 1993; 341, 925-27.\[Reference G6\]**

This is a brief article that reports the results of a prospective
evaluation of perfusion and oxygen consumption (extraction) in 18
patients with their first middle cerebral artery stroke. Strokes were
less than 18 hours in duration and were not associated with hemorrhage.
PET images were taken with the equilibrium method for perfusion and
oxygen consumption parametric images. PET images were taken within an
average of 11 hours (5-18 range) after onset of the stroke. Three image
patterns were identified: 1) pattern I - "greatly reduced perfusion and
oxygen consumption over a larger cortical-subcortical area," 2) pattern
II - "moderate to larger perfusion reduction," a moderate to large
reduction in oxygen consumption or both, and 3) pattern III - increase
in perfusion without associated areas of reduced perfusion and either
normal or small areas of reduced oxygen consumption. Whether the images
were read blindly was not stated in the article.

Patients with pattern I had a poor neurologic course. Patients with
pattern II had a mixed neurologic course (1 died, 2 intermediate, 2 good
recovery), and patients with pattern III had good recovery. Despite the
small sample size, the sponsor reports a statistical significance of
p\<0.005. The authors feel the pattern of responses are consistent with
need to treat patients within 6 hours. Also, they suggest that PET
images might help predict the patient outcome.

*Assessment: This is a prospectively designed small research study that
revealed population differences on the basis of cerebral blood flow.
However, the existence of a bias in image handling cannot be assessed.
The ability to provide prognostic information needs confirmation in
larger studies. This study is considered supportive of the concept of
measuring cerebral blood flow and provides a clinical setting for
further study.*

Cerebral Blood Flow Assessment: The preceding articles on the
measurement of cerebral blood flow include one key study (Grubb) and one
that is supportive of efficacy (Derdeyn). The Kuwabara and Marchal
articles are supportive of the concept.

B. **MAPPING OF FUNCTIONAL AREAS OR AREAS AT RISK**

Within the epilepsy, stroke, aneurysm, AVM and meningioma articles,
there were approximately 15 that employed O-15 water PET imaging to
identify areas of the brain that were at risk of compromise from
progressive disease or at risk during surgical procedures. In these
settings, O-15 water was used in conjunction with other PET drugs, or
MRI co-registration. Of these, two studied patients for abnormalities
that might affect treatment decisions, 13 studied patients to identify
normal areas of the brain. Of the 13 articles, one was a duplicate, two
were summary reviews, four studied 10 - 15 patients, six studied 8
patients. Overall, the Powars 1999 study of sickle cell patients
(discussed in section B.1) is considered to be a key study. The Breier
1997 study of epilepsy is considered to be supportive (section B.2). The
two largest brain mapping studies of 12 and 15 patients (Viñas 1997 and
Duncan 1997) are discussed in section B3 and B4, respectively.

**1. POWARS D. et. al., [Cerebral Vasculopathy in Sickle Cell Anemia:
Diagnostic Contribution of Positron Emission Tomography]{.underline},
Blood, 1999; 93 (1), 71-79. \[Reference G 28\]**

Prospective evaluation of 49 pediatric patients with sickle cell anemia
and stroke. Eligible patients were diagnosed with sickle cell anemia by
current methodologies (hemoglobin electrophoresis, column chromatography
or molecular biology). Patients had either 1) overt cerebral vascular
accidents (category I), 2) previous "hypoxic illness requiring
hospitalization" or "soft signs" with poor fine motor coordination
(category II), or 3) were asymptomatic and without history of a
neurologic event (category III). The study excluded patients with head
trauma, severe brain damage or those who could not cooperate with
imaging. The study evaluated the additive benefit of MRI and PET imaging
to "improve the detection of cerebral vasculopathy" in these patients.
The overall goal is to develop an approach to identify patients at "high
risk for stroke or functional neurologic deficits."

