Coming of Age: How to Include Adolescents in Clinical Trials

HANNAH LIPPITT: Hello and welcome to the Totally Clinical podcast brought to you by Teckro. Totally Clinical is a deep dive into the freshest trends, big-time challenges, and most excellent triumphs of clinical trials. I'm Hannah, your host. Join me as I chat with industry experts, trailblazers, thought leaders and, most importantly, the people benefiting from clinical research. So, tune in, settle back and don't touch that dial. It's time to get Totally Clinical. HANNAH LIPPITT:

This week I am joined by Dr Martine Dehlinger-Kremer. Martine is vice president, scientific affairs, pediatric subject matter expert at ICON. She’s also chair of the Children's Medicines Working Party at the European Forum for Good Clinical Practice, as well as the chair of the Pediatric Working Group of EUCROF. During this podcast, we discuss the challenges and possible solutions with pediatric research, along with considerations to include adolescents in adult clinical trials and how regulators can make a difference. HANNAH LIPPITT: Martine, welcome to the podcast. Let's start at the beginning. How did you become interested in the field of pediatrics? MARTINE DEHLINGER-KREMER: When I was a young adult, I was a counsellor in summer camps, during my holidays, taking care of the children. When the pediatric regulation came into force in Europe in 2007, we created the European Pediatric Working Group, and that is how I started to work on supporting pediatric developments. It was so hard to admit that we have such sophisticated medicines for adults but treat our little ones off-label. I wanted to be part of the change. At ICON now working in the Center for Pediatric clinical development, I have the chance to combine work and passion. HANNAH LIPPITT:

That's great that you found your passion at ICON. On the subject of children's clinical trials. I spoke to Cindy Jackson last year of the Institute of Advanced Clinical Trials in children, and she discussed the problem of lag-time between adult and children's trials. Now in your presentation, you highlighted that most parents don't actually realize that 70% of medicines given to children haven't been tested on them. And for neonates in ICU, it's actually 90% of medicines that are used off-label. So, it's really quite incredible just how many barriers there are to children's clinical trials. Could you explain more about the reasons behind this? MARTINE DEHLINGER-KREMER: You know, the authorities have reacted to the situation of the high off-label use in the pediatric population, and they issued regulation to mandate pediatric development for new medicines or new indications. The US was first with a Pediatric Research Equity Act 2003 and became permanent law in 2012. And this mandates pediatric study plans for NDAs or PLAs for new drugs with the exception of orphan drugs for rare disease when they have an orphan drug status and are not for oncology. And the US also issued the Better Pharmaceutical Act for children, which rewards companies with additional six months of protection. In the EU, the pediatric regulation came into force later on in 2007, so there is only one regulation in the EU covering obligations and reward. This regulation is actually under review at the present time. UK and Switzerland are two other countries mandating pediatric research. When relevant, you would need to have pediatric plan. Canada will follow very soon. Other countries do not mandate pediatric development but have some incentives, such as Japan or Canada. The average time between approval and labeling of a new medicine for adults and children is nearly a decade. So, adolescent trials are typically not initiated until after the benefit risks for a new medicine has been established in adults. So, either late in adult medicine development or even after approval. This off-label availability of added medicine contributes to slow adolescent accrual in pediatric trials further delaying access to effective therapies to children. The off-label use represents also a loss of opportunity to collect those data in a controlled and monitored manner. Efforts to decrease delays in initiation and completion of pediatric studies have not yet resulted in great improvement in timelines for the approval of the drug in children. Hence, it remains really a burden for pediatric patients and also their families seeking access to new therapies. Just as an example, between 1998 and today seven drugs have been approved for UC - Ulcerative Colitis and CD – Crohn’s disease in adults. But only two of those seven drugs have been approved in pediatric UC or CD. And the approvals in children came six to nine years after the approval in the adults. HANNAH LIPPITT: It is incredible to think approval for children’s treatment could take so many more years…. MARTINE DEHLINGER-KREMER:

With such long timeframes between approvals in adults and pediatrics, some medications became standard of care in the pediatric population, and this leads to difficulties with study enrollment. Patients and families are less willing to take an additional burden for trial participation when the drug is accessible to them off-label. Also, clinicians may be less inclined to participate or refer patients to participate in a trial when the therapy is widely regarded as effective based on accumulating anecdotal experience. This also weighs an ethical issue pertaining to the inclusion of vulnerable subjects in research. So, a very critical situation for which a possible solution could actually be taken - early involvement of adolescent in clinical trials. Namely involvement of adolescent in adult trials in a pre-approval setting. There are some prerequisites to include adolescents in adult trials. You cannot just say, “I do this for every trial”. And these prerequisites are you need to look at adequate therapy the adequate preliminary dosing and PK information need to support the dose selection in adolescents. The similarity of pharmacokinetics of the drugs and therapeutic protein between adolescent and adults is important for doing these combined studies. You also have to have adequate non-clinical and pre-clinical information. So, this approach to include adolescents into adult trials, it was new in clinical research and not always welcomed by all the stakeholders. And this is due to some concerns that regulatory bodies have different views – so reluctance to expose pediatric patients to an unknown, the uncertainty regarding whether a small number of enrolled pediatric patients will be adequate to support an early approval below the age of 18 - and the perceived risk to the adult program on part of industry sponsors. HANNAH LIPPITT:

Recently, at the Society for Clinical Research European Site Solutions Summit in Lisbon, your keynote presentation was “Why and how to include adolescents in adult clinical trials?” Why the focus on adolescents in particular? MARTINE DEHLINGER-KREMER: If I take the example of oncology, we have seen adolescents refused into clinical trials because they were a few months younger than the adult age and died because they could not benefit from the new therapy. Staying with oncology also, so European Medicines Agency has approved 169 anti-cancer medicines for use in adults between 1995 and 2021, and only 16 new products received marketing authorization in children. This is the result of anti-cancer drug development almost exclusively focused on the adult conditions with larger patient populations. The small, pediatric population makes drug development more challenging. Therefore, pediatric product development has often been waived or delayed, resulting in poor access for children to innovative drugs, including adolescent and adult trials or running adolescent trials in parallel to adult trials that would allow access to new medicines earlier for the adolescent population and subsequently for the whole pediatric population. It would accelerate marketing authorization of an effective drug in the adolescent population at the same time of adult approval. It will reduce the off-label use, it would increase innovative trials for adolescent children and orient the full pediatric development time and might positively also influence adult drug development for a given drug. The increased knowledge in adolescent drug efficacy resistant mechanisms, giving rationale for future development of molecular-driven trial and personalized medicine. So, when appropriate, enrollment of adolescents into adult clinical trials is a methodology which could expedite adolescent access to therapies, further earlier data generation in adolescents could offer an important source for data leveraging for young children. Such an approach unifying adult and adolescent trials could also enhance research efficiencies related to resource and cost savings and shorten development timelines. HANNAH LIPPITT:

Could you talk me through some of the considerations for including adolescents in trials? MARTINE DEHLINGER-KREMER Indeed, there are some aspects to be considered when you include adolescents in adult trials. In terms of investigators, it would be important to consult pediatric specialists for the protocol development to obtain the expertise and help address logistical issues. For the IRB or ethics committee reviews, for trials involving children should ensure inclusion of pediatric expertise at the IRB or EC. In terms of study sites, it will be important to use established pediatric centers with drug development, expertise and infrastructure to help mitigate operational and regulatory challenges and lack of experience that might otherwise exist within the preliminary adult clinical center. Another aspect to think about is the formulation of the medicine. Young children may not always be able to swallow a big tablet or capsule, so development of pediatric friendly drug formulations should be considered early on. Otherwise, unnecessary delay in pediatric evaluation may occur. It's therefore important that you think about this pediatric formulation early on when you want to include adolescent in adult trials. And also, individual opinions of sponsors, investigators, ethics committee members should not supplant opinion of the adolescent population being asked to participate in the trial. Adolescent input should be sought by sponsors, regulators, ethics committee members doing the study design.Perceived vulnerability should not be a barrier to research. Studies should not be refused in the adolescent population just because they are perceived to be difficult due to ethical, methodological and as well as operational specificities. HANNAH LIPPITT: What

