Generic substitution has been a controversial issue with regard to medications in general. However, with epilepsy it seems to present certain problems. Professor Frank JE Vajda, an internationally known neuropharmacologist, wrote in The Epilepsy Report as far back as October 2006 that: "In areas such as antiepileptics switching can present problems. The proof for drugs to be accepted as generically equivalent is not comparable to the proof of safety and efficacy required to have a drug initially registered." His article ended with a cautionary note.

The debate has continued and is gathering steam as more antiepileptic drugs go off-patent. At the 2007 American Epilepsy Society meeting there were multiple presentations on this topic. We have asked two experts to comment: Michael Privitera, MD, Professor of Neurology at the University of Cincinnati Medical Center and Russell Katz, MD, Director of the Division of Neurology Products of the Food and Drug Administration (FDA). Both Dr. Katz and Dr. Privitera are working on addressing this issue through clinical research. As Dr. Katz noted: "There is a perceived problem which we are trying to address. We are in the midst of discussions about trying to design a study that will address the issues."

COMMENTS OF EXPERTS

Russell Katz, MDRussell Katz, MD

Dr. Russell Katz joined the FDA as a medical officer in 1983, where he is currently the Director of the Division of Neurology Products (previously called the Division of Neuropharmacological Drug Products). He has lectured extensively on various aspects of neurologic drug development as well as written numerous articles on the same issues.

He received his BA in mathematics from Queens College in New York City and his medical degree from Albert Einstein College of Medicine in New York City, and completed his residency in Neurology in 1982 at the Einstein affiliated hospitals in New York.

Michael D. Privitera, MDMichael D. Privitera, MD

Dr. Michael Privitera is Professor of Neurology at the University of Cincinnati Medical Center. He is also director of the Cincinnati Epilepsy Center at the Neuroscience Institute at the University of Cincinnati and University Hospital and Medical Director of UC Physicians. He has participated in 55 different research studies in epilepsy sponsored by the National Institutes of Health or the pharmaceutical industry, has authored more than 100 scientific publications and edited the text "Clinician's Guide to Antiepileptic Drug Use." He has trained numerous fellows, and has directed the epilepsy course at the American Academy of Neurology and the Annual Course of the American Epilepsy Society. He is a member of the Board of Directors of the American Epilepsy Society.


Generic Substitution: Why the Controversy?

Dr. Privitera: The FDA sets standards for bioequivalence between brand name products and generics and between different generic formulations that they believe are safe for patients including people receiving antiepileptic drugs for epilepsy. These bioequivalence standards may not be appropriate for all classes of medicines, for all diseases, and for all patient populations.

Dr. Katz: With regard to the bioequivalence standard – there is a 90 percent confidence interval of 80-125% for the ratio of test/reference on log transformed data. In order for this standard to be met, the ratio has to be (and essentially always has been in thousands of studies) very close to one. Manufacturing standards for generic drugs are essentially identical to those for New Chemical Entities; that is, there are the same quantitative requirements for active substances.

What is the concern regarding breakthrough seizures?

Dr. Privitera: Physicians and other professionals caring for people with epilepsy believe that people with epilepsy have an unacceptable incidence of seizures or side effects when switching formulations. A single seizure can cause physical injury or have a dramatic impact on a patient's quality of life and on activities such as working or driving. These are critical to their well being -- especially if they have had seizure control for many years. But we don't know what the acceptable bioequivalence range is that would sufficiently protect patients from seizure risk and toxicity.

Dr. Katz: We are, of course, aware that there are reports of breakthrough seizures and adverse reactions in association with the use of generics. However, we have seen no credible evidence that the drugs are responsible. All of the support for these claims arises from patient and physician reports, either anecdotally or through surveys, which have used flawed methodologies. These sorts of reports cannot establish that the drugs caused the adverse outcomes.

If there is concern that generic drugs do not perform optimally, what is their value?

Dr. Privitera: Generic drugs are less expensive and everyone wants to reduce health care costs and the costs of medicines. However, our role as physicians is primum non nocere – first do no harm. We need to be assured that the generic drugs are absolutely safe. When someone with epilepsy is affected by an unexpected seizure that can cause loss of driving privileges, loss of job, or severe injury, once again this can dramatically impact their quality of life.

Dr. Katz: As I noted, the belief that generic drugs perform inadequately derives from anecdotal reports or flawed surveys by physicians. It is, of course, natural that when a patient receives a pill that differs in appearance from their previous pill (as when they receive a generic) and an adverse event occurs sometime after that (for example, a seizure), they and perhaps their physician would attribute that adverse event to the new pill. However, we know that patients with epilepsy have breakthrough seizures for many reasons, and even when their blood levels of drug are fine. So, it is not easy or even possible to tell whether that adverse event is related to the treatment or not, and such reports are certainly not evidence of generic failure. Evidence requires adequately designed and conducted trials. Although we are not convinced, at this time, that there are real problems with generic drugs, we of course acknowledge that there is a perceived problem, and we are currently working with the epilepsy community to design studies to address this perceived problem.

What suggestions do you have to the public with regard to generic drugs?

Dr. Privitera: Physicians and patients should be adequately informed before a pharmacy switches a patient to a generic equivalent. When patients call and say they are having increased frequency with seizures, we ask about the usual triggers. Then the next question we often ask is about medication – "Did the pills you took look the same as the ones you have been taking?" That gives us an answer.

Dr. Katz: As I described above, the FDA believes that generic drugs perform perfectly adequately, but we are attempting to design studies to address the questions that have been raised about them.

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