Background
Methods
Data collection
Data analysis
Results
HTA paradigms
Assembly
They emphasized the added relevance of system-level perspective in the prioritization of child health technologies, arguing that standard metrics of priority-setting in HTA may require rethinking to balance conventional concerns with those specific to the epidemiology and management of childhood disease. Disease burden as a principal determinant of HTA priority-setting was a notable example. One participant referenced the need for more nuanced priority-setting based on disease prevalence, noting:“If we want to design and execute a health care system that is evidence-informed and reflects our values, then actually we also have to tackle those higher-level resource allocation decisions.” (PRO3)
In aggregate, a clear concern emerged that the values incorporated into HTA priority-setting, and the assembly of health technologies more broadly, is insufficient. The corollary of this in the paediatric space was a recognition that better incorporation of relevant values could help rebalance priority-setting exercises to correct for an intrinsic bias against child health technologies, which we discuss in greater detail below.“If your view is you have to look first at the most common cancers, one hundred percent of the time children are going to be back of the queue.” (POL2)
The relationship between market dynamics and evidence generation was a major theme voiced by participants, one with broader implications than on HTA assembly alone. We deal with this theme in greater detail below.“We typically only look at the Health Canada approved indications, so, therefore, if it has a restriction of 18 years of age or older…it's our understanding that when we put these recommendations forward, the payers are following the indication for use.” (PRO4)
Assessment
Diverse stakeholders identified the need for more and better paediatric drug safety data, in both pre- and post-market phases. A number identified the existence of provisions in other jurisdictions – notably the US and Europe – to both incentivize and compel industry to generate safety and efficacy data for paediatric indications of drugs new to market; they lamented the lack of comparable provisions in Canada. The perceived upshot of this relative lack of data on paediatric drug safety and efficacy is that “you wind up adopting an adult intervention as the paediatric standard of care, without really the knowledge and the experience to do that safely and well.” (HEA4).“I think from the societal level down to policy-makers, and even people on the front line in health care, there's a sense that in terms of the safety/efficacy balance we need to be more sure with respect to children than adults.” (HEA1)
Conversely, factoring in a drug’s long-term effects can buttress arguments in favour of health system adoption, if the expected toxicity profile is promising relative to existing standards of care. However, it is the absence of confirmatory data on their real effect, coupled with the higher normative bar set for proof of safety in children, that participants viewed as a principal evidentiary barrier in current HTA approaches to child health technologies. The fact that many novel drugs in the era of precision medicine hold promise to reduce toxic side effects, both immediate and long-term, was seen by many as both a potential boon to children, and a factor inadequately recognized by current HTA paradigms.“If you commit an 85-year-old to a drug that affects the bone marrow it has different implications to if you submit a 5-year-old to that, especially if it’s a condition for which they will need treatment for many years.” (HEA6)
To many, the mismatch between epidemiological realities in children and the epistemic demands of HTA justifies a rethinking of our received appraisals of medical evidence. In the words of one participant, “small numbers, small bodies, long outcomes: there has to be a different perspective.” (HEA2) This recognition prompted many stakeholders to weigh and advance evolving notions of evidence in child health, and to catalogue novel approaches to generating evidence on child health technologies. Across the stakeholder groups interviewed, a nuanced sense of the legitimacy of diverse forms of evidence emerged: one that valued statistical confidence but placed greater emphasis on clinical and social context for its interpretation than is routinely exercised in received biomedical paradigms. This idealism was tempered by fidelity to rigour in evidence appraisal and the desire for reliable barometers by which to assess it. Related to this, participants acknowledged that the pace of institutional change would likely slow fundamental shifts in the norms attached to clinical evidence in existing HTA paradigms."When you have children who are being put into very specific baskets of their genomic and genetic markers and being treated for those…this problem of the uncertainty of the evidence is going to really hit an apex. It's going to mean looking at clinical trials and looking at evidence, and trying to figure out what is appropriate evidence, very differently. We're going to have to see a major, major shift." (PAR4)
In an emerging ‘golden age of new therapies’, a strong sense of the need for, and reality of, changing philosophies of treatment emerged. Participants viewed this reality as the foundation for new conceptions of the relative value of alternative forms of medical evidence, and their use in health technology assessment for children.“The numbers are smaller and so while that can be a disadvantage in terms of drug development, it can be an advantage in terms of being innovative in how you approach things. I think we’re starting to change the way we’re approaching the kids. How we change the way the system responds to them is going to be next.” (PAR2)
