Earlier this year, the Mirapex drug that is used to treat Parkinson's disease and Restless Legs Syndrome became the latest example in the ongoing controversy over the full disclosure of unfavorable clinical trial data. Six years ago, cardiac failure was listed in the labeling after being noticed during clinical trials, but causation was never determined. Later, cardiac failure was cited in connection with the drug, but the full story appeared untold.
The background: A study funded by Pfizer, which compared its Dostinex drug against other meds, found a statistically significant increased risk of heart failure with Mirapex. Earlier this year, a study supported, in part, by Boehringer Ingelheim, which sells Mirapex, reached the same conclusion about both drugs. But that latest study yielded some revealing passages suggesting Boeheringer had tracked cardiac failure for some time without any public disclosure.
Briefly, the study cited "internal data" and correspondence from the head of global epidemiology at Boehringer, who provided results of a pooled analysis from randomized Mirapex trials. The study mentioned a “signal of a potential risk of heart failure arose in pooled data from 26 placebo-controlled, randomized trials” in Parkinson’s and RLS patients. But there were differences between the authors and the drugmaker, which never disclosed when it learned of the risk of cardiac failure in the pooled trials.
Last week, though, the FDA issued a warning informing the public about a possible increased risk of heart failure with Mirapex after evaluating a pooled analysis of randomized clinical trials and found that heart failure was more frequent with Mirapex than with placebo. The agency also evaluated two epidemiologic studies that suggested an increased risk of new onset of heart failure with Mirapex use, according to a statement (read here).
In discussing its explanation, the FDA noted that Boehringer provided the pooled analysis in 2008 to the agency and then updated the data two years later. Meanwhile, though, there was no opportunity for independent review, since the drugmaker never publicly disclosed the material that was used as the basis for the study that was published earlier this year in Pharmacoepidemiology & Drug Safety (back story).
Instead, the drugmaker had pointed us toward the labeling, which was revised last year and provides the same language that appeared in 2006, with the addition of one line: “In a pharmacoepidemiological study, pramipexole (Mirapex) use was associated with an increased risk of cardiac failure compared with non-use.” This appears under the post-marketing experience section. As we noted earlier, there was no mention of two studies or undisclosed data.
The FDA, however, offered a couple of caveats about its latest conclusions. For one, the agency cautioned there were study limitations that made it difficult to determine whether excess heart failure was related to Mirapex use or other influencing factors. The FDA also noted that the evaluation of the pooled analysis of randomized clinical trials showing heart failure was more frequent with Mirapex than with placebo was not statistically significant.
Some, however, may argue such a qualifier is unconvincing. Last year, for instance, US Supreme Court Justice Sonia Sotomayor noted that "both medical experts and the Food and Drug Administration rely on evidence other than statistically significant data to establish an inference of causation." She wrote that in a unanimous opinion that a drugmaker may be required to alert investors of adverse events even if statistical significance is lacking (read here).
heart attack pic thx to bart on flickr