(39)
the 11th and 13th
weeks were averaged and the average substituted
for the
missing data. Employees
of Searle's Math-Stat Department who had
worked
on the program for
this experiment are no longer with the
company. Dr.
Clay calculated a
few of the figures from the 11th and 13th
weeks and
stated that it appeared
that the data had been averaged. For the
FDA
recalculation it was
chosen to omit the animals with the missing
weights
from the calculations.
In several instances (For example, C group
males,
mid and high levels
for the 13th week; A group males, high
level for the
99th week) the dietary
concentration shown on the weight sheets
did not
agree with the concentration
listed for that level in the other housing
groups. Dr. Clay assured
us that all the animals of the same sex
in a
given experimental
group received the same dose for the same
week on the
experiment. He also
assured us that the Searle computer program
did not
pick up the doses
from the weight sheets. In the FDA program,
the dietary
concentrations were
taken from the diet calculation sheets
(Exhibit #34).
Certain animals on
the raw data sheets were marked with an
asterisk. Dr.
Clay explained that
the asterisk indicated spillage and such
animals were
omitted from the food
consumption calculations. This practice
was
followed in the FD
computer program. In calculating the food
consumption
(g food eaten/day/
kg body weight) and the dosage (mg test
compound/day/kg body
weight), the body weight used was the
weight at the
end of the period
under consideration, i.e. the current
weight.
In addition to the
calculations which were included in the
Searle
submission, the FDA
program included calculation of the actual
amount of
food ingested, i.e.,
the total amount of diet ingested minus
the test
compound, and of the
food efficiency (g weight gained/100 g
actual food
eaten). The food efficiency
was calculated in order to determine whether
the volume of DKP
in the diet (which exceeded 7% of the
diet for the high
dose males at intervals
during the study) was contributing to
the body
weight depression
seen with DKP> This explanation of
the body weight
depression was discussed
by Dr. John H. Rust, a Searle consultant,
in a
memo dated April 5,
l976 to Dr. R. McConnell; in a memo to
the file dated
September 30, l974
by Dr. McConnell; and in a memo to Dr.
K. S. Rao dated
August 29, l974 by
Dr. G. L. Schoenhard. (Exhibits #36-38).
The average body weights
and weight gain (% change/week) from the
FDA
analysis of the Searle
raw data are presented in Table 1 (Exhibit
#39)
which corresponds
to Table 3 of the Searle submission.
(40)
Weights which differ
from the Searle submission by one (1)
g or more and
weight gains by 0.1
percentage point, or more are underlined.
Fifteen
differences were noted
as follows:
Average Body Weight
Discrepancies
Dose Searle
Days Sex Level Submission
Calculated
280 M M 591.7 589.2
364 F L 353.2 345.1
420 M M 613.2 614.4
700 M C 595.4 579.3
728 M C 594.4 597.2
728 F H 343.1 341.2
784 F C 453.4 459.9
Percent Weight Gain
Discrepancies
Dose Searle
Days Sex Level Submission
Calculated
14 M C 35.11 35.23
21 M C 22.80 22.69
280 M M 0.33 0.21
364 F L -0.16 0.04
392 F L 1.13 0.85
728 F H 0.32 -0.18
756 F H -0.14 0.08
805 F C -0.04 -0.39
The food intake (in
g/day and in g/kg/day) and dosage (in
mg/kg/day) from
the FDA analysis are
presented in Table 2. This table corresponds
to
Table 4 of the Searle
submission. there are numerous discrepancies
(in
excess of 80) of one
(1) gram or greater in the food intake
expressed in
grams/day. Many of
the discrepancies are probably the result
of an error
in the Searle computer
program (see Exhibit #76). Through this
error
there was a failure
to adjust the food intake for the precise
number of
days between weighings
for the individual housing groups. This
programming error
had been pointed out to Searle by the
Task Force but no
amendment to the Searle
submission was made. There are more than
forty
discrepancies of 5
or more grams when the food intake is
expressed in
g/kg/day. The Searle
programming error would contribute to
discrepancies
in this expression
of the food intake. The use of the current
body weight
in the FD analysis
may also be a contributing factor. Most
of the dosage
(41)
calculations from
the FDA program differ from the Searle
submission by 10
or more mg. The two
factors of the Searle programming error
and the use
of the current body
weight in the FDA analysis would contribute
to
discrepancies between
the FDA analysis and the Searle submission.
