Do No Harm: How to Mitigate Risk in Child and FIH Clinical Trials

Mitigating risk to patients in clinical trials is a significant concern for sponsors and researchers. The ultimate pursuit is to find a new treatment, always balanced against the potential harm that can arise in phase I and first-in-human (FIH) trials. 

While keeping all trial patients safe is of paramount important, treating children requires an even greater responsibility in ensuring they experience no harm. In this post we explore how to keep children safe in clinical research and how to mitigate risk in FIH trials.

Fair Subject Selection

Clinical research with children as patients shares a similarity with research into senior citizens: There isn’t much out there. With the former group in particular, however, there is great pressure to avoid any health and safety risks that might befall these patients. However, as NIH guidelines state, any trial recruitment should be directed by the scientific goals of the study, the mitigation of risk to patients and the maximization of health for the broader society. 

Women or children, for example, should not be denied access to clinical trials unless there are scientific reasons to do so. 

Children’s Representation in Clinical Research

In 1989, the NIH mandated that women and minorities be included in research, and nine years later, it extended the reach to include children. The reason for children to be treated as patients in clinical trials arose from the fact that most medical treatments children received had only been tested on adults, explains geriatrician Dr. Louise Aronson.

Inclusion of those populations was significant, but the problem of skewed representation in clinical research remains, Aronson says. Children comprise 24 percent of the US population so this cohort needs greater representation if treatment of pediatric diseases is going to succeed.

Treating Children Requires a Different Approach

The treatment of some diseases in children is different from that required and received by adults. In terms of diabetes, for example, the American Diabetes Association says children need treatment that is tested on them and not derived by that trialled on adults. “The epidemiology, pathophysiology, developmental considerations, and response to therapy in pediatric-onset diabetes are different from adult diabetes.” 

Given the constraints around clinical research in children, treatment recommendations for these young patients will likely be based on expert opinion rather than a wealth of clinical trial evidence. These knowledge gaps need to be filled, the ADA team explains.

Additionally, the team says that the way treatment works should be appropriately explained. So children patients and their parents or caregivers should be provided with information that is culturally sensitive and developmentally and age-appropriate. Clarity is key, as instructions about how the treatment drug needs to be administered must be simple to understand. 

The ADA adds that clinical researchers and healthcare providers need to understand the educational, behavioral, emotional, and psychosocial factors that affect children with diabetes so they can optimize the treatment journey.

FIH Trials

Children Require Clear Information About Trial Processes 

Children and their parents need to know what to expect of a clinical trial before agreeing to participate. Specifically, they want information about what the trial will test and how it will happen, along with any risks and the benefits of the research, according to Dr. Jacqueline M. Martin-Kerry of the Department of Health Sciences, University of York researchers, and her fellow researchers.

Also important to prospective patients is the explicit understanding that they can leave trials should they wish. Information given to patients, therefore, should be clear, concise and credible. Engagement tactics, such as animated characters to help navigate online information on sponsors’ websites, are also effective. 

Consent for Children in Low-Income Countries

Any research into children from low-income countries requires researchers to be aware of the inequalities that arise from socioeconomic factors, along with the cultural and linguistic nuances. This is imperative to ensure informed consent is captured appropriately, researchers Marcela Colom and Dr. Peter Rohloff explain.

They suggest that community engagement can help children and their caregivers understand the consent process. Using verbal consent procedures can also help in low-literacy settings or when the patient’s language is not commonly spoken, Colom and Rohloff add.

Ensuring a child patient’s autonomy is key, which requires researchers engage with the community to understand gender dynamics, leadership hierarchies and how social status may affect patients and their families when giving consent.

Specialist Knowledge Helps Synergize Trials

Expert knowledge in a disease area among clinical research professionals streamlines research processes. This is certainly true in incidences of childhood cancers, says clinical trial manager Dr. Emmanouela Gbandi. Her own expertise makes consulting and aligning various stakeholders easier and also allows her to note synergies and trends between trials to solve any problems with greater responsiveness.

While expertise leads to more streamlined processes across multiple trials, Gbandi says collaboration among international experts — especially those investigating rare pediatric diseases — is desperately needed.

FIH Trials

Patients’ Perceptions of Risk

Let’s broaden our scope from children patients specifically and consider phase I and FIH trials. There’s a paucity of research into healthy patients’ perceived risk regarding phase I clinical trials. Social scientist Jill A. Fisher, however, did lead a study as to how patients consider the overall risks of phase I trials including how they might be personally harmed. She and her team also looked at how a patient’s clinical trial history or sociodemographics influences perceptions of risk.

The study population consisted of 178 healthy volunteers, with an average of 1.9 phase I trials completed. The findings showed that healthy patients have different perceptions of overall risks compared with personal risks. As many as 118 patients thought trials were high risk yet 97 people considered themselves as being personally safe when participating. 

Mitigating risk is important but so too is communicating that risk to patients and making sure they know the possible outcomes because of their participation in a trial.

Expansion Cohorts in FIH Trials

Phase I clinical trials, which can also be first-in-human trials, usually include between 20-80 patients and aim to determine the correct dose, side-effects and pharmacologic actions of a new drug, writes Zachary Brennan at the Regulatory Affairs Professionals Society.

Last year, the FDA published a guidance on multiple expansion cohorts — “trials with a single protocol with an initial dose-escalation phase that also contains three or more additional patient cohorts with cohort-specific objectives,” Brennan explains — with the intention of accelerating drug development by basing effective doses on initial determinations.  

Trials with multiple expansion cohorts help speed up patient access to treatment but also present challenges, says Samantha Eakes at FDA regulatory consulting firm, Greenleaf Health. These include:

  • The manner and frequency that investigators, IRBs and regulators receive safety information. 
  • Potentially incorrect or unsafe doses of the investigational drug administered to patients. 
  • More patients than required receive the drug.
  • Early trial findings are prone to misinterpretation.

But these types of trials also require sponsors to improve their safety monitoring and communication of protocols as they change. Eakes says that multiple expansion cohort trials require the reporting of safety data multiple times in a year. 

Quantitative Systems Pharmacology (QSP) for FIH Trials

QSP uses computational modeling and experimental data to understand how treatment drugs, biological systems and diseases interrelate. And this technology can make first-in-human clinical trials more efficient, writes clinical pharmacologist Piet van der Graaf.

Quantitative systems pharmacology helps researchers to decide on doses and their increases to keep risk to patients at a minimum. Van der Graaf says that in FIH trials, preclinical data lacking any computational model-based approaches will fail to exploit all of the available data. Indeed, researchers using QSP can more accurately predict pharmacodynamic ranges and maximum dose than by relying on preclinical data.

However, Van der Graaf notes that prevailing regulatory and industry opinion requires FIH doses be estimated using preclinical data.

Risk-Assessing Clinical Trials

There are true FIH trials in which the investigational medicinal product is being trialed on humans for the first time. But other trials can also be classified as FIH even when this criterion is not met, explain Jennifer Martin and Kirsty Wydenbach, at the UK’s Medicines and Healthcare Regulatory Agency.

Whether a trial is a true FIH, phase I or early-phase trial, researchers will need to assess risks accordingly and submit this information to regulatory agencies, which will then apply the relevant legislation and guidance. Sponsors that correctly determine or classify their trials and phases of their trials will enjoy a simpler process when complying with legislation and a greater chance at mitigating risk for patients.

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