O-15 water was given in a maximum total dose of 70 mCi. (The higher dose
suggests that this was an infusion equilibrium study. However, this was
not stated in the article.) PET imaging was completed with F-18 FDG to
evaluate glucose metabolic activity. (F-18 FDG is approved for the
identification of regions of abnormal glucose metabolism associated with
foci of epileptic seizures.) O-15 water imaging was completed to
evaluate microvascular blood flow. PET imaging was completed with a
Siemens 953 whole body scanner. The axial resolution was 10.4 cm; the in
plane resolution was 4 mm. The MRI was completed without contrast. PET
images were read blindly without knowledge of the clinical history,
physical exam or the MRI results.

The neuropsychiatric evaluation was completed with rest breaks. The
statistical analysis was completed with a χ^2^ test, and the between
group differences in FSIQ scores[^6] were tested in a multiple
comparisons analysis of variance with a Bonferoni adjustment.

Results: Overall the results of 49 patients (29M, 23 F) were reported.
The patients first onset of neurologic deficit was 1.8 to 16.3 years. At
enrollment these 49 patients were classified as category I - 19
patients, category II - 20 patients, and category III - 10 patients. Of
these, 36/49 (73%) had an abnormal PET image.

Of the 36 patients with abnormal PET images, 28 (78%) had decreased
perfusion and metabolism (i.e., abnormal O-15 water and abnormal F-18
FDG images). There was a trend towards a correlation of the extent of
the decrease with the clinical severity: category I - 16/17 (94%),
category II- 10/13 (77%), category - III 2/6 (33%).

Although a detailed patient by patient analysis was not presented, based
upon the narrative and tables in the article, the following table of
relationships can be compiled. This table presents the clinical
categories in comparison to the imaging results and the neuropsychiatric
testing results. The first column is the number of patients in each
clinical category. The second column shows the proportion of patients
who had abnormal FSIQ scores (note only 40 of the 49 patients were
tested). The third set of columns is the number of patients with
abnormal PET images (i.e., both abnormal O-15 water and abnormal FDG
images, only abnormal O15- water, or only abnormal FDG. The next column
shows the total of all abnormal PET images. The last column shows the
number of patients with abnormal MRIs. The percentages of each row are
the percent of patients in the clinical category (first column).

As shown in the table, regardless of category, more abnormalities were
noted on PET images than on MRI. MRI identified abnormalities in 22
(49%) of the 49 patients. PET identified abnormalities in 36 (73%) of
the patients. Of the 36 patients with abnormal PET images, 22 (49%) had
an abnormal MRI. Also, the combined information from both O-15 water and
FDG provided resulted in identifying more abnormalities than either
alone.

+--------------+----------+-------+------+-------+---------+---------+
| **Table 2:   |          |       |      |       |         |         |
| Comparison   |          |       |      |       |         |         |
| of Clinical  |          |       |      |       |         |         |
| Categories   |          |       |      |       |         |         |
| with         |          |       |      |       |         |         |
| Abnormal     |          |       |      |       |         |         |
| Intelligence |          |       |      |       |         |         |
| Test, PET    |          |       |      |       |         |         |
| Image, and   |          |       |      |       |         |         |
| MRI Image    |          |       |      |       |         |         |
| Results\***  |          |       |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **Categories | **FSIQ   | **Abn |      |       | **Total | **Total |
| (n=49)**     | \< 100** | ormal |      |       | A       | A       |
|              |          | PET** |      |       | bnormal | bnormal |
|              | **N =    |       |      |       | PET**   | MRI**   |
|              | 40**     |       |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
|              |          | *     | *    | **    |         |         |
|              |          | *H~2~ | *H~2 | FDG** |         |         |
|              |          | ^15^O | ~^15 |       |         |         |
|              |          | &     | ^O** |       |         |         |
|              |          | FDG** |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **Cat I -    | *        | *     | *    | **1   | **17/19 | **15/19 |
| CVA**        | *14/15** | *16** | *0** | (0.   | (89%)** | (79%)** |
|              |          |       |      | 5%)** |         |         |
| **N=19**     | *        | **(8  |      |       |         |         |
|              | *(93%)** | 4%)** |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **Cat II -   | *        | *     | *    | **3   | **13/20 | **6/19  |
| Soft signs   | *15/16** | *10** | *0** | (1    | (65%)** | (30%)** |
| N=20**       |          |       |      | 5%)** |         |         |
|              | *        | **(5  |      |       |         |         |
|              | *(94%)** | 0%)** |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **Cat III    | **4/9**  | **2** | **2  | **2   | **6/10  | **1/10  |
| -Normal**    |          |       | (20  | (2    | (60%)** | (10%)** |
|              | *        | **(2  | %)** | 0%)** |         |         |
| **n=10**     | *(44%)** | 0%)** |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **Totals**   | *        | **    | **   | *     | **36/49 | **22/49 |
|              | *33/40** | 28/49 | 2/49 | *6/49 | (73%)** | (49%)** |
| **N=49**     |          | (5    | (4   | (1    |         |         |
|              | *        | 7%)** | %)** | 2%)** |         |         |
|              | *(82%)** |       |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+
| **\*Derived  |          |       |      |       |         |         |
| from article |          |       |      |       |         |         |
| tables 1, 2, |          |       |      |       |         |         |
| and text.**  |          |       |      |       |         |         |
+--------------+----------+-------+------+-------+---------+---------+

