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US FDA's preclinical policies should be 'more closely matched to the complexion of modern technologies,' commissioner explains.



FDA approvals



US FDA Commissioner Scott Gottlieb said the agency is developing new policies for preclinical development of products involving new technology platforms, whereby certain second entry therapies could require less pre-clinical data.



"We're going to be taking other new steps to make sure that our policies governing early, pre-clinical science are more closely matched to the complexion of modern technologies," Gottlieb said in a Sept. 7 speech to Research America's National Health Research Forum in Washington, DC. "One is evidenced in how clinical trials are initially designed. In certain cases, there are a lot of common features across the same platform, even as it's used to target different genes or proteins. There may be a plausible reason to recognize how a product or platform can work across multiple disease states – and leverage the learning from one setting in other opportunities."



One example of FDA acting on these principles came over the summer when Merck & Co. Inc.'s Keytruda (pembrolizumab) became the first cancer treatment to be approved based on a common biomarker rather than the location where the tumor originated. (Also see "Biomarker-Led Claim Is Small Step For Merck's Keytruda, Giant Leap For Cancer Indications" - Pink Sheet, 23 May, 2017.)



In another example, "we may be able to take a more adaptive approach in our pre-clinical evaluation of different therapies that share a lot of common characteristics in the overall platform used to deliver a gene product," Gottlieb said. "Consider two gene therapy vectors that contain CRISPR constructs differing by only one base pair. These two products might not need nearly the same amount of pre-clinical data for the second variant as was required for the first one, if we can borrow what we learn across different clinical applications of the same basic construct."



Sponsors sometimes overestimate the amount of information needed to file an IND, Gottlieb said, which increases the cost of development early in the process.



By comparison, he said that if the CRISPR inserts are different at five or more base pairs, more data may be required.



The agency approved its first gene therapy last week, Novartis AG's chimeric antigen receptor T-cell (CAR-T) therapy Kymriah (tisagenlecleucel) for treatment of B-cell precursor acute lymphoblastic leukemia. In a press briefing announcing the approval, Gottlieb said it involved a new collaborative scientific approach within FDA. (Also see "Novartis CAR-T Therapy's Swift Approval Aided By REMS And New US FDA Review Model" - Pink Sheet, 30 Aug, 2017.)



Gottlieb noted that the agency has 500 active investigational new drugs (INDs) related to gene therapy and 76 active INDs related to CAR-T therapy.



Among other actions related to pre-clinical development, Gottlieb said the agency is adopting new policies for earlier meetings with product developers. He noted that some sponsors sometimes overestimate the amount of information needed to file an IND, which increases the cost of development early in the process.



In addition, Gottlieb said Center for Biologics Evaluation and Research Director Peter Marks will be leading efforts to clarify how the agency will foster development of innovative products through early interactions with sponsors. The agency will be providing educational materials to sponsors that describe this new approach.



Real-world evidence will become more important as products come to market with theoretical risks, such as gene therapy and CRISPR, where you might want to follow patients for a long time, Gottlieb said.



Gottlieb signaled he would be discussing other policy initiatives shortly. At the Regulatory Affairs Professionals Society's annual meeting on Sept. 11 he will talk about steps the agency is taking to make the clinical stages of development more efficient and effective. And at the end of the month he will be speaking at the National Press Club about the broader role of FDA as a medical staff and its post-market obligations.



An audience member asked Gottlieb about real world evidence, especially with respect to gene therapy. He replied that RWE will become more important as products come to market with theoretical risks, such as gene therapy and CRISPR, where you might want to follow patients for a long time.



He then commented on the premarket drug review process, saying the role of review staff needs to be thought of more broadly than just individuals focused on review metrics and goals.



"The drug review process is about more than just meeting deadlines. It's about taking a holistic approach to the life cycle of the product and making sure that the people who work on drug reviews are also very closely integrated into how we think about the postmarket safety of those products," Gottlieb stated. "That's going to become more important especially with some of the new platforms" where they may be providing clinical benefit but the complexity relates to product features and postmarket considerations.

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