IMPACT OF THERAPEUTIC AREA-SPECIFIC DATA STANDARDS FOR PARKINSON’S DISEASE��

Jon Neville1, Steve Kopko2, Joanne Odenkirchen3, Wendy Galpern3, Ken Marek4, David Burn5, Yoav Ben-Shlomo6, Donald G. Grosset7, Matthew Farrer8, Klaus Romero1, Enrique Avilés1, Sue Dubman9, Mark Forrest Gordon10, Arthur Roach11, Diane Stephenson1

(1) Critical Path Institute, (2) Clinical Data Interchange Standards Consortium, (3) National Institute of Neurological Disorders and Stroke, (4) Institute of Neurodegenerative Diseases, (5) Institute of Neuroscience, Newcastle University, (6) SSCM, University of Bristol, (7) Institute of Neurological Sciences and University of Glasgow, (8) University of British Columbia, (9) University of California, San Francisco,�(10) Boehringer Ingelheim Pharmaceuticals, Inc., (11) Parkinson’s UK

Critical Path Institute (C-Path) has played a leadership role in developing consensus data standards and fostering precompetitive data sharing for multiple diseases. These actions are key to the success of future clinical trials. The Coalition Against Major Diseases (CAMD), one of C-Path’s consortia, in partnership with the Clinical Data Interchange Standards Consortium (CDISC), and the National Institute of Neurological Disorders and Stroke (NINDS), has successfully developed consensus data standards for Parkinson’s disease (PD). These therapeutic area-specific standards represent the preferred format by regulatory agencies for submitting new drug applications. Standards are key in data integration, pooling and analyses of diverse data sources (Kush and Goldman, 2014), and have contributed significantly to platforms that have advanced Alzheimer’s disease (Neville et al., 2015).

1CDISC PD Therapeutic area user guide: www.cdisc.org/therapeutic 2http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm268555.pdf3www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm230597.pdf 4www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072339.pdf5http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ucm434382.htmKush, R. & Goldman, M. (2014). Fostering responsible data sharing through standards. N Engl .J Med., 370, 2163-2165.Neville, J., Kopko, S., Broadbent, S., Avilés, E., Stafford, R., Solinsky, C. M., Bain, L. J., Cisneroz, M., Romero, K., Stephenson, D. Development of a unified clinical trial database for Alzheimer's disease. Alz & Dem, 2015 Feb 9. [Epub ahead of print].

Background and Objectives

Acknowledgments: We acknowledge the following colleagues for their participation in the PD data sharing meeting for their contribution to the roadmap shown in Figure 6:  Michele Hu, University of Oxford, Neurology Department; David Burn, Newcastle University, Newcastle; Caroline Williams-Gray, University of Cambridge; Yafit Stark, Teva Pharmaceutical Industries, Israel; Marg Sutherland, NINDS, Bethesda, MD. The authors thank the following experts for their contribution to the development of the NINDS CDEs: Dr. Caroline Tanner, UCSF, San Francisco, CA; Dr. Karl Kieburtz, Univ. Rochester, NY; Dr. Glenn Stebbins, Rush Univ., Chicago, IL. This work was partially funded by FDA grant #5U01FD003865.

Methods

A coalition of academic experts, NINDS, industry members, regulatory agencies, and patient advocacy groups collectively developed data standards in partnership with CDISC. With input from clinical subject matter experts (SMEs) and NINDS, working groups of data standards experts mapped clinical concepts relevant to PD to the CDISC Study Data Tabulation Model (SDTM) and developed controlled terminology to support the construction of standardized databases for research and regulatory submission in PD clinical trials. CDISC PD Therapeutic area user guide: www.cdisc.org/therapeutic.1

Figure 1: NINDS Common Data Elements (CDE) were developed in consensus by teams of clinical subject matter experts. These CDEs served as the inputs to the CDISC Parkinson’s disease V1.0 standard. http://www.commondataelements.ninds.nih.gov/PD.aspx

Figure 2: Relationship between CDEs and data standards highlighting the similarities and differences in the roles they play throughout the various stages of a study. CDE=common data elements; SAP=statistic analysis plan; CRF=case report forms.

Figure 4: FDA guidance documents provide either non-binding advice (Imaging and drug-development tools) or binding guidance (Electronic submissions of data) to study sponsors on issues related to regulatory submissions.

Figure 5: Recent letter of support5 from FDA encouraging the prospective collection of DAT in PD studies, including recommendations for using PD CDISC standards.

ConclusionsFigure 3: Examples of CDISC SDTM domains. Standards development projects make use of existing domains where possible, and develop new domains to represent types of data not previously covered. There are currently more than 40 published SDTM domains.

References

Table 1: Concepts new to CDISC SDTM that were identified as part of Parkinson’s v1.0 development. Concepts are organized by the SDTM domains in which these types of data are represented.

Integration of Modeling and

biomarkers

Disease progression plus SWEDD data

Model-based clinical trial enrichment strategy

Regulatory endorsement: industrial and regulatory application

Disease progression plus genetic and MRI

Comprehensive disease

progression model

• Drug effects (active arms)

• Placebo effect (control arms)

• Drop-out model (both)

Comprehensive clinical trial simulation tool

Regulatory endorsement: industrial and regulatory application

Observational RCTOxfordDC

Tracking PD

CamPaING

PPMI

PDBP

ADAGIO

DATATOP

OTHERS...