have you seen work in encouraging adolescents to participate in clinical research? MARTINE DEHLINGER-KREMER: The inclusion of adolescents in adult trial has been very successful in some disease areas, such as asthma, atopic dermatitis - we also saw it with COVID-19. So, it really balanced consideration. The inclusion of the adolescents in adult trial is one of several potential strategies to achieve the collection of adequate data in pediatric patients to appropriately label drugs for safe and effective use in a timely manner. In order to get there, we need a change in mindset. We need increased collaboration between pediatric and adult-treating physicians. And we need an increased collaboration among all stakeholders involved in pediatric research. Adolescents often are more reluctant than younger children to participate in studies because they prefer to spend less time, free time with friends, sport, school activities. So, it's important to motivate them to participate in clinical trials. This can be achieved by protocols adapted to children such as visits, adapted to school schedules and hobbies, the use of gamification, digital tools to collect the information. Adolescent motivation to participate in clinical trial is, in most cases, a form of altruism. They feel that taking part will help other people, but they also hope that it may have some benefit for themselves, such as assessing treatment faster or receiving a more high-quality intervention. Clearly having highly motivated research assistants and giving them appropriate training support to undertake this task for treating adolescents is essential if a trial is to be successful. Conversely, asking adolescents to fill in questionnaires that are repetitive or time-consuming or that asks questions that do not seem relevant to them is likely to have a negative impact on their willingness to participate in clinical trials. In term of consent, still, more efforts need to be made to ensure that assents are truly informative and friendly for adolescents, helping adolescents to understand what the different interventions involve and how to process will be of advantage to them. So, information sheets need to be fit for purpose. We need to make the information engaging and accessible. So best is to include young people in the design of information sheets and developing innovative methods of explaining studies, rather than relying on more traditional patient information sheets. For example, using interactive smart technology such as tablets to deliver the study information and take consent, might help adolescent to engage with the information more fully. HANNAH LIPPITT: So, parents

can be quite concerned about their children, including adolescents, taking part in trials. What do they need to feel confident? MARTINE DEHLINGER-KREMER: Trust is critical for parents to accept that their child is entering a clinical trial. It is very important to choose the right person to approach the parent. Parents strongly prefer to first hear about a clinical trial participation opportunity from either the child's own pediatrician or from a doctor or healthcare provider caring for them in the hospital, rather than being approached by a person that they don't know at all - a stranger. Being cold called by a researcher about participating in a clinical trial, is off-putting to many parents, even if the researcher is knowledgeable and friendly. For parents, empathy is essential as well. Parents emphasize the importance of empathy from the study team in both the out-patient but also the in-patient setting. Another important aspect for parents is to convey the wide message in terms of benefits, risks and side effects. Parents want to hear that their child safety and well-being will be of primary importance to those performing the trial and how their child would directly benefit from participating in a specific trial. Parents feel reassured when they know that someone from the study team would be available to them 24/7 should there be any problem. HANNAH LIPPITT: Now parent motivation would be first

and foremost the improved health of a child or improvement in their quality of life. Are there other benefits that parents consider? MARTINE DEHLINGER-KREMER: Other benefits that may motivate parents to consider enrolling their child in a clinical trial could be the state-of-the-art medical assessment of the child’s condition. Some parents are enthusiasts about awarding their child - with cystic fibrosis, for example, in a clinical trial because they know that they would receive MRI instead of X-Ray. Medications that would otherwise be unaffordable or unavailable. Taking again the example of cystic fibrosis - the same medication, for example, is provided free in the context of clinical trial, but would cost $4,000 outside the study. HANNAH LIPPITT: I should think awareness

