Exudative retinal diseases, including age-related macular degeneration (AMD), diabetic retinopathy, and venous occlusive disease, are major contributors to vision loss globally. Fortunately, many ocular-specific treatments have been developed over the last decade and many more are in advanced-phase clinical trials with anticipated market release over the next 5 years. Although the specifics in bringing a novel pharmaceutical to market vary among countries, 2 key regulatory steps are often employed that influence the clinical availability and usage of these pharmacologic therapies.
Phase III Clinical Trials: Assessing Safety and Efficacy
Regulatory bodies around the world, including the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Health Canada, employ strict protocols to establish the safety and efficacy of pharmaceuticals prior to market approval by interpreting data from clinical trials. For each approved indication, a drug label is created to provide guidelines for clinical use of the medication. In a rapidly evolving field such as retina, however, the compendium of data regarding the safety and efficacy of a pharmaceutical grows more rapidly and dynamically than can be continuously reflected in a drug label.
For example, in several European countries, AMD patients may have lost vision owing to a past policy that ranibizumab retreatment criteria be solely based on recurrent visual loss of at least 5 letters. These old guidelines were adopted directly from the original 2007 EMA label; although the phase III trials that led to EMA approval of ranibizumab assessed monthly therapy, the label’s posology was based on an unsubstantiated mathematical model that “assumed…the visual acuity decline that triggers an injection is, in principle, reversible by later treatments.” This requirement to demonstrate visual acuity loss likely contributed to the suboptimal outcomes reported in the AURA study analyzing the efficacy of ranibizumab across European countries from 2009 to 2011. Lagging years behind clinical evidence to the contrary, the label was not fully updated until 2014 to include retreatment criteria, “as determined by the physician…assessed by visual acuity and/or anatomical parameters.”
More recently, the FDA-approved label for aflibercept in the management of neovascular AMD, which was released in 2011 and was based on the VIEW1 and VIEW2 trials, was misleading. If just the merged top-line data were considered, the mean visual acuity outcome of monthly dosing was similar to dosing every other month after 3 monthly doses. Among patients with persistent macular edema during the first 3 months of dosing, however, a different and clinically relevant result was obtained. For this approximately 20% of the treatment-naïve study population with the most active disease, visual outcomes were significantly better when monthly dosing with aflibercept was continued, compared with transitioning to dosing every other month. These data were first presented publicly in 2013 and appeared to contradict the FDA-approved label, which stated, “additional efficacy was not demonstrated when aflibercept was dosed every 4 weeks compared to every 8 weeks.” Highlighting this discrepancy, the EMA-approved label states that therapy after the first 3 loading doses “may be extended based on visual and/or anatomic outcomes…determined by the treating physician.” Fortunately, the FDA-approved label was clarified in May 2016, and now includes to reflect these clinically relevant data, and now includes the statement, “some patients may need every-4-week dosing after the first 12 weeks.”
Drug labels are created to reflect evidence of safety and efficacy within a population, not to optimize individual therapy. However, evidence shows that in certain scenarios, strict adherence to labels can yield distinctly suboptimal results. In the accompanying manuscript, the prospective COMRADE-C trial reports that when following the EMA label, ranibizumab is superior to dexamethasone in treating macular edema secondary to central retinal vein occlusion. However, the authors well acknowledge that “The main limitation of the study was that patients were only treated once during 6 months in the dexamethasone intravitreal implant group …treating patients with a single dose of dexamethasone was not sufficient to maintain efficacy over the 6-month study and retreatment should be given more frequently.” If patients are restricted to receive a retinal pharmacologic only according to the labeled dosing, outcomes may suffer.
Bringing a Pharmaceutical to Market: Beyond Safety and Efficacy
After regulatory approval, in most developed countries the price of a pharmaceutical must be established before it can be employed clinically. In the United States, however, drug pricing is not a factor in gaining market approval, as it is not within the scope of the FDA or any other regulatory body. As such, companies set their drug prices at whatever they believe the market will bear. This makes the United States one of the last—if not the last—largely unregulated pharmaceutical markets in the developed world from a pricing perspective.
In many other countries, significant cost-control mechanisms are in place. Like the FDA, the EMA does not take into account the price when considering a pharmacologic application for “centralized marketing authorization.” However, member European states have their own regulatory bodies, which subsequently control usage within their health-care systems. At this stage, a host of price-setting tactics are employed, including direct price negotiations, profit controls, limits on reimbursement, and reference pricing. For example, in the UK, company profit is specifically capped and a drug’s cost-effectiveness is strongly considered. In some European countries, these postapproval price negotiations can span years, substantially delaying widespread introduction of the pharmacologic agent under consideration.
Market availability can also be influenced by regulating how excess pharmaceuticals in “single-use” vials are used. In Canadian provinces such as Nova Scotia, physicians using provincially funded medication are expected to use split vials of on-label therapies including ranibizumab—a practice that may put physicians at risk of committing inadvertent fraud in other countries such as the United States, where the Centers for Disease Control recommends against such practices.
Finally, drug usage can be limited by insurance companies. In the United States, insurance companies may restrict the use of more expensive FDA-approved retinal pharmaceuticals by encouraging or mandating first-line use of cheaper, non-FDA-approved options (eg, bevacizumab). Alternatively, insurance companies may reimburse strictly based on FDA-approved indications despite a similar disease state involving the same pathophysiology. For instance, aflibercept is approved for neovascular AMD, but choroidal neovascularization (CNV) secondary to other etiologies such as myopia is not included on the FDA-approved label and thus may not be covered, despite clinical data demonstrating efficacy and approval by other agencies such as the EMA.