Economics
Those interviewed enumerated challenges in accounting for both the positive and negative implications of therapeutic interventions across the life-course. The latent or chronic side effects of treatment, and their deleterious impact upon health-related quality of life at various life stages, were considered alongside potential gains in economic productivity from the combination of improved disease outcomes and less toxic therapy. Participants spoke to current limitations in measuring or modelling both, and the need to do better in the context of child health.“[What] makes it very difficult is the time horizon, right? So, you know, often the economic models that we or others develop are explicitly for 5 years, or something like 5 years, and with kids, that may not be long enough to show the true effect of the intervention, and so you can of course produce models with a longer time horizon, but if you do that, then the uncertainty is always much higher.” (PRO1)
Integration
This concern for appropriate framework and process frequently dovetailed with perceptions of inadequacy in respect of children. The routine extrapolation of adult recommendations to the paediatric space was seen as a cardinal example of this. Some rendered this a specific instance of the fallacy of decision-making based on population averages. Others identified a distinct and more fundamental problem in the transposition from adult to child: the possibility that, due to differences in biology and social position, adult and child population distributions cannot be superimposed, let alone equated. In recognition of this, many defended the need for an HTA framework tailored to children. Their proposals in this regard incorporated sensitivity to aspects of child life and health such as developmental trajectories, future potential, and family context:“There are some [decisions] that are black and white, and those ones should probably be reproducible. But there are many that are grey…if you had a different day, with a different composition of panel members, they might have voted the other way. The process should be transparent, it should be one where people articulate their reasons for the decision, but I don't know whether it always has to be the same.” (POL7)
The challenge of, and opportunity for, integrating alternative forms of evidence in any framework for child HTA was a paramount concern. Stakeholders related this both to the aforementioned constraints in generating traditional ‘high-quality’ evidence in paediatrics, and to the need to capture socially relevant dimensions of value not routinely represented in trial outcome measures. Some saw a role for enhanced patient and public engagement in this regard, including among children themselves. Related to this, a number of those interviewed spoke to the need for balance between structure and flexibility in child HTA guidelines, arguing that rigid form can stymie both the legitimate play of moral intuitions and the incorporation of scientific progress, including in HTA methods and processes:“An unhealthy child is generally an unhealthy mother and, not uncommonly, an unhealthy father and siblings as well. So, the notion of unit of analysis, I think, is very germane to childhood.” (HEA2)
A number of participants detected myopia in the frame typically applied to technology assessment, adult and child alike, arguing that “[looking] at one drug at a time, in isolation from everything else” (PRO1) gives a decontextualized – and therefore artificial – impression of the value of a given technology. The need to better incorporate system-situating factors like opportunity cost, unmet need, equity, and public priority was a recurrent motif. Many participants stressed the particular importance of broader context for the assessment of child health technologies, alluding to the unique play of evidence and social values in the paediatric space – for instance, the relevance of ideas like vulnerability and protection that often frame societal responsibilities to children as normative considerations to be weighed alongside clinical and cost effectiveness. Current approaches to incorporating social values in HTA for children were deemed especially weak."You want guidelines that are going to be able to give people appropriate constructs to make decisions, but within those guidelines, you want to make sure they are not so hard and fast. Because the world – especially of paediatric cancer – is changing, and if you're creating guidelines which are too rigid that could be a real danger." (PAR3)
However, this risk was often rendered as further proof of the need for a professionally and societally legitimate forum for child HTA: to limit opportunities for reactive or politically expedient decision-making on paediatric drugs and technologies, and to provide a structured forum to disentangle advocacy from dispassionate evaluation. While many participants were at some level invested in optimizing drug access for children, most also viewed objectivity as key to credibility in child-focused HTA. Rather than frame paediatric expertise as a barrier to objectivity, most saw it as a means of validating HTA for children.“I think that group of pediatric experts needs to clearly carry the caveat you are not here to promote pediatric drugs. You are here to assess applicability, cost effectiveness, utility of drugs for pediatric purposes with the same rigor just with the perspective of what is possible on a pediatric evidentiary basis.” (POL5)
