1. The FDA: The Key to Moving Forward. An overview of the Letter of Intent and the SPPB Jack M. Guralnik, MD, PhD

2. FDA and Drug Indications: Most indications are for the treatment, prevention or diagnosis of recognized diseases or conditions, or treatment of manifestations or symptoms of recognized conditions Are sarcopenia, weakness or limited function in the older population potential indications for drug approvals? When indication is established, need outcome measure that reflects benefit for that indication.

3. FDA Clinical Trial Outcome Assessments (COAs) Used to provide substantiation for treatment benefit claims Two processes for FDA submission and review – As part of a drug application review – Under the Drug Development Tool (DDT) Qualification Process

5. Objective Performance Measure of Physical Functioning Assessment instrument in which an individual is asked to perform a specific task and is evaluated in an objective, standardized manner using predetermined criteria, which may include counting of repetitions or timing of the activity as appropriate.

6. Examples of Objective Performance Tests Used to Evaluate Functional Limitations Pegboard test Pegboard test Picking up object Picking up object Lifting 10 pounds Lifting 10 pounds Gait speed Gait speed Chair rise – single and repeated Chair rise – single and repeated Stair climb Stair climb

7. Short Physical Performance Battery Timed standing balance (up to 10 seconds) Timed standing balance (up to 10 seconds) Side-by-side stand Semi-tandem stand Tandem stand Timed 4-meter walk Timed 4-meter walk Timed multiple (5) chair rises Timed multiple (5) chair rises

14. Death Rates According to Individual Performance Tests—Age and Sex Adjusted WalkChair StandsStanding Balance % Distribution 523252622 1920 191015131449 01234 Test Category 0123401234

15. Age and Sex Adjusted Deaths per 100 Person–Years Performance Test Summary Score Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94. Death Rates According to Performance Test Summary Score

16. Age and Sex Adjusted Guralnik JM, et al. J Gerontol Med Sci. 1994;49:M85-M94. Nursing Home Admission Rates According to Performance Test Summary Score

17. 61.3 23.9 14.8 Baseline Prevalence (%) Three-Level Hierarchical Classification of Disability Related to Lower Extremity Function Non-disabled Non-disabled Disabled in higher mobility Disabled in higher mobility –Walking 1/2 mile –Climbing stairs Disabled in ADLs + higher mobility Disabled in ADLs + higher mobility –Transfer from bed to chair –Using toilet –Bathing –Walking across a small room + –Walking 1/2 mile –Climbing stairs ADLs = activities of daily living.

18. Disability Status at Four Years According to Baseline Gait Speed Among Those Non-Disabled at Baseline Guralnik JM, et al. N Engl J Med. 1995;332:556-561.  0.42 0.43 – 0.590.60 – 0.77  0.78 Walking Speed (m/sec) Iowa EPESE ADL = activity of daily living Category1234 Non- Disabled Mobility Disabled ADL + Mobility Disabled

19. Guralnik JM, et al. N Engl J Med. 1995;332:556-561. Iowa EPESE Disability Status at Four Years According to Baseline Summary Performance Score Among Those Non-Disabled at Baseline 0 20 40 60 80 100 456789101112 Summary Performance Score Percent ADL = activity of daily living Non- Disabled Mobility Disabled ADL + Mobility Disabled

20. Age and Sex-Adjusted Proportion of Participants Unable to Complete 400 Meter Walk at 3-Year Follow-Up by Baseline SPPB Score InChianti Study Baseline SPPB Score Unable to walk 400m after three years (%) 0 10 20 30 40 50 60 70 80 90 < 789101112 p for trend <0.001 n 18 4047 126284 Source: Vasunilashorn et al. J Gerontol Med Sci, in press.

21. Iowa EPESE Penninx BWJH, et al. JAMA. 1998;279:1720-1726. Distribution of Change in Performance Score (1992 Score – 1988 Score)

22. Adjusted Mean Change in Physical Performance Score (1992–1988) According to Level of Depressive Symptoms 0-2 N=342 3-6 N=305 7-12 N=289 13-19 N=213  20 N=137 Adjusted for baseline performance score, demographics, behavioral risk factors, and disease status. *P <.1, **P <.05, ***P <.001 compared to CES-D = 0 – 2 Penninx BWJH, et al. JAMA. 1998;279:1720-1726. *** P trend =.001 ** *

23. Odds Ratio* for 1 Point Decline in SPPB Score over 3 Years for 1 st Quartile of Micronutrients vs. Upper 3 Quartiles InChianti Study *Adjusted for age, sex, education, marital status, household composition, smoking, physical activity, number of diseases, BMI, depression, MMSE. Source: Bartali et al. JAMA 2008;299:308-15. 0.0 0.5 1.0 1.5 2.0 2.5 Vitamin EVitamin B 12 Vitamin B 6 Folic acidVitamin DIron

24. Lifestyle Interventions and Independence For Elders A Randomized Clinical Trial of Exercise to Prevent Mobility Disability in Non-disabled Older Persons with Functional Limitations

25. To download: http://www.grc.nia.nih.gov/branches/ledb/sppb/index.htm

26. Age-Adjusted Hazard Ratio for Death per 0.1-m/s Higher Gait Speed Studenski, S. et al. JAMA 2011;305:50-58 Copyright restrictions may apply.

28. Qualification is a conclusion that within the stated context of use, the results of assessment with a DDT can be relied upon to have a specific interpretation and application in drug development and regulatory review. Once qualified, the DDT can be used by drug developers for the qualified context in IND and NDA/BLA submissions without requesting that the relevant CDER review group reconsider and reconfirm the suitability of the DDT. Qualification also creates a collaborative setting where there can be advantages for multiple interested parties (individuals or companies) working together to develop a DDT for qualification. Use of a Qualification

29. Stage 1: Consultation and Advice 1. Letter of Intent (LOI) 2. DDT Briefing Package and Initial Meeting Process for Qualification If CDER accepts the DDT request, the submitter should then submit a briefing package. At this point a Qualification Review Team (QRT) will be created to provide ongoing advice to the DDT submitter about the evidence needed for qualification. A QRT is composed of CDER review staff from various relevant disciplines with expertise appropriate to review of the submission. 3. DDT Investigation and Development Stage 2: Review for Qualification Decision When the submitter believes the data are sufficiently complete to support a conclusion that the DDT is qualified for a specific context of use (i.e., “fit for purpose”) and CDER concurs that detailed, formal data review is warranted, the submitter should submit a formal qualification package. The QRT will review the qualification package, discuss the project at internal meetings, and arrive at a QRT recommendation on the qualification decision.