C-Path Multiple Sclerosis Outcome Assessments Consortium

ASENT February 20, 2014 Richard Rudick, M.D. (Co-Director, MSOAC) Mellen Center for Multiple Sclerosis Cleveland Clinic

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

MSOAC Engages Many Stakeholders

• 43 member international organization • 10 pharmaceutical companies • 27 academic medical centers • 6 MS patient advocacy organizations • Created and managed by C-Path with funding and input from the National MS Society (NMSS).

• FDA Liaison, Dr. Marc Walton • EMA Advisor, Dr. Maria Isaac • MSOAC Co-Directors: • Richard Rudick, M.D., Cleveland Clinic • Nicholas G. LaRocca, Ph.D., NMSS • Lynn Hudson, Ph.D., C-Path

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Mission of MSOAC

MSOAC will develop and support adoption throughout the MS community (patients, clinical investigators, pharmaceutical industry, regulatory agencies, and advocacy groups) of a clinical outcome assessment tool (COA) for future MS clinical trials.

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Purpose of the planned COA The purpose of this COA will be to reflect the impact of an intervention on the disability due to MS. MSOAC will obtain regulatory qualification of the COA for registration trials. Therefore, the COA must be useful for demonstrating clinical, and clinically meaningful, change due to MS.

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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• • •

MSOAC Project Focus

Primary outcome measure for interventions targeting the disease process (not symptom Rx) Selected quantitative neuroperformance measures related to functions directly affected by MS and important to patients Certain symptoms (pain, fatigue, sexual dysfunction, depression, etc) contribute to overall burden of MS, but these are not objectively measurable by observers, so are not intrinsic to the planned COA

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Guidelines for COA Components

1.

2.

3.

4.

5.

Multidimensional (reflect key aspects of MS) Objectively measurable by trained observers Have high reliability (precision), and high validity, including importance to the patient Change over time to permit demonstration of a therapeutic effect Be acceptable to patients, practical, and cost-effective

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Why Do We Need This?

• • Traditional measures – relapse and EDSS – are imprecise, subjective, and have uncertain relationships to the underlying disease process and concept of interest Quantitative neurological and neuropsychological performance testing have favorable psychometric properties and offer an alternative to clinician rating scales

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Framework For Performance Measure for MS Clinical Trials

1. Target Population People with Multiple Sclerosis 2. Concept of interest

A B C

“Disability”

E F

3. Examples of Activities of Daily Living Limited by Disability in MS 4. Bodily Functions Involved in Activities of Daily Living Walking quickly to make an appointment Walking 5. Sub-components of Bodily Functions Speed Keeping up with conversations Higher Level Cognitive functions Remembering to take medications Reading a newspaper Seeing functions Using a knife and fork, writing, using a computer keyboard Muscle Power functions Control of Voluntary Movement Pace of Thought Memory Attention Acuity Fine Hand Use Eye-Hand Coordination 6. Method of measurement (examine options) 7. Generation of measurements 8. “Validation” and Interpretation T25FW SDMT CVLT BVRT 7/24 SRT LCVA Disability measurement (score) 9-HPT Meaning of scores, changes, and differences Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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• • •

Multiple Sclerosis Functional Composite

Rudick, Antel, Confavreux, et al.

Annals of Neurology,

1997 An International NMSS Task Force recommended the quantitative neuroperformance assessment as an alternative to clinician rated outcomes Recommended a 3-part “Multiple Sclerosis Functional Composite”    Walking:

Timed 25-Foot Walk (T25FW)

Manual Dexterity:

9-Hole Peg Test (9HPT)

Cognitive Function:

Paced Auditory Serial Addition Test (PASAT)

Recommended these and other neuroperformance measures be included in clinical trials

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Response to this Recommendation

More than 30 clinical trials and countless clinical studies incorporated the MSFC or its components, providing >15 years worth of prospectively collected data on the MSFC A large collection of datasets containing MSFC, and other outcomes (EDSS, QoL, MRI, relapses, etc.). This data has not been fully analyzed

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Data Acquisition Status

Study

Dose Comparison ACT DEFINE CONFIRM MSCRG AFFIRM SENTINEL CHOICE CombiRx

n

802 313 1237 1232 301 942 1171 230 1008 FREEDOMS FREEDOMS 2 TRANSFORMS CARE-MS 1 CARE-MS 2 TEMSO IMPACT MAESTRO Olympus PROMISE 1272 1083 1153 581 840 1088 436 596 439 943 MS Study Group CUPID Fampridine-SR

Total = 22

547 493 240 IFNß-1a IFNß-1a + MP + MTX BG-12 BG-12 IFNß-1a

Drug

Natalizumab Natalizumab Daclizumab + IFNb-1a IFN+GA Fingolimod Fingolimod Fingolimod Alemtuzumab Alemtuzumab Teriflunomide IFNß-1a Dirucotide (MBP8298) Rituximab GA Cyclosporine Dronabinol Fampridine-SR

MS Type

RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS RRMS SPMS SPMS PPMS PPMS PP/SP PP/SP All

EDSS

√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √

16947 subjects FSS

√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ No ?

√

25FW 9HPT PASAT LCVA SDMT Imaging

√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ ?

√ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ ?

?

√ √ ?

√ √ ?

√ No √ No √ √ No √ No ?

No No No No No No No No ?

√ No No No No No No No No ?

No ?

?

?

?

?

Yes ?

?

?

?

?

?

?

?

No ?

Yes ?

Yes No √ √ No √ ?

No √ ?

No No ?

QENF No ?

MRD, AI √ √

Received In-process PRO

?

?

√ √ √ √ √ ?

√ EQ5D,MFIS,Primus EQ5D,MFIS,Primus EQ5D,MFIS,Primus FAMS, SF-36 FAMS, SF-36 FAMS, SF-36 √ √ ?

MSQLI ?

MSIS-29-Phys √

Contacted PRO Instruments: MSIS-29-PHYS: MS Impact Scale - 29 items, FAMS, SF-36A, MSQLI: MS Quality of Life Inventory- 10 individual scales MFIS - Modifed Fatigue Impact Scale, EQ5D - Euro-QOL, PRIMUS - Patient Reported Indices in MS Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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MSOAC Project

1.

2.

3.

4.

Create CDISC Standard for MS, based initially on elements from the NINDS MS CDE project Create a pooled data set from completed clinical trials containing traditional clinical outcomes (relapses and EDSS), neurological performance measures (e.g. MSFC), and patient reported outcomes Analyze pooled data set to determine components of a neuroperformance based composite outcome measure, and recommended approach to using the composite outcome Seek regulatory approval of a new MS outcome measure Confidential

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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Current Status

1. MS CDISC standard V1.0 completed, being reviewed internally 2. Completing data sharing agreements with pharma and academic investigators 3. Mapping data sets to the CDISC standard to create a pooled data set for analysis 4. Preparing a comprehensive literature review 5. Formulating statistical analysis plan

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

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MSOAC “Deliverables” and implications

1. CDISC data standard for MS: Will improve ability to compare data across studies, to interpret findings, and to analyze pooled datasets. 2. A database of pooled, de-identified clinical trial data mapped to the CDISC standard: Will allow studies of clinical outcomes assessment tools, disease modeling, and potentially imaging or biomarker studies.

3. A new methodology to measure performance: Could provide approved disability endpoint in future MS clinical trials. 4. Use of the EMA and FDA outcome measure qualification pathways: Will provide an example for other groups interested in pursuing better outcome measures through regulatory sciences

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MSOAC Publications and Press

Multiple Sclerosis Outcome Assessments Consortium: Genesis and initial project plan

Richard A. Rudick, Nicholas LaRocca, Lynn D. Hudson and MSOAC

Mult Scler Journal,

published online 20 September 2013

The Multiple Sclerosis Outcome Assessments Consortium: Bringing the Community Together to Shape the Future of Multiple Sclerosis Drug Development

Janet Woodcock and Anne M. Rowzee

Therapeutic Innovation & Regulatory Science,

published online 12 September 2013

An Expanded Role for Patients in Clinical Trial Design

Anne M. Rowzee and Stephen Spielberg http://dij.sagepub.com/site//misc/index/podcasts.xhtml

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)

MSOAC Collaborators

Industry Members Partners

MSOAC Coordinating Committee Members

Jane Haley Matthew Sidovar Craig Sherburne Jacob Elkins Gilmore O'Neill Sanjay Keswani Tanuja Chitnis Jeff Cohen Deborah Miller Richard Rudick Lynn Hudson Krystal Elms Ann Robbins Bess LeRoy Gary Lundstrom Jon Neville Maria Isaac Geoffrey Dunbar Kathy Smith Marc Walton Irina Antonijevic Jennifer Panagoulias Michael Panzara Paul Thompson AbbVie Acorda Alberta MS Research Foundation Biogen Idec Biogen Idec BMS Brigham and Women’s Hospital Cleveland Clinic & ECTRIMS Cleveland Clinic Foundation Cleveland Clinic Foundation C-Path C-Path C-Path C-Path C-Path C-Path EMA EMD Serono Fast Forward (NMSS) FDA Genzyme/Sanofi Genzyme/Sanofi Genzyme/Sanofi GSK Paul Matthews Ellen Mowry Fred Lublin Timothy Coetzee Nicholas LaRocca Weyman Johnson Ursula Utz Frank Dahlke Gordon Francis Laura Balcer Jeremy Hobart Donna Masterman Bruno Musch Giancarlo Comi Joshua Steinerman Volker Knappertz Elizabeth Morrison Raj Kapoor Gary Cutter Ralph Benedict Maria Pia Sormani Rob Motl Brenda Banwell Bernard Uitdehaag Imperial College London Johns Hopkins Mt Sinai National MS Society National MS Society National MS Society NINDS Novartis Novartis NYU Plymouth Hospital Roche/Genentech Roche/Genentech Scientific Institute H.S. Raffaele, Italy Teva Teva UC Irvine UCL Institute of Neurology University of Alabama University of Buffalo University of Genoa University of Illinois University of Pennsylvania VU University Medical Center

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DISCUSSION OR QUESTIONS

Multiple Sclerosis Outcome Assessments Consortium (MSOAC)