Cell/Gene Therapy Manufacturing Readiness Urged As A Condition For US Expedited Designation
Executive Summary
Requiring that certain chemistry, manufacturing and controls conditions be satisfied before awarding breakthrough or regenerative medicine advanced therapy status would help ensure that the quality side of product development keeps pace with the clinical side, says Parexel's Mo Heidaran, a former CMC reviewer in the FDA’s biologics center.
A threshold degree of manufacturing readiness should be required for designation of cell and gene therapies under the US Food and Drug Administration’s expedited regulatory pathways, a former agency reviewer believes.
Requiring that sponsors satisfy certain chemistry, manufacturing and controls conditions before receipt of breakthrough therapy or regenerative medicine advanced therapy designation would help ensure that the quality side of product development keeps pace with the clinical side, said Mo Heidaran, VP-technical at Parexel International Corp.
Heidaran joined Parexel in December after eight years at the agency where he held various positions within the Center for Biologics Evaluation and Research, including as a good manufacturing practices reviewer for cell and gene therapies. He discussed CMC readiness as a condition for breakthrough and RMAT designation during a panel session and in a subsequent interview with the Pink Sheet at the Biotechnology Innovation Organization’s recent annual meeting in Philadelphia.
“What we’ve seen in the world of advanced therapies is they’ll get the clinical data together and they’re still working on the CMC issues, and often the CMC issues really are holding back the timeline of getting … this application in and the product on the market.” – FDA’s Wilson Bryan
Withholding expedited pathway designation pending CMC readiness would incentivize sponsors to pay more attention to manufacturing problems early, before they become a drag on product approvability, Heidaran said. “If there are no incentives to solve some of these problems, they will not be solved.”
His proposal is aimed at addressing an oft-repeated complaint of FDA officials at BIO: cell and gene therapy sponsors need to get a better handle on manufacturing issues earlier in the development process than currently is happening.
“With the development of small molecules, by the time you get the clinical data, the evidence of effectiveness and for safety, you’ve got pretty much everything to be ready and to file your application,” Wilson Bryan, director of CBER’s Office of Tissues and Advanced Therapies, said at BIO. “What we’ve seen in the world of advanced therapies is they’ll get the clinical data together and they’re still working on the CMC issues, and often the CMC issues really are holding back the timeline of getting … this application in and the product on the market.”
If sponsors paid more attention to CMC issues up front, “then we think that we could get these products to the market quicker,” Bryan said.
Manufacturing Not Part Of Statutory Criteria
The criteria for awarding breakthrough therapy and RMAT designation currently do not take into account manufacturing readiness.
Under the FDA Safety and Innovation Act of 2012, a product may be eligible for breakthrough designation if is intended to treat a serious condition, and preliminary clinical evidence indicates the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints.
The benefits of breakthrough designation include intensive guidance from the FDA on an efficient drug development program, and an organizational commitment to involve the agency’s senior management in facilitating development.
The RMAT program, established pursuant to the 21st Century Cures Act of 2016, provides all of the benefits of breakthrough designation, including early interactions to discuss potential surrogate or intermediate endpoints.
To be eligible for RMAT designation, a product must meet the definition of a regenerative medicine therapy and be intended to treat, modify, reverse or cure a serious condition. In addition, preliminary clinical evidence must demonstrate that the product has the potential to address unmet medical needs for the condition.
Under both programs, a designation may be rescinded if a product no longer meets the qualifying criteria. In addition, a sponsor may withdraw the designation if it is no longer supported by emerging data or the drug development program is no longer being pursued.
The number of RMAT designations recently surpassed the number of breakthrough therapy designations for cell and gene therapies and other products regulated by the Office of Tissues and Advanced Therapies. (Also see "BIO 2019 Notebook: Merck; RMAT; Out-Licensing Deals" - Pink Sheet, 3 Jun, 2019.)
While CMC is not part of the statutory criteria for designation, in some cases product characterization issues have resulted in the denial of RMAT designation because sponsors tried to rely on clinical study results for a product that was different than the one for which the designation was requested, Heidaran said.
The agency’s final guidance on RMAT designation reinforces the need for preliminary clinical evidence to be generated using the product the sponsor intends to use for clinical development. However, the guidance also notes that manufacturing changes made to products during development would not necessarily preclude initial RMAT designation or cause a designation to be rescinded. (Also see "Regenerative Medicine Therapies: Manufacturing Changes May Not Impact RMAT Designation" - Pink Sheet, 18 Feb, 2019.)
