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Canada's drug regulator should revisit its approval of a widely used treatment for morning sickness, says a Toronto doctor who has analyzed thousands of pages of previously unpublished documents about a 1974 clinical trial that buttressed the case for the pill's efficacy.
But Health Canada, the Society of Obstetricians and Gynaecologists of Canada (SOGC) and the Quebec company that makes the drug, Diclectin, all say that subsequent studies and decades of use by pregnant women show the medication is safe and it works.
Nav Persaud, a staff physician and associate scientist at St. Michael's Hospital in Toronto, has for several years been raising questions about the quality of the evidence backing Diclectin, a treatment for nausea and vomiting that is prescribed in almost half of all Canadian pregnancies that result in a live birth.
Diclectin is a time-released combination of two ingredients: pyridoxine, better known as vitamin B6, and doxylamine, an antihistamine. Marketed as Diclegis in the United States, the drug made headlines in 2015 when then-pregnant reality-TV star Kim Kardashian praised it on her Instagram account.
Dr. Persaud does not argue that Diclectin is necessarily unsafe; rather, he says there is no solid proof that it eases morning sickness at all.
In his latest effort to probe the evidence, he reviewed more than 7,500 pages of documents released by the U.S. Food and Drug Administration and Health Canada under freedom-of-information laws about a U.S. clinical trial referred to as the "8-way study."
Conducted at 14 different sites in 1974, the study divided 2,308 participants in the first trimester of pregnancy into eight groups, each of which received different combinations of three drugs or a placebo. Although the 8-way study's results contributed to the FDA and Health Canada approving the treatment, the study itself was never published.
The unearthed documents reveal that 31 per cent of the participants did not complete the trial, even though it was only seven days long. At least one investigator was removed for a slew of irregularities with his or her work, including "data recording in absence of patient visits." And a final version of the study was apparently never submitted; the FDA only had an interim report to release to Dr. Persaud.
"I think it's a low-quality study with a large fraction of missing data and questions about data integrity," said Dr. Persaud, whose findings were published Wednesday in the journal PLOS ONE as part of a campaign to bring previously unpublished or misreported clinical studies to light.
"I wouldn't want to prescribe a medication based on a study like this. I don't think anybody should take a medication based on a study like this. Certainly, I don't think a medication should be approved based on a study like this. All of those decisions should now be revisited or revised."
A spokesman for Health Canada disagreed, saying in an e-mailed statement that the federal regulator recently completed a fresh safety review of the drug. A summary of the review, published last July, concluded Diclectin's "benefits continue to outweigh its risks, when used as authorized."
Just last month, the SOGC) published new guidelines on treating nausea and vomiting in pregnancy, the first official update of the recommendations since 2002. After reviewing the evidence, the SOGC advised that either pyridoxine alone or pyridoxine and doxylamine (the combination of drugs in Diclectin) be considered a first-line treatment for morning sickness if non-pharmacological options such as ginger supplements or acupuncture do not help.
Jennifer Blake, the chief executive officer of the SOGC, said the specialists' group did not consider the results of the 1974 8-way study in preparing the new guidelines, but that if it had, the study's conclusion would have supported the effectiveness of the two-drug combination that makes up Diclectin.
"[Diclectin] is one of the most frequently used and extensively tested medications for use in pregnancy," Dr. Blake said. "It would be a pity if women were made to feel that they should be concerned about using a medication that decades of use have shown to be safe."
Dr. Blake acknowledged that the SOGC receives funding from Duchesnay Inc., the company that makes Diclectin, but said none of that money was put toward the development of the new guidelines and that the company had no sway over the SOGC's recommendations.
A spokesman for Duchesnay said in a statement that the two active ingredients in Diclectin "are the most studied drug combination used in pregnancy," with decades of research supporting their safety and efficacy.
But a 2015 Cochrane meta-analysis – a high-quality review that pools the results of previous trials – of interventions to ease morning sickness, including the ingredients in Diclectin, concluded there was a dearth of solid evidence to support any treatment for nausea and vomiting in pregnancy.
"This is not the same as saying that the interventions studied are ineffective, but that there is insufficient strong evidence for any one intervention," the Cochrane review of 41 trials found.
Disagreements over the quality of the evidence for Diclectin are a good reason to make public as much information as possible about older trials, including the 8-way study, Dr. Persaud said. His new paper is part of the Restoring Invisible and Abandoned Trials (RIAT) initiative, an effort to dig up unpublished or misreported studies that the BMJ (formerly known as the British Medical Journal) launched in 2013.
Peter Doshi, an assistant professor at the University of Maryland School of Pharmacy and an associate editor at the BMJ who is spearheading the RIAT initiative, said making information about older trials available can help doctors and patients make the best choices about medications.
"You help patients by allowing for accurate understanding of the harms and the benefits of drugs," he said. "So you actually make an informed decision that weighs both of those. This [RIAT] is a means to that end."
Kelly Grant