A recent op-ed published Monday in STAT insists that proposed FDA guidance for Alzheimer’s drug development is “good news” that “removes unnecessary barriers” to bring new medications to market.
If the guidance is finalized, pharmaceutical companies would no longer have to prove that their drugs impact the endpoints of “cognition and function” when tested on very early-stage patients. Instead, they’d only be required to show that their products positively affect “biomarkers” (which includes things like protein levels in the brain that are linked to the disease).
This change is vital, argues author Howard M. Fillit, MD, founding executive president of the Alzheimer’s Drug Discovery Foundation. In the op-ed, he states that requiring drugmakers to prove that their products improve cognition and function is “likely a contributing factor in the high rate of failure in Alzheimer’s trials.”
At first glance, the op-ed seems like an impassioned plea to modernize outmoded FDA guidance in the name of patient advocacy–what could be more important than helping Alzheimer’s patients get better drugs faster?
But digging deeper, we found the bigger picture is more muddled.
Author has industry connections
First, Fillit has industry connections that are more complex than the bio on his op-ed suggests. These connections should have been disclosed as part of STAT’s author agreement policy–but weren’t when the piece was published. Only after HealthNewsReview.org contacted the author on Thursday was the piece updated with an additional “editor’s note” disclosing that he’s accepted payments from at least nine drug companies.
Specifically, he has received thousands in fees directly from drugmakers over the years, and his foundation lists in its annual report several pharmaceutical donors with Alzheimer’s drugs under development. Yet his bio described him merely as the “founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation.”
The lack of disclosure of conflicts of interest is an ongoing issue with STAT opinion pieces, as we highlighted last summer.
Second, and not unrelated, the FDA’s proposed changes would likely be a financial boon to drugmakers. In effect, they’d no longer have to show their drugs actually work, pointed out Vinay Prasad, MD, an oncologist at Oregon Health and Sciences University who also researches general health policy, evidence-based medicine and medical reversals.
The change could be “a catastrophically foolish decision,” he said. “It means that you could theoretically be treating healthy people for years without any evidence that it’s actually improving anything.”
Geriatric psychiatrist Susan Molchan, MD, was less critical of the FDA guidance, stating that it appeared carefully worded, and included caveats, such as requiring drugmakers to continue to follow patients after approval to show that their drug works beyond simply affecting biomarkers.
What was worrisome to her, though, was the agency’s growing reluctance to make sure that kind of follow-up happens.
“Companies are notorious for not completing the followup studies needed to show effectiveness post-approval,” said Molchan, a former clinical researcher with the National Institutes of Health. “And our increasingly worthless FDA [is] more and more lax on insisting they complete them, leaving worthless and dangerous drugs on the market.”
She also was troubled by Fillit’s insistence that the FDA’s standards were to blame for the failure of so many Alzheimer’s drugs.
“Fillit’s blaming of the FDA criteria for approval as ‘a contributing factor in the high rate of failure in Alzheimer’s trials’ is spoken like a true pharma company hack, to put it nicely,” she said in an email.
What about more advanced disease?
The FDA’s focus on biomarkers mostly applies to drug development for people with “stage 1 Alzheimer’s,” which is when the disease is nearly undetectable to the patient and healthcare providers, but, in theory at least, detectable with biomarkers. (As even the FDA admits, in the final paragraph of the guidance, “currently, there is no consensus as to particular biomarkers that would be appropriate to support clinical findings in trials in early AD.”)
For patients with stage 2 Alzheimer’s, which is detectable on cognition tests but often imperceptible to loved ones, the FDA guidance shifts somewhat, too. Less emphasis would be placed on making sure drugs improve functional impairment, such as completing everyday tasks. Instead, drugmakers would only have to show improvements in cognition, which is generally measured via a standardized test.
That’s not necessarily a win for patients, Prasad said.
“Improving your ability to solve a complex puzzle that may not have anything to do with real life is not making people better off,” he said.
As with early-stage research, the FDA seems to indicate that drugmakers would need to track the progress of stage 2 patients to see if, eventually, the focus on cognition does anything to halt the disease over time.
