By Jessica Cordes, founder, Clinical Excellence GmbH

Clinical trials are essential for developing new and innovative therapies for various diseases and conditions. However, they also involve many uncertainties and challenges that require careful planning and management. Risk management is the process of identifying, measuring, and mitigating the potential risks that may affect the objectives, outcomes, and quality of clinical trials. It is a key component of quality by design, which aims to ensure that clinical trials are designed and conducted in a way that maximizes the benefits and minimizes the harm to the patients and the sponsors.

Oscar Segurado, a medical expert with over 30 years of experience in the biopharma industry, especially in clinical development and medical affairs, discusses the three key areas of risk. Oscar has worked with large and midsize biopharma, biotech, and medtech companies, as well as CROs, and has been involved in several clinical trials for biologics and cell and gene therapies.

3 Key Areas That Demand Risk Management

Segurado says that before starting a clinical trial, sponsor companies must think through possible risks and how they can be identified, measured, and monitored. He emphasizes the need to adopt a structured and disciplined approach to risk management and to use key risk indicators (KRIs) to determine the risk tolerance limits and the actions that need to be taken when the risk is unacceptable or requires intervention.

In particular, Segurado believes three main areas need to be managed in clinical trials: enrollment, retention, and adverse events. He shared his experience and lessons learned from working with different types of clinical trials and therapies, and how he addressed these risks in his clinical programs.

Enrollment: The Number One Risk

Enrollment is the number one risk that needs to be managed in clinical trials, as it affects the feasibility, cost, and timing of the clinical trial. One of the most important steps in managing this risk is to identify and select the right sites and investigators for the clinical trial, and not to rely heavily on the CROs. Segurado learned this lesson from a difficult experience, in which he realized that some of the sites and investigators selected by the CRO failed to meet expectations and enroll the patients as promised. He says it is sometimes better to avoid selecting KOLs as principal investigators, as they may have too many clinical trials and commitments, and instead look for genuine and reliable PIs who are interested and motivated to participate in the trial.

Consider the treatment of inherited diseases and cancer with cell and gene therapy. In inherited diseases, gene therapies aim to modify the expression or function of non-functional or missing genes in target cells, such as immune cells, stem cells, or somatic cells, to treat rare diseases or disorders. In this process, the genetic information encoded in the inserted or modified gene produces a functional product, such as a protein or an RNA molecule. Additionally, gene expression can be regulated at different levels, such as transcription, translation, or post-translational modification.

In oncology, cell therapies include the genetic modification of T cells. T cell receptor (TCR) products are a type of cell therapy that uses genetically modified T cells to recognize and kill cancer cells. TCR products require the expression of two key components: the TCR gene that recognizes a specific antigen on the cancer cell, and the human leukocyte antigen (HLA) type that presents the antigen to the TCR. HLA is a complex of proteins that vary among individuals and play a crucial role in the immune system. Therefore, TCR products need to match both the antigen and the HLA type of the patient, otherwise they may not be effective or could cause adverse reactions.

Matching the antigen and the HLA type is a major challenge for enrolling patients for TCR clinical trials, as it requires screening the patients for both factors. The screening process involves testing the patient's blood sample for the presence of the genetic marker for the antigen and typing the patient's HLA alleles using molecular methods. The screening results determine whether the patient is eligible for the TCR product. However, the probability of finding a double-positive patient, who expresses both the antigen and the compatible HLA type, is very low, as these factors are independent and random. This leads to high screen failure rates, which can exceed 75% and limits the number of patients who can enroll in the clinical trial.

In cell and gene therapies, the key risk indicator for enrollment is the number of patients who are screened and enrolled per site per month, and the risk tolerance limit for this indicator may vary depending on the type and phase of the clinical trial, the indication, and the availability of patients. In clinical trials with gene therapy, the enrollment rates might be very low, reaching only 0.5 patients per month per site. Segurado usually uses a conservative estimate of 50% of what the sites claim they can enroll. In the end, it is important to monitor the enrollment rate closely and take corrective actions if needed.

