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Pink Sheet – Gene Therapy Guidance From US FDA Likely Needs Updating Sooner Rather Than Later

Pink Sheet – Gene Therapy Guidance From US FDA Likely Needs Updating Sooner Rather Than Later

Executive Summary

CBER Director Peter Marks says the “half-life” for the existing six gene therapy guidances likely is two to three years due to the fast pace of scientific discovery.

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Gene therapy sponsors should not expect the US FDA’s latest guidances to maintain a long useful life.


The suite of draft guidances issued in July likely will need to be updated within five years, which is mostly attributable to the innovation in the field, said Center for Biologics Evaluation and Research Director Peter Marks.


“My guess is the half-life is probably two to three years,” he said Nov. 14 during Biopharma Congress IV, sponsored by Prevision Policy and Friends of Cancer Research. “Probably five years from now we’re going to have to start revisiting them because things are going to move so quickly because science is moving so quickly.”


The six gene therapy guidances covered a wide range of issues, including long-term follow-up studies (Also see “Gene Therapies Need Long-Term Follow-Up Plan From Outset Or Risk Clinical Hold ” – Pink Sheet, 11 Jul, 2018.), and chemistry, manufacturing and controls issues (Also see “FDA’s CMC Guidance For Investigational Gene Therapies Reflects Broader CMC Evolution” – Pink Sheet, 11 Jul, 2018.). The agency also gave its thoughts on hemophilia and rare disease gene therapy development. (Also see “Hemophilia Gene Therapy Studies Could Use Non-Inferiority Design, US FDA Suggests ” – Pink Sheet, 16 Jul, 2018.) and (Also see “Familiar Principles In Gene Therapy Guidance For Rare Diseases” – Pink Sheet, 11 Jul, 2018.)


Marks said CBER is making decisions based on the information it has in hand at the time and he expected that “sometimes we’re going to actually make the wrong decision perhaps, but we go back and fix it ultimately.”


CBER does not intend to make gene therapy decisions “cavalierly,” but the center also does not want to refuse to make decisions because of unknowns, Marks said.


CBER likely cannot afford to wait. In 2017, the center received more than 100 new gene therapy INDs and is on pace to receive the same amount in 2018.


“We’re not looking to just make decisions that we’re going to have to revisit,” Marks said. “But one of the things we can’t have is regulatory paralysis because we just can’t figure out how to move forward.”


FDA has approved three gene therapies so far, the most recent Spark Therapeutics Inc.’s Luxturna (voretigene neparvovec-rzyl). (Also see “Spark’s Early Christmas Present: US FDA Approves Luxturna For Vision Loss” – Pink Sheet, 19 Dec, 2017.)

Will Revisions Lead To Uncertainty?

The realization that FDA guidance on an emerging therapeutic area will need revisions soon is not surprising. The agency’s recognition that the field likely will evolve beyond its guidance quickly also may be reassuring to sponsors developing the next generation of gene therapies.


However, guidance development is a long and labor-intensive process, which may mean the agency’s updated thinking may not be available outside of a one-on-one meeting for a while.


FDA experts will need months to write and update the documents. HHS and White House approval also are required before the documents can be released, which substantially lengthens the process. FDA famously refuses to give exact dates it will release guidances because it often does not know when the clearance process will be completed.


“Things are moving fast and we just have to adjust the best way we can to it,” Marks said.


Marks’ comments also may inject some uncertainty into sponsors’ development planning. With the knowledge that changes are expected, sponsors may question whether the advice they receive will change mid-development or worse, mid-review.


Marks admitted some questions about the products may be left unanswered in the short-term.


“I think that’s very true in the area of gene therapy where perfection is going to be the enemy of good,” he said. “There are going to be some uncertainties with gene therapy moving forward.”


Changing FDA thinking on development issues sometimes have created friction with drug sponsors. Special protocol assessments, which were designed to help bring more certainty to the development process, have drawn ire when FDA refused to honor them. (Also see “FDA’s Special Protocol Rescissions Get U.S. Capitol, Venture Capital Attention” – Pink Sheet, 13 Jun, 2014.)

FDA Still Encouraging Gene Therapy Development

FDA willingness to revisit gene therapy guidances is another indicator of the agency’s belief in the sector’s potential.


Several regulatory streamlining measures have been initiated already to help the sector grow. The agency and NIH decided earlier this year that adverse event reports only should be submitted to FDA, and indicator the products no longer needed special oversight. (Also see “NIH Ends Gene Therapy Trial Reporting Requirements In Reg Streamlining Move” – Pink Sheet, 16 Aug, 2018.)


FDA also has implored gene therapy developers to deal with manufacturing issues early, in part to prevent review delays. The agency said pre-built and partially automated facilities could help avoid problems (Also see “US FDA Recommends Use Of Pre-Built Facilities To Ease Scale-Up Process For Cell And Gene Therapies ” – Pink Sheet, 1 Nov, 2018.), and Commissioner Scott Gottlieb offered novel manufacturing ideas to reduce manufacturing and development costs. (Also see ” Gene Therapy ‘Cassettes’ Could Speed, Cheapen Manufacturing, Gottlieb Says ” – Pink Sheet, 23 May, 2018.)


In addition, CBER recently created a new pre-clinical meeting program for biologics and gene therapy sponsors to gain advice about manufacturing and other development issues. (Also see “CBER Implements Pre-Clinical Meeting Program For Biologics, Gene Therapy Sponsors” – Pink Sheet, 22 Jun, 2018.)


The popularity of gene therapies is expected to require more personnel for application review and surveillance within CBER in the coming years. (Also see “US FDA’s Biologics Center Director Expects It Soon Will See ‘Growth Spurt'” – Pink Sheet, 2 Jul, 2018.)…