Two regulatory initiatives have been implemented to spur pediatric drug development. The Best Pharmaceuticals for Children Act (BPCA) essentially provides a carrot to sponsors in the form of exclusivity, while the Pediatric Research Equity Act (PREA) is the stick that requires the performance of pediatric studies. Of pediatric studies currently underway, a little over two-thirds are in response to PREA requirements.
The reason to conduct separate, dedicated pediatric trials has basis in both the science itself and in public health concerns. Safe and accurate drug dosing for children cannot be achieved by reducing the dosage of adult medications according to simple metrics like weight differences. Every organ of the body evolves through a series of distinct developmental stages as infants grow into toddlers, young children, and teenagers. As a result, the physiology of children is fundamentally different from that of adults, with more pronounced and critical differences depending on the therapeutic area, the organ system, the drug’s mechanism of action, and the drug’s route of metabolism. As such, drugs designed for adults may have very different effects on children of different ages. If the disease is not sufficiently similar between adults and children, then it is essential to study the effects of the pharmaceutical products on children directly and to determine safety and efficacy across the pediatric population that is impacted by the disease. This requires a separate but analogous process to adult drug development.
The breadth of age, size, and developmental diversity in pediatric patients requires a very patient-centric approach to pediatric clinical studies. For any disease or condition being investigated, the relevant pediatric age group (defined by the FDA as neonates, newborns up to one month; infants, 1 month to 2 years; children, 2 to 12 years; and adolescents, 12 to 16 years)1 in which the condition typically occurs must be determined. It is possible to combine some age groups in a single study, but that can be challenging if there are safety concerns relevant to a specific age group. In addition, different age groups may prefer different formulation options from pills and capsules (e.g., liquids, orally disintegrating tablets, strips, mini-tabs), and these may need to be developed specifically for the pediatric study.
If there are any safety concerns associated with the therapeutic product, the regulatory agencies may require a stepwise approach to trial inclusion, starting with adolescents and moving sequentially down to the youngest patients (including preterm neonates if the treatment is relevant to them). Advances in clinical pharmacology, including pharmacokinetic/pharmacodynamic modeling, have resulted in better estimations of the optimal pediatric dose for any age and weight. This means that, if there are no safety concerns, trials may be done in the younger cohorts of patients at the same time as the older cohorts. This has significant implications with respect to more efficient studies that require fewer patients and can be accomplished in a shorter time frame.
In some cases, it is possible to study the adolescent population in the adult trial because the clinical manifestations of the disease are usually similar, and the dose of the drug would be the same.
Safety and Physiological Considerations
Safety concerns are paramount when considering the key differences between pediatric and adult clinical trials. In fact, many pediatric studies are purposefully delayed until safety data in adults are amassed. Given the different physiology among pediatric age groups and between children and adults, the first questions that must be answered are whether the disease to be studied occurs in the pediatric population, whether it only occurs in certain ages of pediatric patients, and what potential effects, both from a safety and efficacy perspective, are anticipated.
Regulatory Aspects and Adapted Assessments
Another special consideration for pediatric trials is the regulatory frameworks requiring the prospect of a direct benefit for participating patients, which prevents the use of healthy pediatric volunteers as participants, except in limited cases, including vaccine studies. In addition, patients as young as 7 years of age (in the United States; compared with 2 years of age in Europe) must be provided age-appropriate information about any trial they might participate in, in addition to obtaining informed consent from the parents or guardians.
There are also some unique aspects of informed consent for clinical studies involving adolescents. Parents must be present to give consent while the adolescents assent, which can be awkward for adolescents when a trial involves discussions of contraception, pregnancy, or drug use.
Some trial endpoints for children may also need to be modified from those used in adults. For example, 3-year-old children are not able to perform the 6-minute walk test typically required for adult pulmonary hypertension and cardiovascular trials. The timing of assessments during a site visit can also be much more important for children: cognitive and physical testing generally should not be performed at the end of the day when children may be tired, hungry, and/or stressed by previous assessments throughout the day.
Role of the Parent/Caregiver in Pediatric Research
The impact on caregivers whose children participate in clinical trials must also be factored into study designs. Caregivers are ultimately responsible for getting the patient to and from appointments, and they may already face considerable burdens, including holding a job, keeping a family going, running a household, and dealing with health care issues, before factoring in the burden of clinical trial participation. No matter how much a parent may want to have their child continue to participate in the research, they may be forced to make compromises if the protocol requirements are too demanding. One example is consideration of the burden of the number of visits or blood draws required by a protocol. Such concerns can ultimately be critical determinants of full participation. Understanding those important secondary factors and incorporating appropriate solutions into trial designs to reduce caregiver burden are essential to improving compliance and retention and successfully achieving study outcomes.
