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Mitigate Risk and Increase Success of Lupus Clinical Trials

Andrea Peirce, Peter Lipsky, MD, and Benjamin D. Schwartz, MD, PhD  |  Issue: August 2010  |  

Definition of Improvement

Among outcome instruments used in clinical trials, the British Isles Lupus Assessment Group index (BILAG) is based on an intention-to-treat approach according to an extensive series of criteria to classify a patient’s SLE manifestations arising from different organ systems (see Table 1, p. 36). The BILAG score was used as the primary outcome measure in the unsuccessful trials of Genentech’s rituximab and Bristol-Myers Squibb’s abatacept in lupus, and is currently being used as the primary outcome measure in an ongoing trial of EMD Serono’s atacicept (TACI-Ig).

During the meeting, representatives of all three companies described their efforts to compensate for the BILAG’s limitations, including rigorous physician training programs, the use of adjudication panels to review scores to ensure the authenticity of any changes, and the use of simple questionnaires to allow more subjective measures. In the abatacept trial, the physicians’ subjective reports suggested that the drug was working, even though the BILAG scores and related analyses found no evidence of benefit. Other drug trials presented at the meeting also showed significant differences between physician opinions and BILAG outcomes, which reinforced the prevailing view that the BILAG index is not sufficiently sensitive to detect benefit from the new treatments. Particularly problematic may be the use of BILAG B events as outcome measures of lupus flares.

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In contrast, HGS’s phase 3 trials of belimumab incorporated a combination of assays, characterized as a composite or anchored index, called the SLE Responder Index, or SRI. SRI included the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) as a measure of drug efficacy and the BILAG Index and a physician’s global assessment as measures of patient deterioration.

Although the SLI approach worked in BLISS-52, some critics believe that the amalgamation of several outcome measures into one composite may create an uncertain foundation on which to base results. Some attendees believed that using any one of the component measures would have worked just as well.

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Design Considerations

Clinical trial design considerations were extensively debated, with no clear conclusions; however, there was agreement on the key considerations for future trial design:

Heterogeneity versus homogeneity: Heterogeneity is inherent in lupus. One question discussed was whether it is advantageous in lupus clinical trials to study a more homogeneous population. In trials with heterogeneous populations, researchers must be careful not to overextend application of results. On the other hand, while study of a homogeneous population may produce “cleaner” results, these results are restricted to the particular population studied, and extrapolation to other populations may not be warranted. It was noted that large heterogeneous populations can be subdivided into smaller more homogeneous populations that could be studied in separate trials to detect clinical differences between the effects of study drug and placebo.

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