A New Paradigm

September 1, 2012
Applied Clinical Trials
Volume 21, Issue 9

Practical approaches to new challenges and opportunities in inflammation trials.

The medical and scientific understanding of immune-mediated inflammatory disorders such as rheumatoid arthritis, asthma, psoriasis, lupus, and inflammatory bowel disease has evolved dramatically in recent years. The shift from organ-based symptom relief to mechanism-based treatment and disease modification has led to increased R&D activity, and explosive investment in new mechanism-based targets and therapeutic approaches, generating new challenges and opportunities.

Recent years have seen significant advances in the medical and scientific community's knowledge of immunology and the pivotal role inflammation plays in auto-immune disorders, causing a profound shift in how inflammation is perceived and treated. A leading area, the global inflammatory therapeutics market, is estimated at $55 billion per year and growing. In terms of clinical trials funded and open for enrollment, inflammation is bested only by oncology and CNS trials.

Traditionally, inflammatory disorders such as asthma, inflammatory bowel disease, and rheumatoid arthritis were viewed as organ specific disorders with an inflammatory component. They were often addressed in a piecemeal fashion dictated by the physical site of the disorder (e.g., lungs, gut, joints, etc.), and primarily treated with anti-inflammatory and immunosuppressive agents that had significant toxicity and narrow therapeutic windows between useful and toxic dose.

However, recent discoveries that seemingly unrelated disorders, like arthritis and Crohn's disease, share some common pathways of immune mediation has led to the emerging concept of classifying these disorders as immune-mediated inflammatory disorders (IMIDs). IMIDs represent many chronic autoimmune disorders that share common inflammatory and molecular pathways, affecting 2% to 5% of the population. IMIDs include disorders as varied as rheumatoid arthritis, asthma, psoriasis, ulcerative colitis, and Crohn's.

More than a name and classification, IMIDs represent a significant shift in the management of traditional inflammatory disorders from organ-based symptom relief to a targeted mechanism-based treatment approach that chokes off inflammatory activation before it is fully deployed. This breakthrough is profound because it is the first time specific therapies have been developed that target the immune system at a particular mechanistic level.

For instance, certain biotherapeutic drugs initially designed to treat rheumatoid arthritis by modulating the immune system can also demonstrate efficacy in treating psoriasis and inflammatory bowel disease. It is possible to take advantage of this treatment approach; the disorders share common molecular pathways where there is dysregulation of the body's immune-mediating system of chemical messengers called cytokines. Such targeted anti-cytokine biologic therapies have revolutionized treatment of IMIDs due to their efficacy, speed of onset, and tolerability, and have been effective in treating multiple inflammatory conditions.

While growth in the IMID biopharmaceutical pipeline is driving a wave of development opportunity across multiple areas simultaneously, novel biomarkers are also being leveraged to support rational expedited IMID drug development.

As the list of targeted therapeutic approaches grows, a fundamental concern is the requirement for large study populations in clinical trials. Therefore, biomarkers and genotypic information are starting to be used to improve future clinical trial design. Currently, inflammation biomarkers are being used to: improve patient satisfaction in clinical trials to increase the ability to detect a therapeutic effect with a novel agent; allow expedited human proof of mechanism/concept studies to screen out and fast track promising drug candidates; identify patient subgroups that may benefit from more or less intensive immunosuppressive therapy or use of novel therapy; and predict subject response to treatment allowing closer monitoring of individuals judged to be most at risk of relapse or potential side effects.

As the understanding of inflammation continues to evolve, there is an equal need for an evolution on the operational side, including best practice approaches in optimizing clinical trial design. The shift from organ-based symptom relief to mechanism-based treatment of IMIDs has generated new challenges and opportunities to consider.

Inflammation clinical trials face a number of pitfalls that threaten to undermine the quality of the compound characterization and the ability to identify and understand vital safety and efficacy signals. Examples include placebo response, heterogeneous reporting of patient reported outcomes (PROs), study drug compliance issues, inter- and intra-rater variability, and patient retention challenges.

However, while pitfalls common to inflammation studies abound, operationally approaching IMIDs as one interconnected area makes it possible to leverage experience and best practices across studies.

Some similarities inherent in inflammation studies include standard of care, implementation and standardization of PROs, related laboratory tests, the fact that patients are generally known to sites given the chronic nature of the disorder, good patient compliance, and a strong network of advocacy groups. Given these similarities, best practices learned can be applied across studies. In particular, trial design and site training (e.g., physician assessed study endpoints) are crucial to minimizing placebo response and immediate review of completed PROs, while the patient is still in the clinic, can significantly reduce the amount of spurious and missing data. This latter recommendation is all the more pertinent given the increasing trend/requirement for inclusion of PRO data in label claims.

The increased clinical trial activity in the area of auto-immune inflammatory disorders is also driving the competition for patients, which makes it vital to have a deep understanding of site/patient competition, and to identify the most appropriate sites for an inflammation study.

Understanding the paradigm shift from organ-based symptom relief to mechanism-based treatment is critical to being able to systematically and effectively negotiate the impact on clinical development strategies for IMIDs. By embracing this concept, we can not only benefit from the application of best practices across indications, but also bolster the chance of increasing clinical ROI and most importantly the introduction of new efficacious treatments in a burgeoning area with significant unmet need.

Michael George, MD, is Global Therapeutic Head for Inflammation, and Joan Meyer, PhD, is Executive Director of Operational Strategy and Planning, both at Covance Inc., 210 Carnegie Center, Princeton, NJ.

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