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PRO-ACT: Bigger and Better ALS Database Open for Mining

By Deborah Borfitz 
May 10, 2013 | Amyotrophic lateral sclerosis (ALS) research is getting a major boost from a newly launched Pooled Resource Open-access ALS Clinical Trials (PRO-ACT) platform, which has amassed more than 8,500 de-identified clinical patient records into a single, harmonized dataset. Multiple pharmaceutical companies are now actively exploring PRO-ACT, seeking ways to streamline clinical trials and develop better treatments for the rare and highly heterogeneous disease more commonly known as Lou Gehrig’s disease.
For jointly developing PRO-ACT, the Neurological Clinical Research Institute (NCRI) at Massachusetts General Hospital and Cambridge-based nonprofit Prize4Life share the 2013 Bio-IT World Best Practices Award in the clinical and health IT category. PRO-ACT took nearly two painstaking years to bring to fruition, with funding from the ALS Therapy Alliance, says Alexander Sherman, director of strategic development and systems for NCRI.
A subset of the data last year turned up potential new ways to predict ALS progression early on in the disease, when Prize4Life went crowdsourcing for solutions, says Chief Scientific Officer Melanie Leitner. The algorithms, once validated, could increase the likelihood of future ALS clinical trial success as well as reduce the required number of trial subjects by 23%.
Currently, only five industry-sponsored trials and another 20 or so smaller academic ones are testing remedies for the life-robbing disease in ways ranging from stem cells and viral vectors to drugs and devices—even exercise and diet modifications.  While these trials are designed to demonstrate the efficacy of a particular intervention, they are individually too small to reveal disease patterns by age, gender, or many other defining patient characteristics. 
Merging multiple clinical trial datasets makes those sorts of correlations statistically possible, say Leitner. Disease biomarkers also become more easily identifiable. Some ALS patients (like Lou Gehrig) die within two years and others (like Stephen Hawking) survive for decades. Once progression speed can be predicted, trial design can start to reflect those basic differences.
Information gets organized in PRO-ACT using a disease-specific Common Data Structure (CDS) built according to Common Data Elements used by research consortia and recommendations by the National Institute of Neurological Disorders and Stroke, says Sherman. The platform allows for any necessary re-assignment and sharing of data fields between multiple data elements.
Data curation and mapping is enormously time-consuming given that donated datasets arrive with their own data structure and semantics, and in some cases lack data dictionaries entirely, Sherman adds. The exercise can take anywhere from several weeks to half a year. As the CDS itself may potentially change because of new guidelines and discoveries, PRO-ACT allows those changes to be implemented without data re-importation.
Repurposed Data 
Data from 18 completed ALS clinical trials have to date been donated to PRO-ACT, 13 from four pharmaceutical companies (Sanofi, Regeneron, Teva Pharmaceuticals, and Novartis) and the remainder from academic sites participating in the Northeast ALS (NEALS) consortium. Industry provided valuable treatment-arm as well placebo data. Decades of ALS research have resulted in only a single FDA-approved drug, in the mid-1990s, and many companies have abandoned the effort, says Leitner. “So PRO-ACT gave the data donors the opportunity to do something good with the investment they’d made.”
Prize4Life has a seven-year working relationship with NCRI, the coordinating center for the 104-site NEALS consortium. Clinical datasets from NEALS trials, including more than 60,000 bio-samples from ALS patients as well as disease and healthy controls, have always been freely distributed for legitimate research purposes, says Sherman. PRO-ACT essentially takes that concept to the crowdsourced level.
Users of PRO-ACT currently number 125 and are rising “almost daily” in advance of major outreach efforts, says Leitner. Most of them are neither ALS clinicians nor medical researchers, but biostatisticians and others with quantitative expertise.
Anyone with a valid research purpose who agrees to basic terms and conditions (i.e. no data repackaging and reselling) can download the database or portions thereof from the Prize4Life PRO-ACT website, says Sherman. Data subtypes include demographics, family history, laboratory, vital signs and ALS functional measures, and mortality. PRO-ACT currently contains over eight million longitudinally collected data points, inclusive of nearly 1.7 million laboratory test results, ten times the number previously available from NEALS.
Sponsorship Needs 
PRO-ACT is poised for substantial growth, with at least seven other datasets yet to be added and industry as a whole being noticeably more collaboration-minded, says Leitner. Data from a recently completed phase III ALS trial by Biogen Idec may add between 500 and 1,000 subject records to PRO-ACT by the end of the year. Some other ALS solicitation efforts are being slowed by recent merger and acquisition activity, making the necessary permissions difficult to come by and throwing data possession rights into question.
Charitable funding is being sought to cover the estimated $500,000 annual cost of soliciting, cleaning, and harmonizing data for import into PRO-ACT, says Sherman.  Future ALS trials designed to harmonize with the CDS used by PRO-ACT will make it easier to import resulting datasets into the platform.  
PRO-ACT is expected to promote collaboration among academic researchers as well as between academia, nonprofits, and industry. It can be used as-is by researchers to learn about neurodegenerative diseases other than ALS, says Sherman. But to benefit the more than 7,000 other rare diseases in the U.S., the concept will need to be replicated many times over.
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    Thank you. My mom became a victim of ALS for over ten years. Pro-Act is the best news I have heard ever for families of ALS. Steven H is my hero. Thank you so much. I wish you the very best. Mary Lou

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