STATISTICS IN MEDICINE, VOL. 8,427430 (1989)

SURROGATE ENDPOINTS IN CLINICAL TRIALS: OPHTHALMOLOGIC DISORDERS

ARGYE HILLIS Texas A&M University and Scott and White Memorial HospitalfScott, Sherwood and Brindley Foundation, Temple,

TX 76508, V.S.A.

AND

DANIEL SEIGEL National Eye Institute, National Institutes of Health, Bethesda, M D 20892, V.S.A.

SUMMARY We examined three examples of surrogate observations in ophthalmology. The first‘represents a simple case: the status of one eye is used as a surrogate for the (unobservable) status of the opposite eye in the same individual. The second and third examples represent possible extrapolation of long term results on the basis of early changes. These examples are used to illustrate the assumptions intrinsic in the use of surrogate variables.

KEY WORDS Surrogate variables Ophthalmology Clinical trials Early changes Intraocular pressure

INTRODUCTION

We describe three instances of possible surrogate observations in the field of ophthalmology. By a surrogate observation, we mean an observed variable that relates in some way to the variable of primary interest, which we cannot conveniently observe directly. Our concern is surrogate observations rather than ‘surrogate endpoints’. In ophthalmology we have few true ‘endpoints’. Clinical trials related to eyes tend to involve complex non-fatal events and a patient’s follow-up often continues even after occurrence of a major event.

The first example involves the relationship between hypertensive vascular changes and vein occlusion in the eye. Just as clots may cause damage by blocking blood vessels in the heart or brain, blockage of very small blood vessels on the retina sometimes occurs and causes haemorrhage, damage to the tissues of the eye, and loss of vision. It has been suggested that - again analogously with the cardiovascular system- hypertension may play a role in this process. Eyes, however, differ from brains and hearts in one way: one can observe them non-invasively. Physicians can observe and photograph definitive changes that collectively constitute hyperten- sive retinopathy. A better understanding of the pathogenesis of vein occlusion could follow from knowledge of how frequently one can find these hypertensive vascular changes in eyes that have developed vein occlusion.

* Reprint requests to Dr. Argye Hillis, Scott and White Hospital, Temple, TX 76508, U.S.A.

0277-67 15/89/040427~$05.00 0 1989 by John Wiley & Sons, Ltd.

Received December 1987 Revised August 1988

428

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(1981; 88: 583-600).

Ideally, we would like to measure the hypertensive changes in a group of eyes with vein occlusion, but suppose we cannot measure hypertensive changes in those eyes because haemo- rrhages obscure the retinas. Can we legitimately use hypertensive changes in the unaffected eye as a surrogate? Before we accept the hypertensive changes in the unaffected eye as a surrogate for the affected eye, we would like to know as much as possible about the relationship between hypertensive stages between two eyes for the same patient. Are they related? The data will come from observations made on persons neither of whose eyes is obscured by haemorrhage. The investigator will be reassured if a strong correlation exists between eyes in such data, but there is no guarantee that the same relationship exists between hypertensive changes with and without vein occlusion. It is possible, for example, that the hypertensive changes in the unaffected eye are consistently less severe. In such a case we may underestimate the relationship between hyperten- sive changes and vein occlusion.

The second example is a pseudo-surrogate and comes from the Diabetic Retinopathy Study. One of the first large trials in ophthalmology, the Diabetic Retinopathy Study, initiated in the early 1970s, sought to determine whether panretinal laser photocoagulation provided benefit in the preservation of visual acuity among eyes with proliferative diabetic retinopathy. One eye was randomly selected for laser treatment and the other served as a control. The study plan entailed five year follow-up with evaluation on the basis of cumulative severe loss of vision in the first five years following treatment. Even before recruitment terminated, however, an unexpectedly large treatment effect emerged among the first cohorts of eyes (Figure 1). The cumulative rate of occurrence of severe visual loss was much greater in the untreated eyes and, at 28 months, continued to diverge markedly from the treated curve. Since the study design intended to provide longer term follow-up, the study investigators had to decide whether to publish the two year results or to wait for longer follow-up. There was some lengthy discussion of the possibility that the results might reverse with longer follow-up and the investigators developed analyses that attempted to evaluate this possibility.' The investigators discussed the possibility of delayed complications in treated eyes that would result in reversal of the observed treatment benefits. Estimates based on the limited life expectancy of these patients showed that the substantial gains in the first 24 months after treatment would not be outweighed by late harmful affects over the next 20 years even if the latter were relatively severe. Moreover, follow-up of all eyes was continued

SURROGATE ENDPOINTS OPHTHALMOLOGIC 429

to evaluate late complications, with the recognition that a comparable group of untreated eyes was no longer available. Although some members of the ophthalmological community interpret the Diabetic Retinopathy Study results as surrogate for long-term evaluation of visual acuity, it is important to point out that the authors of the paper quite properly did not present the results in this light. They based their decision to publish on the inherent value of the short-term results, in particular in light of the limited life expectancy of patients with proliferative diabetic retinopathy. Therefore, we cannot cite this as a true surrogate observation. In fact, we would have difficulty modelling it as such without some rather bold assumptions.

In the first example we considered the substitution of a surrogate variable in a cross-sectional study. The second example was a longitudinal study, but did not have a true surrogate variable. The final example addresses the use of an immediately available variable as a possible surrogate for long term outcome in studies of an important public health problem.

