•         2-3 per 1000 newborn babies

•         About 10,000 babies born every year in USA

•         Cost in 2002 for USA patients $ 8.2 billion.

•         over 800,000 Americans are impacted by Cerebral Palsy

•         Average cost $921,000 (2003) per CP patient in a lifetime.

                                         

                

Life long consequences

      

•Burden on individual

•Burden on society

•Burden of disease:  

-loss of years

-loss of productive years

-effort of caretakers

-effect on young parents and disrupting promising careers of parents

-effect on siblings

                                                   

Disproportion of Allocation of Resources

• Funding for CP from NIH as a 2010 estimate: $24 million, approximately one-eighth of that for one neurodegenerative disease such as Parkinson’s disease.

• All neurodegenerative diseases got $1,762 million from NIH in 2010.

                                           

 

Costs are an Underestimate

•Productivity is affected even more because parents are usually young and their careers get affected.

•Siblings are affected also for lack or attention.

 

Who will speak for the Children?

•Children do not vote. They are victims of political expediency. Budget cuts always fall disproportionately on children.

•Parents are too tired to be vocal advocates.

•Collective voice can only come from all those who deal with children. 

 

Parents want a Cure Now!

•There is a long process from laboratory studies to FDA approval to clinical trials to successful completion of clinical trials to getting enough evidence to sway clinicians. This is the lesson learnt from the experience with hypothermia. Even with hypothermia, there is a baseline of injury that does not go away.

• To speed up the process, one must divide the problem and focus on things that make a difference.

• One can learn from lessons learnt on common mechanistic pathways from hypoxic-ischemic encephalopathy and traumatic brain injury.

Why does it take so long?

• Animal studies take years to develop. Validation in larger animals models take years to develop.

• FDA approval takes time and lots of money.

• Clinical trials take long and are expensive. Typically, clinical trials take at least 2-3 years to plan, 3 years to collect data, 1 year to analyze, 6 months to publish.

 

•     

 

Choosing Therapies is Haphazard Right Now

• FDA off label drugs need to be handled differently from non-FDA approved therapies. Many promising FDA approved drugs are “left on the shelf” and not studied.

•The best neuroprotectant is not necessarily studied at the end.

•The best approach may not be chosen. Approaches are somewhat empirically decided.

•Institutions are interested in “bricks and mortar” development.

•Investigators have to develop their career by developing their individual niche.

•Everybody has their pet neuroprotectant. Individual scientists have their personal agenda.

•Many scientists consider it reasonable to make a leap of faith from rodent studies to humans.

Problems with Pharmaceutical Industry

•Development of new therapies requires a “profitability coefficient” for industry.

•In general, pharmaceutical industries are not interested in drug development for the perinatal area for many reasons such as the malpractice climate and unprofitability. Babies do not have disposable income.

Solutions

•Phase II trial design using Futility Design for faster drug development

•Surrogate markers for ruling out drugs.

•Hershey Conferences help every two years to discuss the progress

•Stem cells are the rage right now.

•Need to develop a 2 year and a 5 year plan

•Timing is everything. This is the biggest unknown factor. Assumption is made that birth is time 0 for neuroprotection.

•Antenatal period may be affected also. Need to develop a non-invasive marker for detecting injury. Fetal MRI is a possibility.

•Biomarker development necessary for both antenatal and postnatal periods.

 

Basis of CP-CPR

 

1) To facilitate the close collaboration of scientists and clinicians.

2) To form a Center without needing to build a bricks-and-mortar building. A virtual Center. The Center will facilitate interactions by the latest telecommunication portals.

3) The Center will be a combination of a think-tank with an implementation network.

4) Center should be fast and nimble.

5) Simultaneous study in many animal models especially in those that have direct translational applicability. Explain deficiencies of animal models.

 

CP-CPR was formed by a group of clinicians and scientists in an effort to speedup up the process of getting useful therapies to patients. It has no connection to any lawyers. The purpose of CP-CPR is to find a cure for cerebral palsy and make the speedy availability of a cure for patients and parents.

 

Objectives of CP-CPR

 

1) Facilitate prioritizing therapies.

2) Encourage investigators to forgo their personal agendas.

3) Conduit for conducting studies investigating prioritized therapies and submitted by any laboratory in the world

4) To provide timetables for moving the translational research into the clinical realm.

5) To obtain funding for translational research.

6) Provide a conduit of funds to the various members and their respective institutions.

7) Provide a conduit for Registry of new therapies.

8) Learn from the experience from other disease groups do it. Adoption of STAIR guidelines is an example.

 

Proposed Framework of the First Project to be Tackled by CP-CPR

•Study of stem cells.

•Types of stem cells.

•Studies  done on stem cells for prevention or therapy for CP.

•Animal models to be tested simultaneously:

–Mice

–Rabbits

–Piglets

–Sheep

–Non-human primates

 

Guidelines for Number of Animal Models

 

It is not possible to be sure exactly how many and what sort of preclinical studies are needed before we embark on human controlled trials. Looking back at successful and unsuccessful attempts to translate therapies, key limitations have been use of models that do not accurately represent clinical conditions and pathogenesis of brain ischemia, failure to follow up promising early finding with long-term functional and histological outcome, lack of information on other nonneural effects, and in retrospect, critically, insufficient intra- or postischemic temperature monitoring and control (see review by DeBow and colleagues). No single paradigm or study can provide all of these key endpoints, and particular models will be better suited to examining one or the other. Rodent studies are inexpensive, and lend themselves to long-term follow up, however, rodents have simple lissencephalic brain with little white matter, very accelerated neurodevelopment compared with larger animals, and because of their size it is difficult to monitor more than a few parameters at a time. Conversely, large animal studies are expensive, slow and for most species there is limited experience in behavioral monitoring, but their brains are far more complex, and comparable to the human brain, and detailed brain and systemic monitoring is readily accomplished.

We propose that three high quality studies addressing the major technical requirements for neuroprotection, including at least two nonrodent studies from different species and from different groups, plus at least one long-term follow up study in a relevant rodent paradigm, in addition to promising results from screening studies in small rodent studies, would represent a reasonable minimum to support human trials of neuroprotection.

DeBow SB, Clark DL, MacLellan CL, Colbourne F Incomplete assessment of experimental cytoprotectants in rodent ischemia studies. Can J Neurol Sci. 2003; 30(4):368-74

 

CP-CPR members

Janice E. Brunstrom-Hernandez, M.D.

Associate Professor of Neurology and Pediatrics

Director, Pediatric Neurology Cerebral Palsy Center

Washington University School of Medicine

St. Louis Children's Hospital, St. Louis, MO

 

Alistair Jan Gunn

Professor, Physiology and Paediatrics

Head of Department, Department of Physiology,

Faculty of Medical and Health Sciences,

The University of Auckland, Auckland, New Zealand

 

Sandra Juul, MD.

Professor of Pediatrics

Associate Division Head for Scholarship and Research

Department of Pediatrics

 University of Washington Seattle, WA

 

Carina Mallard

Professor

Perinatal Center

Dept Neuroscience and Physiology

Sahlgrenska Academy

Gothenburg University

Gothenburg, Sweden

 

Nicola J Robertson, MB ChB, FRCPCH, PhD

Reader in Translational Neonatal Medicine

& Honorary Consultant Neonatologist

EGA UCL Institute for Women's Health, London UK

 

Sidhartha Tan, MD

Clinical Professor

Department of Pediatrics

NorthShore University HealthSystem and University of Chicago

Evanston, IL