FDA issues Complete Response Letter to Fibrocell Science BLA

In follow up to an earlier post on Fibrocell Science, Inc., according to the company on 21-December the FDA issued a ‘complete response’ letter that identifies the need to provide histopathology biopsy data on patients treated with the autologous fibroblast product as well as to resolve some manufacturing issues (CMC). The details of the letter provided by the company are not exactly abundant, but my guess is that the request for histopathology data from patient biopsies may relate to some of the potential safety concerns discussed at the FDA Advisory Committee meeting in October.  This is quite interesting since there is a general perception that autologous cellular therapies are inherently safer than an equivalent allogeneic therapy.   It appears at the end of the day it is always going to come down to what does the safety data indicate, regardless of whether or not it is autologous or allogeneic.  To be fair, this is the consistent message that FDA has given all along, though it has at times fallen on deaf ears.  If you are working with autologous therapies, now would be a good time to challenge any assumptions concerning the obvious safety of your product and make sure there is data that verifies your assumption that can be presented to regulators.

What the CMC issues are is not clear, but perhaps issues arose during the FDA preapproval inspection or the company was hoping to implement some changes in the manufacturing process for commercial ‘scale out’ of the autologous manufacturing process and the FDA did not agree their was sufficient data to support the manufacturing change. In my experience, the FDA is appropriately conservative when it comes to allowing CMC changes to be made. It is also my experience that company’s tend to be overly optimistic in the ability to easily implement process changes without first carefully developing a plan and the supporting comparability data that is typically required.   It also a good practice to engage the FDA early in any discussions concerning changes in CMC.

Responding to the FDA’s complete response letter is going to take some time (how long is unknown), but presuming there are no safety signals in the biopsy data and a workable solution can be developed for the CMC issues, it seems that Fibrocell Science is still on a path to an approvable BLA.


#1 Nancy Parenteau on 02.08.10 at 3:01 pm

What I don’t quite understand is why companies continue to miss fundamentals in their cell therapy submissions. The autologous fibroblast product should be fairly straightforward. Perhaps one problem is that companies don’t realize that process validation and quality assurance can be as or more challenging when you are working with patient samples. Genzyme certainly learned this with Carticel and they also set the BLA bar for autologous therapies high.

The perception that autologous cells are inherently safer biologically, is just that, perception. Once you get passed the possibility of disease transmission, immune reaction with the use of allogeneic cells, the possibility of something untoward happening during the in vitro process is the same. In fact, one might argue that the inability to rigorously test autologous samples for biological stability, could put be a risk not present in the use of allogeneic cell banks. Of course, how much these things are issues depends on the process. Patient histories may be important as well.

I agree that delay because of the request for biopsy data and CMC concerns could be significant. At the end of the day, sponsors do have to take a proactive role in supporting every aspect of their product before the eleventh hour. As you point out, meeting with the FDA can be an important part of that.

#2 Darin on 02.09.10 at 7:50 pm

Hi Nancy:

Thank you for sharing your insights. I know you have a wealth of experience in this area. My experience as a consultant is that developers frequently fail to challenge assumptions and most importantly verify the validity of their assumptions with regulators. I think many hesitate to ask regulators questions, not just those concerning safety, because they are rightly concerned that the response from the regulators can cost them both time and money.
However, as you know, asking regulators questions which are put in context with relevant data, can frequently result in a reasonable and thoughtful response. Whether this occurred with Fibrocell/Isolagen is not known. Hopefully, others working with cell-based regenerative medicine product can take some lessons from this.

Thanks again for sharing your perspective.


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