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Lessons Learned from Clinical Trials Treating Dry Eye Disease

Our understanding of dry eye disease has increased dramatically in the past 10 years.1 Much of the information has accrued as a result of the clinical trials that have been conducted to evaluate potential new treatments for dry eye. Along the way we have learned about some unique characteristics of dry eye disease that were not recognized in the past but that must be acknowledged in characterizing the disease and in evaluating any proposed therapy.

♦ The Value and Features of Clinical Trials

The value of a controlled clinical trial is that it not only evaluates a specific therapy but also characterizes clinical features of the disease in a systematic manner that previously may have been described only in anecdotal terms based on multiple personal observations and experience. Standardization of examining techniques and data collection often reveals features of the disease that have gone unnoticed or unappreciated in prior experience. Attempts to control confounding variables in such studies further isolate and clarify features of the disease that may be amenable to ancillary therapy. A further accomplishment of the controlled clinical trial is to establish or verify the placebo response that may accompany any proposed treatment for a patient who is most anxious for the new therapy to be effective, or, alternatively, to identify a nocebo response that reveals an unexpected negative effect of an intervention.^2,3

In the past, most of our gathered information about dry eye disease came from retrospective examination of groups of patients suffering from the disease. A prominent feature of the condition, diminished volume of tears, recommended supplementation therapy or attempts to retain tears.¹ This approach to therapy is still used today, but with better appreciation of the role of inflammation in dry eye disease, we now realize that such therapy is only palliative in most cases. We also understand why some of the treatments not only did not relieve symptoms but even aggravated them in certain cases. One such example is the placement of a punctal plug to retain tears, which in a patient with significant inflammatory dry eye disease retains the volume of tears but also increases exposure to proinflammatory mediators in the tears.⁴

Increasingly, we rely on prospective studies to evaluate the natural course of disease or response to therapy. The first of these is the prospective observational trial that evaluates the progression of disease or response to a specific intervention. The more frequent and more rigorous approach is the prospective randomized masked parallel-group comparative trial that compares different treatments or a treatment with a placebo.^5,6 More recently, it has been advocated to use a controlled adverse environment trial that establishes the conditions to aggravate or exacerbate symptoms and signs of disease to evaluate response to a specific therapy.⁷ Each of these clinical trial designs reveals potentially valuable information about the disease as well as the treatment being tested.

Despite the care in clinical drug trial design, the nature of dry eye disease has often resulted in conflicting outcomes. It is clear that not all dry eyes are equivalent and that the treatment effect of any specific drug depends on which aspect of the disease is influenced. In an attempt to clarify results of clinical trials in dry eye disease, a group of investigators from academia, industry, and governmental agencies convened a workshop to refine the definition and classification of dry eye disease as well as to define the most appropriate parameters to evaluate in clinical trials. This 2-year effort culminated in the publication of summary guidelines of the National Eye Institute (NEI)/Industry Workshop on Clinical Trials in Dry Eyes in 1995.⁸ The major contributions of those guidelines are the establishment of a broad definition of dry eye disease that includes symptoms and signs of disease and recognition of both the tear function and the health of the ocular surface. The recommended classification emphasizes the differentiation of the mechanisms of evaporative and aqueous tear-deficient production in causing dry eye, and it provides caveats as to the appropriate inclusion and exclusion criteria for evaluating therapy in each subtype of dry eye. Although new variants of dry eye have since been recognized, such as the dry eye following laser in situ keratomileusis surgery, the general concept espoused is still valid for clinical trial design.⁹

The specific parameters to be evaluated in a clinical trial are also important features to consider in understanding dry eye disease because the outcomes of the trial are contingent upon the mechanism of action of any evaluated treatment. It follows that the applicability of any treatment in question to any subset of patients with the disease may then be identified. Specifically, inclusion and exclusion criteria employed in a clinical trial will limit the conclusions reached in the clinical trial and may suggest which patients are more likely to respond to the advocated therapy.

♦ What We Have Learned about Dry Eye Disease from Clinical Trials

Symptoms versus Signs

One of the most obvious lessons about dry eye disease that has been demonstrated in multiple clinical trials is that there exists a discordance between physical signs of the disorder and patient symptoms.¹⁰ The more common discordance is when patients with early disease have relatively severe symptoms in the presence of few if any objective signs of disease.¹¹ Tear secretion studies can be relatively normal and no ocular surface staining is demonstrable with fluorescein, lissamine green, or rose bengal, and the only clue to the dry eye problem is tear instability with a rapid tear breakup time. We usually attribute this discordance to the fact that corneal sensation is very acute and the patient with normal corneal sensation is responding to formation of dry spots on the ocular surface due to the rapid tear breakup even before damage occurs to the ocular surface. The converse discordance is also seen, however, when a patient with severe dry eye disease manifested by diminished tear secretion, rapid tear breakup, and significant ocular surface staining complains rather little about discomfort. One explanation for this latter occurrence may lie in the fact that with progression of dry eye disease, probably because of the presence of inflammatory mediators in the tear, the corneal sensation declines, with subsequent reduction ofsymptoms despite significant surface disease.12 A small study demonstrating this outcome correlated the symptom and sign ratio with the degree of surface staining in a group of patients in which the most severe extent of dry eye was associated with the least severe symptoms (Fig. 16-1).¹³

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