Concerns over Efficacy and Safety of 0.1% Cyclosporine a Cationic Emulsion in the Treatment of Severe Dry Eye Disease

Dear Editor,

I read the SANSIKA trial results (1) and am concerned that efficacy has not been convincingly shown and the benefit-risk balance of Ikervis in severe dry eye disease appears negative.

This must undermine the following conclusion: “CsA CE was well-tolerated and effective in improving corneal damage and ocular surface inflammation and confirmed the positive benefit-risk ratio of this new formulation of CsA for the treatment of severe keratitis in dry eye disease” (1).

The SANSIKA trial evaluated patients with dry eye disease (DED) with severe keratitis, who have an increased risk of infection, vision loss, and impaired quality of life. This was defined by corneal fluorescein staining score of 4, Schirmer test score ≥2 mm/5 min and <10 mm/5 min, and Ocular Surface Disease Index score ≥23.

Ikervis does not have an EU licence to treat any other form of DED.

The Association of the British Pharmaceutical Industry code of practice (2) (clause 7) requires outcome to be expressed as absolute risk reduction (ARR) and number needed to treat (NNT): “Referring only to relative risk, especially with regard to risk reduction, can make a medicine appear more effective than it actually is. In order to assess the clinical impact of an outcome, the reader also needs to know the ARR. In that regard relative risk should never be referred to without also referring to the absolute risk.”

The NNT is a measure of the impact of a therapy, estimating the number of patients that need to be treated in order to have a beneficial impact on one person. Not everyone is helped by medical intervention; some are unaffected, and some harmed; number needed to harm (NNT) is a similarly derived measure of harm. The NNT and NNH assist in co-decision-making and informed patient choice.

From the SANSIKA trial, although the relative risk reduction is -0.238 (95% confidence interval [CI] -0.943 to 0.211), the ARR is much less at 0.055 (95% CI -0.161 to 0.062).

The NNT is 18, meaning if 18 are treated with Ikervis, 1 benefits (3).

The SANSIKA trial results demonstrate that Ikervis caused the same symptoms and corneal staining in 1 in 6 subjects, meaning the NNH is greater than then NNT.

This suggests that the harm due to Ikervis outweighs the benefit.

Further concerns arise because in 2.59% of subjects, cyclosporine was detected in peripheral blood.

The trial's main outcomes are set out in an icon array (an easy-to-interpret abacus-like pictograph).

A total of 31.8% of those using active drug experienced neither benefit nor harm.

The benefit was experienced by only 5.5% more than those using the vehicle.

Adverse effects occurred in 15.9% more than the vehicle.