Master of Science
Health and Rehabilitation Sciences
Johnson, Andrew M.
Smith, Maxwell J.
The objective of this retrospective critical appraisal study was to determine if the trials submitted to the Food and Drug Administration for the expedited approval of pimavanserin was of sufficient methodological quality to ascertain its safety and efficacy. After the general metrics of the trials were assessed, the Risk of Bias 2 tool and the PRagmatic Explanatory Continuum Indicator Summary tool were employed to evaluate the risk of bias and the design suitability of the trials. This study suggests that the decision to approve pimavanserin for the treatment of Parkinson’s Disease Psychosis failed to meet the threshold of evidence normally required for FDA drug applications. It also revealed serious risks of bias with the pivotal trial that was foundational to pimavanserin’s delineation as a breakthrough drug, and that the safety studies were also questionably designed. These findings highlight the need to continue monitoring pimavanserin and re-examine expedited drug approval processes.
Summary for Lay Audience
Clinical trials provide the foundational evidence used by the Food and Drug Administration (FDA) and other regulators to assess a drug’s safety and efficacy before being approved for public use. Trials that are poorly designed may lead to a biased or overly favorable interpretation of a drug’s safety and efficacy and may make it difficult for regulators to determine whether a new drug is safe to be used by patients. One of these new drugs, pimavanserin, was recently approved by the FDA for the treatment of Parkinson’s Disease Psychosis. It was approved under a special program that allowed it to be approved more quickly than normal, and its application also received ongoing support from the FDA. These special programs are reserved for promising drugs that are meant to treat serious conditions. Shortly after, however, serious concerns were raised by clinicians and the broader academic community about the FDA’s decision to approve pimavanserin. These concerns revolved around the higher rates of drug side effects, suggesting a potential risk to patients. The goal of this study was to conduct an assessment to determine if pimavanserin’s trials were of sufficient quality, and to determine if there were any potential biases that may have compromised the FDA’s initial assessment. Ultimately, this assessment revealed that the trials were of insufficient length and quality based on the FDA’s own standards, and that the main clinical trial that formed the basis for approval was at risk of bias. In the context of clinical trials, a risk of bias means that the clinical data may present the drug optimistically, usually as more effective, or safer than it is. This is potentially dangerous because it means that clinicians may prescribe the drug without a true understanding of its effects, and this could harm patients. These issues with pimavanserin’s clinical trials suggest that there could be a risk to patients, and that it should continue to be monitored. This project also suggests that the FDA should consider changing how their special expedited programs assess and interpret the quality of clinical trials.
Law, Benson, "Regulatory Implications of Inadequately Designed Pimavanserin Drug Trials Published with Risk of Bias on Expedited Regulatory Approval Processes" (2023). Electronic Thesis and Dissertation Repository. 9309.
Supplementary File A - Summary of Studies
Supplementary File B - ROB 2.xlsm (730 kB)
Supplementary File B - ROB 2 Data
Supplementary File C - PRECIS-2.xlsx (22 kB)
Supplementary File C - PRECIS-2 Data
Supplementary File D - PDAC Transcript.pdf (736 kB)
Supplementary File D - Food and Drug Administration Psychopharmacologic Drugs Advisory Committee Transcript
Thesis Change Report.pdf (38 kB)