FDA report on Searle's submission for NutraSweet approval 1977 - Part 12

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The log of animal deaths in the "tissue masses and deaths" book was

considered the primary data. Animals were allegedly recorded in this book

as they died. When the above discrepancies were pointed out to Searle

personnel, we were told by Tony Martinez on 4-28-77 that this log was

compiled from the body and feeder weight data. When it was pointed out

that the exact date of death could not be determined from the body and

feeder weight data, or from the observation records, we were told that the

primary record of animal deaths was the log organized by Housing Group in

the "Tissue Masses and Deaths" book. We were told that the chronological

log of animal deaths was made by transferring the data from the log

organized by housing group, and therefore the animals being recorded out

of sequence was not significant.


We then pointed out that the chronological record of deaths also contained

the date fixed "in toto" and the date autopsied, neither of which were

found on the log organized by housing group. If the data was transferred

from one record to the other, we wondered where the "date fixed in toto"

and "date autopsied" came from. We posed this question to Searle

personnel and we were finally told on 4-29-77 that the "fixed in toto" and

"date autopsied" columns on the chronological record of deaths was

considered to be primary data, although it was prepared simultaneously

with the pathology sheets, which contained the same data.


Another source of ante-mortem data was the ophthalmoscopic examination

record. Dr. Youkilis performed the eye examinations at periodic intervals

and recorded his findings on the ophthalmoscopic record sheets. These eye

exam sheets were eventually attached to the pathology records, and the

results of the eye exam was incorporated into the Clinical History of the

animal on the pathology sheet.


During our review of the pathology records we noted that there were no eye

exam sheets for 15 animals, all of which had been included in the

individual Ophthalmoscopic Findings in the submission to FDA (Vol. 1,

table 1, pages 122-133). All of these missing eye exam sheets were for

animals that had died during the study. On 6-30-77 we interviewed Donna

Helms, who told us that she would make an attempt to find the missing

records. We advised her that Dr. R. Stejskal had told us on 6-29-77 that

not all of the eye exam sheets were attached to the pathology records, and

that there may be another file of eye exam sheets somewhere.




On 7-1-77 Donna Helms reported that she had found the missing eye exam

sheets in the K-1 File Room in K-Building. After reviewing these records

we found that a few discrepancies still existed. They are as follows:


1.) It appears that animal J3CM on page 125, Vol. l of the

submission to FDA is in error. We could find no records

to substantiate the listed corneal scar and haziness for

this animals. Also, the observation records indicate that

J3CM died at week 78. It appears that the correct animal

on page 125 should be J2CM and not J3CM.


2.) We found eye exam sheets for H26MF and J29CM, yet the

findings were not reported in the submission to FDA.


3.) There seems to be a discrepancy between G16CM and G12CM.

The pathology sheets for both of these animals report the

identical ophthalmoscopic finding, yet there is no eye

exam sheet for G12CM, and only the finding for G16CM was

reported in the submission to FDA (Vol. 1, p. 125).


During our data review, we found an internal memo from Dr. Youkilis to

K.S. Rao, dated 4-28-74. The text of this memo is as follows: "








Note... This entire memo was expunged from the delivered

document, by parties unknown.










A copy of the above memo is included in exhibit #72. Dr. Rao and Dr.

Youkilis are no longer employed by Searle.




When an animal spilled an excessive amount of food, this was noted on the

observation records by means of an asterisk in the "appetite/thirst"

column. The asterisk was also used to denote food spillage on the

Teletype sheets for body/feeder weight data. The amount of food spillage

was not quantitatively determined by the technicians assigned to observe,

feed and weigh the animals, but we were told that they made an effort to

return spilled food to the food cups whenever possible. WE were also told

that food consumption data for those erats marked with an asterisk on the

body/feeder weight sheets was not used in Searle's statistical analysis of

the data.


The "palpation record" in the "Tissue Masses and Deaths" volume shows that

tissue masses were sometimes excised from the animals. The record

indicates that a tissue mass measuring 1.5x1.0cm was excised from animal

B31HF on 2-10-72. The record also shows that a "skin incision over mass"

was performed on animals C22LM and G25LM on Feb. 10, 1972.




DKP levels for the feeding study were multiples of 100, 200 and 400 times

the estimated human dose. The levels in g DKP/kg body weight/day were

0,0.75, 1.5 and 3.0 for the control, low, medium and high treatment

groups, respectively. The doses were mixed in the diet as described in

Calculating Diet Concentration and Blending of Treatment Mixtures.


Individual body weights were recorded weekly for the first four weeks,

once every two weeks for the next eight weeks and once every four weeks

thereafter. The amount of food consumed was measured every week. An

automated weighing system was employed consisting of an Intec balance and

a Teletype machine. The Teletype produces a typewritten sheet and a

machine-readable punched paper tape. All the typewritten sheets for the

study were available. Xerox copies of these sheets were taken to the

Division of Mathematics and technical Operations Staff of the form and

calculated by a computer program designed by Dennis Wilson, Division of



In designing the computer program it was necessary to make certain

assumptions on the handling of the data. One assumption concerned missing

data, e.g. the empty feed cups weights were missing for the "D" housing

group at the 12th week. Dr. George Clay, Group Leader, CNS Pharmacology,

Searle and scientific co-ordinator for the FDA team, was unable to

determine whether these animals were omitted from the food consumption

calculations for that week, or whether the data for these animals from


Continue to Part 13


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