The AAPS Journal

, 11:456 | Cite as

Endpoints and Analyses to Discern Disease-Modifying Drug Effects in Early Parkinson’s Disease

  • Venkatesh Atul Bhattaram
  • Ohidul Siddiqui
  • Leonard P. Kapcala
  • Jogarao V. S. GobburuEmail author
Research Article


Parkinson’s disease is an age-related degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech, as well as other functions. Symptoms can include tremor, stiffness, slowness of movement, and impaired balance. An estimated four million people worldwide suffer from the disease, which usually affects people over the age of 60. Presently, there is no precedent for approving any drug as having a modifying effect (i.e., slowing or delaying) for disease progression of Parkinson’s disease. Clinical trial designs such as delayed start and withdrawal are being proposed to discern symptomatic and protective effects. The current work focused on understanding the features of delayed start design using prior knowledge from published and data submitted to US Food and Drug Administration (US FDA) as part of drug approval or protocol evaluation. Clinical trial simulations were conducted to evaluate the false-positive rate, power under a new statistical analysis methodology, and various scenarios leading to patient discontinuations from clinical trials. The outcome of this work is part of the ongoing discussion between the US FDA and the pharmaceutical industry on the standards required for demonstrating disease-modifying effect using delayed start design.

Key words

delayed start disease modification neuroprotection Parkinson’s disease randomized start 



The authors wish to acknowledge Parkinson’s Study Group, NIH Exploratory Trials in Parkinson’s Disease (NET-PD) Group for providing access to clinical trial data. We are also grateful for the insightful discussions and feedback provided by numerous FDA and academic colleagues, and by professional organizations such as American Association of Pharmaceutical Scientists (AAPS) and Michael J Fox Foundation for Parkinson’s Research.


  1. 1.
    Leber P. Slowing the progression of Alzheimer disease: methodological issues. Alzheimer Dis Assoc Disord. 1997;11(5):S10–21.PubMedGoogle Scholar
  2. 2.
    Mani RB. The evaluation of disease modifying therapies in Alzheimer’s disease: a regulatory viewpoint. Stat Med. 2004;23(2):305–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Clarke CE. A “cure” for Parkinson’s disease: can neuroprotection be proven with current trial designs? Mov Disord. 2004;19(5):491–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol. 2004;61(4):561–6.CrossRefGoogle Scholar
  5. 5.
    Chan PL, Holford NH. Drug treatment effects on disease progression. Annu Rev Pharmacol Toxicol. 2001;41:625–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Guimaraes P, Kieburtz K, Goetz CG, et al. Non-linearity of Parkinson’s disease progression: implications for sample size calculations in clinical trials. Clin Trials. 2005;2(6):509–18.PubMedCrossRefGoogle Scholar
  7. 7.
    Rubin DB. Inference and missing data. Biometrika. 1976;63:581–92.CrossRefGoogle Scholar
  8. 8.
    Little RJA, Rubin DB. Statistical analysis with missing data. New York: Wiley; 1987.Google Scholar
  9. 9.
    The NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology. 2006;66(5):664–71.CrossRefGoogle Scholar
  10. 10.
    Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002;59(10):1541–50.PubMedCrossRefGoogle Scholar
  11. 11.
    The NINDS NET-PD Investigators. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease. Neurology. 2007;68(1):20–8.CrossRefGoogle Scholar
  12. 12.
    Holford NH, Chan PL, Nutt JG, et al. Disease progression and pharmacodynamics in Parkinson disease—evidence for functional protection with levodopa and other treatments. J Pharmacokinet Pharmacodyn. 2006;33:281–311.PubMedCrossRefGoogle Scholar
  13. 13.
    Watts RL, Jankovic J, Waters C, et al. Randomized, blind, controlled trial of transdermal rotigotine in early Parkinson disease. Neurology. 2007;68(4):272–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Korczyn AD, Brunt ER, Larsen JP, et al. A 3-year randomized trial of ropinirole and bromocriptine in early Parkinson’s disease. The 053 Study Group. Neurology. 1999;53(2):364–70.PubMedGoogle Scholar
  15. 15.
    Olanow CW, Kieburtz K, Stern M, et al. Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease. Arch Neurol. 2004;61(10):1563–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Larsen JP, Boas J, Erdal JE. Does selegiline modify the progression of early Parkinson’s disease? Results from a five-year study. The Norwegian-Danish Study Group. Eur J Neurol. 1999;6(5):539–47.PubMedCrossRefGoogle Scholar
  17. 17.
    Parkinson Study Group. A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol. 2002;59(12):1937–43.CrossRefGoogle Scholar
  18. 18.
    Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Parkinson Study Group. JAMA. 2000;284(15):1931–8.CrossRefGoogle Scholar
  19. 19.
    Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med. 2004;351(24):2498–508.PubMedCrossRefGoogle Scholar
  20. 20.
    Palhagen S, Heinonen E, Hagglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology. 2006;66(8):1200–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Chan PL, Nutt JG, Holford NH. Modeling the short- and long-duration responses to exogenous levodopa and to endogenous levodopa production in Parkinson’s disease. J Pharmacokinet Pharmacodyn. 2004;31(3):243–68.PubMedCrossRefGoogle Scholar
  22. 22.
    Ploeger BA, Holford NH. Washout and delayed start designs for identifying disease modifying effects in slowly progressive diseases using disease progression analysis. Pharm Stat 2008, in press.Google Scholar
  23. 23.
    Hendrix SB. AAPS workshop on demonstrating disease-modifying effects for the treatment of Parkinson’s disease: drug development and regulatory issues, Arlington, VA; 2008Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2009

Authors and Affiliations

  • Venkatesh Atul Bhattaram
    • 1
  • Ohidul Siddiqui
    • 2
  • Leonard P. Kapcala
    • 3
  • Jogarao V. S. Gobburu
    • 1
    Email author
  1. 1.Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  2. 2.Division of Biometrics-I, Office of Biostatistics, Center for Drug Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA
  3. 3.Office of New Drugs, Division of Neurology Drug Products, Center for Drug and Evaluation and ResearchUS Food and Drug AdministrationSilver SpringUSA

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