Panel Must Consider Study Bias, Missing Data And Unanswered Questions Before FDA Extends Sapien Indications

In short

FDA’s circulatory panel meets tomorrow (Weds 13th June) to consider Edwards Lifesciences’ Sapien transcatheter transapical valve should be indicated for use in so-called “high risk” patients. The product is currently only indicated for use in inoperable patients following FDA approval in November 2011.

In the executive summary, all 52 pages of which can be viewed here, FDA asks the expert panel to consider many factors in making its recommendation, not least the concerns it has regarding potential bias in the selection of patients for its pivotal comparative study.


FDA’s circulatory devices panel review meeting has been prompted by FDA to address a host of issues that have come out of the PMA and other studies being undertaken by Edwards Lifesciences. That’s neither unsurprising nor unusual, given the first-of-its-kind nature of the technology.

The outcome of the meeting will be a panel vote as to whether the potential benefits for the product in its new indication outweigh the risk of its use in its intended patient population.

The indications being sought by Edwards include:

  • patients who are considered inoperable and in whom existing co-morbidities would not preclude the expected benefit from correction of the aortic stenosis (already approved last year)
  • operative candidates for aortic valve replacement but who are at a greater than or equal to 15% (high) risk of mortality for surgical aortic valve replacement.

So, what are the concerns the panel has been asked to consider? Well, find below a few examples from what is an exhaustive analysis of the company’s submission.

Valve-in-valve implantation: FDA believes this remains unproven and could be proven with a post approval study

  • FDA wants to consider additional, clinically relevant endpoints as part of the totality of the data to evaluate overall safety and effectiveness of the device based on the fact that more is now known about the Transapical valve replacement procedure.
  • Screening and subsequent enrollment practices were not homogenous. The large variation between the ratios of those screened to those enrolled may represent different selection criteria among sites.
  • Enrollment practices related to identification of “inoperable” and “high risk” patients were not homogenous across sites. These data indicate that there may have been variable selection criteria for both deciding on inoperability and determining whether the femoral artery approach was appropriate.
  • Post Approval study is proposed by FDA as a means of collecting data beyond 2 years and also ironing out discrepancies relating to procedures in which for example AVR patients received TAVR treatment.
  • Selection bias confounded interpretation of results.
  • Male vs female data variation demands a gender-specific consideration by the panel.
  • Mortality risk appears higher in the transapical group than the transfemoral group, so the panel is being asked whether the approval should extend to transapical treatment for this new high risk patient indication.
  • Sickness as a reason for withdrawal from the study may not have been homogeneous between groups. Also treatment delays and patients who ended up being treated outwith their designated group all confound the data.
  • Peri-procedural neurological events appear to double in the Sapien treatment groups, which the panel is asked to consider.
  • Aortic regurgitation in the TAVR group appears to be higher than the surgical group. FDA wants this considered in any post approval study.
  • Training looks like a major factor in avoidance of complications and FDA again asks for this to be a consideration in the post-approval phase.
  • Atrial fibrillation data lacking.
  • Long term durability remains unanswered.
  • The trial was promoted (by the sponsor, Edwards Lifesciences) as  a comparison between open operation for valve replacement with transcatheter aortic valve replacement (AVR versus TAVR), yet only a quarter of the patients had only a transcatheter insertion of the SAPIEN THV.
  • Valve-in-valve insertion (into previously implanted bioprosthetic valves) has been widely reported in Europe. FDA is keen to see that labelling prevents this in USA as adequate data does not yet exist.

So there we go. If ever one needed a good example of the lengths to which FDA goes in demonstrating patient safety when faced with a new technology, this is it. You can argue all you like about whether it’s too much, too little or just right, but what is absolutely crystal clear is that no European equivalent to this level of scrutiny exists.

Results awaited with interest.

Source: FDA