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The "Bressler Report" Note: This is the text of an FDA report on Searle (Part 4 of 5 ... Pages 51-68) EIR 4/25/77 to 8/4/77 Searle Laboratories JSA/DME/JT/LF Div. G.D. Searle & Co. 4901 Searle Parkway Skokie, Illinois 60076 (Page 51) As described by Judith R. Schmal (June 7, 1977) the method used from November 1971 to February 1, 1974 was adapted from Fermco Kit Bulletins #20 and 20-1. Urea is hydrolyzed to ammonia and carbonic acid in the presence of urease. Ammonia is detected by the Berthelot reaction to produce indophenol. From February 1, 1974 the "direct serum methond" modified from the method of Marsh et al was used. 4) Phenylalanine Reference: Hill, J. B., Summer, G. K. Pencer, M. W. Resz N.O. (1965) Chin Chem 11, 541 From Nov. 1971 to about Septembe 1972 there is no documenta- tion in file as to method used. From about September 1972 the method used was a flurometric determination in the pre- sence of ninhydrin and l-leucyl-l-alanine as adapted from McCaman and Rubins. (This is a manual method modified for automation by Hill et al - reverenced above) (Judith R. Schmal, June 7, 1977) 5) Calcium: Reference Pybus J., (Pylrus in submission), Feldman, F. J., and Browers (Borrers in Submission) Jr., G. N. (1970) Clin. Chem. 16 (11 in submission), 998. The referenced method involves the measurement of total cal- cium in serum by atomic absorption spectrophotometry. As described by Judith R. Schmal (June 7, 1977) from November, 1961 to February 1974 the procedure used was a colorimetric procedure using Corinth dye as adapted from Kingsley and Robnet. From May 21, 1973 the method used was atomic absorp- tion spectrophotometry, as adapted from Pybus et all (reference above) 6) Total Cholesterol Reference: Levine J. S., Morgenstern, S., and Vlastelica, D. (1968). Automation Anal Chem. pp 25-28, Technicon Symposia 1968. We were unable to check the above reference because of diffi- culty up to now in obtaining a copy of the publication, but as shown below two different procedures were employed to measure total serum cholesterol at different times during the study. (51) (Judith R. Schmal, June 7, 1977). From November 1971 to July 2, 1973 the method involved reacting an isopropanol extract of serum with ferric chloride (modified from Block, Tirret and Levine). From July 2, 1973 the method used was a direct serum method using a modified Lieberman - Burchard reaction. 7) Glucose Reference: Frings, C.S., Ratliff, C.R. and Dunn, R.T. (1969) Advances in Automated Analysis 1, 73 This reference was not checked (because of difficulty up to now in obtaining a copy of the publication) but as shown below two different procedures were employed to measure serum glucose at different times during the study (Judith R. Schmal, June 7, 1977). From November 1971 to October 16, 1972 the method was a glucose oxidase determination (modified Gertrud Acrow) using protein free filtrates. From October 16, 1972 the method was a direct serum O-Toluidine reaction as modi- fied from Frings, Ratlif and Dunn. In the case of four of the above parameters (glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, blood urea nitrogen and calcium) different methodology was used during part of the study then was indicated in the submission. For one parameter (phenylalanine), there was no documentation as to the method used for one period of the study and for two other parameters (total cholesterol and glucose), two different methods were used for each of the parameters while only one was referenced in the submission. Alkaline phosphatase was measured generally as referenced in the submission (McComb, R.B. and Borrers, G.N. (1972). Clin. CHem., 18, 97 in that the method involved measuring the production of p-nitrophenol from p-nitrophenylphosphate However starting July, 1973 there was a "re-optimization of reagent concentrations" (Judith R. Small, June 7, 1977). The above changes in procedure could conceivably result in dif- ferences in the apparent absolute values for the concentration of the substances measured. Changes in the method of conver- sion of raw data to calculated values as was don in the determination of sodium and potassium by atomic absorption spectrophotometry during different periods of the study, (Judth R.Schmal, June 7, 1977) could also possibly produce differences in final values. (52) In an interview with Judith Schmal on June 2, 1977, she did state in response to a question that two levels of "Serum Controls" were used in each run to check the method and instruments and that the data was not reported if the values