Public drug policy for children in Canada

System limitations

Canadian processes for appraising health technologies do not take into account the unique characteristics of children and the scientific evidence pertaining to drug indications and utilization in this population. Data concerning new drugs being brought to market are first submitted to Health Canada for approval of safety and efficacy to permit sale in Canada. Once approved, provided consideration for public funding is desired, a submission is made to the national-level health technology assessment organization, the Canadian Agency for Drugs and Technologies in Health (CADTH), which “reviews drugs and makes reimbursement recommendations to Canada’s federal, provincial, and territorial public drug plans, with the exception of Quebec, to guide their drug funding decisions.”6 Some provinces perform a provincial review, often resulting in different coverage across the country (Figure 1).7

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Figure 1:

Drug approval and funding process in Canada (except in Quebec). Note: CADTH = Canadian Agency for Drugs and Technologies in Health, CDEC = Canadian Drug Expert Committee, CDR = common drug review, DIN = drug identification number, HTA = health techology assessment, NCE = new chemical entity, NOC = notice of compliance — approval of drug safety and efficacy, pCODR = pan-Canadian Oncology Drug Review, pERC = pCODR Expert Review Committee.

Evaluation of a novel drug by either national or provincial committees for a pediatric indication is uncommon; typically, funding recommendations are based on adult indications. This is predominantly due to the industry-driven submission process: in most cases, drug licensing and funding submissions are made by manufacturers or by contract research organizations on their behalf.

The lack of attention to child health technology assessment is partly a consequence of market dynamics. Children typically represent a small fraction of the potential market for a given drug. These limited markets are further fragmented by unique disease biology and special formulation requirements for children. More complex still, some drugs have a similar indication across age groups, albeit with varying evidence of efficacy; others have entirely different disease indications in adults and children; and still others are indicated for use in children only.8 These factors deter industry from generating evidence on the safety and efficacy of novel therapies in children, and by corollary, the submission of cost-effectiveness evidence of such therapies for pediatric health technology assessment review.

Canada lags behind the United States and Europe in regulatory provisions related to pediatric drug development. These jurisdictions have legislated both carrot-and-stick mechanisms to induce drug companies to study and market pediatric indications for their drugs.9 These mechanisms involve, on the one hand, governmental perogative to mandate pediatric studies, and, on the other, the extension of market exclusivity in exchange for the conduct of such studies. The lack of comparable provisions in Canada has abetted a sizable gap in the submission of pediatric trial data to Health Canada compared with the US Food and Drug Administration.8

Compounding the problem posed by new drugs, most existing drugs lack approved pediatric indications, making off-label prescribing the norm rather than the exception.10 There are no routine mechanisms to incentivize or compel the review of drugs already on the market for adult indications for extending public funding recommendations to relevant pediatric indications. Although permitted by CADTH, submissions by providers or patient groups for either new or existing drugs are uncommon, in large part because of the demands of such submissions, which require the compilation and analysis of detailed clinical and pharmacoeconomic evidence.

Finally, in an environment with limited institutional and financial resources, setting priorities on which drugs undergo health technology assessment review determines which drugs get publicly funded. Again, such processes often disadvantage children: some of the most prevalent principles employed to prioritize therapies for review — including disease burden, economic impact, strength of evidence and expected level of interest — are at odds with the epidemiologic and evidentiary realities of childhood diseases.11

Methodologic limitations

There are conceptual challenges to applying health technology assessment to child health that are distinct from the system-level challenges to child-focussed drug reviews. The adjudication of drugs and other health technologies for public coverage in Canada and abroad is premised on three major domains: evidence of safety and clinical effectiveness, value for money and ethics. The relative weight afforded the items within each domain, and the manner in which they are integrated, vary across jurisdictions; however, the overall parameters of assessment are similar.12 In most instances, the normative assumptions present in these domains introduce bias against positive funding recommendations for children.

Evidence-based medicine ranks methods of inquiry by their susceptibility to bias; systematic reviews and meta-analyses of data from randomized clinical trials (RCTs) are considered the most important.13 There is strong epistemological justification for this approach in most adult disease, but it is not useful for pediatrics. Clinical trials in children are constrained by small populations, and further reduced in the age of genomic classification of disease nosology, the complexities of trial enrolment of children and weak industry interest in pediatric drug development.14^,15 Although the child health community has worked hard to overcome these barriers through collaborative research agendas, destigmatization of pediatric research and advocacy in support of legislative reforms to regulatory environments for drug development,16 health technology assessment reviews of drugs for pediatric indications are often non-starters owing to a lack of acceptable high-quaIity evidence.

Standard methods for economic evaluation in health technology assessment also do not capture distinguishing features of child health and illness.17 Principal among these is a lack of sensitivity to life-course dynamics. Lack of data prohibits incorporation of recommended outcome metrics, such as quality-adjusted life years (QALYs), into models that assess the aggregate benefits and burdens of a given treatment over a lifetime.18 This is shown in the current proliferation of novel biologic and immunomodulatory therapies: there is little knowledge of the developmental and late effects of many new drugs that are brought to market, which complicates efforts to accurately assign long-term benefits and costs associated with their use in children. In addition, there are few child-specific, preference-based measures of quality of life, which compromises the calculation of QALYs for use in cost–utility analyses that form the backbone of health technology assessment.

The instruments developed to elicit health-state utilities in children often rely on parental proxies for young children. There is also almost no systematic incorporation — either in theory or in practice — of the economic impacts of a child’s illness and treatment on the family.19 Dependency is a critical component of virtually all childhood experience of illness that is almost never captured in pharmacoeconomic models. The current Guidelines for the Economic Evaluation of Health Technologies from CADTH do not acknowledge these issues. The absence of data is viewed as a form of uncertainty to be handled through probabilistic analysis or consultation with experts.20

Ethical dilemmas are bound up in these approaches to evidence generation and economic modelling. The value of a year at any given point along a life path is commonly assumed to be constant: a QALY gained at age 2 years is routinely deemed equivalent to a QALY gained at 72 years of age.21^,22 The moral legitimacy of this calculus may differ across societies.23 Indeed, many societies may value health gains in children more highly than in adults for many reasons: the social and economic costs of squandered potential; a belief in “fair innings,” or the value of comparable opportunities to experience life; and the intrinsic value placed on childhood itself.24^–27 Social values may also dictate a preference to allocate scarce resources to those who are more vulnerable.28 Children are vulnerable in multiple ways: they may incur intergenerational socioeconomic disparity, they cannot advocate for themselves, and they are usually sociopolitically disenfranchised. These dynamics have equity implications for the systems constructed to conduct such drug appraisals. These systems must include the unique social values that are involved in drug appraisal and funding for children.

Conclusion

Regulatory and health technology assessment systems in Canada give little regard to the unique features of child health. This has abetted an ad hoc approach to public funding decisions for pediatric drugs. Canada must create an integrated public policy framework on decision-making for drug regulation for children that is adequately funded. This will require the development and application of a coherent set of standards for appraising child health technologies, national stewardship to facilitate partnerships among key stakeholders and provincial coordination in the adoption of pan-Canadian funding recommendations.