July 16, 2020

Placebo-controlled clinical trials are the gold standard in drug development, in part to ensure that the safety and efficacy of a new therapy exceeds the placebo response in the indication being studied. The placebo response is a measured improvement in clinical signs and/or symptoms that occurs in patients receiving a sham or “dummy” treatment. The placebo response is a complex psychological, biological and sociological phenomenon that confounds clinical data analysis, particularly for subjective patient-reported outcomes. The placebo response is widely known to compromise evaluation of pain endpoints and has been suggested to contribute to as much as ~2/3 of the measured treatment effect in a pain from various etiologies1, contributing to the high rate of Phase II and III clinical trial failure in this indication2. The placebo response is, however, not limited to pain trials. In fact, the understanding of the impact of this phenomenon in a wide variety of therapeutic areas is growing steadily. This is the third in a series of articles that will examine the impact of the placebo response in drug development in areas beyond pain.

Parkinson’s disease (PD) is a chronic, progressive neurodegenerative disease characterized by both motor and non-motor features. The disease has a significant clinical impact on patients, families, and caregivers through its progressive degenerative effects on mobility and muscle control. The motor symptoms of PD are attributed to the loss of striatal dopaminergic neurons, although the presence of nonmotor symptoms supports neuronal loss in nondopaminergic areas as well. The term parkinsonism is a symptom complex used to describe the motor features of PD, which include resting tremor, bradykinesia, and muscular rigidity. PD is the most common cause of parkinsonism, although a number of secondary causes also exist, including diseases that mimic PD and drug-induced causes (3,4).

PD is one of the most common neurodegenerative disorders. The Parkinson’s Disease Foundation reports that approximately 1 million Americans currently have the disease (5). The incidence of PD in the U.S. is approximately 20 cases per 100,000 people per year (60,000 per year), with the mean age of onset close to 60 years. The prevalence of PD is reported to be approximately 1% in people 60 years of age and older and increases to 1% to 3% in the 80-plus age group. However, an important caveat with these numbers is that they do not reflect undiagnosed cases (6,7). Although it is primarily a disease of the elderly, individuals have developed PD in their 30s and 40s (7). Gender differences pertaining to the incidence of PD are reflected in a 3:2 ratio of males to females, with a delayed onset in females attributed to the neuroprotective effects of estrogen on the nigrostriatal dopaminergic system (8,9). Current treatment is focused on symptomatic management (10) but promising disease-modifying therapies are being developed (11).

Various staging tools are used to assess the progression of PD and to provide parameters for the use of different management strategies. The most commonly used scale for assessing the clinical status of patients with PD, including both motor and nonmotor symptoms, is the Movement  Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). This four-part tool assesses motor features, psychological features, and activities of daily living in addition to complications related to therapy (12). Increases of 2.5 points in the UPDRS motor scores (or 3 points in the MDS-UPDRS), have been recognized as clinically relevant (13-14).

Unfortunatelly, the placebo response has proven to be a significant issue that compromised the evaluation of efficacy of experimental therapeutics in clinical trials for PD (15). Many Phase 2 and 3 clinical trials in PD are abandoned or fail because of the inability to demonstrate clear superiority of the tested drug versus placebo. In PD, the placebo effects are mediated by activation of the entire dopaminergic system, namely both neural circuits involved in the reward system (ventral striatum) and the nigrostriatal pathway involved in motor control (dorsal striatum), which ultimately produces objective motor improvements (16). Moreover, the placebo effect is patient-dependent, strongly influenced by investigator behavior vis-à-vis his/her patient, the patient’s expectations (in terms of drug efficacy and overall well-being), and personality traits (17-23).

Consequently, the patient-specific nature of the placebo effect introduces a bias in randomized clinical trials. This interferes with patient response to investigational treatement evaluations and the ability to clearly demonstrate efficacy of the study drug.

Managing the placebo effect/response in PD may positively contribute to analysis of data from clinical trials and ultimately lead to the identification of more effective treatments (both pharmacologic and non-pharmacologic) in a more timely manner. At Tools4Patient, we have developed a platform solution (Placebell©™ ) to reduce the impact of the placebo response in clinical trials. This approach utilizes multiple factors on an individual patient basis, including demographics, medical history, baseline disease intensity and certain previously-identified important psychological traits.  Initial data from peripheral neuropathic pain (PNP) studies suggest that the Placebell©™ approach can reduce data variability related to the placebo response by as much as 30% in some pain indications. This initial model could be used to predict placebo response in a mild-moderate PD population. Furthermore, implementation of Placebell©™ only requires that our proprietary psychological questionnaire be administered to patients at screening or baseline. To request our scientific whitepaper “Predicting the Placebo Response to Reduce Clinical Data Variability and De-Risk Drug Development”, please contact us.