A definitive statement of what is considered the standard of truth
(e.g., pathologic diagnosis or a clinical diagnosis) was not made in
this article. However, some of the correlations with the intelligence
testing results suggest that these might be considered as clinical
standard of truth. The neuropsychiatric testing was completed in 40
patients. Any FSIQ score \< 100 was considered abnormal. In the tested
patients across the 3 categories, the mean results were similar and had
a wide standard deviation. However, there was a smaller number of
patients with abnormal scores in category III (asymptomatic) patients
(49%) than in the other two categories (93 and 94% for categories I and
II respectively). The article did not present data on other correlates
(education, age and other controls) that might affect intelligence
scores and subset results to compare the PET and MRI results in patients
with IQ scores were not presented. Therefore, a complete assessment of
the relationship to IQ scores cannot be made. Only a trend can be
identified.

The article also presented data that suggest that abnormal PET images
correlate more with abnormalities of gray matter on MRI. (See table 3).
The data suggest that if a gray matter lesion exists (rows 2 and 4),
then an abnormal PET image correlates at 80 to 91.7%. The white matter
lesions only had a correlation of 53%. The article did not present the
correlations for FDG or O15 water alone. *Therefore, these data do not
contribute to the water assessment of this review.*

  -----------------------------------------------------------------------
  Table 3: PET Results Compared to Gray or White Matter Abnormalities on
  MRI.\*

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

  -------------------------------------- --------------------------------
  MRI Results                            FDG or O-15 water

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

+-------------------------------------+----------------+---------------+
|                                     | Normal         | Abnormal      |
|                                     |                | (n=36)        |
|                                     | (n=13)         |               |
+-------------------------------------+----------------+---------------+
| Normal Gray + white (n=19)          | 5 (38%)        | 14 (73.7%)    |
+-------------------------------------+----------------+---------------+
| Abnormal Gray (n=5)                 | 1 (7%)         | 4 (80%)       |
+-------------------------------------+----------------+---------------+
| Abnormal white (n=13)               | 6 (5%)         | 7 (53.8)      |
+-------------------------------------+----------------+---------------+
| Abnormal Gray + white (N=12)        | 1 (7%)         | 11 (91.7%)    |
+-------------------------------------+----------------+---------------+

  -----------------------------------------------------------------------
  \*Derived from article table 3

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

Among other things, the authors presented several observations: Two
asymptomatic patients with abnormal PET had CVA during the study period.
Four patients with abnormal PET were treated with blood transfusions and
had improved metabolic activity. They suggest that O-15 water plus FDG
PET can detect neurophysiologic deficits not seen on MRI. Also, they
recommend a clinical outcomes study on therapeutic interventions that
might be appropriate when abnormalities are identified (e.g., aggressive
transfusions).

