Image source: https://www.lucintel.com/regenerative-medicine-market.aspx
The regenerative medicine (RM) market is highly competitive, with major biopharmaceutical companies and innovative startups vying for dominance. As companies seek regulatory approval and work to establish their presence in this fast-evolving industry, the competitive landscape remains dynamic and ever-changing.
Market growth is significantly driven by promising clinical trial outcomes and increasing investments in cutting-edge technologies, positioning cell therapy as a revolutionary force in the pharmaceutical sector. However, regulation poses a substantial obstacle in the RM field. In North America, the success rate for clinical trials is low: only 14 per cent of clinical trials achieve U.S. Food and Drug Administration (FDA) approval, which creates significant economic pressure.
To streamline regulatory processes, investigators must anticipate the potential regulatory pathways their innovations might encounter. A successful regulatory strategy should begin early, before a product reaches Health Canada or the FDA. Accelerating the clinical adoption of RM relies on an innovation ecosystem that integrates RM technologies and business models into value chains that are supported by adaptive governance. Addressing these challenges requires more flexible regulatory frameworks and innovative approaches to standards and guidelines for emerging technologies. For an overview of the Canadian regulatory system for cell and gene therapy products, read Aileen J. Zhou’s post on this topic.
FDA regulatory challenges for startups in RM
Preclinical research compliance:
Before starting human trials, startups must follow strict preclinical protocols by documenting lab experiments, animal study results, and quality control. For instance, a stem cell therapy startup must show safety in animal models using the final product formulation to mirror human application.
The FDA’s considerations for tissue-engineered and RM products are rooted in a scientific understanding of the product, structured by regulatory frameworks, and aligned with best practices in product development. The evaluation of each product depends on its specific features, the supporting preclinical data, and the proposed clinical trial design.
For preclinical studies to effectively support clinical use, proof-of-concept studies in animal models are critical. These studies must provide both morphological data, such as in vivo differentiation and integration of the cells, and functional data, like the full integration of cell-scaffold constructs as fully functioning tissues.
Additionally, some preclinical animal studies should assess product safety, although relevant safety endpoints can be incorporated into studies designed for other purposes. Postmortem analyses, such as evaluating local inflammatory responses or scar formation, are key to assessing safety. Furthermore, the tumorigenic potential of cell-scaffold products and the fate of implanted cells, including their survival, differentiation and proliferation, are essential considerations in preclinical evaluations. This integrated approach ensures a comprehensive understanding of product safety and efficacy before human trials begin.
Investigational new drug (IND) application:
A step in translational research in RM is securing FDA approval for an IND application. Before the use of any new drug or biological product that isn’t covered by an approved new drug application or biologics license application, an IND authorization is required. the FDA has given IND for non-commercial first-in-human clinical trials with minimum quality and non-clinical data for certification and orphan drug application as special categories.
The regulatory requirements consist of a comprehensive submission that includes the results of preclinical studies, the proposed study protocol for human trials, and manufacturing information. Once clinical trials are completed, the manufacturer will submit another more extensive application, called a Biologics License Application, proving the IND’s efficacy in a clinical trial. The FDA must review and approve the application and carry out a manufacturing site inspection before it allows the product to be licensed for commercial distribution.
Clinical trial oversight:
“Once an IND is approved, startups face the challenge of conducting clinical trials under the FDA’s watchful eye. This involves continuous reporting, adherence to Good Clinical Practices (GCP), and ensuring patient safety” (according to FasterCapital). For example, Adrian P. Gee, in his work “Gap Analysis to Target Therapies,” pointed out that in early-phase clinical trials for cell and gene therapy (CGT) products, the focus is on assessing safety, including the nature, frequency, and dose-related effects of adverse reactions.
Since CGT products often target life-threatening diseases, some toxicities are expected and acceptable, with the goal being to identify a feasible dose rather than the maximum tolerated dose. Trials should also account for special measures, such as devices or adjunctive therapies, and aim to collect preliminary efficacy data.
