FDA Tackles Cellular, Gene Therapies

CBER Director Peter Marks has been working to better structure his center’s ability to manage the surge in research on new cell-based and genetically modified treatments for hemophilia, enzyme deficiencies, cancer, autoimmune disease, and other serious conditions. Although no gene therapies yet have been approved in the United States, novel research and testing methods are moving forward. These programs are being “catapulted forward” by advances in gene-editing techniques such as CRISPR/Cas9, Marks explained at the recent Summit on Rare Diseases sponsored by the National Organization for Rare Disorders (NORD). CBER has received more than 200 investigational new drug applications (INDs) for such products this past year and has more than 500 active gene-therapy INDs under review. The aim is for OTAT to provide more consistency and efficiency in managing these advanced therapies.

Cellular and gene therapies may be eligible for orphan product designation and exclusivity, as well as FDA-expedited development programs, Marks noted. He encouraged manufacturers to contact OTAT regarding novel approaches for developing and testing these treatments and cited opportunities to arrange pre-pre-IND meetings to begin a discussion about an investigational plan. One aim of the CBER reorganization is to better align its oversight activities more with FDA centers for drugs and medical devices. The change will address manufacturing and characterization challenges related to advanced production processes, said Marks, citing the importance of understanding batch-to-batch variability and to develop advanced statistical methods for evaluating these products.

Marks also highlighted the challenges and complexities related to producing cellular therapies at the PDA/FDA Joint Regulatory Conference in Washington D.C. in September 2016. He noted that genetically modified cellular treatments promise to provide important therapeutic benefits with extended duration of effect, but that autologous or allogenic cells that are modified to express a protein or perform a novel function in a cell also raise crucial regulatory issues related to processing and manufacturing, including lot-to-lot variation and issues related to potency, toxicities, and dosing. Process and product tracking, moreover, is critical for ensuring that the correct product is re-administered to the right person.

Clinics fight regulation

While FDA is working to ensure appropriate oversight of cellular manufacturing processes, it also is struggling to determine its regulatory authority over autologous therapies that are “more than minimally manipulated,” and thus considered to involve manufacturing processes that need to be well defined and have controls in place and policies for lot release. Up until now, FDA has held off on setting rules for the hundreds of independent clinics offering treatments and cures for rare diseases and painful conditions through manipulation of and re-injection of an individual’s own stem cells. However, many scientists and clinicians have urged FDA to set standards for these operators, claiming that they charge exorbitant fees for treatments that may have little positive effects and potential dangers.

FDA issued several draft guidance documents in 2014 and 2015 to air its “current thinking” on criteria for where agency premarket review and approval is appropriate for cellular and tissue-based therapies. The documents spurred a deluge of comments, many from clinics that oppose FDA oversight of this area. The proposals were discussed at a September 2016 public hearing and at a CBER workshop on what scientific evidence is appropriate and desired to demonstrate safety and efficacy in those cellular products subject to premarket approval. The agency continues to weigh those presentations and the response to the guidance documents.

Genetically modified cellular therapies represent some of the most complex biologic treatments for diseases and are an “exciting area” for FDA, said Marks at the PDA conference, and the agency is working to “get it right on the first try.” FDA is committed to bringing promising safe and effective therapies to patients as quickly as possible, he said, while also dealing with manufacturing issues and the need to obtain sufficient safety and efficacy data. 

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