A few stakeholders also spoke to the points of overlap between HTA for children and rare diseases, noting that some of the provisions in rare disease frameworks are applicable to technologies for certain childhood diseases. However, most took care to point out that these commonalities did not erase distinct facets of child health that might warrant explicit incorporation in HTA frameworks. The challenge of when and to what degree special concerns related to child health – developmental vulnerability, future potential, family embedding, evidence constraints – apply within and beyond ‘child’ populations is not easily resolved. For most interviewed, these challenges did not diminish the relevance of such concerns to child HTA. They served instead as a cautionary note to unexamined paediatric exceptionalism, and as a means of sketching the defensible boundaries of a child-adapted HTA framework. Still, the potential for systematic bias in funding decisions arising from population-specific HTA frameworks – especially in view of the acknowledged challenge to incorporating opportunity costs into technology assessments – is a critical issue that any such distinct framework for child HTA will need to address.“There is a transition from children to adults…for those conditions that are on the cusp, that affect both children and adults, and you have two separate processes, you can have different decisions, you know, someone turns eighteen, all of a sudden something's not available anymore.” (POL1)
Alongside this, however, a range of stakeholders suggested that a cultural and political shift is underway, toward the routine instantiation of HTA in policymaking on drugs and technologies at various health system levels in Canada. Many saw in this shift the potential to limit caprice in funding decisions. The opportunity for tightened and more effective interface between the various institutional players involved in drug access for children was a recurring theme. Innovative approaches to integrating clinical trial design and HTA processes were alluded to by a number of participants. For example, an adaptive pathways approach to drug development and access – which involves staged approval based on iterative, real-world evidence development and upfront involvement of patients and HTA bodies – was referenced as a means of creatively surmounting the data constraints attached to paediatric drug development. A few also pointed to the need for more and better-articulated HTA processes at the level of individual health care institutions. These stakeholders envisioned opportunities to make smarter and fairer choices among technologies through the application of HTA to resource allocation at the meso- and micro-levels, including global hospital and regional program budgets – particularly where such budgets are a priori allocated to child health.“All it takes is, you know, one article in the front page of a newspaper sometimes to make a minister change their mind.” (PRO2)
Sociopolitical context
Markets
Participants construed the upshot of narrow markets as either industry disinterest in paediatric drug development or pricing tactics to coax profits from limited market space. Such tactics were often seen as illustrative of a fundamental misalignment of corporate and societal goals. Most participants related the disincentives for paediatric drug production to disincentives for HTA submission by industry, noting that “the work involved in an HTA submission, which is quite a lot financially, sometimes doesn’t even pay off for them to bother”. (PRO1).“The market is extremely, extremely small … you're talking about very small, rare diseases, and/or short durations of therapy. So it creates difficulty in developing incentives on the regulatory side for pharma to develop products.” (HEA4)
A few stakeholders also identified the lack of ‘levers’ available to HTA bodies to inform drug R&D dynamics, and underscored the impact of this impotence on drug portfolios where market incentives are lacking or where evidence generation is fraught. Related to the need for enhanced feedback capacity from HTA to industry to direct drug R&D priorities, a number of stakeholders spoke to the potential for governments to take more responsibility for funding novel drug trials in children. They highlighted access barriers related to the often-clumsy interface between industry-funded trials and government drug policy: these included jurisdictional hurdles to accessing trial drugs, resulting in geographic and disease-based disparities in access.“We're finding more acceptance, or interest, from drug pharma, from big pharma that never had any interest in pediatric cancer, in these diseases, because it gives them a potential opportunity as a window to then branch out and use them in the adult population.” (HEA6)
For many, the upshot of such observations was a perceived onus on governments to facilitate system uptake through nimble and creative policies that marry technology development, assessment and funding. These and other proposed corrections to market disincentives relate to the broader manner in which governments seek to mould paediatric drug market dynamics through legislative provisions and regulatory oversight. We explore drug policy and regulation in more detail in the section that follows.“You can go from a plan of research to using [a technology] in a clinical way within months… Now, you're using what was meant to be a research study for clinical action. Totally different paradigm than the classic clinical trial.” (HEA7)
