Expert Review of Clinical Immunology | 2019
The complexity of adverse event assessment and counseling for patients on biologic treatment
Abstract
Although many immune disorders were difficult to manage in the past, recent advancements in biologic therapies have enabled healthcare providers to control such difficult-to-treat pathologies. However, some patients are concerned that using biologics may result in serious adverse events. How to quantify adverse event rates and present those rates to patients are important issues [1,2]. While clinical studies are well-powered to assess the efficacy of a biologic, they are not well-powered to assess rare events. A study of several hundred subjects may be very well powered to detect differences in efficacy between biologics that result in success 70% or more of the time and placebos that achieve success less than 10% of the time. But such studies may not detect differences in rates of adverse events that may occur in only 1 in 100 or 1 in 1,000. Rare events need more power to be quantified and may not be detected at all in clinical trials. For instance, efalizumab, one of the first biologics approved by the Food and Drug Administration (FDA) for the treatment of psoriasis, was voluntarily withdrawn from the market because of potential risk of progressive multifocal leukoencephalopathy. No cases were reported during efalizumab’s clinical trials before its FDA approval. Relatively small sample size and short study periods limit the ability to detect rare adverse events. To better define safety profiles, larger samples are needed and can be obtained through registry studies and post-marketing surveillance [3]. The exclusion of subjects with common comorbidities from clinical trials also limits studies’ power to assess adverse events. This limitation negatively impacts external validity and generalizability of a biologic’s safety profile. Registry studies and postmarketing surveillance can help address this, too [4]. Registries and post-marketing surveillance also allow for evaluation of adverse events associated with long-term drug exposure. However, they also have limitations and do not easily allow for comparison of drug safety relative to not taking the drug since there is no randomized control group available for comparison. And even though regulatorsmay encourage recording of all adverse events related to a medication, post-marketing surveillance reportings are far from complete [5]. Having subjects randomized to a placebo group helps determine whether side effects are due to a drug or not. Although clinical trials often have a placebo group, placebocontrolled periods can only be continued for so long before it becomes unethical to leave patients untreated limiting the ability of studies to assess whether drugs cause higher long term side effect rates. As stated in the Declaration of Helsinki, item 33; ‘The benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best proven interventions [6].’ Although studies address this unethical dilemma by allowing placebo-controlled trials to eventually continue without a control group, such efforts limit the studies’ ability to provide certainty about long-term safety [1,7]. Registry-based randomized control trials may help provide better information on side effect profiles [8]. The compilation of clinical trial data, registries, and surveillance do give us a good picture, albeit incomplete, of a drug’s safety (Table 1). However, after getting that picture of a drug’s safety, we have to communicate the risk to patients, yet another hurdle to address. Patients’ fear of side effects may be out of proportion to real risk [9–11]. Many strategies have been proposed to address this problem; however, there is no ‘one fits all’ strategy. Putting risks into perspective may be helpful when advising patients on treatment options. Simply providing statistics may not be ideal, as human brains were not designed for the mathematics of large numbers. Telling patients that an adverse event occurs in only 1 out of 100 patients – or even 1 in 1,000,000 – may leave patients focused on what it would be like to be the 1. Instead, telling patients that an adverse event will not occur in 99 out of 100 patients on a specific treatment can give a much more reassuring perspective [9]. Pictorial aids may be another approach (Figure 1). These graphical demonstrations help providers counsel patients not only on adverse events but also on improving disease comprehension and treatment adherence. In a randomized placebo-controlled trial of low-literate participants, 73% of participants demonstrated complete understanding of medication labels when provided both text and pictorial aids,