BACKGROUND AND OBJECTIVE: The last decade has seen dramatic changes in the regulatory landscape to support more trials involving children, but child-specific challenges and inequitable conduct across income regions persist. The goal of this study was to describe the attitudes and opinions of stakeholders toward trials in children, to inform additional strategies to promote more high-quality, relevant pediatric trials across the globe.
METHODS: Key informant semi-structured interviews were conducted with stakeholders (researchers, regulators, and sponsors) who were purposively sampled from low- to middle-income countries and high-income countries. The transcripts were thematically analyzed.
RESULTS: Thirty-five stakeholders from 10 countries were interviewed. Five major themes were identified: addressing pervasive inequities (paucity of safety and efficacy data, knowledge disparities, volatile environment, double standards, contextual relevance, market-driven forces, industry sponsorship bias and prohibitive costs); contending with infrastructural barriers (resource constraints, dearth of pediatric trial expertise, and logistical complexities); navigating complex ethical and regulatory frameworks (“draconian” oversight, ambiguous requirements, exploitation, excessive paternalism and precariousness of coercion versus volunteerism); respecting uniqueness of children (pediatric research paradigms, child-appropriate approaches, and family-centered empowerment); and driving evidence-based child health (advocacy, opportunities, treatment access, best practices, and research prioritization).
CONCLUSIONS: Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children, but they contend that inequities and political, regulatory, and resource barriers continue to exist. Embedding trials as part of routine clinical care, addressing the unique needs of children, and streamlining regulatory approvals were suggested. Stakeholders recommended increasing international collaboration, establishing centralized trials infrastructure, and aligning research to child health priorities to encourage trials that address global child health care needs.
- LMICs —
- low- and middle-income countries
What’s Known on This Subject:
Conducting clinical trials in children is complex because of safety concerns, stringent regulatory requirements, lower prevalence of disease, and lack of commercial interest. Recent changes in the regulatory environment have alleviated these challenges somewhat.
What This Study Adds:
This article provides stakeholder views on mitigating the inequities by addressing children’s unique needs, integrating trials into clinical care, streamlining regulatory approvals, building infrastructure, relevant pediatric trials.
The last decade has seen major changes in the regulatory framework for clinical trials in children, resulting in substantial incentivization for industry and investigators to rigorously evaluate new therapies through the conduct of trials.1–3 Several pediatric research networks have also been established to support trials in children, with variable success.4,5 Despite these advances, children all too often remain “therapeutic orphans,” as the majority of medicines prescribed for this age group have still not been adequately tested for safety and efficacy, and disparities exist compared with adults and according to income regions.1
Trials in children are complex and can be challenging due to the unique requirements of this population, safety concerns, stringent ethical requirements, and the lack of commercial interest.6,7 In low- and middle-income countries (LMICs), there are additional challenges related to poverty, fear of exploitation, and mistrust.8,9 The pharmaceutical industry is perceived as reluctant to conduct trials in children, whereas pediatricians’ concerns regarding risks are seen as barriers.1
The goal of the present study was to describe the attitudes and opinions of researchers, regulators, and sponsors regarding the conduct of clinical trials in children. A comprehensive understanding of their values, beliefs, and experiences across different income contexts could inform local and international strategies to improve the number, quality, and appropriateness of trials conducted in children.
The Consolidated Criteria for Reporting Qualitative Research framework was followed for interviews and focus groups.10
Respondent Selection and Practice Setting
Respondents were eligible if they were researchers, regulators, or sponsors involved in trials in children. Consumers (children, families, and the public) were excluded. Respondents were purposively selected to capture a range of age, sex, income settings, and experience in trials. Respondents were recruited via professional networks. A snowball sampling strategy was also used whereby respondents could nominate others who could add a different or important viewpoint. The University of Sydney Ethics Committee approved this study.