Furthermore, in the place of patient-reported outcomes typically collected in adult studies (in addition to clinician-reported data), pediatric trials often must use outcomes reported from parents/caregivers, although it is ideal to collect data from both patients and caregivers when possible. However, studies that rely on medical history data provided by parents and other caregivers through questionnaires can pose additional challenges, as differences related to individual experiences in school or other social environments can lead to significant differences in perception from the parent/caregiver compared with the patient.
Embracing Patient Centricity
Overall, the efficient conduct of pediatric clinical trials requires a heightened focus on patient centricity and consideration of the needs of the children, their parents/caregivers, and the entire family — at every step from design through execution. Keen understanding of the disease and how it impacts the patient and their family, as well as the patient’s journey, needs to be considered in order to ensure the right patient-centric solutions are incorporated into the study design to reduce burden and support overall compliance and retention. For patients with impacted mobility or who live long distances from the research site, travel reimbursement, concierge, home health, or telehealth visits may be most beneficial. Frequent and transparent communication is also key in building relationships with patients and their families; therefore, offering study materials that provide study updates, disease-related information and resources would be advantageous. A great example of such material is an age-appropriate comic book that helps to communicate information about the disease and the study to the patient or their siblings. A relationship with a CRO heavily focused on the patient (and caregiver) experience can make the difference between the success and failure of clinical studies in pediatric populations.
For many pediatric trials, patient and caregiver feedback on the study design often comes once the protocol design has been established, meaning changes based on patient and caregiver feedback are not typically implemented in the protocol. While such information may be essential to modifying the design and implementation of future trials to yield better results and reduce patient burden, there may not be realistic opportunities to adjust a study once it is underway. It is important to reach out to patients and their families as early as possible with respect to protocol development.
For hospital-based trials, including neonatal trials, it is important to gather perspectives and feedback on trial design from nursing staff as early as possible. Protocol requirements for work that will be completed by nurses must be reasonable and must not prevent them from administering care to patients. Otherwise, the trial expectations will simply not be met.
Obtaining the perspectives of both clinicians and caregivers with respect to clinically meaningful outcomes is essential. Collecting data to support the clinical outcomes identified for each pediatric protocol is important. However, sometimes what is clinically meaningful from a regulatory perspective does not align with what the patient or caregiver perceive as important. For example, the protocol may require a specific change with respect to an objective value over time, such as the 6-minute walk test, but the patient may perceive improvement as increased mobility or gained independence. Pediatric patients are eager to have their voices heard with respect to the design and conduct of clinical trials, so researchers should seek the opportunity to connect with patients, caregivers, and advocacy groups, in addition to clinicians and nurses. A robust CRO is instrumental in bridging the gaps between these groups, understanding the distinct outcomes and quality of life assessments, and streamlining the involvement of patients/parents and clinicians/nurses from the outset.
Fortunately, sponsors and their CRO partners are increasingly aware of the need for early engagement from patients, caregivers, nurses, and other stakeholders. In addition, adaptive trial designs are creating new opportunities to incorporate changes based on patient/parent/caregiver feedback as a trial progresses. Future successes with adaptive designs — particularly within pediatric studies — may drive wider adoption and further refinement.
Enrolling participants in pediatric trials necessitates a nuanced approach that caters specifically to both children and their guardians. Providing comprehensive information and education is pivotal during the enrollment phase. Often, children exhibit elevated levels of altruism and enthusiasm for the opportunity to make sacrifices for the greater good.
Leveraging this innate enthusiasm in children can be advantageous in driving enrollment. Organizers can initiate educational workshops and interactive sessions designed to illuminate the clinical trial process. These programs serve to empower parents and caregivers with the insight to make well-informed decisions. Extending outreach through collaborations with patient advocacy groups can also amplify trust and broaden the scope of enrollment endeavors, particularly within rare disease communities. The Multi-Regional Clinical Trials research and policy center of Brigham and Women’s Hospital and Harvard has developed a toolkit that offers tools, checklists, and considerations to support the inclusion of the youth perspective in clinical trials.2
It is essential to acknowledge the busy lives of families; hence, offering flexible scheduling for preliminary study visits or even considering mobile health units can be game-changers in removing logistical barriers. Incorporating technological tools and gamified platforms can make the idea of participation enticing for the younger demographic.
Furthermore, ensuring that the clinical trial team undergoes cultural sensitivity training is paramount. Every interaction should respect the diverse tapestry of backgrounds, addressing unique concerns and reinforcing trust of all ages of children and their families. By interlacing these strategies, the enrollment phase in pediatric clinical trials can be both effective and empathetic, setting a positive tone for the entirety of the study.
