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hubie [soylentnews.org] writes:

The decline of science at the FDA has become unmanageable [bmj.com]:

Before 1962, US federal law did not require pre-marketing proof of effectiveness for drugs. But senate hearings revealing widespread false advertising of drugs—along with the thalidomide safety disaster—spurred Congress into action. From then on, approval of a New Drug Application (NDA) by the US Food and Drug Administration required proof of "substantial evidence" of effectiveness. This proof was defined as results from "adequate and well-controlled investigations, including clinical investigations," with such evidence also required to advertise claims of safety and effectiveness. A National Academy of Sciences review underscored the need for these mandates, finding over 30% of pre-1962 marketed drugs to be ineffective.

The FDA's legally enforceable regulations detail what "substantial evidence" and "adequate and well-controlled investigations" mean in greater depth, supplemented by guidelines to industry which, although not legally binding, explain the FDA's current interpretation of drug manufacturers' legal obligations. However imperfect, the FDA's enforcement of these provisions assures prescribers, patients, and payers that effectiveness claims are based on science, not science fiction. A published FDA review showed efficacy deficiencies, in whole or in part, underlying initial rejection of 89 of 151 NDAs (59%), highlighting the continuing need for vigilance on this front.

However, as Peter Doshi reports in The BMJ, the FDA subverted the legal standard for effectiveness in its 2019 approval of Recarbrio, a fixed dose combination of imipenem, cilastatin, and relebactam. While the FDA has previously approved products with marginal evidence of effectiveness, approval of the Recarbrio NDA was shocking given its lack of substantial evidence of effectiveness and the complete absence of adequate and well controlled clinical investigations on the actual indication of interest.

[...] What accounts for this descent into cargo cult science? Much of the blame must go to the FDA's reliance on industry paid user fees. Over the past three decades the proportion of the FDA's annual drug budget made up of such fees has risen from less than 10% (fiscal year 1994) to more than two thirds (fiscal year 2023). In addition, the alluring "regulatory flexibilities" provided by the FDA Modernization Act of 1997 and the 21st Century Cures Act have become habit forming, enabling the FDA's leadership and managers to deny scientific reality by defining effectiveness downward. In its quest to avoid difficult choices and hard decisions the FDA has increasingly embraced non-inferiority trials (or vice versa), ignoring the serious regulatory, clinical, and ethical problems caused by their misuse.

However, the corruption of the FDA's scientific culture remains the primary culprit driving the deterioration of safety and effectiveness standards. During my tenure at FDA, managers would admiringly speak of "crafting an approval," as if it were a skilful demonstration of regulatory legerdemain rather than an act of scientific fabrication. The Recarbrio approval illustrates that the situation has, if anything, worsened since then. FDA leadership's continued hostility towards meaningful peer review, transparency, and accountability dims the prospect for institutional self-renewal. So has the failure of much touted internal pathways for disagreement, which have amounted to little more than virtue signalling

[...] The Recarbrio approval is a sentinel event, warning of a return to an era when drug effectiveness was an afterthought. Although the FDA crowed about this approval, it would have been better advised to remember that "for a successful technology, reality must take precedence over public relations, for nature cannot be fooled."

Details of the Recarbrio approval can be found in the linked companion piece [bmj.com].

Original Submission