FDA report on Searle's submission for NutraSweet approval 1977 - Part 9

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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).




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




of telephone conversation betwen J. Bressler and Mr. Bickley

is attached as Exhibit #33.




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



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


Continue to Part 10


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