Anticonvulsant Screening Program Report - February 27, 2012

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A report from the NINDS Anticonvulsant Screening Program Working Group, of the National Advisory Neurological Disorders and Stroke (NANDS) Council

February 27, 2012


Program History and Description

The NINDS Anticonvulsant Screening Program (ASP) was established in 1975, as part of a larger Antiepileptic Drug Development (ADD) program that included basic and clinical research, and extra- and intramural components.  The ASP arm was added to address a critical need for new anti-seizure medications and to promote industry interest in their development, and it is the only remaining component of the original ADD program today.  An external vendor was identified, and an ASP contract was awarded to the University of Utah and continuously renewed since the program’s inception (current principle investigator: H. Steve White, PhD; average annual funding 2004-2012: $2.24M).  An internal NINDS ASP program office with a staff of five, led since 2000 by Jim Stables, MS Admin, RPh, oversees the contract and the ASP program.

The anticonvulsant screening process involves researchers from academia and industry in the U.S. and abroad (“ASP participants”) submitting compounds to the ASP for tests of anticonvulsant efficacy in a series of animal (rodent) seizure models.  These tests are performed on a blinded and confidential basis through a written agreement between the NINDS and the ASP participant at no cost to the ASP participant.  The NINDS ASP program office reports test results to participants and provides advice on future development steps for promising compounds, while protecting confidentiality and intellectual property.  Approximately 30,000 compounds have been screened to date, and the ASP has contributed to bringing 9 currently available antiepileptic drugs to market since 1990, with a major role in some and a minor role in others.  In 2007, a second screening track, focused on identifying countermeasures against chemical nerve agent exposures, was added to the ASP contract.  This track is supported separately by the Department of Health and Human Services (HHS), with funds distributed through the NIH Office of the Director (average annual funding 2008-2012: $1.02M). 

ASP Working Group and Review

The overall ADD, including the ASP, was previously reviewed by ad hoc external advisory committees in 1982, 1987, 1992, and 1996.  The current working group (roster below) was formed in May 2011, as a working group of the National Advisory Neurological Disorders and Stroke (NANDS) Council, and was broadly charged with evaluating the effectiveness of the ASP over the last 15 years, considering the program’s value to epilepsy research and drug development within the current scientific and pharmaceutical landscape, and making recommendations for the future of the program, in terms of its focus, strategies, and configuration (charge appended).  The group reviewed data and background information on the ASP compiled by NINDS and convened for a one-day site visit and meeting on October 13, 2011, at the ASP contract site at the University of Utah.  During the meeting, they toured the contract facility, and they heard presentations from and held question and answer sessions with NINDS and ASP contract site staff.  Working group members quickly reached unanimous consensus on overall conclusions and general recommendations for the future of the ASP.  This report summarizes their findings and final recommendations, developed at the October meeting and refined over subsequent conference calls and emailed correspondence.

Overview of Findings

The working group acknowledged that the ASP has been successful in meeting its originally intended goals to facilitate,  accelerate, and incentivize the development of new anti-seizure medications, and that the program continues to contribute to the epilepsy research landscape.  Indeed, since the program’s establishment, numerous new anti-seizure medications have received marketing approval, including drugs with fewer drug-drug interactions, less detrimental hypersensitivity, and improved seizure control in some patients.  However, despite the introduction of new treatments, the issue and magnitude of treatment-resistant epilepsy has not changed substantially:  available treatments still fail to achieve adequate seizure control in an estimated one third of people with epilepsy.  Moreover, no treatments exist to modify the course of disease or prevent its development in those at risk.  The working group therefore recommends that support for the ASP continue at its current level, but that the ASP shift its focus to meet the most urgent current needs, and also adapt to an epilepsy drug development landscape that has evolved considerably over time.  As detailed further below, effective implementation of this shift will require a number of changes to the program’s current organization, operations, and ongoing oversight.

The working group presented this report to the NANDS Council on February 16, 2012. Discussion focused on improving integration between the ASP and other NINDS programs and on possible funding strategies for the program.  The NANDS Council voted unanimously to accept the working group’s recommendations.

