(6)
G. Clinical Laboratory Procedures
1. Laboratory records of
one sort or another for all assays report-
ted in the submission were
obtained. In some cases data sheets
were noted with results of
assays carried out at treatment days
not indicated in the protocol
or protocol amendment. For example,
serum cholesterol determinations
were done at days 796 and 798
(terminal bleeding) but not
included in the submission to FDA.
Because the submission to
FDA (Vol. 1 p. 286) reported a signi-
ficant decrease in serum
cholesterol that was more perceptible
towards the end of the study,
and may have been related to
compound administration,
the omitted data is of some importance.
2. No data was seen for two
assays (serum insulin and serum ornit-
hine carbamyl transferase)
which were called for in an amend-
mend to the protocol.
3. Original data was not
always available for authentication of
results or examination of
procedures for conversion of raw
data into the calculated
values submitted to FDA.
4. Data pages for clinical
chemistry and urinalysis were initialled
by a technician who transcribed
data but apparently was not
directly involved in the
assays indicated. He stated in an
interview that Dr. Rao told
him to initial the data sheets.
5. The methodology as referenced
in the submission to FDA is incom-
plete and not always an accurate
reflection of the methodology
actually used in the study.
The fact that more than one method
was sometimes used for a
particular assay during different times
of the study was not indicated
in the submission to FDA.
6. A total of 21 disparities
between individual clinical laboratory
analysis values appearing
in the submission Volume I and those
values appearing in data
sheets and/or laboratory notebooks were
found.
7. A total of 49 disparities
were noted between statistical
computations reported by
Searle in the submission and
those calculated by FDA.
The disparities are constituted
by the values for 6 means,
23 standard errors, and 20 signi-
ficant differences (as measured
by T tests).
8. Some of the data sheets
for urinalysis had erroneously
labeled the phenylketones
test values as "phenylalanine".
(7)
PURPOSE OF INVESTIGATION
Assignment memo dated may
16, 1977 from Donald Healton, Acting
Director of Regional Operations,
confirmed an earlier oral
assignment to Chicago District
for a directed inspection of cer-
tain non-clinical studies
submitted to FDA in support of a food
additive petition for the
sweetener aspartame.
The investigation began on
4/25/77, and encompassed the authen-
tication of all data, both
raw and summary, relating to the
studies jointly chosen for
review by Bureau of Foods and EDRO.
Two studies actually done
at G.D. Searle were selected for initial
coverage, and a decision
to expand the investigation to a third
study was made at a later
date.
Following are the titles
of the three studies selected for review:
1.) E-5 (P.T. #851S70), Evaluation
of the Embryotoxic and Teatogenic
Potential in the Rat, conducted
with SC-18862 (aspar-
tame).
2.) E-89 (PT #1218S75), An
evaluation of the Embryotosic and Tetato-
genic Potential in the Mouse,
conducted with SC-18862 (aspar-
tame).
3.) E-77/78 (PT #988S73),
115 Week Oral Tumorigenicity Study in the
Rat, conducted with SC-19192
(diketopiperazine).
This report is concerned
only with study E-77/78. The report of
E-5 and E-89 was submitted
separately.
HISTORY OF BUSINESS
G. D. Searle & Co. provides
a wide range of health care products
and services on a worldwide
basis. Its business is divided
among three principal areas:
pharmaceuticals, medical instru-
ments and optical products,
and hospital and laboratory products.
The firm's corporate offices
are located in Skokie, Illinois,
with various branches and
facilities throughout the world.
Effective June 1, 1977, Donald
H. Rumsfeld assumed duties as
President and Chief Executive
Officer. Mr. Daniel C. Searle,
formerly Chief Executive
Officer is now Chairman of the Board,
while William L. Searle and
Wesley M. Dixon, former Chairman
and President respectively,
are now Vice-Chairmen.
(8)
Effective March 1, 1977,
the firm underwent a major realignment,
shifting to a managerial
system based on product lines. This
resulted in the establishment
of four main product-line groups,
which are: Pharmaceutical/Consumer
Products, Diagnostics,
Hospital Supplies and Optical
Products. Each group is headed
by a President who will report
to Searle's Executive Vice-Presi-
dent for Operations, Dr.
James A. Buzard. A copy of the G. D.
Searle & Co. annual report
for 1976 which is attached as Exhibit
#1 further expands on the
firm's operations and lists Corpor-
ate Officers.
Mr. O. B. Parrish is President
of the Pharmaceutical/Consumer
Products Group and also a
Corporate Vice-President. An organi-
zational chart for this group
is attached as Exhibit #2. Mr.
Guy Labrosse is now Group
Executive Vice-President for U. S.
Commercial Pharmaceutical
Operations. In the U. S., this is known
as Searle Laboratories. The
facility at 4901 Searle Parkway,
Skokie, Illinois is a part
of the U. S. Operations, e. g. Searle
Laboratories, yet houses
the majority of the Research and
Development Group.
Worldwide Pharmaceutical
Research and Development is also a
part of the Pharmaceutical/Consumer
Products Group, but not of
Searle Laboratories. The
Research and Development OF aspartame
is a function of this group.
Copies of organizational charts
for this group are attached
as Exhibit #3. Dr. Robert A. Moe
recently resigned and his
position is temporarily being filled
by George V. O'Bleness, Corporate
Vice-President for Compliance
and Administration.
Commercial aspects of Aspartame
are being handled by an "aspar-
tame Division", under
the direction of Elwood H. Ensor, Corpor-
ate Vice-President. There
is no longer a division entitled
"New Ventures".
PERSONS INTERVIEWED
Credentials were shown and
a written Notice of Inspection was
issued to Dr. William M.
Merino, Directory, Domestic Pharmaceu-
tical Products, Regulatory
Affairs Department on April 25,
1977. The following Searle
personnel were present at the
initial meeting on 4-25-1977.
