FDA report on Searle's submission for NutraSweet approval 1977 - Part 21

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When this study was reviewed by the Bureau of Foods in l975, the

dose-related incidence of uterine polyps was noted. The appropriate

slides were requested by FDA at that time and were reviewed by three

groups of pathologists: 1.) The Division of Pathology, Bureau of Foods,

2.) Armed Forces Institute of Pathology, 3.) Massachusetts Institute of

Technology. Copies of the reports submitted by the 3 groups and related

correspondence were obtained and are attached as exhibits #43-45.


Dr. Rudolph Stejskal was responsible for the microscopic findings and

accuracy on these findings in the submission to FDA. Only Dr. Stejskal's

name appears on the submission. However, a Dr. Joseph H. Smith, M.D. also

read slides for this study and his initials appear on some of the

microscopic examination sheets. Dr. Frith questioned some of the

terminology used in describing tissues. Dr. Stejskal stated that Dr.

Smith had come directly to SEarle from a hospital situation. Due to his

human pathology background, his description of animal tissues was somewhat

different than that used by veterinary pathologists.


Dr. Stejskal joined SEarle in July of l973, therefore, he had no input

into the pathology protocol, since E-77/78 was initiated in November of



No microscopic worksheets or other "raw data" relating to microscopic

pathology could be found for study E-77/78. We were told by Searle

personnel that the original microscopic findings were dictated by the

pathologists (Stejskal & Smith) onto belts, and then typed onto sheets

which were placed in a binder. The belts were then discarded and

apparently the bound microscopic pathology sheets were either discarded or

lost, after the study report was written. Therefore our verification of

the microscopic findings submitted to FDA was limited to a complete

inventory of the slides and tissue blocks and microscopic examination of a

representative number of slides by Dr. Frith.


Our inventory of the slides and tissue blocks for each animal

included a complete list on the tissues sectioned, the number

of slides made from each tissue, and a complete count of the

total number of slides and blocks for each animal. We also checked

the identification numbers on every slide and tissue block. We

examined a total of 7,872 slides and 7,360 tissue blocks. The

average number of organs submitted for tissue processing was




20 per animal. No errors in slide identification were noted,

although in many cases the number of organs submitted for sec-

tioning was less than specified in the protocol. A detailed dis-

cussion of this can be found under the heading PROTOCOL.


In addition to the discrepancies noted by Dr. Frith, some other errors

were noted in the submission to FDA. A mammary tumor found in rat F27CF

was described as a papillary cystadenoma on the individual pathology sheet

(page 105, Volume II of the submission to FDA) and as an adenocarcinoma on

the summary table 12, page 96, Volume I of the submission to FDA.


Page 92, Volume I of the submission to FDA (a summary table) reports that

animal J23CM was found dead after 754 days on study, while the individual

pathology sheet for this animal (page 56, Volume II of the submission to

FDA) reported that the animal was found dead after 620 days on study.

The correct figure is 620 days, since J23CM was placed on the study on

11/17/72 and was found dead on 7/29 /73.


In several instances the histopathology technician made notes at the

bottom of the gross pathology sheet to indicate that certain organs were

not present in the bottle of fixative. (and were therefore not available

for sectioning). Yet in three of these instances (animals A4CM, K23CF,

and J3CM) a diagnosis appears in the submission to FDA.




It was necessary to construct a number of charts, diagrams and tables to

facilitate our review of the data. For example we constructed a chart, by

housing group, showing the identification and complete pathology history

of each of the 360 animals. We also rearranged this chart into dosage

groups, a copy of which is attached as exhibit #35.


To compare survival data it was necessary to construct a survival table.

This also involved devising a calendar to show days and weeks on study for

each housing group, taking into account the starting dates for each group.

This also included tables showing the numbers of days and weeks animals

were on study and a table comparing the survival data from various



We constructed a chart showing diet calculations (gm./kg) and total

amounts of DKP used (gm./batch). This is attached as exhibit #30.




Three tables were constructed which summarize the FDA statistical analysis

of body/feeder weight data. They are attached as exhibits #39-41.