The interview guide was based on a systematic review of trials in children and discussion among the study team.1 It focused on the challenges and strategies to improve trials relevant to child health (Supplemental Table 4). From October 2013 to August 2014, the lead author (P.D.J.) conducted face-to-face interviews in offices or meeting rooms or via telephone. Respondent recruitment ceased when theoretical saturation (ie, when little or no new information was being obtained from subsequent interviews) was reached.11,12 We audio-recorded and transcribed all interviews.
Transcripts were entered into HyperRESEARCH version 3.5.2 software (ResearchWare Inc, Randolph, MA). Based on grounded theory13 and thematic analysis,12 the lead author (P.D.J.) coded transcripts line-by-line and then translated similar and different concepts into existing or new codes, respectively, as they emerged in the data. Similar concepts were grouped into themes and subthemes, and the coding structure was revised until all concepts relating to barriers and enablers of trials in children were captured. Relationships and patterns between themes were identified to develop a thematic schema. To enhance the comprehensiveness and validity of the thematic framework, the preliminary findings were discussed among the research team (investigator triangulation) and then e-mailed to all respondents, who were given 2 weeks to include additional viewpoints (ie, member checking). Their feedback was coded and incorporated into subsequent revisions of the analytical framework.
In total, 35 (88%) of the 40 invited stakeholders participated. They were from 10 countries; 20 stakeholders were from high-income countries, and 15 stakeholders were from LMICs (Table 1). Nonparticipation was due to nonavailability or institutional restrictions. The duration of the interview ranged from 20 to 70 minutes. Eight interviews were conducted face-to-face.
Five major themes were identified: addressing pervasive inequities, contending with infrastructural barriers, navigating complex regulatory and ethical frameworks, respecting uniqueness of children, and driving evidence-based child health. These themes are described with illustrative quotations in Table 2 and Supplemental Table 5. Figure 1 shows the conceptual relationships among themes and subthemes.
Addressing Pervasive Inequities
Paucity of Safety and Efficacy Data
The growth in the number of trials in diseases specific to children was perceived to be less than expected. Clinicians were concerned that children could potentially be harmed due to “treatment uncertainties” and “practicing unresearched health care” because trials were still “skewed” with data from the adult population. In particular, respondents felt there was a paucity of safety and efficacy data in diseases with a high burden in resource-poor settings, rare childhood diseases, older off-patent medicines, and younger age groups.
Researchers believed that they were perceived by some pediatricians, the community, and politicians to be “using” children and were described as “vampires after your blood.” Some respondents believed that parents in the West were “pretty informed and educated,” whereas researchers in LMICs had to contend with language barriers and lower health literacy in parents.
The entrenched social disadvantage, local political instability, and corruption in certain LMICs were offered as the main reasons for insecurity and hesitation among local researchers to conduct trials in children. Historical fears were believed to have damaged public trust of trials involving children (eg, the unethical trials conducted during World War II in Germany).
Challenging Double Standards
The “double standard” of the bureaucratic burden and regulatory requirements to conduct trials in children, compared with the ease of using untested interventions in routine clinical care, was questioned. There was controversy regarding the proposal of using placebos or inferior treatments as comparators in trials in LMICs, where the international standard of care was not routinely available. Regulators in the United Kingdom and the United States queried why it was “illegal” to pay children anything beyond reimbursement for trial expenses, whereas in adult trials, it was “fair to pay” for participation.
Ensuring Contextual Relevance
A “disconnect” between the pediatric burden of disease and countries in which trials were conducted was reported by respondents. Researchers believed “data which are not Indigenous” may not be relevant to local settings because of “pharmacogenomic differences” and variability in health care.
Respondents believed industry would “leverage their resources” in trials in which there was greater “financial reward” rather than for “humanitarian reasons.” Clinicians argued that most trials were focused on diseases in adults, driven by political and economic influences, and the regulatory incentives for involving children in trials only helped to “tie the pediatric caboose to the adult marketing train.” They surmised that it had been “a happy marriage between industry and regulators” to conduct trials in children with a large sample size as a “preauthorization marketing tool.”