1. Häuser W, Bartram-Wunn E, Bartram C, Reinecke H, Tölle T. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy – Magnitude and patient-related predictors. Pain. 2011;152(8):1709-1717. doi:10.1016/j.pain.2011.01.050

2. Dumitrescu TP, McCune J, Schmith V. Is Placebo Response Responsible for Many Phase III Failures? Clin Pharmacol Ther. 2019;106(6):1151-1154. doi:10.1002/cpt.1632

3. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord. 2003;18:19–31. [PubMed] [Google Scholar]

4. National Institute for Health and Care Excellence (NICE) Parkinson’s disease: diagnosis and management in primary and secondary care. NICE clinical guidelines 35. Jun, 2006. Available at: Accessed April 28, 2015

5. Parkinson’s Disease Foundation Statistics on Parkinson’s. Available at: Accessed June 19, 2014.

6. Driver JA, Logroscino G, Gaziano JM, et al. Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology. 2009;72:32–38.

7. De Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol. 2006;5:525–535.

8. Miller IN, Cronin-Golomb A. Gender differences in Parkinson’s disease: clinical characteristics and cognition. Mov Disord. 2010;25:2695–2703.

9. Rumayor MA, Arrieta O, Sotelo J, et al. Female gender but not cigarette smoking delays the onset of Parkinson’s disease. Clin Neurol Neurosurg. 2009;111:738–741.

10. Oertel W. and Schulz. B. J. Current and experimental treatments of Parkinson disease: A guide for neuroscientists. JNeurochem. (2016) 139 (Suppl. 1), 325–337

11. Poewe W., Seppi K., Marini K., Mahlknecht P. New hopes for disease modification in Parkinson’s Disease. Neuropharmacology 171 (2020) 108085

12. Goetz  CG,  Tilley  BC,  Shaftman  SR,  et  al.  Movement  DisorderSociety-Sponsored Revision of the Unified Parkinson’s Disease Rat-ing Scale (MDS-UPDRS): scale presentation and clinimetric testingresults. Mov Disord 2008;23:2129-2170.

13. Shulman LM, Gruber-Baldini AL, Anderson KE, et al. The clinically important difference on the unified Parkinson’s disease rating scale. Arch Neurol. 2010;67:64–70.

14. Goetz CG, Stebbins GT and Tilley BC. Calibration of unified Parkinson’s disease rating scale scores to movement disorder society-unified Parkinson’s disease rating scale scores. Mov Disord 2012; 27: 1239–1242 

15. Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK; Parkinson Study Group, Leurgans S. Placebo response in Parkinson’s disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008 Apr 15;23(5):690-9.

16. Quattrone A., Barbagallo G., Cerasa A., Stoessl A.J. Neurobiology of Placebo Effect in Parkinson’s Disease: What We Have Learned and Where We Are Going. Movement Disorders, 2018, Vol. 33, No. 8, 1213

17. 16 de la Fuente-Fernandez R, Schulzer M, Stoessel AJ, de la Fuente-Fernández R, Schulzer M, Stoessl AJ. The placebo effect in neurological disorders. Lancet Neurol. 2002;1(2):85-91.

18. de la Fuente-Fernandez RD La, Stoessl A. The placebo effect in Parkinson’s disease. Trends Neurosci. 2002;25(6):302-306.

19. de la Fuente-Fernández R, Schulzer M, Stoessl a J. Placebo mechanisms and reward circuitry: clues from Parkinson’s disease. Biol Psychiatry. 2004;56(2):67-71.

20. Gruber-Baldini AL, Ye J, Anderson KE, Shulman LM. Effects of optimism/pessimism and locus of control on disability and quality of life in Parkinson’s disease. Park Relat Disord. 2009;15(9):665-669.

21. Lidstone SC, Schulzer M, Dinelle K, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry. 2010;67(8):857-865.

22. Keitel A, Wojtecki L, Hirschmann J, et al. Motor and cognitive placebo-/nocebo- responses in Parkinson’s disease patients with deep brain stimulation. Behav Brain Res. 2013; 250: 199-205.  

23. Schmidt L, Braun EK, Wager TD, Shohamy D. Mind matters: placebo enhances reward learning in Parkinson’s disease. Nat Neurosci. 2014;17(12):1793-1797.

24. Benedetti F. Placebo and the New Physiology of the Doctor-Patient Relationship. Physiol Rev. 2013;93(3):1207-1246.


Related content


Leveraging Historical Data For High-dimensional Regression Adjustment, A Machine Learning Approach

Samuel Branders, Ph.D., Data Mining and Statistical Research Scientist of Tools4Patient (T4P) recently presented cutting-edge research at the...

Read More

Compilation Of Frequently Asked Questions About Placebell©™

In May 2018, Tools4Patient (T4P) presented a webinar entitled “Characterization of Individual Patient Placebo Response: Impact on the...

Read More

Predicting The Placebo Response In Chronic Pain Patients

There is substantial scientific literature describing the placebo response in pain, including characterizing the magnitude and duration of...

Read More

The next frontier in clinical research & patient management

We’re proud to be leading the charge into the next era of drug development.
Cognivia helps clinical trials reduce data variability, empower decision-making, and accelerate the launch of new therapies.
Tell us about your clinical trial below and we’ll be in touch.

"*" indicates required fields

This field is for validation purposes and should be left unchanged.