Including off-label drug indications in HTA jeopardizes patient health and discourages innovation

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Nigel SB Rawson, Ph.D.


The innovative development of anti-vascular endothelial growth factor (anti-VEGF) drugs is examined, together with the impact that these drugs have had on patient health. The health technology assessment (HTA) review of anti-VEGF drugs that took place in Canada in 2015 is considered from both innovation and patient health perspectives.

Anti-VEGF Drugs

Anti-VEGF drugs are used to treat retinal conditions such as the wet form of age-related macular degeneration (wAMD) which is responsible for 80-90% of the vision loss associated with AMD.  Avastin, Lucentis and Eylea are anti-VEGF drugs. Avastin was developed as a systemic treatment for cancer. It was also considered for retinal conditions, but evidence showed that systemic exposure to Avastin increases the risk of thromboembolic events. Using knowledge gained from Avastin, decades of innovative research led to the development of Lucentis and Eylea, which are administered by intravitreal injection into the eye. Lucentis and Eylea are approved by Health Canada for retinal conditions, whereas Avastin is not. Avastin has a serious warning in its product monograph (or ‘label’) that it is ‘not formulated and has not been authorized for intravitreal use’. Nevertheless, Avastin is prescribed off-label by clinicians to treat retinal conditions because it is less expensive than the other drugs.

Issue: including unapproved or off-label indications in the HTA

In early 2015, provincial governments requested that the Canadian Agency for Drugs and Technologies in Health (CADTH) compare Lucentis, Eylea and Avastin for retinal conditions, which meant that the HTA process that guides public drug plan coverage decisions would include a drug that did not have Health Canada safety approval for the indication being reviewed. CADTH also excluded some studies from its review that suggested greater safety risks with Avastin compared with Lucentis, predisposing the HTA review to the conclude that Avastin and Lucentis have similar efficacy and safety profiles. This led to a recommendation that Avastin can be used as the preferred initial anti-VEGF therapy over Lucentis or Eylea.


CADTH has changed the rules in the HTA process to accommodate provincial government cost-containment objectives, despite Health Canada’s warnings of increased morbidity and mortality risks. Including off-label drug indications in HTA jeopardizes patient health and discourages innovation.

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