OFF PATENT GLAUCOMA DRUGS

W ithin the next several years a large number of patents will expire on brand-name glaucoma ophthalmic products in Europe and North America. While generics are beneficial in terms of cost, there are concerns in the ophthalmology community that generic drops of all types may come with risks not seen in the brand-name versions. A key issue is that eye-drops have non-active ingredients in them, such as antimicrobial preservatives, and compounds that affect pH and tonicity. While a generic may contain the same drug as the brandname, these other agents aren't required to be the same, according to Cindy Hutnik MD, professor of ophthalmology and pathology at the University of Western Ontario. She spoke at the recent 51st Walter Wright Annual Ophthalmology and Vision Sciences Symposium in Toronto.

'Non-active ingredients can affect the bioavailability of the drug by interfering with its solubility and ocular penetration, and inactive ingredients may ultimately affect the drug's effectiveness,' she said. She noted that changes in non-active ingredients can affect the pH of the eye-drop to a patient, or affects its texture. Patients will stop using drops that sting or feel gritty, meaning compliance decreases and disease can go untreated. According to the European Generic Medicines Association (EGA), 'Generic medicines must comply with exactly the same standards of quality, safety and efficacy as all medicinal products.' However, while standards for production may be the same, some ingredients can vary, Dr Hutnik says, and this is where problems can occur. For instance, the concentration of an active drug in eye-drops can vary between production lots. One study of glaucoma drops showed concentrations of active drugs in several products ranged from 85 to 120 per cent.

'Unfortunately, we can't regulate eyedrops as much as we can regulate pills; liquid medications are harder to control,' she said. Also, proving a generic gets to the part of the body where it is needed as well as the brand name is tough because testing for bioavailability is not possible with ophthalmics, said Dr Hutnik. 'With a pill, you take it, and it can be measured in the blood. But with an eyedrop there is no mechanism to make sure it has really gone in or how active it is. The definition of ‘equivalence' has become very loose for these products by the regulating authorities. We really have no idea what patients are really getting with the generics,' she told EuroTimes. In many places, physicians are required to prescribe generics, unless there are specific problems with individual patients. It can be difficult for physicians to switch patients to a brand name, and sometimes pharmacies don't carry brand-name products if a generic is available, she said. At least this is true in parts of Canada. Other factors such as dropper size, and how squeezable the bottle is can affect dose too.

Often, generic companies don't have access to the original recipe or data pertaining to a brand-name drug, and have to reverse engineer products to figure out the ingredients and proportions, according to Richard Fiscella PharmD, MPH clinical professor emeritus of pharmacy practice at the University of Illinois. Generic companies make best guesses for some of the nonactive ingredients, he said. Dr Fiscella has published a number of studies pertaining to ophthalmics and spoke to EuroTimes in a phone interview. This is confirmed by a statement on the EGA Generics website which states: 'Generic medicines applications do not make use of any data from the originator registration file. In fact, the data of originator products are never revealed to third parties, and so cannot be used by generic medicines researchers. Instead, generic medicines producers research and develop their own formulation of the product...'.

How much of a problem?
How much of a problem this represents in clinical practice is hard to say, but there have been some worrying incidents, said Dr Fiscella. Generally, generics are of good quality and effective, but more scientific studies are needed to better determine safety and efficacy of generic ophthalmics, he said. There were severe problems with the generic version of the NSAID diclofenac in 1999. After about a year on the market, there were case reports of corneal melting and some patients required corneal transplants. The product was removed from the market. Here, the solubizing agent and other inactive ingredients differed from the brand name and lead to serious problems, Dr Fiscella said.

Another example was with a generic form of prednisolone acetate. Reports showed that in some generic versions the drug didn't suspend well in the solution. This meant there were inconsistent amounts of steroid in each dose, Dr Fiscella said. The FDA in the US now requires studies of ophthalmic suspensions be performed before a generic is approved. In another example, a generic version of latanoprost from India proved to be less effective than the brand name in lowering intraocular pressure in glaucoma patients. Adding to the confusion, there are multiple manufacturers who produce generic versions of latanoprost (there are at least seven in the US alone). In addition, many ophthalmic products and many of the raw materials used in them are manufactured in other countries. With multiple sites located around the world, Good Manufacturing Practice (GMP) standards can be difficult to monitor, he said.

More research is needed in this area, in part because many reports of problems with ophthalmic generics are anecdotal, Dr Fiscella said. Conducting small, randomised clinical trials to compare safety and efficacy of brand name versus generic drugs before they are brought into the market would be useful. However, for many generic manufacturers doing this would be prohibitively expensive, and might discourage many companies from producing generics in the first place. This would lead to fewer affordable drugs on the market. A post-marketing data gathering system would help – not just for tracking major side effects, but for minor problems too, such as redness or irritation. It's important to pay attention to minor complications from drops because even slight differences can affect patient compliance, he said. In the meantime, ophthalmologists and optometrists should ask patients to bring all their eye-drops in to appointments. Look for differences in effectiveness, comfort and side effects, he advised. 'See if the patient was switched from a brand to a generic. Note the manufacturer in the chart, so follow-up can be done, and if there is any concern,' Dr Fiscella said.