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Why FDA May Not Approve Bristol-Myers Squibb's Ipilimumab

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So what is the FDA's Richard Pazdur going to do on March 26 about the initial application? He has three options.

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Bristol-Myers Squibb (BMY) announced on Monday their pivotal Phase III clinical trial for ipilimumab succeeded in first-line Stage III/IV melanoma patients. Despite no details on the magnitude of efficacy or side effects, success in this so-called "024" study is a big deal.

A bigger deal will be the FDA's decision on approval of ipilimumab in earlier-stage disease -- a decision supposed to arrive March 26. The FDA canceled an advisory panel meeting on this indication, creating additional confusion about approval of this drug.

In my opinion, the approval of ipilimumab on the basis of the earlier so-called "020" study is no slam dunk. In fact, if the FDA holds to its traditional strict interpretation of biostatistics they are unlikely to approve Bristol-Myer's application.

When Medarex designed the earlier 020 pivotal trial, it was thought ipilimumab didn't have the strength to work on its own. It needed to work in combination with other therapies. This particular clinical trial was a rather complicated one with three treatment arms. It sought to determine whether ipilimumab plus a peptide-based immunotherapy called gp100 would effectively treat these melanoma patients who failed prior therapies.

  • Arm 1: ipilimumab + gp100
  • Arm 2: gp100 alone
  • Arm 3: ipilimumab alone


This 020 trial came out positive, but with a twist. Arm 1 and Arm 3 both beat the control arm, but there was no appreciable difference between the outcome between Arm1 and Arm 3. This is a problem since only Arm 1 was prospectively defined as the "treatment arm" for purposes of biostatistical analysis. In lay terms, Bristol-Myers was shooting for approval of ipilimumab + gp100 as combination therapy.

It turns out the data show gp100 adds nothing to efficacy beyond the treatment of ipilimumab alone. If you're the logical sort, you'll conclude that's better for BMY anyway since they now don't need to bother with gp100. That is logical, but it doesn't fit with the FDA's conservative view of biostatistics.

In 2007, the FDA turned away Dendreon's (DNDN) Provenge even though it demonstrated a survival advantage solely because survival wasn't the primary endpoint of their trials. In 2004, the FDA turned away drugs from Genta and Allos (ALTH) despite indications of efficacy also because of issues with lack of prospectively-defined endpoints. Richard Pazdur, head of the FDA's oncology division, holds to a strict interpretation of biostatistics that demands if the outcome wasn't prespecified it doesn't count. These are not the only examples of Pazdur's bias in this area.

Bristol-Myers prespecified the outcome they were looking for was ipilimumab + gp100 would be superior to controls. However, Bristol-Myers submitted to the FDA for approval of ipilimumab alone. In other words, it's asking for approval on a retrospectively defined endpoint -- and Pazdur hates retrospectively defined endpoints.

Proponents of approval of ipilimumab on the basis of the 020 trial have two core arguments. The first is based in logic. While I agree with the logic, there are a number of drugs turfed by Pazdur with similarly logical conclusions simply because they don't fit his conservative biostatistical view. The second argument is Pazdur has called dacarbazine, the chemotherapy typically used for these patients, a "toxic placebo."

Proponents believe the logical leap is not too far for Pazdur given his stated dislike for the alternative therapy. As noted, I don't object to this line of thinking but I also believe it is anything but a sure thing. It's worth mentioning Bristol-Myers' attempt to get approval based upon single-arm ipilimumab trials in later-stage melanoma patients didn't work.

So now we have the results of the 024 study showing ipilimumab + dacarbazine is superior to dacarbazine alone in the front line patient population. I can argue this is powerful evidence ipilimumab works in melanoma patients -- powerful enough that it should trigger approval in both first- and second-line indications.

So what is the FDA's Pazdur going to do on March 26 about the initial application? He has three options:

  1. Approve ipilimumab as a monotherapy for melanoma patients failing prior therapy
  2. Issue a complete response letter asking for additional data
  3. Delay approval so the FDA can review the data from the 024 study


Bristol-Myers would have been providing safety data all along from the 024 study, right up until probably January of this year. The efficacy data, however, would be brand new to both Bristol-Myers and the FDA.

My guess is the FDA canceled the ODAC panel because Bristol-Myers told them results from the 024 trial were imminent. Bristol-Myers would have known this because the unblinding of that trial was event-driven, and they know the event rates. By this point in March, I'd also expect Bristol-Myers to be sharing preliminary -- very preliminary -- data with the FDA from the 024 trial.

If I was a betting man, I'd bet on option 3 above. I think Pazdur delays approval at least 90 days so the FDA can analyze the results from the 024 trial. Then I think Pazdur and Bristol-Myers work to amend the existing application to reflect the new data. The FDA will issue an approval for "ipilimumab plus dacarbazine for the treatment of Stage III/IV melanoma." This tactic allows Pazdur to dodge the thorny biostatistical issues posed by the 020 trial.

I'll note March 26 is Saturday. The FDA occasionally meets Saturday deadlines on Friday, but more typically the following Monday. Given the issues here, I'd expect Monday. This should not affect most investors, except for an extra weekend of nail biting.




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