1. Alzheimer’s Drug Therapy Initiative: Seniors Medication Study (SMS) Ging-Yuek Robin Hsiung, MD MHSc FRCPC FACP Assistant Professor Division of Neurology, Dept. of Med, Malcolm Maclure, ScD, Professor Dept. Anesthesiology, Pharmacology & Therapeutics University of British Columbia

2. Disclosure Dr. Hsiung have received research support from Baxter, Bristol-Myers-Squibbs, Elan, Janssen-AI, Pfizer, Hoffman-La Roche, and Genentech as an Alzheimer clinical trial centre at UBC None of the medications discussed today are related to any of the clinical trials sponsored by the above

3. Drug Payer Policy: Coverage with Evidence Development “In April 2005, the Centers for Medicare and Medicaid Services (CMS) posted on its Web site a draft guidance document describing a new approach to coverage policy called Coverage with Evidence Development (CED). CED offers an option for coverage of promising drugs, biologics, devices, diagnostics, and procedures that would not otherwise meet Medicare’s evidentiary standards for being ‘reasonable and necessary’. ”

4. Alzheimer’s Drug Therapy Initiative “ Provides eligible B.C. residents with PharmaCare coverage of medications used in the treatment of Alzheimer’s disease while gathering evidence on their effectiveness.”

5. Original RCT Trial Design of SMS: Continuing vs. Stopping vs. Switching Initial Estimated N of 3000 Positive Response Indeterminate Response Non-Response Continue Stop Switch Randomization Dx6 mo Continuing users Stoppers due to intolerance 30,000 2,000 10,000 Unwilling 12,000 New AD cases 10,000 Existing AD, new users 10,000 3000 1,000

6. Seniors Medication Study – stumbling blocks page 1 No incentives for patients or their doctors to participate in trial. Coverage available to all who fit clinical criteria. One ethics committee argued it would be coercive for PharmaCare to limit coverage of drug costs to patients who agreed to be in the trial. Another ethics committee judged it unethical to do a small trial that had insufficient power to rule out a small but clinically important effect. A drug plan might interpret an inadequately powered study that is ‘not significant’ as meaning ‘evidence of no effect’.

7. Seniors Medication Study – stumbling blocks page 2 We took 1 year to develop and test tools and protocol for randomization in busy general practictioners’ office BC Medical Association opposed Special Authority form without financial compensation Only a few patients were randomized after 12 months. A Medical Services Plan billing code was created: fees for referrals and Clock Drawing Tests. These had only a small impact on randomization, but increased enrolment into the plan. Fair Pharmacare is not “free”, but based on income tax SMS became an observational cohort study with validation/reproducibility study of Standardized Mini- Mental State Exam and various scales.

8. Current Observational Study (SMS) N ~ 200 Positive Response Indeterminate Response Non-Response Continue Stop Switch Doctor & Patient Choice Initiation of treatment to one of three ChEIs (doctor & patient choice) 6 mo Eligible AD cases

9. Seniors Medication Study (n~200) Start of Coverage6 mo12 mo18 mo SMMSE SMMSE (10-26) OPAR & GDS OPAR & GDS OPAR & GDS GDS Clock* Clock* Clock* TICS*TICS**TICS** *Clock Drawing Test **Telephone Interview of Cognitive Status SMMSE = standardized Mini Mental State Examination OPAR = Overall Patient Assessment Rating GDS = Global Deterioration Scale

10. Average SMMSE vs. yrs of schooling at baseline/enrolment

11. SMMSE vs TICS (6 mon) SMMSE TICS Correlation = 0.59 Low SMMSE means low TICS (i.e. good negative predictive value)

12. Correlation of SMMSE with Components of the Telephone Interview of Cognitive Status (TICS) TICS (n=111)SMMSE Orien- tation Lan- guageRecall Compre- hension Orientation0.49 Language0.340.30 Recall0.470.410.31 Comprehension0.470.420.220.50 Attention, Calculation0.420.480.360.390.38

13. SMMSE vs Clock Drawing Test SMMSE Clock Drawing Test Correlation = 0.58

14. Clock Drawing Test vs. TICS Clock Drawing Test TICS Correlation = 0.57

15. SMMSE vs GDS: low correlation SMMSE GDS Correlation = - 0.22 5 4

16. TICS vs GDS: low correlation GDS TICS Correlation = - 0.18

17. Clock Test vs GDS: low correlation Clock Drawing Test GDS Correlation = - 0.15

18. Correlations among measures SMMSE GDS TICS Clock Drawing n = 122 n = 111 n = 74 0.59 0.58 - 0.22 0.57 - 0.15 - 0.18

19. Lessons learned RCT in “phase 4” setting is not feasible – but can do observational study for effectiveness analysis Limited data collection in real life doctor’s office – can only be a brief test; need to compromise between efficiency & comprehensiveness Clock Drawing Tests conducted by GPs, faxed to researchers for scoring, enabled patients to be assessed without confounding by financial incentives or telephone/hearing problems. Good correlation between SMMSE & TICS, SMMSE & CDT, CDT vs TICS, (validate use of SMMSE in doctor’s office setting) Low correlation between GDS vs TICS, and GDS vs CDT: the test measure different domain – Functional vs Cognitive Limitation of using SMMSE only as the criterion for eligibility for drug funding and outcome measure

20. Further Studies Await long term outcome (12 & 18 months) of the study Compare trajectory of changes in each outcome measure by different ChEIs SMMSE can be applied in real life with good validity, but limited domains Will need to include multiple eligibility criteria (SMMSE, CDT, GDS) and multiple outcome measurements