were more than two standard deviations greater than that for the expected values. NO evidence was obtained that any attempts were made to determine whether or not DKP cold interfere with any of the clinical lab- oratory tests conducted. For that matter no information was made available to us as to whether DKP itself or related compounds did appear in the blood or the urine of rats fed diet containing this compound. Neither, as a result of interviews held or reference to available laboratory notebooks were we able to obtain information helpful in explaining the unusually low values for BUN for the control males at treatment days 189 and 364 and for all the treated male groups at treatment day 364. No raw laboratory data in reference to this could be found and may have been recorded on discarded teletype sheets referred to previously. In reference to the low BUN values, Page 29 of the submission contains the following statement: "BUN" values for the control males at treatment day 189 were unusually low and may possibly be related to a technical artefact; as a result, the group mean values for all treated males at this interval were significantly higher but, in fact, these values were in the normal range. BUN values both in control and al treated male groups at treatment day 364 were unusually low; this again reflects a possible technical artefact." F. 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 found (Table 4). Of these, 17 were in hematology, one in clinical chemistry, and three in urinalysis. As a result of the discussion with Robert Bost, it was apparent that some of the hematology discrepancies may have resulted for Searle personnel mistaking recorded instrument readings for calculated values. In two cases no value or crossed out values appeared in the laboratory notebooks while values were found entered onto the appropriate places in the data sheets. For animal number A01HM and treatment day 546 four discrepancies (hematocrit, hemoglobin, RBC and WBC) were noted. (53) G. Discrepancies Found In Statistical Analysis: The mean and standard errors for the three dose levels and the controls for the various measurements using the values in the submission Volume I or values noted in the data sheets (where there values differed from those found in the submis- sion) were calculated by the Division of Mathematics, FDA. Also supplied were the results of the T-TEsts comparing the con- trols to the treated groups. See memo to Leonard Friedman from Dennis Wilson, dated July 20, 1977 with attached Tables 1 and 2 (Exhibit #87). A total of 49 disparities were found, which were comprised of 6 means, 23 standard errors and 20 significant differences. As stated in the memo, in all cases where there is a disparity, it appears to be due to differences in the data. Calculations were also carried out for cholesterol data found in the data sheets but not reported in the submission. As shown in Table 5 the mean values for the median and high level treated females and the high level treated males were significantly lower than the mean values for the respective controls. To illustrate the possible significance of these changes and disparities between the values calculated by Searle and FDA for cholesterol data at the other time periods of treatment, table 5 was constructed. Very few disparities are seen between the calculated values obtained by FDA and those in the submission but a fairly consistent trend is seen for treatment related lowering of serum cholesterol, particularly at the two highest dose levels and for the female rats. Because additional disparities were recently noted in individual hematology values after these statistical computations by FDA were completed (due to the discovery of additional laboratory notebooks), and addendum to this report regarding the statistical disparities reported here will be forthcoming. (54) TABLE 5 TOTAL SERUM CHOLESTEROL (MG/DL) TREATMENT 42 92 189 364 734 798 GROUP - - - - - - THIS ENTIRE PAGE OF DATA GUTTED BEFORE RELEASE OF THIS REPORT UNDER THE FREEDOM OF INFORATION ACT! WHAT DID THE FDA DECIDE TO KEEP FROM THE PUBLIC IT "PROTECTS"? - - - - - - - - (55) GROSS PATHOLOGY The pathologists responsible for the microscopic examination (Rudolph Stejskal and Joseph smith) did not perform the necropsies. Necropsies were performed by Tony Martinez, David Kie and Robert Spaet, with the two pathologists avilable for consultation. The submission to FDA (Vol 1, p. 7) reported that "Rats found dead during the study were autopsied immediately whenever possible. In cases where the ncropsy could not be performed promptly, the