More than 20 companies currently are evaluating treatments for lupus in randomized studies – more than ever before. The recent approval of belimumab (Benlysta), the first drug developed specifically for lupus in over 50 years, ended a 2-decade-long drought for lupus treatment development, by finally providing evidence that a drug has benefits when compared to background treatments alone. Until now, this progress was impeded by the heterogeneous nature of the disease, the complex process of selecting volunteers for clinical trials, the imprecision of clinical trial end points, and the highly complex and often confusing instruments used to measure disease activity that comprises these end points.
Joan T. Merrill
But even as the causes of lupus are becoming clearer and basic research is beginning to produce multiple, potential, finely tuned molecular targets for treatment, the completion of phase III trials has been proceeding more slowly than one would hope for.
So what are the factors impeding progress?
For one, multiple, competing, international-scale trials require multiple, well-trained, international trial sites. Although training of new investigators at new trial sites around the world is underway, the process has been slow and the results imperfect. Clinical trials also require experienced clinical scientists who can conform to international regulatory practices, but the rules are enormously complex and sometimes arcane. These clinical scientists must also be trained in lupus outcome measures that are even more complex and sometimes even more arcane. What’s more, in both cases the rules are frequently revised.
As understandably risk-adverse companies find themselves conducting international-scale clinical trials for a poorly understood and serious disease, recent phase III trials have become increasingly restrictive in setting limits on volunteers who are allowed to participate. Sometimes there are pages of entry criteria, making it difficult to recruit enough volunteers from real-world clinics.
Clinical studies that limit enrollment to patients who meet the American College of Rheumatology’s (ACR’s) Classification Criteria for systemic lupus erythematosus (SLE) have put trial participation out of reach for many patients with severe lupus syndromes in only one organ, such as primary discoid lupus, antiphospholipid syndrome, and other blood disorders such as immune-mediated microangiopathy. But patients with multiple organs that are mildly involved can often enter these same trials on a technicality.
One consequence of these increasingly formidable issues in entry criteria for trials is that once a drug is approved, only those people with lupus who meet the criteria may be deemed eligible for the drug by regulatory authorities. Therefore, the treatments will not be available for many or even most of the population we are trying to help. Some insurers have gone even further to require that patients exactly match the entry criteria for trials. They demand that a patient to be covered for treatment match the trial eligibility criteria by having certain scores on the disease activity measurement indices used for the studies, usually the SLE Disease Activity Index (SLEDAI) or the British Isles Lupus Assessment Group (BILAG) index. But most practicing physicians are not trained to use these measurement scales.
Sandra C. Raymond
Because lupus is a serious and potentially life-threatening disorder, there has been resistance to using trial designs that include placebo groups. One approach to this would be to compare a new agent to a standard-of-care medication. However, very few medications are approved for lupus, illustrating another problem: the difficulty in getting a drug approved for lupus because of clinical trial issues specific to the disease.
Right now, for example, the first-line standard of care agent for lupus nephritis is cyclophosphamide. A number of clinical trials found that mycophenolate mofetin (CellCept) is at least equivalent to cyclophosphamide for the treatment of acute lupus nephritis. This included at least one large international registrational trial (the ALMS study) that was designed as a possible approval pathway for mycophenolate. However, the Food and Drug Administration decided not to approve mycophenolate because proving equivalency to cyclophosphamide was not enough – it had to be proved superior. That is because regulatory agencies consider all unapproved treatments to be the same as placebo. For this reason, most clinical trials are being designed as "add on" studies, in which all patients receive standard of care with the addition of either the study agent or placebo.
Added to this is the fact that the regulatory agencies require yearlong studies in order to prove that efficacy can be sustained. No patient would enter a clinical trial for a year and risk receiving a placebo unless some accommodation was made for their safety and comfort by allowing some increases in their current (often fairly effective) background treatments. This increases the likelihood that the placebo group can do well, limiting the differences that can be seen between a given treatment under study and the placebo population.