Advances in targeted therapy: safety of biological agents.

Tumour necrosis factor (TNF) antagonists have set a new therapeutic standard for rheumatoid arthritis (RA). The agents including infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira) have been shown to substantially improve the signs and symptoms, disability, and quality of life while significantly inhibiting joint damage in early and longstanding RA. As with any agent, safety issues in concert with efficacy determine a risk/benefit ratio and hence a position in the therapeutic algorithm. With TNF antagonists key safety considerations include (a) infection, both common and opportunistic; (b) cytopenias; (c) demyelinating disease; (d) lupus-like syndromes; (e) congestive heart failure (CHF) and malignancies, particularly lymphomas. In March 2003 the United States Federal Drug Administration (FDA) convened a meeting to update safety issues related to TNF antagonists, specifically focusing on solid tumours and lymphomas. Safety data from controlled clinical trials were presented for the three TNF antagonists with post-marketing safety data for etanercept and infliximab. All the data are available on the FDA website. The current review will focus on infection, CHF, and malignancy. Much of the information in this review was obtained from the FDA, Arthritis Adviser Committee, the National Databank for Rheumatic Disease (NDRD) of Dr Fred Wolfe, from data on file with Abbott Pharmaceuticals, Amgen Incorporated, and Centocor Incorporated. Safety data may be obtained from a variety of sources, including placebo controlled, randomised clinical trials, post-approval databases, particularly the USA FDA MedWatch spontaneous reporting programme, and long term registries such as the NDRD of Fred Wolfe as well as registries in Sweden and Germany and England. A number of factors significantly influence the interpretation of adverse event data. Within clinical trials issues of ascertainment bias in enrolling patients into trials, population homogeneity, lower comorbidities, restricted concomitant drugs, short trial duration, and a relatively small sample size may have substantial influences on the safety profile. Post-approval (post-marketing) adverse event reporting although influenced to a far lesser extent by population homogeneity, comorbidities, restricted concomitant drugs, duration of follow up, and sample size, still has significant limitations. Post-approval data are limited by substantial underreporting, incomplete and unverifiable data acquisition, and ascertainment bias, particularly with spontaneous reporting such as that in the US FDA MedWatch programme. It has been estimated that <1% of serious adverse events are reported to the FDA. The seriousness of the event also influences the propensity for reporting. Another factor affecting reporting is the duration that the drug has been on the market because the number of events reported occur early, particularly within the first two years. Unexpected adverse events are also more likely to be reported. Interpretation of post-approval adverse event data also depends on how those data are ascertained and reported. For example, for etanercept, data on drug exposure are readily obtained through the prescription numbers, whereas for infliximab difficulty in ascertainment arises as a consequence of bulk shipments to providers and weight based dosing. As a result, patient-year exposure with etanercept is expressed as the length of time for which the drug has been taken, whereas infliximab exposure is expressed as the time which has elapsed since initiation of the drug, regardless of whether it is continued or not. Constituents of the database also influence reporting rates. Thus, for etanercept, juvenile arthritis and psoriatic arthritis data are often included, whereas data on Crohn’s disease are often included with infliximab (table 1). Intensity of surveillance will also influence the number of events reported to the company and hence FDA. Finally, the availability of a drug also has an effect on the adverse event profile. Thus only infliximab is approved for funding in America for patients over 65 years of age. This elderly population will have a higher rate of tuberculosis, heart failure, and lymphoma. The characteristics of the TNF antagonists currently approved differ, particularly in their structure, binding target, half life, capability of in vitro cell lysis, dosing, and efficacy in Crohn’s disease (table 2). Whether in vitro cell lysis accounts for differential efficacy in Crohn’s disease of TNF producing cells and incidence of granulomatous infections such as Mycobacterium tuberculosis remains unclear. Recent data suggest that lymphocyte apoptosis in the lamina propria of patients with Crohn’s disease influences its efficacy.