thoracic and abdominal cavities of dead rats were opened and the entire animal was immersed in neutral buffered formalin fixative for subsequent gross examination and dissection". Our examination of gross pathology records showed that 98 of the 196 animals that died during the study were fixed in toto and autopsied at some later date, in some cases more than one year later. A total of 20 animals were excluded from the study due to excessive autolysis. Of these, 17 had been fixed in toto and autopsied at a later date. Following are the twenty animals excluded from the study: Animal No Date Found Dead Date Autopsied C21CM 7/3/73 1/11/74 G16CM 9/21/73 1/11/74 G18CM 8/11/73 10/4/73 G26CM 4/2/73 1/11/74 J2CM 5/21/73 1/11/74 J5CM 10/30/72 11/8/72 L10CM 3/29/73 1/11/74 L15/CM 9/9/73 1/11/74 L21CM 4/13/73 1/11/74 L11LM 5/6/73 1/9/74 A14MM 5/21/73 1/9/74 G28MM 1/5/74 1/7/74 J25MM 5/24/73 5/24/73 A3HN 6/17/73 1/9/74 C15HM 1/7/74 1/7/74 (56) Animal No Date Found Dead Date Autopsied G13HM 7/25/73 **1/9/74 H24CF 4/29/73 1/11/74 D4HF 7/11/73 7/11/73 D16HF *4/2/73 1/8/74 F6HF 1/5/74 1/7/74 *Although the date found dead was listed as 4/12/73 on the gross pathology sheet, the "Tissue Masses & Deaths" book listed this date as 4/1/73. **Although the date found dead was listed as 1/9/74 on the gross pathology sheet, the "Tissue Masses & Deaths" book listed this date as 7/25/73. The gross pathology sheet for one of the above animals, F6HF, described a tissue mass measuring 5.0 X 4.5X2.5 cm. This tissue mass was first observed on 8/24/73 according to the pathology sheet (Exhibit #79), the observation records (Exhibit #70), and the palpation record in the "Tissue Masses and Deaths" book (Exhibit #65). The submission to FDA (Exhibit #8) reported no tissue mass and the animal was excluded from the study due to marked autolysis. In addition to the above twenty animals that were excluded from the study, many other animals exhibited marked autolysis. For example, D27LF, M25CF, and H12CF are all described grossly in the submission to FDA as follows; "all organs examined grossly were markedly autolyzed". Records for approximately 30 animals showed substantial differences between gross observations on pathology sheets, when compared with the individual pathology summaries submitted to FDA. Following is a detailed comparison of ten of these. (Copies of all the gross pathology sheets, and the pathology summaries submitted to FDA are attached as Exhibits #78, #79, and #86). A2CM Submission to FDA: Lung - Focal adhesion Adrenal - Moderately enlarged (57) All other organs examined grossly were unremarkable. Original Pathology Sheet: Pituitary - Missing Lung - Left, mid-portion adheres to the medial area of the rib cage by a "fibrous" type of tissue. (Sub- mitted together with relevant portion of the rib cage). Right, post-caval lobe has undergone consolidation. Contains grayish-yellowish nodules measuring 2 x 2 mm. (Entire lung submitted in toto) Lymph NOdes, Pancreatic - Slightly enlarged Adrenal - Left, moderately enlarged. Right and left, covered with tiny yellow spots measuring 1.0 x 1.0 mm. Lymph Nodes, Mesenteric - moderately enlarged. Mass - previously described on 8/20/73 has since then regressed. Prostate - Marked atrophy, all lobes Seminal Vesicles - Marked atrophy, bilaterally All other organs examined were grossly normal and unremarkable. M15CF Submission: Mammary gland - subcutaneous mass located in mid-thoracic region measuring 7 x 6 x 2.5 cm. Urinary bladder - papillary growth in the lumen. All other organs examined grossly were unremarkable. Original: Mass #1 - Previously described in the left inguinal region on 2/9/73 has since then regressed. (58) Masses #2 and # - Located in the mid-axillary-cervical regions are all on mass now measuring 7.0 x 6.0 x 2.5 cm and may be described as irregular in shape, multi- nodular, smooth-surfaced, non-glistening, No Spinal Cord yellowish-purpulish in color, non-adherent to the VL underlying muscle and containing a whitish-yellowish firm tissue within. (Submitted in toto together with remainder of tissue). Heart - Left Ventricle - dilitation and walls thin. Spleen - Slightly enlarged Liver - Prominent lobular architecture. Adrenal - Left, slightly enlarged. Right, unremarkable. Ovary - Right, small cyst measuring 4.0 x 4.0 mm and distended with a clear yellow fluid. All other organs examined were grossly normal and unremarkable. G10LM Submission: Testis - Marked atrophy, unilaterally. Kidney - Moderate enlargement, mottled appearance, bilaterally. Small and large intestine exhibited moderate autolysis, no sections submitted. All