FDA report on Searle's submission for NutraSweet approval 1977 - Part 17

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G. Discrepancies Found In Statistical Analysis:


The mean and standard errors for the three dose levels and

the controls for the various measurements using the values

in the submission Volume I or values noted in the data sheets

(where there values differed from those found in the submis-

sion) were calculated by the Division of Mathematics, FDA.

Also supplied were the results of the T-TEsts comparing the con-

trols to the treated groups. See memo to Leonard Friedman

from Dennis Wilson, dated July 20, 1977 with attached Tables

1 and 2 (Exhibit #87).


A total of 49 disparities were found, which were comprised of

6 means, 23 standard errors and 20 significant differences.

As stated in the memo, in all cases where there is a disparity,

it appears to be due to differences in the data.


Calculations were also carried out for cholesterol data found

in the data sheets but not reported in the submission. As

shown in Table 5 the mean values for the median and high

level treated females and the high level treated males were

significantly lower than the mean values for the respective

controls. To illustrate the possible significance of these

changes and disparities between the values calculated by

Searle and FDA for cholesterol data at the other time

periods of treatment, table 5 was constructed. Very few

disparities are seen between the calculated values obtained

by FDA and those in the submission but a fairly consistent

trend is seen for treatment related lowering of serum

cholesterol, particularly at the two highest dose levels

and for the female rats.


Because additional disparities were recently noted in

individual hematology values after these statistical

computations by FDA were completed (due to the discovery

of additional laboratory notebooks), and addendum to this

report regarding the statistical disparities reported here

will be forthcoming.








TREATMENT 42 92 189 364 734 798



























The pathologists responsible for the microscopic examination (Rudolph

Stejskal and Joseph smith) did not perform the necropsies. Necropsies

were performed by Tony Martinez, David Kie and Robert Spaet, with the two

pathologists avilable for consultation.


The submission to FDA (Vol 1, p. 7) reported that "Rats found dead during

the study were autopsied immediately whenever possible. In cases where

the ncropsy could not be performed promptly, the thoracic and abdominal

cavities of dead rats were opened and the entire animal was immersed in

neutral buffered formalin fixative for subsequent gross examination and



Our examination of gross pathology records showed that 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.


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. Following are the twenty animals excluded from the study:


Animal No Date Found Dead Date Autopsied


C21CM 7/3/73 1/11/74

G16CM 9/21/73 1/11/74

G18CM 8/11/73 10/4/73

G26CM 4/2/73 1/11/74


J2CM 5/21/73 1/11/74

J5CM 10/30/72 11/8/72

L10CM 3/29/73 1/11/74

L15/CM 9/9/73 1/11/74

L21CM 4/13/73 1/11/74

L11LM 5/6/73 1/9/74

A14MM 5/21/73 1/9/74

G28MM 1/5/74 1/7/74

J25MM 5/24/73 5/24/73

A3HN 6/17/73 1/9/74

C15HM 1/7/74 1/7/74




Animal No Date Found Dead Date Autopsied


G13HM 7/25/73 **1/9/74

H24CF 4/29/73 1/11/74

D4HF 7/11/73 7/11/73

D16HF *4/2/73 1/8/74

F6HF 1/5/74 1/7/74


*Although the date found dead was listed as 4/12/73 on the gross pathology

sheet, the "Tissue Masses & Deaths" book listed this date as 4/1/73.


**Although the date found dead was listed as 1/9/74 on the gross pathology

sheet, the "Tissue Masses & Deaths" book listed this date as 7/25/73.


The gross pathology sheet for one of the above animals, F6HF, described a

tissue mass measuring 5.0 X 4.5X2.5 cm. This tissue mass was first

observed on 8/24/73 according to the pathology sheet (Exhibit #79), the

observation records (Exhibit #70), and the palpation record in the "Tissue

Masses and Deaths" book (Exhibit #65). The submission to FDA (Exhibit #8)

reported no tissue mass and the animal was excluded from the study due to

marked autolysis.


In addition to the above twenty animals that were excluded from the study,

many other animals exhibited marked autolysis. For example, D27LF, M25CF,

and H12CF are all described grossly in the submission to FDA as follows;

"all organs examined grossly were markedly autolyzed".


Records for approximately 30 animals showed substantial differences

between gross observations on pathology sheets, when compared with the

individual pathology summaries submitted to FDA. Following is a detailed

comparison of ten of these. (Copies of all the gross pathology sheets,

and the pathology summaries submitted to FDA are attached as Exhibits #78,

#79, and #86).




Submission to FDA:


Lung - Focal adhesion

Adrenal - Moderately enlarged


Continue to Part 18


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