1. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 1 SGRQSGRQ 3 Domains: –Symptoms: cough, sputum production, wheeze, breathlessness, duration and frequency of attacks of breathlessness –Activity: physical activities that either cause or are limited by breathlessness –Impacts: employment, being in control of health, panic, stigmatization, need for medication, side effects of medication, expectations for health, disturbance of daily life 3 Domains: –Symptoms: cough, sputum production, wheeze, breathlessness, duration and frequency of attacks of breathlessness –Activity: physical activities that either cause or are limited by breathlessness –Impacts: employment, being in control of health, panic, stigmatization, need for medication, side effects of medication, expectations for health, disturbance of daily life

2. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 2 SGRQSGRQ Included at baseline and at the following visits: –114/115: Weeks 7, 13, 25, 37, 49 –122A/122B: Weeks 7, 13, 26, 39, 52 –130/137: Weeks 8, 16, and 24 Total Score: Tiotropium statistically and clinically (  4 units) superior to comparator: –114/115: 2/10 –122A/122B: 1/10 –130/137: 0/6 Included at baseline and at the following visits: –114/115: Weeks 7, 13, 25, 37, 49 –122A/122B: Weeks 7, 13, 26, 39, 52 –130/137: Weeks 8, 16, and 24 Total Score: Tiotropium statistically and clinically (  4 units) superior to comparator: –114/115: 2/10 –122A/122B: 1/10 –130/137: 0/6

3. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 3 SGRQ: Activity Score Tiotropium was statistically superior to comparator: Study 114:2/5 Study 115:4/5 Study 122A:0/5 Study 122B:1/5 Study 130:0/3 Study 137: 1/3 Tiotropium was statistically superior to comparator: Study 114:2/5 Study 115:4/5 Study 122A:0/5 Study 122B:1/5 Study 130:0/3 Study 137: 1/3

4. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 4 SGRQ: Symptoms Tiotropium was statistically superior to comparator: Study 114:2/5 Study 115:0/5 Study 122A:0/5 Study 122B:0/5 Study 130:3/3 Study 137:0/3 Tiotropium was statistically superior to comparator: Study 114:2/5 Study 115:0/5 Study 122A:0/5 Study 122B:0/5 Study 130:3/3 Study 137:0/3

5. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 5

6. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 6 BDI/TDIBDI/TDI Interviewer asks open-ended questions. Interviewer interprets responses and selects a score. The majority of other dyspnea indices are completed by the patient. Interviewer asks open-ended questions. Interviewer interprets responses and selects a score. The majority of other dyspnea indices are completed by the patient.

7. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 7 Dyspnea Indices BDI/TDI [Interviewer] Medical Research Council Breathlessness Scale [Patient] American Thoracic Society Dyspnea Scale [Patient] Chronic Respiratory Questionnaire (Dyspnea component) [Patient] UCSD Shortness of Breath Questionnaire [Patient] Modified Borg Dyspnea Scale [Patient] Shortness of Breath Questionnaire (Archibald, 1987) [Patient] Dyspnea Index (Lareau, 1994) [Patient] Oxygen-cost diagram (visual analog) [Patient] Visual Analog Scale [Patient] BDI/TDI [Interviewer] Medical Research Council Breathlessness Scale [Patient] American Thoracic Society Dyspnea Scale [Patient] Chronic Respiratory Questionnaire (Dyspnea component) [Patient] UCSD Shortness of Breath Questionnaire [Patient] Modified Borg Dyspnea Scale [Patient] Shortness of Breath Questionnaire (Archibald, 1987) [Patient] Dyspnea Index (Lareau, 1994) [Patient] Oxygen-cost diagram (visual analog) [Patient] Visual Analog Scale [Patient]

8. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 8 “Reliability and Validity of Dyspnea Measures in Patients with Obstructive Lung Disease” BDI –“In our experience, to use this instrument reliably, it was necessary for our four raters to discuss and standardize questions and to come to some consensus as to how ratings should be made on each one of the three scales. Ongoing assessment of inter-rater reliability to check for tendencies of each rater to stray from initial standardization was also needed.” BDI –“In our experience, to use this instrument reliably, it was necessary for our four raters to discuss and standardize questions and to come to some consensus as to how ratings should be made on each one of the three scales. Ongoing assessment of inter-rater reliability to check for tendencies of each rater to stray from initial standardization was also needed.” [Eakin EG, et al. International Journal of Behavioral Medicine, 1995]

9. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 9 “Reliability and Validity of Dyspnea Measures in Patients with Obstructive Lung Disease” TDI –“may be affected by bias on the part of the patient and interviewer because it asks both individuals to make judgements about improvement versus deterioration in the patient’s status since baseline. Like the BDI, the TDI lacks standardized questions for raters.” TDI –“may be affected by bias on the part of the patient and interviewer because it asks both individuals to make judgements about improvement versus deterioration in the patient’s status since baseline. Like the BDI, the TDI lacks standardized questions for raters.” [Eakin EG, et al. International Journal of Behavioral Medicine, 1995]

10. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 10

11. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 11 Mean Trough FEV1, by TDI Response (Study 137, at 6 months) TDI “non-responders” Tiotropium PlaceboSalmeterol Trough FEV1: 0.029L -0.056L 0.038L TDI “responders” Tiotropium PlaceboSalmeterol Trough FEV1: 0.107L 0.032L 0.087L TDI “non-responders” Tiotropium PlaceboSalmeterol Trough FEV1: 0.029L -0.056L 0.038L TDI “responders” Tiotropium PlaceboSalmeterol Trough FEV1: 0.107L 0.032L 0.087L

12. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 12 FEV1 Response* by TDI Response (Study 130, at 6 months) *defined as improvement  12% in trough FEV1, compared to baseline

13. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 13 FEV1 Response* by TDI Response (Study 130, at 6 months) *defined as improvement  12% in trough FEV1, compared to baseline

14. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 14 FEV1 Response* by TDI Response (Study 137, at 6 months) *defined as improvement  12% in trough FEV1, compared to baseline

15. Pulmonary-Allergy Drugs Advisory Committee September 6, 2002 15 FEV1 Response* by TDI Response (Study 137, at 6 months) *defined as improvement  12% in trough FEV1, compared to baseline