NINDS Anticonvulsant Screening Program Working Group, May 2011

Robert E. Pacifici, PhD, Chair and NANDS Council member
CHDI Management / CHDI Foundation

Susan Axelrod
Citizens United for Research in Epilepsy (CURE)

Amy Brooks-Kayal, MD
Children's Hospital Colorado

Henrik Klitgaard, PhD
UCB Pharma

James McNamara, MD
Duke University

Jeffrey L. Noebels, MD, PhD
Baylor College of Medicine

Roy Twyman, MD
Vice President, Global Head of CNS Development
Johnson and Johnson

ASP Working Group Recommendations 

Program mission, leadership, and strategy:

Revise and refine the mission of the program to focus on disease modification, treatment resistant epilepsies, and true comorbidities of epilepsy.  The ASP was established at a time when few antiseizure medications existed and when the pharmaceutical industry had little interest in or incentive for their development.  Since that time, the ASP has made important contributions to the development of several of the currently available antiseizure medications, which together effectively control seizures in as many as two thirds of people with epilepsy.  Now that numerous medications are available, this provides a variety of choices for physicians and epilepsy patients, and the development of additional anti-seizure medications is no longer the most urgent need.  The landscape and incentive structure for industry involvement in this arena have also changed and will continue to evolve.  For adequate reimbursement, new drugs for epilepsy must have proven differentiation with respect to existing drugs or provide an appropriate value proposition for current and future patient needs.  Therefore in order to tackle the unmet medical needs of people with epilepsy, both now and as they evolve in the future, the ASP should shift its focus to:

  • Disease modification, including
    • prevention of epileptogenesis
    • modifying the course or progression of disease
  • Pharmacoresistant epilepsies
    • the remaining one third of cases that do not respond to currently available treatments
  • True comorbidities of epilepsy
    • only target indications beyond seizures that are truly comorbid conditions, as broad indications such as pain and migraine are no longer useful incentives for bringing industry interest to epilepsy drug development 
  • Targeted and optimized interventions
    • specific epilepsy subtypes
    • specific unmet needs within affected populations

Recruit a new leader for the program who can articulate this mission and envision and implement a strategy for its pursuit.  This new direction requires strong scientific leadership.  The leader should hold a medical or doctoral degree in a relevant field, have experience in drug discovery, and understand the current landscape for epilepsy drug development.  S/he should have superior communication skills that will allow him/her to build an effective team at NINDS to oversee the program and integrate it within the broader portfolio of NINDS epilepsy and drug development research programs.  S/he should embrace transparency and encourage scientific exchange regarding the program’s operations with the contract site staff, external advisors, and the broader epilepsy research community.  As a first deliverable, the new leader of the ASP should develop a strategy document for implementing the shift in the program’s mission to focus on disease modification, pharmacoresistant epilepsies, true comorbidities, and targeted and optimized interventions.  In light of the revised mission and focus, NINDS and the new leader may also choose to evaluate optimal staffing and consider renaming the program.

Reshape the ASP as a translational program and integral component of NINDS epilepsy research.  The ASP should continue to provide a drug-screening service to facilitate the identification and development of new drugs.  However, the current screening process should be streamlined (as described below), and the revised strategic direction also requires new processes in order to identify transformational new drugs.  Given that this is a new direction without validated models, the program should strive for continuous improvement of its experimental procedures, animal models, and translational approaches.   The program should also incorporate more opportunities to leverage research activities and scientific expertise, including more scientific coordination between NINDS and the ASP contract site staff, who have broad expertise in epilepsy research to contribute.  In addition, the ASP contract investigators could play an important role in validating preclinical findings or novel epilepsy animal models first developed in laboratories outside of the program, and they could potentially engage in more direct scientific interactions with ASP participants.  (The latter would require revisiting the current ASP-ASP participant agreement process and contract language.)  Moreover, the ASP should be better integrated with other NINDS-supported epilepsy research programs, especially those with a shared focus on drug resistant epilepsy and disease modification, including the new epilepsy Centers without Walls program and other translational and clinical research efforts. 

Develop a clear mission and approach for the CounterACT component of screening, and define its relationship with the ASP.  Since 2007, the ASP contract has included a second track focused on screening compounds that may be effective countermeasures for chemical nerve agents.  This track is supported with funds from HHS made available to the NIH Office of the Director and is part of the NIH CounterACT (Countermeasures Against Chemical Threats) program, a broader NIH effort to develop countermeasures for chemical terrorism threats.  The epilepsy and countermeasures tracks of the ASP have promising synergy for identifying neuroprotective compounds that may also be effective for disease modification or the treatment of pharmacoresistant epilepsy.  However, communication between these two tracks needs improvement.  In addition, the program needs to develop a rationale for selecting compounds for the countermeasures track and a strategy to pursue following positive screening results, as both are currently lacking. 

