The Regulatory Pathways and Breakthrough Designations for Cell & Gene Therapies

By: Stephen Moore

IND to BLA: Regulatory Experiences with a Platform Cell and Therapy Autologous Fibroblast Program

John Maslowski, SVP Scientific Affairs at Fibrocell Scientific Inc., launched the morning session with a discussion on the FDA regulatory pathways a company can take when developing a new therapy. These include the Fast Track, Accelerated Approval, Priority Review, and Breakthrough Therapy pathways. He discussed the qualifying criteria and advantages for each pathway and emphasised that the Fast Track and Breakthrough Therapy pathways could be used with the investigational new drug (IND) program. He focussed on lessons learnt at Fibrocell when they sought IND approval for a biologic called FCX-007 and BLA approval for another therapeutic call LAVIV, including timeline considerations. One key point that was brought up was the possibility that the regulatory committee may require additional data, thus additional financial burden may be placed upon the submitter, which needed to considered. John then discussed in depth the key review focus of the FDA based on Fibrocell’s experience with an autologous cell product. Focus was placed on CMC, Clinical, Logistics, Labeling, and the Advisory Committee. For example, for Logistics the FDA was interested in logistical requirements that did not lie within manufacturing facility. These included the procedures to track the product throughout its entire life-cycle and customer service policies, including physician training and the handling of shipping errors. He finished his presentation by discussing what steps to take when changes to the manufacturing process are made after approval has been granted by the FDA.

Leveraging Regulatory Pathways to Accelerate Development of Cell and Gene Therapies: Breakthrough Therapy Designation.

The second presentation was given by Dennis Williams, the Head of Global Regulatory Affairs at Adaptimmune. Dennis addressed the use of the Breakthrough Therapy Designation (BTD) in advanced therapies, which was introduced by the FDA in 2012. The criteria for this designation is that the therapy under consideration must treat a serious condition, and clinical evidence must demonstrate that it shows a substantial improvement over available therapies. The BTD delivers a number of benefits:

  1. Timely advice/interaction with FDA
  2. Involvement of FDA senior managers and experienced review staff
  3. Assignment of FDA cross-disciplinary project lead
  4. Ensure efficient trial design

Furthermore, FDA review of the application occurs within a 60 day window. Once the BTD application is received the FDA reviews whether the program criteria are met, then the review division recommends a grant or denial, a final FDA determination is made and a grant/denial letter is sent. Using the BTD can expedite development by making greater use of accelerated approval, by decreasing FDA marketing application review times, by reducing pre-market development times, and can lead to more marketing approvals based on early clinical data. However, there are a number of considerations with using the BTD. One needs to consider the strategic timing of BTD. Is the clinical evidence sufficient? Where is the project in development? How will the BTD be used? Also, it is an expedited pathway, which means a lot of work for both the sponsor and the FDA. Finally, forward strategic planning needs addressing once the BTD is received.

EU Falsified Medicine Detection (FMD) and US Drug Quality and Security Act (DQSA).

David Brindley, Managing Partner of IP Asset Ventures at University of Oxford concluded the session with a discussion on the implementation of a system to identify counterfeit medicines in secondary care. Between 2005 and 2011, 17 medications from Lipitor and Viagra, to Truvada were found to be counterfeit. Most of the counterfeiting was found to be very sophisticated and with reported returns of 100,000x it is very profitable. This issue has led to the establishment of the Falsified Medicine Directive (FMD) in Europe. Under this directive two safety features are to be introduced. These are unique 2D identifiers to be placed on medical products at the point of manufacture  and tamper proof seals on the packaging. The unique identifiers will be stored in a global database. All points in the supply chain will have to be monitored by scanning of the 2D identifiers and once the medication reaches the patient, the identifier is destroyed.

According to David, counterfeiting of cell therapies is considered to be low risk but there is a potential risk during the transiting of autologous therapies. As such cell therapies will be covered by the FMD. The United States is to implement the FMD in 2019, with it going live in 2021.


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