Six studies published in three journals that assessed properties of fospropofol disodium have been retracted because of unresolved assay problems that produced flawed pharmacokinetic and pharmacodynamic data in company-sponsored, early-stage clinical trials.

In a letter published Feb. 19, 2010, in Anesthesiology, the corresponding and senior study authors requested the retractions, saying the sponsoring drug company had failed to reanalyze a revised assay of the drug within a 12-month deadline imposed collectively by the three journals in November 2008.

“As such, we, the undersigned corresponding and senior authors from the six original articles, in the name of all coauthors, request that the articles in question that provide flawed pharmacokinetic-pharmacodynamic [PK/PD] data be retracted. We regret that we are unable to successfully resolve the problem within the given timeframe.” The letter was signed by Michel M.R.F. Struys, MD, PhD, anesthesiology chair at the University of Groningen, The Netherlands, and Jörg Fechner, MD, Jürgen Schüttler, MD, and Helmut Schwilden, MD, PhD, all of the Department of Anesthesiology at the University of Erlangen-Nuremberg, in Germany.

The retractions are qualitatively different from those involving the studies of Scott S. Reuben, MD, former chief of the acute pain service at Baystate Medical Center in Springfield, Mass., who pleaded guilty to fraud in connection with falsifying and fabricating research involving Pfizer Inc.’s painkiller Celebrex.

In that case, Dr. Reuben’s fraudulent results helped lay the foundation for an emerging area of perioperative care known as multimodal analgesia. In the current case, the existence of the faulty assay was disclosed promptly by the company and resulting data were not used in PK studies submitted to the FDA for drug approval. There is no evidence that patients were affected in any way.

Fospropofol (Aquavan, MGI Pharma Inc.; Lusedra, Eisai Inc.), is a water-soluble prodrug of propofol that was approved by the FDA in December 2008 for monitored anesthesia care in adult patients undergoing diagnostic or therapeutic procedures. After injection, fospropofol is converted by alkaline phosphatase enzymes into propofol. It creates clinically useful sedation and suppression of brain activity with less respiratory depression than propofol. Pain at the injection site, a common effect with propofol, was not reported with fospropofol. Side effects included paresthesias, pruritus, hypotension, hypoxemia and nausea.

“Eisai supports the retraction of the fospropofol disodium PK/PD manuscripts in peer-reviewed journals,” said Judee Shuler, Eisai’s senior director of corporate communications. “The prescribing information does not include the flawed data,” she told Anesthesiology News. Eisai “will continue to communicate with anesthesiologists about fospropofol in accordance with our approved prescribing information,” she said, adding the company plans to begin a new study in the coming months.

Multiple Owners

The drug has changed hands through a series of company acquisitions. Guilford Pharmaceuticals, which was acquired by MGI Pharma in 2005, developed and validated the drug and assay and sponsored the Phase I and II studies that were conducted in Europe. The assays for all six studies were performed at MDS Pharma Services, an external lab in Montreal. Both the academic and sponsor-based investigators co-authored the study results, which were published in Anesthesiology (2003;99:303-313; 2004;101:626-639; 2005;103:718-729; 2005;103:730-743), Anesthesia and Analgesia (2005;100:701-706) and the European Journal of Anaesthesiology (2003;20:182-190).

In November 2008, the MGI Pharma co-authors published a letter to the editor in the three journals disclosing the existence of a faulty assay that “may have” affected the measurement of propofol plasma concentrations. “The originally reported propofol pharmacokinetic and pharmacodynamic results and the derived conclusions could be inaccurate,” the researchers wrote (Anesthesiology 2008;109:937; Anesth Analg 2009;108:32; Eur J Anaesthesiol 2009;26:81). The assay problems affected the quantification of propofol, not fospropofol, concentrations, they added.

In a published consensus reply, the editors-in-chief of the three journals issued an ultimatum: They gave the researchers 12 months to submit a manuscript validating the new assay, analyzing the likely error and bias in each of the six articles, and determining how the error influences the conclusions. Otherwise, they would retract all six articles.

At the time, the MGI Pharma researchers claimed they had already fixed and validated the assay and had conducted additional studies to assess the pharmacokinetics and pharmacodynamics of fospropofol in healthy volunteers and patients. “We plan to publish these results shortly,” they wrote in November 2008.

In a recent interview with Anesthesiology News, Dr. Struys said the sponsoring drug company was responsible for the assay and all decisions concerning its use. “We are an independent scientific center and this was a sponsor-initiated research trial,” Dr. Struys said. “We drew the blood samples and sent it to the lab per the sponsor’s request.”

Dr. Struys said the 12-month deadline imposed by the journal editors was reasonable, and probably would have been met had not the company once again changed ownership. “From a scientist’s point of view, 12 months is an adequate request from the editors-in-chief. It should have been OK if, six months after the request, the company [MGI Pharma] had not been sold to another company [Eisai],” he said. “As with mergers of companies, this caused a delay. The new company had to pick up the drug, set up a team, name a new medical director and all these kinds of things. This takes months.”

Ms. Shuler said Eisai had informed the FDA about issues with the assay in early Phase I studies when it submitted the New Drug Application. “It is important to note that the fospropofol FDA-approved prescribing information contains accurate PK/PD data,” she said. “Our goal is to begin a new fospropofol PK/PD study in Q1 FY2010 [year ending March 31, 2011].”

 The FDA confirmed it “was aware of the issues with the assays, and evaluated their potential implications as we did our review,” said Crystal Rice, a spokeswoman for the agency. In its clinical pharmacology review of the drug, the FDA noted Eisai did not use unreliable PK data. Separately, the agency did not address the question of why it did not recommend use of fospropofol during the propofol shortage that has affected U.S. hospitals and clinics since last July.