other organs examined were grossly normal and unremarkable. Original: Mass which was initially palpated on 2/9/72 (86 days Rx) in the left inguinal area was actually the left testis which ascended and went thru weakened left inguinal ring into the subcutaneous area. Testis - Left (ascended) appears atrophied (submitted in toto). Kidney - MOderate, diffuse and uniform enlargement, mottled, bilaterally (submitted in toto). Small and large intestines are moderately autolyzed (no sections submitted). Thyroid - Moderately enlarged, bilaterally. A 2 mm in dia., dis- crete, sl raised, moderately firm yellowish-grey lesion is located in the posterior tip, bilaterally. (Thyroid submitted in toto wrapped in a lens paper). All other organs examined were grossly normal and unremarkable. (59) L11LM Submission: Kidney - Mottled appearance Testes - Marked atrophy, bilaterally Prostate - Marked atrophy All other organs examined grossly exhibited marked autolysis. Original: Adrenal - Pale yellow, bilaterally Kidney - Pale yellow, bilaterally, rough-surfaced, bilaterally, moderately autolyzed, bilaterally, tiny spaces in the cortex region measuring about 1 mm in diameter, bilaterally. Testes - Marked atrophy, bilaterally, marked autolysis, bilaterally. Prostate - Marked atrophy, all lobes Seminal Vesicles - Marked atrophy, bilaterally Spleen - Marked autolysis Pancreas - Marked autolysis Stomach - Marked autolysis. A glandular portion - numerous, tiny, pitted ulcerations measuring 1 -4 mm in diameter. Lymph Nodes, Mesenteric - Marked autolysis Heart - Wall of left ventricle thin Brain - Marked autolysis Pituitary - Marked autolysis Liver - Marked autolysis All other organs examined were grossly normal and unremarkable. M17LF Submission: Pituitary - Marked enlargement. Adrenal - Markedly enlarged and hyperemic, bilaterally. Mammary Gland - Mass 1, located subcutaneously in left axillary region, measuring 3 X 3 X 2.5 cm; mass 2, located subcutaneously adjacent to mass 1, measuring 3 X 2 X 1 cm; mass 3, located subcutaneously in the right axillary region, measuring 2.5 X 2 X 1 cm; mass 4, (60) located subcutaneously in the left inguinal region, measuring 3 X 1 X 1 cm; mass 5, located subcutane- ously in the right inguinal region, measuring 2 X 1.5 X 1 cm. All other organs examined grossly were unremarkable. Original Pit - appears markedly hyperemic Adrenal - Exhibits numerous minute greyish spots on the serosal surface bilaterally. It appears markedly enlarged. Mass (1) - A 3 X 3 X 2.5 cm. spheroidal, multinodular, yellowish white, slightly firm mass located subcutaneously in the left axillary area. Mass non-adherent to the surrounding muscles or tissue (submitted in toto). Mass (2) - A 2.5 X 2 X 1 cm spheroidal, smooth, yellowish white firm mass located subcutaneously and adjacent to the above described mass (submitted in toto) mass non- adherent to the surrounding muscles or tissues. Mass (3) - A 2.3 X 2 X 1 cm. irregularly shaped, multinodular, yellowish white, firm mass located subcutaneously on the rt. axillary area. Mass non-adherent to the surrounding muscles or tissues (submitted in toto). Mass (4) - A 3 X 1 X 1 cm. elongated, multinodular, yellowish white, firm mass located subcutaneously on the left inguinal area. Mass non-adherent to the surrounding muscles or tissues (submitted in toto). Mass (5) - A 2 X 1.5 X 1 cm. flat, multinodular, yellowish white, firm mass located subcutaneously on the rt. inguinal area. Mass non-adherent to the surrounding muscles or tissues (submitted in toto). All other organs examined were grossly normal and unremarkable. C1MM Submission Kidney Marked enlargement with yellowish discoloration. Testis Marked atrophy, bilaterally. (61) Tissue mass located subcutaneously in the right inguinal area measuring 2.5 X 1 cm. All other organs examined grossly were unremarkable. Original: Mass - Previously described on 12/9/72 and located subcutaneously in the right inguinal area now measures 2.5 X 2.0 X 1.0 cm and may be described as smooth-surfaced, purplish- yellowish in color, non-glistening, firm, multi-nodular, non-adherent to the underlying muscles and containing a firm yellowish-whitish tissue. (Submitted in toto together with a portion of the skin and underlying muscle with remainder of tissue). Heart - Left ventricle has undergone a moderate amount of dili- tation. Wall, left ventricle is thin. Liver - Prominent lobular architecture. Lung - Right, post-caval lobe-consolidation. Kidney - Markedly enlarged, yellow and rough-surfaced, bilaterally. Dilitation of the pelvis. Adrenal - Covered with tiny yellow spots measuring 1 mm in