Retaining pediatric patients requires careful consideration of a range of factors important to the children involved. For instance, children and adolescents generally do not want to be seen as being different from their peers. Being pulled from the middle of a class to visit the nurse for treatment can be a real negative for many — as is missing school twice a week for visits to the clinic or missing out on afterschool activities.
One way to encourage retention is to support the natural desire of children to be part of a community and to make a contribution to improving the world. Today, building a sense of community for pediatric patients, even among geographically dispersed groups, is simplified by digital solutions, such as apps for their phones — this is particularly effective for adolescents. In some cases, this sense of community and participation can be enhanced by the incorporation of gamified apps or platforms where children earn points or rewards for adhering to study protocols, regular attendance, or participating in community-building events and activities.
Establishing and maintaining real trust with parents and caregivers is also critical to ensuring that they continue participating for the duration of the trial. Parents need to feel that, by having their child participate in a study, they are acting in the best interest of the child, which requires trust in the site, the sponsor, and the investigator. CROs need to be mindful of actions that can be taken at the site level to encourage and facilitate the development of that trust. That includes having experienced staff running clinical trials who know how to effectively interact with families and perform procedures on children. The physical site should also be set up for pediatric patients with the appropriate equipment, properly sized furniture, and an inviting atmosphere. The issues related to trust can be magnified for minority and immigrant populations, who may have reservations about placing their trust in the medical system, particularly when it comes to their children.
Connections also need to be made with the children themselves. One approach involves the use of stuffed animals on which the children perform the procedures that they are undergoing to better understand and cope with the requirements of their participation. Another involves the creation of tailored content, such as comics in which superhero characters themselves share the specific illnesses of children in the relevant studies. These comics are used to share information, knowledge, and study details, providing both educational and emotional support. For longer studies, it is also important to ensure that these approaches evolve with the children in a study as they grow and develop and their interests change.
Decentralized pediatric trials and digital tools offer means to reduce the burden of study participation for patients and their parents and caregivers, which has the potential to improve trial retention. As discussed earlier, parenting a child with chronic medical needs can be demanding, and participation in a trial adds even more expectations. It is essential for stakeholders to always be mindful of what can be done to minimize these burdens.
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Case Study: An Observational Study in Immunocompromised Pediatric Patients Required Decentralized Solutions Challenge:
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Examples include having a nurse conduct home visits to collect samples rather than requiring parents to bring their children to the investigator site. Digital tools, such as electronic diaries located on a smartphone or tablet, can eliminate the need to record information on paper and reduce time demands for outcomes reporting. Fortuitously, children are generally much more accepting of wearable devices and other technologies, simplifying the implementation of newer, digital clinical trial solutions that may aid in overcoming some of the challenges associated with the inclusion of pediatric patients in trials.
Decentralized approaches to clinical trials increase the ability for families located in distant and rural areas to participate in the trials. However, some patients, including many with rare diseases, may prefer to visit the site to see the doctor in person because the child and family have a very strong and supportive connection with the child’s physician. Rather than mandating either onsite visits or TeleVisits for all participants, providing both options and letting families choose may be the most effective strategy.
In pediatric trials, extensive follow-up is frequently necessary, which can have a range of implications. An effective CRO partner can aid in anticipating these challenges to ensure that trial integrity and feasibility are maintained throughout.
Embarking on a partnership with the PPD clinical research business of Thermo Fisher Scientific ensures that a clinical trials sponsor is supported by a wealth of pediatric expertise built on years of globally recognized trials managed within PPD’s Rare Disease and Pediatric Center of Excellence. The PPD team, which comprises more than 60 dedicated experts in pediatrics spanning all therapeutic areas, ensures that pediatric clinical studies benefit from the insights of 28 board-certified pediatricians and 28 statisticians with pediatric specialization. But it is not just about numbers — it’s about the unparalleled support and dedication these professionals bring to the table.
The longstanding experience of the PPD clinical research business in conducting traditional, hybrid, and decentralized pediatric trials is more than a testament to our capabilities — it is a promise of quality to our partners. With each trial, we gather invaluable feedback and lessons that are then channeled into optimizing subsequent trials. This continuous cycle of positive feedback and optimization ensures enhancements in patient centricity, efficiency, cost-effectiveness, and data quality. For our partners, this translates to minimized risks associated with pediatric clinical trials, improved recruitment and retention strategies tailored for each study and ultimately a more streamlined, efficient, and successful clinical trial process.
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