Program operations and experimental procedures:

Refine the operating procedures of the ASP to allow rational decision making and to maximize the quality of compounds screened.  Currently, the ASP only requires the structure of a compound for submission, and other information – including drug-like properties, pharmacological characteristics, and purported target or mechanism of action – is rarely obtained.  In addition, although program staff searches the ASP database for similar previous submissions to avoid redundancy and to provide some guidance regarding which screening to conduct, the program does not take full advantage of other information about compounds that may exist in searchable chemical databases.  As a result, the NINDS ASP staff members are insufficiently informed to assess the quality or novelty of a new compound relative to existing therapies, and they have no way of optimizing structure activity relationships (SAR) other than iterative rounds of in vivo testing.  Moreover, the current procedures tend to incentivize quantity over quality of submitted compounds, given the free service and limited requirements from participants. 

  • Obtain a more complete biological dataset on submitted compounds, beyond the chemical structure.  This dataset should include some rationale for potential as an epilepsy drug, such as a mechanism of action (MOA) or a target; measures of drug-likeness (PSA, cLogP); pharmacokinetic and pharmacodynamic data (PK, PD); and additional information gleaned from other sources, such as PubChem and CAS.  As some participants may not have the ability to generate these data themselves, NINDS should incorporate means for obtaining them, whether at the main ASP contract site or outsourced elsewhere.
  • Define clear criteria for the inclusion/exclusion of compounds submitted for testing.  Use the dataset described above to exclude compounds that appear redundant to existing drugs, or that are unlikely to have superior efficacy or differentiation.   This more stringent selection process moves away from the current model of broadly screening many compounds in a high throughput model to a more restricted, deep  dataset and more thorough understanding of fewer but more rationally selected molecules.
  • Consider a fee-for-service model.  NINDS and the new leader of the ASP should consider options for charging a fee for participation in the program, at least for non-academic participants.  Such a model would help to offset the costs of the ASP and could further improve the quality of submissions. 
  • Lower the bar for entry into the ASP for pharmaceutical compounds.  Compounds that have already been developed or partially developed for other uses may have promise for indications discovery in epilepsy.

Optimize screening procedures to allow for valid conclusions based on screening results.  In addition to obtaining more data about submitted compounds prior to their selection, further steps would improve the quality of the data generated through screening in the ASP. 

  • Define appropriate procedures for experimental blinding.  Currently, the full contract site staff remains blind to the identity, structure, and any other information about tested compounds, yet they are not blinded with respect to the administration of a compound versus a placebo (if used) or to dosing.  These procedures should be amended so that experimenters are blind to the intervention administered, and also so that at least one member of the contract site staff can access information about tested compounds to guide the use of appropriate screening and bioanalytical methods.
  • Define rationales for key aspects of screening protocols.  With limited information about tested compounds, screening protocols are currently generalized across the program.  Defining a rationale for choices about several aspects of screening would improve the quality of data generated.  These include the species, strain, and age of animals; methods for seizure initiation, termination; recording and typing procedures; group size and active comparator; parameters for adverse effect observations; and treatment dosing and schedule.
  • Define a procedure for pharmacokinetic measures to verify sufficient chronic exposure levels of the experimental compound throughout the treatment period.  Such measures will help to determine whether compounds successfully cross the blood-brain barrier, so that negative results do not reflect the inability of a compound, or an active metabolite, to access the brain.

Determine and implement a process for selecting or developing new models for incorporation into the ASP.  Continuing to use the existing models designed for the identification of anticonvulsant compounds is unlikely to lead to novel treatments targeting the most critical current needs.  New models should more closely replicate clinical epilepsy syndromes, allow testing against known biological targets, and facilitate the development of therapeutics targeting pharmacoresistant epilepsy, disease modification, and specific epilepsy subtypes.  NINDS and the new leader of the ASP should develop a strategy for incorporating new and emerging models into the program.  Potential options include:

  • Task the contract site team with identifying redundant assays and with exploring novel assays for antiepileptogenesis, pharmacoresistant epilepsy, and pediatric and genetic epilepsies.  
  • Task an external group of experts with identifying, critiquing, and prioritizing novel genetic models, including non-mammalian models.
  • Partner with other academic laboratories to develop and validate new screening models.
  • Hold a workshop for broader recommendations and input regarding epilepsy models.

