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.

New FDA Proposed Rule will Impact Regenerative Medicine Products

For those involved in creating regenerative medicine products that combine cells with various biomaterials, such as natural or synthetic scaffolds, you should be aware that the FDA recently issued a new Proposed Rule for these types of medical products.  In regulatory speak these are “combination products” since each component can be regulated separately.  For example, cells are regulated as biological products and most scaffolds are regulated as medical devices. So a regenerative medicine product consisting of cells and scaffolds is defined by the FDA as a biologic-device combination product.

The new Proposed Rule describes in somewhat confusing detail when the drug-biologic good manufacturing practice (GMPs) will apply to these products versus the medical device quality systems regulations (QSRs).  In a nutshell, the manufacturer of a combination product can decide to either adopt QSR regulations or adopt GMP regulations for the manufacturing or choose a hybrid approach.  Here are the 3 main choices i gleaned from my quick read of the rule:

  1. If you already have a quality system based on the medical device QSR regulations you can continue to use this system.  However, you may need to augment your quality system to include some GMP specific requirements.
  2. If your firm already has a quality program based on the GMPs, you can continue using the GMPs, but may need to augment some elements of the medical device QSRs that are missing.
  3. The alternative either of those approaches is to apply medical device QSRs to only the medical device component and GMPs for the biologic component.  For example, if your regenerative medicine product consists of ex vivo expanded cells that are seeded onto a synthetic scaffold, one could envision a hybrid quality program that ensures the cells (biological product) are manufacturing according to GMPs and the scaffold would be manufactured according to medical device QSRs.

One issue that is not entirely clear, particularly for a regenerative medicine product, is how the designation of a “Lead” FDA Center will influence the choice in the quality approach that is most appropriate.  The “Lead” FDA Center is the group that will review and ultimately approve the medical product.  While there are a lot of similarities between QSRs and GMPs, I’m not sure I would want to choose the QSRs if my combination product is going to be reviewed by CBER, which is more familiar with the GMPs.  Similarly, choosing the GMPs for a combination product that is reviewed by medical device reviewers in CDRH, would probably not be a wise decision.

Like any new proposed rule, I am sure there will be a number of comments from stakeholders in industry and academia. If you want to make a comment on this proposed rule, here is the link to do so online.  Comments are due by 22-December 2009.