1. Academic Consortia: Clinical Trial Networks Karl Kieburtz, MD, MPH Director, Ctr for Human Experimental Therapeutics University of Rochester Medical Center Rochester, NY March 5, 2010

2. Clinical Trial Networks Two Recent Examples Dana Foundation/NINDS – HIV Dementia NINDS – PD program (NET-PD) General Thoughts

3. Clinical Trial Networks Dana Foundation interested in advancing trials in HIV dementia Consortium formed: Columbia, JHU, Rochester Natural history definitions, novel interventions

4. Clinical Trial Networks Recruited a large diverse group with advanced HIV Followed longitudinal clinical course Performed a series of pilot clinical trials - safety

5. Clinical Trial Networks Outcomes – Understanding of clinical progression Several trials completed Leveraged NIH funding (NARC, NEAD) Publications- Progression of Illness Metholodology Clinical trial results Additional studies

6. Factors associated with incident human immunodeficiency virus-dementia. Stern Y, McDermott MP, Albert S, et al. Archives of Neurology, 2001;58:473-479. Incidence of and risk factors for HIV-associated distal sensory polyneuropathy. Schifitto G, McDermott MP, McArthur JC, et al. Neurology 2002;58:1764-1768.

7. Clinical Trials in HIV-Associated Cognitive Impairment: Cognitive and Functional Outcomes. Schifitto G, Kieburtz K, McDermott MP, et al. Neurology 2001;54:415-418. Inter-rater reliability of a clinical staging of HIV-associated cognitive impairment. Marder K, Albert SM, McDermott MP, et al. Neurology 2003;60:1467-1473.

8. Safety and tolerability of the antioxidant OPC-14117 in HIV- associated cognitive impairment. The Dana Consortium on the Therapy of HIV Dementia & Related Cognitive Disorders. Neurology 1997;49:142-146 A randomized, double-blind, placebo-controlled trial of deprenyl & thioctic acid in human immunodeficiency virus- associated cognitive impairment. The Dana Consortium on the Therapy of HIV Dementia & Related Cognitive Disorders. Neurology 1998;50:645-651 Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Schifitto G, Sacktor N, Marder K, et al. Neurology 1999;53:391-396.

9. Autonomic performance and DHEAS levels in HIV infect individuals: Relationship to TH1 and TH2 cytokine profile. Schifitto G, McDermott MP, Evans T, et al. Archives of Neurology 2000;57:1027-1032. Disease progression in HIV-Positive women with moderate to severe immunosuppression: The role of depression. Vedhara K, Schifitto G, McDermott M, et al. Behavioral Med 1999;25:43-47

10. Transdermal selegiline in HIV-associated cognitive impairment: Pilot, placebo-controlled study. Sacktor N, Schifitto G, McDermott MP, et al. Neurology 2000; 54:233-235. A randomized clinical trial of CPI-1189 for HIV- associated cognitive-motor impairment. Clifford DB, McArthur JC, Schifitto G, et al. Neurology 2002;59:1568-1573.

11. Clinical Trial Networks Resources that facilitated trials - Active cohort of research subjects to recruit - Standardized research protocol - Established funding for a series of trials - Dedicated, focused team

12. Clinical Trial Networks NINDS – NET-PD Program Separate RFA to establish: - clinical centers - coordination center - statistical center Task is to run a single large study and any pilot studies to define interventions and outcomes

13. Clinical Trial Networks NET-PD - Statistical & coordination centers identified and funded one year before sites - sites selected independent of centers - external guidance on effort (OSB, DSMB)

14. Clinical Trial Networks Outcomes - Group (with oversight) planned 2 pilot studies - Enrollment brisk - Outcomes achieved

18. A responsive outcome for Parkinson’s disease neuroprotection futility studies. J Elm, C. Goetz, B. Tilley, et al. Ann Neurol 2005;57:197-203 Optimizing the ongoing search for new treatments for Parkinson disease: Using futility designs. BC Tilley, YY Palesch, K Kiebutz, et al. Neurology 2006;66:628-633. Non-linearity of Parkinson’s clinical progression: implications for sample size calculations in clinical trials. P. Guimares, K Kieburtz, C. Goetz, et al. Clinical Trials 2005;2:509-518.

19. Self-reported adherence versus pill count in Parkinson’s disease: The NET-PD Experience. Elm JJ, Kamp C, Tilley BC, et al. Movement Disorders 2007;22(6):822-7. The impact of depressive symptoms in early Parkinson’s disease. Ravina B, Camicioli R, Como P, et al. Neurology 2007;69(4):342-7

20. Caffeine and progression of Parkinson’s disease. Simon DK, Swearingen C, Hauser RA, et al. Clin Neuropharmacology 2008;31(4):189-196. Minority enrollment in Parkinson’s disease clinical trials populations. Schneider MG, Swearingen CJ, Shulman LM, et al. Parkinsonism Relat Disorder, 2008 Aug 8 (Epub ahead of print).

21. Clinical Trial Networks Resources that facilitated trials: - Standardized research protocol - Performance centers individually funded - Established funding for a series of trials - Focused team

22. Academic Consortia General Thoughts: Structure Mind set Leadership

23. Academic Consortia Structure: Standardized protocol Established funding for a block of time Centers “incentivized” Core infrastructure: ‘ARO’

24. Academic Consortia Mind Set: Cohesion – team identity Focus – clear & limited goals Urgency – time limits Ownership – limited sponsor control unlimited sponsor participation

25. Academic Consortia Leadership: Well defined leadership and “followership” Opportunities for “project” leadership Strive for productivity Limit identification of program with leadership