“That is measurable, and I would agree, reasonable,” Molchan said. “It would also take, optimistically, 5 years, but trials do go on for 5 years. The bigger the effect size of the drug, the more obvious it would be sooner.”
Roy Poses, MD, clinical professor of medicine at Brown University, agreed.
“To do a prevention trial right, it should be run long enough to detect whether treated patients have less progression of disease in terms of cognition or function than untreated patients,” he said via email. “Of course, doing such a trial would be more difficult and more expensive than simply doing a trial that used surrogate outcomes.”
Molchan also pointed out a reality the STAT op-ed did not: A single-minded focus on finding a blockbuster drug may backfire, and therefore addressing “non-drug interventions are important,” too, as discussed in this New England Journal of Medicine Perspective piece:
“In fact, population-based studies have convincingly demonstrated that the vast majority of dementia cases, especially those occurring very late in life, tend to involve a mixture of Alzheimer’s disease, vascular disease, and other degenerative factors. Research on preventing late-life dementias should explore ways of reducing risk factors at both the societal and the personal levels.”
‘It should have been disclosed to the reader’
It’s perhaps not surprising that the drawbacks around weakened drug standards weren’t brought up in the STAT op-ed. After all, the author works for a drug-research foundation that lists several pharmaceutical companies as donors, and he himself has received direct payments from a number of companies developing Alzheimer’s drugs.
Fillit told HealthNewsReview.org he didn’t disclose these relationships to STAT because the publication asks for “disclosures on organizations that are ‘referenced in the article or stand to benefit from this article’s publication.’”
“The First Opinion piece included no references to pharmaceutical companies or specific drug programs,” he said. “It was an opinion on a new FDA guideline, particularly as it impacts the development of new drugs for early stages of Alzheimer’s disease and the role of biomarkers.”
Paul Thacker, who helped draft the Physician Payments Sunshine Act when working on the Senate Finance Committee for Sen. Chuck Grassley (R-Iowa), called this a “dance-around explanation.”
“Obviously, shifting standards for drug approval will have an impact on any drug getting approved. Seems simple and obvious,” Thacker, now an investigative reporter, said.
That’s why it’s so important that STAT carefully vet their authors and disclose conflicts of interest. Adding in Fillit’s industry connections — retrieved within seconds via the Open Payments database — helps readers see the forest for the trees.
“Given his undisclosed conflicts of interest, and the undisclosed institutional conflicts of interest of the foundation he runs, there is a concern that he may be excessively sympathetic to the financial interests of industry, and that may have somehow influenced him to be so enthusiastic about surrogate variables [such as biomarkers],” Poses said.
STAT’s first-rate news operation offers a model for how journalists can proactively identify conflicts of interest and provide this critical context to readers. Earlier this week, in fact, STAT contributors reported on a study detailing millions of dollars in undisclosed payments to the authors of a popular medical textbook.
And yet, the First Opinion commentary section repeatedly fails to apply such scrutiny to articles running under the STAT banner. Thacker, who has written for First Opinion, said that the author agreement was one of the best he’s ever seen and he commends the publication for trying to improve.
“But while they are trying, they keep messing up,” he said.
“I don’t think this case is as egregious as some of the others, but it’s still problematic,” said Charles Seife, a journalism professor at New York University, in an email. “The whole issue essentially boils down to hidden financial influences over a person’s writing. …In this case, STAT got part of the way there. Disclosing that Fillet was a major force behind an Alzheimer’s research advocacy organization gives some sense of the potential issues.
“But the fact that Fillet was taking money from a number of drug companies whose Alzheimer’s pipelines were supposedly damaged by these FDA regulations, well, that’s a much more direct potential avenue of influence. It should have been disclosed to the reader.”
Until STAT updated the piece four days after it was first published, there was no such disclosure. This means readers could have come away thinking that these proposed FDA changes must happen–that they represent progress, at least from the mindset of a concerned doctor who knows a lot about these things.
But, is it progress for patients, or progress for shareholders? As we’ve seen time and again, it’s often the latter.