Executive Summary

Academic institutions confused about agency standards are overly cautious in requiring early-phase studies be conducted under full GMPs, experts say; CBER Director Marks highlights regulatory flexibility but cautions that formal written guidance could be misused by those in stem cell industry.

Calls for the US Food and Drug Administration to clarify its flexibility on cell therapy development standards must be balanced against concerns about how such formalized leniency could be interpreted among purveyors of stem cell therapies, an agency official said.

At a meeting on the future of cell therapies, industry representatives and researchers urged the agency to clarify its view of the clinical and manufacturing standards applicable to exploratory studies of new cell therapies, such as chimeric antigen receptor T-cells.

Clarity is needed to help overcome academic institutions’ cautious approach of requiring that such early-phase studies be conducted under rigorous good manufacturing practice standards, speakers said.

A new white paper spearheaded by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy is aimed at facilitating early-stage trials of new cell therapies by easing some of the procedural and manufacturing burdens.

However, FDA officials and others said the agency already shows great flexibility on early clinical studies of such products, and that academic institutions need to come talk to the agency so they can capitalize on this regulatory flexibility.

“Particularly in the early stage process … we have a lot of flexibility,” Center for Biologics Evaluation and Research Director Peter Marks said. “I think it’s a question of how we make known that flexibility with a level of comfort so that academic institutions can feel comfortable taking advantage of that flexibility when appropriate.”

While there may be room for the FDA to clarify its view on manufacturing and clinical standards applicable to such early-stage trials for cell therapy, it must tread carefully in doing so, Marks said.

“Unfortunately we’re in a field here in this CAR-T cell and T-cell immunotherapy field which is directly adjacent to the stem cell field, and whatever we do in this area we have to be cautious that we don’t create a situation that we unintentionally put other people at risk in that field,” Marks said.

The CBER director previously has criticized the proliferation of commercial stem cell therapy providers that make unsupported efficacy and safety claims. (Also see “Unlicensed Stem Cell Clinics Are ‘Surrogate’ For Right To Try, US FDA’s Marks Says” – Pink Sheet, 21 Nov, 2018.) He cited the close proximity between the cell therapy and stem cell therapy fields.

New White Paper

The 17 May meeting was convened Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy to discuss a new, multi-stakeholder white paper aimed at facilitating early-stage trials of new cell therapies by easing some of the procedural and manufacturing burdens on such studies.

The white paper discusses potential ways to accelerate development, including:

• Expanding the exploratory IND paradigm, which is currently limited to studies involving limited human exposure with no therapeutic or diagnostic intent, to early clinical studies in which small numbers of patients are dosed at therapeutic levels and with therapeutic intent;
• Flexibly applying phase-appropriate GMPs to the manufacture and testing of plasmids, viral vectors, ancillary materials and reagents, and T-cell based infusion products for early exploratory trials;
• Developing a “parent-child” IND framework to reduce the regulatory burdens associated with clinical testing of multiple potential candidates. The parent IND would contain common information relevant for the to-be-tested initial candidates, and a “child” IND would be submitted for each candidate or manufacturing alteration; and
• Adopting regulatory pathways that allow for manufacturing process changes based on patient or patient-specific raw material information to maximize product quality for all patients without having to conduct costly and length clinical studies.

The goal is to use small, data-intensive clinical exploratory studies to optimize the selection of cell therapy candidates to advance into full clinical development, particularly for solid tumors, when such information cannot be gained through currently available nonclinical models.

“The problem that we were trying to solve for was this need to be able to get more early candidates into clinical trials in order for sponsors, whether academic or at the company level, to be able to use that clinical information to iterate on the designs of those concepts or to eliminate CAR-T concepts that are not destined to work,” said Anne Keane, VP of regulatory affairs at Lyell Immunopharma.

Confusion About GMP Requirements

Panelists bemoaned the challenges of trying to shoehorn the development of cell therapies into the existing regulatory paradigm for biologics.

They said academic institutions are hesitant to allow early-phase exploratory studies to take place under more relaxed clinical development and GMP standards. This is due to uncertainty about how the FDA will view such studies, as well as concerns about liability and indemnification.

“We need to provide them with more guidance that can get them comfortable, that can get their legal departments comfortable, with the idea that they don’t have to have a fully GMP-certified facility in order to manufacture reagents or plasmids to be able to do these early studies.” – Lyell Immunopharma’s Anne Keane

“I think there is a lot of confusion out there about what are the GMP requirements for these very early studies,” Keane said.

Currently, only a small number of manufacturers are able to provide reagents, plasmids or vectors at full GMP scale, which creates a bottleneck for industry. “We want to open that up so that very competent academic facilities … or small companies could do more of their own manufacturing for these early studies, so that we could free up some of those full GMP facilities for the full product development cycle,” she said.

For academic institutions, “we need to provide them with more guidance that can get them comfortable, that can get their legal departments comfortable, with the idea that they don’t have to have a fully GMP-certified facility in order to manufacture reagents or plasmids to be able to do these early studies,” Keane said.

Stephen Rosenberg, chief of surgery at the National Cancer Institute, said the FDA has shown extraordinary flexibility when approached about the design of cell therapy development programs.

Although existing FDA guidances have enormous flexibility built into them, “it’s the institutions that are confused by all of the comments that are not highly specific, but are interpreted by institutions in different ways,” Rosenberg said. This confusion and uncertainty results in institutions imposing late-phase development standards on early exploratory trials. “Individual institutions are so risk-averse that they’re not allowing the flexibility that the FDA already provides.”

Like others on the panel, Rosenberg called on the FDA to clarify its expectations in a way that will convince local institutions studies can be conducted without the enormous expense of full GMP compliance.

Getting Academic Institutions To Come In And Talk

Marks pushed back on the notion that more specificity through formal guidance will necessarily fix the problem.

“We need not just the scientists to come into these meetings, but the administrators to hear it from our mouths that it’s really OK to do things, because I do get the sense that some of this is institutional inertia. It’s not wanting to take the risk.” – Peter Marks

“There’s some challenges there about how we put out guidance because we want to be very flexible about how things are done,” Marks said. “But when we put things in guidance and in black and white, sometimes that can be used both by those who seek to advance knowledge, and those who seek to avoid advancing knowledge while making money.”

The FDA probably can go “some of the way” in clarifying its view of what is acceptable and what is not, Marks said. Nevertheless, “I think a lot of this goes to breaking down the barrier of people coming in to speak with us. Because when people come in and talk with us, oftentimes we’re very open to being adaptable.

“We don’t hold people doing cancer trials to the same standards as we do vaccine trials for preventative vaccines,” Marks said. “And a lot of this focus is around us understanding the benefit/risk of what’s going on, and that really happens best from the dialogue.”

However, an academic institution should consider sending more than just its clinical investigators to meet with the agency, Marks said.

“For some of these we need not just the scientists to come into these meetings, but the administrators to hear it from our mouths that it’s really OK to do things, because I do get the sense that some of this is institutional inertia. It’s not wanting to take the risk, not so much FDA preventing people from doing something.”

https://pink.pharmaintelligence.informa.com/PS125320/Cell-Therapies-US-…