1. 12/10/02Harry Bushar1 Computerized Thermal Imaging Breast Cancer System 2100 (CTI BCS2100) Radiological Devices Advisory Panel December 10, 2002 Statistical Presentation Harry F. Bushar, PhD

2. 12/10/02Harry Bushar2 Outline of Statistical Presentation Clinical Study Protocol Objective Design Population Demographics Evaluation (Effectiveness + Safety) PMA Clinical Study Effectiveness + Safety Amendment 4 Clinical Study Effectiveness Amendment 5 Clinical Study Effectiveness Amendment 7 Adjustment Effectiveness Statistical Conclusions

3. 12/10/02Harry Bushar3 Clinical Study Protocol Study Objective –“The objective of the study is to determine if the CTI System, when used in conjunction with clinical examination and/or diagnostic mammography, increases the ability of physicians to differentiate benign from malignant, or suspicious, breast abnormalities.”

4. 12/10/02Harry Bushar4 Clinical Study Protocol Study Design –prospective –blinded-to-histology –multi-center –intended to compare Level of Suspicion (LOS) (0-5) of malignancy of suspicious breast lesions for clinical examination or diagnostic mammography before BCS to LOS + (BCS Index of Suspicion (IOS) (0.00 – 100.00) of malignancy of suspicious breast lesions) – biopsy as the “gold standard” for pathology.

5. 12/10/02Harry Bushar5 Clinical Study Protocol Study Population –Original study population = 600 patients with biopsy. –Actual study population = 2,407 patients with biopsy.

6. 12/10/02Harry Bushar6 Clinical Study Protocol Study Demographics –Gender 2,364 Female 15 Male 28 Unknown –Ethnicity 53% Caucasian 30% African American 13% Latino 2% Asian 1% Other 1% Unknown –Age 12% (< 40) 55% (40 – 60) 32% (> 60) 1% Unknown

7. 12/10/02Harry Bushar7 Clinical Study Protocol Primary Effectiveness on Overall Population –Evaluation Area Under the ROC * Curve (AUC) to compare results of diagnostic mammography (LOS) without BCS (IOS) and diagnostic mammography with BCS (LOS + IOS). Sensitivity Specificity –“The CTI System will be considered effective if its performance in conjunction with diagnostic mammography and/or clinical examination is clinically better than mammography and/or clinical examination alone.” * ROC = Receiver Operating Characteristic

8. 12/10/02Harry Bushar8 Clinical Study Protocol Secondary Effectiveness on Subpopulations –Mammographic Lesion Type Calcifications Masses Distortions –Mammographic Lesion Size < 0.5 cm 0.5 – 1.0 cm > 1.0 cm –Mammographic Lesion Depth As available

9. 12/10/02Harry Bushar9 Clinical Study Protocol Safety Evaluation –occurrence of adverse events.

10. 12/10/02Harry Bushar10 PMA Clinical Study Population The sponsor acquired BCS images from 2,407 patients at 6 US clinical sites from 12/20/96 through 4/30/01. The sponsor actually analyzed only those patients with both –mammography, not those with just clinical examination, and –biopsy within 60 days.

11. 12/10/02Harry Bushar11 PMA Training Clinical Study 700 patients, consisting of the first 220 patients + 480 patients randomly selected from among the next 1,912 patients, were used to set the following BCS IOS cut-off: ≥ 20.59 implies a recommendation for biopsy of a given lesion and < 20.59 implies a recommendation for short- interval follow-up of a given lesion.

12. 12/10/02Harry Bushar12 PMA Testing Clinical Study 1,432 patients, enrolled from 12/20/96 through 10/30/00, were initially available to test the effectiveness of the BCS both in the original PMA and in Amendment 4. 769 patients, with 187 malignant lesions + 688 benign lesions, were actually included in the effectiveness evaluation both in the original PMA and in Amendment 4. Note that each patient had 1 to 4 lesions. Note also that the sponsor assumes that lesions within patient are independent.

13. 12/10/02Harry Bushar13 PMA Clinical Study Results Primary Effectiveness by ROC AUC –The sponsor found, after excluding calcifications alone, a statistically significantly greater ROC AUC for (IOS + LOS1) than for mammography LOS1 scores (1-4) alone at significance level = 0.05. –The sponsor found, after again excluding calcifications alone, but expanding mammography LOS1 scores beyond (1-4) to include 2 additional intermediate categories (3.50 & 3.75), no statistically significant difference between ROC AUC for (IOS + LOS2) & (LOS2 alone) at significance level = 0.05.

