Role of Patients and Parents in Pediatric Drug Development

Abstract

Patient engagement in health care has been an emerging priority in the global effort and move toward the consideration of patients as experts of their own conditions. However, the input of pediatric patients and their families have not been consistently requested nor regarded as valuable when deriving protocols for, as well as assessing the outcomes of, pediatric clinical trials. Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials for children and adolescents result in the increased use of off-label prescribing and risk of adverse effects. While recent changes to European and North American legislation contributed to the inclusion of children and youth in pediatric drug development, the lack of systematic guidelines and methodologies in literature serve as barriers for practical application. When combined with the work of external pediatric advocacy and patient advisory groups, the hope is that pediatric patient voices can be brought forward for the future. This article brings together international experts to review current best practices, progress from regulatory agencies, as well as global advocacy efforts to involve patients and families in the pursuit of drug development processes that value the voice of children and youth.

Background

Over the past few decades, great strides have been taken around the world to move towards patient engagement in health care.¹ With the ease of access that the technological era brings, patients and their families are also driving improvements through active participation in, and increased knowledge of, their own health.^2,3 This knowledge further acts as a catalyst to motivate researchers and clinicians to include the voices of patients in order to perform patient-centered research projects.

Shared decision-making strategies in medicine have become more commonplace.^4–7 Under this model, physicians share expertise in disease pathways, medication, and treatment options while patients lend subjective opinions about their experience of illness and personal goals and preferences.⁸ Both of these aspects are equally important and should not be disregarded when developing treatment plans. While the shared decision-making model is widely used among the adult population, there have been difficulties adapting these practices for a pediatric audience.^1,6,9 Among these challenges are topics such as surrogate decision making and managing longitudinal disease models common for chronic diseases that start in child-hood.¹⁶ This fragmentation of involvement extends into the realm of pediatric drug development where the involvement of children and young adults in the life cycle of clinical trials is not standardized.

In recent years, legislative and regulatory impetus for pediatric drug development has extended collaborations between biopharmaceutical companies and patients. Patients can share their experience and contribute personal insight around disease progression and patient preferences to help address issues met in the research process.^10,11 Extending this mutual collaboration further upstream is important, especially in the area of pediatric drug development where the lack of formalized trials on children and adolescents result in the increased use of off-label prescribing and risk of adverse effects.¹² Thus, the input of pediatric patients and their families is especially important in drug development, with substantial potential for improved success in the trial process and subsequent health outcomes. This is the best way to design protocols of clinical trials accordingly with the needs and features of the pediatric patients. Traditionally, studies for pediatric populations that come from adult approved medicines do not consider these features that differentiate between pediatric and adult populations. Children are not little adults and medicines prescribed to minors need special consideration during development.¹⁴

There are many other benefits for the inclusion of children in research. Throughout study design and implementation, youth voices around the decision-making table help ensure that research stays patient-centered and relevant.^15,16 Not only are patient priorities more clearly heard and taken into account by researchers, it has also been shown to improve the scientific rigor of research results.¹⁷ For example, involvement of youth opinions reflective of their patient demographic has been shown to improve the success of pediatric clinical trials in particular around the areas of recruitment and retention of participants.¹ The benefits of patient involvement often extend beyond improvements for end-product development and study goals. Evidence shows that children and young people also benefit in the process of lending their opinions to new health care initiatives and, more often than not, appreciate the opportunity to have their voice heard.^15,18 Young patients are keen to make a difference and use their experience to benefit other children and young people.^19,20 Examples of recent breakthroughs include the development of the Patient-Centered Outcomes Research Institute, as well as involvement and empowerment of patient advocacy groups in the field of drug development.^3,4 The Patient-Reported Outcomes Measurement Information System program was also created by the National Institutes of Health to better record patient experience and priorities for health care professionals.⁵ It is critically important that these measures be put into place and regarded as invaluable input when measuring the outcomes of pediatric clinical trials.

