Doubt is being cast on the efficacy of Diclegis – the only prescription drug approved in the United States for treating nausea and vomiting in pregnancy – after researchers exposed flaws in previously unpublished data that served as the basis for the drug’s approval.

But the larger point, according to the researcher who brought the unpublished study to light, is the danger of relying too heavily on hidden data.

“It’s not like there’s some special concern over the safety of Diclegis. It’s that there is this commonly prescribed medication that hasn’t been proven to be effective,” Navindra Persaud, MD, a family physician and researcher at St. Michael’s Hospital in Toronto, said in an interview.

The original data, and a detailed analysis of it, cowritten by Dr. Persaud and his family practice colleague Rujun Zhang, MD, is published online in PLOS ONE (doi: 10.1371/journal.pone.0167609).

The 8-Way Bendectin Study was a double-blind, multicentered, randomized, placebo-controlled study of 2,359 women with morning sickness in the first trimester, conducted in the United States across multiple sites in 1976 by the now-defunct Wm. S. Merrell Co. The aim was to find a replacement formulation of a three-agent formula (Bendectin) for morning sickness, after one of the ingredients – dicyclomine hydrochloride – was determined ineffective for pregnancy-related nausea and vomiting.

Participants in the study, which had seven treatment arms and one control group, were asked to keep diaries for a week, detailing their bouts of nausea and vomiting. Clinicians then evaluated and rated the diary entries. In all, data for 1,599 of the women were analyzed, with all seven treatment arms besting placebo. Doxylamine-pyridoxine was rated “moderate or excellent” with a 21% absolute difference, compared with placebo (95% confidence interval, 11-30). The most commonly reported side effect across the study was drowsiness.

Dr. Persaud said he thinks the study was never published because of multiple flaws. For instance, there was not a clear baseline for symptoms, or clear parameters for how the clinicians rated those symptoms; outcome data for more than a third of controls were missing, as were completed reports about potential adverse outcomes; and P values were one sided and not adjusted to account for all eight study arms, he said.

“While the analyzed data indicate differences from placebo for several combinations, the questionable data integrity, high dropout rate, and other methodological concerns mean that the prescribing of this medication should not be based on this trial,” wrote Dr. Persaud and Dr. Zhang in their analysis.

The newly published analysis brings back the rocky history of morning sickness treatments in the United States, notably the withdrawal of Bendectin in 1983 following a barrage of teratogenicity claims against the drug maker that made it unprofitable to continue marketing.

“The totality of the data, observational and otherwise, did not support Bendectin as being a cause of birth defects,” Christina Chambers, PhD, MPH, professor of pediatrics and director of clinical research at Rady Children’s Hospital, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego, said in an interview. Regarding the treatment’s current formulation, Dr. Chambers said she would not be concerned about there being any potential for harm to the fetus if a pregnant woman planned on taking the treatment for morning sickness.

This is all beside the point, according to Dr. Persaud. “For every medication, you’re going to find some of these associations. They might be real; they might be not. So you have to weigh potential harm against the benefit. The real problem here is that there is no demonstrated benefit even though the claim seems to be that there is,” he said.

Duchesnay defended the efficacy of the drug.

“The conclusions expressed in the report published in PLOS ONE are highly inconsistent with the large and comprehensive body of evidence regarding this combination drug,” Michael Gallo, Duchesnay vice president for regulatory and medical affairs, said in a statement posted on the company’s website. In its response to Dr. Persaud and Dr. Zhang’s analysis, the company also said that doxylamine succinate and pyridoxine hydrochloride – the two agents in the treatment – are “ the most studied drug combination used in pregnancy. The safety and efficacy of [Diclegis] have been proven in 16 cohort studies, two meta-analyses, an ecological study, a neurological development study, and numerous others.”

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But after more than 5 years spent poring through more than 36,000 pages of documents obtained from both Health Canada and the Food and Drug Administration through freedom of information requests, interviewing numerous sources, and rigorous review of the literature, Dr. Persaud said he does not agree the treatment, in any of its forms, has ever been proven effective.

“It’s unclear if the [unpublished] study was carefully reassessed in the lead-up to the recent approval of Diclegis,” he said. “The available FDA review documents for the recent approval of Diclectin [pyridoxine/doxylamine] do not mention the problems with the study.”

One factor in the treatment’s place in standard of care might be anecdotal influences from some of the more than 35 million women around the world thought to have used the treatment, according to Dr. Persaud. “Lots of women have taken this medication and felt better shortly after, so they feel strongly that the medication is effective,” he said, but because nausea and vomiting in pregnancy is common in more than three-quarters of women, and typically does not last more than several weeks, most likely the patients would have gotten better over time anyway.

“Some women suffer greatly and do seem to get relief from medication,” Dr. Chambers said, but noted that Diclegis is not the only option available for women.

When Bendectin was pulled from the U.S. market, for example, Dr. Chambers said women turned to combinations of vitamin B₆ and over-the-counter medications that contain the antihistamine doxylamine.

Dr. Persaud said his interest in the review started after a patient expressed her concerns over the medication. “She was reluctant to take it, and asked me if I was sure about it. I reassured her, but then after she left, I did wonder if I was correct,” he recalled. He said he checked all the guidelines, but could not find anything to justify its use other than the manufacturer’s monograph.

He said he suspects this is not the only prescription medication that would not withstand such scrutiny, but that uncovering the necessary data would be very difficult. “I was shocked it was very difficult to get access to this information as a clinician,” he said, adding that it also is impractical to expect physicians to spend 5 years to track the information down.

In their analysis of the study, Dr. Persaud and Dr. Zhang stated that their objective is to contribute to a movement across all of medicine to end the risks of data secrecy, and instead “restore invisible and abandoned trials” (RIAT). The U.S. Department of Health & Human Services has been pushing to make more clinical trials data public through ClinicalTrials.gov, including issuing federal regulations requiring information to be made public for certain trials involving drugs and devices regulated by the FDA.

As for how his own practice has been impacted by this research, Dr. Persaud said he no longer prescribes Diclegis.

Dr. Persaud, Dr. Zhang, and Dr. Chambers had no relevant financial disclosures.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

Unpublished study on Bendectin prompts questions on hidden data