How To Determine Country Feasibility For Cell And Gene Therapy Clinical Trials

By Jessica Cordes, senior consultant and trainer, Clinical Excellence GmbH

Choosing the right geography for your clinical trial can affect your overall trial success and eventual product launch speed and potential. Consider the following questions and guidelines for pursuing your next clinical trial in your home country and across the world.

Why Is Determining Country Feasibility So Crucial For CGT Clinical Trials?

By performing a robust country feasibility analysis to help decide on the most suitable countries for your clinical trial, you’ll likely have greater success in meeting your patient enrollment and data collection goals on time and within budget. The feasibility analysis helps you better understand the clinical trials landscape and avoid or minimize possible challenges and risks that could affect your clinical trial, such as delays in regulatory approval, difficulties in patient recruitment, problems with site quality, or disruptions in delivery. If you then select the most affordable and efficient countries for your clinical trial, you can optimize your budget and timeline and make the best use of your resources. Also, choosing a country with the highest ethical and scientific standards can enhance your clinical trial quality, especially your data validity and reliability. Finally, by demonstrating that your clinical trial meets local as well as international regulations and requirements, you can increase your chance of getting regulatory approval and market access.

What Happens If You Skip A Country Feasibility Assessment?

Determining country feasibility is a critical and strategic step in your CGT clinical trial journey. It can make or break your clinical trial and product commercialization. If you skip it, you may face serious consequences, such as:

• Choosing wrong or unrealistic countries for your clinical trial could result in low recruitment or retention of target patients, especially if the country does not have the right patient demographic or disease prevalence.
• You could face unexpected and expensive setbacks or hurdles in the trial, such as regulatory changes, site closures, investigator turnover, and supply issues.
• Your trial data quality, reliability, and trustworthiness may be lowered if you are unable to follow the local and global rules and standards or have high dropout or protocol deviation rates.
• You could put your patients' safety, rights, and well-being at risk by making them deal with unnecessary or unsuitable risks or burdens (i.e., if you are not allowed to import the drug required for emergency treatment).
• You might risk your regulatory approval and market access by creating insufficient or invalid proof of your product's safety and efficacy or by breaking the local and global laws and regulations.

But How Do You Conduct A Robust Country Feasibility Assessment?

After you define the clinical trial design, you need to evaluate how suitable a country is for a clinical trial. You can use internet research or existing databases, but you also need to align with all internal stakeholders from various functional areas (i.e., medical, regulatory, operational, production, lab, and more). These are some of the selection criteria to consider:

Planned Market Position Of Product

Review the business case that supports the drug development plan and identify a list of possible countries for this market position.

Market Access And Reimbursement

Evaluate the product's market opportunities and competitive threats in each country, considering the current and future treatments, cost, and payment policies.

Consider the example of an allogeneic CAR-T therapy for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), a type of blood cancer that has a poor prognosis and limited treatment options. A sponsor company plans to target the U.S. and EU markets, where there is a high prevalence and incidence of DLBCL, as well as a strong demand and reimbursement potential for innovative cell and gene therapies. But it also intends to expand to other regions such as Asia-Pacific and Latin America, where there is a growing awareness and interest in cell and gene therapies and where the product could benefit from the existing infrastructure and partnerships of the sponsor.

Patent Environment

Evaluate the rights to the intellectual property. You should also anticipate having a sufficient “freedom to operate” in the business market.

Consider an example of a sponsor of a cell and gene therapy that does not understand the patent environment for its lentiviral vector-based CAR-T therapy for the treatment of acute lymphoblastic leukemia (ALL), a type of blood cancer that affects children and young adults. The product aims to target the CD19 antigen, which is expressed on most B cells, including malignant ones. However, the product may face significant challenges in terms of patent protection and freedom to operate. The field of CAR-T therapy is highly competitive and crowded, with many patents covering various aspects of the technology, such as the design of the CAR construct, the choice of the viral vector, the methods of cell manufacturing and administration, and the selection of the target antigen. The product may infringe on existing patents or be blocked by patent oppositions or litigations from other parties. Moreover, the product may have difficulty obtaining its own patents, as the novelty and inventiveness of the product may be challenged by the prior patent authority and the existing products on the market. Therefore, the sponsor company should conduct a thorough patent landscape analysis and a freedom to operate assessment before proceeding with the development and commercialization of the product.

Patient Population

Find out which countries have the potential patient population that you plan to enroll based on the disease prevalence, the confirmed disease cases, and the number of preconditions.

Consider an example of a cell and gene therapy sponsor that has not adequately examined the patient population for its oncolytic adenovirus expressing IL-12 for the treatment of recurrent glioblastoma multiforme (GBM), a highly aggressive and incurable brain tumor. The product faces heterogeneity and diversity of GBM tumors, which may affect the viral delivery, infection, and replication, as well as the immune response and resistance mechanisms. You might not find enough eligible patients or even not get the response rate you expected for your drug.

