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Regulatory/Quality Compliance

The FDA is Shifting Focus to Both Ends of the Product Development Spectrum The Food and Drug Administration (FDA) recently announced measures it plans to take in order to process and approve progressively more complex novel and generic therapies. There are some key areas expected to boom over the next few years, including two in particular. The first is novel cell and gene therapies, more specifically CAR-T therapy, a transformative new category of medicine. This new and complex area of development brings possible treatments for those diseases which, until now, have had a poor prognosis in terms of patient outcomes and offers pharma companies a new avenue of development. The second boom area, at the other end of the development spectrum, is generic medications. These will provide healthcare professionals with the option of less expensive solutions to diseases that previously may have been incredibly expensive to treat, helping to tackle the high cost of treatments to government providers, insurance companies and patients across the US. From the most complex innovations to the generic, the rapidly evolving regulatory processes mean that pharma companies have to work intensely to master the updated paradigms in order to maximise their FDA interactions and ensure fast product approval. Technology and Capability Advances are Driving the Surge in Cell and Gene Therapy Submissions Cell and gene therapy research and development has grown rapidly in past years and continues to accelerate. This is due to two key aspects: firstly, advanced technology, both biological and digital, has been made increasingly available to a wide variety of organisations from universities to pharma companies. This has allowed for greater understanding and visualisation of some of the intricate mechanisms behind disease that have previously been hidden. Secondly, an increase in investments from private and public sectors has provided pharmaceutical companies with the capability, scale and space required to investigate and produce hard to develop medicines. Additionally, the Center for Biologics Evaluation and Research (CBER), the regulatory body for cell and gene therapies within the FDA, will be providing a wide range of support for the development of these treatments. This support will include proactive scientific and regulatory advice for both researchers and manufacturers in the area of novel product development, as well as new guidelines on the development and approval of medicines within this field. The aim is that this additional support will ultimately allow new product submissions to be reviewed and approved more efficiently than is currently possible. There has already been a surge of regulatory submissions in this area; the FDA had over 800 investigational new drug (IND) applications for cell and gene therapies on its books at the start of 2019 and it is expecting this number to rapidly increase, with a further 200 IND applications each year for the next ten years. By 2025, CBER are expecting to approve between 10 and 20 cell 50 INTERNATIONAL BIOPHARMACEUTICAL INDUSTRY

and gene therapies annually, a huge increase when considering that only around 20 therapies have been approved by the FDA to date. To help accommodate the inevitable increased pressure this will bring on the review and approvals process, the FDA is planning a significant expansion in personnel to oversee the clinical development process and review of cell and gene therapy applications.1 There are also new, comprehensive guidance documents issued and planned to help pharma companies navigate through product development challenges. The FDA are specifically creating new guidance on innovative trial design and common manufacturing protocols, with the intention that these may then allow smaller groups, e.g. academics, to conduct their own clinical trials and therefore help develop even more novel cell and gene therapies. It remains to be seen whether these new trial designs will be embraced, however, but the pragmatism and sense of urgency by the FDA should be applauded. One research area in particular receiving intense focus is chimeric antigen receptor (CAR-T) products specifically, which the FDA will need to nurture and support the most due to the huge medical impact that they are expected to have. This groundbreaking method of treatment reprogrammes the body’s own T-cells so that they attack specific cells, e.g. cancer cells, directly. These treatments could potentially provide a cure for some of the hardest to treat cancers, such as B cell acute lymphoblastic leukaemia in children. However, the engineering and development of CAR-T therapies has proved by no means to be a straightforward process. The FDA has demonstrated its commitment to this promising area of medicine by developing a policy to clarify how it will apply its existing expedited development pathways, including breakthrough designation products, to products in the CAR-T cell and gene therapy classes. The FDA hopes to ease the development and review process by guiding companies in crafting their study design, data collection and regulatory submissions for these life-changing treatments. Once a treatment has been through an expedited development process and is in market, the FDA would likely require post-market, confirmatory studies that provide real-world evidence and allow for larger data sets to help confirm the clinical benefit. These studies would provide additional evidence on the product’s safety, efficacy or optimal use, and may be essential to further evaluate the risk/benefit of the product. It’s important to remember that, no matter how impressive these treatments may first appear, there are nonetheless always some key safety concerns which must be considered in the post-marketing setting. Some CAR-T therapies have shown a risk of severe toxicity from cytokine release syndrome (CRS) in patients, so the FDA is conscious of being accused of pushing these therapies through their review too quickly or not requiring adequate post-marketing followup. To help manage this side-effect in practice, the FDA has included specific requirements that any hospitals or healthcare professionals prescribing CAR-T therapies must have received special training in order to be able to recognise, diagnose and treat CRS. Summer 2019 Volume 2 Issue 2