FDA report on Searle's submission for NutraSweet approval 1977 - Part 13

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the 11th and 13th weeks were averaged and the average substituted for the

missing data. Employees of Searle's Math-Stat Department who had worked

on the program for this experiment are no longer with the company. Dr.

Clay calculated a few of the figures from the 11th and 13th weeks and

stated that it appeared that the data had been averaged. For the FDA

recalculation it was chosen to omit the animals with the missing weights

from the calculations. In several instances (For example, C group males,

mid and high levels for the 13th week; A group males, high level for the

99th week) the dietary concentration shown on the weight sheets did not

agree with the concentration listed for that level in the other housing

groups. Dr. Clay assured us that all the animals of the same sex in a

given experimental group received the same dose for the same week on the

experiment. He also assured us that the Searle computer program did not

pick up the doses from the weight sheets. In the FDA program, the dietary

concentrations were taken from the diet calculation sheets (Exhibit #34).

Certain animals on the raw data sheets were marked with an asterisk. Dr.

Clay explained that the asterisk indicated spillage and such animals were

omitted from the food consumption calculations. This practice was

followed in the FD computer program. In calculating the food consumption

(g food eaten/day/ kg body weight) and the dosage (mg test

compound/day/kg body weight), the body weight used was the weight at the

end of the period under consideration, i.e. the current weight.


In addition to the calculations which were included in the Searle

submission, the FDA program included calculation of the actual amount of

food ingested, i.e., the total amount of diet ingested minus the test

compound, and of the food efficiency (g weight gained/100 g actual food

eaten). The food efficiency was calculated in order to determine whether

the volume of DKP in the diet (which exceeded 7% of the diet for the high

dose males at intervals during the study) was contributing to the body

weight depression seen with DKP> This explanation of the body weight

depression was discussed by Dr. John H. Rust, a Searle consultant, in a

memo dated April 5, l976 to Dr. R. McConnell; in a memo to the file dated

September 30, l974 by Dr. McConnell; and in a memo to Dr. K. S. Rao dated

August 29, l974 by Dr. G. L. Schoenhard. (Exhibits #36-38).


The average body weights and weight gain (% change/week) from the FDA

analysis of the Searle raw data are presented in Table 1 (Exhibit #39)

which corresponds to Table 3 of the Searle submission.




Weights which differ from the Searle submission by one (1) g or more and

weight gains by 0.1 percentage point, or more are underlined. Fifteen

differences were noted as follows:


Average Body Weight Discrepancies


Dose Searle

Days Sex Level Submission Calculated

280 M M 591.7 589.2

364 F L 353.2 345.1

420 M M 613.2 614.4

700 M C 595.4 579.3

728 M C 594.4 597.2

728 F H 343.1 341.2

784 F C 453.4 459.9


Percent Weight Gain Discrepancies


Dose Searle

Days Sex Level Submission Calculated

14 M C 35.11 35.23

21 M C 22.80 22.69

280 M M 0.33 0.21

364 F L -0.16 0.04

392 F L 1.13 0.85

728 F H 0.32 -0.18

756 F H -0.14 0.08

805 F C -0.04 -0.39


The food intake (in g/day and in g/kg/day) and dosage (in mg/kg/day) from

the FDA analysis are presented in Table 2. This table corresponds to

Table 4 of the Searle submission. there are numerous discrepancies (in

excess of 80) of one (1) gram or greater in the food intake expressed in

grams/day. Many of the discrepancies are probably the result of an error

in the Searle computer program (see Exhibit #76). Through this error

there was a failure to adjust the food intake for the precise number of

days between weighings for the individual housing groups. This

programming error had been pointed out to Searle by the Task Force but no

amendment to the Searle submission was made. There are more than forty

discrepancies of 5 or more grams when the food intake is expressed in

g/kg/day. The Searle programming error would contribute to discrepancies

in this expression of the food intake. The use of the current body weight

in the FD analysis may also be a contributing factor. Most of the dosage




calculations from the FDA program differ from the Searle submission by 10

or more mg. The two factors of the Searle programming error and the use

of the current body weight in the FDA analysis would contribute to

discrepancies between the FDA analysis and the Searle submission. Despite

the discrepancies the FDA analysis shows dosage levels corresponding to

the intended levels of 0.75, 1.5 and 3.0 g/kg/day. The test compound

would have to be homogeneously mixed into the basal diet in order for

these calculated dosage levels to be actually consumed. All

discrepancies between the Searle submission and the FDA analysis shown in

Tables 1 and 2 are underlined.