Industry Sponsorship Bias
Industry-sponsored trials were noted to be almost always multinational and of higher quality because of adherence to regulatory standards for obtaining marketing authorization. In contrast, investigator-initiated trials were deemed to be of “poor quality,” “curiosity-driven,” or for academic promotion. Clinicians suspected that investigators reluctantly participated in industry-sponsored trials so that they could “pay the rent” and subsidize their own research. Industry sponsors believed that the majority of industry “get tainted in that stigma” by the minority of pharmaceutical companies who conduct research unethically. They believed the position “damned if they do and damned if they don’t” involves children from LMICs in trials.
Dissuaded by Prohibitive Costs
The “manifold costs” of regulatory oversight were perceived as a “double-edged sword” for investigators who had to conduct trials “on shoestring budgets or no budgets.” Trials in children were perceived to be a “financial risk” to industry because of the small pool of eligible patients, longer follow-up, and the increasing site costs. Industry sponsors were polarized regarding the perception that they were “shifting” research to the LMICs where it was a “cheaper” option.
Contending With Infrastructural Barriers
Overwhelming Resource Constraints
Researchers stated that “funding was the bane of doing research” in children, as pediatric trial facilities and resources were scarce, especially in disadvantaged settings.
Dearth of Pediatric Trial Expertise
Respondents noted a critical lack of expertise in pediatric trials. Some researchers from LMICs acknowledged that they developed expertise from participating in industry-sponsored trials. Many felt that clinicians required appropriate rewards and “career pathing” to enhance participation in trials.
Traversing Logistical Complexities
All respondents had to confront logistical complexities such as shipping samples overseas. Logistical difficulties were particularly challenging in LMICs. For example, researchers in Nigeria had to contend with electricity disruptions, unreliable telecommunication, and difficulty in following up respondents who frequently relocated.
Navigating Complex Ethical and Regulatory Frameworks
Researchers believed that “draconian” ethical and regulatory oversight was a barrier to conducting trials in children. Navigating the long, heterogeneous, and duplicative process of obtaining multiple approvals was considered “cumbersome,” and the informed consent requirements were described as onerous and impractical. Some respondents were frustrated that research funds were wasted on “unreasonable bureaucracy,” while acknowledging that without a “robust governance and safety system we would prejudice our research.”
Many felt that the variability in the quality of ethical deliberations and “ambiguous” trial guidelines “drives people crazy” and potentially leads to “unequal protection.”
Fear of Exploiting the Vulnerable
Some respondents believed that children in LMICs were exploited to address the health care needs primarily of wealthy nations. Ethics committee members opposed “exposing children to inappropriate level of research risk absent of any prospective direct benefit” (eg, inserting a central line for placebo administration). The new mandatory requirement of audio-visual consent in India was believed to protect respondents, although some considered this requirement to be excessive and could stigmatize adolescents who preferred to be de-identified.
Excessive Paternalism and Unwarranted Exclusion
Researchers and sponsors believed that parents and regulators had “paternalistic attitudes” and were “overcautious” about including children in trials. However, some argued that excluding children was discriminatory because “the way we should protect children is not from research, but through research.” Researchers reasoned that ethics committees and guidelines were there to protect children from “unreasonable, potential risk.” Some believed that it was easier to justify trialing medicines in neonates, in whom there is limited or no clinical practice evidence, than trialing treatments that are currently used in children without evidence.
Precariousness of Coercion Versus Volunteerism
Researchers were uncertain about the morality surrounding investigator and parent’s inducement to participate in trials, particularly in the context of LMICs. Industry sponsors maintained that the amount of reimbursement could not be universally standardized and should be reflective of the economy, as payment of disproportionately high amounts of reimbursement could unduly influence participation.
Respecting Uniqueness of Children
Embracing Pediatric Research Paradigms
Respondents advocated for stakeholders to “embrace pediatric paradigms” and consider the “uniqueness” of children regarding treatment response, disease pathophysiology, and expression. Clinicians prioritized impact on quality of life and long-term neurocognitive outcomes. Respondents recommended novel, pragmatic trial designs for small populations of rare diseases in children.
