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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 Regulationsas 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 endpointhat 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. 

Comments

  1. TC, did Brigatinib go through this process? We know that P3 trial for Brigatinib (now Alumbrig) is not completed yet but the drug was approved at the end of April this year.

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    Replies
    1. Exactly, Jess, Brigatinib (Alumbrig) was approved BEFORE P3 was finished. Thanks for remind me!!

      Delete
    2. There is a pretty compelling case to be made for approving Voclosporin before the end of phase 3. Knowing that, it is likely that Glickman may already have been contacted by BP to begin the process of a buyout. BP is aware that the drug may be approved earlier than expected and it is logical to assume that they want to pay as little as possible to buy the company so there should be some urgency to get the negotiations underway. All speculation but it makes sense.

      Delete
  2. Note that the ALTA was designed as a pivotal phase 2 trial from the beginning. This is not the case for AURA LV... Aurinia has never said anything about submitting an NDA based on phase 2 data (despite the great results)

    http://investor.ariad.com/phoenix.zhtml?c=118422&p=irol-newsArticle&ID=1911706

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    Replies
    1. Thanks for that Neil, o wasn't aware of that. Does "pivotal trial" have a specific meaning? And could Aurinia decide they want to submit based on P2? Seems like the trial protocol for P3, so I'm told. ..is nearly identical to P2. And...if the 24 week data were just outrageously good (whatever that means...) I assume the trial could in fact be halted, no??

      Hope everyone has a great weekend.

      John (aka TC)

      Delete
    2. Yes, "pivotal" essentially means that the sponsor and FDA have agreed that the trial results would be acceptable as the basis for an application for approval (NDA). Phase 3 trials are assumed to be pivotal. Very few phase 2 trials are pivotal. So when they are, companies publicize this fact at every opportunity (as ARIA did with ALTA).

      AURA LV was a relatively small exploratory study (only about 80 pts per arm). At the start, they didn't know which dose would perform better. They didn't know that the 48 week data would outshine the 24 week data. Now that they have this information, they have to confirm it with a larger study.

      AURORA is actually a substantially larger study (~160 pts per arm). So positive results would be that much more compelling.

      I believe that the company has had extensive discussions with the regulatory bodies in arriving at this trial design. There are some features that they can use in their favor (like better site selection and 52 week endpoint) and others that work against them (relatively larger number of patients required, no interim analyses).

      I'm still uncertain whether the trial could be stopped early for efficacy. The criteria have to be agreed upon by all parties up front. Imagine an early termination followed by a rejected NDA for insufficient data. If the FDA was going to allow an interim analysis, it would have been in the company's interest to include it in the protocol.

      Ok, sorry. I have rambled on too long... and my son wants someone to play Mario Kart with him, so will end here

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    3. A belated thanks, Neil, for this very thoughtful reply. Super helpful. Somehow I got it in my head that n = 220 or so for phase 2b, but it seems I got that wrong. Alas, time to kick back and resign ourselves to a rather long wait!

      Best regards to all,

      TC

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    4. No, you are right. ~240 pts split into 3 arms in the Ph 2b, ~80 in each

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    5. Ahhhh, so we are both right. Now that's a happy ending. :-)

      Have a great weekend.

      TC

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  3. Neil, are you sure you're not BR?

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    Replies
    1. LOL, I thought someone might think that. No, I'm not BR. I'm nferna on iHub. I'm​ just trying to get to the ground truth on Voclosporin (I own too many shares not to)

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    2. Hhahaha, what's happening on liHub these days? I've been avoiding it and am feeling much healthier. :-)

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    3. Neil is definitely not BR. Totally different syntax.

      Delete

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