JAMA Publishes Trial Results Delayed 5 Years. Here's Why

Marcia Frellick

April 30, 2021

A treatment for shortening the painful episodes of sickle cell disease (SCD) is not effective, results published in JAMA indicate. But the effort it took to publish the findings is an important part of the story and reveal problems with data ownership, company motivations, and public resources that go well beyond a single clinical trial or experimental agent.

Topline neutral results for the trial of poloxamer 188 by James F. Casella, MD, in the Department of Pediatric Hematology at Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues were announced in 2016, but it has taken until this month for them to be published.

This Study Contradicts Previous Findings

JAMA deputy editor Jody Zylke, MD, wrote in an accompanying editor's note that normally, JAMA would not publish results from a study that ended 5 years ago. Several reasons convinced the editors to do so.

One was that these trial results contradict those from a previous study of poloxamer 188 for reducing vaso-occlusive episodes in patients with SCD. That 2001 study was also published in JAMA.

In the previous study, researchers found a modest, statistically significant reduction in the duration of SCD episodes with poloxamer 188 in comparison with placebo among 255 hospitalized adults and children (141 hours vs 133 hours; difference, 9 hours; P = .04).

But the newly reported trial, which was funded by Mast Therapeutics Inc (previously Adventrx Therapeutics Inc) did not find similar benefit. Casella's phase 3 randomized, placebo-controlled clinical trial of poloxamer 188 was conducted in 66 hospitals in 12 countries. Investigators enrolled 388 children and adults with SCD who had moderate to severe pain requiring hospitalization.

Casella and colleagues found that the average time to last dose of parenteral opioids during vaso-occlusive episodes was 81.8 hours, vs 77.8 hours with placebo, but the difference was not statistically significant.

Zylke said the difference in the results may be partially explained by the researchers' choice of primary outcome and that Casella's results were more easily verifiable.

Zylke points out that there is significant unmet need for an agent that can shorten such episodes. The results thus remain clinically relevant. Tests of other drugs to shorten the duration of episodes ― including inhalational nitric oxide, intravenous magnesium, and intravenous sevuparin — have failed.

Article Points to Problems in Research Process

Zylke also emphasizes that the 5-year delay in publishing the results holds clues to barriers to publishing data from many clinical trials, another reason JAMA editors found it important to publish this article.

In the case of Casella's study, she says, the research hit a roadblock when the company that funded the trial, Mast Therapeutics, was sold to another company, Savara, along with the rights to the trial, immediately after the negative results were announced.

She says the authors report that the new company was not interested in publishing the results and that the data were no longer available to the investigators. After several years, one of the investigators reported that he was able to use his own resources to complete the analysis.

Asked to respond to the company's interest in poloxamer 188, Savara media representative Anne Erickson told Medscape Medical News, "In October 2017, Savara sold the assets related to the vepoloxamer program that had been acquired from Mast, including any data and study reports, to LifeRaft Biosciences Inc."

Robert Martin Emanuele, PhD, is LifeRaft's president and CEO. Efforts to reach Emanuele were not successful.

Zylke did not respond to Medscape Medical News' requests for comments.

Casella declined to talk with Medscape Medical News for this article and would not confirm which investigator used his own resources.

Unusual Example of a Wider Problem

Andrew Althouse, PhD, assistant professor of medicine with the Center for Research on Healthcare at the University of Pittsburgh, Pittsburgh, Pennsylvania, told Medscape Medical News that this is an unusual example of a common problem that occurs when trial results are negative.

Sometimes journals bear some of the blame for not publishing negative results, he said. Sometimes it's a matter of business.

A company might logically ask, "Why would we keep paying our people to keep working for something we're not pursuing?" said Althouse, who was not involved in the study or the editorial decision to publish the article.

He draws a distinction between declining to further fund a trial that had negative results for an agent that is of no further benefit to the company and "a more nefarious reason" of trying to hide negative results.

Althouse says that although he understands the business argument for a company not committing more resources or declining to put in the effort to have negative results published, he still believes all trial results should be published, positive or negative.

"If patients agreed to participate in research, in my opinion, the results ought to be shared publicly," he said. "We owe it to the patients who participated in the research to disseminate the results, and we owe it to the scientific community to publish results."

With publicly funded trials, Althouse notes, there is also an obligation to taxpayers, although this trial was originally funded by industry.

Zylke also noted that shifts in priorities should not govern disclosure of results.

"[R]esults of clinical trials should not be discarded because of financial interests, disinterest, or shift in priorities on the part of the funders," she writes. "Not publishing negative results can lead to research duplication, as well as waste of the resources committed to the trial."

It could also cause harm, Zylke points out, if one trial yields positive results and a later trial shows potential harm but is not published.

Althouse notes that Casella's trial results have not been published on clinicaltrials.gov.

If investigators run into problems having the data published in a peer-reviewed journal, Althouse said, they should ― at minimum ― publish the results on clinicaltrials.gov.

"At least then you have fulfilled your minimum obligation of disclosure to the scientific community," he said. "There's really no excuse for having nothing publicly available."

The clinical trial was funded by Mast Therapeutics Inc (previously Adventrx Therapeutics Inc). Casella has received grants from Mast Therapeutics Inc (previously Adventrx Pharmaceuticals Inc) and an honorarium, travel expenses, and salary support through Johns Hopkins for providing consultative advice during development of the clinical trial and for serving as the principal investigator for the clinical trial. He is also an inventor and a named party on a patent and licensing agreement to ImmunArray through Johns Hopkins for a panel of brain biomarkers for the detection of brain injury and holds a patent for aptamers as a potential treatment for sickle cell disease. Several coauthors were previously employed by Mast Therapeutics Inc and participated in manuscript preparation after severance from the company. A full list of disclosures is available in the original article. Zylke and Althouse report no relevant financial relationships.

JAMA. Published online April 20, 2021. Abstract

Marcia Frellick is a freelance journalist based in Chicago. She has previously written for the Chicago Tribune and Nurse.com and was an editor at the Chicago Sun-Times, the Cincinnati Enquirer, and the St. Cloud (Minnesota) Times. Follow her on Twitter at @mfrellick.

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