Despite
the discrepancies
the FDA analysis shows dosage levels corresponding
to
the intended levels
of 0.75, 1.5 and 3.0 g/kg/day. The test
compound
would have to be homogeneously
mixed into the basal diet in order for
these calculated dosage
levels to be actually consumed. All
discrepancies between
the Searle submission and the FDA analysis
shown in
Tables 1 and 2 are
underlined.
Table 3 presents the
food efficiency (g gained/100 g actual
food consumed)
calculated in the
FDA analysis. There is no corresponding
table in the
Searle submission.
Tables 1, 2 and 3 and the computer printout
of the FDA
analysis are Exhibits
# 39-42. Statistical analysis of the body
weight
and food consumption
data was made and is shown as exhibit
#73.
ORGAN WEIGHTS
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, pp. 222-226) with the original
data on the gross
pathology sheets. A total of eleven (11)
errors were
noted in transcribing
the raw data from the pathology sheets,
to the
tables in the submission
to FDA.
The errors are tabulated
below:
Wt. Shown In Wt. Recorded
on
Animal No. Organ Submission
Original Pathology Sheet
A12CM Kidneys 3.75
G 3.45 G
L28LM Ven. Prostrate
747 mg. 474.7 mg.
C0lMM Kidneys 9.40
G 9.219 G.
C02HM Kidneys 1.46
G 4.259 G
E14HM Kidneys 11.74
G 4.746 G
J12HM Pituitary 3.0
mg. 3.3 mg.
J30HM Ven. Prostrate
444 mg. 444.8 mg.
F17CF Ovaries 36.7
mg. 233.5 & 36.7 mg.
H30CF Liver 9.4 G
9.493 G
B20HF Uterus 1115
mg. 1155 mg.
K11HF Adrenals 799.1
mg. 797.1 mg.
(42)
Copies of the applicable
pages of the submission, appendix table
5, with
errors indicated,
are attached along with copies of the
gross pathology
sheets documenting
the errors. (See exhibit #83)
DISEASES
The submission to
FDA (Vol. 1, P. 10) reported that an unidentified
infectious disease
spread among the animals between 12 and
14 weeks of
treatment, and that
a second unidentified infectious disease
occurred in
high incidence between
48 and 52 weeks of treatment. In both
cases, the
control and treated
rats were reportedly affected with equal
frequency and
severity. The same
page of the submission also stated that
over a period
of two weeks, a total
of 17 animals (8 control, 3 low dose,
4 medium dose,
and 2 high dose) died.
A memorandum dated October 13, 1972, and
that more
animals were morbid.
Dr. Rao reported that this primary antemortem
symptom observed was
inappetance and labored respiration. Postmortem
examination of dead
animals revealed primary lesions in the
lungs, and
lungs exhibited patchy
pneumonia, according to Dr. Rao. The memo
indicates
that Dr. Rao intended
to administer 10,000 units of penicillin
G,
intramuscularly, to
all the animals 2 to 3 times per day beginning
10/30/72. A copy of
Dr. Rao's memo is attached to the protocol
(See
Exhibit #77, Section
1).
The submission to
FDA (Vol. 1, P. 10) stated that, "to
prevent further
loss of animals, all
morbid rats were injected IN with 20,000
units of
potassium penicillin
G daily for 4-8 days."
A review of the injection
records (attached to Vol. A of Exhibit
#75)
showed that some animals
were treated between approximately 51
and 60
weeks, and in one
instance, a high dose animal, kB3HF, received
at least
10 injections. In
addition, some animals received 30,000
units per day
(10,000 units 3 times
per day) rather than the 20,000 units
reported in
the submission.
The records also indicated
that penicillin was administered to four
rats
beginning on May 16,
l973, and continued daily through May
28, l973. This
third occurrence of
infectious disease and penicillin administration
was
not reported in the
submission to FDA.
