This article concerns the development of advanced therapies and the challenges and complexities of getting them through the developmental pathway, which the authors call the trip. The authors examine at strategic levels the importance of some of the fundamental building blocks for the development program and highlight some commonly encountered challenges (trip hazards) for cell and gene therapies and offer bench-to-bedside and chemistry, manufacturing, and controls (CMC) considerations and advise on nonclinical and clinical investigations. They conclude that early contact with regulators can help avoid trip hazards.IntroductionThe advanced therapy sector has grown rapidly, reflecting the tremendous interest for these complex biologic products with potentially curative effect. Advanced therapy products, including cell and gene therapies, as well as tissue-engineered products, have shown great promise for addressing medically unmet needs, particularly for orphan diseases and in oncology. The Alliance for Regenerative Medicine reported a 32% growth in clinical investigations of regenerative medicine products from 2014 to 2018.1 Currently, there are more than 2,000 product candidates under development. Although forecasts of compound annual growth rates and predicted market values vary among different reports, the cell and gene therapy market was valued at more than US$1 billion in 2018 and by 2025, is likely to exceed US$10 billion.2However, product development for advanced therapies still poses a number of potential trip hazards, even though supporting guidance has matured to a good level. Potential challenges may occur at all stages of nonclinical, process, and clinical product development. These hazards include, but not limited to, technology transfer; CMC; clinical investigations; and stage-appropriate good practice considerations. It is paramount to be aware of trip hazards before they occur, because they can equate to time- and cost-related program impacts.In this article we will highlight, at a strategic level, the importance of some of the fundamental building blocks for the development program and highlight some commonly encountered challenges (trip hazards) for cell and gene therapies, in which things frequently go wrong, and sometimes critically so. For simplicity, tissue-engineered products are not covered in the scope of this article but share certain commonality with cellular-based products.What makes advanced therapies different?It is imperative to understand the product itself for the successful development of any therapeutic product. Small molecules are very well understood because they are a single molecule of low-molecular weight and produced through a defined chemical synthesis that yields mathematically identical copies. As such, they can be straightforwardly characterized. Biologics, such as monoclonal antibodies, cytokines, and other recombinant products, can also be generally well defined but they have higher structural complexity and posttranslational modifications. The fact that these are manufactured in living producer cells also reduces the ability to control production of identical copies. There is, therefore, inherent heterogeneity in the product, making biologics generally more sensitive to external conditions and stability. Many of the traits associated with biologics also apply to advanced therapies. So, what makes them so different?Advanced therapies add an additional layer of complexity to the traditional biologic product. These definitions are paraphrased from the European Medicines Agency (EMA)3 and US Food and Drug Administration (FDA)4 definitions for cell and gene therapies:

CMC considerationsProduct diversity is a key point for understanding advanced therapies in that there is greater multiplicity of cellular/gene/tissue products. Therefore, a one-size-fits-all approach does not work precisely, with there often being specific and novel nuances across products.The goal of any drug product development is to manufacture a product to a predefined quality and to realize a process that is robust and reproducible. The objective is to deliver a product that meets quality, safety, and efficacy requirements.For any drug product development program, CMC is directly on the critical path. Although it may be possible to compact some time and cost aspects through strategic consideration, the wake-up call is that there are no shortcuts for the attributes of quality and safety. The CMC is the clinical product, so it must be pitch perfect. Advanced therapies have more complex parts, with which developers must deal in terms of their characterization, manufacture, controls, and applied specifications. All these factors need adequate development time to apply the appropriate measures, or else the entire development program runs the risk of stumbling and falling at some point thereafter.Some exemplary common CMC consideration points (not exhaustive) where cell therapy (CT) and gene therapy (GT) programs can be tripped are:Manufacturing process