Explore precompetitive and other options for making data on submitted compounds available.  Data on over 30,000 compounds submitted to the ASP remains largely unavailable for research use due to confidentiality agreements with participants.  Moving forward, NINDS should consider changes to the current ASP participant contract to facilitate expanded access to data in the future.  For example, confidentiality could be time-bounded, or data could be presented in a de-identified form.  In addition, NINDS should explore options for making existing data available to the extent possible, while respecting the need to protect intellectual property.  This should include options for reporting screening results for submitted compounds (past and future), with a goal to provide transparent and timely information that has utility beyond knowing whether a tested compound ultimately reaches the clinic.  Mining these data could provide insights into mechanisms of action and reasons for success or failure in ASP models or in later drug development stages, which could suggest new targets to pursue.

Program oversight and evaluation

Establish an external advisory body that can oversee changes to the ASP, provide ongoing scientific and strategic guidance, and monitor progress.  The current ASP working group could serve as the core of such a body, and new members should be added with appropriate expertise to assess potential new models and assays for the program.  NINDS should establish regular scientific meetings between this oversight body and ASP leadership and staff to assess progress, monitor the ongoing value of the program, and discuss future directions.

Develop processes and metrics for tracking program progress.  Metrics should allow NINDS and external advisors to monitor program operations and outcomes on an ongoing basis. They should not focus exclusively on operations (processing and screening of submitted compounds), but on deliverables such as the outcomes of testing and the usefulness of data generated, whether screening results are positive or negative.  These metrics should be built into ASP procedures, reported regularly, and tied to performance evaluations of ASP staff.

Charge to the NINDS Anticonvulsant Screening Program Working Group

Background: In 1975, the NINDS established the Anticonvulsant Screening Program (ASP) to promote the development and evaluation of new anticonvulsant drugs.  The ASP provides a resource for academic and industry investigators from the U.S. and other countries.  The ASP tests compounds submitted by these investigators in several standardized animal seizure models and provides results and advice on further drug development, while protecting confidentiality and intellectual property rights. The testing is performed via contract at the University of Utah.  The NINDS ASP staff convey the test results and provide advice to ASP participants.  NINDS staff also create and maintain a database of chemical structures and test results that is designed to provide insights on structure activity relationships. 

The Epilepsy Research Benchmarks, which present the goals of the epilepsy research and patient community, provide a broad frame for consideration of the ASP role.  In particular, the working group should note that the goals of the epilepsy community have evolved since the ASP began, with increased emphasis on preventing the development of epilepsy, on treatment of resistant epilepsy, and on co-morbid conditions.  Likewise, there have been significant changes in many relevant scientific areas, in drug development technology, and in private sector and NIH supported drug development programs generally.

Purpose of the Working Group: The ASP was reviewed by different external advisory groups in 1982, 1987, 1992, and 1996, but has not been reviewed for the last 15 years.  Hence, the current working group has a broad mandate to advise NINDS on the effectiveness of the ASP over that period, on the value of the program within the current scientific and drug development landscape, and on what the Institute should be doing to promote preclinical epilepsy drug development in the current context.  

In particular, the Working Group should:

  • Evaluate the drug screening contract of the ASP over the last 10 years, and, more importantly, whether the program has adapted sufficiently to the current scientific, technical, and drug development context.
  • Consider the performance and value of the NINDS staff-directed components of the ASP program, including the advisory role and structure-activity database efforts.
  • Advise the NINDS on the scope, configuration, and scientific strategies of its future commitments in preclinical epilepsy drug development and the role of the ASP.     
  • Working Group Composition:  The Working Group will include 7 members, all from outside the NIH, including one member of the NANDS Council.  Their collective experience brings expertise in adult and pediatric epilepsy, in drug development generally, and in the interests of the epilepsy patient advocacy community.  A roster of members and their relevant affiliations is attached at the end of this document.

Advisory Panel Activities and Deliverables:

  • The Working Group will work closely with NINDS staff to identify data or other background requirements that will help the Group formulate its recommendations to the Institute.  The NINDS staff will serve as the Group’s liaison to the Institute, providing data and other support to the Group.
  • The Group will conduct a site visit of the Utah contract activities of the ASP.
  • The Group may conduct additional virtual or in person interviews with NINDS site staff as the Group determines appropriate.
  • The Group may discuss and deliberate among themselves via conference calls, email, or other means as they deem appropriate, with or without NINDS staff participation.  If the Group determines that an in person meeting in addition to the Utah site visit is appropriate, NINDS will organize such a meeting.
  • The final product of the Group will be a written summary report and a set of recommendations to be delivered in 2012. Since this is a working group of the NANDS Advisory Council, the report will be presented in open session.