Ravi Samavedam, Chief Innovation Officer, Azzur Group 05.23.23
The trend toward “umbrella trials” in cell and gene therapy, combined with the FDA’s November 2022 Guidance for Industry for such trials, have made one thing quite clear when it comes to manufacturing: The best course of action may be neither outsourcing work to CDMOs nor investing in facility construction exclusively, but a blended hybrid model in which aspects of both solutions are applied, depending on the maturity of the company.
By embracing cleanroom licensing, biopharma companies of all sizes are mitigating risk in R&D while ensuring that they embrace a “fail fast” approach to clinical trials that will allow for flexibility and faster speed to market in this increasingly competitive space.
Umbrella trials and their role in manufacturing
It’s clear that cell and gene therapy research hinges on a “fail fast” philosophy. It’s best to understand as quickly as possible whether a particular therapy/drug is clinically and commercially viable will clear all the hurdles required to get through the manufacturing process. The ability to discover the non-viability of a product, early on in the development lifecycle, allows companies to pivot to a more viable option earlier. This provides a competitive advantage to companies vying for the same indication or competing in the same technology space.
That’s far from a ground-breaking realization in the industry. As early as 2015, FDA’s Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products acknowledged the built-in risks of undertaking cell and gene therapy. The subtext throughout the Guidance made it clear even then that time will always be of the essence, and that manufacturers should take that into account when developing strategies.
“If a problem occurs in product manufacturing,” according to the Guidance, “there may be no product available to administer to an intended recipient. It is helpful to try to gain an understanding from early-phase trials of the likelihood of manufacturing failure and any subject factors that may relate to such failures.” The same document noted that, “This information can facilitate design of subsequent trials by suggesting subject selection criteria to reduce the chance of failure, or by prompting the development of a treatment protocol with a formalized manufacturing failure contingency plan.”
In the R&D portion of manufacturing, many pharmaceutical companies – early stage as well as established companies – are now embracing an “umbrella study” approach to clinical trials as one means of failing fast without losing momentum. That trend led the FDA to issue its above-mentioned November 2022 Guidance for Industry, outlining how such trials work together with the FDA’s Investigational New Drug (IND) application process.
“Sponsors have expressed interest in gathering preliminary evidence of safety and activity using multiple versions of a cellular or gene therapy product in a single clinical trial. Although multiple versions of a product can be studied together in a single clinical trial, each version of the product is distinct and is generally submitted to FDA in a separate investigational new drug application (IND). The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies.”
Traditional trial designs typically evaluate only one product in a single clinical trial. By contrast, umbrella trials use a single-trial infrastructure, design, and master protocol, which allows multiple products for a specific condition to be evaluated at the same time. This allows for greater efficiency in product development.
“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development,” according to the FDA’s most recent Guidance statement. “Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may streamline early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective.”
Rethinking the manufacturing process
The notion of failing fast is woven into the very fabric of cell and gene therapy R&D and manufacturing. But the sheer volume of what’s on the horizon requires a re-thinking of the entire process, including the nuts and bolts (so to speak) of how manufacturing will be done in this fast-growing category.
In September 2022, findings from the management consulting from McKinsey & Company on the pipeline of products in Phase III clinical trials, indicated that “in 2024 alone, up to 21 cell therapy launches and as many as 31 gene therapy launches—including more than 29 adeno-associated virus (AAV) therapies—are expected.” The FDA has also been widely reported as estimating that they will approve up to 20 cell and gene therapy products per year by 2025.
And therein has the industry found itself increasingly pinned between the horns of a dilemma – whether to invest millions of dollars and years of time to build and validate their own facilities, or to outsource R&D and clinical trials to CDMOs, which can risk technology transfer failures, delays and an overall lack of control over manufacturing schedules. For early phase development where the process is still being developed and changes are necessary to develop the requisite process knowledge, this lack of control and flexibility, can further exacerbate the time to clinic.
