New York, NY—How do findings from clinical trials differ from actual clinical practice in the treatment of immune-mediated inflammatory diseases (IMIDs)? And what are the implications? Three experts answered those questions during a presentation from IAS.
Discussing adverse events (AEs) associated with the use of biologics to treat IMIDs, Leonard H. Calabrese, DO, Case Western Reserve University, said that clinicians must look for severe AEs. This is especially true as new agents come to market. These AEs can be predictable, unpredictable, or paradoxical. “Predictable toxicities” are defined as infectious and noninfectious events that may be predicted based on evidence from the immunology tool box (ie, preclinical models). “Unpredictable effects” lack prior evidence; and “paradoxical effects” are autoimmune reactions.
Epidemiologists evaluate long-term tolerance to an agent by analyzing results of randomized controlled trials (RCTs) versus placebo, extensions of RCTs, registries/observatories, and postmarketing follow-up. Assessing toxicity based on RCT results can be problematic as they tend to have high dropout rates in the placebo group and are not powered for AEs. When interpreting data from registries, there may be issues with confounding, variations in follow-up, and difficulty controlling for bias.
Therefore, Dr Calabrese concluded, physicians treating IMIDs and prescrib- ing biologic agents must be familiar with the underlying immunologic science for these agents. Despite familiarity with the “immunology tool box,” however, vigi- lance for unpredictable and paradoxical AEs is always warranted.
As far as applying comparative effectiveness research (CER), Joel M. Gelfand, MD, MSCE, University of Pennsylvania Health System, drew on his experience with psoriasis. The problem with CER, he noted, is that in a clinical trial, patient selection criteria are stringent, patients are highly motivated, and physicians have expertise with the study drug. In actual practice, patients are more susceptible to AEs, they are less motivated, and their physicians are probably not as knowledgeable about the drug as other experts.
CER for commonly used therapies for moderate-to-severe psoriasis have found that effectiveness is lower in a real-world setting, with most patients failing to achieve long-term disease control. Results have also shown dosing is often not optimized for safety and efficacy. Dr Gelfand concluded that although short-term comparative efficacy data are emerging and long-term real world effectiveness data are limited, thus far, treatment persistence appears to be the best marker for success.
Stephen B. Hanauer, MD, Northwestern Feinberg School of Medicine, discussed maintenance treatment. He reviewed the different levels of maintenance therapy:
• maintenance of response
• maintenance of clinical (or postop-erative) remission
• maintenance of mucosal healing
• prevention of hospitalizations/surgery • disease modification
Even with maintenance therapy, however, loss of response is common, and with anti-TNF biologics, dose adjustment should be anticipated along with diminishing returns with a second and/or third agent. Dr Hanauer also indicated that when monitoring therapeutic efficacy of biologics, trough levels may be a better predictor of continued response, as has been seen in studies with infliximab.
Implications of low trough levels are disease recurrence and development of anti-drug antibodies, leading to eventual loss of response. Such loss may be due to immunogenicity, pharmacology, or loss of mechanism. A clinician’s options are to:
• increase the dose;
• switch to another anti-TNF or another biological;
• immunosuppress; or
• recommend surgery.
Anti-TNF clinical trials, he continued,have taught us that:
• anti-TNF therapies are effective for the treatment of Crohn’s disease and ulcerative colitis;
• all monoclonal antibodies are immunogenic;
• high-dose induction and regular maintenance and immunomodulators reduce immunogenicity; and
• combination therapy is more efficacious than monotherapy.
The implications for practice, Dr Hanauer concluded, are careful patient selection, as well as continuous assessment.—Mary Mihalovic