It is important to note that these statutory timelines may not accurately apply to all GMO-based products during the current COVID-19 health emergency. In June 2020, the European Commission issued a proposal to relax requirements specifically for clinical trials exploring GMO-containing COVID-19 treatments and vaccines. The proposal suggests allowing temporary derogation from requirements of Directives 2001/18/EC and 2009/41/EC for products to treat or prevent COVID-19 for the duration of the pandemic.8 This temporary relaxation of requirements does not apply to treatments for other diseases. Readers are advised to enquire with individual national agencies about any changes in process and timelines during the COVID-19 pandemic because these may be updated frequently.LogisticsWhile additional approval requirements on the critical path might directly affect the clinical trial start-up time, various other logistical considerations at site level can also influence the timeline and/or overall feasibility of the trial. The logistical challenges will depend on the type of product. For example, products based on living cells, such as cell therapies and cell-based gene therapies, have an inherently short shelf life at ambient temperatures so careful consideration should be given to transportation logistics from the site of the source biopsy to the manufacturing facility, and to the return to the clinical site for autologous/allogeneic patient administration. Handling of the starting material (such as the patients own cells for an autologous cell-based therapy) and the final drug product may require use of specialized equipment, such as laminar flow hoods, cryogenic storage, special centrifuges. Staff must be appropriately trained to use the equipment and handle the products. Moreover, certain advanced therapy products require the co-use of specific medical devices.The preceding considerations are a small fraction of the overall logistical requirements for conducting a global advanced therapy clinical study. Contract research organizations, or CROs, have a key role in providing training for nurses, physicians, pharmacists, and other site staff, as well as providing clinical logistics coordination to oversee patient and sample transportation and tracking in close collaboration with sites and sponsors.

Patient counseling and eligibilityGenetic counseling as a prerequisite to genetic testing to evaluate patient eligibility for a clinical trial is an additional steppingstone in numerous countries. Some countries may require the general availability of counseling, whereas others mandate genetic counseling before genetic testing can be done. Also, specially trained personnel might be necessary to conduct the genetic testing. The specific national requirements should be factored in during clinical trial planning to ensure availability of qualified personnel as required and possibly included in the informed consent forms.Regulatory authority guidanceAdvanced therapy product development must follow all good practice requirements for small-molecule and biologic products. However, owing to the complexity of the products and added risks to clinical trial subjects, there are further specific requirements for advanced therapies. In addition, clinical trial design may need to encompass specifically tailored trial designs including single-arm studies and/or study designs using a synthetic control arm. In many cases, it is not feasible and/or ethical to conduct standard double-blind studies for advanced therapies because of the invasive methods used to extract human source material or administer the advanced therapy product, and ease of distinction between placebo and investigational product.Furthermore, all advanced therapies require extended, long-term follow-up periods and/or the establishment of registries. The use of tailored trial designs is critical to ensure a time and cost-effective development program leading to patient and payer acceptance.Global regulators recognize the value of advanced therapies, particularly given their potentially curative effect, and they have provided ample guidance for all stages of product development. Recent guidance on clinical study design also addresses the need for deviation from traditional study designs to those involving more real-world data. Available key guidance documents in the European Union and the US will be the subject of an upcoming publication.Early interactions with regulatory and health authorities is encouraged to obtain supportive direction and acknowledgment of the approaches to be taken in the development program. Key regulators have pointed out it is pertinent to understand the product and its aims as early as possible to provide proactive advice with this further alluding to the avoidance of common trip hazards. This also further opens the door to priority advanced therapy support vehicles, such as EMA and FDA early scientific advice (e.g. INTERACT, pre-investigational new drug meetings), participation in the regenerative medicine advanced therapy and the EMAs priority medicines schemes, where possible, and other more widely available mechanisms supporting efficient product development.ConclusionAdvanced therapies are a dynamic and fast-growing sector of the pharmaceutical industry. Due to their additional complexity over traditional biologics, they require added ingenuity in line with the particular nature of the cell or gene therapy product type, demanding a carefully considered technical and regulatory development approach to anticipate and mitigate potential risks upfront.Regulatory agencies have implemented additional requirements for overall product development, the conduct of clinical trials and/or data needed for product approval. It is therefore imperative to conduct an in-depth regulatory intelligence collection with national requirements for countries intended to be included in the clinical trial. The investigation of associated timelines, particularly for GMO-based products, will also ensure a country selection that supports an achievable timeline for study start-up in a global environment.Developers of advanced therapies also need to include strategies beyond the clinical development to ensure patient access with a sound understanding of not only regulatory expectations but also the health technology assessment/payer evidence requirements to ascertain approval and reimbursement. The important take-home messages are to begin with the end in mind and to develop sound technical and regulatory strategies, to better anticipate and avoid many of the trip hazards that could prove costly, both in time and money, all of which could critically affect the overall clinical study program.AbbreviationsCMC, chemistry, manufacturing, and controls; CT, cell therapy; EMA; European Medicines Agency; EU, European Union; FDA, [US]Food and Drug Administration; GT, gene therapy; GMO, genetically modified organisms; NIH, National Institutes of Health; RAC, Recombinant DNA Advisory CommitteeReferencesAll websites were accessed on 31 July 2020.

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Advanced therapies: 'Trip hazards' on the development pathway - Regulatory Focus

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