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.

Will Fibrocell Sciences be the 1st Regenerative Medicine Product Approved by the FDA in over 12 Years?

I had a chance to attend part of the October 09, 2009 FDA Cellular, Tissue and Gene Therapies Advisory Committee meeting to discuss the biologic license application (BLA) for Fibrocell Science’s autologous fibroblast product intended to treat nasolabial fold wrinkles.

Don’t be surprised if you have never heard of Fibrocell Science, Inc. Prior to filling for Chapter 11 bankruptcy and reorganizing, they were known as Isolagen, Inc.

Based on the discussion at the meeting and in the FDA briefing document, it appears Fibrocell Science’s clinical data is adequate to demonstrate clinical efficacy.  Despite the challenges inherent in manufacturing of autologous products and given the relative ease of culturing fibroblasts, it appears there were no major manufacturing issues identified by the FDA.  The presentation given by Fibrocell Science at the meeting an other supporting information can be found at a separate link. I was not able to stay for the entire meeting, but in general the members of the advisory committee seemed satisfied with the clinical efficacy data.  However, there was a lengthy discussion about the overall evidence for clinical safety, due in part to question #1, posed by the FDA to the committee (note: “IT” refers to Isolagen Therapy, since at the time of the BLA submission in May 2009, the company was still going by the name of Isolagen:

Tumorigenicity: If approved, IT will be the first cellular product for this indication, and the first fibroblast product that is an injectable cell suspension. Uncontrolled cell growth and/or tumor formation could be potential risks of cultured fibroblasts due to their proliferative nature. In addition, there is a theoretical risk of the post-auricular biopsy transferring abnormal or malignant cells that may not be detected in the quality controls of product manufacturing. Long term follow-up data are limited. One case of basal cell cancer occurred near the site of injection; however, the relationship of IT to this case cannot be assessed.

As a result, the committee voted 11 (yes) to 3 (no) that the autologous fibroblast product demonstrated efficacy for the proposed clinical indication, but 6 (yes) to 8 (no) that the clinical data demonstrated safety for the proposed indication.  This is quite interesting since in order  for FDA to issue a BLA, the product must be demonstrated to be both safe and effective.  Usually efficacy is the primary issue in a BLA, at least for cell-based therapies.  From what I understand from the discussion at the advisory committee meeting there was no pattern, or other clear evidence, that the autologous fibroblast product presents a safety risk to patients.  However, the FDA must ensure the potential benefits to patients outweigh the risks.  Given the non-life threatening indication (wrinkles), it is prudent for the FDA to be cautious.  Despite this, I am cautiously optimistic that a BLA will issued for this product, albeit with post-approval (Phase IV) commitments to further study the short and long term safety profile of the product.  If you were at the meeting or have other insights regarding this product, please share them in the comments.


ChondroCelect is First Advanced Therapy Medicinal Product Approved in EU

For those following the commercialization of regenerative medicine products, there has been some promising news this month. Tigenix, based in Belgium, received authorization on October 09, 2009 from the European Commission to market ChondroCelect, its autologous chondrocyte implantation (ACI) product.  This is the first medicinal product to be approved as an Advanced Therapy Medicinal Product (ATMP).  While this may not be the most exciting example of a regenerative medicine product, I do consider it important from the regulatory perspective in that it validates that cell-based products can be approved under the ATMP regulation.

If anyone has insights regarding other regenerative medicine products that may be approved in the near futue in the EU, I’d love to hear about them in the comments.


Human Tissues: Never Trust, Always Verify

On October 13, 2009, the FDA posted on its website a news release from the U.S. Attorney concerning a California man who on multiple occasions falsified records related to the suitability of human tissues for clinical use.  This is unfortunately just one example of problems with those supplying human tissues.  Follow this link to the FDA’s website to see recalls involving human tissues. I find this personally disturbing on a number of levels, particularly given the important role donated human tissues play in addressing a number of medical conditions and the generally low level of donation of tissues and organs.  Reports such as these, certainly can’t help those striving to improve the rates of tissue and organ donation.

Since many regenerative medicine products utilize cells and tissues as ‘starting materials’ to create new medical products, this news release should remind all of us to never assume the cells or tissues you are using are suitable, unless you have reviewed the documents and verified they meet the donor eligibility requirements under the FDA’s good tissue practice (GTP) regulations.  Of course verifying the quality of materials should be done for all components used in the manufacturing process, but additional emphasis must be given to human or animal origin materials.

It would be ‘nice’ if you could trust your suppliers from the very beginning, but unfortunately, there are unscrupulous individuals who are either ignorant of the requirements, or just don’t care.  Fortunately, there are an increasing number of ‘quality aware’ suppliers for the regenerative medicine field. Our task to always think about the patients who may receive our products and to ensure that the materials used to create them are of the highest quality possible.


