Fast-forward to 2007, when the same company sought FDA approval for etoricoxib (Arcoxia), a new drug in the same class. Merck had initially proposed — and the agency had approved — a study comparing etoricoxib with diclofenac, an NSAID that many worried carried its own cardiac risk. Several years and millions of dollars later, Merck presented the FDA with trial evidence that etoricoxib caused roughly the same number of cardiac events as diclofenac. But this time, the FDA allowed its sharpest internal critic, David Graham, to present data to the advisory committee on the implications of approving another cyclooxygenase-2 inhibitor with potentially dangerous cardiac side effects. Had the company used a more appropriate comparator, naproxen, Graham and the others argued, the increased cardiovascular risk would have been clear. The committee voted overwhelmingly against approval. If diclofenac also presented a cardiac risk, the committee agreed, then the FDA should not approve a new product with no proven advantage that might confer the same hazard. Not only did this decision fly in the face of the original study design, it was also a sharp departure from the conventional FDA view that a new drug in an established class need not be any safer or more effective than its predecessors. The committee’s vote was so lopsided that the agency, still embarrassed at having missed the risk of myocardial infarction associated with rofecoxib during 5 years of widespread use, could not but agree with its recommendation.
I’m guessing FDA didn’t cite embarrassment in its non-approval letter to Merck (NYSE:MRK). I’m also guessing that no one in power at FDA regards its view that any new drug need be no safer than a predecessor as “conventional”. Rather, I’m fairly certain that they regard it as the letter of U.S. federal law. I’m sure I’ve posted relevant content from the Food Drug and Cosmetic Act previously, but here it is again. The Act states that approval is granted for a new drug application unless one of the following criteria is met:
(d) If the Secretary finds, after due notice to the applicant in accordance with subsection (c) and giving him an opportunity for a hearing, in accordance with said subsection, that (1) the investigations, reports of which are required to be submitted to the Secretary pursuant to subsection (b), do not include adequate tests by all methods reasonably applicable to show whether or not such drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling thereof; (2) the results of such tests show that such drug is unsafe for use under such conditions or do not show that such drug is safe for use under such conditions; (3) the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug are inadequate to preserve its identity, strength, quality, and purity; (4) upon the basis of the information submitted to him as part of the application, or upon the basis of any other information before him with respect to such drug, he has insufficient information to determine whether such drug is safe for use under such conditions; or (5) evaluated on the basis of the information submitted to him as part of the application and any other information before him with respect to such drug, there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof; or (6) the application failed to contain the patent information prescribed by subsection (b); or (7) based on a fair evaluation of all material facts, such labeling is false or misleading in any particular; he shall issue an order refusing to approve the application. If, after such notice and opportunity for hearing, the Secretary finds that clauses (1) through (6) do not apply, he shall issue an order approving the application. As used in this subsection and subsection (e), the term ‘‘substantial evidence’’ means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof. If the Secretary determines, based on relevant science, that data from one adequate and well-controlled clinical investigation and confirmatory evidence (obtained prior to or after such investigation) are sufficient to establish effectiveness, the Secretary may consider such data and evidence to constitute substantial evidence for purposes of the preceding sentence.
You’ll notice that the law makes no mention of evidence of superiority to predecessor drugs. In the Arcoxia case, FDA did not act out of embarrassment, nor did it have to skirt the law to deny approval of Arcoxia, as Avorn suggests. There were several legitimate–that is, legal–grounds for nonapproval.