14. 12/10/02Harry Bushar14

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16. 12/10/02Harry Bushar16 PMA Clinical Study Results Safety –The following 4 adverse events occurred out of 2,407 subjects (12/20/96 through 4/30/01): 2 “mild”, possibly-related, resolved adverse events were both associated with patient discomfort during positioning. 1 “serious” and 1 “mild”, not-likely-related, resolved adverse events were hospitalization for treatment of a pre-existing metabolic disorder and dizziness when sitting up after thermal imaging, respectively.

17. 12/10/02Harry Bushar17 Amendment 4 Clinical Results Overall (187 malignant + 688 benign) –Sensitivity = 97.1% with 95% CI * = (94.1%, 98.8%) –Specificity = 14.3% with 95% CI = (12.1%, 16.6%) * CI = Confidence Interval

18. 12/10/02Harry Bushar18 Amendment 4 Clinical Results Calcifications * (105 malignant + 368 benign) Sensitivity = 94.8% with 95% CI = (89.6%, 97.8%) Specificity = 9.2% with 95% CI = ( 6.9%, 12.1%) Masses (90 malignant + 322 benign) Sensitivity = 100% with 95% CI = (96.7%, 100%) Specificity = 18.0% with 95% CI = (14.6%, 21.9%) Distortions (16 malignant + 15 benign) Sensitivity = 100% with 95% CI = (82.9%, 100%) Specificity = 16.7% with 95% CI = ( 3.9%, 40.2%) * The sponsor interpreted these effectiveness clinical results by lesion type to specifically exclude calcifications alone.

19. 12/10/02Harry Bushar19 Amendment 4 Interpretation The sponsor’s initial rejection of overall effectiveness, followed by the sponsor’s differential findings among the 3 lesion type sub-populations clearly indicates exploration: –which does require confirmation, –which must be based on new data.

20. 12/10/02Harry Bushar20 PPMA * Amendment 5 Population Study population = 275 additional patients. –Gender 274 female 1 male –Ethnicity 65% Caucasian 31% African American 3% Latino 1% Asian or Unknown –Age 13% (< 40) 60% (40 – 60) 27% (> 60) * PPMA = Post-PMA

21. 12/10/02Harry Bushar21 PPMA Amendment 5 Study 275 additional patients, enrolled from 11/1/00 through 4/30/01 at 3 of the 6 original US clinical sites, were initially available for confirmation of the effectiveness of the BCS in Amendment 5. 173 patients, with 43 malignant + 159 benign lesions, were actually included in the Amendment 5 effectiveness evaluation. Note that each patient had 1 to 3 lesions. Note also that the sponsor assumes that lesions within patient are independent.

22. 12/10/02Harry Bushar22 PPMA Amendment 5 Results Overall (43 malignant + 159 benign) –Sensitivity = 93.8% with 95% CI = (84.0%, 98.5%) –Specificity = 20.0% with 95% CI = (14.9%, 26.0%)

23. 12/10/02Harry Bushar23 PPMA Amendment 5 Results Calcifications (24 malignant + 87 benign) Sensitivity = 93.1% with 95% CI = (77.9%, 99.0%) Specificity = 17.4% with 95% CI = (11.1%, 25.5%) Masses * (15 malignant + 63 benign) Sensitivity = 93.3% with 95% CI = (72.1%, 99.7%) Specificity = 25.4% with 95% CI = (16.6%, 36.0%) Distortions (8 malignant + 4 benign) Sensitivity = 75.0% with 95% CI = (40.0%, 95.4%) Specificity = 25.0% with 95% CI = ( 1.3%, 75.1%) * The sponsor interpreted these effectiveness results by lesion type to specifically include only masses.

24. 12/10/02Harry Bushar24 Amendment 7 Adjustment The sponsor’s attempted Bonferroni adjustment, in response to FDA deficiency 1.a), by –widening sensitivity/specificity CI estimates, which are –based on a simple direct combination of exploratory + confirmatory clinical data (PMA/Amendment 4 + PPMA Amendment 5), to –test a theoretically possible hypothetical set of hypotheses for 7 (lesion types) or 63 (lesion types, sizes, & depths), –which hypotheses are not explicitly included in the protocol, Is not statistically acceptable, because –the sponsor simply estimates sensitivity/specificity CI’s for various sub- populations, –without actually statistically testing any hypotheses. Therefore, there are no multiple comparisons requiring adjustment.

25. 12/10/02Harry Bushar25 Statistical Conclusions Diagnostic mammography, not just clinical examination, is required for use of BCS. The sponsor’s primary effectiveness demonstration, using ROC AUC, loses statistical significance, when mammography LOS (1-4) is expanded by just 2 additional intermediate categories (3.50 & 3.75), after excluding calcifications alone. The sponsor’s initial rejection of overall sensitivity, followed by rejection of calcification-alone sensitivity, indicates exploration: –which requires confirmation, –which requires new data. The sponsor’s attempted Bonferroni adjustment, by widening sensitivity/specificity CI estimates, is not statistically acceptable.