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Perry Cohen, Ph.D. presents Sham Neurosurgical Procedures in Clinical Trials:  Patient Activists’ Perspectives at the NIH conference
Sham Neurosurgical Procedures in Clinical Trials for Neurodegenerative Diseases: Scientific and Ethical Considerations
held on June 30 and July 1, 2010

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Analysis of Failed Trials

Late in 2008 after the findings from the Ceregene 120 trial echoed the  ‘failure to meet primary endpoints’ results for previous promising  new treatments, we began to examine three consecutive sham brain surgery controlled studies for possible explanations for the dramatic differences in the phase I versus phase II results. We knew that placebo effects did not account for all of the differences because some of us participated personally in these studies, and we were in direct contact with other participants.

After a review of the recent research literature on placebo response which provided evidence that was consistent with our observed results, we formulated the hypothesis that

Using sham brain surgery as a placebo control, where the power of the placebo response reaches maximum levels, could violate the assumptions of the standard linear analytic experimental model sufficiently to render the results to be inaccurate. Thus, failure to adjust for significant interactions between the placebo response and treatment in initiation of therapeutic benefit could result in a type 2 error

We have now added to the analysis the findings from earlier fetal tissue transplant studies as well as DBS trials with no sham control group for contrast, and the same pattern has held. Our analysis was presented at the 2009 ASENT annual meeting, where I brought it to the attention of Dr. Federoff, who decided to recommend organizing this conference.

Lasting 3 or more years for all therapies up to 10 years and counting Phase 2, pivotal RCT, sham control

  • Improvements less than half of phase 1 for both groups reflects lower expectations and other factors

  • Little or no separation between treatment and control groups

  • Later follow-up analysis showed statistically significant differences as early as 18 months.

No doubt part of the improvement found in the open label studies was from placebo response to the brain surgery. These benefits have been surprisingly strong, lasting for as much as a year or more. However, follow up for two of the studies showed significant differences between treatment and control groups emerging as early as 18 months indicating that placebo effects do wear off eventually as the reality of disease progression overtakes the patients’ expectations and beliefs.  Peggy Willocks who participated in the Spheramine open label has testified that she continues to benefit 10 years after she received her open label treatment. Autopsy data from research subjects in other trials has shown nerve growth. So something else must be going on.

PWP with advanced disease need new treatments NOW to restore functioning. DBS helps but is not good enough.  I ask, DO we know enough about the placebo effect interactions with treatments and outcomes to dismiss it as ‘bias”?

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