‘Don’t put baby in the corner’: overcoming challenges in paediatric drug development
A study by Rutgers University has found clinicians are increasingly prescribing drugs off label to children although there is no evidence of efficacy or safety. Allie Nawrat explores the challenges to paediatric drug development and asks, why there are still so few drugs developed specifically for children?
esearchers at the Rutgers University in the US have found that physicians in the US are increasingly prescribing drugs to under-18s, collectively known as paediatric patients, off-label. This means the Food and Drug Administration (FDA) has not explicitly approved the drug for paediatric patients.
Although off-label prescription is legal and some “drugs approved only for adults may also be suitable for children”, lead author of the study and assistant professor of paediatrics Daniel Horton notes there is limited evidence about the safety and efficacy of many of the drugs prescribed off-label to children. In a statement, he added: “They [paediatric patients] may not respond as desired to these drugs and could experience harmful effects.” This is due a lack of sufficient studies of drugs in paediatric populations.
This trend of rising off-label prescription for vulnerable paediatric patients is occurring despite the introduction of regulations, particularly in the US and Europe over the past decade, trying to rectify the situation and encourage industry to conduct paediatric clinical studies. Not only will having effective drugs for children benefit that patient sub-population, the FDA argues it will bring benefit to health of the entire population.
“Children are not just sized-down adults”
The primary issue with off-label prescription of drugs only approved for adults to paediatric patients is that, as paediatric oncology drug development charity aPODD foundation founder and chairman Cesare Spadoni notes in a 2018 article: “children are not just sized-down adults”.
Paediatric patients have developmental, physiological and psychological differences from adults, even within the same disease. There is less known about disease states in children, which is only compounded by the heterogeneity of the paediatric patient population in general.
The peculiarities and complexities of paediatric diseases, as well as the small patient populations, make them similar to orphan diseases, which have also historically been overlooked in drug development.
Investing in developing and bringing to market drugs for small, high risk patient populations is economically unattractive to pharma companies. However, industry reluctance to develop drugs for paediatric indications expands beyond economics.
Compared to adults, there is less clinical trial infrastructure for children.
Compared to adults, there is less clinical trial infrastructure for children, creating logistical issues in conducting paediatric clinical trials. For example, paediatric clinical research units are rare and children’s hospitals are often not set up to perform clinical trials.
In addition, researchers Angelica Intini, Donato Bonifazi and Giovanni Migliaccio argue in their 2019 peer-reviewed chapter that human cell lines used in pre-clinical studies are derived from adult sources meaning they are not appropriate models of paediatric disease.
These economic and logistic barriers are only compounded by additional ethical issues associated with dealing with a more vulnerable patient population. Exposing children to unknown treatment effects or adverse events is largely unaccepted in society; this is worsened by how best practice for clinical trials is a placebo arm, where participants receive no treatment effect.
Regulatory attempts to overcome challenges
Regulation introduced since 2007 in both the EU and the US has sought to overcome these challenges and highlight the need for the pharma industry to study their drugs in paediatric populations.
The three main regulations in question are the Paediatric Medicine Regulation (PMR), which came into effect in the European Union (EU) in 2007, and two US acts: Best Pharmaceuticals for Children Act (BPCA) (2002) and the Pharmaceutical Research Equity Act (PREA) (2003) – these were made permanent in 2016.
Horton explains they have: “Incentivised and mandated drug companies to conduct paediatric clinical trials and expand labelling to include paediatric indications. These laws also had provisions to stimulate research on off-patent drugs used commonly in children.”
Regulations have encouraged the establishment and consolidation of investigator networks and trial sites for paediatric research.
While the EU’s PMR combines obligations, rewards and incentives into one piece of legislation, the US divides obligations and incentives between the two Acts; the PREA requires companies to assess the safety and efficacy of new drugs in paediatric patients and the BPCA offers an extra six months of patent exclusivity if a company voluntarily carries out paediatric clinical studies.
In addition, these regulations, particularly the EU’s PMR, have encouraged the establishment and consolidation of investigator networks and trial sites for paediatric research. Examples include the EU Innovative Medicines Initiative-funded Connect 4 Children and the European Paediatric Translation Research Infrastructures project – both of which were identified as promising, new initiatives in the field by Intini, Bonifazi and Migliaccio.
Solutions to continuing neglect of paediatric patients
Horton notes that “these laws have helped improve the level of evidence of drugs used in children and expand paediatric drug labelling.”
However, he notes: “even those these laws were passed over one decade ago, we found that off-label prescribing has been steadily increasing in the US.” The expectation was that these regulations would put this practice into the past.
Off-label prescribing has been steadily increasing in the US.
The 2017 decade-long review of the PMR in the EU found that although there had been an increase in medicines approved for children in many therapeutic areas – Spadoni’s article concludes this increased from 33% in 2007 to 70% of new medicines in 2017 - limited progress had been made in diseases that only affect children or where there are significant pathological differences between adults and children with the same disease.
This outcome is not surprising when the EU and US regulatory legislation primarily talks about paediatric clinical trials as an add-on to studies in adults. Paediatric studies should not be afterthought, they should be considered at the beginning of the development progress.
New approaches, and stricter enforcement, will be paramount
Continuing off-label prescription and slow progress in paediatric drug development suggests that new approaches need to be taken to further tackle the remaining barriers and ensure this needy population has access to efficacious and safe drugs.
Horton suggests stricter enforcement of enacted laws: “For example, if regulatory agencies granted fewer exemptions and more aggressively enforced requirements for completion and reporting of paediatric trials.”
Under PREA, companies can receive an exemption from mandated paediatric clinical trials if they can show the disease does not exist in children, studies are impossible to conduct, the drug may be ineffective or unsafe in the population or it would not bring meaningful benefit over existing therapies.
Our study exposes the desperately frustrating barriers that children still face in receiving new treatments.
However, the granting of exemptions is not water tight; they are often used as loopholes even when drugs might actually be effective in paediatric patients. Research by the UK’s Institute of Cancer Research (ICR) found that 50% of children studied had mutations in their tumours that could be treated by adult targeted cancer drugs.
ICR clinical research fellow and The Royal Marsden consultant paediatric oncology Dr Sally George said: “Our study exposes the desperately frustrating barriers that children still face in receiving new treatments – barriers which lie in the regulations controlling how drugs for children are developed and approved.” It is essential that children are not excluded from significant advancements in the medical field simply because it is a hassle to conduct trials in that population.
Breaking logistical barriers to successful trials
To help overcome logistical barriers in paediatric clinical trials, Intini, Bonifazi and Migliaccio talk about how, instead of using adult-derived human cell lines, paediatric studies could make the most of technological advancements, such as induced pluripotent stem cells and organs-on-a-chip. This would also contribute to knowledge about the
Another option might be to move away from clinical trials alone. Horton argues embracing “real-world evidence through high-quality observational studies and pragmatic trials may be a means to improve our understanding about the effects of drugs [in paediatric patients].
Spadoni concluded that for future paediatric clinical development to be successful, there is a need for all stakeholders – industry, academics, physicians and patients – to continue to work collaboratively together and continue to push for an improvement to the status quo in paediatric drug development.