Indication-Specific Key Opinion Leaders And Physician Networks

Review existing literature and talk to local experts and influential leaders to assess the current level of care and medical practice, the gaps in medical needs, and the possible challenges and enablers for joining and staying in the trial in each country. Remember to sign a confidential disclosure agreement with the experts before sharing your synopsis, protocol, or any other information.

Experience With Cell And Gene Therapies

Assess how well the doctors and places in a country can deal with cell and gene therapies, which are new biological treatments. Cell and gene therapies need special care for storing, handling, administering, and observing, which may impact the possibility and quality of the study.

Consider an example of a local expert treating patients at a brain tumor center. She has extensive experience in treating GBM patients with various modalities, including surgery, radiation, chemotherapy, and immunotherapy. She has also conducted several clinical trials of novel agents and approaches for GBM, such as gene therapy, CAR T cells, and oncolytic viruses. She might even be a member of the American Society of Clinical Oncology or the International Society for Cellular Therapy. She can provide valuable insights into the unmet medical needs of GBM patients, the current standard of care and challenges in implementing it, and the potential benefits and risks of cell and gene therapy for GBM.

Regulatory Requirements

Even though the EU-Clinical Trial Regulations unify the EU with approval timelines for CGT of 61 to 111 days, countries outside the EU may have different approval timelines and start-up timelines (i.e., 30 days with the FDA). Therefore, you may encounter various timelines for starting a clinical trial. These factors may influence the possibility and overall duration of a clinical trial in a specific country.

Competitive Clinical Trials Running Per Country

The number and type of clinical trials taking place in each country may influence the possibility and readiness of sites and patients to join a new clinical trial. It may also suggest the degree of rivalry and overcrowding in a certain treatment field or disease.

Country Experience And Performance

Consider a country's performance and accomplishments in managing clinical trials, such as the number of clinical trials it has completed, the quality of its data collection, the speed of its patient recruitment, and the duration of its patient retention. Also, evaluate the infrastructure and capacity of the clinical sites and investigators in each country, such as the skill and knowledge in running clinical trials with cell and gene therapies, the access to adequate facilities and equipment, the staff training and qualification, and the ethics and governance standards.

An example of a country that has not conducted many clinical trials but is still experienced and performs well is Singapore. According to the Clinical Trials Landscape Report 2018 by IQVIA, Singapore ranked 23rd in the world and fourth in Asia for the number of active clinical trials, with 248 clinical trials as of December 2017. However, Singapore also scored high in terms of quality, speed, and efficiency of clinical trials, ranking third in the world for data quality, fifth for site initiation cycle time, and sixth for patient recruitment rate. Singapore has a strong reputation for conducting clinical trials in various therapeutic areas, especially oncology, infectious diseases, and ophthalmology. Singapore is also a regional hub for cell and gene therapy research, with several academic and industry collaborations.

Overall Clinical Trial Costs

The location of the sites and the related costs, such as staff wages, site charges, travel expenses, and regulatory fees, are some of the main factors that influence the total cost of a clinical trial. The economic development, market competition, and regulatory complexity of different countries may affect the budget and timeline of a clinical trial.

Calculate the costs and timelines of running the clinical trial in each country, taking into account the fees and processes for getting the regulatory and ethical approvals, the importation and distribution of the cell and gene therapy, the enrollment of and follow-up with the patients, and the reporting and management of the data and adverse events.

Country Coverage For Patient Insurance

Research how each country's patient insurance covers and pays for the trial, as well as what could go wrong or cost more for the sponsor and the sites. Find any problems or difficulties that could impact the trial's plan, process, and results.

Reported Level Of Corruption

Assess the degree of corruption in each country using the Transparency International Corruption Perceptions Index or other trustworthy sources. Think about how corruption may affect the trial’s quality, accuracy, and clarity, as well as the moral and legal consequences for the sponsor and the sites.

Making The Final Decision

Evaluate and order the countries according to the feasibility criteria and choose the ones that are most appropriate for your clinical trial.

For each country, document the corresponding values based on your collected country feasibility data. At the end, make the final decision for each country by comparing the feasibility data and selecting the ones that are within a certain range (e.g., top five).

About The Author:

Jessica Cordes started her clinical operations career in 2009, working at various companies including Big Pharma and several small to midsize biotech companies. She gained extensive experience on different levels from country study management, global study management, and since 2018, leadership in clinical operations. During her time at Medigene and Immatics, she structured the clinical operations department, built cohesive global teams, and implemented GCP and ATMP compliant processes. For more than 12 years, she has been working in oncology clinical trials (including hemato-oncology as well as solid tumors) and with ATMPs since 2018. Since 2023, she has been working as an independent consultant and trainer, supporting small companies in building their clinical operations group and setting up their clinical trials for success. She also issues a clinical research bi-weekly newsletter and hosts a quarterly roundtable discussion.