Each option on its own has considerable limitations. Internalizing manufacturing activities entirely, as opposed to outsourcing, requires not only a multi-million-dollar facility build-out, but also requires a significant initial capital outlay for the personnel, equipment, quality and electronic systems to be deployed to get to cGMP readiness. In addition to the initial capital outlay, the operational costs for these cGMP facilities should be considered before internalizing manufacturing. For companies starting their cGMP journey, with either a few early phase clinical batches or only a few molecules, these operational costs may not be justified. The utilization of such facilities need to be significantly high to offset the maintenance and operational costs.
The accounting and professional services firm Deloitte, in an article on pharmaceutical innovation, noted that “the decision on whether to invest in capital infrastructure is perhaps the most challenging and cost-prohibitive for CGT companies.” Companies in preclinical and clinical stages of development are often stymied by how to scale their manufacturing processes.
According to Deloitte, the decision to build or outsource comes down to several factors, including “the nature of the therapy (allogeneic vs. autologous), the disease state and the volume of drug required, and the availability of external capacity and expertise.” Ultimately, the choices companies make in their clinical stages may shape their destiny for commercial scale operations, because early-stage process decisions can dictate their future technology requirements. In the case of a product failure, a company may find itself hamstrung with expensive, inoperative infrastructure.
Many early-stage companies have relied on CDMOs because they lack the capital required to invest in their own facilities, and because of the pressing need to continually improve speed to market. The CDMO route, however, can mean that these companies give up some measure of control over the manufacturing process. In many cases they may also have to relinquish some of the intellectual property related to their research – which for early-stage companies constitutes a considerable amount of the capital of their business.
Nonetheless, market forces have made outsourcing an important option for cell and gene therapy manufacturing, which has overwhelmed the current operating capacity of CDMOs. Fast-growing entrepreneurial companies are considering other options. Recent findings from Industry Standard Research (ISR), which focuses on pharmaceutical trends, indicate that the percentage of cell and gene therapy companies outsourcing their manufacturing may drop from 44% to 22% over the next five years.
The benefits of a blended approach
A more reasonable solution for many companies may be a blended, or hybrid, approach to manufacture. According to Deloitte, such hybrid models—where companies make smaller upfront investments for earlier-phase trials and then work with CDMOs for later-phase trials—are gaining in popularity.
Blended or hybrid models create an opportunity for companies to license on-demand cleanrooms, particularly for early-stage R&D and manufacture. A blended approach also enables companies to have access to good manufacturing practices (GMP) support, materials management, and facility services. This is particularly important for fast-growing entrepreneurial companies with a background in academia rather than business. Having a support structure to help navigate the waters of product manufacture allows such companies to focus on science, leaving matters of regulatory compliance or other business issues to their licensing partners.
Even for mid-stage or established organizations, a blended approach to manufacturing focusing on cleanroom licensing can preserve much-needed capital until the organization has scaled sufficiently to build and maintain its own more comprehensive facility.
What’s more, a blended on-demand cleanroom licensing model allows biopharma developers to cost-effectively regain control over scheduling, prioritization, and timelines – which is often a concern with CDMO arrangements. This control improves speed to market, and favorably balances risk against capital outlay. This hybrid solution is beneficial for companies who may not have sufficient internal subject matter expertise.
Other factors to consider when deciding on a manufacturing strategy are the compound’s stage of development, the compound/drug requirements, the size and scale of needed materials, and environmental specifications.
There are many decisions involved in developing a service delivery model for cell and gene therapy. Going exclusively down one road or the other in choosing between construction or outsourcing could saddle a company with technological and process decisions they made early on in their product development. A blended approach offers flexibility throughout the life cycle of a company and its products.
Ravi Samavedam is a Biochemical Engineer with more than 20 years of experience in the pharmaceutical and biotechnology industries. Prior to his appointment as Chief Innovation Officer at Azzur Group, he was President and COO of Azzur Cleanrooms on DemandTM. In 2019, Ravi was a General Manager of Azzur Boston, and has been with the company since 2012. Prior to Azzur, Ravi has been part of the Technical Operations, Quality/Validation departments at Baxter, Amgen, and Shire.
