Mitigating diagnostic errors in clinical trial participants: The role of drug safety/pharmacovigilance
A diagnosis identifies a patient’s health problem and is a key to accessing the care and treatment they need.
A diagnostic error is the failure to establish a correct and timely explanation of a patient’s health problem, which can include delayed, incorrect, or missed diagnoses, or a failure to communicate that explanation to the patient.
Diagnostic safety can be significantly improved by addressing the systems-based issues and cognitive factors that can lead to diagnostic errors.
- The WHO World Patient Safety Day Website
Clinical trials, especially Phase I and I/II, are frequently populated with participants at advanced stages of disease, often those with cancer. Patients may become candidates for trials due to late diagnoses or misdiagnosis. Even when patients bring forth concerns in a timely fashion, the medical community may fail to assign an accurate diagnosis. In this article, we’ll consider the challenge that diagnostic errors present to potential study participants, ways to reduce the occurrence of these errors during the clinical trial, and the role that drug safety/pharmacovigilance (DSPV) plays.
The problem defined
In the United States, an estimated one in 20 adults (12 million people, 5.1% of the population) experience an outpatient diagnostic error each year, half of which are potentially harmful.1 Inpatient diagnostic errors are responsible for 6%-17% of adverse events.2 Over the course of a lifetime, most people’s lives will be touched by a diagnostic error.3 Of the highest-severity harms after misdiagnosis, cancer represents the biggest segment (37.8%).4
The World Health Organization (WHO) suggests that improving diagnostic safety can be achieved by addressing both cognitive (clinician training, stress) and systemic (communication, teamwork) factors. These recommendations are aimed at clinical care settings, including study sites. In contrast, in the drug development space, potential risks are constantly examined in great detail across disciplines and measures put in place early on to mitigate failures of any kind. And yet, errors still occur in the conduct of clinical trials because, among other factors, studies are conducted at these facilities that are susceptible to making diagnostic errors for the reasons stated.
So, how do we ensure that these errors don’t adversely impact our trials?
Suggested solutions
One way to mitigate risk is by a process utilised at City of Hope in Duarte CA, USA. They engage a centralised team of clinical content specialists comprised of nurses and pharmacists to cohesively review protocols, cell therapy, and pharmacy manuals and other study documents for inconsistencies and errors. Of the almost 600 oncology trials examined by this team, nearly half had issues requiring intervention and 17% of these were potential patient safety issues, most often involving drug dosing. These occurred in Phase I studies more than any other phase, and investigator-initiated trials had the greatest number of patient safety concerns compared to other types of sponsors.6
Another risk-reduction strategy is assuring care coordination between the study site and the study participant’s other healthcare providers. This is challenging if the institutions involved aren’t linked in any way. In one study, although 29.3% of subjects had at least one medical appointment with non-investigator physicians during the course of the trial, the patients’ participation was not documented in any of their medical records, indicating that these physicians were unaware of their patients’ enrolment in clinical research.5
Third, the Agency for Healthcare Research and Quality (AHRQ), a US governmental body under the auspices of the Department of Health & Human Services, has awarded substantial grants to establish Diagnostic Safety Centers of Excellence in order to pilot projects aimed at reducing diagnostic errors by studying the problem at a very granular level and developing novel solutions (systems, measures, and new technologies).
The patient’s journey: Impact of misdiagnoses on clinical trial participation
Finding oneself at an advanced stage of disease is devastating and may diminish one’s hope for the future. Participation in a clinical trial may restore some of that hope, if not for extended survival, then for the legacy of a meaningful impact on others. However, these patients often have significant challenges.
Patients diagnosed late may be medically fragile and ill with co-morbidities that render them more vulnerable to experiencing adverse events. They may be less constitutionally robust to withstand the administration of an investigational product with an as-yet-unknown safety profile, and less able to cope with the rigours of trial participation, including intense monitoring procedures and protocol required follow-up visits to the study site.
Once enrolled on-study, pre-treatment screening tests, which are crucial to including or excluding appropriate participants, are required. These laboratory tests and imaging scans, which measure progress, protocol adherence, and response to the investigational product, may be some of the very same tests, scans, and diagnostic procedures – and the same medical personnel who first interpreted them – that previously failed to accurately diagnose the patient. Distrust and anxiety are natural emotions as patients navigate through the screening period.
During the course of the study, if complications arise, the risk of adverse events or serious adverse events (SAEs) increases, which could jeopardise the participant remaining in the study. Dose-limiting toxicities encountered early may mean the trial is put on hold to further enrolment temporarily and higher dose groups never accrue patients.
