Branded vs. Generics

Eye Presents Unique Challenges for Drug Evaluation

Developing a drug for use in the eye is, to say the least, challenging. Unlike other organs in the body, the eye is made up of several different fluids, structures and layers, each with its own physiologic function. The front of the eye in particular serves to prevent the entry of foreign substances. Therefore, to have a therapeutic effect, a topically applied ocular drug must be precisely formulated to overcome the barrier of the eye's efficient drainage system. If the drug acts inside the eye, it must penetrate the cornea or conjunctiva and sclera to be absorbed.

“When it comes to ophthalmic drugs, formulation really matters,” says Gary D. Novack, PhD. Novack is a clinical pharmacologist and president of PharmaLogic Development Inc., which helps firms navigate the drug and device development processes including FDA approval. Not only is it difficult to formulate an ocular drug to be effective, Dr. Novack says, it's also difficult to evaluate its pharmacokinetics (how much drug is present) and pharmacodynamics (how the drug is behaving) in the eye.

“The concentration of a systemic drug in its target tissue can be determined by looking at levels in the blood at various time points,” he said. “But similar, continuous monitoring cannot be done in the eye. Areas of interest, such as the aqueous humor, vitreous or trabecular meshwork, cannot be repeatedly sampled in a safe manner, or in a manner that in itself would not alter the drug's action in the eye. Therefore, we don't know the pharmacokinetics in the human eye for most of the drugs used in ophthalmology.”

Comparing Generic and Innovator Ophthalmic Drugs

Dr. Novack explained how the hurdles inherent to development of new ocular drugs carry over into attempts to compare one drug to another, including an innovator drug to a proposed generic in the FDA approval process. “If you're going to make an ophthalmic generic, you can't say it's going to be within a certain percentage of the innovator drug in concentration in the target tissue because in most cases, you don't know what those concentrations are. So what do you do? If your drug is in the form of a solution, you can provide the FDA with chemical analyses to show your active and inactive ingredients sufficiently match that of the innovator solution. You may not be required to perform testing in humans because FDA is confident based on the chemistry that your solution will perform in a similar manner to the original.

“A formulation more complicated than a solution, however, brings more variables to the table. It would be less clear how differences between your formulation and the original might impact how similarly they perform. In that case, you could expect FDA to require some type of testing in humans. However, again, since the clinical ocular pharmacokinetics of the innovator are not known, you would need to test the efficacy of the generic in comparison to that of the innovator product in a study in humans.”

Balancing Act

It's important to understand that FDA's process for approving generic drugs is based on legislative mandates, mainly the Hatch-Waxman Act of 1984, Dr. Novack says. “The Act was designed to make it easier for generic drugs to gain approval. The current process is how FDA interprets its mission to protect the health of the American people based on available science, but also the laws that govern it.” As such, Dr. Novack continued, how to compare the efficacy of two drugs, and how studies to that end might be financed, are major health policy issues. “In America, we want innovation, but we also want to decrease healthcare costs. This creates tough questions for not only doctors but our whole country to address.”

Dr. Novack says technological advancements that can improve the ability to develop and evaluate ophthalmic drugs should also improve the ability to answer these difficult questions. He says he looks forward to the availability of new tissue sampling techniques and pointed out that future imaging technologies may enable the tracking of drugs through the eye. ■