Table 3 presents the food efficiency (g gained/100 g actual food consumed)

calculated in the FDA analysis. There is no corresponding table in the

Searle submission. Tables 1, 2 and 3 and the computer printout of the FDA

analysis are Exhibits # 39-42. Statistical analysis of the body weight

and food consumption data was made and is shown as exhibit #73.




Organ Weights were entered on the gross pathology sheets at the time of

autopsy. We compared all of the individual organ weights on appendix

table 5 in the submission to FDA (Vol 1, pp. 222-226) with the original

data on the gross pathology sheets. A total of eleven (11) errors were

noted in transcribing the raw data from the pathology sheets, to the

tables in the submission to FDA.


The errors are tabulated below:


Wt. Shown In Wt. Recorded on

Animal No. Organ Submission Original Pathology Sheet


A12CM Kidneys 3.75 G 3.45 G

L28LM Ven. Prostrate 747 mg. 474.7 mg.

C0lMM Kidneys 9.40 G 9.219 G.

C02HM Kidneys 1.46 G 4.259 G

E14HM Kidneys 11.74 G 4.746 G

J12HM Pituitary 3.0 mg. 3.3 mg.

J30HM Ven. Prostrate 444 mg. 444.8 mg.

F17CF Ovaries 36.7 mg. 233.5 & 36.7 mg.

H30CF Liver 9.4 G 9.493 G

B20HF Uterus 1115 mg. 1155 mg.

K11HF Adrenals 799.1 mg. 797.1 mg.




Copies of the applicable pages of the submission, appendix table 5, with

errors indicated, are attached along with copies of the gross pathology

sheets documenting the errors. (See exhibit #83)




The submission to FDA (Vol. 1, P. 10) reported that an unidentified

infectious disease spread among the animals between 12 and 14 weeks of

treatment, and that a second unidentified infectious disease occurred in

high incidence between 48 and 52 weeks of treatment. In both cases, the

control and treated rats were reportedly affected with equal frequency and

severity. The same page of the submission also stated that over a period

of two weeks, a total of 17 animals (8 control, 3 low dose, 4 medium dose,

and 2 high dose) died. A memorandum dated October 13, 1972, and that more

animals were morbid. Dr. Rao reported that this primary antemortem

symptom observed was inappetance and labored respiration. Postmortem

examination of dead animals revealed primary lesions in the lungs, and

lungs exhibited patchy pneumonia, according to Dr. Rao. The memo indicates

that Dr. Rao intended to administer 10,000 units of penicillin G,

intramuscularly, to all the animals 2 to 3 times per day beginning

10/30/72. A copy of Dr. Rao's memo is attached to the protocol (See

Exhibit #77, Section 1).


The submission to FDA (Vol. 1, P. 10) stated that, "to prevent further

loss of animals, all morbid rats were injected IN with 20,000 units of

potassium penicillin G daily for 4-8 days."


A review of the injection records (attached to Vol. A of Exhibit #75)

showed that some animals were treated between approximately 51 and 60

weeks, and in one instance, a high dose animal, kB3HF, received at least

10 injections. In addition, some animals received 30,000 units per day

(10,000 units 3 times per day) rather than the 20,000 units reported in

the submission.


The records also indicated that penicillin was administered to four rats

beginning on May 16, l973, and continued daily through May 28, l973. This

third occurrence of infectious disease and penicillin administration was

not reported in the submission to FDA.


Continue to Part 14


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