FDA report on Searle's submission for NutraSweet approval 1977 - Part 1

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The "Bressler Report"


(Note: This is the text of an FDA report on Searle)


EIR 4/25/77 to 8/4/77



Searle Laboratories

Div. G.D. Searle & Co.

4901 Searle Parkway

Skokie, Illinois 60076




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.




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.




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-



Continue to Part 2


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