CHALLENGES AND OPPORTUNITIES FOR PRAGMATIC CLINICAL TRIALS SHOULD EUROPE AND THE UNITED STATES APPROACH THEM DIFFERENTLY?

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1 CHALLENGES AND OPPORTUNITIES FOR PRAGMATIC CLINICAL TRIALS SHOULD EUROPE AND THE UNITED STATES APPROACH THEM DIFFERENTLY? Bryan R. Luce, PhD, MBA Chief Science Officer Patient-Centered Outcomes Research Institute (PCORI) ISPOR 20 th Annual Meeting Philadelphia ISSUE PANELS - SESSION II Tuesday, May 19, :00 AM - 12:00 PM << Develop infrastructure for D&I >> REVIEW Don P Buesching, Bryan R Luce & Marc L Berger /CER Future Medicine Ltd 1

2 Findings Manufactures: reluctant to invest in PCTs : 53 Publications total 9 sponsored by pharma industry PCTs have, in general, not differentiated products in terms of comparative effectiveness or costs; Payers/health plans: not been demanding PCTs; PCTs: relatively new, still largely undefined: neither manufacturers nor payers/ health plans/regulators seem to fully understand; Not convinced that PCT evidence accepted as legitimate for market access; FDA has provided no guidance to date with respect to whether PCT-derived evidence would meet its requirements for promotional claims (and it probably would not under present policies). Source: Buesching et al., 2012 Source: Buesching et al

3 Proposed Novel PCT Design Modification* Other Potential Improvements to PCT Designs Consider adding a 3rd clinically indicative care (CIC) arm (~ best practice arm) in addition to usual care Protocol prescribed care where protocol is treatment guideline or health system guideline driven Could align with P4P initiatives May be more consistent with regulatory requirements including delineation of safety profile pre-registration *Source: Buesching et al., 2012 Design-related (to sort out drug effect) Relax elements of pragmaticism (e.g., delay switching opportunities) Learn then adapt from Phase 3 to 3B to 4 (progressively more pragmatic) (Bayesian adaptive design approach) Statistically-related (to sort out drug effect) Policy-related Regulatory guidance (and support) for beginning in Phase 3B FDA permissiveness for using PCT evidence in promotion Source: Buesching et al.,

4 US Situation Updated to Today Pharma industry position: not much change FDA and payer/health plan positions: ditto Public funding sector leading way: AHRQ: 10 PCTs (ARRA: circa 2010) NIH Collaboratory Pragmatic Trial Network Low Cost PCT Initiative (2013)* PCORI Pragmatic Clinical Studies Initiative (2014)* PCORnet NIH s Low-Cost, Pragmatic, Patient-Centered Randomized Controlled Intervention Trials Cooperative Agreement mechanism Anchored in EHR 5 years, Two Phases Max $350/$500K Direct Costs: Total = $2.35M 4

5 PCORI s Pragmatic Clinical Studies Initiative PCORI Priority Topics Seek to produce information that can be directly adopted by providers: Compare two or more options for prevention, diagnosis, treatment, or management of a disease or symptom Address critical clinical choices faced by patients, caregivers, clinicians, systems Often conducted in routine clinical settings Though often large, usually less complex protocols than traditional trials Topics of special interest from stakeholders, Institute of Medicine, Agency for Healthcare Research and Quality Opportunity Snapshot Number of Anticipated Awards Per Funding Cycle: Six to Nine Funds Available Per Cycle: Up to $90 Million Maximum Project Duration: 5 Years Maximum Direct Costs Per Project: $10 Million Winter 2015 announcement: identified 22 topics Examples of priority topics: Treatment strategies for patients with autism spectrum disorder Treatment options for patients with multiple sclerosis Treatment strategies for adult patients with migraine headache* 5