Post-Designation Silence
Even though both the breakthrough and RMAT programs are aimed at increasing interactions with the agency early in development, sometimes the agency will hear nothing from a sponsor after a designation is granted. (Also see "RMAT Designation Requests May Rise Or Fall On Manufacturing Changes, Clinical Data Breadth" - Pink Sheet, 27 Jun, 2018.)
One reason for this silence, according to Heidaran, is that sponsors are struggling with manufacturing issues.
“In some cases, the manufacturers become very quiet for a number of months, and in fact sometimes a year or two, after they are awarded the breakthrough, after they have the press release and receive the attention,” Heidaran said. “As a result, it has been my position when I was at the agency that CMC readiness has to be a requirement for expedited program [designation], because if it’s not there’s no incentive for manufacturers to follow up and continue to work on those issues as they go forward” with the same focus and effort that they put into the clinical development side.
“When you don’t get comments from FDA in respect to your manufacturing, when you’re getting the expedited designation, when that pressure does not exist, it gives an erroneous impression to the CEOs, the decisionmakers within these companies, that your manufacturing is under control.” – Parexel’s Mo Heidaran
A case could be made for factoring manufacturing progress into a designation decision because the Center for Drug Evaluation and Research has taken back breakthrough designation in some cases when there has been insufficient activity in a development program generally, Heidaran said.
CDER told the Pink Sheet said its review teams and Medical Policy Council review the status of all breakthrough-designated programs annually to see if the designation criteria continue to be met. The drugs center has rescinded a total of 15 breakthrough therapy designations as of 31 March. (Also see "Breakthrough Therapy Designations" - Pink Sheet, 7 Feb, 2017.)
In CBER, a committee performs a periodic summary review on the status of breakthrough-designated development programs every six to 12 months, or at a greater frequency agreed upon at the first breakthrough therapy review committee meeting with the sponsor. “The purpose of this review is to assess the continued adequacy of the proposed overall product development plan. The frequency of the periodic summary review may be adjusted as the development program progresses,” CBER said. CBER has not rescinded any breakthrough therapy designations as of 31 March.
Annual reviews to assess progress under breakthrough and RMAT are important to ensuring that companies are actively engaging with the agency, Heidaran said.
“When you don’t have that engagement, then you’re really not fulfilling the requirements for an expedited program, and that is what is happening in some cases,” he said. “And if that engagement is absent over the long term, then there are some question marks about whether the expedited program is actually serving its intent.”
Making some level of CMC readiness a condition for breakthrough or RMAT designation would also bring greater attention to manufacturing issues by senior management and investors, Heidaran believes.
“When you don’t get comments from FDA in respect to your manufacturing, when you’re getting the expedited designation, when that pressure does not exist, it gives an erroneous impression to the CEOs, the decisionmakers within these companies, that your manufacturing is under control,” he said.
Little Problems Become Big Problems
Heidaran also expressed concerns that given the large treatment effects for breakthrough and RMAT-designated products, agency staff may feel pressure to approve a product even if its CMC is not up to snuff, and then manufacturing challenges become magnified at the commercial scale after approval.
In separate session at BIO, Denise Gavin, chief of CBER’s gene therapy branch, had some advice for sponsors when it comes to their manufacturing programs.
CBER’s Denise Gavin said she sees “a lot of funny statistics and really just hand waving and, ‘Everything’s fine.’ But then when you try to do a larger scale, you end up really messed up.”
“You need to make sure that you have enough quality data to actually understand what’s important for the critical quality attributes, so when you’re making all these changes through development that you have enough data that you can actually figure out what’s important,” Gavin said. “If you don’t have enough quality information, enough characterization of your product, you end up … just guess-working what’s important.”
Gavin said she sees “a lot of funny statistics and really just hand waving and, ‘Everything’s fine.’ But then when you try to do a larger scale, you end up really messed up.”
She urged sponsors to retain product from every single lot manufactured, even for preclinical use. “Instead of making huge lots of stuff, I would make smaller lots and try to treat people in the different trials with different lots of products,” she said. “Then you have a wider range of information about your product” when a sponsor seeks licensure.
[Editor's note: This story was revised on 19 June to correct Denise Gavin's title.]