FDA report on Searle's submission for NutraSweet approval 1977 - Part 3

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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



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".






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-



2.) E-89 (PT #1218S75), An evaluation of the Embryotosic and Tetato-

genic Potential in the Mouse, conducted with SC-18862 (aspar-



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.




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.




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".




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.


Continue to Part 4


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