Did This Clinical Trial Succeed or Fail?

Did This Clinical Trial Succeed or Fail?

November 16th, 2012 // 3:23 pm @ jmpickett

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Did a clinical trial for an opioid constipation medicine being developed by AstraZeneca and Nektar Therapeutics actually fail even, though the drugmakers maintained that “positive” top-line results were harvested? The possibility was raised courtesy of a reference in a press release that the trial database was unlocked and then locked again prior to analysis.

The disclosure came as the drugmakers released findings earlier this week from two Phase III trials and one safety extension trial to evaluate the safety and efficacy of naloxegol, a pill that is being developed to treat opioid-induced constipation, which is a common side effect of prescription opioids.

Now consider this statement buried in the press release: “After initial locking of the database for KODIAC-05 (trial), data associated with one patient that was previously assessed as non-retrievable was found to be retrievable. These data were added to the database and the database was again locked and underwent a final analysis” (here is the press release).

As Adam Feuerstein at TheStreet points out, locking and unlocking a database can raise questions about the extent to which proper procedures are followed. “Once a clinical trial database is locked, it needs to stay locked. Locking and unlocking a database raises the risk that data can be improperly altered or manipulated,” he writes.

He notes AstraZeneca (AZN) “insists proper procedures were followed and the naloxegol analysis presented Monday is accurate. But it’s also plausible to believe AstraZeneca found no statistically significant difference in response rates between naloxegol at either the 12.5 mg or 25 mg dose, compared to placebo. AstraZeneca admits the 12.5 mg dose showed no benefit.”

The implication is that the drugmakers may have undertaken what he calls “a hunt” to find additional data from a “non-retrievable patient” after recognizing the possibility that the trial was a failure. By locking, unlocking and then throwing that extra patient into the mix, the results then yielded a desirable outcome.

Can one patient matter? Well, why not? Consider that the 25 mg dose registered a p value of 0.021 and the trial required a p value less than 0.025 to reach statistical significance, he writes. And, he adds, if additional data from one patient did not have a material effect on the trial, then why make a point of disclosing the maneuver?

For its part, AstraZeneca stands by its actions. “The topline results announced today reflect an analysis of a dataset that includes all the accessible patient records,” a spokesman told TheStreet. “Ultimately, that’s the only analysis that matters and that is why we only report the result based on the most accurate and complete dataset. Any earlier analyses would have been based on an incomplete dataset and we, therefore, would not consider them meaningful.”

However, the drugmaker acknowledged that unlocking the database and fishing for extra data is not the norm. “Although unusual, this is not unprecedented and entirely appropriate under the circumstances to ensure data from all patients who took part in the trial are included where possible,” the spokesman said. And what did Nektar (NKTR) have to say? Nothing.