Current State/Progress to Date

Children have been described as “therapeutic orphans” considering the financial barriers and practical difficulties in conducting pediatric clinical trials.^21,22 These factors among others serve as challenges for pharmaceutical companies driving advancements in medication development for children. With less than 25% of the world’s population younger than 15 years,²³ recruitment in this narrow age bracket for pediatric trials compounded with the heterogeneity of young patients creates additional barriers. Difficulties locating an appropriate number of pediatric participants with specific conditions in locations feasible for collaborative studies increases this challenge.²⁴ Consequentially, small study sizes result in decreased generalizability and representation among disease-specific pediatric populations.²⁵

This contributes to the lack of information regarding safety profiles and appropriate dosing and routes of admin-istration.^26,27 The fact that 50% of the medicines prescribed for young people do not have adequate labeling guiding their use in this population further strengthens this point.²⁸ Potential adverse effects also pose a risk to the health and safety of one of society’s most vulnerable populations—our children and young adults.^29,30 Simply put, this current reality warrants the increased participation of pediatric patients and their families not only as participants in clinical trials but also as advocates, consultants, and partners for researchers and drug companies alike.

Independent research groups have conducted studies and interviewed patients and families using qualitative methods to document examples of successful engagement in their respective fields.^17,18 Specifically, studies in the field of pediatric oncology document various methods for pediatric patients to be actively engaged. Because of the natural history and relatively acute disease progression in many cancers, many patients have only minor influence on decision making.³¹ Despite this, the studies emphasize that children and young people can participate in meaningful ways through the giving and receiving of information. Though the level of direct patient involvement differs on a case-by-case basis, noted efforts of collaboration between the patient, parent, and physician is marked by improved patient satisfaction.³² Researchers and families alike require training and education to be able to involve the patient in a sensitive manner.³³ Ultimately, despite bottom-up initiatives, the trajectory toward systemic change in pediatric drug development requires meaningful collaboration across a broad group of stakeholders (eg, industry, academia, regulatory agencies, and patients).

Regulatory Environment and Drug Development

Legislative mandates have helped to stimulate pediatric drug development. In 1997, the US Congress passed legislation under the Food and Drug Administration Modernization Act that mandated including subjects younger than 18 years of age in clinical trials, This was followed by the Best Pharmaceuticals for Children Act (BPCA, 2002) and the Pediatric Research Equity Act (PREA, 2003) which became permanent in 2012.³⁴ BPCA provides the incentive of additional marketing exclusivity to sponsors who voluntarily complete pediatric studies in response to a Written Request issued by the FDA, while PREA gives FDA the authority to require pediatric studies for certain drugs and biological products. The goal of studies done under both BPCA and PREA is labeling for products used by children.³⁵

In 2012, FDA established the Patient-Focused Drug Development (PFDD) initiative to obtain information from patients and families with respect to their significant symptoms, the impact of the condition on their daily life, and their experiences with current approaches to therapy. The PFDD meeting initiative was the beginning of a larger effort by the FDA to include the patient’s voice in drug development and evaluation.³⁶

The FDA encourages patient groups to conduct their own externally led PFDD meetings where FDA has tried, when possible, to attend the meetings.³⁷ In addition, FDA has recognized the need for stakeholder guidance on how to provide patient experience data to the Agency. As a provision of the 21st Century Cures Act (2016), the FDA will be developing guidance to “enable more widespread development of such patient experience data to inform regulatory decision-making.”³⁸ In May of 2017, FDA issued a Plan for Issuance of Patient-Focused Drug Development Guidance with a roadmap for public workshops and guidance development over the next 5 years.³⁹ However, it is unknown if this guidance document will include recommendations on interactions with youth for PFDD.⁴⁰ The focus of these guidance documents will be

• methodological approaches to ensure that patient experience data are accurate and representative of the intended population, including methods to collect meaningful patient input through the drug development process and methodological considerations for data collection, reporting, management, and analysis;

• methodological approaches to identify what is most important to patients with respect to burden of disease, burden of treatment, and the benefits and risks in the management of a patient’s disease;

• approaches to develop methods to measure impacts to patients that will help facilitate collection of patient experience data in clinical trials;

• methodologies, standards, and technologies to collect and analyze clinical outcome assessments for purposes of regulatory decision making; and

• how a person seeking to develop and submit proposed draft guidance relating to patient experience data may submit such proposed draft guidance.

In Europe, the Pediatric Regulation brought sweeping changes into the regulatory environment for pediatric medicines.^11,41 It was designed to better protect the health of children in the EU with the main change being the creation of the Paediatric Committee (PDCO) at the European Medicines Agency (EMA)—a multidisciplinary scientific committee responsible for the assessment and agreement of “pediatric investigation plans” (PIPs).⁴²

The Regulation also introduced a system of obligations, rewards, and incentives to encourage manufacturers to research and develop medicines for children’s specific therapeutic needs; for example, marketing-authorisation applications for new medicines must now include the results of studies conducted in the pediatric population, in compliance with an agreed PIP, unless the EMA grants a deferral. Furthermore, medications are eligible for 6 months’ supplementary protection, and for orphan-designated medicinal products, the 10-year period of market exclusivity is extended to 12 years. This also applies when applying for a new indication, a new pharmaceutical form, or a new route of administration to an existing marketing authorisation. Existing medicines developed specifically for pediatric use with an age-appropriate formulation can benefit from a pediatric-use marketing authorisation (PUMA), with a 10-year period of data/market protection as an incentive.

