Clinical trials insight: paediatric trials

pharmaphorum spoke to Alex Cvetkovich Muntañola about the current status of paediatric trials and the challenges that lie ahead.

Could you give an overview of where paediatric clinical trials are in 2015 – and the future direction?

This is a remarkable time to be involved in paediatric clinical trials. If a company has the right treatment for the right paediatric population, the potential for improving and extending lives is enormous. We are also now seeing a great blossoming of knowledge about rare and inherited diseases of childhood in particular, and a number of new treatments have transformed the outlook for children with these conditions.

Examples of this include my own fields of expertise, respiratory medicine, where there is a ground-breaking new cystic fibrosis treatment. Another example is in the rare Fabry disease, where enzyme replacement therapy is now helping children grow up healthier, and is likely to allow them to live much longer lives.

There have also been many advances in paediatric oncology. Less than 5 per cent of adults with cancer take part in a trial, whereas in contrast, more than 50 per cent of children with cancer take part in a trial worldwide. In children under five years old, this figure rises to more than 90 per cent – so that's almost all children. The progress seen in paediatric trials over recent years is undoubtedly linked to this high level of research. Thankfully, there are many more compounds in the cancer pipelines, so it is an exciting and hopeful time.

"An estimated 70 per cent of all medicines on the market today are not licensed or suitable for paediatric use"

Still, there is also much more work to be done to improve care: an estimated 70 per cent of all medicines on the market today are not licensed or suitable for paediatric use. This means a huge proportion of prescribing for children is not evidence-based, and therefore that many paediatric patients are at risk of receiving a dose that is too high or too low.

Over the last decade, legislation in the US and Europe has obliged companies to carry out research into paediatric populations in any new drug (or else apply for a waiver), and for existing drugs twinned with incentives, this is helping to accelerate progress.

But we must not underestimate the many challenges of developing new drugs for paediatric populations.

At the same time, pharmaceutical companies need to also consider the costs of its paediatric programmes and trials, and how to maximise the potential commercial benefits, in line with the potential clinical benefits to patients. The number of paediatric clinical trials and the number of paediatric patients enrolled in a clinical trial can be reduced by using extrapolation, modelling and innovative protocol designs. This can be done, but will require expertise, experience and some fresh thinking.

Just how different are paediatric trials to adult ones?

The challenges of paediatric trials are unique and frequently different from those of adult trials, and may require a distinct approach, if the study is to be successful.

These challenges fall into five broad areas: clinical questions, ethics, site selection, recruitment and retention and trial design.

Clinical questions

One of the most common reasons for the challenges we have faced in the past has been pharma companies that attempt to simply transfer clinical trial design and study assessments from adult studies to paediatric ones. This approach must be avoided at all costs – the physiological differences in the paediatric population, and differences in pharmacokinetics across and within age groups, cannot be ignored. If these issues are not addressed, it will almost certainly result in delays in ethics committee approvals, poor enrolment, high levels of dropouts, and ultimately poor data and high costs.

Study rationale, rationale for the dose selection, drug administration, selection of study endpoints, safety procedures, and other study assessments are just some of the questions that should be carefully addressed in the protocol.

At the outset, the paediatric drug development strategy depends on the paediatric age groups that should be included. Trials should be conducted in each age group in which the investigational product will be used or the indication is relevant. All other age groups should be excluded from the protocol, and waivers agreed with regulatory agencies.

A commonly used age-group scheme has been developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), and is accepted by the FDA:

• Pre-term newborn infants

• Term newborn infants (0 to 27 days)

• Infants and toddlers (28 days to 23 months)

• Children (2 to 11 years)

• Adolescents (12 to 16-18 years (dependent on the country)

Depending on the indication and the safety profile of the investigational product, the enrolment of different age groups can be in parallel, back-to-back or a mix between these two approaches.

Having selected which age groups are to be included in the trial, this paediatric protocol must then be designed to balance the risks and benefits to participants in each of these groups.

Don't forget – the child's growth and development could also be influenced by the treatment, especially in younger paediatric populations, which is, of course, not a consideration in adults, and this places an extra burden of responsibility on the trial protocol. There are many aspects to this: the safety and efficacy endpoints might need to be adjusted; drugs may need to be reformulated for easier administration to children.

Adverse events are often far more frequent in paediatric trials than in adult ones, and planning ahead to manage these risks will pay dividends as the study progresses.

This is all part of a 'child-friendly' mindset which is required to make your trials a success, and a theme I will return to later.

What sort of ethical questions arise in these trials?

There are many ethical considerations which are unique to paediatric trials. The first consideration is of course the welfare of the children: these are sick children who are physically and psychologically vulnerable in a way that most adults are not. That makes the questions of safety and efficacy, and the eligibility of the patient for your trial, even more important than in adult trials.

Another key lesson is to view not only the child as the trial participant, but to consider the whole family as being the trial participant. That way, all of the issues relating to benefit/risk and consent can be considered holistically. This is particular relevant in the area of consent, which of course must be given by the parent or guardian, and the assent – although regulations on the age of assent do vary from country to country. There are some country-specific differences with respect to whether both parents should sign the consent form, but legislations are not always precise when it comes to children being required to sign the assent form or in respect to definitions of parents and guardians, especially in the case of unmarried or divorced parents or fathers that have not always recognised their child.

