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Greater clarity on the application of existing regulations will accelerate development of cell and gene therapies.
Cell and gene therapies continue to show great potential to treat if not cure serious diseases that have previously been untreatable. Three new products were approved in 2017 by FDA, chimeric antigen receptor (CAR) T-cell cancer therapies from Novartis and Kite Pharma and a retinal gene therapy from Spark Therapeutics. Markets and Markets estimates the value of the regenerative medicine market (including cell and gene therapies, immunotherapies, and tissue engineering) will grow at a compound annual growth rate of 23.6% from $13.41 billion in 2016 to $38.7 billion in 2021 (1).
According to the International Society for Cellular Therapy (ISCT), the approval of the first CAR T-cell therapies is “direct evidence of the commercializing potential of CAR-T therapies” and indicates that “cell therapy is now a sector that has emerged today, not evolving in the future” (2). ISCT also expects the recent approvals to spark considerable investment across all stages of drug development from fundamental research within academia to commercial manufacturing by Big Pharma and contract service providers, as well as within other support industries from equipment manufacturers to logistics companies.
FDA Commissioner Scott Gottlieb recognizes that cell-based therapies are “one of the most promising fields of science.” At the same time, the “area’s rapid growth, dynamism, and complexity” are creating unique challenges and thus the need for a “clear, efficient pathway for product developers” that ensures “the safety and efficacy of these medical products so that patients can benefit from these novel therapies” (3).
The original regulatory framework for regenerative medicines, established in 2005, has not kept pace with changes that have occurred. Gottlieb is concerned that “unscrupulous actors” are “jeopardizing the legitimacy and advancement of the entire field” (3). To support the innovation pursued by responsible product developers, he believes FDA must “advance a modern, efficient, and least burdensome framework that recognizes the breakneck speed of advancement in the products we’re being asked to evaluate, while ensuring patient safety.”
To that end, the agency introduced in mid-November 2017 a new comprehensive framework comprising four guidance documents (two draft and two final) that incorporate proposed novel and modern approaches to regulation and allow FDA to adapt its regulatory model to meet the needs of next-generation medicines. One such approach involves the use of common manufacturing protocols within academia and industry to allow the sharing of clinical trial data.
The framework also implements the Regenerative Medicine Advanced Therapy (RMAT) designation program as required by the 21st Century Cures Act. This program is designed to expedite the development and review of regenerative medicine advanced therapies and is managed by FDA’s Center for Biologics Evaluation and Research (CBER). Applicants that receive the RMAT designation will have early interactions with FDA staff and may receive priority review and accelerated approval (4).
As a further requirement of the Cures Act, FDA is working with the National Institute of Standards and Technology (NIST), members of academia, and the pharmaceutical industry to develop standards for regenerative medicines (4).
Because the new framework provides increased opportunity for developers of regenerative medicinal products to obtain expedited reviews and greater access and collaboration with CBER staff, Lonza, a contract development and manufacturing organization, believes it will also provide opportunities for its customers. “The new guidance is a significant development that will enable us to work with our customers to improve patient access to novel cell and gene therapies,” observes Alison Keene, head of global regulatory affairs for the pharma and biotech segment of the company. “We welcome the progressive regulatory approach FDA is adopting, which takes into account the innovation that is required for the development of regenerative therapies,” she adds.
Lonza anticipates that its customers will be evaluating the opportunities that the new framework provides. “We have customers in both early- and late-stage clinical development, some of whom would be seeking to leverage this new guidance,” says Keene.
In addition, because Lonza takes a science-based approach to the development of advanced therapy medicinal products (ATMPs) while at the same time evaluating risk, the new regulations lay the groundwork that will hopefully enable the company to work even more closely with its customers, according to Keene.
“We expect to see more customers seeking opportunities to commercialize using the new framework, and thus much faster, and also earlier on, than under previous regulations. We also anticipate an overall increase in demand as a wave of new therapy developers enters the clinical trial stage and subsequently commercialization,” she notes.
Indeed, developers of new regenerative medicines will require robust platform processes, such as automation technologies and 3-D bioreactors, to maintain consistency and ensure effective upscaling and out-scaling. Such factors must be considered in order to support market coverage through a clearly defined manufacturing expansion plan, according to Keene.
Lonza anticipates that customers will require the ability to increase scale and capacity efficiently to keep pace with clinical development needs, which in some cases may conflict with the increased speed into the clinic. The reason: with current available technology, early-stage clinical material will for the most part be manufactured with manual, small-scale methods. “Parallel development of processes that provide up-scaling or out-scaling of the manufacturing process can be built into the clinical development or commercial development plan, however, and discussed with regulators upfront,” Keene comments.
