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Commentary

OA drug development needs patient-focused approach to biomarkers and outcome measures

Publish date: December 13, 2016

By

Amanda Niskar, DrPH

Sarah Yim, MD

Virginia Kraus, MD, PhD

And Rocky Tuan, PhD

Advances in our understanding of the development and treatment of osteoarthritis have led to renewed interest in leveraging these insights to establish more ways to evaluate potential drug candidates in clinical trials, particularly through the use of qualified biomarkers as meaningful outcome measures.

It is with this goal in mind that the Arthritis Foundation and the Food and Drug Administration held the Accelerating Osteoarthritis Clinical Trials Workshop in Atlanta in February 2016,¹ to discuss ways of enhancing the likelihood of successful OA trials, including possible “qualification” of biomarkers that can be used as endpoints in trials of OA treatments. Clinical trial endpoints would ideally be known to be clinically meaningful to the patient (such as pain, fatigue, functional status, etc.)² and would reflect treatments that enable patients to feel and function better.

Dr. Amanda Niskar

Workshop participants recognized that involving patients as early as the study design phase of trials is a priority for identifying clinically meaningful outcomes and trial endpoints, and it is important that the rationale for their use is clearly delineated in the study protocol.² The participants also noted the importance of finding points in the research and development continuum where clinical trial sponsors and regulators can engage patients from the bench to the bedside and back.³

Patient engagement in different steps of the development process might be possible through patient registries, social media communities, smart phones, and wearable devices to be used as tools for capturing patient perceptions and mobility. These means for capturing dynamic data about domains of high interest to OA patients may lead to the development of better outcome measures that can be used as clinical trial endpoints.⁴ Researchers at the workshop presented new ways in which they are beginning to specialize in these techniques and methods that will be useful for turning the patient experience into usable data to aid in precision medicine.

Dr. Sarah Yim

Participants discussed how informed patients who are trained in the clinical trial approach are uniquely positioned to inform our understanding of benefit expectations, risk tolerance, and attitudes toward uncertainty. Clinical benefit results when a patient experiences improvement in quality of life. Endpoints in trials of OA treatments, whether symptomatic or disease-modifying, need to demonstrate the clinical benefit directly or at least be interpretable with respect to the clinical benefit to be expected. Drugs approved for OA to date have been approved based on pain and function patient reported outcomes (PROs), such as the Western Ontario and McMaster Universities Osteoarthritis Index (pain, function, stiffness), Visual Analogue Scale function and pain ratings, patient global, investigator’s global, Lequesne score, knee injury and OA outcome score, and the International Knee Documentation Committee knee examination form. The FDA is open to other PROs and recommends discussing other PRO options ahead of time.

Imaging outcomes and biomarkers are attractive for their potential to demonstrate an effect on the structural and pathophysiologic elements of OA in the time frame of a clinical trial, but rely on well-characterized relationships between those structural and pathophysiologic elements of OA and the clinical outcomes of OA. A recent advance is data showing that semiquantitative knee joint features, including cartilage thickness and surface area, meniscal morphology, and bone marrow lesions, were associated with clinically relevant OA progression and could be potentially useful as measures of efficacy in clinical trials of disease-modifying interventions.⁵ Being able to describe the clinical benefit to be expected from such changes is essential to use these outcomes in the benefit-risk assessment. How to include structural outcomes in OA trials will depend on the level of information available to characterize clinical benefit. With less information, structural outcomes may still be useful as adjunct or secondary endpoints. To be used as the primary endpoint to support approval, a high level of characterization would be needed about the relationship of the endpoint to anticipated clinical benefit. The FDA recommends that sponsors proposing such a primary endpoint should engage with the agency early in the development program.

Dr. Virginia Kraus

Workshop participants suggested potential strategies to take advantage of information gathered in future OA drug development clinical trials. One option might be to seek initial approval based on OA signs and symptoms, with structural endpoints potentially described in the label as a pharmacodynamic assessment. The clinical relevance of the structural endpoint would not be known or described pending further data characterizing the link between structure and long-term outcomes.

Another option discussed was to study an accelerated OA population, that is, subjects (prior to joint replacement) with a history of trauma to a joint and other injuries predictive of early OA. In that setting, the study duration needed to demonstrate the relationship of structural and clinical outcomes may be more feasible.

A third option discussed was an end-stage OA trial that could enroll subjects who meet criteria for joint replacement. Such a study could possibly have outcomes that include delay in time to surgery, reduction in need for surgery, and clinical outcomes, such as need for concomitant analgesics, patient pain, and patient function. In any OA population, demonstrating a treatment’s effectiveness on clinical outcomes could be the sole basis for approval, in the context of an acceptable safety profile.

Dr. Rocky Tuan

As a direct result of the workshop, the Arthritis Foundation is convening a series of events culminating in an Arthritis Foundation–led OA Patient-Focused Drug Development meeting on March 8, 2017. The meeting is expected to identify clinical trial endpoints that are clinically meaningful to patients living with OA.

Dr. Niskar is national scientific director of the Arthritis Foundation. Dr. Yim is supervisory associate director of the division of pulmonary, allergy, and rheumatology products in the Office of New Drugs at the FDA’s Center for Drug Evaluation and Research. Dr. Kraus is professor of medicine, pathology, and orthopedic surgery at Duke University, Durham, N.C., and is a faculty member of the Duke Molecular Physiology Institute. Dr. Tuan is director of the Center for Cellular and Molecular Engineering and Distinguished Professor of Orthopedic Surgery at the University of Pittsburgh.

Dr. Niskar reports that the Arthritis Foundation received a donation from Samumed and a cosponsorship grant from the FDA to implement the Accelerating OA Clinical Trials Workshop. Dr. Kraus reports an Arthritis Foundation Delivering on Discovery Award that is outside of this editorial. Dr. Yim and Dr. Tuan disclosed no conflicts. Dr. Yim is relaying her personal views in this editorial, and they are not intended to convey official FDA policy, and no official support or endorsement by the FDA is provided or should be inferred. Samumed did not have a role in the writing of this editorial.

References

1. Bioworld. 2016;27:1-4.

2. Osteoarthritis Cartilage. 2015 May;23[5]:677-85.

3. Clinical Trials Transformation Initiative. PG engagement across the research & development continuum. 2015.

4. Sci Transl Med. 2016;8:336ps11.

5. Arthritis Rheumatol. 2016 Oct;68[10]:2422-31.

OA drug development needs patient-focused approach to biomarkers and outcome measures

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