Since its inception in 2005, EMA’s Management Board endorsed a framework of interactions defining the structure and formalization of the engagement, also tackling the challenges to ensure the children’s voice can be heard throughout the Agency’s different activities in a manner that is mutually beneficial. Over the years, patient engagement at EMA has progressed significantly, and patients are now systematically involved throughout the medicine’s life cycle—as members of its committees, but also as individual experts contributing to specific discussions on medicines evaluation.

As the opportunities for involvement developed, the numbers of patients participating increased, as can be seen in Figure 1. The EMA, together with the PCWP, created the “Principles on the involvement of young patients/consumers within EMA activities,” which were adopted by the EMA management board in May 2007.⁴² These principles establish the framework under which children and/or their guardians can be consulted by EMA scientific committees in relation to discussions on the development and assessment of pediatric medicines.

Figure 1.

Participation in EMA activities.

Consulting with “young people” at the EMA typically refers to adolescents who are able to respond to the type of questions a scientific committee may ask and depends on their individual knowledge, experience, and maturity. For this reason, no specific age limit has been defined. Prior to their involvement, the format of contact and dialogue for consultation will be agreed upon and the young person will be made fully aware of the proposed nature and scope of the engagement, including their expected contribution and what support they can expect to receive. Due consideration will also be given to the protection of personal data and the privacy of the young patients.

EMA is now working together with youth networks across Europe (eYPAGnet) to prepare appropriate support and educational materials for young people to help them understand the regulatory arena and, together with EnprEMA and the other EMA-eligible patient/consumer organizations, are working on establishing appropriate contacts with youth groups across Europe, which will be the primary source of contact with young persons.

Models for Involving Children and Young People

Great strides have been made to establish models and best practices for involving and engaging children and young people in the drug development process across different countries.

The International Children’s Advisory Network (iCAN) is a network of young persons’ advisory groups around the world, which serves as a platform to increase youth and patient voices in medicine through collaborations with researchers, industry, regulators, societies, and patient advocacy groups.^15,19 The local teams are commonly named KIDS teams (Kids and Families Impacting Disease through Science) or some variation such as KidsCan in North America. Teams in Europe are simply named Young Person’s Advisory Groups.

ICAN and its chapters around the world have also participated in an increasing number of collaborations in the area of drug development. Specifically, groups are often consulted on consent and assent forms for pediatric clinical trials, as well as the acceptability of study protocols.^15,19 A pharmaceutical company recently engaged iCAN for a revision of the assent template from a youth health literacy perspective. This interaction followed initial work by the company’s Parent Volunteer program and a formal health literacy evaluation from a vendor. The iCAN input resulted in significant revision to images provided by the vendor and terminology used in the assent templates. Ultimately the youth input helped to achieve the company goal of making the assents clear and meaningful to children in a measurable way using the Suitability of Assessments Materials scale (SAM).⁴³

The iCAN recommendations can be applied to other clinical trial materials:

• Youth appreciated efforts to structure the assent in ways that allowed them to better read and understand the information.

• Colorful photographs and images help to make the assent less intimidating and provide natural breaks in reading that aid comprehension.

• Youth thought it was very important to understand who will benefit from the study.

• Youth want to know what to expect if they choose to participate, including what will happen and how often.⁴⁴

• Youth want to be thanked for considering participation even if they decline the study.

Examples like these highlight the importance of global initiatives like iCAN that increase the methods available for global patient participation. Encouraging young people to take part in research and development and providing relevant training to facilitate these processes help to ensure appropriateness and acceptability of new innovations. iCAN’s local chapters around the world also work bottom-up to make changes in hospital policies and site-specific pediatric drug development protocols.

European Young Person’s Advisory Group Network (eYPAGnet)

The European Young Person’s Advisory Groups Network (eYPAGnet) is a member of the iCAN network. The groups work collaboratively to share best practices, standardize materials, and define the process for global input from YPAGs. The eYPAGnet has the recognition of EnprEMA (European Networks of Peadiatric Research of the European Medicines Agency) and works at the European level with the aim to centralize and standardize the involvement of young people along the drug development pathway.

eYPAGnet members have extensive experience involving children and young people in pediatric clinical research initiatives and pediatric clinical trials. The first YPAG in the world was established in Alder Hey Children’s Hospital (Liverpool-UK) in 2006.

