Sara: Can you explain what clinical trials are and what they entail?
Jonathan: Clinical trials aim to test various methods of diagnosing and treating patients and their influence on patient outcomes. Classically, you can think of it as a comparison between two methods. In a clinical setting, these methods are applied to patients, and their progress is monitored to determine if the different approaches lead to different results. It's a structured experiment to identify the most effective treatments for specific conditions.
Wiktoria: What was your involvement in clinical trials?
Jonathan: My first exposure to clinical trials was at international meetings where the results of trials were presented, and I found them fascinating. While many early critical care trials revealed no difference between treatment groups, they have allowed us to refine our practice toward efficient and effective care.
I was fascinated by how these experiments were organised and conducted across multiple countries, involving large communities of clinical professionals and thousands of patients. After completing my training, I decided to work with a prominent trialist in Australia known for conducting extensive trials in our field. Upon returning to Manchester about ten years ago, I decided to focus on conducting clinical trials here and becoming part of the UK community dedicated to addressing these bedside questions. I believe this is where all clinical trials should begin.
In the ICU, we often treat patients with critical and life-threatening conditions. However, it may surprise many that much of what we do lacks solid evidence in improving patient outcomes. Many treatments are empirical, based on scientific rationale and physiological principles to support patients until they recover. However, there remains uncertainty about whether these treatments genuinely benefit patients and if the benefits of treatment outweigh potential harm due to side effects. Countless questions arise at the bedside—when to administer a treatment, whether to wait or act immediately—that could easily become clinical trials. Therefore, the starting point for clinical trials is often the questions that arise directly from patient care.
Mahesh: Medical practices were often based solely on scientific theories for several decades. For example, if a treatment was found to lower blood pressure, it was frequently implemented without considering potential side effects. However, every treatment carries risks along with its benefits, and the overall balance is crucial. Thus, there was a growing consensus that real evidence from large cohorts of people was necessary before adopting new practices. This approach is known as evidence-based medicine, emphasising the importance of empirical evidence over theoretical assumptions. This context laid the foundation for introducing clinical trials, which have since played a dominant role in medical decision-making.
Sara: How important is it for these trials to be conducted ethically and morally, in your opinion?
Jonathan: Ethical and legal regulatory standards govern all our research, whether it involves enrolling patients on ventilators in the ICU or testing cell cultures in the lab. Everything must be conducted ethically. This is somewhat different from how you design a trial. It's essential to start with a clear research question and be thoroughly knowledgeable about the current evidence base surrounding that question. Suppose a question has already been answered through previous research it may not be necessary to repeat this work. It's beneficial because we can change practice or apply that answer without wasting time and resources on unnecessary trials. Understanding the context of your research question is essential before embarking on a new trial.
Mahesh: The term 'ethics' can be defined narrowly or broadly as necessary. For example, when conducting a clinical trial, the obvious question is whether it will harm people. Therefore, an independent panel needs to evaluate the balance of risk versus benefit, as the person conducting the trial is likely to emphasise its benefits.
Another aspect is whether people feel coerced into participating, maybe via financial incentives or fear. The doctor-patient or healthcare professional-patient relationship creates a power hierarchy, and patients might feel obliged to participate, fearing that refusal could affect the care they receive. This indirect pressure can make individuals feel obliged to participate even if it goes against their beliefs. Large clinical trial companies or pharmaceutical firms might offer financial inducements to participants, which can also prove problematic.
Individuals who typically wouldn't have access to personal data will review patient notes, raising concerns about confidentiality. This potential for breach of confidentiality underscores the importance of ethical review processes, which, though time-consuming, are essential to protect the integrity of the patient-doctor relationship.
In clinical trials, stringent protocols are implemented to safeguard patient data from unauthorised access or breaches. Only the clinical team responsible for patient care can access identifiable patient information. Research teams, integrated within the clinical setting, undergo training identical to that of clinical staff. Identifiable data is only accessed when necessary. After uploading, the data undergoes meticulous de-identification (encryption), ensuring complete anonymity and security in the study database. This process complies with UK laws, including the Data Protection Act.
Sara: Does the standardisation of legislation and uniform guidance by ethics committees aid in risk mitigation? How do you handle tough conversations with patients and their families?
Jonathan: The process undergoes rigorous scrutiny. For example, when seeking regulatory approval for a Phase I clinical trial involving a new drug's first dose in a critically ill patient on a ventilator, I expect extensive questioning about safety and preclinical data. The project will be reviewed by specific ethics committees and regulatory approval panels, such as those focused on paediatric patients, individuals with mental illness, and critical care research.
In critical care, we often enrol participants who cannot consent, such as sedated patients on life support. We adhere to an ethical protocol to enrol these patients and seek their consent after recovering. The UK has robust guidelines and a strong track record for ethical conduct of research involving such vulnerable patient groups.
Engaging with patients is essential. Once a research question is identified and existing evidence is reviewed, the next step is patient involvement. In the UK, we excel in patient and public engagement and involvement. We collaborate with patient groups who have undergone similar care pathways to co-design clinical trials and apply for funding with their input. This partnership helps us understand patients' questions if approached to join a clinical trial. This engagement is crucial to designing a clinical trial. It is carried out in tandem with consultations with statisticians and health economists.
