Protecting children in and through research
PART ONE: The Challenges
The MRCT Center’s Promoting Global Clinical Research in Children project sought to examine the ethical, regulatory, privacy, and confidentiality concerns that impede the conduct of global clinical trials in children, with a particular emphasis on ex-US countries and low- and middle-income countries (LMICs). Understanding the challenges encountered in conducting global pediatric clinical trials informed the direction of the work and the development of the project products.
The health of a population is reliant on the development and administration of safe and effective therapeutic products for children. Because children often face diseases that do not affect adults and metabolize and respond to treatments differently than adults, data from clinical research and/or health care involving adults cannot reliably and consistently be extrapolated to pediatric populations. Therefore, ensuring that children have access to safe and effective medicines is generally contingent upon the conduct of trials that enroll children. The incidence in children of many pediatric-specific conditions in children, however, is low, and the pool of potential pediatric research participants is often small and geographically dispersed. Thus, it is often necessary to conduct multisite and multinational pediatric studies to secure sufficient enrollment for study completion. Given the dearth of relevant data and the challenges of working across jurisdictions, the pressing need to overcome existing barriers to multinational pediatric research remains. Further, regulatory complexities render approval of product for children challenging, and once approved, access to and payment for medicines to pediatric populations must be enabled to ensure the availability of approved products to those who need them.
PART TWO: Principles to guide the work
The array of starting tenets offered to guide the work with children and teenagers in support of the belief that children should be protected in and through research. Children should only be enrolled in research that follows established ethical principles. All ethical principles relevant to the conduct of clinical research in the general population also apply to pediatric clinical research. National health authorities should regulate pediatric clinical research in accordance with internationally accepted ethical principles (e.g., CIOMS). Children’s rights, as stated, for example, in the UN Convention on the Rights of the Child, must be respected within the clinical research context. Evidence of potential for clinical benefit to the enrolled children must justify the risks of participation, especially when those risks are significantly greater than those encountered in everyday life. Additionally, children should only be enrolled in research that has scientific and social value related to the health of children or diseases that originate in childhood. The burdens of research participation should be minimized, and efforts to accommodate the needs of children and their families and caregivers should be undertaken to minimize harm and disruption. Importantly, throughout the research process, children are entitled to have a voice in making decisions to the extent their capacity allows. Taken in its entirety, these starting principles undergird the project foci.
PART THREE: Equitable Access
The larger body of project work supports the very basic premise that pediatric patients deserve equitable access to medicines. Children and their health needs are an important research priority, and this access includes safe and effective healthcare services, including vaccines, diagnostics, therapeutics, and disease prevention measures. There are ethical considerations to weigh, including that a child’s access to medicines (and healthcare) is often dependent on where that child lives. A product may be deemed safe and effective by a jurisdiction’s guiding regulatory body and the same jurisdiction’s health technology assessment body may determine that the product in question is not cost effective, thereby preventing access to that product. Children may take on the risks of participating in a clinical trial without benefit either to themselves or others if the interventional product is not available at the end of the trial to the population for whom it was intended. Investigators and sponsors have responsibilities to the child who has participated in research after the research has ended. This includes access to individual and overall research results, if desired, and post-trial access to the therapeutic intervention if found to benefit the child.
PART FOUR: unique ethical dilemmas around the globe
Research with children presents a number of unique ethical dilemmas despite the premise that research involving children follows the same ethical foundation of research involving adults—respect for persons, beneficence, non-maleficence, and justice. For example, children’s decisions are generally subject to the authority and influence of parents, guardians, and/or other authorities, which can complicate how to best consider, discern, and honor children’s preferences during the process of the adult (parent/guardian) providing permission for the minor child’s participation. Assessment of potential risks and benefits is especially challenging in the context of pediatric research, given that the burdens of trial participation may vary with a child’s age, maturity level, medical condition, and situational factors. Finally, some research that may be permissible among adults following their informed consent may not be permissible among children who cannot give informed, autonomous consent, even though assent is desired if not required.
Part 5: regulatory and governance complexities
There are significant differences in country-specific regulations and/or guidance internationally that give rise to regulatory complexities, including the fact that guidance is a recommendation rather than a requirement, rendering practice even more discordant. Such complexities include issues of exploitation and vulnerability, ambiguity around the definition of minimal risk, inconsistencies in the required timing of pediatric development plans, and confusion regarding what constitutes undue inducement and coercion. That some countries do not have regulations or guidance addressing pediatric research at all, and that existing regulations are not harmonized, renders multi-national pediatric research difficult, burdensome, and sometimes impossible. The COVID-19 pandemic served as a pointed reminder highlighting the need for consideration and inclusion of children, improved efficiencies, and global cooperation.
Part 6: Role of health technology assessment bodies
The clinical trial enterprise is fueled by the desire to provide access to medicines for children worldwide, and different stakeholders have different remits that together impact access. Regulators are charged with assessing a medicinal product for safety and efficacy independent of price, while Health Technology Assessment (HTA) bodies are charged with assessing individual and societal value considering not only the cost but also available alternatives. In many countries, the assessments of the HTA authorities of pediatric medicines determine access. The perspectives of regulators, industry, academia, clinicians, patients and patient advocates, and HTA bodies were considered in an effort to develop a common understandingof the evidentiary requirements that HTA bodies need to render a comprehensive value assessment for pediatric populations. The work to promote understanding of the different roles and responsibilities for patients, parents and caregivers, investigators, and the public is ongoing.
Part 7: Elevating the voice of young people
The Promoting Global Clinical Research in Children project sought to collaboratively identify and propose solutions to various regulatory, ethical, and operational challenges encountered in the conduct of international pediatric clinical trials. Of the many topic areas discussed over the course of the effort, a consistent thread of dialogue, almost irrespective of the starting point of any particular discussion, was the importance of soliciting, hearing, respecting, and responding to the pediatric patient voice. While not routinely solicited or included in product development or the clinical research enterprise, there are meaningful ways to engage patients including children, adolescents, and their families. We continue to learn how to make research stronger and build public trust by including the youth perspective in a thoughtful, systematic, and representative way. To that end, an array of deliverables focused on amplifying the voice of children and adolescents has been produced with more forthcoming.