FDA report on Searle's submission for NutraSweet approval 1977 - Part 2

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6) No reserve samples of any of the lots of DKP used in this study

were retained by Searle.


7) Three different sets of specifications for DKP were found, and

Searle could not determine with any degree of certainty which

of the three were applicable to the 7 lots of DKP used in the



8) The analytical records for DKP lots IR through 5R refer to

reference standard IR #3701. None of the three sets of DKP

specifications lists reference #3701. No data was made avail-

able as to dates, methods of preparation and authentication

of DKP reference standards.


9) Analytical records A-9129 for DKP lot 5R showed an assay of

1000%. Examination of laboratory notebooks showed

that eleven (11) samples had been analyzed from this lot, and

the analytical record only reflected an average of the last

three of theses. The other assays (not reported) ranged from

87.93% to 114.83%.


C. Dosage, Body Weight and Food Consumption


1) Examination of the raw data sheets revealed the following



a. Empty feed cup weights were missing for the D hous-

ing group at the 12th week, in the raw data sheets. (See

exhibit #75.)


b. In several instances, the dietary concentration shown

on the weight sheets did not agree with the concentra-

tion listed for the same level in the other housing

groups. (For example; C group Males, mid & high levels

for week 13,; A group Males, high levels for week 99.)


2) Comparison of the Searle submission and the independent FDA

analysis of the raw body weight and food consumption data

revealed the following discrepancies:


a. We found a total of 15 differences of 1 gram or more in

the average body weight and of 0.1 percentage points

or more in weight gain. (See table 1.)




b. We found approximately 82 discrepancies of one gram or

or more in the food intake when expressed in grams/day.

(See table 2.)


c. We found approximately 40 errors of 5 or more grams in

food intake when expressed in grams/kg./day. (See

table 2.)


d. Most of our dosage calculations differed from Searle's

dosage calculations by 10 or more mg., when the dosage

is expressed as mg/kg/day. (See table 2.)


D. Gross and Microscopic Pathology


1) 98 of the 196 animals that died during the study were fixed

in toto and autopsied at some later date, in some cases

more than one year later.


2) A total of 20 animals were excluded from the study due to

excessive autolysis. Of these, 17 had been fixed in toto

and autopsied at a later date.


3) Records indicated that animal F6HF, a high dose female, was

found dead at 787 days of treatment and the gross pathology

sheet reported a tissue mass measuring 5.0 X 4.5 X 2.5 cm.

The submission to FDA reported no tissue mass and the

animal was excluded from the study due to marked autolysis.


4) Records for approximately 30 animals showed substantial

differences between gross observations on pathology sheets,

when compared with the gross observations on pathology sheets

submitted to FDA. A detailed description of 10 of these is

included in the report. Copies of all the gross pathology

sheets, and the pathology summaries submitted to FDA are

attached as exhibits.


5) Dr. Charles H. Frith, D.V.M., Ph.D., Directory, Pathology

Services, NCTR, examined slides for a total of 150 animals,

or about 42 percent of the animals on study. He noted

the following discrepancies:


a. The reporting of a mass (by Searle) as missing which was

actually present (animal M1LF.)




b. The finding of a polyp of the uterus which was not

diagnosed by Searle (animal K9MF). The finding of

this additional uterine polyp by Dr. Frith increases

the incidence in the midi dose to 5 of 34. (15 percent.)


c. The finding of ovarian neoplasms in animals H19CF, H19C,

and H7HF, and the finding of diffuse hyperplasia in animal

D29CF, which were not diagnosed by Searle.


d. The finding of additional inconsistencies in 21 animals.


6) No microscopic worksheets or other "raw data" relating to

microscopic pathology could be found for this study.


7) A mammary tumor found in animal F27CF was described as a

papillary cystadenoma on the pathology summary sheet, (page

105, Vol. II of the submission) and as an adenocarcinoma on

summary table 12 (p. 95, Vol. I of the submission).


8) In several instances the histopathology technician made notes

at the bottom of the gross pathology sheet to indicate that

certain organs were not present in the bottle of fixative

(and were therefore not available for sectioning). Yet, in

three of these instances (animals A4CM, K23CF, and J3CM) a

diagnosis appears in the submission to FDA.


E. Organ Weights


1) Organ weights were entered on the gross pathology sheets at

the time of autopsy. We compared all of the individual organ

weights on appendix table 5 in the submission to FDA (Vol. 1,

pgs. 222-226) with the original data on the gross pathology

sheets. A total of eleven (11) errors were noted in transcrib-

ing the raw data from the pathology sheets to the tables in the

submission to FDA.


F. Survival


1. We were unable to determine the exact method used by Searle in

constructing the survival table in the submission to FDA.

We constructed a survival table using the body/feeder weight

Teletype sheets. A Life Table Analysis was constructed from

our survival table by Dennis Wilson, FDA Department of Mathe-

matics. The female control population differed from the high

level population (p 0.05) and the mail control population

differed from the mid and high level population (p 0.05). In

all cases the differences are due to higher mortality in

the controls.


Continue to Part 3


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