Advertisement

Forgotten No More: How Policy Guideline Changes Are Bringing Newborns, Infants, and Children to the Forefront of Drug Discovery and Testing

Published:September 21, 2017DOI:https://doi.org/10.1016/j.clinthera.2017.09.004
      In Great Expectations, Charles Dickens wrote, “In the little world in which children have their existence whosoever brings them up, there is nothing so finely perceived, so finely felt, as injustice.”
      • Dickens C.
      Great Expectations.
      For decades, children have been an afterthought of drug discovery, regulation, and development. Currently, only a fraction of adult therapies have undergone the same rigorous safety profile and efficacy testing in children, forcing caregivers to choose between no treatment or off-label prescribing, with unknown risks and side effects. This grave injustice to our most vulnerable patients has not only placed children at risk for serious medical complications, morbidities, and mortality, but also has resulted in significant delays in drug discovery aimed at combatting diseases affecting this population. Children have become the orphans of pharmacology, with historically little interest in the development and testing of therapeutics aimed at ameliorating their symptoms and improving their outcomes. While the US, Canadian, and European regulatory bodies have all had longstanding policy statements regarding drug testing in children, perceived barriers of the risks—physiological, psychological, economical, and ethical—associated with testing drugs in newborns, children, and adolescents, limited study initiatives aimed at our youth. However, the US Food and Drug Administration (USFDA) recently mandated that drug, biological and nutritional products, devices, and therapies be rigorously tested across the human age spectrum before approval.
      • Califf R.M.
      Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. Status Report to Congress.
      Combined with the emergence of child advocacy groups, international consortiums, and networks for pediatric drug development and testing and, importantly, newfound support from the pharmaceutical industry, children are no longer an afterthought in the therapeutic marketplace. As Dr. Christina Bucci-Rechtweg writes in this Special Topic Issue of the Journal, there has now been a shift “toward drug development research ‘for’ children rather than simply ‘in’ children.”
      • Buccci-Rechtweg C.
      Enhancing the pediatric drug development framework to deliver better pediatric therapies tomorrow.
      Throughout this Specialty Update, we highlight a new era in drug development and testing aimed specifically at the pediatric population. Driven in large part by new obligations and incentives put forth in emerging policy from the USFDA, European Medicine Agencies, and Canadian Office of Pediatric Initiatives, pediatric drug trials and de novo pediatric drug discovery are becoming a priority.
      • Califf R.M.
      Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. Status Report to Congress.
      • Buccci-Rechtweg C.
      Enhancing the pediatric drug development framework to deliver better pediatric therapies tomorrow.
      • Rieder M.J.
      Canadian Peditric Society; Drug Therapy and Hazardous Substances Committee
      Drug research and treatment for children in Canada: a challenge.
      • Davis J.M.
      • Baer G.R.
      • Portman R.
      • et al.
      Enrollment of neonates in more than one clinical trial.
      This evolution offers great promise to dramatically increase the arsenal of drugs available to treat childhood diseases and significantly impact care. Drugs that have long been used off-label in newborns and children will now undergo the stringent testing required for use in adults. Economic incentives aimed at engaging pharmaceutical companies to invest time and resources in the discovery of treatments for diseases unique to this population are in place. And, international consortiums and networks have formed to sufficiently power clinical trials for rare pediatric diseases and conditions. Turner et al
      • Turner M.
      • Hischfeld S.
      Frameworks for evaluating medicines in children.
      highlight the importance of these networks to “benefit all stakeholders by providing a multifunctional platform that promotes the quality and timeliness of clinical drug development” for children. However, while these strategies offer great promise, so too, do they bring their own challenges moving forward.
      As a practicing neonatologist, I am continually reminded of the impact that the paucity of USFDA-approved therapeutic agents for use in the newborn has had on clinical care. Prescribing drugs based solely on adult safety profile and efficacy data has resulted in hard-to-learn lessons about unforeseen side effects that have often had long-term consequences for these infants, whose unique physiology and ongoing development may alter pharmacokinetic properties, drug−drug interactions, and side effects. With the new mandates to test drugs across the age spectrum, commonly used and newly emerging therapeutics are now being evaluated through national and international clinical trials. However, many of these trials are targeted at extremely premature infants, who are in great need of therapeutic agents to treat or eliminate the significant morbidities they are most at risk of developing. With <3% of births worldwide occurring at the extremely premature age (<28 weeks gestation), trials must compete to enroll premature infants. Determining which babies should be enrolled in which trials is a new challenge to the field. This uncharted territory of ethical and scientific considerations requires guidelines and suggested roadmaps by regulatory bodies. Dr. Jonathan Davis and colleagues from the USFDA and European Medicine Agencies provide a thoughtful outline on when it is appropriate to enroll infants into more than one clinical trial, as well as the ethics associated with approaching families for more than one study.
      • Davis J.M.
      • Baer G.R.
      • Portman R.
      • et al.
      Enrollment of neonates in more than one clinical trial.
      Importantly, the article highlights the need to maximize participation in clinical trials whenever possible, with the important caveat that, in so doing, we cannot undermine the work. Co-enrollment must never compromise the science.
      Arguably more impactful than any federal or international mandate to increase pediatric drug trials are the voices of the children who have been directly impacted by the lack of available drugs and clinical trials to address their health needs. Founded in 2015, the International Children’s Advisory Network (iCAN) is a worldwide consortium of children and their families.