*Assessment: This is a prospectively designed, blindly read evaluation
of a difficult to study population. The clinical protocol and method of
analysis are described. The major weakness is the lack of clear
identification of the clinical standard of truth. In addition, the
incomplete comparison to the intelligence scores could overestimate the
correlations. Overall, the results indicate that the combined use of
O-15 water in conjunction with F-18 FDG identified functional neurologic
abnormalities that were not identified by MRI. The use of both PET and
MRI appears to provide clinically useful information in this population
of pediatric patients with sickle cell disease. The differential uptake
in white and gray matter is consistent with other articles that suggest
that O-15 water assessments are better in gray matter. The study
describes a clinical setting with anticipated direct benefit to the
individual patient. As such it is considered to be a key study (with
some deficiencies) in the overall assessment of the clinical usefulness
of the function assessment of cerebral blood flow with O-15 water to
identify areas of the brain that are at risk from progressive disease.
Exactly how the information will be used is strongly suggested, but it
is not confirmed.*

**2. BREIER, J. et. al, [Effects of Duration of Epilepsy on the
Uncoupling of Metabolism and Blood Flow in Complex Partial
Seizures]{.underline}, Neurology, 1997; 48, 1047-1053. \[Reference
D2\]**

This study evaluated the prospective results of F-18 FDG and O-15 water
PET images in 16 control subjects without CNS disorders and 34
consecutive patients with intractable complex partial seizures (CPS)
that were pending temporal lobectomy; (total N = 50). Clinical
evaluations of the CPS patients included 24 hour EEG (via video
telemetry), neuropsychiatric testing, MRI, SPECT imaging, sodium
amobarbital for lateralization of language and memory area, cerebral
arteriography. Exclusion criteria included movement during scanning,
seizure during scanning, structural lesions, head injury, and FSIQ[^7]
of ≤ 69. PET imaging was performed with O-15 water and F18-FDG. Images
were obtained with a TOFPET I camera and POSICAM 6.5 camera. The primary
outcome measure and statistical plan were not stated; however, the study
reported the observational differences between the asymmetry index and
the duration of the seizure disorder. A standard of truth was not
identified.

PET image analysis evaluated the mesial and lateral temporal lobes with
transaxial regions of interest. Asymmetry in the hemispheres was based
upon pixel counts using the formula "(right-left)/(right + left)\*2."
The regions of interest were identified blindly. The statistical plan
was not described.

Results: There was a statistically significant correlation between the
degree of asymmetry and the duration of symptoms since the first seizure
onset (p\<0.0001). (See figures from the article on page 16). Although
the difference was somewhat greater if the first seizure was on the left
side, the significance held regardless of the hemisphere of origin. The
correlation with glucose metabolism was somewhat greater than the
correlation with blood flow. Other demographic factors were not
significant. The intelligence test results were not presented.

(See figures on the next page

Using F-18 FDG and O-15 water to assess importance of hemispheric
asymmetries, the authors determined that the duration of seizure
disorders might influence the interpretation of the asymmetries and how
to determine the surgical field. They suggest that PET, especially O-15
water, might not be of value in short duration seizure disorders, but
could be of value in patients with longer duration of seizures

*Assessment: This is a prospectively designed, blindly read study of
patients and control subjects. A statistical plan is not described
(e.g., what difference in asymmetry is the null hypothesis, at what
significance level). The study reports descriptive results that are
supportive of the type of data and the potential impact the research
will have on long term treatment planning for patients with seizure
disorders. The use of O-15 water with F18-FDG is suggested, however, the
clinical utility is not defined fully. This article is supportive of the
concept of using cerebral blood flow measurements to identify abnormal
areas that might be surgically evaluated**.***