diameter, bilaterally. Testes - Marked atrophy, bilaterally. All other organs examined were grossly normal and unremarkable. Tiss. Trimming - Nodules discovered immediately posterior (2.0 cm) to the pyloric portion of the stomach within the adipose tissue. Nodules may be described as firm, yellowish brownish in color. Non-glistening measuring 1.2 X 1.0 mm to 4.0 X 4.0 mm. E27MM Submission: Lung - Moderate diffuse hyperemia. Eye - Opaque cornea, bilaterally. All other organs examined grossly were unremarkable Original: Lungs - All lobes exhibit moderate diffuse and uniform hyperemia. (62) Kidney - Moderate autolysis. Eye - The entire cornea is opaque, bilaterally. Spleen - Moderately autolyzed. Stomach - Numerous 1-2 mm. hemorrhagic ulcerations are located on the glandular mucosa. Entire small and large intestines are moderately autolyzed. Brain & Pituitary - Moderately autolyzed. All other organs examined were grossly normal and unremarkable. A1HM Submission: All organs examined were grossly unremarkable. Original: Testes - Markedly atrophy, bilaterally Lung, Rt - Middle lobe exhibits a 1 X 1 cm consolidation on the posterior portion. Liver - All lobes appear olive green otherwise unremarkable. All other organs examined were grossly normal and unremarkable. L27HM: Submission: Testes - Right, slightly enlarged; left, mild atrophy. All other organs examined grossly were unremarkable. Original: Testes - lt./appears markedly atrophy rt./appears to be distended with yellowish white substance Seminal V- Appears markedly atrophy bilaterally. Intestinal - Large, markedly distended with "gas". All other organs examined were grossly normal and unremarkable. P.M. Testes - Also, small black areas are noted within along with the yellowish areas. Black areas measuring 1.0 X 1.0 to 4.0 X 4.0 mm in diameter. (63) J30HM Submission: Lung - Moderate consolidation of all right lobes. Testis - Moderate atrophy All other organs examined grossly were unremarkable. Original: Pituitary - Markedly enlarged; slightly hyperemic. Heart - Left Ventricle has undergone dilitation walls thin. Lung - Right, anterior, medial and post-caval lobe have undergone consolidation. Testes - Marked atrophy, bilaterally. Seminal Vesicle - Marked atrophy, bilaterally. All other organs examined were grossly normal and unremarkable. Dr. Stejskal told us that the other pathologist (Dr. Joseph Smith) who made microscopic evaluations of the slides, came from a hospital background (human pathology) and therefore his descriptions and terminology were a little bit different than one would expect from a veterinary pathologist. MICROSCOPIC PATHOLOGY We have assisted in our review of the Microscopic Pathology of Study E-77/78 by Charles H. Frith, D.V.M., Ph.D, Director, Pathology Services, NCTR. Dr. Frith arrived on 6/22/77 and spent 3 days with the FDA team. He examined slides for a representative number of animals, the selection of which was made jointly by Dr. Frith and the other members of the FDA team. A Searle Pathologist was not present during Dr. Frith's review of the slides. However, Dr. Frith did meet with Dr. Rudolf Stejskal, SEarle Pathologist, at the conclusion of this review and discussed some of his findings with him. The first phase of Dr. Frith's review consisted of the examination of the tissues of 25 of the surviving control females and 11 of the non-surviving control females for a total of 36 animals. All of the slides were examined for each animal and the results were compared to the microscopic reports provided by Searle Laboratories. The inconsistencies (findings that differed from those reported by Searle) are listed below: (64) In most cases the inconsistencies represent findings that were not diagnosed or reported by Searle. Copies of Searle's microscopic pathology reports for each of the animals listed below are attached as exhibit #60. Female Rat No. F13CF (Path. No. 95617) Small Intestine - Diverticulum with mucosal necrosis and cellular inflammatory infiltrate. Female Rat No. F15CF (Path No. 95618) Pancreas - Focal hyperplasia Female Rat No. F16CF (Path No. 95619) Heart - Focal Fibrosis. Kidney - Mild chronic nephritis. Female Rat No. H10CF (Path 95624) Ovary - Neoplasm - probably granulosa cell tumor. Female Rat No. H19CF (Path. No. 95626) Kidney - Focal calcification. Ovary - Neoplasm - probably granulosa cell tumor. Female Rat No. H30CF (Path. No. 95628) Kidney - Focal calcification. Female Rat - No. K25CF (Path No. 95630) Kidney - Focal calcification. Female Rat No. K29CF (Path No. 95631) Heart - Focal fibrosis Kidney - Focal calcification Female Rat No. M4CF (Path No. 