Governance
The fact that industry will routinely forego paediatric testing of already-developed medications with known clinical utility in children was seen as illustrative of the thorough lack of market incentives for paediatric drug development, and deep industry disinterest in the same. Participants highlighted resultant problems at all points along the research-to-market pipeline, among which are: lack of knowledge on paediatric drug safety, efficacy and dosing; inappropriate product formulation for children’s varying size and developmental needs; lack of industry licensing submissions and market entry for paediatric indications; and, as a result of the foregoing, lack of HTA submission by industry for most drugs used in or relevant to children.“There are a gazillion drugs that are completely standard of care for paediatrics that have no licensed indication for paediatrics… We're always piggybacking and trying to alter an adult solution to an adult problem to suit our needs.” (HEA4)
Many identified access disparities issuing from weak governance and system fragmentation. The challenge of balancing access to medicines with sound and legitimate resource stewardship was felt to be particularly susceptible to the vagaries of a fractured political system. Participants identified these fractures at all levels of the health system, and across various sectors with bearing on drug policy and governance. The perceived result was disparity in drug access for children by geography, disease, and socioeconomic status, as well as relative disparity as compared to adults:“The payers know what's happening on their level, the pharma [companies] know what's happening on their level, and the patients know what's happening on their level – but no one actually really understands what's happening in each other's worlds.” (PRO2)
The corollary need for better harmonization of drug funding policy among system players was emphasized by a number of participants. In addition to cross-institutional policy coherence and broad stakeholder buy-in, one of the most salient benefits of such harmonization was felt to be integration of the component parts of drug policy – along the continuum from development and production to licensing and funding. Importantly, select stakeholders argued that the goal of rationalized system structure and governance need not preclude varied policy choices along provincial lines. Indeed, a few contended that differing provincial contexts necessitated jurisdictional autonomy on drug coverage decisions:“The other challenge in the paediatric context for when we get that drug in, expensive or not, that drug still has to be funded out of the institution's global budget. There's no unique funding envelope for these types of agents for children.” (HEA3)
Provincial budgetary priorities notwithstanding, the vast majority of participants detected opportunities to improve the ways that drug policy for children is made and implemented in Canada. They collectively described a role for enhanced system stewardship at the federal level, to knit together the invested stakeholders and the component part of drug access over which they have influence.“Why is everyone looking for even-Steven? Equity doesn’t mean equal, right?...If BC needs to make a decision that addresses the needs of BC's population, in the context of the budget that they have and the means and the resources – if that's our federated model – then BC should have the right do that.” (POL5)
Politics
As a corrective to this natural state of political disempowerment, cause-specific advocacy was felt to play a critical role in marshalling attention to drug access barriers faced by children and pressing for political solutions. A range of stakeholders spoke to the increasingly vocal and impactful role played by patients and their families in advocating to government for enhanced access to child health technologies:“Right now kids aren't figuring, aren't in the picture… because relative to adults there's so few of them getting sick. They don’t run lobby groups, they don't vote, they don't make contributions to political parties, so they really don't have a voice.” (HEA1)
Participants pointed to the HTA-to-policy trajectory a key nidus for such advocacy. They identified a set of conditions susceptible to influence by advocacy groups, both for better and for worse, at distinct points along this trajectory. At the stage of HTA reviews, participants noted structured points for patient and family input into drug reviews, and associated opportunities to enrich the social values tranche of HTA. Importantly, a range of stakeholders was skeptical of the value of this input in its current form, noting that the perspectives given voice are typically narrow and biased:“[Patients] are a much more powerful lobby than they were 10, 15, 20 years ago. And so they're driving the bus, a little bit. They're not sitting at the back of the bus any more, they're sitting right behind the driver. And I think that's going to change the way that policy is developed.” (HEA2)
