ACTION Going Forward: A Proposed Strategic Plan Dennis C. Turk, Ph.D. Associate Director, ACTION University of Washington

Mission of ACTION To identify, prioritize, sponsor, coordinate, and promote innovative activities — with a special interest in optimizing clinical trials — that will expedite the discovery and development of improved analgesic treatments for the benefit of the public health.

 Facilitate collaborations among stakeholders  Sponsor analyses of pooled legacy data  Develop more efficient clinical trial designs  Reduce patient burden and study costs  Explore biomarkers and patient phenotyping Research

 Provide research fellowships and grants  Conduct workshops and consensus meetings  Develop training materials for study subjects and study staff Education

 Expand therapeutic armamentarium  Accelerate the development of mechanism- based treatments Treatment

Proposed activities and projects to accomplish mission of ACTION Strategic Plan

 Conduct scientific meetings, workshops, and roundtables to be held at FDA White Oak facility and in conjunction with various professional meetings.  Annual Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meetings. The mission of IMMPACT is to develop consensus reviews and recommendations for improving the design, execution, and interpretation of clinical trials of treatments for pain. Scientific Meeting & Workshops

 Conduct initial hypothesis-generating root cause analyses of several analgesic development programs to identify obstacles in the development of new treatments.  Conduct and publish the results of a full-scale root cause analysis of multiple analgesic development programs in both acute and chronic pain conditions to prioritize future methodological research and other activities that will expedite the development of improved analgesic treatments. Root Cause Analysis

Research Initiatives  STANDARDS -- STandardized ANalgesic DAtabase for Research, Discovery, and Submissions  REPLICATE -- Retrospective Evaluation of Patient-Level Information from Controlled Analgesic Trials of Efficacy  REPORT -- Resource for Evaluating Procedures and Outcomes of Randomized Trials  REACT -- Repository of Existing Analgesic Clinical Trials A case of Acronymphilia

Research -- STANDARDS  Preparation and publication of a comprehensive Clinical Data Interchange Standards Consortium ( CDISC)- compliant analgesic clinical trial database structure.  Facilitate transformation and pooled analyses of data from analgesic trials that have been submitted to FDA and also providing a recommended database format for the preparation and submission of future analgesic trials.  Make it possible to conduct pooled analyses of multiple clinical trials and thereby establish an evidence-based approach to increasing analgesic clinical trial assay sensitivity and efficiency.

Research -- REPLICATE  Analysis and publication of existing analgesic clinical trial raw data provided by FDA and industry, focusing on factors associated with assay sensitivity and placebo group improvement.  Once the STANDARDS project is complete, the data from numerous completed acute and chronic pain trials made available by FDA will be transformed so that analyses of pooled analgesic clinical trials can be conducted.

Research -- REPORT  Preparation of coded databases of published and publicly-available analgesic clinical trials, and analysis and publication of analyses of assay sensitivity and placebo group responses.  The objectives of the analyses of disease specific databases are to address multiple questions that can inform the design, conduct, and interpretation of future analgesic trials.  To ensure the comprehensiveness of the REPLICATE and REPORT projects, a registry and repository of clinical trial results and raw data that are not otherwise available will be created and maintained.

Research -- REACT  Develop a registry and repository of clinical trial results and raw data from otherwise available sources.  Solicit data from failed trials conducted by industry and academic investigators.

