A previously unpublished study has raised questions about the efficacy of a common morning sickness drug.
The research was conducted by scientists from the Merrell-National Laboratories - which is now defunct - in the 1970s, and it sought to test the effects of pyridoxine-doxylamine in more than 2,300 pregnant women experiencing morning sickness.
Although the results of the study were not published at the time, it has emerged that both Health Canada and the United States Food and Drug Administration (FDA) used the data to help inform their decision to approve pyridoxine-doxylamine.
However, Dr. Nav Persaud, a family physician and researcher at St. Michael's Hospital in Toronto, Canada, has identified a number of flaws in how the study was conducted and how the results were analyzed. He says that these factors raise questions about the benefits of the drug.
Dr. Persaud recently published the 40-year-old study in the journal PLOS One.
The history of pyridoxine-doxylamine
While the precise mechanisms behind the medication are unclear, pyridoxine hydrochloride is believed to help combat morning sickness by raising pyridoxine levels, as low levels can trigger nausea and vomiting in pregnancy. Doxylamine succinate is an antihistamine, and it can block specific natural substances that contribute to nausea and vomiting.
Pyridoxine-doxylamine was first approved by the FDA in 1956 under the brand name Bendectin, which was manufactured by Merrell Dow. The drug became a leading treatment for morning sickness and was used by more than 33 million women across the globe.
Bendectin was voluntarily withdrawn in 1983, after allegations that it was a cause of birth defects. However, a review by the FDA concluded that there is "no adequate evidence linking Bendectin with an increased risk of birth defects."
In April 2013, the FDA approved pyridoxine-doxylamine once again under the brand name Diclegis, manufactured by Canadian pharmaceutical company Duchesnay Inc.
The FDA reached their decision after reviewing the results of a randomized controlled trial that analyzed the safety and efficacy of the drug in 261 women who experienced morning sickness for 7-14 weeks.
The study revealed that Diclegis was much more effective than a placebo for morning sickness, with drowsiness being the most commonly reported side effect.
FDA and Health Canada documents reveal information on study
According to Dr. Persaud, original approval for pyridoxine-doxylamine was based largely upon the decades-old study he recently published in PLOS One. The research was published as part of the restoring invisible and abandoned trials (RIAT) initiative.
The RIAT initiative aims to encourage "institutions that funded and investigators who conducted abandoned trials to publish (in the case of unpublished trials) or formally correct or republish (in the case of misreported trials) their studies [...]."
Dr. Persaud came across his information by analyzing more than 36,000 FDA documents retrieved through a Freedom of Information request. These documents included the original study report, the protocol, and the summary of the findings.
He also retrieved documents from Health Canada, which approved pyridoxine-doxylamine under the brand name Diclectin in 1957.
The 40-year-old trial - which was conducted at 14 clinics across the U.S. - included 2,308 women who were experiencing morning sickness during the first 12 weeks of pregnancy.
The women were randomly allocated to eight groups. One group received a placebo, one group received pyridoxine-doxylamine, while the remaining groups received other drug combinations.
Study flaws question efficacy of morning sickness drug
Summary data from 1,599 of the women revealed that, compared with a placebo, all seven treatment groups showed a reduction in morning sickness, with pyridoxine-doxylamine associated with the greatest reduction, at 14 percent.
However, Dr. Persaud identified some discrepancies, which he believes challenge the study findings.
Firstly, he notes that the final results of the study are unavailable; only the summary results can be identified. Furthermore, outcome data was only available for 37 percent of women in the placebo group.
Additionally, even though the trial only lasted 1 week, there were a high number of participants who failed to complete it. The technique the researchers used to score symptoms of morning sickness was also ambiguous, according to Dr. Persaud.
Furthermore, Dr. Persaud found a 1975 letter from the Commissioner of Food and Drugs ordering the exclusion of 30 study participants; the letter referred to "data recording in absence of patient visits."
Dr. Persaud notes that he was unable to contact any of the original study researchers, and many of the investigators have passed away since the study was conducted.
Still, he believes that his findings raise questions about the efficacy of pyridoxine-doxylamine for the treatment of morning sickness.