(53)
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.
(54)
TABLE 5
TOTAL SERUM CHOLESTEROL
(MG/DL)
TREATMENT 42 92 189
364 734 798
GROUP
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THIS ENTIRE PAGE
OF DATA GUTTED
BEFORE RELEASE OF
THIS REPORT
UNDER THE FREEDOM
OF INFORATION ACT!
WHAT DID THE FDA
DECIDE TO KEEP FROM
THE PUBLIC IT "PROTECTS"?
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(55)
GROSS PATHOLOGY
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
dissection".
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
(56)
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).
A2CM
Submission to FDA:
Lung - Focal adhesion
Adrenal - Moderately
enlarged