Mahesh: An essential component of our approval process is the provision of a detailed information leaflet that outlines all potential risks, regardless of their severity or frequency. This leaflet must be given to participants well in advance, allowing ample time for them to read, understand, and consider the information. They should also have the chance to ask questions before agreeing to participate and signing the consent form. This is known as the informed consent process, a cornerstone of ethical conduct of research.
In our projects, dedicated teams are trained to assist participants through the informed consent process. It's unacceptable to ask someone to join a study on short notice, as this could exert undue pressure. Participants must receive the information leaflet at least 24 to 72 hours beforehand. The leaflet includes contact details for any questions they may have. Only after a thorough review and consideration should participants sign the consent form. This ensures they are fully informed and willing to consent.
Sara: In the context of the UK, what additional safeguards should be implemented to protect vulnerable individuals, such as those with cognitive impairments, during their participation in clinical trials?
Jonathan: In the ethics application process, researchers must articulate precisely how their experimental design deviates from standard care for patients with a specific illness within the healthcare system. This involves specifying every alteration, such as additional blood pressure management, new questionnaires, blood sampling, or extra diagnostics like X-rays. Each deviation must be justified with a solid evidence-based rationale, weighing its benefits against any potential burdens for the patient. Ethics committees are crucial in evaluating these justifications, ensuring that proposed changes are proportionate to the study's objectives and do not unnecessarily burden participants. This approach aims to streamline clinical trials by gathering essential data while minimising unnecessary data collection, thereby optimising efficiency in research practices.
Wiktoria: When an established drug is proven effective for a disease under study, would it be ethically justified to incorporate a placebo into the trial design?
Jonathan: When evaluating a new drug, the ethical consideration for using a placebo arises. Typically, comparing the latest treatment with the established one or in other words, comparing the added benefits of using the new drug against standard care only would be the standard approach under these circumstances. Placebos traditionally come into play when no existing treatment exists for the studied condition. However, there is a shifting perspective on the necessity of placebos, especially given their high costs and the logistical challenges of blinding participants and assessors in trials. They can be costly and might not always be essential, especially when blinding is feasible among patients, assessors, and statisticians.
Wiktoria: Do the participants have any entitlement to access this proven treatment once the trial has concluded?
Mahesh: When conducting a clinical trial, our goal is to demonstrate the effectiveness of a drug in achieving specific outcomes. However, even if the trial shows promising results, we cannot immediately implement widespread changes in medical practice. In the United Kingdom, a structured process follows to ensure that any new treatment is not only effective but also socially/culturally viable, and economically viable or cost effective. This decision-making process is overseen by the National Institute for Health and Care Excellence (NICE). This additional rigorous evaluation ensures that broader considerations of effectiveness and acceptability in the healthcare landscape and inform decisions regarding new treatments.
Jonathan: In academic research, particularly in clinical trials, evaluating cost-effectiveness often involves considerations beyond the trial's immediate objectives. As researchers, our primary focus is designing and conducting trials to evaluate treatments and report outcomes. Whether a treatment merits public funding falls under the purview of external bodies such as NICE.
In commercially funded research, especially in critical fields such as cancer or rare degenerative diseases, contractual agreements often govern interactions between participants and drug providers. For instance, in double-blind randomised controlled trials (RCTs), participants may receive either the treatment or a placebo. Suppose the treatment proves effective and is approved. In that case, participants who received the placebo might be able to receive the active treatment first. These potential benefits must be agreed before-hand and are carefully regulated under ethical and contractual guidelines, including participants consenting to receive trial updates and treatment alternatives.
However, providing treatments post-trial raises ethical and scientific complexities, potentially compromising the trial's blinding. Despite these complexities, such practices aim to balance scientific integrity with providing potential benefits to participants engaged in pivotal research efforts.
Sara: When the vaccine was developed in high-stakes situations like the global COVID-19 pandemic, would it typically undergo a clinical trial under normal circumstances? How do we uphold efficacy and ethical standards during such critical times?
Jonathan: During the COVID-19 pandemic in the UK, all trials on vaccines and new treatments strictly followed standard practices and regulatory protocols. Despite the urgency of the pandemic, all necessary steps were followed without cutting corners. This focused approach and a surge in eligible participants facilitated rapid advancements in our research. Despite the urgency of the situation to our knowledge, all regulatory approvals from bodies like the MHRA (Medicines and Healthcare Products Regulatory Agency) and HRA (Health Research Authority) were rigorously adhered to, ensuring the integrity and safety of the trials.
The Medicines and Healthcare Products Regulatory Agency (MHRA) scrutinises clinical drug trials. Other bodies may be involved in changes in care pathways. Overall, the Health Research Authority (HRA) is the umbrella organisation for health research in the UK, integrated within NHS infrastructure. This structure supports a unified network of ethics committees, ensuring they adhere to the same guidelines and laws with similar compositions and operating practices.
