AED IX - Highlights of Day Two: Special Considerations with AEDs for Children, the Elderly, and Women

The Ninth Annual Antiepileptic Drug Trials Conference sponsored by the University of Pennsylvania Medical Center and the Epilepsy Therapy Development Project, explored:

• Development of new drugs to prevent epilepsy and treat epilepsy, and how to test drugs and devices – Day One.
• Special populations, formulations, and secondary endpoints – Day Two.
• Drugs in the pipeline – Day Three.

There are three populations that appear to have special needs in terms of epilepsy therapies – children, the elderly and women. Day Two focused on these groups as well as on formulations, and secondary endpoints for epilepsy studies.

Epilepsy Therapies for Children

Donald Shields, MD, Professor of Neurology and Pediatrics, and Director of the Pediatric Epilepsy Program at UCLA, spoke about one of the more devastating epilepsy syndromes – infantile seizures. He noted that one of the problems with infantile seizures is timely diagnosis, and emphasized that early diagnosis and treatment may affect developmental outcomes of babies with infantile seizures, and therefore prompt diagnosis was essential.

John Pellock, MD, Professor and Chairman, Division of Child Neurology at Virginia Commonwealth University, also spoke of the difficulties with studying neonates with regard to clinical trials. In talking with epilepsy.com, he said: “These are very sick babies. To do any kind of trial will require total body monitoring, unless it is an IV formulation. But this is problematic because you don’t know what is going to be absorbed. We need a drug that works. The problem is that developing drugs for these children isn’t likely to be profitable for drug companies, because we may need a drug that will be used only for a short time and not used for the rest of the child’s life. But we need to do something because it is the right thing to do.”

He added, “We also need to study kids with Lennox-Gastaut, who are typically 4 to 8 years old. There are problems with the existing system of drug studies for children with epilepsy. The pediatric studies have failed. We may need to ask for studies for both approved and unapproved drugs.”

Dr. Pellock is another proponent of multi-center trials. “I believe that we will have to develop a trial where there are multiple centers looking at young children with difficult-to-control epilepsy. I am suggesting something that is more like a natural history study, a study similar to a cancer protocol. The more children that we begin to follow and watch, the more we will learn about the individual epilepsy syndrome and how many children respond. For example, not all seizure types respond in the same way at different ages. For some children, we may be dealing with developmental effects.”

“I don’t believe that a single pharmaceutical company will be willing to fully support this type of study. Funding may have to come from voluntary groups initially to get preliminary data. Then perhaps after showing that the structure can work, we could get a government agency to fund this. Then a central trials database could be created. This will help us to say, ‘We have two years of data and no one has gotten better. Or we have two years of data and some of the children have gotten better.’ However, what we are really talking about here is a major planning grant from the National Institutes of Health.”

With regard to AED trials in infants, Dr. Pellock pointed out that issues still exist such as informed consent, risk to benefit ratios, FDA regulations, and placebo control.

Other presentations in this segment included: placebos and equipoise in new-onset pediatric epilepsy; implications for monotherapy trials and pediatric exclusivity.

Epilepsy Therapies for the Elderly

Speaking as an advocate for elderly patients with epilepsy, Ilo Leppik, MD, Professor of Pharmacy at the University of Minnesota and Director of Research, MINCEP Epilepsy Care, told epilepsy.com, “My dream would be to have research done in nursing homes handled by physicians who know how to diagnose epilepsy. Neurologists never go to nursing homes, whereas the nursing home physicians, who know very little about epilepsy, are the ones who are prescribing seizure and non-seizure medications. There is a real gap here.”

Dr. Leppik said, “For example, we prescribed Dilantin for a 60-year-old woman using all of the proper criteria. Yet her Dilantin levels bounced all over the place. Why? Her Dilantin was interacting with her cardiac medication.”

Another issue that concerned him was whether patients in nursing homes who were prescribed AEDs did in fact have a diagnosis of epilepsy. He said, “We need to ask, ‘Do nursing home patients really need the meds?’ This is a very timely issue. There are a lot of drugs being used that may not be appropriate for the diagnosis, and we want to bring attention to this issue to the NIH.”

Dr. Leppik sees the need for a lobbying effort to support nursing home patients. “I have a great Congressman named Jim Ramstad (Minnesota’s 3rd District) and I talked to him about these issues,” he said. “But Jim’s answer to me was pretty clear. Jim agrees with me but tells me that he never gets letters about epilepsy and nursing homes. So I think it is time for a national organizational effort of handwritten notes to our congress people. This is the only way we are going to see this issue resolved.”

As the Baby Boomer generation ages, Dr. Leppik sees an increase in the problem of the elderly and possible misdiagnosis of epilepsy. “Eighteen years ago, at the first AED meeting, it didn’t appear as if there were any elderly with epilepsy on the horizon. I had done research on women and believe it made a difference. Now we have this population of the elderly and I am speaking about it whenever I can to bring the needs of the elderly with epilepsy into a much more visible arena,” he concluded.

Women’s Treatment Issues

Cynthia Harden, MD, Associate Professor of Neurology and Neuroscience at the Weill Medical College of Cornell University in New York City, was moderator for the panel on women and AEDs. Dr. Harden, in reviewing the panel presentations, said: “What we presented were the in utero effects of antiseizure medications from studies that were carefully performed in a prospective manner. Also, we were looking at drugs with regard to interactions with oral contraceptives as well as long term effects of drugs in utero.

“The questions we ask are straightforward: Who should pay for this type of long-term surveillance? It could be a combination of industry and government or some other partnership. Where does the current evidence lead us going forward? What questions do the studies raise? What do we need to do in the future to get information sooner rather than later in the case of drug use in utero?”

In talking with epilepsy.com, Dr. Harden said “I would like to see industry become more magnanimous and more aggressive rather than defensive in finding out the effects of drugs on women and women in child bearing years -- rather than as an afterthought after years of marketing. Other pharmaceutical companies could take their cue from Glaxo, which has had a pregnancy registry for a long time. To me it reflects some measure of true concern for women and children on their part.”

It was a further suggestion from Dr. Harden that “the FDA might become more aggressive as a public health advocate and require that medications intended for long term use in persons of childbearing potential have a pregnancy registry associated with them.”

Other talks included:
Pregnancy registries: What do they teach us?; AED interactions with oral contraceptive steroids and hormones: How and when to test; and results of the NEADS study.

Formulations and secondary study endpoints

This session on formulations included: Long acting formulations: what is the goal?; Lessons learned in the development of extended-release AEDs: an industry perspective; and Alternate routes for AED administration. The session on secondary endpoints included: Positive effects of new AEDs on cognition and memory; Assessment of the positive psychiatric impact of AEDs; and fixed vs flexible dosing.

After the panel, Joyce Cramer, Associate Research Scientist in the Department of Psychiatry at Yale University School of Medicine told epilepsy.com, “We learned from this panel that formulation is important not just for extended release but also for the type of bioavailability. We also learned that secondary outcomes are not secondary. They are very important assessments of information beyond counting seizures (the traditional endpoint).”

With regard to patient reported outcomes, Ms. Cramer noted: "We are often concerned about patient reported outcomes -- most importantly a patient’s perception of severity and quantity of adverse effects and how these impact on the overall quality of life. All of these factors can be associated with a common underlying depression that colors so much of what is reported.”

As participants reflected on the current challenges discussed throughout Day Two, they looked forward to updates on compounds in development on Day Three that could potentially address these unmet needs.

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