One participant noted that rheumatoid arthritis (RA) was considered a heterogeneous systemic disease 30 years ago. Today, trial entry is based on the number of active joints, suggesting that heterogeneity may not be important.
Another consideration was activity of disease among patients studied (e.g., more active versus less active patients). A targeted biologic, for example, which treats some features of lupus, might not show benefit in an active patient who is flaring but might show benefit in patients with chronic disease of lower activity, or vice versa. In the BLISS-52 phase 2 trial, the higher the baseline disease activity, the better the response was over time.
Drug mechanism: The success of the BLISS-52 trial suggests that drug mechanism may be critical to trial design. However, there is also the risk that some drugs might make patients worse. Hypothetically, an agent that is effective for active disease might make a patient with quiescent disease worse. Because lupus may have different pathogenic mechanisms in different people, it may be advantageous to select the trial population based on the drug’s mechanism. Participants at the meeting acknowledged that such a selection might be difficult to accomplish but that the approach should be considered.
The value of “withdrawal” trial designs: This is when all enrolled patients initially receive the drug for a period of time before one group switches to placebo. Though common in pediatric trials, withdrawal designs are rare elsewhere, partially because of the difficulty of structuring the trials to meet ethical, business, and FDA requirements in a chronic, slow-developing disease like lupus. Withdrawal trials are also difficult to conduct with a new drug because it is best to have some initial evidence that the drug is of some benefit before initiation of a withdrawal trial. In the absence of an approved “gold standard” therapy, it might be difficult to establish such benefit. Moreover, in the absence of gold standard therapy, superiority and not equivalency or noninferiority trials are required.
New and different clinical design elements: Participants also discussed several other elements that could be used to inform the design of trials, including biomarkers, randomized delayed treatment design (placebo, then drug versus drug, then placebo in different groups), durability studies, and human observational studies.
Return on investment: Attendees agreed that companies sponsoring clinical trials should consider testing SLE drugs for narrower indications, noting that studies of rigorously defined patient subpopulations may offer lower initial financial returns but also present lower risks of outright failure.
