(64)
In most cases the
inconsistencies represent findings that
were not
diagnosed or reported
by Searle. Copies of Searle's microscopic
pathology
reports for each of
the animals listed below are attached
as exhibit #60.
Female Rat No. F13CF
(Path. No. 95617)
Small Intestine -
Diverticulum with mucosal necrosis and
cellular inflammatory
infiltrate.
Female Rat No. F15CF
(Path No. 95618)
Pancreas - Focal hyperplasia
Female Rat No. F16CF
(Path No. 95619)
Heart - Focal Fibrosis.
Kidney - Mild chronic
nephritis.
Female Rat No. H10CF
(Path 95624)
Ovary - Neoplasm -
probably granulosa cell tumor.
Female Rat No. H19CF
(Path. No. 95626)
Kidney - Focal calcification.
Ovary - Neoplasm -
probably granulosa cell tumor.
Female Rat No. H30CF
(Path. No. 95628)
Kidney - Focal calcification.
Female Rat - No. K25CF
(Path No. 95630)
Kidney - Focal calcification.
Female Rat No. K29CF
(Path No. 95631)
Heart - Focal fibrosis
Kidney - Focal calcification
Female Rat No. M4CF
(Path No. 95632)
Liver - Focal hyperplasia
Female Rat No. M10CF
(Path No. 95634)
Kidney - Focal calcification.
Pituitary - Adenoma
Ovary - Fibrosis and
Pigmentation.
(65)
Female Rat No. M15CF
(Path No. 95635)
Pituitary - Adenoma.
Ovary - Cyst.
Female Rat No. B30CF
(Path No. 95801)
Kidney - Focal calcification.
Female Rat D29CF (Path
No. 95803)
Urinary Bladder (1)
Chronic diffuse inflammation.
(2) Diffuse mild hyperplasia.
The second phase of
the review consisted of the microscopic
examination of
all tissues from the
high dose females - a total of 36 animals.
The
inconsistencies are
listed below:
Female Rat No. B14HF
(Path. No. 95657)
Eye was reported as
not examined but eye was present and
normal.
Female Rat No. F25HF
(Path. No. 95823)
Urinary Bladder -
Mild diffuse hyperplasia.
Female Rat No. H7HF
(Path No. 95623)
Ovary - Neoplasm -
probably granulosa cell tumor.
Female Rat No. H9HF
(Path No. 95665)
Heart - Focal fibrosis.
Urinary Bladder -
Mild focal hyperplasia.
Female Rat No. H15HF
(Path No. 95665)
Lymph Node - The diagnosis
of lymphoma, benign, was present on
the Searle microscopic
report. According to Dr. Frith, lymphoma
is generally not considered
to be benign and he would diagnose
lympphosarcoma.
Female Rat NO. H18HF
(Path No. 95667)
Pituitary - Adenoma.
Brain - Mild bilateral
hydrocephalus.
Female Rat No. K18HF
(Path No. 95824)
Pituitary - Adenoma
Female Rat No. K24HF
(Path. No. 95671)
Mass noted grossly
- nothing consistent with mass reported
microscopically.
(66)
Female Rat No. - M2HF
(Path. No. 95672)
Uterus - Chronic mild
endometritis.
Female Rat No. M30HF
(Path. No. 95343)
Kidney - Focal calcification.
Uterus - Chronic mild
endometritis.
Female Rat No. M30HF
(Path. No. 95675)
Pancreas - Focal hyperplasia.
The third phase of
this review consisted of microscopic verification
of
all masses reported
grossly at necropsy from all female animals
not
examined in phases
1 and 2 and included a total of 73 animals.
The
inconsistencies are
listed below:
Female Rat No. D10Lf
(Path No. 92521)
Subcutaneous mass
was diagnosed as an angiofibroma on Searle
report. The lesion
is more consistent with an angiosarcoma.
Female Rat No. K9MF
(Path. No. 95707)
Uterus - Polyp.
Female Rat No. M1LF
(Path. No. 95844)
Tissue mass seen grossly
was reported as missing and not
available for microscopic
examination. The tissue was
present and was a
mammary fibroadenoma.
In summary, Dr. Frith
reviewed:
1) All 36 high dose
females (all slides) including 3 that
had
been excluded from
the study due to autolysis.
2) 36 (one-half) of
the control females (all slides) including
1 animal that had
been excluded from the study due to auto-
lysis.
3) Remaining 73 female
animals with grossly observed masses.
(sufficient slides
were reviewed to substantiate the masses)
4) 5 additional animals
selected by the investigators (A1HM,
A9HM, A29HM, C2CM,
C24HM).
(67)
The slides reviewed
in the first two categories above constituted
20% of
the total animals
on the study. Dr. Frith reviewed these
slides blindly
and then compared
his findings with the Searle microscopic
reports.
According to Dr. Frith,
his findings were in agreement with those
of
SEarle, for the most
part. In his opinion, some of the lesions
that he
reported as inconsistencies
were small, and might be considered
insignificant by some
pathologists. Dr. Frith did feel, however,
that the
ovarian neoplasms
(animals H10CF, H19CF, and H7HP, and chronic
cystitis
and diffuse hyperplasia
(animal D29CF) should have been reported.
Dr. Frith also considered
two other discrepancies to be significant.
They
were:
1) The reporting of
a mass (by Searle) as missing which was
actually present (MlLF).
2) The finding of
a polyp of the uterus which was not diagnosed
by Searle (K9MF)
The second of the
above two discrepancies assumes even more
significance
in view of the following:
The Histopathologic
Summary table (table 11) in Volume I of
the submission
to FDA lists the following
incidence of Uterine Polyps on page 87:
Incidence of Uterine
Polyps
Controls Low Medium
High
1 of 69 1 of 34 4
of 34 6 of 33
(1%) (3%) (12%) (18%)
The finding of one
additional uterine polyp by Dr. Frith
(in animal K9MF)
increases the incidence
in the mid dose to 5 of 34 (15%).
On page 82 of Volume
I of the submission to FDA, is the statement:
"other
sporadic findings
is included endometrial hyperplasia, polyp,
cyst,
congestion and squamous
metaplasia." The term "sporadic
findings" was
used to characterize
the incidence of uterine polyps, in spite
of the fact
that Searle had done
a statistical analysis of these findings.
