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.
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