On the 31st January 2022, The Clinical Trials Regulation ((Regulation (EU) No 536/2014)) became effective and replaced the previous Directive (EC) 2001/20/EC and corresponding national legislation. The Clinical Trials Regulation (CTR) coordinates the review and regulatory process for drug clinical trials across the EU. Prior to the implementation of the new CTR, clinical trial sponsors were required to submit clinical trial applications separately to national competent authorities and ethics committees in each country to gain regulatory approval to run a clinical trial.
The new CTR enables sponsors to submit a single application via an online platform known as the Clinical Trials Information System (CTIS) for approval to run a clinical trial in up to 30 EEA countries. The goal is to optimise the clinical trial process and make it more efficient to conduct pan-European trials. The regulation seeks to provide a single, unified portal and database for both trial sponsors and regulatory agencies in each member state. For sponsors, the portal will be the main platform to submit applications and notifications allowing regulators to conduct their assessments and supervise the trial. During a clinical trial, users of CTIS can collaborate with national regulators while recording the results. In addition to this, the CTIS enables the monitoring of results and assessing safety-related data in this single integrated online platform.
The CTR and CTIS aims include the implementation of clinical trial regulations, to improve the efficiency and transparency of drug clinical trials and ensure the highest safety standards for trial participants. Under the new CTR, clinical trial sponsors can use the Clinical Trials Information System (CTIS) from 31 January 2022, but are not obliged to use it immediately, in line with a three-year transition period. National regulators in the EU Member States and EEA countries will use CTIS from 31st January 2022. The Clinical Trials website can be visited here and the CTIS can be visited here where you can find out more information.
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Personalised medicines involve an increased degree of complexity when it comes to manufacturing and supply in comparison to traditional pharmaceuticals. The Horizon 2020 Advisory Group defines personalised medicine as ‘a medical model using the characterisation of individuals’ phenotypes and genotypes (e.g. molecular profiling, medical imaging, lifestyle data) for tailoring the right therapeutic strategy for the right person at the right time, and/or to determine the predisposition to disease and/or to deliver timely and targeted prevention.’ Personalised medicine focuses on treating patients based on their individual clinical characteristics, the diversity and severity of symptoms, and genetic traits. Cell and gene therapies (CGTs) are an increasingly important segment of personalised treatments. CGTs are typically expensive treatments manufactured in low volume. Due to the time-sensitive nature and challenging temperature conditions associated with manufacturing, handling and treating patients with cell and gene therapies, this article outlines some considerations for the handling and supply of CGT products.
Consideration 1: Transportation
Many CGTs are transported and stored at ultra-low temperatures including cryogenic temperatures below -80 °C. Primary materials and therapies may be required to be shipped from the site of manufacturing to the clinical setting within 40 to 50 hours typically. Maintaining the integrity of cell and gene therapy products during shipping, as well as ensuring that they arrive on time and within the appropriate temperature constraints, is a major challenge. CGT companies should consider:
Has the optimal courier been selected who has experience with transporting high-value, temperature-sensitive cell and gene therapies?
Is the selected shipping system suitable and validated for transporting the materials?
Has a risk assessment been performed to mitigate any delays or incidents that may arise during transportation?
Is the necessary documentation available to successfully export and import the CGTs across territories?
What processes are in place at the receiving site to ensure the CGTs arrive undamaged, viable and fit for administration?
Issues experienced during transportation can be possibly devastating for patients and highly costly for clinical trial sponsors as CGTs can cost $200,000–2,000,000 per dose. A commercially viable supply chain is recommended to be in place at the start of clinical trials (even in Phase 1) as many of these therapies are given orphan (US) and prime (EU) status which could allow them to gain approval in a shortened timeframe should the clinical trials be successful.
Consideration 2: Sourcing of Materials
Materials and equipment used in the manufacturing and supply of cell and gene therapies may be more challenging to acquire in contrast to traditional pharmaceutical products. For example, high quality specialised reagents are critical to maintaining healthy cell cultures that perform optimally and consistently. In many cases, companies may only have single-source suppliers and this may increase the risk of supply chain disruption. With CGTs requiring specialised raw materials and unique manufacturing equipment, CGT companies commonly chose to outsource manufacturing to CDMOs with experience in small volume, high value manufacturing and the ability to manage specialised packaging and labelling.
CGT companies may take into consideration:
Has an inventory management system been developed to ensure there are optimal levels of materials available?
Are there alternative suppliers of materials and equipment that may be qualified as a back-up source?
Have your key suppliers been qualified for use and audited?
Have Critical Quality Attributes (CQA) and Critical Process Parameters(CPP) been defined and agreed with suppliers?
Has a Business Continuity Plan (BCP) been developed and implemented?
Selecting and qualifying the optimal vendors to support your clinical and commercial needs is a crucial activity. Identifying risks to the provision of materials and implementing mitigation strategies could prevent detrimental impacts to product supply and ultimately to patients. Furthermore, effective communication with suppliers to coordinate and schedule activities is essential to avoid disruption.
Consideration 3: End-to-end Visibility
End‑to‑end traceability from manufacturing to final delivery of CGTs to patient treatment centers is an important consideration for successfully providing personalising treatments. A CGT supply chain may involve many different entities including contract development and manufacturing organisations (CDMOs), thermal shipping system suppliers, diagnostic companies, specialised couriers and distributors. Ensuring there is alignment between all entities should be a key area reviewed during the pre-clinical and clinical development phases.
A Chain of Identity (COI) linked to the unique identifier should be generated at patient enrolment. This identifier should be visible and traceable throughout a patient’s personalised treatment. For example, as part of the COI, an autologous donor’s patient number should be associated with their unique donation number (e.g. Donor identification number/DIN) and the manufacturing batch number. Chain of custody (COC) refers to the ownership/stakeholder ‘in‑custody’ of the cells or drug product, at any stage of the value chain. COC typically incorporates numerous critical parameters to ensure high quality standards and integrity of the cells at every step. COI and COC are key components to ensure traceability over the course of the personalised treatment and to safeguard patient safety. This can present more challenges that the traditional biopharmaceutical product supply model as adequate infrastructure and systems must ensure the correct CGT is available in time for the scheduled administration at the correct treatment site for the correct patient. Autologous cell therapies, for instance, must have robust controls in place to ensure patients receive the CGT from their own donor cells and not another patient’s cells. Important areas to closely examine in relation to end-to-end visibility include:
Have the COI and COC requirements been reviewed and defined?
Is there full traceability from the start to the finish of the CGT product lifecycle?
If using a CDMO, how will manufacturing activities be monitored and how will key updates be provided?
What processes are in place to ensure the correct CGT reaches the correct patient?
Advanced technologies including software systems can support the coordination of last mile deliveries with treatment centers. As the CGT industry continues to grow rapidly, so too will the development of technologies to provide end-to-end traceability.
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Cell and Gene Therapy products and other Advanced Therapy Medicinal Products (ATMPs) have to comply with European Medicines Agency (EMA) legislation at different stages of the development process, including Good clinical practice (GCP), Good manufacturing practice (GMP) and Good Laboratory Practice (GLP) requirements. Potential new Cell and Gene Therapies or Advanced Therapy Medicinal Products firstly require laboratory tests and clinical trials to evaluate their benefits and side effects. Understanding the EU legal and regulatory framework, providing details of the benefits and risks of the products and obtaining approval from regulatory authorities for their use is therefore essential to providing the best possible treatments for end users. So this article will cover the basic EMA regulation of Cell and Gene Therapies (CGTs).
Research and development of Cell and Gene Therapies: