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With Fibcrocell (NYSEMKT:FCSC) experiencing a surge in interest and trading volume (3x average trading volume Monday) as we get closer to Wednesday’s PDUFA for laViv azfibrocel-T for smile wrinkles, I decided to take a closer look at the 2009 FDA committee meeting that put in motion the current NDA.

In October 2009, the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee reviewed azfibrocel-T. The committee voted 11 yes to 3 no that the data presented on azfibrocel-T demonstrated efficacy, and 6 yes to 8 no that the data demonstrated safety, both for the proposed indication.

Although no surprise based on the votes, the members of the committee were very concerned about the safety of laViv. The committee commented on the lack of sufficient data related to the processing, characterization and collagen production of the injected cells. Some committee members expressed concern that due to a lack of data on the mechanism of action, there was insufficient information to assess the safety of the product and recommended collection of long-term follow-up data. There was general consensus that as this is a novel cellular therapy for a non life-threatening condition, safety standards should be set at a high level.

In a discussion of additional studies that could be performed to increase safety assurance, the committee commented on the need to determine if efficacy is derived from normal collagen production versus scar formation. Longer-term studies (greater than one year) may be necessary to determine whether implanted cells remain productive. Some safety concerns could also be addressed by further product characterization, such as karyotyping, and analysis for tumor markers. Additional safety and mechanistic data could be obtained by conducting a clinical study in which cells are injected into a less visible area on the body followed by taking serial biopsies for analysis. Some committee members stated it may be possible to obtain safety and efficacy data from previous commercial use of the product in Europe.

As the vote suggests, the comments on efficacy were a lot more bullish. A majority of the committee agreed that the available data demonstrated efficacy in the narrowly defined application: nasolabial fold wrinkles. Dissenting members voiced concern about the lack of objective and long-term efficacy data. The committee suggested additional studies are needed to evaluate the product in elderly, non-Caucasian and male populations and recommended a registry be created and maintained to gather information on ethnicity, race, age and sex.

One other point: There were several comments from the committee expressing concern that, if licensed, the product will inevitably be used off-label to treat other facial wrinkles.

Two months later, the FDA followed the committee’s advice and issued a complete response letter to Fibrocell. The letter requested that the firm provide data from a histopathological study on biopsied tissue samples from patients following injection of azficel-T. The letter also requested finalized chemistry, manufacturing and controls information regarding the manufacture of azficel-T as follow-up to discussions that occurred during the BLA review period, as well as revised policies and procedures regarding shipping practices, and proposed labeling.

In 2010, the company completed the requested trial and submitted a response to the CRL at the end of last year. The company’s response contained data from a 29-patient blinded study (IT-H-001). The FDA participated in the design of the protocol, and consented to the unblinding of the study data. At three months, there were no unexpected results, and the study provided additional data to support the safety profile seen in the clinic. There were no safety concerns raised.

If the FDA’s committee thinking is any close to the FDA’s NDA review process, then this will be a close call. There was only a two vote difference between the Yes’s and No’s during the committee meeting. However, there seemed to be a lot of concerns for just a two vote difference. The fact that the committee kept harping on the need of long-term safety data may weigh on the FDA’s decision. The company’s data submission only amounted to three-month data.

Separately, laViv has had prior human use. The product was marketed for a short time in the United States prior to submission of an Investigational New Drug (NYSE:IND) application in 1999. It was also marketed in the United Kingdom between 2002 and 2007. The commercial manufacturing experience and patient administration experience in Europe were considered sufficient to support clinical studies under U.S. IND. The cumulative experience with the product includes over 6,000 subjects treated.

Source: Fibrocell Science: Interest Increasing With Wednesday's FDA Action