The June 14th edition of the NEJM (http://content.nejm.org/cgi/content/short/356/24/2472) contains an article describing a trial of anidulafungin, a new echinocandin antifungal agent similar to the more familiar caspofungin, in invasive candidiasis. The comparator agent was fluconazole. This is a proprietary agent, and the study was was fully funded by the pharmaceutical sponsor.
The trial was a non-inferiority trial, and the chosen "delta" (the treatment difference which was determined to be clinically insignificant) was 20%. This means that the authors would consider a difference in clinical response between the 2 agents of 19% to be clinically insignificant. No justification for this delta was provided, as is recommended (http://jama.ama-assn.org/cgi/content/abstract/295/10/1152?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=non-inferiority&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT). It is not clear if clinicians agree with this implicit statement of clinical insignificance, and no poll has been taken to determine if they do.
Which begs a question: should there be a requirement that clinicians be polled to determine what THEY, rather than the study sponsors think is a clinically insignificant difference? After all, clinicians are the folks who will be using the drug (if it is approved by the FDA.)
The design of non-inferiority trials is, in my experience, poorly understood among clinicians, and this may be due to inadequate reporting as reported in the above article and in this one (http://jama.ama-assn.org/cgi/content/abstract/295/10/1147?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=equivalence&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT).
Interestingly the difference in the agents favored anidulafungin by 15.4%, a difference that the authors did not emphasize as clinically insignificant.
I am left wondering if individual patients or society are better off now that we have another drug of the echinocandin class available. I would be more convinced that they were if anidulafungin had been compared to 800 mg of fluconazole (rather than 400 mg) or to caspofungin, but alas, it was not. I don't know what the cost of developing and testing this drug was, but I expect that it was on the order of tens to hundreds of millions of dollars - not to mention the costs of subsequent testing, advertising and marketing.
And the opportunity costs - the other possibilities. What else could have been done with that money that may have benefited individual patients or society more than another echinocandin agent?
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