      International Children’s Advisory Network 2016. https://www.icanresearch.org/. Accessed September 5, 2017.

      Now with 20 chapters worldwide, iCAN serves as both an advocacy group and a forum to educate and inform families about pediatric health care, medicine, and research on both a local and international level. We feature iCAN in this Update and highlight the voices of 2 young individuals whose own lives and unique medical conditions have been affected directly by their ability to enroll in clinical trials.
      • Gwara M.
      • Smith S.R.
      • Woods C.
      • et al.
      International Children’s Advisory Network: a multifaceted approach to patient engagement in pediatric clinical research.
      Each faces medical uncertainty, but both are committed to sharing their personal experiences to help other children. Their future depends on an unwavering commitment by the USFDA, European Medicine Agencies, and Pharma to make children a priority, combined with what Dr. Mark Turner and colleagues highlight in this Update is a “greater understanding of pediatric issues relevant to decision-making frameworks and research communities.”
      • Turner M.
      • Attar S.
      • de Wildt S.N.
      • et al.
      Roles of clinical research networks in pediatric drug development.
      Only then will we be able to develop therapeutics to combat rare diseases affecting this population, as well as generate a better understanding of the age-specific pharmacokinetic profiles of existing drugs so that they can be prescribed without the risk of adverse effects. As Charles Dickens reminds us, “The most important thing in life is to stop saying ‘I wish’ and start saying ‘I will.’ Consider nothing impossible, then treat possibilities as probabilities.”
      • Dickens C.
      David Copperfield.
      We have an unprecedented opportunity in pediatrics to right the injustice served to our youth. Our children should have great expectations that we will deliver for them.

      References

        • Dickens C.
        Great Expectations.
        Penguin Books Ltd, London, England1996
        • Califf R.M.
        Best Pharmaceuticals for Children Act and Pediatric Research Equity Act. Status Report to Congress.
        Department of Health and Human Services Food and Drug Administration, Washington, DCJuly 2016
        • Buccci-Rechtweg C.
        Enhancing the pediatric drug development framework to deliver better pediatric therapies tomorrow.
        Clin Ther. 2017; 39: 1920-1932
        • Rieder M.J.
        • Canadian Peditric Society; Drug Therapy and Hazardous Substances Committee
        Drug research and treatment for children in Canada: a challenge.
        Pediatr Child Health. 2011; 16: 560
        • Davis J.M.
        • Baer G.R.
        • Portman R.
        • et al.
        Enrollment of neonates in more than one clinical trial.
        Clin Ther. 2017; 39: 1959-1969
        • Turner M.
        • Hischfeld S.
        Frameworks for evaluating medicines in children.
        Clin Ther. 2017; 39: 1949-1958
      1. International Children’s Advisory Network 2016. https://www.icanresearch.org/. Accessed September 5, 2017.

        • Gwara M.
        • Smith S.R.
        • Woods C.
        • et al.
        International Children’s Advisory Network: a multifaceted approach to patient engagement in pediatric clinical research.
        Clin Ther. 2017; 39: 1933-1938
        • Turner M.
        • Attar S.
        • de Wildt S.N.
        • et al.
        Roles of clinical research networks in pediatric drug development.
        Clin Ther. 2017; 39: 1939-1948
        • Dickens C.
        David Copperfield.
        Penguin Books Ltd, London, England2004