6 First 10 PCORI Funded PCTs First 10 PCORI Pragmatic Clinical Studies Breast cancer screening tailored to individual risk and preferences vs. annual mammography for detecting breast cancer and minimizing screening-related harms in women Annual vs. biennial surveillance CT scanning in patients found to have small, potentially cancerous growths on initial CT scan. Standing order entry system for guiding use of colony stimulating factor vs. usual oncology practice for reducing over- and underuse of this medication and preventing complications in patients with breast, lung, colorectal cancer. Comprehensive transitional care program of early discharge and in-home support services vs. usual care in improving functional status and preventing hospital readmissions and mortality in stroke survivors? Primary care plus prompt referral to physical therapy and cognitive behavioral therapy vs. usual primary care to prevent acute back pain from becoming chronic. Healthy lifestyle intervention plus metformin therapy vs. health lifestyle intervention alone for reducing weight gain and metabolic problems associated with certain antipsychotic medications in youth with bipolar disorders? Anti-TNF factor vs. anti-tnf plus low dose of methotrexate in children with Crohn s disease for induction, maintenance of remission, patient-reported outcomes, and adverse events? Nerve blocking regional anesthesia vs general anesthesia in older adults undergoing surgery for hip fracture on acute post-operative pain, satisfaction with care, inpatient morbidity, and ability walk without assistance at 60 and 180 days, health and disability, pain, ability to return home after fracture, and mortality. Exercise coaching program vs. usual care for older adults who have experienced a lowimpact fracture as a result of a fall for preventing further injuries and improving health. Proton-beam vs. photon-beam radiation therapy post-mastectomy in women with Stage II or III for outcomes of recurrence, mortality and cardiovascular disease complications of radiation therapy. 6

7 PCORI Requires Extensive Engagement: One Example Pragmatic Trial of More vs. Less Intensive Strategies for Active Surveillance of Patients with Small Pulmonary Nodules Engagement with patients led to the development of patient-centered outcomes; partners include American Cancer Society, American Lung Association, Center for Medical Consumers, and Free to Breathe; investigators also have a working relationships with guideline developers 7

8 The National Patient-Centered Clinical Research Network (PCORnet) PCORnet: The World s First Network Infrastructure To: 11 Clinical Data Research Networks (71 health systems) Health system-based networks, such as hospital systems; $76.8 million awarded 18 Patient-Powered Research Networks (80 organizations) Patients with a single condition form a research network; $16.8 million awarded Coordinating Center Provides technical and logistical assistance under the direction of a steering committee and PCORI staff Be based primarily on EHR data, rather than claims data Support both large observational studies and embedded randomized pragmatic clinical trials Involve patients, clinicians, and health systems leaders in governance and use of the network 8

9 PCORnet Vision To enable rapid, large-scale, patient-centered clinical research in real-world care delivery systems and communities. Research Infrastructure Done Differently PCORnet Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Study Aims: Compare effectiveness of two daily doses of Aspirin (81mg vs 235mg) in reducing composite of allcause death and hospitalization for nonfatal MI, or nonfatal stroke in high-risk patients with a history of MI or documented CAD. Primary safety endpoint is major bleeding complications. Develop and refine PCORnet infrastructure for conducting faster, cheaper clinical trials Study Design: Individual RCT Sample Size/Priority Population: 20,000 high-risk patients with CAD Outcomes: Composite endpoint of all cause mortality and hospitalization for nonfatal MI, or nonfatal stroke Major bleeding complications PROs Maximum Follow-up Time: 30 months Total Budget: $14,016,506 9

10 PCT-Related Issues PCORI is Debating Defining concept and boundaries PCORI s Clinical Trial Advisory Panel drafting a policy document Comparator: Whether/definition of Usual care as a treatment arm Design issues Integration within learning HC system concept Trial simulation, Bayesian, adaptive, platform trial CLINICAL TRIALS DESIGN Clinical Trials 201 3; 10: Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study Jason T Connof1 1 b Bryan R Lucec, Kristine R Brogliod, K jack /shake, C Daniel Mullins', 1 David } Vanness 9, Rachael Fleurencec, Elijah Saundersh and Barry R Davis; The Author(s), Reprints and permissions: /

11 PCTs in U.S. Going Forward VIEWPOINT The Platform Trial An Efficient Strategy for Evaluating Multiple Treatments Berry, Connor, Lewis JAMA Published online March 23, 2015 Copyright 2015 American Medical Association. All rights reserved. Opinion Public Sector funding leading the way Will develop experience and proof of concept for decision-making Patient-centeredness Patient and multi-stakeholder engagement Design & efficiency innovations: Building off existing EHR and claims data Use of novel adaptive and platform methods FDA, payer & health plan policies uncertain 11

12 Thank You Dr. Bryan Luce Chief Science Officer, PCORI 12