**3. VIÑAS, et al. [\[^15^O\]-Water PET and Intraoperative Brain
Mapping: A Comparison in the Localization of Eloquent
Cortex]{.underline}., Neurological Research, 1997; 19, 601- 607. \[Ref
C9\]**

This is a small prospective clinical usage study of 18 patients who
required surgical resection of brain lesions. All patients had an O-15
water PET scan before surgery. Surgery was an MRI or CT image guided
craniotomy with intra-operative electrical stimulation to map areas of
language, vision, cognitive tasks or fine motor function. For surgery,
the PET and MRI scans were co-registered clinically. For analysis, the
results of the intraoperative functional map were compared to the
pre-operative PET image. Whether this step was blinded is not clearly
stated in the article.

The PET images were obtained with O-15 water in radioactive doses of 25
mCi per image in adults and 0.357 mCi/kg in pediatric patients
administered over 20 seconds. For both adults and children the O-15
water was diluted in 6 ml of normal saline. The PET image data were
analyzed by an automated package. The article contained detailed
information on the computerized PET and MRI image collection and
co-registration process. It appears to be adequate and will not be
discussed in this review. Approximately 10 image sets were obtained
(five tasks, each repeated twice). Repeat scans were separated by at
least 10 minutes. The tasks were "resting (with eyes closed and
covered); opposing finger-thumb movement of right/left hand; listening
to 10 short sentences; listening and immediate repetition of 8 sentences
of similar type; and stimulation of right/left visual half-field by
means of simple geometric objects displayed on the right/left of a
fixation cross on a computer monitor, which is positioned in the
patient's field of view."

Results: The study population consisted of 18 patients (12 women, 6 men)
with a mean age of 36.3 years (range 8 - 74). Of these patients, 15 were
studied for localization of language and 5 for localization of motor
function areas (apparently 2 patients had more than one area). Except
for one patient with an AV malformation, all patients had brain tumors.
In all 5 patients with motor function stimulation, the PET and MRI
images were concordant (especially in the gray matter). The white matter
fibers did not co-register. For language all areas were concordant. In
addition, the one patient that had visual stimulation that was
concordant. In all patients, the image guided surgical techniques were
able to minimize neurologic damage. Three case examples were given to
demonstrate the positive clinical outcomes.

The authors concluded that O-15 water PET is useful to preoperatively
identify gray matter functional areas of the motor, language and visual
cortex; and, therefore, is useful in planning surgery near these areas.
MRI intraoperative mapping is their choice for identifying white matter
lesions.

*Assessment: This is a small study that describes a useful clinical
setting for O-15 water in identifying healthy functioning areas of the
brain. MRI functional intraoperative mapping and clinical post-operative
outcomes are the clinical standard of truth. The weakness is that the
study is very small and image reading bias cannot be excluded, and a
statistical plan with primary outcome measures is not provided. This
study is considered supportive of the concept of O-15 water assessments
of cerebral blood flow to identify normally functioning areas of the
brain.*

**4. Duncan, et. al., [Use of Positron Emission Tomography for
Presurgical Localizaton of Eloquent Brain Areas in Children with
Seizures]{.underline}., Pediatric Neurosurgery, 1997; 26, 144-156.
\[Reference D1\]**

This appears to be a prospectively designed retrospective analysis of 16
pediatric patients to "test the hypothesis that PET activation optimizes
presurgical evaluation in children with seizure." The patients" charts
had presurgical evaluation with PET imaging and MRI of the brain. The
images were co-registered with a three dimensional automated process.
O-15 water PET images were obtained after 25-50 mCi were injected.
Repeat image sets were obtained at 10-15 minute intervals. Task
activities focused on language as the visualization of written words,
speaking written words (or pictures), and responding to a simple
question about the word or picture. Statistical methods were not noted,
but the report was descriptive.

