Hiding fandom in the underwear drawer since 1977

https://www.science.org/content/blog-post/fda-cracks-down-tavneos

We have quite a regulatory situation developing around a drug called avacopan (Tavneos), which is given to patients with a particular type of vaculitis. That’s a complex disease area, and comes in several varieties, but a common theme in many of them is an autoimmune attack against various proteins found in neutrophils. The drug is an antagonist of the complement 5a receptor in the innate immune system, and it’s given along with other immunosuppressants. 

It was developed recently by a company called ChemoCentryx, who ran a pivotal trial in 330 patients. Half got the standard of care plus a placebo and half got that standard plus the drug over 52 weeks, and the endpoints were remission at 26 and 52 weeks. Both endpoints were similar, and both showed a real benefit to the patients. Tavneos was approved by both the FDA and the European CHMP in 2022, and Amgen went on to purchase the entire company.

But earlier this year, the CHMP announced that they were starting an investigation based on reports of loss of data integrity in that trial. And the CDER at the FDA is proposing to have it withdrawn from the US market over the same issues. It’s very, very bad - here’s the FDA statement:

. . .new information that only became known to CDER more than three years after approval shows that unblinded study personnel manipulated the results of the pivotal clinical study so the drug looked effective when the original analysis did not support that conclusion. The applicant also did not disclose the original analysis to FDA, in violation of FDA regulations. CDER can no longer conclude that there is, or has ever been, a valid demonstration that TAVNEOS is effective for its approved use.

Ohhh boy. This is about as bad an accusation as you can make about a clinical trial, i.e. “The unblinded data were ugly, so we hocused the numbers until it looked like the drug worked”. I occasionally meet uninformed cynics who assume that this is how we always do things in the drug industry, but oh no, we don’t. We have an 85% failure rate in the clinic! Why would any clinical trial ever fail if we had constant recourse to bullshit like this?

For more details, this FDA document at the Federal Register is the place to go. This all came to light due to a lawsuit against the company for securities fraud, which included a consultant’s report about the avacopan/Tavneos trial process. That all came about because during the initial approval process ChemoCentryx made numerous public statement about how straightforward the trial was and how uneventful their interactions with the FDA had been, but in May of 2021 the FDA review committee hearing instead detailed a whole list of pointed questions the agency had had about the trial design and the interpretability of the results. That sent the stock down about 80%, and that will get you a shareholder lawsuit every time.

But as it turns out, the hapless shareholders don’t seem to have known the half of it. The consultant report introduced as evidence during the lawsuit claims that the initial analysis of the clinical trial showed it missing the primary endpoint, and that the company picked a number of cases for “readjudication”. Wouldntjaknowit, enough of these flipped over to positive during this reanalysis to cause the whole trial to meet its statistics. The report says that ChemoCentryx employees stated as much even before the reworking, calculating how many patient outcomes would need to be flipped. But none of this was disclosed in any way to the FDA, obviously, and yes, that is all flagrantly illegal if it’s what happened. 

The FDA says that it requested a detailed account of the data handling for the trial, and that Amgen’s response a month later “confirmed the key factual allegations” above. But the company went on to claim that the data in the NDA are accurate and that the patient readjudications were appropriate. (As it turns out, the lawsuit was later dismissed without ever addressing these accusations, so it doesn’t have any bearing on this situation).

The case for the data changes being valid rests largely on patient glucocorticoid dosing or missing data, and I won’t get into the merits of that argument. But what seems beyond doubt is that ChemoCentryx made sure that the FDA never heard about it and made sure to submit only the freshly polished data set. Such readjudication-after-unblinding was, as you would imagine, absolutely not permitted under the study protocols. The FDA notes that one of the patients was initially marked down by ChemoCentryx as a non-responder due to missing data at week 26, but that same patient got helpfully moved to the “in remission” category after the unblinding. That’s precisely why you are not supposed to do that sort of thing.

There’s even more bad news: not only are there doubts about the efficacy, the safety profile is looking bad, too. The FDA has received numerous reports of liver toxicity, which was a concern even during approval (Tavneos already has a label warning to that effect). But since getting on the market there have been several fatalities, some of which involve the extremely-alarmingly-named “vanishing bile duct syndrome”, which I had never heard of until now. It’s just what it sounds like: the bile ducts through the liver tissue deteriorate and disappear, and that is clearly just as bad as you think it is. Most of those have been reported in Japan, for reasons unknown, but man, you don’t want that showing up anywhere. I feel pretty sure that a “Whatever happened to the bile ducts” finding during the trials would have shut things down right there. One has the impression that Amgen might have been better off if they'd never heard of this drug at all instead of being shackled to defending it.

The drug was approved with a requirement for a postmarketing study covering both safety and efficacy, but the FDA says that as of the most recent report, only 21 of the planned 300 patients had been enrolled. I’ve written about this problem before - too often, companies have an incentive to draaaaag their feet on these requirements and collect the data at glacial speed, and that may be just what we’re seeing here.

But as it stands, I would agree with the FDA’s contention that the trial results “are uninterpretable and cannot be salvaged with further analysis”. What’s more, it would seem that the company made materially false statements to the agency during the application process. This is all really, really unfortunate - for vasculitis patients most of all, but for the integrity of the whole clinical trial and drug approval process as well. We really don’t need this sort of thing right now - hell, we never have, but especially not now.

https://www.science.org/content/blog-post/fda-cracks-down-tavneos