Research – Composite Outcome Measures  Development, validation, and evaluation of the responsiveness of composite outcome measures for analgesic clinical trials.  The composite outcomes that will be developed to include but not limited to:  pain and physical functioning  pain and use of rescue analgesia  pain and adverse events (ie, the “risk- benefit ratio” or “therapeutic index”)

Composite Outcome Measures Process  Review literature to identify composite approaches to risk- benefit in other therapeutic areas and evaluate strengths and limitations  Conduct focus groups and consensus meetings with patients and clinicians to identify key aspects of composite measures of analgesic benefit and tolerability/safety  Develop preliminary composite measures using raw data from a clinical trials made available by FDA and/or industry  Compare reliability and validity of the most promising subset of measures in raw data from multiple clinical trials  Select most valid and informative patient-level composite measure(s)  Determine whether these patient-level measures can also be used in meta-analyses of published analgesic trial group-level data

Research – Subject and Staff Training  Develop and evaluate educational programs for subjects enrolled in analgesic clinical trials and for study staff conducting these trials.  Determine whether such instructional programs enhance the assay sensitivity of analgesic clinical trials.  Identify barriers to the successful use of these programs to improve methods and procedures.

Research – Evaluating Misuse and Abuse Related Outcomes  Develop methods for evaluating evidence of misuse and abuse in chronic pain clinical trials with pain primary endpoints and with misuse and abuse primary endpoints.  Development of these methods will be based on the Columbia University classification and rating systems for suicidal ideation and behavior  Designed to be used retrospectively with completed trials and prospectively in new trials.

Research – Factors Affecting Analgesic Clinical Trial Efficiency  Develop a definition of clinical trial efficiency,  Identify factors that could influence efficiency that are at least partially independent of assay sensitivity (eg, study duration, recruitment rate, electronic data capture, geographic region).  Examine trial- and patient-level clinical trial data to evaluate relationships between these factors and study efficiency, ideally in tandem with the analyses of assay sensitivity described above.

Research – Diagnostic Classification  Develop an evidence-based classification that includes diagnostic criteria for acute and chronic pain conditions.  This taxonomy will be designed to stimulate new research intended to refine the definitions and classifications.  This project will seek collaboration with appropriate national and international pain organizations.

Research – Epidemiology  Existing data on the epidemiology of acute and chronic pain is either limited or non-existent. State-of-the-art approaches to determining the incidence and prevalence of common disorders require substantial resources but provide extremely valuable information.  Establish a task force that will design a comprehensive approach to determining the epidemiology of pain in the US and develop strategies for funding this critically important research program.

Research – Pain Biomarkers  Develop and publish approaches and consensus recommendations regarding qualification, validation, and certification of biomarkers and surrogate endpoints for pain outcomes that can be used in analgesic clinical trials.

Research – Grant Program  The supported grants will be awarded to investigators who prospectively test relationships between patient, study design, study site, and outcome measure factors and – 1. assay sensitivity 2. placebo group improvement, and 3. study efficiency.

Research – Responses to RFI  Improved safety assessment incorporated in the design of future analgesic trials including description of endpoint adjudication  Subgroup analyses based on levels of psychopathology and psychiatric comorbidity  Comparing placebo and treatment effects for different routes of administration  Prevention of pain and disability

Education – Fellowship Program  An essential ingredient for expediting the development of improved analgesics and establishing an evidence-based approach to clinical trial design is the availability of well- trained methodologists, statisticians, and clinical investigators with interests in analgesic drug development.  There is currently a critical shortage of such individuals, and ACTION will undertake a number of initiatives to address this challenge.

Education – Fellowship Program  Trainee fellowships to provide support for junior investigators to be mentored by established investigators directly related to analgesic drug development.  Visiting scholars program to support mid-level and senior investigators from academia and industry to visit research facilities.  Analgesic Trials Advanced Research Institute (ATARI). Annual scientific retreat for senior scientists from academia, government, and industry to spend an intensive week focusing on novel solutions to obstacles in the development of improved analgesic drugs and devices.

Education – Consumers  Develop recommendations on consumer education to help foster understanding of the importance of clinical trials for the development and availability of new medication.  Develop an educational booklet to explain the process of clinical trials.  Develop materials enumerating the responsibilities of subjects, trial sponsors, and trial-site personnel.  Develop a glossary of terms encountered associated with clinical trials.

ACTION Strategic Plan – Ambitious??? The need is great The goal is worthy The time is now The only limiting factor is the availability of resources to fulfill the mission