How the FDA became Dependent on Accelerated Approval and User Fees

“You don’t survive as a senior official at the FDA unless you’re pro-industry. The FDA has to pay attention to what Congress tells them to do, and the industry will lobby to get somebody else in there if they don’t like you. Staffers know “you don’t get promoted unless you’re pro-industry.”

--Thomas Marciniak, former FDA medical team leader and critic of how drug companies handle clinical trials

When The Media Says "Experts" They Mean Paid Corporate Shills (Part 21)

In the first two phase three trials, Acadia Pharmaceuticals failed to demonstrate that Nuplazid, a drug they created to treat Parkinson’s-related psychosis, was even marginally beneficial compared to a placebo. However, after getting permission from the FDA to revise the original scale used to measure clinical benefit, but had never been used in a RCT, they found a borderline statistically significant clinical benefit for Nuplazid over the placebo in a third phase three trial with less than 200 patients. The FDA gave Nuplazid a breakthrough therapy designation, allowing it to go to market with only one instead of two positive RCT results. When one medical officer found that you would have to treat 91 patients with Nuplazid for 7 to get the clinical benefit and that 5 of the 7 would suffer SAEs while 1 would die he recommended against approving it with the breakthrough therapy designation for having “an unacceptably increased, drug-related, safety risk of mortality and serious morbidity” so the FDA convened an advisory panel of 15 outside “experts” to deliberate on the matter. This is where Acadia Pharmaceuticals loaded the dice. Out of the 15 outside “experts” on the advisory panel, 3 were paid shills of Acadia Pharmaceuticals, 4 were represented Parkinson’s advocacy organizations funded by Acadia Pharmaceuticals and 3 more were relatives of Parkinson patients whose travel expenses were paid for by Acadia Pharmaceuticals. 2 more, a daughter and granddaughter of a woman with Parkinsons had no prior financial support from the company but the granddaughter became a paid “brand ambassador” (another term for shill) after sitting on the advisory panel. Unsurprisingly, the only panel member who urged the FDA to reject approval was a National Center for Health Research Scientists with no financial support from the drugmaker. Overall, the panel voted 12-2 to recommend accelerated approval of Nuplazid. The FDA director of the psychiatric products division used this overwhelming vote of confidence to grant accelerated approval of Nuplazid in 2016 over the objections of the medical officer who was part of the team that reviewed their one positive RCT. Two years after it was approved to treat Parkinson’s related Psychosis Nuplazid was responsible for 887 deaths and 400 exacerbated hallucinations, but Acadia Pharmaceuticals paid physicians thousands of dollars in consulting fees to ensure their new drug was prescribed to medicare recipients in nursing homes.

The precedent for accelerating the approval of drugs like Nuplazid based on a lower standard of evidence was started by one of the most unlikely causes. In the late 80s and early 90s HIV activists agitated for accelerated approvals of antiviral treatments for HIV and accused the FDA of holding back cures. They went so far as to invade FDA HQ in Rockville, MD in 1988 and conduct “die ins.” That same year congress created fast track regulations and in 1992 introduced user fees, through the Prescription Drug User Fee Act, so drug makers could pay for priority review and accelerated approval. In 1993, user fees only paid for 27% of the FDA’s drug research budget. As I mentioned in (Part 2), user fees now pay for almost half of the FDA budget and 75% of their drug research budget. The 2012 congress created the “breakthrough therapy” designation that allowed drug makers like Acadia Pharmaceuticals to get their product approved with only one RCT showing marginal clinical benefits. Following the 2012 statute, the FDA approved 28% of new drugs as breakthrough therapies while giving accelerated approval to 68% of all new drugs between 2014 and 2016. Nuplazid isn’t the only dubious medication that received accelerated approval over the objection of medical officers and advisory committee experts. Exondys 51, a drug developed to treat Duchenne muscular dystrophy, was approved despite failing to show clinical benefit in a RCT with 12 participants because the head of the FDA Center for Drug Evaluation and Research was concerned about the solvency of the company that made it, a concern, I might add, that was never delegated to the FDA by congress. The FDA’s European counterpart, the EMA, rejected the NDA for Exondys 51 on the basis that the clinical endpoint used to measure the drug’s effectiveness, a marginal increase in dystrophin production, does not actually demonstrate clinical benefit. Some drugs like Folotyn, developed to treat patients with peripheral T-cell lymphoma, received accelerated approval without even a placebo controlled RCT; all 107 participants in that RCT were in the treatment group and only 13 had some measurable clinical benefit after 14 weeks. In 2012 the FDA granted accelerated approval to a TB treatment developed by Johnson & Johnson on the basis that it killed more bacteria in the sputum when combined with the traditional regimen than the traditional regimen does alone. It also increased patient mortality 5x over the traditional regimen alone but the FDA resolved this by just slapping a black box warning on the package insert and gave Johnson & Johnson a voucher for a 6 month priority review of their next NDA.

Source: ProPublica: FDA Repays Industry by Rushing Risky Drugs to Market