(25)
Additional evidence
of homogeneity problems was revealed when
a former Searle employee,
Raymond Schroeder, was interviewed
buy the other FDA
team on 6-22-77 concerning teratology
studies
E-5 and E-89. At
that time Mr. Schroeder volunteered the
information that
homogeneity may have been a problem in
the
DKP diet mixtures,
but not ion the aspartame diet mixtures.
A
follow-up phone call
to Mr. Schroeder was made on 7-13-77,
and
at that time he stated
that he observed the DKP diet mixtures
being fed to the
animals, and that in his opinion, the
particles
of DKP were large
enough to allow the rats to discriminate
between the DKP and
basal diet. (See Thomas F. X. Collins
memos (2) dated 7-14-77
(attached as Exhibit #31). An interview
was arranged for
July 18, 1977 between Mr. Schroeder and
members
of the FDA team investigating
study E-77/78. The interview was
conducted at [information
blanked out to protect the individual],
Mr.
Schroeder's current
place of employment. Also participating
in
the interview by
means of a conference phone were Thomas
F.X.
Collins, and Leonard
Friedman. Mr. Schroeder stated that he
was not certain of
the date, or even the year, when he observed
the rats being fed
DKP diets. He further stated that he could
not be absolutely
certain that the rats he observed were
on
study E-77/78. He
was not certain about the dose levels
of the
diets he observed,
and could not remember how many times
he
observed the DKP
diets. He estimated that he observed the
DKP
diets "one or
two times". When he was shown an
actual-size
enlargement of the
DKP diet mixture (See Exhibit #29) he
stated
that to the best
of his knowledge, the white particles
that he
observed were not
as large as the largest particles in the
photo, but may have
been similar to the smaller white particles.
He said that he may
have mentioned the appearance of the DKP
diets to Dr. Rao.
Mr. Schroeder seemed
reluctant to make any positive state-
ments during this
interview. Dr. Collins reminded Mr.
Schroeder that he
had previously volunteered the information
that the DKP diets
appeared to be non-homogeneous and that
the
rats could probably
discriminate between the DKP particles
and
the basal diet. Mr.
Schroeder replied that he had had some
time to think over
his previous statements and now wasn't
sure about them.
He told us that there must be people at
Searle who know more
about the DKP diets than he did. (see
memo dated 7-19-77,
attached as exhibit #32,which describes
our interview with
Mr. Schroeder).
(26)
When we arrived at
[ address expunged ] on 7-18-77 at approximately
2:40 P.M., we were
asked by the receptionist to sign a log
book. While signing
the log, we noted that a G.D. Searle
employee (W. R. Pool)
had signed in on 7-15-77. W. R. Pool
works in the Toxicology
Section (Safety Assessment Division)
at Searle Laboratories.
During our interview,
we asked Mr. Schroeder if he had been
contacted by anyone
from Searle during the period from June
22, 1977-July 18,
1977. He replied that he had not.
We again interviewed
Tony Martinez on 7-19-77, and specific-
ally asked him if
he was aware of any homogeneity problems
with the DKP diet
mixtures fed the rats in study #988S73
(E-77/78). He replied
that he was not aware of any problems.
We asked whether
any samples of DKP had been retained by
Searle Laboratories.
We were told that a small quantity of
DKP remained in the
compound file, but that it was a lot
other than those
used in study E-77/78. Upon request, we
were
then shown a jar
containing 4.9 grams of DKP, lot #TJT-12-32.
Its appearance was
that of a fine white crystalline material
with a tendency to
adhere to the sides of the jar. Mr. Martinez
said that this was
the only lot of DKP remaining at Searle.
We also interviewed
Teratologist Alan Mitchell, on 7-19-77.
We had previously
noticed his name on one of the DKP com-
pound inventory cards,
and his name had also been mentioned by
Raymond Schroeder,
in connection with DKP. Mr. Mitchell stated
that he had done
two teratology studies with DKP, both
with
rats, and both in
1972. In one study the DKP was administered
I.G. (as a suspension),
and the other was a dietary feeding
study. Mr. Mitchell
told us that he didn't recall any problems
with homogeneity
in the dietary feeding study. He said
he
never remixed or
reground any DKP diets. He admitted, however,
that when he prepared
the diet mixtures, he first sifted the
DKP through a hand
flour sifter.
We attempted to interview
a former Searle employee, Dr. Rao,
after learning the
the still lived in the Chicago area. Dr.
Rao had been in charge
of the DKP stability study and was
the monitor for study
E-77/78. After reaching Dr. Rao by
telephone on July
25, 1977 he stated that he would like
to
talk to his attorney
before consenting to the interview. We
then received a call
from his attorney, Mr. John H. Bickley,
Jr., who told us
that the interview would be of no advantage
to his client, and
he therefore refused to allow it. A memo
(27)
of telephone conversation
betwen J. Bressler and Mr. Bickley
is attached as Exhibit
#33.
CALCULATING DIET
CONCENTRATION & BLENDING OF TREATMENT
MIXTURES
There were no batch
records to show the quantities of DKP
and
basal diet weighed,
type of mixer used, mixing time, dates,
or names of individuals
performing the weighing and blending
operations. We were
told that mixing was performed in a
Hobard mixer, and
that mixing times were about 10 minutes.
There was no evidence
that any tests had been done to deter-
mine theblending
charactoeristics of the mixer, or to validate
the 10 minute mix
time. Fresh batches were mixed on a weekly,
bi-weekly, or monthly
basis, and batch size ranged from 6
kilograms to 28 kilograms
during the study.
The concentration
of DKP in the basal diet was calculated
by
the Mat-Stat Department
on a weeklly, bi-weekly, or monthly
basis (based on the
food consumtion for the previous time
period), and submitted
to the Path-Tox Department as a Food
Concentration Prediction
record. The concentration was ex-
pressed as grams
of DKP per kilogram of basal diet. The
Path-Tox Department
PErsonnel thenmultiplied the grams
of compound indicated
on the prediction record by the number
of kilograms of diet
mix needed to arrive at the proper
quantities of DKP
and basal diet to be blended. THe concen-
trations were calculated
to yield the proper dosage levels
of 9.75, 1.5, and
3.0 grams of DKP per kilograms of body
weight per day, for
the low, medium, and high dose groups.
(Copies of Diet Calculation
Records are attached as Exhibit
#34). At the end
of each treatment period, the remaining
treatment mistures
were discaded and fresh batches were
made.
Now reserve sample
of either the DKP or the DKP/diet mixtuures
used in this study
were retained according to Searle.
DKP was withdrawin
from stock by means of a compound inven-
tory card, which
was filled out by the person requesting
the material. Tony
Martinez was the person that usually
requested DKP for
use in study E-77/78. We examined eighteen
(18) compound inventory
cards which accounted for 177.0 kg
of DKP withdrawon
from stock. According to our calculations
a total of 152.81
kg of DKP would have been necessary