The role of drug safety/pharmacovigilance (DSPV) in safeguarding patient safety and public health
As DSPV professionals, we take seriously our obligation to safeguard patient safety, and by extension public health, by proactively advocating for participants’ interests in every aspect of clinical trial conduct. According to Godfrey et al, DSPV “monitoring may […] increase the willingness of individuals to participate in trials due to greater confidence in the conduct of the study.”7 We provide input to early protocol development, author the Safety Management Plan, work with data managers to design accurate data collection forms, configure and test the safety database, which stores SAE cases and generates reports notifying global regulatory agencies. We critically evaluate the available information and formulate a patient safety narrative that accurately reflects the participant’s experience, in particular how the event was diagnosed and treated, as well as the outcome.
We diligently follow up, ask pertinent and probative questions, all in service of telling the patient’s story in the most accurate way possible. This narrative will be reported to and read by officials at the US Food and Drug Administration (FDA) and regulatory bodies all over the world. They’ll also appear as part of a New Drug Application, a Biologic License Application or a 510(k) Premarket Notification for an investigational medical device that’s submitted to these same agencies, seeking approval to market the product. It’s imperative that we respect the patients who have entrusted us with their care by shepherding their data carefully, so that the drug, biologic, or device that could possibly extend their lives continues to be available to them, receives regulatory approval, so other patients can also benefit, or – in rare instances – is removed from testing or from the commercial market because it presents harm to them and others.
In summary, a misdiagnosis may deliver some patients to a trial, as their only remaining option, in a more fragile state of physical and emotional health. DSPV is an integral part of ensuring participants remain enrolled so that they can continue to receive the possibility of benefit, as well as restoring their trust in the diagnostics and the people behind them, which will chart their progress forward and, hopefully, herald their success.
References
- Hardeep Singh et al., “The Frequency Of Diagnostic Errors In Outpatient Care: Estimations From Three Large Observational Studies Involving US Adult Populations,” BMJ Qual Saf 23, no. 9 (2014):727–31.
- National Academies of Sciences, Engineering and Medicine, Improving Diagnosis in Health Care (The National Academies Press, 2015), https://doi.org/10.17226/21794.
- Kendall K. Hall et al., Making Healthcare Safer III: A Critical Analysis of Existing and Emerging Patient Safety Practices (Agency for Healthcare Research and Quality, 2020), https://www.ahrq.gov/research/findings/making-healthcare-safer/mhs3/index.html.
- David E. Newman-Toker et al., "Serious Misdiagnosis-Related Harms In Malpractice Claims: The ‘Big Three’ – Vascular Events, Infections, And Cancers" Diagnosis 6, no. 3 (2019): 227-240, https://doi.org/10.1515/dx-2019-0019.
- Satish Chandrasekhar Nair et al., “Optimizing Patient Safety In Clinical Trials By Improving Transitions Of Care,” Jt Comm J Qual Patient Saf 46, no. 4 (2020): 232-233, https://doi.org10.1016/j.jcjq.2020.01.001.
- Vivian C. Loo et al., “Preventing Potential Patient Harm Through Clinical Content Interventions During Oncology Clinical Trial Implementation,” Journal of Patient Safety 19, no. 7 (2023): 460-464, https://doi.org/10.1097/PTS.0000000000001154.
- Catherine Godfrey, et al., “Ensuring Participant Safety and Trial Integrity With Clinical Trials Oversight,” Journal of Acquired Immune Deficiency Syndromes 65, Suppl 1 (0 1) (2014): S40-S43, https://doi.org/10.1097/QAI.0000000000000041.
About Advanced Clinical
Advanced Clinical is a clinical development and strategic resourcing organisation committed to providing a better clinical experience across the drug development journey. Our goal is to improve the lives of all those touched by clinical research – approaching each opportunity with foresight, character, resilience and innovation. Based on decades of experience, we help our clients achieve better outcomes by conducting candid conversations and anticipating potential issues through our customised solutions. Visit our website to learn more: www.advancedclinical.com.
About the author
Tracie L. Russell, RN, BS is a Senior Safety Service Specialist in Global Safety Services at Advanced Clinical LLC. She’s a former paediatric oncology nurse and the former Amy C. Potter Nurse Fellow in Cancer Epidemiology at Dana-Farber Cancer Institute. Russell has worked in various capacities in the biopharmaceutical industry since 1991 and specialises in pharmacovigilance writing.
