menu
AZ

Research into Parkinson’s Disease has been stymied in recent years due to an increase in placebo response rate among patients in Phase III trials. This unexpected consequence may have sidelined drugs that had positive potential as a treatment for this terrible disease -- and we wanted to find out why.

Substantial improvement of Parkinsonian symptoms is observed in placebo groups of many Parkinson’s Disease clinical trials contributing to a number of negative and failed studies. The Neurology Center of Excellence team at Quintiles conducted a retrospective analysis of 20 pivotal Phase III global clinical trials, performed from 2000-2014, of patients with early and advanced Parkinson's Disease, to identify factors contributing to increased placebo responses. Here’s what we found:

Awareness of placebo effect is key to success of clinical trials in Parkinson’s Disease

Of the total number of studies analyzed, 12 had positive outcomes, in which the investigative product was effectively controlled and results were significantly different from the placebo group. Eight of the trials were either negative or failed to show significant difference from the placebo group -- of those, five showed high placebo response rates.

The review of data,  including the trial parameters, the trial methodology, the recruiting process, and the experience of the investigator, from the five trials, showed a number of recurring factors that directly contributed to the high placebo response:.

  • High patient and investigator expectations when investigators were extremely positive about the drug and the potential outcomes of the trial, that enthusiasm was conveyed to patients who became overly optimistic about their progress.
  • Non-awareness of placebo effects when performing clinical trials neglecting the responsibility of an increased placebo response in the failure of clinical trials.  There is always a placebo response rate and PIs should be aware of this and how to mitigate the risk.
  • Rater dependent factors – consistent rating by highly performing and impartial raters is essential in reducing placebo effect.
  • Accelerated recruitment in high number of sites that are not necessarily movement disorders centers, further contribute in increasing the “background noise.
  • Decreased rigor when designing clinical trials; basically, inclusion / exclusion criteria that were vague and open to interpretation.

In summary, the analysis of twenty PD pivotal trials from Quintiles illustrative database and published literature shows that 60% of these were positive while 25% had high placebo responses. The results of our analysis are in alignment with the general literature where placebo improvements were observed in up to 50% of patients. Controlling some of the factors, listed above, contributing to this effect, such as increasing awareness of the mechanism of the placebo response would improve the chances of successful trials in PD

None of these errors are malicious. They are often simply the result of lack of experience combined with perceived external pressures to meet certain goals. But if the intentions are good, the result is that promising investigative products may not make it to market because trial data is inaccurate.

Lessons learned

To avoid the ‘placebo effect” in Parkinson’s Disease trials – or any phase III effort – trial designers need to focus on two things:

  1. Training. Investigators need more rigorous training on how to communicate with patients, how to set neutral expectations, and how to collect outcomes data without injecting their own expectations or opinions into the results. This training should include discussions about why it is so important to rein in positive expectations, and how unchecked enthusiasm can potentially damage trial outcomes. Our research shows that the best trained investigators consistently deliver the most reliable data.
  2. Recruiting Methodology. To ensure the patient population are appropriate for the trial, recruiting criteria must be clearly defined and rigorously adhered to. That means investigators must have quantifiable characteristics for trial participants, and that meeting these criteria are considered a higher priority than meeting time or cost goals.

Addressing these two issues in the trial design may add time and cost up front, but it ensures that a good treatment option won’t get sidelined by bad data. 

Topics in this blog post: Clinical Trials, Recruiting