Healthy volunteers are generally unsuitable for CGT trials due to the high risks, and the selection of participants should balance anticipated risks and benefits, often focusing on patients with no other treatment options. Control groups and blinding are beneficial but may be challenging in early-phase CGT trials. For pediatric populations, additional safeguards must be in place as per regulatory guidelines.
Navigating post-market surveillance:
Once a product enters the market, companies are required to conduct post-market surveillance to monitor any adverse events or long-term safety concerns.
This is where real-world evidence (RWE) becomes invaluable. RWE refers to clinical data derived from everyday health care sources, such as electronic medical records, insurance claims, patient registries and patient-generated information, rather than from randomized clinical trials. It provides critical insights that can inform various regulatory decisions, including postmarket surveillance, exploring new uses for approved products, and even supporting premarket approvals. The FDA’s guidance on using RWE to meet postmarket evidentiary requirements is vital, along with their oversight to ensure the quality and reliability of this evidence. This will help address concerns that RM products may be approved before they are fully tested.
(Source for this section: FasterCapital.)
Insights from industry experts on regulatory advancements in cell and gene therapy
During my research, I came across an insightful discussion on CCRM’s podcast. Guests Michael Rosu-Myles, Health Canada, and Josephine Lembong, Alliance for Regenerative Medicine, elaborated on how the FDA, European Medicines Agency, and Health Canada have established new offices and regulatory frameworks to enhance their capacity for assessing CGT applications. I recommend listening to the episode titled “Regulators’ Strategies for Managing the Surge in Cell and Gene Therapies,” to learn about important advances.
Establishment of the Office of Therapeutic Products (OTP)
The FDA’s establishment of the OTP super office in 2023 demonstrates its strong commitment to managing the rapid growth of CGT products. This new office, part of the Center for Biologics Evaluation and Research, replaces the former Office of Tissues and Advanced Therapies (OTAD). It includes six sub-offices designed to provide oversight, flexibility, and coordination across various programs.
New FDA initiatives
The FDA has also introduced several initiatives to support the development of innovative therapies. The START pilot program allows participants to engage in frequent, ad hoc communication with FDA staff to address specific product development challenges. Additionally, the Rare Disease Endpoint Advancement Pilot Program enables sponsors to collaborate with the FDA throughout the efficacy endpoint development process, offering more structured and continuous guidance.
Global collaboration efforts
On the global stage, the FDA has focused on collaboration with international regulatory bodies. The International Council for Harmonisation (ICH), which includes members from the U.S., EU, Canada and Japan, has partnered to streamline the review process for gene therapy products. This collaboration facilitates shared internal meetings and reviews, aiming to improve the efficiency of global regulatory reviews. The pandemic underscored the importance of cooperation, as global regulators realized their processes were more aligned than divergent.
Health Canada’s Advanced Therapeutic Products (ATP) pathway
Health Canada has taken a similar approach with its ATP pathway, which offers a flexible regulatory framework tailored to the specifications of each product. If a therapy does not fit within the existing regulatory structure, Health Canada engages with manufacturers and industry experts to develop new policies and guidance. This ensures that novel therapies can enter the market while maintaining high safety and efficacy standards, improving access to innovative treatments for Canadians.
The RM sector faces a highly competitive landscape, with startups and established companies working to secure regulatory approval while navigating significant challenges. For RM startups, it is crucial to thoroughly understand product risks, manufacturing processes, and critical quality elements. Transparent communication with regulators and early engagement are essential for ensuring a high-performing, safe product. By understanding regulatory frameworks and collaborating with authorities, companies can streamline the approval process, bringing life-saving therapies to market more efficiently. Ongoing advancements in regulatory frameworks, such as the FDA’s OTP super office and initiatives like the START pilot, play a critical role in supporting innovation in RM. Global collaboration and adaptive regulatory pathways, like Health Canada’s ATP pathway, further emphasize the importance of flexible governance in accelerating the clinical adoption of RM technologies. Overcoming these regulatory challenges is key to ensuring that RM products reach the market, offering life-saving solutions while navigating complex approval processes.
Laya Kiani
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