toxicology ocular in psychophysics and electrophysiology of role The •   PART 4  

In the case of multifocal ERGs, improved quality can be achieved by averaging the rings of the trace array. Retinal localizations of equal eccentricity are thus summed up together, the signal- to-noise ratio is greatly improved and four rings of retinal function can still be discerned from the central retinal function.

It also should be noted that some companies (e.g. Diagnosys UK Ltd) provide the possibility of hooking up their devices to a single server via the internet. This improves quality since not only is a central reader (e.g.www.stz-biomed.de) involved in checking the quality at a time point very near to the recording but also errors of data transmission are greatly reduced.

Limits of normality

There are several publications on normal values in volunteer populations (Birch and Anderson 1992; Jacobi et al 1993a, b). From these publications clinical concern is raised if there is loss of ERG Ganzfeld amplitude of more than 50% of the amplitude in an individual or there are prolongations of implicit time of > 2 standard deviations.

Conclusion

In recent years, electrophysiological non-invasive testing has increasingly become important in preclinical and clinical studies for efficacy and safety as well as the identification of the possible origin of drug-induced pharmacological or toxicological effects in the visual system. Proper standards for all tests, EOG, ERG, multifocal ERG, PERG and VEP as well as calibration procedures, are available (see www.iscev.org). Knowledge of the origin of electrophysiological responses as well as the circuitry, cell types and transmitters, modulators, channels, enzymes and biochemical processes has increased enormously. All these prerequisites have led to a new era of electrophysiological testing in preclinical and clinical studies, requested by regulatory authorities in order to rely on objective data for risk benefit considerations. The design of preclinical and clinical studies, especially multi-center studies, therefore requires special expertise not only in retinal function, retinal diseases, retinal circuitry and biochemistry but also in selecting the proper markers on the basis of expert knowledge for appropriate endpoints in testing particular compounds. Quality has to be ensured by extended SOPs and CRFs that also implement data that test the quality of procedures and calibrations. Moreover, presently networks of validated centers are being set up and internet-based technology is available that makes electrophysiological testing in the eye much easier in terms of quality, quality control, central reading and monitoring as well as data management.

Nevertheless planning multi-center clinical trials with electrophysiological testing is still a challenge. In order to properly meet this challenge, investigators must strictly adhere to validated ­international SOPs, technical assistants must be well trained, electrophysiological reading centers must be involved, experienced ophthalmic monitoring must be performed by monitors that understand electrophysiological recording and, most of all, electrophysiological recordings must be based on targeted function testing that is complemented by appropriate psychophysical tests such as color vision, visual field, dark adaptation, glare ­sensitivity testing and assessment of the clinical morphology of the retina and optic nerve.

Acknowledgment

I am very grateful to Mrs Doina Ruppert for helping with assembling the manuscript and the references and to Mrs Regina Hofer for producing the illustrative figures.

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Rationale

In a specialized area, such as ophthalmology, it is not common for a practitioner or even a group of practitioners to see the patient volume necessary to make a correlation between possible cause and effect of medication-related ocular disease. Postmarketing observational studies from multiple sources permit the evaluation of drug safety in a real-world setting where off- ­label use and various practice patterns occur. There is no question that this has limited ability to determine causation, but it can detect ‘signals’ that alert the clinician as to adverse drug events. In subspecialty areas of medicine with comparatively limited markets, sometimes this is all that we have. A national registry specifically interested in a specialized area of medicine has filled a need, as shown by the three-plus decades of the ­National Registry of Drug-Induced Ocular Side Effects.

The National Registry, which is based at the Casey Eye Institute in Portland, Oregon, USA (www.eyedrugregistry.com), is a clearinghouse of spontaneous reports collected mostly from ophthalmologists from around the world. It is the only database which collects only eye-related ADRs. The Medwatch program run by the US FDA (www.fda.gov/medwatch/index.html) collects ADRs on all organ systems in the USA and is another source to report data to and request data from. The Uppsala Monitoring Center, a branch of the World Health Organization (WHO, Uppsala, Sweden, www.who-umc.org) collects spontaneous reports on all organ systems from around the world and has more than 70 national centers that report to them, including the FDA. Finally, clinicians and patients frequently report an ADR directly to the drug company, who in turn periodically submit these spontaneous reports to the FDA.

Regardless of where an ADR is submitted, the various organizations mentioned above can be contacted with questions about an ADR or how many types of reports exist for specific drug/ADR combinations. The National Registry provides this information free of charge to ophthalmologists and the FDA is required to provide this information to the public through the Freedom of Information Act. The WHO may charge a fee, depending on the type of information requested. The information from pharmaceutical companies should eventually end up in the FDA’s Medwatch­ database.

Recently, spontaneous reporting databases have adopted a statistical analysis method of interpreting ADRs. At the Uppsala Monitoring Center, for instance, a quantitative method for data mining the WHO database is part of the signal detection strategy. Their method is called the Bayesian Confidence ­Propagation Neural Network (BCPNN) (see references). An Information Component (IC) number is calculated based on a statistical dependency between a drug and an ADR calculated on the frequency of reporting. The IC value does not give evidence of causality between a drug and an ADR, it is only an indication

or signal that it may be necessary to study the individual case reports in the WHO database. The IC value calculation is a tool that can guide the WHO to create a hypothesis of association between drugs and ADRs among the over 3 million case reports in the WHO database.

This method of analysis is also being adopted within the pharmaceutical industry and at the FDA. The National Registry is also able to use the IC values as we are consultants to the WHO. If a clinician suspects an ADR, especially if it may be a new drug-induced ocular side effect, he/she is encouraged to report this to the National Registry. Membership on the website is free and it only takes 1–2 minutes to register. Frequent updates are also available on the website, informing clinicians as to what is the latest in ocular pharmacovigilance.

Objectives of The National Registry

•To establish a national center where possible drug-, chemical­ - or herbal-induced ocular side effects can be accumulated­ .

•To review possible drug-induced ocular side effects data collected­ through the FDA and the WHO Monitoring Center­ . To record data submitted by ophthalmologists worldwide to the National Registry.

•To compile data in the world literature on reports of possible drug-, chemicalor herbal-induced ocular side effects.

•To make available these data to physicians who feel they have a possible drug-induced ocular side effect.

How to Report A Suspected

Reaction

The cases of primary interest are those adverse ocular reactions not previously recognized or those that are rare, severe, serious or unusual. To be of value, data should be complete and follow the basic format shown below.

Age:

Gender: Suspected drug:

Suspected reaction – date of onset: Route, dose and when drug started:

Improvement after suspected drug stopped – if restarted, did adverse reaction recur?:

Other drug(s) taken at time of suspected adverse reaction: Other disease(s) or diagnosis(es) present:

Comments – optional (your opinion if drug-induced, probably related, possibly related or unrelated):

Your name and address (optional):

We are expanding the National Registry from only drugs to include chemicals and herbs, which may have the potential for ocular toxicity.