of risk factors is a consideration as well for parents? MARTINE DEHLINGER-KREMER: Parents want to be made aware where there is a possible risk and side effects that child could experience as a result of participating in a trial. This information would not only help parents to weigh risk and benefit when deciding whether to enrol a child, but also could give them an idea of what to look for and what to do in case of side effects. A further important aspect is the choice of the wording, which plays a role in parents' willingness to participate in a clinical trial. Some parents prefer the term “study” to “clinical trial.” Also, the use of more common names of medication is important, so not to intimidate parents. Parents are also more comfortable having their child participate if the drug has been, for example, approved in adults for another condition, another indication. Several parents whose child participated in trials and try to determine dosages for children said that having FDA-approved gave them more confidence in the safety of the medication. Last but not least, the motivation of the child does impact the decision of the parent. HANNAH

LIPPITT: So, during Cindy's podcast, she talked about how regulation and education are two of the solutions needed to progress in pediatric trials. What can be done in both of these areas when it comes to adolescents and trials? MARTINE DEHLINGER-KREMER: The pediatric regulations for the US and Europe and ICH guidelines do not object to the inclusion of adolescents into adult trials. The new ICH E11A guidelines on extrapolation if you go under point 52 it addresses the inclusion of adolescents in adult trials and clearly states that when the disease and response to treatment are sufficiently similar between adolescents and adult subjects, there should be a strong justification for why adolescents are not being included in an adult clinical trial or being studied in a parallel trial. So, the enrollment of adolescents into adult clinical trials may hasten adolescent access to safe and effective treatment, as well as accelerate the gathering of needed pediatric data. In terms of education, participation into clinical trials is not so well known. It would be important to educate better the general public about clinical research. Once better known, there will be less reluctance to participate. On the contrary, there might well be an increased wish to participate in clinical trials. If we could educate children already at school informing them that clinical research is one way of treating diseases and accessing medicine, we would certainly increase awareness and have less difficulties to motivate children and adolescents to participate in clinical trials. HANNAH LIPPITT:

And how optimistic are you that we will see adolescents included in adult trials in the next few years? MARTINE DEHLINGER-KREMER: Inclusion of adolescents in adult trials or the conduct of parallel adolescent trials would present important methodological approaches to advance drug development in pediatric patients when justified scientifically and ethically. This should be considered the default position in innovative product development. Restricting initial Phase III development to adults should be based on there being substantial differences between adult and adolescents regarding the pathophysiology of the target disease or the anticipated response to study therapy. Confidence that efficacy experience in adults alone, combined with safety data in adolescents would justify regulatory approval and labelling of a new product for use by adolescents, or a risk of inclusion of adolescents based on pre-clinical data or clinical data in adults that cannot be justified, giving the potential benefit of the therapy being studied. Trial sponsors, investigators, regulators and ethics committees are encouraged to challenge research orthodoxy related to adolescent inclusion and adult research and seek trial solutions grounded in science rather than legal definition of age alone. EFTC Children’s Medicine Working Party has developed an adolescent inclusion decision tree to facilitate discourse on trial design consideration to facilitate the timely inclusion of adolescents in research. So, I'm confident we will see more adolescents included in adult trials. I can see this from recent trial design from various sponsors. HANNAH LIPPITT: Great to end

on an optimistic note – and thank you so much for your time today, Martine discussing adolescent clinical trials. HANNAH LIPPITT: And that's your dose of Totally Clinical. For all the listeners our there, you can follow Teckro on Linkedin and Facebook and subscribe to our YouTube channel. And of course, you can download the Totally Clinical podcast on Apple, Spotify and Google. See you on your next visit and remember to bring your friends. Thanks for listening! Goodbye! [MUSIC PLAYING]