A Third Approvable Letter

J0385349 On Friday, it was announced that Encysive Pharmaceuticals received a third approvable letter for its NDA for THELIN(tm) (sitaxsentan sodium), for the treatment of pulmonary arterial hypertension.  At 8 AM Eastern Time this morning the company is holding a Web cast.  This posting is made prior to the Web cast.

J0385349_2"We believe we adequately addressed the issue raised by the FDA in the second approvable letter and we are deeply disappointed in their decision. Encysive remains committed to THELIN in Europe, Australia and Canada, where it has been approved for sale," commented Bruce Given, M.D., President and CEO of Encysive J0385349_3Pharmaceuticals Inc. – from the company press release.

This development raises two important questions (i) what makes it possible to get a third approvable letter, and (ii) do products that receive them ever achieve approval?

The answer to the first question is – I don’t know, but I can guess.  There is no way to know for sure without reviewing the exact circumstances involved – what the FDA asked for and what the FDA received in response – so being on the outside of those circumstances, I can only speculate.  But I do recall one past experience where I watched a prescription heartburn treatment try to go over-the-counter and fail to get an advisory committee recommendation of approval not only once, but twice. 

The problem?  Both times, the committee and the FDA reviewer outlined fairly specific issues with the way the company presented the data and asked for some revision as a result.  But each time the company came back, as I watched their presentation, it was immediately clear that the company was not answering the questions as directed.  I’m sure the company believed it was answering the question – but they weren’t.  They were taking shortcuts and answering the question they way they wanted to – not the way the FDA and committee wanted them to.   How does such a thing happen? 

  • First, to any company’s credit – it is likely that responses are being made by people who so completely believe in the product, that they have a hard time answering the regulatory demands objectively – and objectivity is really what is necessary. 
  • Second, the people who put these responses together are from regulatory backgrounds because people think this is a regulatory issue about data – and it is.  But it is also a communications issue about building your best case.  If you are only paying attention to the data, and not how you are stating it,  it is a mistake.   

The answer to the second question – do products receiving a third approvable letter ever get approval?  The answer is yes.  I found one instance.  There was a Pharmacia (now residing with Pfizer) application for a product called Xalatan – an intraocular pressure lowering agent used to treat glaucoma and ocular hypertension and was already approved in Sweden and the European Union.  But the product received its third approvable letter in late 2001 and was finally approved in July 2003.  This was the only example I could confirm. Is there a lesson in this for others?  Probably not – each circumstance is different. 

But two things I can recommend for any company facing an approvable letter situation – it is important as you prepare your response to have the material reviewed by an outside, independent and objective consultant – someone with no ties to the company, no stock ownership and a keen eye.  Then, listen to him or her.  Second, have it looked over by someone who knows communications.  It could be the difference between an eventual approval or another approvable letter.  I  am not suggesting in any way that in this case the company did not do this, I am only suggesting that it is a prudent course of action. 

Lastly, of course, no matter what the company ends up doing, the data has to be there. 

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