Pediatric clinical research and patients’ involvement in Europe has a common framework due to several initiatives:

• Pediatric Regulation: Launched in 2007, establishes the different procedures to perform pediatric clinical trials, considering different scenarios: medicines that have been studied with adults that will be studied with children with the same condition, drugs addressed only to pediatric conditions, the process for the orphan drug designation, etc.

• Conect4children⁴³: This is the pan-European Network of Pediatric Clinical Trials funded by Innovative Medicines Initiatives. The objective of this project is to centralize and standardize all the procedures to perform pediatric clinical trials in Europe. Members of eYPAGnet are involved in the project to ensure that this new European infrastructure is patient centered and includes the voices of the children in the activities of pediatric clinical trials.

The main objectives of eYPAGnet are as follows:

• improve the capacity of collaboration with the different agents, who participate in the research process and development of innovative drugs.

• gather a variety of experience related with different pathologies.

• promote the planning and development of clinical research initiatives for children, on an European level.

• consolidate the curriculum of capacity-building and empowerment training programs to the young patients.

• promote and lead the creation of new groups.

• empower the selection of professional careers in the scope of science, among the youth.

Facilitators to Participation

The strength of the patient/family-physician relationship is a critical factor in participation. Parents as well as children report increased levels of interest and compliance in participation and feedback in the drug development process if their pediatrician or attending physician was involved—particularly in the process of patient recruitment.⁴⁵

Altruism is often cited as a common motivation for young patients and families to agree to take part in clinical trials.^15,21 Treatment protocols and current medications would not have come about if not for the willingness of past patients to participate in clinical trials. The desire to pay it forward to help develop future medications and treatment protocols for pediatric patients with similar conditions is a strong motivator for involvement.^15,19 Below are thoughts shared by a youth from KIDS Ohio, (a local iCAN chapter in the USA) at a pediatric research conference:

“I think that there can be a disconnect during the transfer from bench research to clinical trial, especially in pediatric research. I am sure that most sponsors and pharmaceutical companies do not get the opportunity to speak to the patients that they are affecting. I hope that by hearing our testimonies they were able to see research in a more humanistic view. Overall, the portion of the conference that I was able to participate in was very unique and I think that helped to make a bigger impact” (E. Wentzel, personal communication, July 12, 2018).

Pediatric patients also express feelings of autonomy when given the choice to participate in a trial or study. Comments such as “I know what it’s like to be a kid,” “I want to voice my opinion and engage in projects that will help children in need of innovation,” and “adults will be in need of a child’s perspective for different medical circumstances that involve children” show that youth wish to be engaged in their own health care and are empowered when asked to take part.^15,21 These quotes were given by children and youth when asked about why they wanted to join KIDS Connecticut, local group of children who provide feedback to pediatric researchers.

Barriers to Participation

In general, care must be taken in the involvement of children and youth in clinical trials to minimize the frequency of requests, to consider the busy lives of children and families (eg, school, work, and siblings), to factor in the availability of medicines outside of the clinical trial environment, and to be cognizant of patient comfort and compliance and minimize distress.²⁶ These latter factors may be barriers for parents to want to enroll young patients as participants in clinical trials.⁴⁶ Nuances around patient demographics such as socioeconomic status, race, or current patient health must also be taken into consideration. Other barriers include methodology-related variables such as recruitment strategies, associated risks, or the type of study.

Often legal or logistical barriers such as timing and scheduling also deter participation. For example, standard operating procedures in pharmaceutical companies may create barriers for youth input in patient-focused drug development.⁴⁷ Company procedures are typically established for interaction with adult patients who can independently sign nondisclosure and contractual agreements related to participation.^48,49 These barriers can be overcome but require careful, proactive discussion with the company’s legal, privacy, and compliance divisions. Young people advisory groups may also lack operating procedures on interactions with industry.