Glaucoma is a common and preventable cause of severe visual loss. As far back as the time of Hippocrates physicians noted that some patients had a characteristic disease associated with elevated intraocular pressure and blindness. In recent years the concept has developed that glaucoma is ‘an eye disorder in which an intraocular pressure that is too high for the health of the eye causes the optic disc to become cupped and atrophic and the visual field to develop characteristic nerve bundle defects’.* The disease develops in two separate but related pathogenic stages. First, the drainage of the aqueous humor from the eye becomes impaired, which causes the intraocular pressure to rise. Second, the high intraocular pressure, aided by other less well identified pathogenic factors, damages the optic nerve and produces cupping and loss of visual field.

The concept of glaucoma is somewhat complicated by ‘incomplete glaucoma syndromes’. In one type of incomplete glaucoma syndrome, patients have high intraocular pressure but normal optic discs and visual fields. Some of them will eventually develop optic nerve damage but most will continue to have normal optic discs and visual fields for the remainder of their lives. There is controversy in the terminology associated with elevated intraocular pressure in anatomically and functionally normal eyes. Some authorities call it ‘ocular hypertension’ or label the patient a ‘glaucoma suspect’ while others prefer the terms ‘early glaucoma’ or ‘glaucoma without damage’. The second viewpoint emphasizes that every eye with high pressure has risk of optic nerve damage and mandates consideration as diseased. There is also another incomplete syndrome, called ‘low tension glaucoma’, in which an eye with normal intraocular pressure develops optic disc cupping and visual field loss, possibly due to a ‘frail optic nerve’ unusually susceptible to damage at levels of intraocular pressure usually well tolerated.

Our third example is the use of intraocular pressure as a surrogate for long term visual function in glaucoma trials. One measures intraocular pressure quite easily and changes in intraocular pressure appear early in the usual course of the disease. Whether it is an appropriate surrogate depends upon the validity of several assumptions, including:

1. that elevated intraocular pressure is a direct cause of ocular damage in glaucoma, not just a variable associated with damage;

2. that lowering intraocular pressure will result in improved long term function (for example, by preventing further damage from occurring);

3. that we can measure the degree of potential danger satisfactorily by techniques available for measuring intraocular pressure (for example, a single isolated daytime reading in the physician’s office).

To glean the extent to which studies of glaucoma employ intraocular pressure as a surrogate variable, we reviewed the eight therapeutic trials of glaucoma therapy listed in the 1985 Index

430 A. HILLIS AND D. SEIGEL

Medicus and appearing in one of four leading ophthalmological journals (American Journal of Ophthalmology, Acta Ophthaimoiogica, Archives of Ophthalmology, and ophthalmology). In particular, our interest was whether this early change is in fact used as a surrogate for late morbidity, and, if so, the rationale presented for doing it.

All eight trials used intraocular pressure as an outcome variable. Three added short-term field changes as a dependent variable, one added short-term visual acuity, and one used all three dependent variables. None discussed results beyond about two years after initiation of treatment.

Only two of the eight articles used the words ‘glaucoma treatment’ or ‘treatment of glaucoma’ in the title. Two others mentioned ‘effect . . . on pressure elevation’ or ‘reduction of intraocular pressure’. The remaining four were trials involving surgery (trabeculoplasty or trabeculectomy) and simply named the treatment in the title with some phrase such as ‘results of’. Neither of the articles that mentioned treatment of glaucoma contained any rationale for or discussion of the limitations of the use of intraocular pressure as the major outcome variable. Two other trials were direct evaluations of short-term pressure changes and in these pressure did not in any way appear as a surrogate.

Only one article addressed the surrogate variable problem; the author pointed out that an arbitrary definition of success in terms of intraocular pressure was ‘bothersome’ and cited one report that laser-induced normalization of intraocular pressure does not necessarily prevent further deterioration of the visual field.

So what do we have? We have looked at three different situations that involved a conscious decision not to measure the variable of interest, but instead to substitute another measurement.

The first case described a true surrogate measure (hypertensive changes in the companion eye). This case was particularly simple, because the problem was strictly one of observing related parts of a natural phenomenon and did not involve any intervention into that phenomenon or extrapolation into possible future changes. The utility of this surrogate depends upon whether the correlation between eyes in degree of hypertensive change in unaffected patients pertains to patients with vein occlusion in one eye.

Both of the other examples, the Diabetic Retinopathy Study and the glaucoma trials, involved an intervention and an interest in long term but unobservable results, that is, long term visual function. In the DRS, the early resuits had sufficient importance in and of themselves to justify publication. In glaucoma trials, the use of intraocular pressure as a surrogate depends upon the validity of a generally accepted set of assumptions as to the etiologic role of intraocular pressure in the progression of glaucoma. Ophthalmologists have long treated glaucoma by lowering the intraocular pressure so that they feel pretty comfortable about its use as a surrogate for long term visual outcome. In trials in which we had little understanding of pathogenesis, we should exercise great caution with the use of surrogates. We might fool ourselves by treating a symptom or, like the ancients, kill the bearer of bad tidings.

REFERENCES 1. Ederer, F., Podgor, M. J. and the Diabetic Retinopathy Study Research Group. ‘Assessing possible late

treatment effects in stopping a clinical trial early: as case study’, DRS Report 9, Controlled Clinical Trials,

2. Phelps, C. D. ‘Glaucoma: general concepts’, in Duane, T. D. (ed.) Clinical Ophthalmology, Harper and 5, 373-381 (1984).

Row, Philadelphia, Vol. 3, Chapter 42, 1-8, 1986.