Transcript AED IX: an antiepileptic drug meeting

AED IX: an antiepileptic drug
meeting
Jacqueline A. French, M.D.
Department of Neurology
University of Pennsylvania
AED meeting: The beginning
• Meeting began in 1991, as a practical
“how to” course on performance of AED
trials
– Emphasis on regulatory, contracts, hiring coordinators, etc
The Present
“With nine new AEDs already approved, there is
a unique opportunity to learn from the past as we
move into the future. This symposium will bring
together representatives from academia, industry,
the NIH, and the FDA to review what has been
learned and to discuss strategies to enhance
AED development.”
www.aedtrials.com
Format
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3 day freestanding meeting
25-30 faculty
150-200 participants
Support:
– Registration fee
– Independent grants from Pharma, device
companies
Format
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20 minute talks
Long discussion sections
Round-tables
Final day: Drugs in Development and
“CNS/Epilepsy company Forum”
– Partnership & Financing Opportunities in
Epilepsy and CNS: Corporate and VC
Perspectives
• From the first meeting, the following
elements were present:
– Basic scientists involved in translation
– Thoughtful presenters who were involved in
active clinical trials
– Europeans and US
– Industry representatives
– FDA representation
– NIH
Written Output
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2 Books
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French, J.A., Dichter, M.A., Leppik, I.E. (eds)
Elsevier 1993. New Antiepileptic Drug
Development: Preclinical and clinical aspects.
Epilepsy Research Supplement 10, 1993.
French, J.A., Leppik, I.E., Dichter, M.A. (eds)
Lippincott-Raven Advances in Neurology:Volume
76, 1997, Antiepileptic Drug Development
Conference Proceedings
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Epilepsy Research, Volume 68 pp19-94, 2006
Topics that have been emphasized
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Animal Models: Translation to human studies
Proof of principle trials
Outcome measures
Special populations
– Women
– Elderly
– Children
• Drugs in the pipeline
• Monotherapy
Animal Models
• Relationships of effective dose in animal
models vs human trials
• Validation of new animal models
• Anti-epileptogenesis
Proof of Principle
• How to determine:
– Brain penetration
– Effect on epileptic activity
– Spectrum of activity
– Appropriate dose range
• Before moving to larger trials
Outcome measures
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Is seizure counting enough?
Seizure severity
Quality of Life
Mood
Special Populations
• Elderly
– Are trials necessary?
– How do metabolism, absorption differ?
Children
• What is ethical in regards to studies in
infants?
• What are current FDA regulations?
• How to get pediatric exclusivity
PEDIATRIC EXCLUSIVITY
(Russ Katz, 2002)
• TYPICALLY, WE HAVE ASKED FOR ONE
OR TWO CONTROLLED TRIALS, SAFETY
DATA, PHARMACOKINETIC DATA
• PHARMACOKINETIC DATA TYPICALLY
CAN COME FROM FORMAL STUDIES OR
FROM THE CONTROLLED TRIAL(S)
• EXCLUSIVITY IS INDEPENDENT OF THE
RESULTS OF THE TRIAL(S)
Monotherapy
• Approval of new AEDs as monotherapy
lagging behind general approval
• Reason: conflict between rigorous
scientific methodology and
ethics/feasibility
– Placebo-control, and “superiority studies are
preferred, but not ethical
HISTORICAL CONTROL
• Instead of using placebo as control group,
use “expected” behavior of placebo, based
on prior trials
• Not the same as “natural history”, because it
is linked to a specific trial design and
population.
• Acceptable (barely) to FDA
• We looked at existing data from trials to
generate a historical control, to validate use
of active control equivalence studies
40
• T
• A
% seizure free
• HC
Treatment
Historical control: Current status
• FDA has confirmed that if new AED beats
the “bar” in a properly conducted historical
control study, they will grant monotherapy.
In summary, why is it useful?
• Bouncing ideas off each other
• Bouncing ideas from basic scientists to
clinicians (and back)
• Bouncing ideas off FDA