All of the charts, diagrams and tables that we constructed are attached to

the report as exhibits and are referred to in various sections of the





#1. G.D. Searle & Company Annual Report for l976.

#2. Organizational Chart of Pharmaceutical/Consumer Products Group.

#3. Organizational Chart of World Wide Pharmaceutical R&D Group.

#4. Organizational Chart of Preclinical R&D Group.

#5. Organizational Chart of Product Safety Assessment Group.

#6. Copies of Computer-Generated Randomization Tables used by Searle

to assign the Dose & Housing Groups.

#7. Diagram showing Typical Housing Group of 30 animals, containing

a random distribution of control and treated animals.

#8. Diagram showing arrangement of food cups on cart, used in feeding

the animals.

#9. Copy of "Glossary of Terms for Aspartame and its Diketopiperazine"

and "Analytical Data and Specifications of Food Grade Aspartame".

#10. Copy of shipping labels for rats received from


#11. Copy of protocol with amendments for Study P.T. 988S73 (E-77/78).

#12. Copies of CV's for principal persons involved in study E-77/78.

#13. Copies of Batch Records for the manufacture of DKP, lots 1R through


#14. Copies of pages from SEarle chemist Jack Drogt's notebook, con-

cerning the manufacture of DKP.

#15. Copies of Analytical Reports for DKP, lots 1R through 7R.

#16. Copy of Searle memorandum dated 12/4/69, concerning DKP Specifica-


#17. Copy of DKP Specification Sheet (not dated) entitled

"Tenative Specifications for SC-19192".




#18. Copy of DKP Specification Sheet entitled "Specifications for

SC-19192, Specification #C40606C".

#19. Copies of pages 75-84 & 285 of lab notebook #AR-39, concerning

assay of DKP, lots 1R, 2R & 3R.

#20. Copies of pages 60-63 of lab notebook VSH-I, and page 269 of

lab notebook book #AR-23, pertaining to analysis of DKP lot 4R.

#21. Copies of pages 250, 251 and 257 of lab notebook #AR-57, and

pages 44-49 of lab notebook #AR-68, pertaining to analysis of

DKP lot 5R.

#22. Copies of pages 83-86 of lab notebook #AR-77, concerning analysis

of DKP lot 6R.

#23. Copy of page 31 of lab notebook #AR-93, concerning analysis of

DKP lot 7R.

#24. Copy of protocol for DKP stability study, dated 1/13/72.

#25. Copies of pages 51-56 of laboratory notebook #AR-49, assigned to

C. Seul. These pages describe a preliminary TLC Test for

recovery of DKP from the diet mixture.

#26. Copies of pages 53-59, 67-72, 88-89, 106-107, 144-145, 156-157,

and 284-285 of laboratory notebook #AR-51, assigned to Barbara

Bickford. These pages refer to the assay procedure and methods

for the DKP Stability Study.

#27. Copies of Analytical Reports for DKP Stability Study.

#28. Copies of DKP Compound Inventory Cards.

#29. Two photographs showing a non-homogeneous sample of DKP diet mixture.

#30. Chart showing diet calculations (gm.kg.) and total amounts of DKP

used (gm./batch).

#31. Two memos dated 7/14/77 from Thomas F.X. Collins concerning interview

with Ray Schroeder.

#32. Memo dated 7/19/77 from Thomas F. X. Collins describing the 7/18/77

interview with Ray Schroeder.

#33. Memo of Telephone Conversation between Jerome Bressler and Attorney

John H. Bickley Jr., dated July 25, l977.

#34. Copies of records concerning calculation of diet concentrations, food

concentrations prediction records, dates of bath mixing, and calcu-

lation of mean food intake values.

#35. Charts organized by dose group, showing the identification and

pathology history of each of the 360 animals on study.

#36. Memo dated April 5, l976, from Dr. John H. Rust to Dr. R. McConnell.

#37. Searle memo dated September 30, l974, by Dr. McConnell.


Continue to Part 22


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