Drug Authorization


Research Summary.

Quality of Evidence considered by Health Canada in granting full market authorisation to new drugs with conditional approval: A retrospective cohort study

In his recently published study, entitled Quality of evidence considered by Health Canada in granting full market authorisation to new drugs with a conditional approval: a retrospective cohort study, Joel Lexchin examines the characteristics of studies that Health Canada uses to grant full marketing authorisation for products given a conditional approval between 1 January 1998 and 30 June 2017. The paper analyses information that was contained in journal publications that result from the confirmatory studies from the cohort of drugs that fulfilled their conditions. Specifically, the paper assesses the evidence about study and patient characteristics that Health Canada evaluates when it approves new medicines.


The key clinical evidence that Health Canada uses to establish the safety and efficacy of the new drugs come from pivotal trials that Health Canada defines as ‘trials of high scientific quality, which provide the basic evidence to determine the efficacy, properties and conditions of use of the drug’. Health Canada treats industry-funded clinical information on safety and efficacy as confidential business information and will only release it with the consent of the company, even if an access to information request has been filed. In the absence of this information from Health Canada, the one indirect source for gaining a partial understanding into the quality of the evidence that Health Canada considers regarding efficacy is the confirmatory studies required when a drug or a new indication is approved through Health Canada’s Notice of Compliance with conditions (NOC/c) guidelines.


The authors compiled a list of all drugs with a NOC/c and those that fulfilled the conditions from the time that the programme started from four sources: articles by Lexchin and Law that listed NOC/c and investigated whether they had been fulfilled, the Notice of Compliance database, and the Notice of Compliance website. The authors recorded the generic and brand-names of the drugs, the approved indication for the drug, the dates the drug received its NOC/c, the date it fulfilled its conditions and the names of the companies marketing. The qualifying notices for products that had fulfilled their conditions were obtained from either the NOC/c website or by directly contacting Health Canada. A web search was undertaken to determine whether a possible clinicaltrials.gov identifier and/or journal publication(s) should be identified for each study listed in the QN. If there was no publication given in clinicaltrials.gov then two scientific journal databases were searched to look for journal publications.

A letter was then sent to the companies making each product outlining the nature of the research, quoting a description of the confirmatory study or studies from the qualifying notifications, giving the possible clinicaltrials.gov ID (if one was found) and the possible publication (also if one was found) and asking the company to confirm that the publication corresponded to the study or if not, to provide a citation to a publication. Information on the characteristics of the study and the study methodologies and characteristics of the parties enrolled were then extracted from the journal articles. Information was extracted from the journal articles by the author and CO in two areas:


Eleven companies confirmed 36 publications for 19 products (21 indications). Twenty-nine out of the 36 studies were randomised controlled trials (RCTs) but only 10 stated if they were blinded. Twenty used surrogate outcomes. The median age of patients was 56 (IQR 44-61). The median number of men per study/trial was 184 versus women 141.   


Based on the results of the analysis of 36 publications resulting from confirmatory studies, the following characteristics of those studies were acceptable to Health Canada in granting full market authorisation: 29 (80.6%) were RCTs versus 7 (19.4%) that were observational studies, 21 (72.4%) of the RCTs had active controls, but only 10 (34.5%) of them definitely stated that they were blinded. Twenty (55.6%) of the 36 studies used surrogate outcomes, the median age of patients in all of the studies and in each of the three groups of indications was under 60 years of age and except for 4 (14%) out of 29 studies, men outnumbered women.

The author found that although the studies required by Health Canada had more rigorous methodology than those required by either the FDA or MEA, there were still significant limitations in their design. Lexchin writes that observational studies are useful for obtaining information about rare side effects that the confirmatory studies were meant to establish efficacy, not to search for rare side effects. He concludes that reliance on observational data to evaluate drug efficacy is problematic, given the inherent weaknesses of such studies and that the bias is, on average, often larger than the estimated effect.

  • H. Webster


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