Mahesh: In fact, there was considerable pressure, especially with certain medications other than vaccines, to bypass the trials and proceed directly because of the urgency and fatal nature of the disease. A notable example is hydroxychloroquine. However, the UK generally resisted such pressures and adhered to the established processes and good practice.
Jonathan: After administering a new trial, one of our primary concerns is monitoring adverse events to determine if any short- or long-term harm may be related to their research participation or their underlying illness. We swiftly identified adverse events during the COVID-19 trials due to the extensive recruitment efforts and rapid vaccine administration. This resulted in rapid changes to the vaccine formulation to prevent recurrence. This process would have been much slower in traditional vaccine trials due to longer intervals between adverse events. Despite criticisms, particularly regarding now-withdrawn vaccines using older technology, our approach enabled us to establish the safety profile much quicker due to the high volume of participants involved simultaneously. It highlights that our research isn't solely about efficacy but also focuses on long-term safety considerations.
Wiktoria: How are participants screened to ensure their eligibility, mainly when testing a drug for multifactorial conditions?
Jonathan: We generally use a mnemonic called PICO (Population, Intervention, Comparison, Outcome) to guide the screening process for clinical trials. It's crucial to describe the population sampled for a clinical trial clearly and to ensure that it closely matches the end population that might be prescribed the new diabetic drug.
For instance, in sepsis trials, there is no definitive diagnostic test. Instead, we rely on a set of inclusion criteria that patients must meet and exclusion criteria that would exclude them. Creating these criteria involves balancing broad and narrow definitions. A broad inclusion criterion might yield a diverse study population with high external validity, meaning the results widely apply to real-world settings. Conversely, narrow inclusion criteria focus on a specific patient population, offering high internal validity (strength of the study results) but may be less applicable in everyday clinical practice.
Sara: How can researchers ensure that the selection of participants for clinical trials is fair and unbiased, representing the diversity of the population?
Jonathan: From an NHS perspective, ensuring fair and unbiased participant selection in clinical trials is crucial. Our policy is that every patient who enters our facilities is given the opportunity to be included in appropriate trials. We conduct comprehensive screenings daily, from Monday to Friday, particularly in the ICU, to identify eligible participants without discrimination. We make a concerted effort to avoid discrimination of any kind.
For instance, if participant information sheets are only available in English, are lengthy, and require a high reading level, individuals who are non-native English speakers or have lower literacy levels may be excluded. Similarly, suppose follow-up procedures require participants to return to the hospital. However, they cannot do so due to distance or lack of transportation. In that case, these participants are effectively excluded from the study.
Mahesh: Moreover, when the study is written up as a report or formal paper, the results section typically includes a detailed description of the study population. This description typically includes details such as the mean or median age, the age range, and various demographic characteristics. Comparing the study population's demographics to the general population. This practice helps control for demographic variables and ensures that the study's findings are accurately contextualised.
Sara: Could you explain how the integration of machine learning and deep learning might improve the success rate of clinical trials if implemented successfully?
Jonathan: AI has immediate potential to enhance the efficiency and cost-effectiveness of clinical trials. For instance, electronic patient records (EPRs) already streamline patient screening, automatically identifying eligible candidates based on specific criteria like antibiotic prescriptions for infections. This automation saves time and labour. Additionally, AI could facilitate faster data transfer and transcription, further optimising trial processes.
Moreover, AI could facilitate data management and transfer improvements, further optimising trial operations. However, challenges remain, particularly in integrating and harmonising data across different healthcare settings and regions. Current data systems are not yet fully interconnected at the level required for comprehensive analysis and personalised decision-making.
Looking ahead, younger generations of healthcare professionals may increasingly rely on AI at the bedside to inform clinical decisions. Yet, AI is unlikely to replace the human element of patient care, which involves nuanced decision-making and compassionate communication with patients and families. As such, while AI offers promising advancements, its role will complement rather than replace healthcare professionals in delivering patient-centred care.
Mahesh: Throughout history, every technological advancement has sparked fear and anxiety about potential disruptions and consequences. Artificial intelligence (AI) is no different. The consensus is that AI holds immense potential benefits but also risks causing harm. Like any technology, its outcomes depend on how humanity chooses to utilise it, and the regulatory frameworks put in place
Sara: How can we ensure patient data protection amidst concerns about AI's susceptibility to cyberattacks and other security risks?
Jonathan: Within the UK healthcare infrastructure, NHS digital plays a crucial role. Suppose we can effectively harmonise data across different platforms. In that case, we can achieve labour-saving efficiencies in the short term, with long-term benefits expected from harmonising data across different NHS platforms. However, as you have pointed out data security is important and is an absolute priority for the NHS. Several systems are in place in our own Trusts, Universities and the wider NHS to ensure data security. Specialist units and experts are employed to ensure that all precautions are in place to protect the integrity of data, and these systems are subject to regular audits and checks by internal and external authorities.
The Editorial Team and the writers would like to thank Professor Niroshini Nirmalan for her assistance with establishing a connection with the featured collaborators for this article.