95632) Liver - Focal hyperplasia Female Rat No. M10CF (Path No. 95634) Kidney - Focal calcification. Pituitary - Adenoma Ovary - Fibrosis and Pigmentation. (65) Female Rat No. M15CF (Path No. 95635) Pituitary - Adenoma. Ovary - Cyst. Female Rat No. B30CF (Path No. 95801) Kidney - Focal calcification. Female Rat D29CF (Path No. 95803) Urinary Bladder (1) Chronic diffuse inflammation. (2) Diffuse mild hyperplasia. The second phase of the review consisted of the microscopic examination of all tissues from the high dose females - a total of 36 animals. The inconsistencies are listed below: Female Rat No. B14HF (Path. No. 95657) Eye was reported as not examined but eye was present and normal. Female Rat No. F25HF (Path. No. 95823) Urinary Bladder - Mild diffuse hyperplasia. Female Rat No. H7HF (Path No. 95623) Ovary - Neoplasm - probably granulosa cell tumor. Female Rat No. H9HF (Path No. 95665) Heart - Focal fibrosis. Urinary Bladder - Mild focal hyperplasia. Female Rat No. H15HF (Path No. 95665) Lymph Node - The diagnosis of lymphoma, benign, was present on the Searle microscopic report. According to Dr. Frith, lymphoma is generally not considered to be benign and he would diagnose lympphosarcoma. Female Rat NO. H18HF (Path No. 95667) Pituitary - Adenoma. Brain - Mild bilateral hydrocephalus. Female Rat No. K18HF (Path No. 95824) Pituitary - Adenoma Female Rat No. K24HF (Path. No. 95671) Mass noted grossly - nothing consistent with mass reported microscopically. (66) Female Rat No. - M2HF (Path. No. 95672) Uterus - Chronic mild endometritis. Female Rat No. M30HF (Path. No. 95343) Kidney - Focal calcification. Uterus - Chronic mild endometritis. Female Rat No. M30HF (Path. No. 95675) Pancreas - Focal hyperplasia. The third phase of this review consisted of microscopic verification of all masses reported grossly at necropsy from all female animals not examined in phases 1 and 2 and included a total of 73 animals. The inconsistencies are listed below: Female Rat No. D10Lf (Path No. 92521) Subcutaneous mass was diagnosed as an angiofibroma on Searle report. The lesion is more consistent with an angiosarcoma. Female Rat No. K9MF (Path. No. 95707) Uterus - Polyp. Female Rat No. M1LF (Path. No. 95844) Tissue mass seen grossly was reported as missing and not available for microscopic examination. The tissue was present and was a mammary fibroadenoma. In summary, Dr. Frith reviewed: 1) All 36 high dose females (all slides) including 3 that had been excluded from the study due to autolysis. 2) 36 (one-half) of the control females (all slides) including 1 animal that had been excluded from the study due to auto- lysis. 3) Remaining 73 female animals with grossly observed masses. (sufficient slides were reviewed to substantiate the masses) 4) 5 additional animals selected by the investigators (A1HM, A9HM, A29HM, C2CM, C24HM). (67) The slides reviewed in the first two categories above constituted 20% of the total animals on the study. Dr. Frith reviewed these slides blindly and then compared his findings with the Searle microscopic reports. According to Dr. Frith, his findings were in agreement with those of SEarle, for the most part. In his opinion, some of the lesions that he reported as inconsistencies were small, and might be considered insignificant by some pathologists. Dr. Frith did feel, however, that the ovarian neoplasms (animals H10CF, H19CF, and H7HP, and chronic cystitis and diffuse hyperplasia (animal D29CF) should have been reported. Dr. Frith also considered two other discrepancies to be significant. They were: 1) The reporting of a mass (by Searle) as missing which was actually present (MlLF). 2) The finding of a polyp of the uterus which was not diagnosed by Searle (K9MF) The second of the above two discrepancies assumes even more significance in view of the following: The Histopathologic Summary table (table 11) in Volume I of the submission to FDA lists the following incidence of Uterine Polyps on page 87: Incidence of Uterine Polyps Controls Low Medium High 1 of 69 1 of 34 4 of 34 6 of 33 (1%) (3%) (12%) (18%) The finding of one additional uterine polyp by Dr. Frith (in animal K9MF) increases the incidence in the mid dose to 5 of 34 (15%). On page 82 of Volume I of the submission to FDA, is the statement: "other sporadic findings is included endometrial hyperplasia, polyp, cyst, congestion and squamous metaplasia." The term "sporadic findings" was used to characterize the incidence of uterine polyps, in spite of the fact that Searle had done a statistical analysis of these findings. (68) |
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