Still other important themes that contribute to participation include previous experience and adverse effects while participating in other clinical trials. Ultimately, underlying these factors is the hope of the majority of parents to protect their children and optimize their health outcomes.⁴⁸

Many of these facilitators and barriers are evident in the following excerpt as Kalee and her mom Melissa from KIDS Georgia share their experience participating in a pediatric clinical trial to decrease the dosage of an antirejection medication after two liver transplants:

“Kalee felt excited about getting off her medicine, that and the idea of helping other children made her decide to participate. Kalee said it made her feel like she had a choice when they asked her to sign the consent form, it made her feel good about herself. She didn’t like all the questions that she was asked at each visit, each visit she had to answer a survey…. Kalee also felt that it wasn’t about the money, it was about her helping other kids and getting off her medicine.

From a parents’ perspective, it was exciting and fearful all in the same breath. Understanding that you are signing up for the very thing that could cause your now stable child to possibly be sick again was a hard decision to make, but understanding the long-term benefits outweighed everything…. This research helps me feel like Kalee and I are taking the path to a choice.” (M. Polk, personal communication, April 28, 2018)

Opportunities and Needs

Despite guidelines and frameworks to improve patient and family engagement in pediatric drug development, there remains a need for better training and resources for these important stakeholders to be equipped as partners.¹⁷ Work also needs to be done to minimize conflicts of interest with sponsors while working closely with patients.^2,50 Research around conflicts between parents and pediatric patients regarding involvement in clinical trials and drug development must also be explored and findings disseminated on strategies for peaceful resolution and compromise.¹⁷ iCAN/eYPAGnet and other models of engaging with young people seeks to meet the developmental needs to ensure children and young people are maximally engaged and benefiting from their work. The goal is not simply to add to research data by children and young people via the completion of surveys to provide input into trial design but to change the nature of pediatric research and ensure that their input has impacted the project in a substantial way. To this end, systematic feed-back tools need be created to enable this process.

Every year, the iCAN teams come together in a Research and Advocacy Summit. With the fourth annual summit in Edinburgh having just concluded, the network is abuzz with takeaways. From informative workshops on the development of clinical rials to the ethics of research involving children, the sessions brought together youth, policy makers, drug developers and regulators, as well as health care professionals in collaborative discussions all week long. The collaborations between iCAN and eYPAGnet especially around standardization of materials for child and youth involvement in medicine has gained momentum and will be continually developed in the coming years.

Future Directions

Moving forward, focus must be placed on areas such as

• Standardization of education and training materials for international patient advocacy groups;

• Development of metrics to measure impact of patient engagement;

• Increased publication efforts to highlight the impact of patient projects on both study design and on young people themselves;

• Greater collaborations between and within the different stakeholders;

• Collaborative efforts to improve public awareness of the importance of research and development; and

• Guidelines from professional organizations and regulatory agencies to guide industry engagement with youth for patient-focused drug development.

When measuring the significant impacts of patient and family involvement, researchers must be cognizant about what part of the research study they wish patients to be involved in and how to properly educate patients and families to empower them to take part as active and informed participants.^15,17,19 To this end, iCAN and Connect4Children are currently facilitating initiatives that will result in a common standard curriculum for all groups.

Meaningful metrics should also be created to measure the impact of patient engagement as well as to better account for confounders and other variables that may skew study results in order to isolate and replicate the specific ways patient and family involvement creates impact. At the European level, the PARADIGM project⁵¹ will contribute to deliver systematic metrics that can be implemented worldwide to measure the impact of the involvement of patients along the lifecycle of medicines. FDA’s PFDD program serves as a wonderful springboard for the development of meaningful patient input, especially for special populations such as pediatric patients. Such measures coupled with patient and physician education have proved to yield effective and high-quality methods of patient engagement, which can be replicated and standardized in all trials.⁵²

Summary

It is widely agreed upon that the participation and empowerment of pediatric patients and their families in the patient’s treatment process is important.^8,11 Collaborations between patient groups and researchers/sponsors have become more commonplace in the recent decade, yet best practices and impacts are still rarely documented in literature.^49,52 As a result, few systematic guidelines or replicable methodologies for the inclusion of children and young people in future trials and clinical practice are available.¹⁷ However, recent changes to legislation in both Europe and North America has seen an increase in the inclusion of children and youth in pediatric drug development. Coupled with the work of external groups such as iCAN/eYPAGnet, the hope is that pediatric patient voices can be brought forward for the future.

Ultimately there needs to be an increase in the number of collaborations within and between related organizations. This could include partnerships between patient groups and researchers, advocacy and community organizations, or private partners. In discussion of private partners, there is a need for the development of standardized guidelines from professional organizations and regulatory agencies to set standards for partnerships between industry and young patients. Such collaborations will ultimately serve to improve public awareness of the importance of research and development.