Patient Retention: The Key To Quality Data

Patient retention is another risk that needs to be managed in clinical trials, as it affects the quality and completeness of the data that are collected from the patients. Retention can be challenging, especially for gene therapy clinical trials that require a long follow-up period, and it is important to design the protocol in a way that is convenient and acceptable for the patients. One of the ways to improve patient retention is to use hybrid or decentralized clinical trials (DCTs), where some of the procedures and assessments can be done remotely or at the patient's home, instead of requiring them to visit the site frequently. This also can reduce the burden and cost for the patients and the sites and increase patient satisfaction and engagement.

The key risk indicator for retention is the percentage of patients who complete the clinical trial according to the protocol, and the risk tolerance limit for this indicator should be very high, ideally 90% or more. Listening to the patient's voice and feedback when designing the protocol is crucial to plan quality by design (QbD) into the protocol and educate the patients and the investigators on the importance and benefits of staying in the clinical trial.

Adverse Events: The Priority Is Patient Safety

Adverse events (AEs) are another risk that needs to be managed in clinical trials, as they affect the safety and well-being of the patients, as well as the regulatory approval and reimbursement of the therapy. Working on Phase 1 and Phase 2 clinical trials with cell and gene therapies, patient safety is especially critical and uncertain. These patients often suffer from serious adverse events (SAEs), i.e., cytokine release syndrome or tumor lysis. Regular medical data review and close medical monitoring are the keys for these clinical trials, to ensure understanding and addressing any safety issues that may arise.

The key risk indicator for adverse events is the number and severity of the AEs reported and classified according to the MedDRA guidance, and the risk tolerance limit for this indicator is 100%, meaning that no compromise or deviation is acceptable for patient safety. Using inclusion and exclusion criteria, informed consent, investigator's brochure, and safety monitoring plan to prevent and manage adverse events is one aspect. The other is to teach patients and investigators how to identify and report adverse events.

Additional Risk Management Takeaways From ICH E6(R3)

ICH E6(R3) defines risk management as "a systematic process for the assessment, control, communication, and review of risks to the quality of the drug (medicinal) product across the product life cycle." The ICH guideline E6(R3) on Good Clinical Practice (GCP) provides some principles and recommendations for risk management in clinical trials, which are summarized below:

• Risk management should be integrated into all stages of clinical trial design, planning, conduct, analysis, reporting, and oversight. It should be aligned with the scientific objectives and ethical principles of the trial and consider the characteristics of the drug, the trial population, the trial setting, and the trial methodology.
• Risk management should be proportionate to the level and nature of risk associated with the trial and should consider both the probability and impact of potential risks. Risk management should not impose unnecessary burden or complexity on the trial conduct or oversight, or compromise the validity and reliability of the trial results.
• Risk management should be based on reliable information and evidence and should use appropriate tools and methods for risk identification, assessment, control, communication, and review. Risk management should be documented and justified and should be updated as new information or changes occur during the trial life cycle.
• Risk management should involve all the stakeholders responsible for the trial, such as the sponsor, the investigator, the CRO, the ethics committee, the regulatory authority, and the patients. Risk management should foster a culture of trust, transparency, collaboration, and accountability among the stakeholders and should ensure that roles and responsibilities are clearly defined and communicated.
• Risk management should aim to protect the rights, safety, and well-being of the trial participants and to ensure the quality and integrity of the trial data and the trial outcomes. Risk management should also consider the potential benefits and risks of the trial for public health and society at large and should balance the interests of the individual and the collective.

Risk management is a vital part of clinical trials, as it helps to ensure that the trials are conducted in a way that maximizes the benefits and minimizes the harm to the patients and the sponsors. Risk management is not only a technical skill but also a mindset that requires creativity, flexibility, and discipline.

About The Experts:

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, to 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 provides a GCP refresher course via her Clinical Excellence Training Academy.

Oscar Segurado started his clinical development and medical affairs expertise working at large companies including Abbott, AbbVie, AstraZeneca, BMS, and Becton Dickinson. He gained extensive experience as an executive medical director and chief medical officer at numerous biotech and medtech companies. During his time at AbbVie, he led the medical affairs strategy and execution for several immunology and oncology products, overseeing the launch and life cycle management of the blockbuster drug HUMIRA. For more than 30 years, he has been working in immunology and oncology, with a focus on immunotherapy and cell and gene therapies. He is also the founder and executive director of MedicAffairs Consulting LLC, a digital platform that provides advice and targeted consulting support for clinical development and medical affairs across therapeutic and medtech areas.