An example of flawed data reporting and bias in clinical trials can be found in the evidence reporting the outcomes of the new drug Exparel® (Bupivacaine Liposome Injectable Suspension, Pacira Pharmaceuticals, San Diego, CA). Exparel is an extended release liposome injection of bupivacaine designed to achieve long-acting postoperative analgesia. The drug consists of microscopic, spherical, lipid-based particles (the DepoFoam drug delivery system) composed of a honeycomb of numerous, nonconcentric, internal aqueous chambers containing the encapsulated bupivacaine. Each chamber is separated from adjacent chambers by lipid membranes. This product was originally named Skye 0402 and then following transition of ownership of the product by Pacira was termed generically as DepoFoam® bupivacaine and ultimately Exparel.
The clinical findings reported in the literature for Exparel seemingly allow the manufacture to make claims as a powerful new modality in improving patient care, and also suggest it as a new means for improving economic and operational efficiencies in patient care. However a review of the evidence for Exparel illustrates how various forms of bias in the design, conduct, and analysis associated with the studies performed on the drug can lead to inaccuracies in reporting and potentially mislead the medical community.
The Food and Drug Administration of the United States (FDA) approved Exparel after a review of twenty-two studies including three Phase III studies which focused on hemorrhoidectomy and bunionectomy procedures. Two of the three Phase III studies demonstrated a significant effect over placebo (saline) for the primary outcome of cumulative pain scores over a period limited to less than 24 hours, as noted in the description of the results by the FDA medical reviewer. In the bunionectomy study, the FDA concluded that, “…Exparel demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between Exparel and placebo treatments on mean pain intensity”. For the Hemorrhoid study, “Exparel demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between Exparel and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated” [2
]. As illustrated in the discussion of these studies below, the opioid reducing benefit was realized only in the first 12 hours post drug administration (Figure 1). This lack of efficacy beyond 12 hours is apparent in the results that are illustrated in medical and statistical review by the FDA. In a third Phase III study submitted to the FDA as part of the new drug application, a 204-patient hemorrhoidectomy study conducted vs. bupivacaine, none of the 60 endpoints reviewed illustrated a beneficial effect over a single injection of unencapsulated bupivacaine. In fact, in this study a single injection of plain bupivacaine illustrated better results than Exparel. It is of interest as well that this study has never been published outside the medical review by the FDA.
The FDA medical reviewer for this product further summarized the effect of Exparel in the Clinical Review dated October 7, 2011. In his review he stated; “In the placebo controlled studies, Exparel was significantly better than placebo for reducing pain intensity during the first 12 hours following administration. This effect diminished over the next 12 hours such that by 24 hours after administration there was no clinically relevant difference in the pain experienced by subjects treated with Exparel compared to those treated with normal saline. Based on the demonstration of Exparel’s efficacy versus placebo, its pharmacodynamics being similar to that of unencapsulated bupivacaine HCl, the benefits were considered to outweigh the risks. This finding however is limited to the two surgical procedures studied in the placebo-controlled pivotal studies. The manner in which Exparel was administered and the doses used in those studies were so dissimilar that it is not possible to extrapolate a dose or method of administration that would be efficacious for other surgical procedures. To resolve this issue, additional adequate and well-controlled studies would be needed.” It is unfortunate that these studies have not been performed as the current evidence for this drug does not reveal any benefit over the currently marketed unencapsulated formulations of bupivacaine.
The pharmacodynamics section of the FDA review reveals the details of the onset and duration of activity of this drug in an explicit manner often overlooked in the clinical manuscripts published on this drug. This report highlights that, “The onset of action of Exparel was evaluated in clinical trials that assessed pain intensity and other outcomes. These studies demonstrated that the onset of action for Exparel was less than 2 minutes, and was similar to conventional bupivacaine HCl. In the clinical trials described in the medical review, the duration of Exparel’s analgesic effect appears to be no more than 24 hours and not longer than that of unencapsulated bupivacaine HCl” [4
At first glance, the placebo-controlled hemorrhoid study appears to have demonstrated the superior efficacy of Exparel over saline injections in the publication by Gorfine et al. [5
] suggesting that the primary endpoint for the hemorrhoidectomy study, AUC0-72 for NRS of pain intensity, is superior for the entire 72 hours. This is not the case. As described in the Medical Review section 6.1.9, the analgesia derived from Exparel does not differ from placebo, at least in a clinically meaningful way, beyond 24 hours.”
Subsequent to the review and approval of Exparel, adequate and well controlled studies have not been performed. It is the intent of this paper to illustrate the inadequacies and the lack of adherence to good clinical design and reporting that have plagued the efforts of scientific dissemination of information about this product since its approval.
How is it possible that the messages delivered in peer reviewed journals are permitted to be published without question? It is a perfect illustration in bias in reporting in the medical literature and ultimately an injustice to the to the entire medical publication peer review system. In order to illustrate this form of bias, a review of the published studies for this drug is necessary.
Many of the studies conducted with Exparel use a cumulative outcomes analysis (either cumulative opioid use or cumulative pain scores). Cumulative data is used to distract and disguise the truth. The use of discontinuous data permits the interpretation of the effects of a drug or device at specific time points. This not the case with continuous analyses. In the case of the study by Gorfine, the statistics reported out in the paper would not have shown a meaningful difference between the use of Exparel and placebo after 12 hours. Without the use of discrete data, the reader is distracted from this point by assuming that an initial measurable difference was sustained throughout the entire period of study. In order to make a strong statement about the efficacy of a product these discrete data points need to illustrate significant benefits. The need to summarize data with continuous analyses suggests weak associations, at best. The difficulty in interpreting continuous data in this fashion is that the analysis masks what happens at each discrete time-point. Table 1 is taken from the manuscript authored by Gorfine [4
] and provides the analysis of opioid rescue medications in a cumulative fashion. By breaking out the data into 12 hour time-points rather than in a cumulative manner the actual difference between Exparel and placebo (saline) is limited to the first 12 hours (Table 1).
As you can see from these examples, while there was a significant difference noted at the 0-12h time point, the differences at each time-point after that were not statistically significant nor were they clinically relevant and from the 12 hour time point through 72 hours the results favoured the placebo therapy numerically. The authors of this study would lead you to believe that the use of opioid rescue medication was significantly reduced throughout the 72 hour time frame when in actuality a significant effect was illustrated only in the first 12 hours, following that the two therapies are virtually equivalent (Table 2).