'High risk of bias': Doctor raises doubts over study into morning-sickness drug

A medication commonly prescribed in Canada for nausea in pregnancy was approved in part based on a 40-year-old study with a major flaw, says a family doctor who has now published the information.

The drug pyridoxine-doxylamine, sold in Canada under the brand name Diclectin, is used in half of Canadian pregnancies that result in a live birth and the rate of prescribing has increased in the last 15 years, says Dr. Nav Persaud, a family physician and researcher at St. Michael's Hospital in Toronto.

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Now, Persaud has published the 40-year-old study by the drug's manufacturer in the online journal PLOS One and highlighted concerns he has with missing data.

The publication is part of an initiative to restore invisible and abandoned trials (RIAT) containing unpublished or misreported studies.

Persaud and co-author Rujun Zhang concluded that data from that trial "should not be used to support the efficacy of doxylamine, pyridoxine or dicyclomine for the treatment of nausea and vomiting during pregnancy because of the high risk of bias."

The safety of the drug is not in question. Persaud's main issue with the U.S. randomized trial is missing data. 

"If data for 31 per cent of the participants is missing, that's a very big problem," Persaud said in an interview.

"The reason for that is if you don't know what happened to those 31 per cent of women then you don't really know about the effects of the medication so depending on what happened to those [participants], the results and the conclusions could be very different."

'It's disappointing'

Whenever there are questions about the integrity of a study, it's difficult for doctors and regulators such as Health Canada and the U.S. Food and Drug Administration to know what do with the information, he said.

"This example shows why it's important for the clinical trial information to be available to the public and it's disappointing that it hasn't been for more than 40 years.

"There might be other medications that were approved a long time ago based on older studies or even medications that were approved recently based on newer studies where the public availability of the clinical trial study reports would change our conclusions and change clinical practice so all of those reports should be made publicly available immediately."

It's the same drug that reality TV celebrity Kim Kardashian was paid to endorse on social media, which the FDA said violated drug promotion rules.

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Diclectin, sold in the U.S. as ​Diclegis, is manufactured in Quebec by Duchesnay Inc.

The trial was conducted in the 1970s at 14 clinics in the United States and enrolled 2,308 patients in the first 12 weeks of pregnancy who were experiencing nausea and vomiting.

The trial is known as the eight-way Bendectin Study after an earlier version of the drug. Women were randomly assigned to eight groups. Of those, one received a placebo and the other seven a variety of drugs including the combination for Diclectin. The drug now contains an antihistamine and vitamin B6.

Persaud, who is also an assistant professor at the University of Toronto, has reviewed thousands of pages from the FDA and Health Canada on Diclectin through access to information requests.

Persaud said he couldn't find a study demonstrating the medication was effective.

He no longer prescribes Diclectin. Instead, he tells pregnant women about non-medical options as well as other medications.  

Specialists, Health Canada stand by drug

In December, Canada's Society of Obstetricians and Gynaecologists (SOGC) published updated guidelines on nausea and vomiting of pregnancy. It recommends women eat whatever pregnancy-safe food appeals to them.

The society says safe options to help relieve symptoms include ginger (particularly pharmaceutical-grade ginger), pyridoxine (vitamin B6) and self-administered acupressure.

A small percentage of women with nausea and vomiting in pregnancy get dehydrated or suffer severe metabolic effects, Carson said.

For women with high risk of nausea and vomiting in pregnancy, the society recommends vitamin B6 or Diclectin.

"Our guideline did not in fact rely on the paper that is being criticized," said Dr. George Carson, president of the SOGC and an obstetrician in Regina. "It's not relevant to the evidence that's used to formulate our guideline."

Carson said the society's guidelines go through a meticulous review process and the group accepts no funding for them.

Drug recently reviewed

Health Canada said the previously unpublished study was part of the information it used to approve the drug. Evidence continues to support Diclectin in the treatment of nausea and vomiting during pregnancy, the regulator said.

"It is important to note that since the initial review of evidence that supported Diclectin's approval in Canada, Health Canada re-assessed Diclectin in 1989 and has also reviewed submissions on Diclectin, updated the label as necessary, and continued to monitor its safety profile," a spokesman for the regulator said in an email.

"The totality of available evidence always supported Diclectin in the treatment of nausea and vomiting during pregnancy."

Health Canada said its position is consistent with the U.S. Food and Drug Administration's position.