A treatment to shorten the painful episodes of sickle cell disease (SCD) is not effective, it turns out published inside JAMA indicate. But the effort made to publish the results is an important part of the story and reveals problems of data ownership, company motivations and public resources that go far beyond a clinical trial or an agent. experimental.
In 2016, first-line neutral results were reported for the poloxamer 188 assay by James F. Casella, MD, in the Department of Pediatric Hematology, Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues, but it has taken until this month for them to be published.
This study contrasts the above conclusions
JAMA the assistant editor, Jody Zylke, MD, wrote in an attached document editor’s note that normally JAMA would not publish the results of a study that ended 5 years ago. Several reasons convinced the editors to do so.
One was that these results of the trial contradict those of previous studies of poloxamer 188 to reduce vasoclusive episodes in patients with SCD. This 2001 study was also published in JAMA.
In the previous study, researchers found a modest and statistically significant reduction in the duration of SCD episodes with poloxamer 188 compared with placebo among 255 adults and hospitalized children (141 hours vs. 133 hours; difference, 9 hours; Pg = 0.04).
But the new trial, which was funded by Mast Therapeutics Inc. (formerly Adventrx Therapeutics Inc.), did not find a similar benefit. The placebo-controlled randomized phase 3 randomized clinical trial of Casella of poloxamer 188 was conducted in 66 hospitals in 12 countries. The researchers enrolled 388 children and adults with SCD who had moderate to severe pain who needed hospitalization.
Casella and colleagues found that the mean time to the last dose of parenteral opioids during vasoclusive episodes was 81.8 hours, compared with 77.8 hours with placebo, but the difference was not statistically significant.
Zylke said the difference in results can be partially explained by the choice of the researchers’ primary outcomes and that Casella’s results were more easily verifiable.
Zylke points out that there is a significant unmet need for an agent who can shorten these episodes. The results remain clinically relevant. Trials of other drugs to shorten the duration of episodes, including inhaled nitric oxide, intravenous magnesium, and intravenous sevuparin, have failed.
The article points to problems in the research process
Zylke also points out that the 5-year delay in publishing the results has clues about the barriers to publishing data from many clinical trials, another reason JAMA the editors considered it important to publish this article.
According to her, in the case of Casella’s study, the investigation hit an obstacle when the company that funded the trial, Mast Therapeutics, was sold to another company, Savara, along with the rights to the trial, immediately. after announcing the negative results.
She says the authors report that the new company was not interested in publishing the results and that the data was no longer available to researchers. After several years, one of the researchers reported that he was able to use his own resources to complete the analysis.
Asked to answer the company’s interest in poloxamer 188, said Anne Erickson, Savara’s media representative Medscape Medical News, “In October 2017, Savara sold the vepoloxamer program-related assets that had been acquired from Mast, including data and study reports, to LifeRaft Biosciences Inc.”
Robert Martin Emanuele, Ph.D., is President and CEO of LifeRaft. Efforts to reach Emanuele were unsuccessful.
Zylke did not answer Medscape Medical News’ requests for comments.
Casella refused to talk to him Medscape Medical News for this article and would not confirm which researcher used their own resources.
Unusual example of a larger problem
Andrew Althouse, PhD, assistant professor of medicine at the Center for Research on Healthcare at the University of Pittsburgh, Pittsburgh, Pennsylvania, said Medscape Medical News that this is an unusual example of a common problem that occurs when test results are negative.
Sometimes magazines are partly to blame for not publishing negative results, he said. Sometimes it’s a matter of business.
Logically, a company may ask itself, “Why would we keep paying our people to keep working for something we don’t pursue?” said Althouse, who was not involved in the study or editorial decision to publish the article.
He makes a distinction between refusing to further fund a lawsuit that had negative results for an agent that is of no benefit to the company and “a more nefarious reason” for trying to hide negative results.
Althouse says that while he understands the business argument for a company not to commit to more resources or refuse to strive to publish negative results, he still believes all test results should be published, positive or negative. .
“If patients agreed to participate in research, in my opinion, the results would have to be shared publicly,” he said. “We must disseminate the results to patients who participated in the research and we owe it to the scientific community to publish the results.”
With publicly funded trials, Althouse points out, there is also an obligation to taxpayers, even though this trial was originally funded by the industry.
Zylke also noted that changes in priorities should not govern the disclosure of results.
“[R]“The results of clinical trials should not be ruled out due to financial interests, disinterest or changing priorities on the part of funders,” he writes. “Failure to publish negative results could lead to duplication of investigation, as well as a waste of resources committed to the trial.”
Zylke can also cause damage, if a trial yields positive results and a subsequent trial shows potential harm, but is not published.
Althouse notes that the results of the Casella trial have not been published at clinictrials.gov.
If researchers have trouble publishing the data in a peer-reviewed journal, Althouse said, they should publish the results to at least clinictrials.gov.
“At least you have met your minimum disclosure obligation to the scientific community,” he said. “There really is no excuse for not having anything publicly available.”
The clinical trial was funded by Mast Therapeutics Inc. (formerly Adventrx Therapeutics Inc.). Casella has received grants from Mast Therapeutics Inc. (formerly Adventrx Pharmaceuticals Inc.) and a fee, travel expenses and salary support through Johns Hopkins to provide advisory advice during the development of the clinical trial and to serve as principal investigator of the ‘clinical trial. He is also an inventor and designated party to a patent and licensing agreement at ImmunArray through Johns Hopkins for a group of brain biomarkers for the detection of brain damage and holds a patent for aptamers as a potential treatment for sickle. Several co-authors had previously been hired by Mast Therapeutics Inc. and were involved in manuscript preparation following the company’s separation. There is a full list of disclosures in the original article. Zylke and Althouse do not report relevant financial relationships.
JAMA. Published online April 20, 2021. Summary
Marcia Frellick is a Chicago-based freelance journalist. She has previously written for the Chicago Tribune and Nurse.com and was editor of the Chicago Sun-Times, the Cincinnati Enquirer and the St. Cloud (Minnesota) Times. Follow her on Twitter at @mfrellick.