FDA report on Searle's submission for NutraSweet approval 1977 - Part 20

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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.




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



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



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





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-



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).




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



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.


Continue to Part 21


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