PRECEPT

Results

The use of consensus data standards maximizes efficiency in regulatory review and facilitates analyses across diverse studies. Importantly, CDISC standards will be required by FDA for regulatory submission as early as fiscal year 2017. These standards foster the collection of clinical trial data and the integration and analysis of existing or anticipated data across various stakeholders’ systems independent of the particular platform. The PD CDISC TAUG is readily available to sponsors, data scientists and researchers for wide implementation (http://www.cdisc.org/therapeutic)1; TAUG= therapeutic area user guide.

> Parkinson's Disease

Parkinson's Disease

Data Standards Overview History and Acknowledgements References Updates Feedback and Suggestions

The National Institute of Neurological Disorders and Stroke (NINDS) and other Federal agencies and international organizations have thecommon mission of developing data standards for clinical research. Through the efforts of subject-specific working groups, topic-driven dataelements have been created. The first set of Common Data Elements (CDEs) for Parkinson’s Disease was developed in 2010. The Core dataelements to be used by an investigator when beginning a research study in this disease/disorder are listed in the Start-up Resource Listing.

Many of the CDEs will overlap across study types, which allows for comparisons and meta-analysis across studies. Consistency of the dataelements and the CDE formats is kept in order to ensure the ability to transfer critical medical information electronically from one center toanother. This consistency also allows for continuity across different disease areas. The goals of the NINDS CDE initiative are to increase theefficiency and effectiveness of clinical research studies and clinical treatment, increase data quality, facilitate data sharing, and help educatenew clinical investigators.

CDEs

Tools Learn

NINDS Common Data Elements Harmonizing information. Streamlining research.PROJECT OVERVIEW CDE SEARCH CRF SEARCH FORM BUILDER CONTACT

CDEs Tools Learn

Interventions

Con Meds

Exposure

Substance Use

Events

Adverse Events

Disposition

Medical History

Clinical Events

Deviations

Findings

ECG

Incl/Excl Exceptions

Labs

Subject Characteristics

Physical Exam

Vital Signs

Drug Accountability

Questionnaire

Microbiology Spec.

Microbiology Suscept.

Findings About

PK Concentrations

PK Parameters

Special Purpose

Demographics

Comments

Subject Elements

Subject Visits

Trial Design

Trial Elements

Trial Arms

Trial Visits

Trial Summary

Trial Incl/Excl

Unstandardized Data CDISC Data StandardsStandardized Datasets Facilitate Review & Analysis

Figure 6: Roadmap from May 2013 Parkinson’s UK/CAMD alliance meeting. The diagram outlines the sources of data for building an integrate PD database and a proposed regulatory strategy to support the development of quantitative PD models and the regulatory path for such proposed tools. Key: RCT: randomized controlled trials, SWEDD: Scans without evidence of dopaminergic deficiency. Abbreviations: CamPaIGN: Cambridgeshire Parkinson’s Incidence from GP to Neurologist; OxfordPD: The Oxford Parkinson’s Disease Centre (OPDC) Discovery cohort; TrackingPD ProBaND: Parkinson’s Repository of Biosamples and Networked Datasets; PPMI: Parkinson’s Progression Marker Initiative; ADAGIO: Attenuation of Disease progression with Azilect Given Once Daily; DATATOP: Deprenyl and tocopherol antioxidative therapy of parkinsonism); PRECEPT: (Parkinson Research Examination of CEP-1347 Trial); SWEDD: Scans without evidence of dopamine deficiencyFrom Stephenson et al., Precompetitive data sharing as a catalyst to addressing unmet needs in PD, J. Parkinson’s disease, in press.

.

-

A2 B3 C4

A CDISC therapeutic-area data standards user guide was developed for PD based on the CDISC SDTM foundational standards, recognized by the FDA. The PD Therapeutic Area User Guide (TAUG) originated from the comprehensive common data elements(CDEs) developed by the PD Common Data Elements (CDE) Work Group (http://www.commondataelements.ninds.nih.gov/pd.aspx#tab=Data_Standards).Concepts covered by the PD CDISC user guide include family history, deep brain stimulation, microscopic findings (neuropathology), biospecimens (tissue sample handling/tracking), and neuroimaging (MRI, PET/SPECT, Spectroscopy and associated imaging protocol information). Clinical outcome assessments include UPDRS, MDS-UPDRS and a variety of additional endpoints.

We encourage the use of this biomarker in clinical trials to evaluate its utility for the identification of patients likely to show clinical progression of Parkinson’s motor symptoms. We will consider data collection on this biomarker to be exploratory in nature. When including this biomarker in clinical trials, sponsors will be encouraged to employ consensus PD Clinical Data Interchange Standards Consortium (CDISC) standards for data harmonization. We believe that sharing and integrating data across trials can foster a more efficient path to biomarker qualification. If sponsors intend to include analyses of this biomarker to support regulatory decision making for a given IND drug development program, they should prospectively discuss their plan with the Division of Neurology Products in CDER.

Procedures (PR) Associated Persons (AP)

Morphology (MO)

Device Identifiers

(DI)

Family history of PD and other neurological disorders

Device in-use Properties (DU)

Device-subject Relationships

(DR)

Microscopic Findings (MI)

Biospecimen (BS)

Deep Brain Stimulation procedure record (DBS)

DBS indication

Details of DBS procedure

MRI, MRS, PET/SPECT procedure record

Brain MRI findings

Spectroscopy findings

Degree of relation of affected family member

Pre-operative MRI for prior to DBS implantation

DAT Scan findings

Macroscopic neuropathology findings

Device typeScan parameters: pulse sequence information, etc.

Device make, model, and serial number

Captures all devices associated with each subject

Microscopic neuropathology findings

Tissue sample handling

Tissue sample properties (quantity, etc.)