Results: Fifteen children (10 male, 6 female) with a mean age of 11
years (range 2.9 - 19 years). The cause of seizures included tumor,
encephalitis, infarction, and rarer disorders. Co-registration produced
concordance between the PET and MR anatomic locations in 15/16 patients.
(In one patient mapping was not competed because of seizures and low
intellect.) The information on the functional areas affected surgical
plans by causing a change in the operative approach, guiding surgery, or
choosing a medical treatment instead of surgery.

The authors conclude that O-15 water is able to identify task activated
portions of the brain on the basis of increased blood. This information
can be obtained in cooperative pediatric patients and can be used to
guide surgical decisions.

*Assessment: Because this is a pediatric population clinical usage
study, it has increased importance. However, this is a retrospective
analysis and the article does not exclude selection bias nor image
reading bias. Furthermore, the analytic approach to test the authors'
hypothesis is not stated. This is considered supportive of the concept
of identifying normally functioning brain areas.*

Functional Imaging Assessment: These set of articles describes several
settings where O-15 water cerebral blood flow measurements are used in
conjunction with other imaging modalities to identify areas of the brain
that are functioning normally and are at risk from progressive disease
or surgical intervention. The Powars article in sickle cell anemia
patients is considered as a key study. The other collective set of
articles are considered to be supportive; however, over the period of
years there are ongoing clinical controversies on how the data are to be
best used in clinical management of seizures. The brain mapping of
normal areas for use in pre-operative planning is an emerging science.
Although other data might be available, the submitted materials did not
include information to validate the task techniques or to confirm the
false positive and false negative rates. Since the disease specific
therapies are not the purview of this review, these issues will not be
addressed further.

SAFETY:

None of the identified articles systematically reported the results of
the safe use of O-15 water. Typically, the studies did not report a
specific safety monitoring plan nor the results of monitoring. O-15
water was not included in a recent review article on the safety of
radiopharmaceuticals[^8] and O-15 water does not contain a ligand.
Instead it is essentially radioactive water. The water itself is not
expected to be toxic. Therefore, the safety is primarily a function of
the radioactive dose and any manufacturing exipients or impurities. The
latter could be analyzed on an application specific basis. The radiation
risk is expected to diminish in 15 minutes. Adult radiation dosimetry
data were not available in the submitted literature.

**OVERALL SAFETY and EFFICACY ASSESSMENT:**

PET O-15 water literature studies published from 1983 to 1999 were
reviewed to establish the efficacy in measuring cerebral blood flow.
These included a variety of small articles that covered the spectrum of
ischemic abnormalities (secondary to stroke, aneurysms, sickle cell or
unusual disorders) to presurgical evaluations and brain mapping, to
series reports of clinical usage studies. All of the pathologic
disorders in which it is used have the common denominator of cerebral
vascular abnormalities that result in decreased cerebral blood flow and
are associated with abnormal neurologic sequelae. Thus, the underlying
use of O-15 water is to measure cerebral blood flow. How the CBF
measurement is used in conjunction with other medical information
varies. In some cases the results are mapped against approved

agents (F-18 FDG or MR) and in other cases against other PET agents
(O-15-oxygen and O-15-carbon dioxide).

Of the specific articles, there are three literature references that are
considered to have adequate and well-controlled protocol designs. These
are the Grubb, Derdeyn and D. Powars articles. All three are
prospectively designed, blinded studies of approximately 50 or more
patients. The protocol and statistical analytic methods are described,
and the disposition of all patients is reasonably stated. Each of these
articles has some limitations (e.g., full generalization to all
subgroups studied is not sufficiently supported (Grubb); limited details
reported (Derdeyn); incomplete presentation of all correlations; and
lack of a clearly identified standard of truth (D. Powars)). However,
collectively these articles are sufficient to document the use of O-15
water to measure cerebral blood flow. The other articles discussed in
this review possess at least one of the following weaknesses: not
prospectively designed, not blinded, lack of a statistical plan, lack of
identified primary outcome variables, or insufficient sample size.

