When this study was
reviewed by the Bureau of Foods in l975,
of uterine polyps was noted. The appropriate
slides were requested
by FDA at that time and were reviewed
groups of pathologists:
1.) The Division of Pathology, Bureau
2.) Armed Forces
Institute of Pathology, 3.) Massachusetts
of the reports submitted by the 3 groups
obtained and are attached as exhibits
Dr. Rudolph Stejskal
was responsible for the microscopic findings
accuracy on these
findings in the submission to FDA. Only
name appears on the
submission. However, a Dr. Joseph H. Smith,
read slides for this
study and his initials appear on some
sheets. Dr. Frith questioned some of the
in describing tissues. Dr. Stejskal stated
Smith had come directly
to SEarle from a hospital situation. Due
human pathology background,
his description of animal tissues was
different than that
used by veterinary pathologists.
Dr. Stejskal joined
SEarle in July of l973, therefore, he
had no input
into the pathology
protocol, since E-77/78 was initiated
in November of
No microscopic worksheets
or other "raw data" relating
pathology could be
found for study E-77/78. We were told
personnel that the
original microscopic findings were dictated
& Smith) onto belts, and then typed
which were placed
in a binder. The belts were then discarded
apparently the bound
microscopic pathology sheets were either
lost, after the study
report was written. Therefore our verification
the microscopic findings
submitted to FDA was limited to a complete
inventory of the
slides and tissue blocks and microscopic
examination of a
of slides by Dr. Frith.
Our inventory of
the slides and tissue blocks for each
included a complete
list on the tissues sectioned, the number
of slides made from
each tissue, and a complete count of the
total number of slides
and blocks for each animal. We also checked
numbers on every slide and tissue block.
examined a total
of 7,872 slides and 7,360 tissue blocks.
average number of
organs submitted for tissue processing
20 per animal. No
errors in slide identification were noted,
although in many
cases the number of organs submitted for
tioning was less
than specified in the protocol. A detailed
cussion of this can
be found under the heading PROTOCOL.
In addition to the
discrepancies noted by Dr. Frith, some
were noted in the
submission to FDA. A mammary tumor found
in rat F27CF
was described as
a papillary cystadenoma on the individual
(page 105, Volume
II of the submission to FDA) and as an
the summary table
12, page 96, Volume I of the submission
Page 92, Volume I
of the submission to FDA (a summary table)
animal J23CM was
found dead after 754 days on study, while
pathology sheet for
this animal (page 56, Volume II of the
FDA) reported that
the animal was found dead after 620 days
The correct figure
is 620 days, since J23CM was placed on
the study on
11/17/72 and was
found dead on 7/29 /73.
In several instances
the histopathology technician made notes
bottom of the gross
pathology sheet to indicate that certain
not present in the
bottle of fixative. (and were therefore
Yet in three of these instances (animals
and J3CM) a diagnosis
appears in the submission to FDA.
It was necessary
to construct a number of charts, diagrams
and tables to
facilitate our review
of the data. For example we constructed
a chart, by
housing group, showing
the identification and complete pathology
of each of the 360
animals. We also rearranged this chart
groups, a copy of
which is attached as exhibit #35.
To compare survival
data it was necessary to construct a survival
This also involved
devising a calendar to show days and weeks
on study for
each housing group,
taking into account the starting dates
for each group.
This also included
tables showing the numbers of days and
were on study and
a table comparing the survival data from
We constructed a
chart showing diet calculations (gm./kg)
amounts of DKP used
(gm./batch). This is attached as exhibit
Three tables were
constructed which summarize the FDA statistical
of body/feeder weight
data. They are attached as exhibits #39-41.
All of the charts,
diagrams and tables that we constructed
are attached to
the report as exhibits
and are referred to in various sections
#1. G.D. Searle &
Company Annual Report for l976.
Chart of Pharmaceutical/Consumer Products
Chart of World Wide Pharmaceutical R&D
Chart of Preclinical R&D Group.
Chart of Product Safety Assessment Group.
#6. Copies of Computer-Generated
Randomization Tables used by Searle
to assign the Dose
& Housing Groups.
#7. Diagram showing
Typical Housing Group of 30 animals, containing
a random distribution
of control and treated animals.
#8. Diagram showing
arrangement of food cups on cart, used
#9. Copy of "Glossary
of Terms for Aspartame and its Diketopiperazine"
Data and Specifications of Food Grade
#10. Copy of shipping
labels for rats received from
#11. Copy of protocol
with amendments for Study P.T. 988S73
#12. Copies of CV's
for principal persons involved in study
#13. Copies of Batch
Records for the manufacture of DKP, lots
#14. Copies of pages
from SEarle chemist Jack Drogt's notebook,
cerning the manufacture
#15. Copies of Analytical
Reports for DKP, lots 1R through 7R.
#16. Copy of Searle
memorandum dated 12/4/69, concerning DKP
#17. Copy of DKP
Specification Sheet (not dated) entitled
#18. Copy of DKP
Specification Sheet entitled "Specifications
#19. Copies of pages
75-84 & 285 of lab notebook #AR-39,
assay of DKP, lots
1R, 2R & 3R.
#20. Copies of pages
60-63 of lab notebook VSH-I, and page
lab notebook book
#AR-23, pertaining to analysis of DKP
#21. Copies of pages
250, 251 and 257 of lab notebook #AR-57,
pages 44-49 of lab
notebook #AR-68, pertaining to analysis
DKP lot 5R.
#22. Copies of pages
83-86 of lab notebook #AR-77, concerning
of DKP lot 6R.
#23. Copy of page
31 of lab notebook #AR-93, concerning
DKP lot 7R.
#24. Copy of protocol
for DKP stability study, dated 1/13/72.
#25. Copies of pages
51-56 of laboratory notebook #AR-49, assigned
C. Seul. These pages
describe a preliminary TLC Test for
recovery of DKP from
the diet mixture.
#26. Copies of pages
53-59, 67-72, 88-89, 106-107, 144-145,
and 284-285 of laboratory
notebook #AR-51, assigned to Barbara
Bickford. These pages
refer to the assay procedure and methods
for the DKP Stability
#27. Copies of Analytical
Reports for DKP Stability Study.
#28. Copies of DKP
Compound Inventory Cards.
#29. Two photographs
showing a non-homogeneous sample of DKP
#30. Chart showing
diet calculations (gm.kg.) and total amounts
#31. Two memos dated
7/14/77 from Thomas F.X. Collins concerning
with Ray Schroeder.
#32. Memo dated 7/19/77
from Thomas F. X. Collins describing the
interview with Ray
#33. Memo of Telephone
Conversation between Jerome Bressler and
John H. Bickley Jr.,
dated July 25, l977.
#34. Copies of records
concerning calculation of diet concentrations,
records, dates of bath mixing, and calcu-
lation of mean food
#35. Charts organized
by dose group, showing the identification
of each of the 360 animals on study.
#36. Memo dated April
5, l976, from Dr. John H. Rust to Dr.
#37. Searle memo
dated September 30, l974, by Dr. McConnell.