You Had To Be There

On Monday I decided to listen to the webstream of the important FDA Advisory Committee hearing
on Sarepta's eteplirsen for DMD.  You've probably read the news accounts by now, but you had to be there (or at least listening as the drama unfolded) to grasp the significance for ALS.

The FDA's Dr. Woodcock set the stage.  This hearing was about the Accelerated Approval path.  This is important, not only for DMD, but for a lot of quickly fatal diseases with no existing treatments.  She made a comment that she has made before about the significance of making a Type 2 error -- rejecting a therapy that actually works -- with this disease.

In the morning we heard well-designed and polished presentations from the drug developer and investigators.  We got the gist that this stuff was doing something good for a well-defined subset of DMD kids.  We heard about measures.  We learned about what's important in DMD kids' disease progression (a term I hate).  We learned about the logic of the drug's target.  But during question periods, there were FDA Advisory Committee comments constantly dripping into the conversation about this not being a double-blind, placebo controlled trial.  The committee was slipping in boxer's jabs regarding historical controls that really didn't land any individual wallop but were accumulating.

By the afternoon it was the FDA's turn to present, and it was anything but polished or logical to follow, but the discomfort with a trial that did not have a placebo control group kept bleeding through.  There were more jabs about endpoint measures and meaningfulness of the drug target. I kept wondering if this was really about the science and the medicine, or was it all about giving a panel a comfort level with the way they had always made decisions.  Bold they weren't.

And then there were the parents and kids and DMD physicians who got their turn to talk.  The press accounts talk about the emotion they stirred, but it wasn't all emotion.  They spoke to data.  They spoke about their experiences with the drug.  They spoke about what is important to them.  They spoke to looking at the patients in the room and seeing some results.

At the end of the day there were some votes on questions that I guess were supposed to constitute the committee's "advice."  They were difficult questions to grasp as was reflected by the number of abstentions on several.  There was a terrible quality to the voting moments, especially when we heard some of the voters' comments.

The votes reflected MDs who were not comfortable with the historical controls.  They kept saying that historical controls can work, just not these historical controls. The constant drip of discomfort with anything but a double-blind, placebo-controlled trial won.

A wise physician once said to me that you can have all the studies and data in the world, but you have to look at and treat the patient in front of you.  That was certainly missing in the Advisory Committee's comments on their votes.

I'm pretty sure that most everyone in that hearing room felt that the drug was working on some DMD kids and that it was doing no harm.  The data just weren't speaking to it well enough for the FDA to feel comfortable.

There is always a chance that any FDA decision is wrong.  That's a fact. Even the most comfortable ones for them could be wrong.  That's a fact we live with.  Why can't they?  Some there want to be perfectly comfortable in decision-making while people are dying.

The final FDA decision for Sarepta comes in the next month.  It's not looking optimistic, but just maybe some regulator will realize that the odds are that the Type 2 error was made on Monday, and that's devastating for a nasty disease with no effective therapies.

This is a big deal for the fight against ALS.  Accelerated Approval is a path that was designed for diseases like DMD and ALS, yet the FDA does not seem comfortable with it.  DMD has an FDA Guidance document.  Did that make a hill of beans of difference?  Is anyone working on the FDA Guidance draft for ALS (which is modeled closely in process and in content after the DMD document) talking to Sarepta and the DMD groups to find out how a difference in the FDA Guidance document could have changed Monday's results?

It was a difficult, draining day to listen on Monday.  We must learn from it.