Considering Child-appropriate Approaches
Researchers and ethics committee members thought that industry neglected child-specific issues when designing protocols. Respondents proposed that protocols be developed to include child-specific considerations such as microanalysis techniques that require smaller volumes of blood. They recommended a child-friendly research environment with distraction therapies, and using pictures or audio-visual aids and plain language to explain trials. Some suggested that clinical visits or assessments should be scheduled to minimize interference with school attendance.
Facilitating Family-centered Empowerment
Involving families in setting child health care research priorities, as well as the designing and conducting of trials, was proposed by researchers and regulators. The clinical team highlighted that when “recruiting a child, you are recruiting the whole family.” In the United Kingdom, families and children involved in trial networks have lobbied to have trial results provided to respondents.
Driving Evidence-based Child Health
Promoting Research Advocacy
Although “great strides” in benefits of children’s participation in trials was recognized, further behavioral and cultural shifts through a massive awareness campaign was deemed essential. The ethical case that “children deserved evidence-based care,” the economic justification of return on investment by health care cost savings, and involving families to obtain “public acceptance” and policy makers’ support were encouraged.
Creating and Seizing Opportunities
Proponents of trials in children encouraged global “societal commitment” to dedicate funds and attract investment in pediatric trials. Respondents believed that strong networking opportunities contributed to the success of trials in pediatric oncology. Researchers from LMICs welcomed opportunities for participation in international trials. They advocated for research to improve the health system and philanthropic investment to build local trial and health care capacities.
Supporting Best Practice
Respondents supported the development of consensus trial regulations and resources that could be adapted to local contexts. They believed that it would be “utopia” to have 1 “amalgamated” national ethical review process. However, some regarded this scenario as a “double-edged sword” because a central ethical review would eliminate the inherent quality control provided by multiple reviewers. Many encouraged collaboration and sharing of expertise, and they emphasized the need for a centralized trials infrastructure with research “intra-operable tools” to support a range of study designs.
Improving Access to Treatment
Trial participation gave children the opportunity to access new or better treatments that may otherwise be “unreachable,” expensive, or unavailable. Thus, respondents advocated for trials to be embedded in clinical care. They endorsed harmonization and augmentation of regulations and stronger partnerships between researchers, regulators, and industry to support well-designed developmental pipelines for therapeutic agents for children. More efficient dissemination, translation, and implementation of pediatric research into practice and policy were encouraged.
Prioritizing Research Productivity
Multi-stakeholder collaboration to improve trials in child health care globally and reduce research waste was deemed crucial. Prioritization of child health care needs based on analysis of epidemiologic or trial registries data was recommended. Burden of disease, balanced by scientific opportunities in rare diseases, was considered important to justify expenditures in prioritizing funding universally.
A broad range of stakeholders involved in the conduct of trials in children recognized that much had been done to promote trial-informed clinical care of children but that large-scale cultural and behavioral changes, coupled with substantial infrastructural enhancement, were still required to promote the conduct of more trials that were relevant and of high quality. They believed that there was still a scarcity of child health care safety and efficacy data, most notably in LMICs, child-specific diseases, neonates, off-patent medicines, and child-appropriate formulations. Challenges and specific pediatric disparities were believed to arise from fears of harming children, political and economic influences, lack of resources for pediatric trials, and the bureaucratic regulatory framework. Global multi-stakeholder collaboration, integration of trials as part of clinical care, sustainable centralized trials infrastructure, harmonization of regulatory approvals, and alignment of the pediatric research agenda through analysis of trial registries and epidemiologic data were believed to enhance global capacities to conduct pediatric trials.