By embracing cleanroom licensing, biopharma companies of all sizes are mitigating risk in R&D while ensuring that they embrace a “fail fast” approach to clinical trials that will allow for flexibility and faster speed to market in this increasingly competitive space.
Umbrella trials and their role in manufacturing
It’s clear that cell and gene therapy research hinges on a “fail fast” philosophy. It’s best to understand as quickly as possible whether a particular therapy/drug is clinically and commercially viable will clear all the hurdles required to get through the manufacturing process. The ability to discover the non-viability of a product, early on in the development lifecycle, allows companies to pivot to a more viable option earlier. This provides a competitive advantage to companies vying for the same indication or competing in the same technology space.
That’s far from a ground-breaking realization in the industry. As early as 2015, FDA’s Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products acknowledged the built-in risks of undertaking cell and gene therapy. The subtext throughout the Guidance made it clear even then that time will always be of the essence, and that manufacturers should take that into account when developing strategies.
“If a problem occurs in product manufacturing,” according to the Guidance, “there may be no product available to administer to an intended recipient. It is helpful to try to gain an understanding from early-phase trials of the likelihood of manufacturing failure and any subject factors that may relate to such failures.” The same document noted that, “This information can facilitate design of subsequent trials by suggesting subject selection criteria to reduce the chance of failure, or by prompting the development of a treatment protocol with a formalized manufacturing failure contingency plan.”
In the R&D portion of manufacturing, many pharmaceutical companies – early stage as well as established companies – are now embracing an “umbrella study” approach to clinical trials as one means of failing fast without losing momentum. That trend led the FDA to issue its above-mentioned November 2022 Guidance for Industry, outlining how such trials work together with the FDA’s Investigational New Drug (IND) application process.
“Sponsors have expressed interest in gathering preliminary evidence of safety and activity using multiple versions of a cellular or gene therapy product in a single clinical trial. Although multiple versions of a product can be studied together in a single clinical trial, each version of the product is distinct and is generally submitted to FDA in a separate investigational new drug application (IND). The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies.”
Traditional trial designs typically evaluate only one product in a single clinical trial. By contrast, umbrella trials use a single-trial infrastructure, design, and master protocol, which allows multiple products for a specific condition to be evaluated at the same time. This allows for greater efficiency in product development.
“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development,” according to the FDA’s most recent Guidance statement. “Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may streamline early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective.”
Rethinking the manufacturing process
The notion of failing fast is woven into the very fabric of cell and gene therapy R&D and manufacturing. But the sheer volume of what’s on the horizon requires a re-thinking of the entire process, including the nuts and bolts (so to speak) of how manufacturing will be done in this fast-growing category.
In September 2022, findings from the management consulting from McKinsey & Company on the pipeline of products in Phase III clinical trials, indicated that “in 2024 alone, up to 21 cell therapy launches and as many as 31 gene therapy launches—including more than 29 adeno-associated virus (AAV) therapies—are expected.” The FDA has also been widely reported as estimating that they will approve up to 20 cell and gene therapy products per year by 2025.
And therein has the industry found itself increasingly pinned between the horns of a dilemma – whether to invest millions of dollars and years of time to build and validate their own facilities, or to outsource R&D and clinical trials to CDMOs, which can risk technology transfer failures, delays and an overall lack of control over manufacturing schedules. For early phase development where the process is still being developed and changes are necessary to develop the requisite process knowledge, this lack of control and flexibility, can further exacerbate the time to clinic.