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.


IXA Statement on Xenotransplants for Type 1 Diabetes

For those of you following developments in the field of xenotransplantation, the International Xenotransplantation Association (IXA) has recently developed a proposed Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes.

In my quick read of the statement it appears to be a comprehensive, well thought out document that encompasses ethical and public health considerations as well manufacturing, preclinical and clinical considerations.    The statement was drafted by an number of thought leaders in the field, such as Bernhard Hering, Greg Korbutt, Clive Patience, Harold Vanderpool and Henk-Jan Schuurman.  It also appears that the FDA provided some informal feedback on the statement, since Keith Wonnacott from FDA is mentioned in the acknowledgments.

I get the general impression that many assume the field of xenotransplantation is “dead,” because of  the challenges the field has faced due to public health concerns such as porcine endogenous retrovirus (PERV).  However, it appears the field has now been able to largely address those concerns.

Since it is clear that there continues to be  large unmet medical needs that are not yet met by any existing medical products, there has been a small but dedicated group of individuals who are attempting to determine if animal-derived cells and tissues can help.  In my view, xenotransplantation, as a cell replacement therapy,  fits within the scope of regenerative medicine.

I think this consensus statement from IXA represents one example of how complex areas of medical research, which raise an number of important issues in the minds of the public, can progress in a responsible manner.  Let me know your thoughts in the comments.


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Stem Book – An Excellent Information Resource

For anyone looking for a credible source of information on stem cell biology, I highly recommend checking out StemBook from the Harvard Stem Cell Institute. As is states on it’s website:

Stem Book is an open access collection of invited, original,
peer-reviewed chapters covering a range of topics related to stem cell biology written by top researchers in the field at the Harvard Stem Cell Institute and worldwide

The site covers a variety of topics ranging from basic stem cell biology, to potential therapeutic uses.  Granted, most of the information is from a basic research and academic perspective, but I think it  could be a potentially useful resource resource for those wearing product development hats.  For example the section on genomics and proteomics provides a sense of the possibilities for characterization of stem cells and therapies derived from stem cells that regulatory authorities are always interested in.  Hope you find it useful as well.  If you are aware of other  useful websites on stem cells and/or regenerative medicine, please let me know in the comments.


Cautionary Tale: Tumors Caused by Neural Stem Cells

I usually avoid commenting on current events occurring in the field of regenerative medicine, primarily because I can’t keep up!  In this case,  I believe the recent publication by Amariglio et al, has FDA regulatory implications for the clinical development of therapies based on stem cells.  The under-lined portion of the title of the publication says it all:

Donor-Derived Brain Tumor Following Neural Stem Cell Transplantation in an Ataxia Telangiectasia Patient”

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My 2008 Presentations & Articles Relevant to Regenerative Medicine

2008 was an extremely busy year for me, as I am sure it was for you as well. The net result is that I have been slow to post updates and thoughts regarding translation of regenerative medicine products to the clinic. In the ‘better late than never” category, I thought I would share some of the presentations and relevant articles I have written over the past year.

Links are provided for most of the presentations and articles I have generated over the past year.

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13 Tips for Successful FDA Meetings

There are many reasons for meeting with the FDA during development of a regenerative medicine product. Some regenerative medicine products are more novel than others, meaning they are so unique they have never been studied in human clinical trials. Others may not be first of its kind, but may be used in novel clinical applications or be manufactured in new ways in comparison to competitor products. The nuts and bolts of preparing to meet with the FDA will be covered in a separate posting.

There are a number of opportunities for informal and formal communications with the FDA. For the purpose of this post, I am assuming you have requested a formal meeting with the FDA, perhaps to discuss the filing of an investigational new drug (IND) application to initiate human clinical studies.

Usually, to reach this point you will have expended a significant amounts of time and money. Therefore you don’t want to blow it by not being prepared to meet effectively with the FDA. Below is my list of tips to help the process go more smoothly:

  1. Remember, The FDA Wants You to Succeed
  2. Leave the “Dog & Pony” Show at Home
  3. Safety is the FDA’s Primary Focus
  4. Provide Clarification for FDA Identified Issues
  5. The FDA Will Have Questions, Lots of Them
  6. Designate a Spokesperson to Lead the Discussion
  7. Unity is a Virtue
  8. Take Time to Summarize
  9. Call in Early
  10. Call a “Time Out” if Needed
  11. Identify yourself
  12. You May Get the FDA’s Comments Early
  13. Overall, Remain Calm, Be Factual and Enjoy the Experience.

Read on, for my thoughts on how each of these tips can be used to ensure a smooth meeting with the FDA.

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