On the basis of the Grubb, Derdeyn and Powars articles O-15 water is
demonstrated to be effective in measuring cerebral blood flow. The first
two articles studied the use of the CBF measurement in an ischemic
stroke model. The Powars article reported the results in sickle cell
patients with cognitive deficits that presumably developed after
repeated sickle cell related ischemic insults.

The other supportive articles were consistent in their description of
the cerebral blood measurements. Most of these articles are small and
describe research or academic evaluations of the mechanisms of disease
and other disease or evaluation models. Several conclude that more
studies are needed to determine how the imaging results will affect the
treatment of the various diseases. Therefore, disease specificity is not
clearly demonstrated in all cases.

The brain mapping articles describe how O-15 water might be used to
detect normally functioning areas of the brain that could be used during
surgical procedures. These studies report clinical outcomes after using
the mapping studies with cognitive and motor tasks, Although to some
extent, the brain mapping findings appear to be intuitively obvious,
these studies are small. Also, the studies do not contain information on
the reproducibility of the task results and do not contain information
on the false positive or false negative rates.

Therefore, in the provided literature categories there are limited data
to support definitive disease specific or patient management
indications. Instead, the data support a functional, physiologic
indication in a variety of cerebrovascular disorders that are associated
with blood flow abnormalities. The cerebral blood flow data are useful
in identify hemodynamic abnormalities associated with a variety of
diseases and in identifying functioning areas of the brain that might at
risk.

A functional indication for O-15 water is consistent with indications
for other radiopharmaceuticals that are approved for the assessment of
CBF. These radiopharmaceutical approvals document the value of the
functional, physiologic assessment of a wide variety of disorders. PET
imaging with O-15 water goes a step further and measures the actual
blood flow. These measurements in conjunction with other PET drugs
(e.g., FDG) appears increase the value of a CBF measurement alone.
Additionally, O-15 water with/without FDG appears to enhance the
information provided by anatomic imaging with MRI.

Prior to approval additional useful information would be the following:

• Radiation dosimetry in adults

• Chemistry data on exipients and impurities

Preliminary Indication:

> "O15 water is indicated for use in positron emission tomography (PET)
> imaging to measure cerebral blood flow in patients with cerebral
> vascular disorders associated with ischemia, hemodynamic
> abnormalities, occlusion, and other vascular abnormalities."

[^1]: Phelps, M. Ph.D., "Positron Emission Tomography (PET)", in
    [Clinical Brain Imaging: Principles & Applications.]{.underline},
    Ed. Mazziotta, J & Gilman S., Pub F.A. Davis Company, 1992; Chapter
    3, p91. (paraphrased)

[^2]: ^2^One article presented the clinical outcome of 130 patients who
    received radiosurgery for intracranial vascular disorders; however,
    only 2 patients had PET imaging and that was with ^82^Rubidium.
    015-Water was not used. \[Reference \# C11\]

[^3]: ^3^Mintun, MA et.al., [Brain Oxygen Utilization Measured with O-15
    Radiotracers and Positron Emission Tomography]{.underline}, J
    nuclear Medicine 1984; 25: 177-187.

[^4]: The variables included age, sex, prior infarction, recurrent
    symptoms, number of days between last symptom and PET, contralateral
    carotid stenosis ≥ 50%, hypertension, prior myocardial infarction,
    diabetes mellitus, cigarette smoking, alcohol, parental death from
    stroke, hemoglobin, fibrinogen, HDL cholesterol, LDL, TG levels,
    length of warfarin or no warfarin, length of treatment or no
    treatment, Stage II hemodynamics on PET.

[^5]: Reportedly, patients have stenosis of the internal carotid.

[^6]: FSIQ = Full Scale IQ score on Wechsler Adult Intelligence Scale
    Revised (WAIS-R)

[^7]: ^6^ FSIQ = Full Scale IQ score on Wechsler Adult Intelligence
    Scale Revised (WAIS-R)

[^8]: Silberstsein, et al., [Prevalence of Adverse Reactions in Nuclear
    Medicine]{.underline}, J. Nuclear Medicine, 1996; 37, 185-192.