Each option on its own has considerable limitations. Internalizing manufacturing activities entirely, as opposed to outsourcing, requires not only a multi-million-dollar facility build-out, but also requires a significant initial capital outlay for the personnel, equipment, quality and electronic systems to be deployed to get to cGMP readiness. In addition to the initial capital outlay, the operational costs for these cGMP facilities should be considered before internalizing manufacturing. For companies starting their cGMP journey, with either a few early phase clinical batches or only a few molecules, these operational costs may not be justified. The utilization of such facilities need to be significantly high to offset the maintenance and operational costs.
The accounting and professional services firm Deloitte, in an article on pharmaceutical innovation, noted that “the decision on whether to invest in capital infrastructure is perhaps the most challenging and cost-prohibitive for CGT companies.” Companies in preclinical and clinical stages of development are often stymied by how to scale their manufacturing processes.
According to Deloitte, the decision to build or outsource comes down to several factors, including “the nature of the therapy (allogeneic vs. autologous), the disease state and the volume of drug required, and the availability of external capacity and expertise.” Ultimately, the choices companies make in their clinical stages may shape their destiny for commercial scale operations, because early-stage process decisions can dictate their future technology requirements. In the case of a product failure, a company may find itself hamstrung with expensive, inoperative infrastructure.
Many early-stage companies have relied on CDMOs because they lack the capital required to invest in their own facilities, and because of the pressing need to continually improve speed to market. The CDMO route, however, can mean that these companies give up some measure of control over the manufacturing process. In many cases they may also have to relinquish some of the intellectual property related to their research – which for early-stage companies constitutes a considerable amount of the capital of their business.
Nonetheless, market forces have made outsourcing an important option for cell and gene therapy manufacturing, which has overwhelmed the current operating capacity of CDMOs. Fast-growing entrepreneurial companies are considering other options. Recent findings from Industry Standard Research (ISR), which focuses on pharmaceutical trends, indicate that the percentage of cell and gene therapy companies outsourcing their manufacturing may drop from 44% to 22% over the next five years.
The benefits of a blended approach
A more reasonable solution for many companies may be a blended, or hybrid, approach to manufacture. According to Deloitte, such hybrid models—where companies make smaller upfront investments for earlier-phase trials and then work with CDMOs for later-phase trials—are gaining in popularity.
Blended or hybrid models create an opportunity for companies to license on-demand cleanrooms, particularly for early-stage R&D and manufacture. A blended approach also enables companies to have access to good manufacturing practices (GMP) support, materials management, and facility services. This is particularly important for fast-growing entrepreneurial companies with a background in academia rather than business. Having a support structure to help navigate the waters of product manufacture allows such companies to focus on science, leaving matters of regulatory compliance or other business issues to their licensing partners.
Even for mid-stage or established organizations, a blended approach to manufacturing focusing on cleanroom licensing can preserve much-needed capital until the organization has scaled sufficiently to build and maintain its own more comprehensive facility.
What’s more, a blended on-demand cleanroom licensing model allows biopharma developers to cost-effectively regain control over scheduling, prioritization, and timelines – which is often a concern with CDMO arrangements. This control improves speed to market, and favorably balances risk against capital outlay. This hybrid solution is beneficial for companies who may not have sufficient internal subject matter expertise.
Other factors to consider when deciding on a manufacturing strategy are the compound’s stage of development, the compound/drug requirements, the size and scale of needed materials, and environmental specifications.
There are many decisions involved in developing a service delivery model for cell and gene therapy. Going exclusively down one road or the other in choosing between construction or outsourcing could saddle a company with technological and process decisions they made early on in their product development. A blended approach offers flexibility throughout the life cycle of a company and its products.
Ravi Samavedam is a Biochemical Engineer with more than 20 years of experience in the pharmaceutical and biotechnology industries. Prior to his appointment as Chief Innovation Officer at Azzur Group, he was President and COO of Azzur Cleanrooms on DemandTM. In 2019, Ravi was a General Manager of Azzur Boston, and has been with the company since 2012. Prior to Azzur, Ravi has been part of the Technical Operations, Quality/Validation departments at Baxter, Amgen, and Shire.