The "Bressler Report"
(Note: This is the text of an
FDA report on Searle)
EIR 4/25/77 to 8/4/77
JSA/DME/JT/LF
Searle Laboratories
Div. G.D. Searle & Co.
4901 Searle Parkway
Skokie, Illinois 60076
SUMMARY OF FINDINGS
Authentication of this study
was performed primarily by com-
paring available raw data with
the submission to FDA. This
was a problem, at times, due
to the lack of some data and
difficulty in locating other
material. The majority of
material relating to Aspartame
was already under FDA seal
at Searle. However, during this
investigation we discovered
various documents and notebooks
that were not.
In some cases original data could
be recorded in several areas,
making it difficult, and sometimes
impossible to determine
which was actually the original.
This was a particular problem
in dealing with dates of deaths,
as some conflicted on the
"source" documents.
Many of the responsible individuals invol-
ved with the study, including
stability testing of DKP, are no
longer employed by Searle. Dr.
K.S. Rao, Study Monitor,
the only individual who could
have possible answered some quest-
tions, had left Searle. He was
contacted, but permission for
an interview was refused by his
attorney. Due to the absence
of various individuals it was
not always possible to a accurately
determine methods used in some
analyses and operations carried
out in conducting this study.
In a number of areas, including
chemistry, statistics, diet preparation
and feeding, it was
necessary to use assumptions,
or information supplied by current
employees who were not involved
with the study.
At the beginning of this investigation
, Mr. James R. Phelps,
Vice-President and General Counsel
for G.D. Searle & Co., advised
us that an attorney and scientific
coordinator would have to be
present at all times to protect
their interest in the data.
This did not present any insurmountable
problems, but on several
occasions an attorney would question
our request for data,
stating that it was not relevant
for authentication. At no time
did we make any statement to
the effect that our goal was to authen-
ticate the study. Two memos were
discovered dealing with reaction
of animals to the diet. This
was a significant factor in the
study. Permission to copy them
was initially refused, but
finally granted after Searle
was contacted by FDA General Coun-
sel. We were not allowed to make
xerox copies of any documents
for about two and one-half weeks,
due to Searle's concern over
confidentiality. This was eventually
reconciled between Searle
and FDA General Counsel.
(1)
The major discrepancies concerning
Study PD 988S73, SC-19192:
115 Week Oral Tumorigenicity
Study in the Rat, are as follows:
A. Design and Conduct of Study
1) Control and treated animals
were randomly distributed
on the same rack. (See diagram
of housing group
attached as exhibit 7.)
2) No ear clips or other methods
of uniquely identifying
each animal were used. Identification
consisted of two
types of cards attached to the
front of each cage.
3) Compound inventory cards were
deficient in that only one of
18 such cards stated the purpose
(study 988S73) for with-
drawing the compound from inventory.
Three of the cards
did not include the date withdrawn,
amount withdrawn, or
signature of requestor. Therefore
it was impossible to
Reconcile the amount withdrawn
and the amount used.
(See exhibit #28.)
4) Food jars were not individually
identified, yet all the
filled jars for a given housing
group (control, low, mid,
and high dose) were placed on
a mobile cart, which was
wheeled to the housing rack.
The position of the jar
(in rows) on the cart was the
only means of identifying
the proper dose level. The arrangement
of the food cups
on the cart is shown in exhibit
#8.
5) A total of 79 "observations
for drug effects" records were
not signed or initialed.
6) Observation records indicated
that animal A23LM was alive at
week 88, dead from week 92 through
week 104, alive at week
108, and dead at week 112.
7) Records indicated that at
the scheduled 104 week bleeding,
animal E2CM was substituted for
animal A11CM. Records also indica-
ted that animal A11CM was alive
on this date and therefore
should have been bled as scheduled.
8) Records indicated that penicillin
was administered to four
rats beginning on May 16, 1973,
and continuing daily through
May 28, 1973. This third occurrence
of infections disease
and penicillin administration
was not reported in the sub-
mission to FDA.
(2)
9) In many cases the actual number
of tissues embedded was less
than the 24 (control and high
dose) or 19 (low and mid dose)
specified in the final histology
lab protocol dated 1/21/74.
10) Ophthalmoscopic examination
records were present for animals
H26MF and J29CM, yet the findings
were not reported in the
submission to FDA. Two other
discrepancies of this type
were noted.
11) Records indicate that a tissue
mass measuring 1.5 x 1.0 cm
was excised from animal B3HF
on 2/12/72, and that a "skin
incision over mass" was
performed on animals C22LM and G25LM
on Feb. 10, 1972.
B. Stability and Homogeneity
of DKP in Diet Mixtures
1) There were no batch records
to show the quantities of DKP
and basal diet weighted, type
of mixer used, mixing time,
dates, or names of individuals
performing the weighing and
blending operations.
2) There was no evidence that
any tests had been done to deter-
mine the blending characteristics
of the mixer, or to vali-
date the mixing time.
3) No homogeneity tests were
performed on any batches of diet
used in the study, and to stability
study assay reports
(A7738 and A7739) indicated that
samples were not homogene-
ous. (See exhibit #29.)
4) A stability study was conducted
with DKP
in 1972. However, the 115 week
rat stud employed
Basal Diet from week 2 to its
conclusion, and to stability
studies had been conducted with
Basal Diet.
5) Methods of assay for DKP in
the diet were deficient in that:
The titration method was discontinued
after 1 week of the
stability study. Some of the
TLC photographs showed no DKP
reference standards and photographs
also showed that there
was something in the basal diet
itself producing a spot
on the TLC plate which had an
Rf value corresponding to
DKP. Only one solvent system
was used for development of
the TLC Plates. Some of the chromatograms
showed poor separa-
tion.
