A drug commonly prescribed to women to treat morning sickness has recently been demonstrated to not be effective. Although this finding, impacting health providers and pregnant women across the country, is newsworthy, it is the conflicted and controversial history leading up to this discovery that has caused great concern by health policy experts, physicians, researchers and media alike. The story stems back 60 years, and involves legal claims of malformations, conflicts of interest and influence by the pharmaceutical industry, and hidden clinical trial results, and it highlights the practices of secrecy at Health Canada, following a physician’s seven-year quest for industry data.
There are over 300,000 prescriptions written annually for Diclectin, the only prescription drug approved by Health Canada to treat symptoms of morning sickness during pregnancy. Diclectin is made up of an antihistamine (doxylamine succinate) and vitamin B6. The drug costs approximately 90 dollars a month, or 174 dollars for 100 tablets, and is covered by publicly-funded provincial drug plans. Dr. Nav Persaud, a Family Doctor and Researcher at St. Michael’s Hospital in Toronto, was one of many doctors prescribing the drug when a patient asked about its efficacy. When reviewing the scientific literature, he was unable to find any data. It was at this point, in 2011, that he requested information about the drug from Health Canada. The request was denied; the information was classified as confidential business information. This was the beginning of a multi-year effort to examine the clinical trial data and effectiveness of the drug.
The 60-year History of Diclectin
In the Spring of 2015, Dr. Persaud’s story and concerns about Diclectin began to be published. One of the publications on the matter was a detailed history of Diclectin in an article published by MacLean’s Magazine. This was not the first time concern had been raised about Diclectin.
This history starts with a morning sickness drug called Bendectin, first approved by the FDA in 1956, produced by Richardson-Merrell, Inc. The drug contained three ingredients: doxylamine succinate (an antihistamine), pyridoxine hydrochloride (vitamin B) and dicyclomine hydrochloride (an antispasmodic). In 1976 the drug was reformulated and the antispasmodic was removed. It was shortly thereafter, in 1977, that the first of approximately 2000 claims were brought forward in the U.S., alleging the drug was responsible for birth defects. These lawsuits exposed that the research into the drug was extremely limited. However, federal judges shut down these cases through variety of procedural means, and verdicts in favour of plaintiffs were overturned. In 1983 Bendectin was removed from market, the manufacturer citing financial reasons for its removal. Canada remained the only country to continue to make pyridoxine-doxylamine, available in a generic version. It was produced by Quebec-based Duchesnay Inc.
By 1989, political concern arose about Diclectin. At the time, reports were being released that Canadian lawyers were reviewing hundreds of birth-defect cases. In response, both Liberal and NDP MP’s began applying pressure on the Government to review the drug. That same year a Health Canada Advisory panel assessed Diclectin and found it did not increase the risk of malformations; however, the efficacy of the drug was not discussed by the panel.
A vocal advocate for Diclectin was physician and clinician Gideon Koren, founder of Sick Kid’s Motherisk program. The Motherisk program offered critical information services for both doctors and expectant mothers about drugs, and operated a ‘morning sickness hotline’. The Motherisk program endorsed Diclectin and Koren frequently wrote and spoke advocating for its use. Not only was Koren a paid consultant of Duchesnay, but Duchesnay partially sponsored the program’s morning sickness hotline. From 2000 to 2013, Duchesnay provided $4.3 million in research funding, all of which went to Motherisk (with exception to a small donation). The impact of the relationship between Duchesnay and Motherisk was significant; in 1989 less than 3% of pregnant women took the drug and today it is taken by 50% of pregnant women.
Health Canada Provides the Data under Vanessa’s Law
More than a year after Persaud made an initial request to Health Canada for information on Diclectin, they provided Persaud with 359 pages of information, 212 of which were completely censored and other pages had redacted sections under headings such as “adverse events”. The reasoning: this was confidential business information.
Following this, three and a half years after his initial request, Dr. Persaud was able to make a request for information under the newly passed Vanessa’s Law. Vanessa’s Law (Protecting Canadians from Unsafe Drugs Act) was passed in 2014. The law improved Health Canada’s ability to collect safety information about therapeutic products and created new and important legislative powers, some of which are related to transparency. Vanessa’s Law allows for Health Canada to treat drug safety and effectiveness information as property under confidential business information. However, it also provides Canada’s Health Minister with discretion to release this data without the drug maker’s prior consent if he or she “believes that the product may present a serious risk of injury to human health”. Vanessa’s Law says nothing about the ways in which the sharing of confidential business information can happen.
Health Canada finally provided Persaud with the manufacturer’s 2009 trial data, in the form of thousands of pages of data, so that he could pursue his research. However, this data was accompanied by a strict confidentiality agreement between Dr. Persaud and Health Canada. It was so strict that he couldn’t share the data with colleagues to help with the research.
As Effective as a Placebo
Once Persuad reviewed the data, the results were staggering. The results from the Diclectin trial were only supposed to be considered clinically important if Diclectin performed at least three points better than a placebo on a 13-point scale of symptoms. The difference was only a mere 0.7 points. Persuad indicates that company data showed no matter whether women took a placebo pill or actual pill they felt better by the second-week of the study.
CBC news reported that in recent years, both the FDA and Health Canada reports indicate that the effect of diclectin is small. The FDA approved the drug in 2013 and noted that “the treatment effect was small” and the Health Canada advisory panel that conducted a review in 2016 noted the results of the study were “not definitive” and the clinical benefit “unclear”. Health Canada continues to support the use of Diclectin, and the Society of Obstetricians and Gynaecologists of Canada has recently released statements that Diclectin is a safe and effective treatment for nausea and vomiting in pregnancy.
A move towards greater transparency
The extensive media coverage on Persaud’s story of Diclectin reiterates and supports arguments health policy experts such as Matthew Herder at Dalhousie University have been making. The story of Diclectin is only one illustration of what Herder describes as an “institutionalized practice of secrecy” at Health Canada. In 2015 article, Herder and Trudo Lemmens, another health policy and bioethics expert, argue that if Health Canada were committed to transparency, it should exclude drug safety and effectiveness data from the scope of “confidential business information” described in Vanessa’s Law.
Health Canada is starting to publicly recognize the need for greater transparency and its benefits for Canadians and the health care system. In the spring of 2017, Health Canada sought public input on a discussion paper, “Public release of clinical information in drug submission and medical device applications”, and has since published draft regulations that propose to make clinical information in drug and medical device submissions publicly available after the Department has completed its regulatory review process.
Hopefully these efforts will increase transparency so that the next time a doctor receives a question from a patient and requests information from Health Canada, it won’t take 7 years to provide an answer.