FDA report on Searle's submission for NutraSweet approval 1977 - Part 11

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This procedure was repeated for all cages proceeding from left to right.

It is important to note that none of the food jars were identified in any

manner, as to animal number or dose level. The position of the jar on the

cart was the only means of identifying the proper dose level.


This procedure was used when concentrations were changed. At other times,

the feeder jars were weighed; filled with the appropriate diet/dose,

weighed and replaced in the cage. If a feed container was almost empty,

or contained feces, it would be replaced with a new container.




No ear clips or other methods of uniquely identifying each animal were

used. Animals were individually housed (one animal per cage) and a color

coded card containing the cage number, compound number, project number

(Path-Tox No.), and dose level was attached to each cage. When an animal

died during the study, the color coded identification card was removed

from the cage and accompanied the animal to the necropsy laboratory.


Also attached to each cage was a Mylar Card which identified the an imals

for the Computer System.


At the time of death or sacrifice the animals were assigned a pathology

number which was used to identify the animal during tissue processing, and

on all records pertaining to pathology. The pathology number was a

five-digit sequential number assigned by the pathology department. An

example of a pathology number is 94.893. The number was etched on all

slides as a permanent identification.


All animals that died during the study were assigned an additional number

called a "Master Number". The master numbers denote the chronological

order in which the animals died during the study, by dose group. For

example, CM38 would be the 38th Control Male to die during the study.

Master numbers were noted only on the gross pathology sheets and not

recorded for all animals. Four animals that died during the study had no

master numbers. We were not able to locate any other records providing

the missing numbers. Also, two of the master numbers (CM28 and CM29) were

out of sequence.




A chart was made by the FDA team, which shows the animal number (cage #),

pathology number, master number, and the complete pathology history of

each animal. The chart is organized by dose group, and is attached as

Exhibit #35.




"Observations for Drug Effects" records are attached as exhibits #70 & 71.

These records were completed on a weekly basis for the first four weeks,

every two weeks through week 12, and every 4 weeks thereafter. each

record lists the animals in a specific housing group, and entries are made

for the following parameters: appearance and awareness, rales, eyes, motor

activity sensory loss, urine/feces, appetite/thirst, and tissue

masses/lesions. There is also a space for notes, and masses are routinely

described on the reverse side of the sheet. The top of the sheet has

blocks for entering the date of observations, number of weeks on

treatment, and signature or initials of the person making the

observations. It was noted that many of the observation records were not

signed or initiated. Following is a tabulation of the numbers of records

in which the person making the observations is not identified.





A 6 (wks 80, 92, 84, 88, 93, 94)

B 6 (wks 80, 84, 88, 92, 93, 96)

C 5 (wks 80, 84, 88, 92, 96)

D 7 (wks 79, 80, 84, 88, 92, 94, 96)

E 6 (wks 76, 80, 84, 88, 92, 96)

F 9 (wks 76, 77, 80, 81, 84, 88, 92, 93, 96)

G 5 (wks 80, 84, 88, 92, 96)

H 11 (wks 1, 68, 76, 80, 81, 83, 84, 88, 92,

95, 96)

J 6 (wks 76, 80, 84, 88, 92, 96)

K 8 (wks 71, 76, 80, 84, 88, 92, 93, 96)

L 5 (wks 76, 80, 84, 92, 96)

M 5 (wks 76, 80, 84, 92, 96)

TOTAL 79 records not signed or initialed


In addition to the lack of signatures, it was noted that many of the

records were not originals, but appeared to be xerox copies of the

originals. Surprisingly, some of the xerox copies had "original"




initials. It was obvious that the initials had been placed on these

sheets sometime after the sheets had been filled out, and after they had

been copied.


Some examples of discrepancies of this type are as follows:


1.) In housing group A, 26 of the 39 observation records were xerox

copies with original initials.

2.) In housing group B, 27 of the 43 observation records were xerox

copies with original initials.

3.) The record for week 76 of housing group A was a xerox copy but the

date, initials, an week are all original.

4.) For week 96 of housing group K, both an original and xerox copy of

the observation record are present. The xerox copy has original

initials and a "B" entered in the "tissue masses and lesions"

column. There is also an entry in the "notes" column for rat

#K25CF. The original record also has a "B" entered in the

"notes" column. All of the above entries had obviously been

made sometime after their original record had been completed and

the xerox copy made.

5.) A record dated 4-27-73 for housing group M does not have the date

entered. The observations were made for this animal on sheets

covering weeks 92, 96, 100 and 104, indicating that the animal

was dead. The record for week 108, however, shows that the

animal is alive, with motor activity, appetite, and thirst. The

record for week 112 again shows that the animal is dead.


In addition to the discrepancy noted above, there is also an obvious error

in the dating of these records; the observation sheet for week 92 is dated

June 13, l973, and the observation sheet for week 88 is dated July 16,



Ante-mortem observations were also made on other types of records. A

volume entitled "Tissue Masses and Deaths" (exhibit #65) has a record of

the date that each animal died during the study. The deaths are recorded

in two different ways in this volume. One record has a chronological list

of deaths, and another record has a list of deaths organized by housing




group. This volume also has a "palpation Record", which describes each

tissue mass, and lists the date that it was initially detected.


It was noted that many of the animals in the sequential record of deaths

were listed out of sequence. Following is a tabulation of the animals

that were out of sequence.


(* indicates animal is listed out of sequence)




E6HN 8-12-73 640

E24HM 8-16-73 640

G10LM *8-14-73 638


L11CM 5-6-73 535

C17CM *5-4-73 542

A14MM 5-21-73 560


A24HM 10-15-73 707

C14HM *10-27-73 718

E22CM 10-19-73 707

E29LM 10-25-73 714

A4CM 10-26-73 718


E26CM 11-15-73 735

C12LM *11-14-73 736

L20CM 11-19-73 732


AllCM 11-25-73 748

A18CM *11-18-73 741

J19MM 12-10-73 754


F25HF 6-10-73 576

D21CF *6-9-73 577

H6CF 6-17-73 579

M12CF *6-16-73 575


F18CF 7-22-73 615

H22LF *8-20-73 641

D25MF 7-25-73 623


G2LM 10-5-73 689

G7CM *6-14-73 567


Continue to Part 12


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