For some companies, however, a post-approval switch to a more robust process may be a more suitable option. “We expect that these customers will also benefit from the new regulations, and Lonza’s Process Development team has started seeing a growing number of enquiries of this nature,” Keene says.
With the new regulation and continued positive clinical results, more and more therapies will be entering the market in the coming years. As a result, there will be growing demand for manufacturing capacity. There are already capacity constraints around viral manufacturing that are impacting the ability of companies to get cell and gene therapies to the patient (5). Lonza will be opening a new and largest-of-its-kind dedicated cell- and gene-manufacturing facility in Houston, TX, early in 2018, in direct response to these concerns.
In addition to manufacturing capacities as a whole, there will be a need for implementation of efficiencies to reduce cost of goods, facility footprints, and equipment overhead, Keene also asserts. Lonza also expects to see further convergence of manufacturing technologies across therapeutic fields and more defined ‘gold standards’ through, for example, ‘GMP-in-a-box’ systems and the ability to significantly automate key elements of the manufacturing process. To this end, Lonza is collaborating with Canadian medical technology developer, Octane Biotech, to develop their Cocoon platform for broad manufacturing use. This GMP-in-a-box system aims to deliver on scalability and cost-of-goods reduction, and to provide a robust solution for personalized therapies such as CAR-T often requiring small-scale manufacturing.
Longer-term developments will still need to take place in order to fully remove the manual elements for activities like isolation and tissue manipulation, and GMP requirements for these new automated systems will need to be developed and discussed with regulators, manufacturers, and sponsors, according to Keene. “Ultimately,” she observes, “these changes will need to be reflected in cost-of-goods reductions to support pricing and reimbursement so that these novel therapeutic approaches can find broad market acceptance and patient access.
While Lonza looks favorably on FDA’s new regulatory framework for regenerative medicines, there are some issues they hope the agency will keep top of mind. “FDA needs to work closely with industry to ensure that a mutual understanding is developed regarding areas of innovation. In addition, the agency needs to be sure to take into account the uniqueness of cell- and gene- therapy products,” Keene says.
As importantly, she notes that FDA must be aware that some of the well-established manufacturing and quality systems used to support the production of well-established medicinal products may not always be appropriate for some cell and gene therapies. Lonza also would like drug developers and their service providers to have manufacturing flexibility to move quickly through the clinical development phases when a promising therapy is identified.
On a final note, Keene points to the autologous (patient-specific) therapies and their unique requirements. “Further consideration will need to be given to the production of autologous products and personalized medicines and how to accommodate those patients for whom an individually manufactured treatment is required. We look forward to further development of the regulatory framework to cover this important area.”
One of the key benefits provided by the new regulatory framework is the increased opportunities for dialogue with FDA, which can be crucial to success of a project. “Several of our cell- and gene-therapy customers are pre-commercial, and many have a close dialogue with regulatory authorities supported by Lonza,” Keene says. “Having a broad range of technical and regulatory subject matter experts to support customers with these interactions and provide advice on phase-appropriate manufacturing standards in order to achieve speed to the clinic within the financial constraints of early stage developers is essential in this rapidly changing market,” she concludes.
1. Markets and Markets, “Regenerative Medicine Market by Therapy (Cell Therapy, Tissue Engineering, Immunotherapy, Gene Therapy), Product (Cell-Based, Acellular), Applications (Orthopedic & Musculoskeletal Disorders, Dermatology, Oncology, Cardiology)-Forecast to 2021,” February 2017.
2. International Society for Cellular Therapy, “International Society Forecasts Significant Investment and Funding Throughout Entire Cell and Gene Therapy Sector,” Press Release, Aug. 30, 2017.
3. FDA, “Statement from FDA Commissioner Scott Gottlieb, MD, on FDA’s Comprehensive New Policy Approach to Facilitating the Development of Innovative Regenerative Medicine Products to Improve Human Health,” Press Release, Nov. 16, 2017.
4. J. Wechsler, Pharm. Techn. 41 (9) (2017).
5. G. Kolata, “Gene Therapy Hits a Peculiar Roadblock: A Virus Shortage,” New York Times, Nov. 27, 2017, .
Vol. 31, No. 2
When referring to this article, please cite it as C. Challener, " FDA Framework Spurs Advanced Therapies," BioPharm International 31 (2) 2018.