June 9, 2017: Early Approval Redux

Voclosporin will likely be approved well before the P3 trial runs it course.

Here's how it's going to work. 

First, there's a legal and regulatory path for this approval.  While I quote the relevant passage below, here's the link to the FDA Regulations, as well as a list of drugs that received accelerated approval. 

Sec. 314.510 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.

FDA may grant marketing approval for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.

Second, what is a "surrogate endpoint?"   According to the FDA, a surrogate endpoint is "a laboratory measure or a physical sign that is intended to be used as a substitute for a clinically meaningful endpoint."  There are two relevant surrogate endpoints for Voclosporin, and the first is UPCR.   Per a National Institutes of Health document,  "Proteinuria is a major predictor for progression of renal disease, including diabetic nephropathy. In a post hoc analysis of the ORIENT, a double-blinded randomized trial of 566 type 2 diabetic patients with nephropathy, we examined the risk association of composite renal outcome [end-stage renal disease, ESRD, doubling of serum creatinine (SCr) and death] with baseline, change and residual urinary protein/creatinine ratio (UPCR)."   Soooo, if the UPCR is falling at a rate consistent with with the P2 trial, that indicates you're en route to a positive clinical outcome.

Now add in the SLEDIA Index (Systemic Lupus Erythematosus Disease Activity Index), which is "a list of 24 items, 16 of which are clinical items such as seizure, psychosis, organic brain syndrome, visual disturbance, other neurological problems, hair loss, new rash, muscle weakness, arthritis, blood vessel inflammation, mouth sores, chest pain worse with deep breathing and manifestations of pleurisy and/or pericarditis and fever."  

Punch line: If UPCR and SLEDAI are on track and consistent with Phase 2 data with similar P-Values, it is entirely possible that Vocloporin will receive accelerated approval.  If that happens, the P3 trial would continue,  and additional data would be collected during the marketing phase to assure the decision to market is supported by robust clinical evidence.