British Medical Journal (The BMJ)The Decline of Science at the FDA has Become Unmanageable

The FDA’s controversial approval of Recarbrio in 2019 marked a deviation from the expected standards of drug effectiveness.

Before 1962, US drug approvals didn’t require pre-market proof of effectiveness. Following Senate hearings and the Thalidomide disaster, however, the law changed. Nowadays, FDA approval for new drugs requires substantial evidence of effectiveness from well-controlled investigations. Strikingly, a National Academy of Sciences review found over 30% of pre-1962 drugs to be ineffective, highlighting the importance of these regulations.

FDA’s regulations provide a detailed explanation of what constitutes substantial evidence. Though not perfect, these regulations reassure prescribers, patients, and payers of the scientific basis of drug efficacy claims. It’s important to note that an FDA review found 59% of rejected NDAs had deficiencies in efficacy evidence.

Nevertheless, the FDA’s controversial approval of Recarbrio in 2019 raised eyebrows. This drug, a combination of imipenem, cilastatin, and relebactam, was approved despite lacking substantial evidence of effectiveness and proper clinical investigations. Disturbingly, FDA officials cited animal and laboratory studies as substantial evidence, a move contrary to legal and regulatory norms.

Moreover, the Recarbrio approval showcased other troubling departures from regulatory principles. The FDA failed to require proof of each active component’s contribution to the claimed effect. Office directors offered only perfunctory “reviews” in support of approval, far from the expected thorough analysis.

Contrary to expectations, the FDA decided not to present the deficient NDA to an advisory committee. Astonishingly, the agency granted Recarbrio a priority review, reducing the approval time by 40%. They even qualified Recarbrio for financial incentives aimed at encouraging the development of drugs for resistant infections, despite the lack of solid evidence that Recarbrio treats such infections.

These events point to a troubling erosion of the FDA’s scientific culture. An increased reliance on industry-paid user fees and the “regulatory flexibilities” provided by recent Acts may be contributing to this decline. Disturbingly, the FDA’s leadership has begun to favor non-inferiority trials, overlooking the issues they pose.

To address this, acknowledging the problem and reducing the FDA’s dependence on user fees would be vital first steps. Secondly, enhancing public access to FDA’s information, reasoning, and decisions could improve transparency, allowing more meaningful peer review and engagement. The FDA’s controversial approval of Recarbrio serves as a warning, suggesting that we may be returning to an era where drug effectiveness is an afterthought. The protection of public health requires us to heed this cautionary tale.