(3)
6) No reserve samples of any
of the lots of DKP used in this study
were retained by Searle.
7) Three different sets of
specifications for DKP were found, and
Searle could not determine
with any degree of certainty which
of the three were applicable
to the 7 lots of DKP used in the
study.
8) The analytical records for
DKP lots IR through 5R refer to
reference standard IR #3701.
None of the three sets of DKP
specifications lists reference
#3701. No data was made avail-
able as to dates, methods of
preparation and authentication
of DKP reference standards.
9) Analytical records A-9129
for DKP lot 5R showed an assay of
1000%. Examination of laboratory
notebooks showed
that eleven (11) samples had
been analyzed from this lot, and
the analytical record only
reflected an average of the last
three of theses. The other
assays (not reported) ranged from
87.93% to 114.83%.
C. Dosage, Body Weight and
Food Consumption
1) Examination of the raw data
sheets revealed the following
discrepancies:
a. Empty feed cup weights were
missing for the D hous-
ing group at the 12th week,
in the raw data sheets. (See
exhibit #75.)
b. In several instances, the
dietary concentration shown
on the weight sheets did not
agree with the concentra-
tion listed for the same level
in the other housing
groups. (For example; C group
Males, mid & high levels
for week 13,; A group Males,
high levels for week 99.)
2) Comparison of the Searle
submission and the independent FDA
analysis of the raw body weight
and food consumption data
revealed the following discrepancies:
a. We found a total of 15 differences
of 1 gram or more in
the average body weight and
of 0.1 percentage points
or more in weight gain. (See
table 1.)
(4)
b. We found approximately 82
discrepancies of one gram or
or more in the food intake
when expressed in grams/day.
(See table 2.)
c. We found approximately 40
errors of 5 or more grams in
food intake when expressed
in grams/kg./day. (See
table 2.)
d. Most of our dosage calculations
differed from Searle's
dosage calculations by 10 or
more mg., when the dosage
is expressed as mg/kg/day.
(See table 2.)
D. Gross and Microscopic Pathology
1) 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.
2) 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.
3) Records indicated that animal
F6HF, a high dose female, was
found dead at 787 days of treatment
and the gross pathology
sheet reported a tissue mass
measuring 5.0 X 4.5 X 2.5 cm.
The submission to FDA reported
no tissue mass and the
animal was excluded from the
study due to marked autolysis.
4) Records for approximately
30 animals showed substantial
differences between gross observations
on pathology sheets,
when compared with the gross
observations on pathology sheets
submitted to FDA. A detailed
description of 10 of these is
included in the report. Copies
of all the gross pathology
sheets, and the pathology summaries
submitted to FDA are
attached as exhibits.
5) Dr. Charles H. Frith, D.V.M.,
Ph.D., Directory, Pathology
Services, NCTR, examined slides
for a total of 150 animals,
or about 42 percent of the
animals on study. He noted
the following discrepancies:
a. The reporting of a mass
(by Searle) as missing which was
actually present (animal M1LF.)
(5)
b. The finding of a polyp of
the uterus which was not
diagnosed by Searle (animal
K9MF). The finding of
this additional uterine polyp
by Dr. Frith increases
the incidence in the midi dose
to 5 of 34. (15 percent.)
c. The finding of ovarian neoplasms
in animals H19CF, H19C,
and H7HF, and the finding of
diffuse hyperplasia in animal
D29CF, which were not diagnosed
by Searle.
d. The finding of additional
inconsistencies in 21 animals.
6) No microscopic worksheets
or other "raw data" relating to
microscopic pathology could
be found for this study.
7) A mammary tumor found in
animal F27CF was described as a
papillary cystadenoma on the
pathology summary sheet, (page
105, Vol. II of the submission)
and as an adenocarcinoma on
summary table 12 (p. 95, Vol.
I of the submission).
8) In several instances the
histopathology technician made notes
at the bottom of the gross
pathology sheet to indicate that
certain organs were not present
in the bottle of fixative
(and were therefore not available
for sectioning). Yet, in
three of these instances (animals
A4CM, K23CF, and J3CM) a
diagnosis appears in the submission
to FDA.
E. Organ Weights
1) 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,
pgs. 222-226) with the original
data on the gross pathology
sheets. A total of eleven (11)
errors were noted in transcrib-
ing the raw data from the pathology
sheets to the tables in the
submission to FDA.
F. Survival
1. We were unable to determine
the exact method used by Searle in
constructing the survival table
in the submission to FDA.
We constructed a survival table
using the body/feeder weight
Teletype sheets. A Life Table
Analysis was constructed from
our survival table by Dennis
Wilson, FDA Department of Mathe-
matics. The female control
population differed from the high
level population (p 0.05) and
the mail control population
differed from the mid and high
level population (p 0.05). In
all cases the differences are
due to higher mortality in
the controls.
