Chronic Kidney Disease Trials Could Gain New Surrogate Endpoints

FDA is considering the use of 30% and 40% reductions in glomerular filtration rate as surrogate endpoints for the development of kidney failure in clinical trials; the current standard is 50%.

FDA is considering using new surrogate endpoints for studies of drugs to treat chronic kidney disease, which could speed up drug trials and get industry involved earlier in research.

Kidney disease progresses very slowly and is often asymptomatic until the stage of kidney failure. Currently, FDA accepts a 50% reduction in glomerular filtration rate – measured as a doubling of serum creatinine levels – as an acceptable surrogate endpoint for the development of kidney failure in clinical trials.

FDA held a joint scientific workshop with the National Kidney Foundation in December to evaluate whether both a 30% and 40% decline in GFR would also be acceptable surrogate endpoints. Participants looked at data on more than two million patients, including observational studies and 30 randomized clinical trials.

“Our hypothesis was that by analyzing data we already have we would probably be able to make an association between lessening decline in GVR and kidney disease,” Kerry Willis, NKF’s senior VP for scientific activities, said in an interview. She noted that the use of a 30% or 40% reduction in GFR as an endpoint would cut the time to conduct a clinical trial in half.

The 130 people participating in the two-day workshop included representatives from FDA, the European Medicines Agency, National Institutes of Health, the pharmaceutical industry and other professional organizations.

The data presented at the workshop is to be published in the future. Willis said the data were enthusiastically received by the workshop attendees, who endorsed use of these surrogate endpoints. No one is currently using these endpoints, which must now be validated in clinical trials.

New Endpoints May Enable Earlier Drug Testing

An estimated 26 million people in the U.S. have chronic kidney disease. Willis said that 70% of kidney disease is caused by a combination of diabetes and hypertension. The only available treatments are blood pressure drugs that slow the decline in kidney function. But there is no drug that halts the loss of kidney function or reverses kidney damage.

Abbott Laboratories Inc. and Reata Pharmaceuticals Inc. had been developing bardoxolone methyl with the endpoint of delaying progression to renal failure. But Reata halted a Phase III trial in October due to serious adverse events and death in patients receiving the drug (Also see "Bardoxolone Blow-Up: Reata/Abbott CKD Drug Halted In Phase III" - Pink Sheet, 18 Oct, 2012.).

Several of the leading participants at the NKF/FDA workshop discussed the significance of the new GFR surrogate endpoints in a video posted by the National Kidney Foundation. Lesley Inker, director for quality improvement at Tufts Medical Center, noted that a trial to show that an intervention prevents dialysis is time intensive. She said the endpoint of doubling of serum creatinine also takes a long time to achieve and as a consequence trials are very long and expensive.

“We need an endpoint that is valid but doesn’t take such a long time so that trials are less expensive and industry is willing to engage in drug development even from the very early phase,” Inker said. “So our goal was to have a change in GFR that’s still very much in the pathway to kidney failure but doesn’t take quite as long to achieve as it does actual kidney failure, dialysis or doubling of serum creatinine.”

Andrew Levey, chief of the Division of Nephrology at Tufts Medical Center, said the data presented at the conference show that under certain circumstances the change in GFR doesn’t need to be as large as 50%. Smaller changes in GFR occur earlier in kidney disease and may make it possible to test drugs a little earlier and in a slightly smaller number of patients, he said. “Both of those things would be a big advance.”

FDA’s Norman Stockbridge, director of the Division of Cardiovascular and Renal Products in the Office of Drug Evaluation I, said it was very beneficial to have the NKF and academic researchers provide more data and expertise on these endpoints. “We were interested in this same question – exploring the impact of small changes in GFR on the likelihood of later events – need for dialysis or death.”

Stockbridge said the agency would be discussing these endpoints internally and would likely make comments “mostly in the form of how we respond to individual drug development programs as they come forward and make specific proposals to us.”

FDA has repeatedly expressed its willingness to consider new surrogate endpoints in general. In September the agency held a workshop on new endpoints for clinical trials of drugs to prevent kidney transplant rejection (Also see "Kidney Transplant Endpoints Strive For Acceptance At FDA Workshop" - Pink Sheet, 1 Oct, 2012.).