A recent systematic review of stakeholder views of trials in children in LMICs identified challenges related to social disadvantages, idiosyncratic cultural beliefs, and historical disempowerment, with community engagement as the main enabler.9 In our study, more challenges were identified by respondents in LMICs, where few trials are conducted despite the enormous pediatric disease burden. Some respondents were concerned about safety and exploitation of children, whereas others maintained that trial participation protects children from harm caused by non–evidenced-based health care.14,15
In addition to the frustration engendered by what was regarded as shortcomings in the technical capacity of ethics committees and ambiguities in the regulatory requirements,16–18 researchers in the present study questioned the legitimacy of being explicit about treatment uncertainties and enrolling children in trials as opposed to the ease of giving the same untested treatment in routine clinical practice. Some felt that it was unethical and discriminatory not to involve children in trials. Stakeholders supported harmonizing and expediting ethical review and developing local and international standards. They believed this approach would reduce duplication and improve efficiency of ethical approval.19,20 Professional stakeholders were polarized regarding the current regulations forbidding payment to children for participation in trials.21
Stakeholders encouraged regulators worldwide to adopt appropriate regulations for the conduct of trials in children. They recognized that market exclusivity incentives supporting patent protection were not designed to meet the current needs of children, and this observation was corroborated in a recent examination of drugs granted exclusivity.22 Stakeholders endorsed improved regulations and incentives addressing child-specific therapeutic needs, off-patent medicines, and rare childhood diseases.23,24 To accommodate the low disease prevalence in children, innovative and optimum methods were suggested.25–27
Amalgamated government and philanthropic investments with strengthened multi-stakeholder partnership were regarded as necessary to improve drug development for pediatric use. Stakeholders supported multicenter collaborative trials and open disclosure of trial results through registries to reduce research waste and increase clinical benefit. Investment in a global governance framework of registries was encouraged to assist expedient availability, translation, and implementation of trial results.28 Incorporating analysis of epidemiologic and registries data to inform clinical research needs in children was supported, and integrating trials as part of routine clinical care was considered essential to bring interventions to the bedside in a sustainable manner.
Greater investment in training and resources is urgently required to help progress investigator-initiated trials to the regulatory standards that are required to inform labeling changes of medicines for use in children. Guidance and standards to improve pediatric trial design, conduct, and reporting are recognized as vital, with some initiatives underway.4,29,30 Establishing networks to collaborate and support trials was deemed essential by stakeholders. Investing in a centralized trial infrastructure with sustainable funding that could support different studies was considered crucial to promote more high-quality trials in children. This infrastructure has been shown to be beneficial, as illustrated in the highly successful UK Medicines for Children Research Network.31
Our international study highlights a wide spectrum of opinions of pediatric trial experts and decision-makers across different income and health care settings. We applied member checking to ensure that the analysis reflected the range and depth of the data collected. Our study outlines those recommendations that will be of interest to all stakeholders, including policy makers, to enable more high-quality trials primarily by making more explicit and informed decisions concerning child health research priorities (Table 3). However, there are some potential limitations. The transferability of the findings to countries that were not included in our study is uncertain. We recommend extending similar research to other countries that have different health systems, regulations, culture, and resources.
Stakeholders acknowledge that changes in the regulatory environment have encouraged more trials in children to be undertaken, but they contend that inequities and political, regulatory, and resource barriers still exist. Embracing unique pediatric needs and creating a culture of embedding trials as part of routine clinical care are recommended. International collaboration, sustainable centralized pediatric clinical trials infrastructure, development of pediatric trial expertise, and alignment of research to child health care priorities are suggested to encourage more high-quality, appropriate trials that address the health care needs of children globally.
The authors thank the stakeholders who shared their perspectives in the study.
- Accepted July 22, 2016.
- Address correspondence to Pathma D. Joseph, BPharm, MPharm, PhD, The Pharmacy Department, The Children’s Hospital at Westmead, Corner of Hawkesbury Rd and Hainsworth St, Westmead, NSW Australia 2145. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: Supported by a National Health and Medical Research Council Postgraduate scholarship (1039338).
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2016-2150.
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- Copyright © 2016 by the American Academy of Pediatrics