Recruitment and patient retention are some of the most challenging aspects of conducting clinical research. With paediatric clinical trials, these challenges are even more pronounced.
Children make up 27% of the world’s population but at least 50% of all drug products may still lack labelling with paediatric information.
Part of the issue is that proving a drug is safe and effective in paediatric populations requires separate research, and separate investment. As US-based paediatric specialist contract research organisation (CRO) Paidion Research says: “kids are not just little adults.”
“Children’s body systems mature at different rates all the way through childhood,” says Paidion Research chief operating officer Betsy Reid. “From being an infant to being an adolescent – they metabolise things much differently, so you can’t just do weight-based dosing.”
Drugs that have not conducted proper clinical research in paediatric patients greatly increase the risk of unexpected adverse events – in 2008, 211,209 visits to the emergency room were by children 12 or younger due to adverse drug reactions, Kayentis reports.
It was only in the last few decades that legislation really started to evolve to make trials done in children a requirement. The pharmaceutical industry’s increased commitment to paediatric studies and boosted efforts in finding treatments for rare diseases has greatly increased the demand for clinical trials done in children.
But lack of experience in this area combined with unique challenges means that failure rates are high with around one in five paediatric clinical trials failing.
Paediatric trial challenges: enrolment and retention
The paediatric patient population in most therapeutic areas is a lot smaller than the adult equivalent – this is partly because there just aren’t as many children in the world as there are adults, and partly because thankfully, younger people are a lot less likely to have serious illnesses.
“Trials are never done on healthy children – they have to have the disease or a need for the medication, so recruitment in paediatric trials is typically slower than in adult trials,” says Reid. “Children don’t have the same comorbidities as adults so there are a lot fewer serious adverse events.”
Additionally, many paediatric illnesses are rare diseases, adding another factor that complicates the task of bringing small, geographically disparate patient populations together to meet statistical requirements. To make matters more difficult, rare paediatric disorders often don’t share similar disease progression with the adult forms of disease.
Consequently, simply extrapolating data from adult studies becomes invalid, and a full, well-controlled pharmacokinetics/pharmacodynamics (PK/PD) study with an ample pool of patients is required.
Unless the child is of consenting age, it falls on parents to decide whether their child should take part in a trial. This can be an incredibly difficult decision for a parent as putting a child through a clinical trial can be strenuous on the whole family, and a calculated risk in terms of outcomes.
“With kids, it’s not just the sick child,” says Paidion director of clinical operations Jamie Wardynski. “It’s a sick family in a way, because we have to factor everybody into that equation.”
Logistical hurdles affecting the family, such as transportation, arranging childcare for other children, and balancing the considerable commitments of time and effort, often result in lengthy recruitment times and narrower patient populations for paediatric clinical trials, as well as a heightened risk that young participants will be withdrawn.
Keeping patients and parents engaged
Reid says one of the biggest challenges involved in paediatric clinical trials is keeping children and family engaged throughout the entire trial period. This can be very difficult, especially with longer treatment periods.
“When the parents and the child sign up for a paediatric trial that might have 12 office visits, they have to think about packing the kids up in the car, they may not have a babysitter, something might change at home, they might move, they might have another baby,” says Reid. “There are a lot of things that could change. There are more dynamics in that child’s life than there are typically in the adult world.”
What’s more, children bore easily, need to be entertained and are much more likely to get distressed and cause disruption.
“What are you going to do with a two-year-old when you are trying to get blood draws over the course of six hours?,” says Wardynski. “You have to entertain them and figure out what to do with their siblings. You may have to make sure they have support and you have to explain everything you do in a different way. You can’t just say, ‘Hey, we’re gonna poke you six times.’ You have to find a fun way to do that.”
Aside from difficulties in testing owing to the fact you are working with children who must be kept calm and entertained – there are other issues that must be considered such as laws that mean the amount of testing being done on a child is often greatly reduced.
PK testing requires blood draws, and as Reid says, “nobody wants to stick a child with a needle. They cry, which upsets the parents and that upsets the nurses withdrawing the blood.”
However, on the other side, a common issue Paidion faces with clients is them wanting the child to come in more often than absolutely necessary and wanting to take more blood than is reasonable or allowed by regulation.
“This is something we have to manage and streamline with clients,” says Wardynski.
Decentralisation: the way forward for paediatric trials?
Decentralised and hybrid trials are helping to overcome a lot of these challenges when conducting clinical research on paediatric patients.
“With decentralisation, the goal is to take the trial out of the clinic setting and put it into the lives of the patients,” says Wardynski. “It’s more of a patient-centric model.”
With Covid-19 boosting the adoption of decentralised trial models, there are opportunities to make paediatric trials more accessible to families. Paidion aims to introduce home health care visits rather than in-clinic visits wherever possible, as well as sending nurses to children’s schools.
“We have done those home health care visits at school because if the child can just go down to the nurse’s office, get whatever assessment has to be taken, and then go back to class, that’s much less disruptive than missing school for the day or leaving early,” says Reid. “We try to keep the family in mind whenever we look at a protocol design because the family has to be able to handle the operational aspects.”
All of this remote care, of course, needs to be supported by a raft of digital technologies, from telehealth systems to wearable devices and remote monitoring equipment – a complex array of tech that is developing in an increasingly competitive market. “There are a lot of tech companies trying to figure out that end-to-end solution because the patient experience is really important,” says Wardynski. “You can’t have them hopping back and forth between different platforms and technologies. So a lot of firms are developing all-encompassing platforms that include telemedicine, capturing electronic data, ePROs [electronic patient-reported outcomes] and solutions to speed up recruitment and find patients.”
Some of the technologies that Reid and Wardynski are particularly excited about include gamification and virtual reality (VR).
There are companies such as KindVR that specialise in VR programs and headsets that can engage young trial participants during uncomfortable or dull moments. If a child needs to be lying back and looking up, for example, a VR-enabled game might take them underwater, looking up at the fish floating by.
“You can use virtual reality to not only distract [children] and reduce stress but also to keep them in the position you need them in or to keep them still, depending upon the type of virtual reality used,” says Reid. “I’m very excited about this because it’s going to make our lives, the kids’ lives and the parents lives so much easier.”
More challenges to overcome
While decentralisation is certainly helping to overcome many of the difficulties that paediatric trials face, with new methods and technologies come new challenges.
“One of the challenges we didn’t anticipate with decentralised trials was responsiveness from patients,” says Wardynski. “I think we overlook the fact that when you set up an appointment with a doctor in the clinic, it sets a standard – you know you have to be there.”
With decentralised trials, there can be a lot of drop-off and “ghosting” from participants.
“I hate to say it but it’s a little bit of a sales relationship and you have to gain their trust,” says Wardynski. “They’re not going into the clinic or talking to the receptionist – all those environmental factors influencing them that you get at the clinic.”
Home health visits are helping with this, Wardynski adds, “because it’s more of a tangible feel”.
Reid, meanwhile, argues there needs to be more development in the rare disease space.
“Doing research in paediatric rare diseases is going to necessitate some innovation because you can find the patients but they may live really far from the physician with the expertise in that disease who is willing to participate in the trial,” she says.
“Some may not want to participate in the trial – so trying to match those treating physicians with a physician with research experience and infrastructure that can help is one of the biggest challenges. There needs to be collaboration to get care for the child – but I think it is going to require more innovation on how we collaborate from one institution to another and how we keep subjects engaged long-term.”