An Open Letter to Health Canada

Regulators are mandated to provide structured guidance on drug development. They approve drugs based upon their scientific and medical merits. They negotiate a disclosure of a drug’s profile—the label. And they provide ongoing monitoring of manufacturing, use, and safety once the drug is marketed. Posting of guidance documents notwithstanding, the foregoing are conducted behind closed doors and subject to coveted decision processes. The warnings and directions provided in the drug label are for the most part warranted. On occasion, the warnings and requirements are restrictive and unwarranted. The recent US Food and Drug Administration (FDA) approval and release of the brodalumab label bears witness.

Brodalumab (Siliq), an IL-17R antagonist, was evaluated for the treatment of Crohn disease, ¹ psoriasis, and psoriatic arthritis (NCT02024646, NCT02029495). Six completed suicides occurred across all development programs, 4 within the psoriasis studies. One of the suicides reported in the psoriasis program was adjudicated as an accidental overdose of illicit drugs. ² With more than 4000 patients and nearly 10 000 patient years of exposure, ³ the approximate suicide event rate of 30 per 100 000 patient years is marginally greater than the range of rates reported in the adult US population: 12 to 24 per 100,000. ⁴ Depression is a known comorbidity of psoriasis. We know that depression is the major risk factor for suicide ideation, suicide attempts, and completion. Interestingly, depression scores improve in psoriasis populations receiving effective therapy, as do patients treated with brodalumab.^5-7

The US Siliq label contains a boxed warning that advises physicians to be aware of the potential for depression and take action should a patient be at risk of suicide. ⁸ Warnings of this sort deserve attention for all populations at risk. The label clearly states that no causal association with suicide ideation or completed suicide and brodalumab was found. Absence of implied and mechanistic causality, the cornerstones of Hill’s hypothesis, argues for statistical fluctuation within the sample population. Still, the monograph imposes an onerous burden on prescribers. The boxed warning and registration requirements appear orthogonal to a balanced and scientifically derived statement of facts. Motivation for inclusion of the boxed warning is obscure and unjustified.

The Canadian health care system is undermanned and our patients underserviced. Imposing burdensome risk mitigation programs will do little more than impair access and limit therapeutic options available to our patients. As concerned clinicians, we respectfully request Health Canada provide scientifically and clinically sound guidance for brodalumab and not mime the United States.