LONDON – Many recently performed rheumatology drug trials ran into the ethical trap of treating control patients with an ineffective regimen, with the result that some patients experienced ongoing pain and joint dysfunction and continued disease progression.
"I would propose that we change the trial design for the placebo control to use an active comparator against the [investigational] drug," Dr. Aaron Juche said while presenting a poster at the annual European Congress of Rheumatology.
Dr. Aaron Juche
In most cases for current studies testing a new drug aimed at controlling rheumatoid arthritis pain, dysfunction, and progression, "the standard of care would be a tumor necrosis factor [TNF] inhibitor as the active comparator," said Dr. Juche, a rheumatologist at Johanniter Hospital in Treuenbrietzen, Germany. Because TNF inhibitors are so effective, a study that uses this treatment in the comparator arm would likely have to be a noninferiority study and would also probably have to involve a relatively large number of patients, he said in an interview.
Dr. Juche said he first became interested in this issue because he "wondered whether placebo-treated patients [in recent drug trials] were being treated as I would treat a patient in standard practice." The standard approach for drug-trial design in patients with rheumatoid arthritis (RA) in recent years has been to follow a model that’s more than a decade old, dating back to the first studies on TNF inhibitors during the 1990s: "Patients who did not adequately respond to immunosuppressive drugs were randomly assigned to either an experimental condition under which they received the new substance, or to a control condition under which they continued their formerly inefficient treatment and received a placebo."
To more systematically assess the scope of the problem, he and his associate reviewed 17 recent, published clinical trials that drug companies used to document the safety and efficacy of three new drugs, abatacept, golimumab, and tocilizumab, to the European Medicines Agency. Dr. Juche said these studies fairly represented most recently performed drug efficacy trials for patients with RA.
Of the seven studies he reviewed that tested abatacept, none used a control therapy that effectively treated the patients’ disease. In all seven studies, patients remained on treatment with a disease-modifying antirheumatic drug (DMARD) that they had already failed on, most commonly methotrexate. During these studies, "patients experienced a persistent, high disease activity," Dr. Juche reported in his poster.
Among four pivotal studies involving golimumab, one enrolled methotrexate-naive patients and then used methotrexate as the control drug. The other three used control groups that either received placebo and nothing else, or placebo plus methotrexate for enrolled patients who had already failed methotrexate.
A similar pattern existed for the six studies of tocilizumab that Dr. Juche reviewed. One of the six studies used methotrexate as the comparator in a trial that enrolled methotrexate-naive patients. The other five studies used comparator groups on either placebo alone or placebo plus a DMARD to which the patient had already not responded.
Dr. Juche added that he did not believe that rheumatology was a unique medical specialty in having so many of its trials involve ineffective regimens in the control groups, but he did not systematically assess efficacy trials done in other specialties. As a rheumatologist, he focused his attention only on those studies from his specialty.
These designs run counter to the stipulations of the 2008 Declaration of Helsinki of the World Medical Association, Dr. Juche noted. The Declaration said: "The benefits, risks, burdens, and effectiveness of a new intervention must be tested against those of the best current proven intervention, except ... where no current proven intervention exists or where, for compelling and scientifically sound methodological reasons, the use of placebo is necessary to determine the efficacy of an intervention and the patients who receive placebo or no treatment will not be subject to any risk or serious or irreversible harm."
Dr. Juche said that he has received travel expense support from Actelion.