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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6 Responses to A Third Approvable Letter

  1. Sol Luzon says:

    So Encysive’s (via todays CC) explains that the FDA has done an “Ad Hoc” analysis of Thelin’s pivotal Stride II trial, and Encysive believes this is a clear violation of SPA law. As a result of the FDA changing the rules, and applying different retrospective criteria (post SPA) they have invalidated the p value of Thelin’s pivotal Stride II trial.
    Encysive plans a dispute resolution based on this violation of the SPA.
    Considering the EMEA, Australian and Canadian regulatory agencies approved this drug: What’s your take on the Encysive’s chances in dispute resolution?
    Encysive’s CEO also commented that this post SPA analysis was highly controversial within the FDA. Giving the Class II assignment of Thelin’s second approvable which coincides with Gilead’s ambrisentan review; Might not this be a case of political abuse of the FDA process?

  2. Mark Senak says:

    I wish I had been able to listen to the call. Thanks for your comment. But I couldn’t hazard a guess on the outcome of such an appeal because I really have no knowledge of the data, what was presented and what was asked for. As far as moving the bar – I think in general – if a regulatory agency can demonstrate that because conditions have changed, it had to change its approach in evaluation, then it will be perceived as justified in doing so. But as to the specifics of this situation – again I have no basis for making a guess. Respecting the action of the FDA vis a vis any other company’s product, I know of no such evidence that would suggest a link.

  3. Sol Luzon says:

    Thanks much for your take and blog efforts!
    I think the subsequent assigning of a Class II on the one outstanding issue: which was originally assigned a Class I on the first approvable is why I suggested the political link/abuse. Now that Encysive has aired out this one issue as basically a statistical issue; it sure seems like it should have been a Class I.
    Well. if you do get some time, it was one of the more interesting calls I’ve listened to regarding an FDA/Drug Co. dispute. From the Encysive press release
    “A replay of the webcast will be available on the Company’s web site through July 18, 2007. Additionally, a replay of the call will be available until Friday, June 22, 2007 at 11:59 p.m. ET. The call replay can be accessed by calling:
    Number: (320) 365-3844
    Access Code: 877197”

  4. Annomymous says:

    The FDA changed the SPA sometime between the 2nd and 3rd approvable on Encysive. Encysive also mentioned that they witnessed an error made by the FDA on the SPA.
    GILD never received not 1 approvable for their drug which is equal, or not as good as Encysive’s Thelin. Interesting that Rumsfeld is on the BOD at GILD. There are also tons of articles were John Jenkins (Director of New Drugs), Bush, Rumsfeld, and FDA Commissionar are linked.
    This smells of political foul play for Encysive. I hope the company recovers, and they get their drug approved. Otherwise someone needs to find the bad apple here.
    Thanks for the chance to comment.

  5. Mark says:

    That would be conjecture. You present no evidence. I am not saying you are right or wrong, but speculation is not going to benefit anyone.

  6. poppover says:

    I looked up the BOD for GILD here is what they list, I am not vouching for accuracy of this list. But if Rumsfeld were on the BOD I’d have no problem believing political motives but there is no listing for D.R. on the BOD
    Our esteemed Gilead Board of Directors provides the leadership and guidance necessary to execute our mission and realize our vision.
    James M. Denny
    Chairman, Gilead Sciences Board of Directors
    Paul Berg, PhD
    Cahill Professor, Emeritus, Stanford University
    John F. Cogan, PhD
    Senior Fellow, Hoover Institution, Stanford University
    Etienne F. Davignon
    Minister of State
    Vice-Chairman, Suez-Tractebel
    Carla A. Hills
    Chair and Chief Executive Officer, Hills & Company, International Consultants
    John W. Madigan
    Retired Chairman and Chief Executive Officer of Tribune Company
    John C. Martin, PhD
    President and Chief Executive Officer, Gilead Sciences
    Gordon E. Moore, PhD
    Retired Chairman and Chief Executive Officer of Intel Corporation
    Nicholas G. Moore
    Retired Global Chairman, PricewaterhouseCoopers
    George P. Shultz, PhD*
    Distinguished Fellow, Hoover Institution, Stanford University; Director Emeritus, Gilead Sciences Board of Directors
    Gayle Edlund Wilson
    Director, Education Financing Foundation of California and Ralph M. Parsons Foundation
    * Director Emeritus

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