A scientific journal has revamped its whistle-blower coverage amid a dispute over the integrity of analysis underlying an experimental Alzheimer’s drug.
In a 1 November 2022 editorial in The Journal of Scientific Investigation (JCI), editor-in-chief Elizabeth McNally wrote that whistle-blowers had raised considerations in August 2022 about probably doctored photographs in analysis papers revealed by a number of journals, together with JCI. A few of the papers have been associated to the experimental drug simufilam, developed by biopharmaceutical agency Cassava Sciences, primarily based in Austin, Texas, whereas others have been authored by a scientist concerned within the remedy’s early testing.
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However, McNally says, the whistle-blowers didn’t disclose conflicts of curiosity after they lodged their grievance — and she or he alleges that they’ve profited from short-selling Cassava inventory, a apply through which people guess that an organization’s inventory will fall, and earn money when it does. “This represents a brand new technique of manipulating the scientific-publishing trade,” she writes.
Sometimes, when a whistle-blower contacts a journal about considerations over manipulated photographs or in any other case questionable information, the allegations are taken on good religion, McNally informed Nature. The concept that whistle-blowers might be doing this for their very own monetary acquire “was very eye-opening to me”, she says.
The group of 4 whistle-blowers who complained to JCI and different journals deny any wrongdoing and stand by their allegations, with three saying that they made solely comparatively small quantities of cash from buying and selling Cassava inventory. When writing to the journals, they flagged attainable picture manipulation in 32 papers revealed by Hoau-Yan Wang, a medical researcher on the Metropolis College of New York (CUNY) who was accountable for a lot of simufilam’s preclinical testing. (5 of the papers have been revealed by Springer Nature, which additionally publishes Nature; Nature’s information group is impartial of its writer.)
“Our so-called conflicts of curiosity even have completely nothing to do with the target info in play, that are manipulated photographs and information,” says Adrian Heilbut, one of many whistle-blowers, who’s a computational biologist and impartial marketing consultant primarily based in New York Metropolis. Cassava denies any wrongdoing.
A drug-development controversy
The corporate says that simufilam, a small-molecule drug, combats Alzheimer’s by stabilizing an important scaffolding protein within the mind referred to as filamin-A that’s impaired by the illness. Different Alzheimer’s medication use monoclonal antibodies to focus on clumped amyloid proteins for elimination from the brains of individuals with the illness.
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Amid the allegations about Cassava’s information, researchers have expressed concern over how simufilam works. Other than the preliminary research by Cassava and its collaborators, the technique of stablilizing filamin-A to sort out Alzheimer’s hasn’t been on anybody’s radar, says George Perry, an Alzheimer’s researcher on the College of Texas at San Antonio. “The truth that it hasn’t been extensively studied implies that it hasn’t been confirmed.”
In an announcement, a lawyer appearing on behalf of Cassava informed Nature: “The scientific group is rethinking the causes of Alzheimer’s illness and seeking to different explanations and potential options.” Final yr, two analysis teams, not affiliated with Cassava, revealed papers wanting on the function that filamin-A may have in Alzheimer’s illness1,2, the assertion provides.
Cassava reported interim information from a medical trial of simufilam in a September 2021 press launch. Fifty individuals with Alzheimer’s who have been handled with the small molecule for 12 months had improved cognitive check scores from after they began the trial, in accordance with the discharge. The trial was ‘open label’, nevertheless, which means that contributors knew they have been receiving the remedy, with no placebo group to make sure the development was brought on by simufilam.
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A month earlier than the corporate launched these outcomes, a pair of quick sellers impartial of the whistle-blowers who contacted JCI filed a petition with the US Meals and Drug Administration (FDA), pointing to potential picture manipulation in Cassava’s simufilam analysis and asking the company to halt medical trials. Cassava inventory was at a excessive of US$135 per share earlier than the petition was filed; shortly afterwards, the inventory’s worth had plummeted by 55%.
The US Securities and Alternate Fee is investigating, in accordance with media studies. However the FDA introduced in February 2022 that it could not intervene in Cassava’s medical trials as a result of the petition was not an applicable option to request that the company take this motion.
The corporate has mentioned that such ‘citizen-petition’ accusations are unsubstantiated and factors out that “no authorities company has accused Cassava Sciences of any sort of dishonest behaviour”.
A minimum of 5 papers authored by Wang and others have been retracted over considerations about picture manipulation, and different investigations are ongoing. Thus far, journals that revealed two3,4 of the three key analysis papers supporting simufilam as a possible Alzheimer’s remedy have issued expressions of concern and corrections. These journals informed Nature that they haven’t closed the circumstances as a result of they’re ready for the outcomes of a CUNY investigation into Wang’s work. Cassava disputes this for one of many journals. Within the case of the opposite, the journal says that it performed its personal investigation and located no compelling proof of information manipulation with the intent to mislead.
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The third key paper, revealed in The Journal of Prevention of Alzheimer’s Illness5, was investigated, however one in every of its editors informed Nature that it additionally discovered “no convincing proof of manipulation of information or intent to mislead”, and subsequently took no motion. (This journal is revealed by Springer Nature.)
A spokesperson for CUNY informed Nature that the college takes allegations of analysis misconduct severely and can’t remark till its investigation is full. Wang didn’t reply to Nature’s request for remark.
Final month, Cassava filed a lawsuit towards the FDA petitioners, an funding firm and the 4 whistle-blowers who contacted JCI: Heilbut; Jesse Brodkin, a pharmacologist who owns a preclinical-research gear improvement firm primarily based in Basking Ridge, New Jersey; Enea Milioris, an impartial portfolio supervisor who runs a life-sciences funding agency in London; and Patrick Markey, a medical psychologist at an outpatient mental-health centre in Munich, Germany. Cassava says in its submitting that the defendants unfold “factually inaccurate and defamatory data”.
Heilbut and Markey informed Nature that they’d no remark. Brodkin and Milioris say that as a substitute of offering proof to counter their claims, the corporate is attacking them.
McNally says she hopes that her JCI editorial will remind different journals to pay attention to conflicts of curiosity. (JCI’s investigation of the allegedly doctored picture in its paper didn’t substantiate the whistle-blowers’ declare, she says.) “Going ahead, whistleblowers, identical to authors, editors, and referees, will probably be requested to tell us of current, ongoing, and potential conflicts of curiosity,” she wrote in her editorial.
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One journal has already mentioned that it’d observe McNally’s lead. Louk Vanderschuren, editor of Behavioural Pharmacology, says that the journal will “undoubtedly take into account asking for disclosure of a monetary battle of curiosity, ought to an allegation of misconduct be reported to us” in future. The publication investigated allegations about one of many papers by Wang that has been scrutinized, however took no motion as a result of it obtained a passable response from Wang, Vanderschuren informed Nature.
Heilbut responds to McNally’s motion, saying he and different whistle-blowers in his group disclosed their monetary positions on-line. Brodkin tells Nature that though he has no issues declaring conflicts of curiosity, he worries about requiring disclosures from whistle-blowers. In some circumstances, he says, “whistle-blowers ought to be granted particular protections towards reprisal, together with an possibility to lift considerations anonymously”.
Cassava started two part III medical trials in October and November final yr, through which it plans to check simufilam on about 1,750 individuals.