Wiley A. Chambers MD All drug products have some risk. If there is pharmacologic activity due to the drug product, there is also a risk of adverse events from the pharmacologic activity. Risk is generally best assessed in controlled clinical studies. Unfortunately in the case of low incident events, this is not always possible. A risk may not be identified until after the drug product has been commercially marketed. At that time it is often difficult to determine the number of people who have been exposed to the drug product. If the number of people exposed cannot be accurately determined, the exact frequency or likelihood of a side effect cannot be accurately determined. The assessment of risk generally improves as more individuals receive the drug product. While it would be extremely helpful to know the full risk profile of every drug product prior to release into commercial marketing, usually the full risk profile is not completely known until after the drug product has been marketed, and sometimes not until years later. There is a wide variety of diagnostic testing modalities that may be used to detect and evaluate a suspected ocular toxicity. While it is theoretically possible to perform each of these tests on any individual that is suspected to have an abnormality, the time, expense, resources and ability of the patient to cooperate must be taken into consideration. In broad terms, these tests may be divided into two main categories. The first covers methods capable of detecting objective anatomic changes, and the second covers methods capable of detecting functional changes. The former category of tests is not necessarily better than the latter; they simply measure different things. The number of tests needed to characterize an abnormality (or deviation) will vary with the abnormality being evaluated and the extent to which it needs to be characterized. While screening tests may be used to superficially scan for irregularities without fully quantitating the extent of the anomaly, there should be a justified reason for the selection of each test. Each test should be appropriate for the type of potential event in question. As noted above, it may be theoretically possible to perform many tests, but consideration of the following questions can help narrow the choice: 1. What are the findings from any nonclinical toxicology studies in nonhuman animals? 2. What abnormalities are expected based on the known pharmacologic action of the drug? 3. What is the route of administration of the drug? 4. How widely is the drug distributed throughout the human body? 5. How serious is the potential abnormality? 6. How likely is the test to detect an abnormality? When possible, it is recommended that nonclinical toxicology studies be conducted prior to conducting human toxicology studies. Ideally, nonclinical studies should be conducted using higher multiples (2×, 10×, 100×) of the doses proposed for humans (based on concentration and/or frequency of administration). The duration of dosing should be at least as long as planned in humans (up to nine months). It is helpful to compare multiple different dose levels in these studies. The findings of the nonclinical toxicology studies should then be used to help guide the initial tests to be conducted in humans. While the events observed in nonhuman studies may not be duplicated in human studies, there is frequently some overlap. It is therefore important to assess the potential for these events. For example, an important characteristic that may be determined in nonclinical studies is whether or not a drug product binds to melanin. Melanin is found widely in the eye, and products that bind to melanin may cause ocular toxicities. If a drug product has been found to bind to melanin, it would be important to know whether the nonclinical studies demonstrated abnormalities in electroretinograms (ERGs). If a drug product is found to bind to melanin and demonstrates ERG abnormalities in animals, it would be prudent to monitor best corrected distance visual acuity, color vision, automated threshold static visual fields, ocular coherence tomography (OCT) and dilated fundus photographs of subjects in clinical studies. Histopathology in the nonclinical studies can be important. If in nonclinical studies, a retinal lesion or retinal drug deposit is observed in animals, best corrected distance visual acuity, color vision, threshold static visual field, OCT and fundus photographs should be monitored in clinical studies of humans. Drug products that cause retinal lesions and ERG changes in nonhuman animals often cause toxicity in humans as well. If in nonclinical studies, lens opacity is observed in animals, then best corrected distance visual acuity and lens photography or the use of a standardized lens grading system should be included in clinical studies of humans. The structure of the drug, nonclinical pharmacology studies and clinical pharmacology studies may be helpful in identifying the expected pharmacologic actions of the drug. To the extent that the pharmacologic action potentiates or interferes with ocular functions, ocular tests may be planned to quantitate the enhancement or interference of the function. For example, drug products that affect the sympathomimetic system are likely to affect intraocular pressure and pupil size. It is therefore important to perform tonometry and pupil size measurements to quantitate the expected changes. Drug products that affect the cholinergic system are likely to affect intraocular pressure, pupil size, tear production and the corneal surface. Tests such as tonometry, pupil size measures, Schirmer tear tests, and rose bengal or lissamine green corneal staining may be useful. The seriousness of a potential adverse event should influence the effort spent on characterizing the likelihood of the event to occur and any factors that may mitigate or enhance its occurrence. It is most helpful to be able to predict events that can cause irreversible changes and in particular events that can lead to irreversible blindness. To the extent that these events are associated with warning signs or symptoms, some of these events may be preventable. The frequency of a potential adverse event occurring will influence the methods used to characterize the event. For the reasons discussed below, the likelihood of detecting rare events (such as those that occur in fewer than 1 per 10,000 subjects) in controlled clinical studies is rare. Other methods must be used to study the events. In cases where the frequency of events is dose dependent and increases with increasing dose, it may be possible study in a clinical trial the potential for the event in patients by administering artificially high doses in study subjects. The frequency of a potential event occurring in the general population, and more importantly in the population of patients likely to take a particular drug product, may make recognizing an association with that particular drug product difficult. Ocular events such as nonarteritic ischemic optic neuropathy (NAION) occur very rarely. NAION events occur most frequently in patients with known risk factors for NAION events, such as crowded optic disks, coronary artery disease, diabetes, hyperlipidemia, hypertension, older age and smoking. If patients who have any of these conditions take a drug product and then have a NAION event, it is extremely difficult to determine whether the drug product, the other risk factors or both contributed to the NAION event. It should also be recognized that some serious events may occur too infrequently to be able to be adequately studied. Taken at the extreme, if an event is so rare that it is expected to occur in 1 in 7 billion patients, even if it results in total blindness the frequency is so low that no one would expect to ever see another case. The route of administration will affect the particular areas of the eye that are exposed to the drug product. Direct application of a drug product to the eye increases the likelihood that significant concentrations of the drug reach the eye. As a general rule, the following tests are recommended for all subjects of all drug products administered topically to the eye: 1. best corrected distance visual acuity 2. dilated slit lamp of anterior segment 3. dilated indirect fundoscopy or photography 6. assessment of symptoms in the first minute following topical application. Additionally, a subset of patients receiving a drug product topically administered to the eye should have corneal endothelial cell counts. The order of conducting the tests is important. A number of tests are capable of producing temporary ocular abnormalities or temporarily masking ocular abnormalities. If the order of the tests is not chosen carefully, some of the temporary ocular abnormalities caused by earlier tests will be detected by later tests and incorrectly attributed to the drug product. For example, applanation tonometry requires the use of an anesthetic agent. The anesthetic’s effect may last up to 30 minutes and may mask ocular discomfort produced by the test product. Whenever possible, the inclusion of a baseline test before exposure to a drug product is extremely helpful in the interpretation of any suspected abnormalities. It is also helpful to have a post drug-exposure test to determine whether any abnormality is reversible or permanent. Besides these two time points, additional testing is dependent on the drug and the particular test.
Methods for evaluating drug-induced visual side effects
Risk
Selecting Diagnostic Tests
Frequency
Topical Administration
Order of Testing
Timing of Testing
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