If This Was Easy, Wouldn't Everyone Be Doing it?

discovering dry eye

If This Was Easy, Wouldn't Everyone Be Doing it?

May 2000

We have a saying around our office regarding clinical patient-based research ­ "If this was easy, everyone would do it." This phrase is remarkably appropriate for dry eye research. The Restasis (cyclosporin 0.05%) case is a perfect example of the difficulties inherent in clinical research, in this case dry eye research. The results were presented to the FDA panel: cyclosporin, a T-lymphocyte inhibitor, is effective in reducing the signs and symptoms associated with dry eye. Interestingly, cyclosporin's vehicle, a castor oil-based emulsion, also reduces the signs and symptoms, but to a lesser degree. The panel was not convinced that the difference between cyclosporin and the vehicle alone is significant.

The Restasis case is the perfect example of the difficulties inherent in clinical research, in this case dry eye research. Every patient is different. In a world where differences between people are celebrated, wouldn't it be nice if everyone was the same when it came time to do a trial on a promising drug like Restasis? In planning the Restasis study, researchers attempted to minimize patient differences by establishing entry criteria (Table 1).

TABLE 1: Restasis Phase 2 Key Ocular Inclusion Criteria

  • Schirmer test without anesthesia ¾ 7mm

  • Corneal fluorescein staining >=+1 (0 = none, 3 = severe)
  • At least one subjective symptom >= +2 (0 = none to 4 = very severe)
  • KCS despite conventional management
  • With or without Sjögren's syndrome
  • Normal lid anatomy and blinking function
  • Best corrected Regan visual acuity >1.00

The Elusive Gold Standard Test

Dry eye is a challenging field in that every study has a different set of entry criteria. Unlike dry eye, other disorders have a gold standard test which defines the disorder with high frequency. Hyper-tension is the best example. Blood pressure measurements are taken, and if the pressure is above the established normal level, high blood pressure is diagnosed. Blood pressure cuff measurements are accepted as valid and repeatable by researchers.

In contrast, no single diagnostic test is agreed to be paramount in diagnosing dry eye. Clinicians utilize several diagnostic tests, including assessment of symptoms, tear break-up time, Schirmer test (or phenol red thread test), fluorescein staining of the cornea, rose bengal (or lissamine green) staining of the conjunctiva and assessment of the tear meniscus. The order in which the tests are performed, whether the patient wears contact lenses, changes in medication use or the local environment can alter the diagnostic test results. In planning clinical trials, the challenge is to develop an entry criterion that unifies the trial group(s) without sacrificing generalizibility of the results.

Let's Face it...We're Different

Even with the best study design, patient responses to treatment vary. When a disease is very difficult to characterize, or if the treatment effect is variable, statistically significant differences can be hard to find. This doesn't mean the results do not have any clinical significance. In the Restasis example, both groups improved. Perhaps this indicates that the vehicle could be marketed as a new "lubricating solution." Maybe patients require more severe dry eye for cy-closporin to be effective. We cannot write off these results as "failed." Allergan should be congratulated for attempting to make headway in the arena of dry eye treatment. After all, if this was easy, wouldn't everyone be doing it? 

Dr. Nichols is a graduate research associate at The Ohio State University College of Optometry in the area of dry eye research.