At the stage of HTA uptake into policy, stakeholders pointed to a number of opportunities for influence by advocates. They recognized that governments lack meaningful knowledge about drug access issues for children, that stories related to child drug funding are often hot-button, and that opportunities exist to leverage the political optics of such stories in favour of children’s interests. Conversely, a few of those interviewed noted that the logic of re-election cycles often serves as a disincentive to investment in priorities with delayed or long-term returns. As the most compelling arguments to fund childhood health interventions, including drugs, often centre on their life-course impacts, a number of participants were less sanguine about political commitment to child drug funding in the face of high upfront costs:“[Patient advocacy groups] inevitably have almost irreparable conflicts of interest, because they're usually funded by the manufacturer of whatever thing we're reviewing. Their ability to elicit the values of their entire community is not good, it tends to be small numbers of particularly vocal patients.” (PRO4)
In recognition of the parochial and highly politicized nature of many current advocacy endeavours, a few participants suggested creative means to improve advocacy to better align individual patient and societal goals. A focus on teaching and promoting ‘advocacy for the cause’ – as opposed to advocacy to advance access to discrete technologies – was a notable example:“It's hard to make the case to government to make decisions that will be financially fruitful many years down the road. We're saying invest in kids now because they're going to cost more if you don't later on. But they might not be in power later on.” (HEA5)
Stakeholders also emphasized the role of the media in influencing governmental decision-making on paediatric drug funding, including the manner in which HTA recommendations are handled. They identified media impact on public perceptions about drug access for children, and cited examples of ‘public pressure’ influence on political decisions about specific drug coverage. Many saw these dynamics as detrimental to both HTA institutions and collective societal interests, in their circumvention of transparent, dispassionate processes for technology evaluation and resource stewardship:“When I say advocating for the cause it’s advocating because we need to change the regulations. We've done it drug by drug, but taking the generic case to the government really hasn't been done adequately… ” (PAR4)
Such reactive governance was juxtaposed with the careful, laborious, and resource-intensive process of HTA to demonstrate the bounded role for scientific evidence in the public domain, and to emphasize the importance of colloquial evidence and political calculation in ultimate coverage recommendations. In light of this, various stakeholders affirmed the need for an explicit and reliable process for adjudicating the value of child health technologies – one that not only leverages the transparent and deliberative approach of existing national HTA reviews, but incorporates a child-specific evaluation framework into its assessments.“The things [for which] the government tends to override our decisions, I've found anecdotally, are generally things we recommend not to list that they end up listing because of public pressure.” (PRO1)
Discussion
Domain | Sample Problem | Potential Solutions |
---|---|---|
HTA Paradigms | ||
Assembly | Priority-setting: • Manufacturer-driven process, minimal incentive for paediatric submissions | Transition from ‘push’ to ‘pull’ system for technology assembly: • National priority-setting framework • Resources for public sector-initiated HTA submissions • Patient/public engagement on social values to guide priority-setting |
Assessment | Evidence appraisal: • Structural barriers to RCT-level evidence in paediatrics | Innovative trial design and evidence appraisal: • Basket trials, n-of-1 trials • Real-world evidence and performance-based funding mechanisms • Child health expertise in HTA bodies |
Economic evaluation: • Weak incorporation of child-specific considerations (developmental trajectory, preference elicitation) in pharmacoeconomic models | Advancement of science on child health economic evaluation: • Child-centred preference elicitation, family utility generation • Research on public preferences for resource allocation to children, including inquiry into life-course QALY weights | |
Integration | • Poor integration across phases and sectors involved in drug regulation and reimbursement | • Adaptive pathways approach to drug development, market access, and iterative evidence appraisal • Ring-fenced funding for paediatric drugs and health technologies • Engagement with child health experts throughout drug life-cycle |
Sociopolitical Context | ||
Markets | • Weak industry incentives for paediatric drug development and licensing | • Federal regulatory mechanisms to incentivize/compel development and submission of paediatric clinical data • Public funding to subsidize novel drug trials in children |
Governance | • Lack of formal paediatric indications, widespread off-label prescribing • Vertical and horizontal system fragmentation | • Dedicated paediatric expertise and resources within federal regulator and HTA bodies • Improved system integration along pharmaceutical value chain • National framework for drug regulation and funding for children to drive policy harmonization |
Politics | • Weak political voice for children • Politically charged funding environment | • Enhanced receptors for child and family perspectives in drug regulation and funding decisions • Child-specific HTA framework to drive transparency and legitimacy in paediatric technology assessments, and mitigate potential for politically motivated drug funding decisions |