Research shows that there can often be a negative public perception of paediatric clinical trials, depending on the age group in question and different local cultures and customs. These factors must also be considered when assembling the strategic plan for the trial and making the appropriate country/region selection.

What challenges are presented in terms of site selection?

The growth in the number of paediatric trials being conducted means that the industry has had to widen its net in terms of site selection.

This, combined with the growing demand for paediatric data, makes running these trials increasingly complex and costly.

Emerging countries could be the solution to escalating costs, as many of these nations have a very large paediatric population. The most notable among these are the big emerging nations: China, India, Russia, Mexico and Brazil.

Running costs are significantly lower in these countries, and there is a high proportion of treatment-naïve patients. In addition, there is also a greater motivation to take part in research in many of these countries, and often a good relationship and high levels of trust between the physician and patients.

On the other hand, there is a great variability in the clinical standards and access to medicines for patients in these countries, which can make trials in these regions unpredictable.

Patient recruitment

A great deal of care needs to be taken when approaching parents in order to potentially recruit their children to a trial.

First of all this needs to be done in the proper environment, and an appropriate time; parents mustn't be approached in a hospital corridor, for instance. Also, it is important that only experienced physicians with authority should approach parents/guardians. They should be given all the necessary time to hear the information, and ask questions.

There is evidence to show that enrolment and retention rates correlate directly with how well the initial interaction and consent issues are handled.

The other important aspect of patient recruitment is the protocol. Sponsors should also look into paediatric-friendly protocols. The timing of study visits should respect the everyday activities of different paediatric age groups (e.g. school) for studies with outpatient enrolment and for hospitalised children study assessments should coincide with the standard of care assessments regardless of the clinical trial.

How is technology changing the way you conduct your clinical trials?

The demand from regulators for more paediatric data is making paediatric trials much more complex and expensive. For that reason, we have to keep trying to improve our drug development methods: we need to make them more ethical, more feasible and less costly.

"One technology which is really making an impact is the use of modelling and simulation software"

One technology which is really making an impact is the use of modelling and simulation software. This is being used in a number of applications allowing us to recruit fewer patients. Modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data has been suggested as a useful tool for analysing paediatric data. PK data alone can be used to extrapolate efficacy from adults to paediatric patients and between paediatric patients of different ages, if similar systemic exposure can be assumed to produce similar efficacy in those sub-groups. The main expectation from the modelling of the influence of maturation on the various physiological systems involved in the PK and the PK-PD relationship is to estimate the value of the PK and PK-PD parameters and to predict the optimal dose regimen as a function of age without any new investigation. The validation of these mathematical predictions could be performed using sparse samples therefore dramatically alleviating the burden of clinical studies on children and accelerating drug evaluation in this population.

Another area of great potential is wider use of dried blood spot testing (DBS) as opposed to conventional blood taking. DBS is a biosampling technique which involves collecting blood samples on dried filter paper, with these samples then shipped to a lab where methods such as DNA amplification are used to analyse the sample. I believe we can use this technique much more widely, and its convenience for trial participants and investigators would be considerable. Using dried blood spots means you can do away with a centrifuge, you can keep your samples at room temperature and ship them at room temperature. This makes everything easier and cheaper. Of course it cannot be used in every setting, but I think its wider application would bring very significant benefits. However, it is important to agree in advance with FDA/EMA if they would accept it for some specific assessments.

Innovative trial design

Randomised clinical trials (RCT) are still the gold standard, however other trial designs must be considered to avoid the problems commonly encountered in paediatric trials. Where you have small populations – which is particularly the case in rare diseases – the standard RCT will often be challenging in respect to enrollment. So you have to look at different designs, usually called innovative trial designs.

It is crucial for any company considering using an innovative trial design to gain agreement from the authorities in advance that it is applicable.

• Adaptive design

• Sequential design

• Data dependent design

• Randomised withdrawal

• Randomised placebo stage design

• Three-stage clinical design.

These are not just for use in paediatric trials – you can use these in any patient cohort, but they are especially useful in paediatric trials because of the frequent difficulties in finding enough patients to enrol.

My personal opinion is that we are not using these innovative trial designs are often as we should. The first step to correcting that is for there to be greater awareness of these options, and their strengths and weaknesses – then you have viable alternatives for when RCTs are impractical.

What is the best advice you would give to pharma companies looking to enter your therapy area?

I think my first piece of advice is that an expert in paediatric trials should be involved from the beginning. This will help prevent any rudimentary errors, which will cost you time and money to rectify later on. In addition, enlist paediatricians across your regions – they know the standard of care best, the culture and the wider patient cohort, and this will prove invaluable insight.

Second, I would recommend making a selection of regions for enrolment in advance, so that you will be aware of the specific advantages and disadvantages of those territories.

Finally, you need to have expert paediatric trialists in your team, because there are so many questions relating to clinical matters and trial design that are specific to this field. They can also help you design the trial and select the region in a way that will help make the trial as clinically and commercially feasible as possible.

Reference

Innovative clinical trial design for paediatric therapeutics

About the interviewee:

Alex Cvetkovich Muntañola, MD, Paediatrician, is the Executive Director Clinical Development at INC Research, leading the Paediatric Focus group at INC Research. He has over 25 years in paediatric drug development including the medical and clinical research arenas as a paediatric clinician with expertise in pulmonology and paediatric and neonatal intensive care, and a researcher in the clinical trials arena. He has published several articles regarding the specifics of paediatric clinical trials and is a frequent presenter at paediatric conferences.

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