Urgent call for guidance supporting gene-based drug dosing in children and adolescents

Abstract

In the past decade, there have been tremendous advancements in the field of genomics that have led to significant progress in redefining the concept of precision medicine. Pharmacogenetics (PGx) is one of the most promising areas of precision medicine and is the ‘low hanging fruit’ of this individualized approach to medication dosing and selection. Although a variety of regulatory health agencies and professional consortia have established PGx clinical practice guidelines, implementation has been slow given numerous barriers faced by health care professionals. Many lack the training needed to interpret PGx and there are no paediatric specific guidelines. As the field of PGx continues to grow, an emphasis on collaborative inter-professional education, coupled with ongoing efforts to increase accessibility to advancing testing technology are necessary to translate this branch of precision medicine from the bench to the bedside.

Pharmacogenetics (PGx) is an emerging field of precision medicine that can transform care by analyzing genetic variants that predict responses to various medications. The use of genetic information has played a major role in the development of the concept of precision medicine allowing the shift from a one-size-fits-all approach, to delivering health care that is tailored to each patient's unique characteristics. As the ‘low hanging fruit’ of precision medicine, PGx analyses allows for the identification of patients who are likely to respond to certain medications, as well as those in whom there is a high probability of developing severe adverse drug reactions (ADRs) or potentially life-threatening toxicity (1). Many medications prescribed by paediatricians are included in drug–gene guidelines outlining specific actions to be taken if certain genetic variation is found (2). For example, variants in the CYP2C19 metabolizer gene are of particular interest as this enzyme is chiefly responsible for the breakdown of proton pump inhibitors and selective serotonin reuptake inhibitors, as well as the activation of clopidogrel (2). Differences in enzyme activity may contribute to therapeutic failure or ADRs, thus this individualized approach to medication selection and dosing can result in substantial changes to patient care. Genetic testing options have become more widely available and less costly over recent years. Despite this, the routine use of PGx in clinical care has been slowed by several barriers, including lack of government funding for implementation and the need for educational and decision-making support to effectively integrate results into practice.

Over the last decade, a variety of regulatory health agencies and professional consortia including the Clinical Pharmacogenetics Implementation Consortium (CPIC) have worked to provide updated evidence-based, peer-reviewed guidelines to support the implementation of PGx and address barriers hindering its utilization (2). Genetic determinants contributing to variability in medication responses are also recognized by the FDA and Health Canada, and the labels on more than 400 medications now carry warnings about PGx variants associated with deviation from standard medication regimens to prevent ADRs or treatment failure (3).

While most PGx guidelines target the adult population, there are paediatric specific recommendations. Despite this, there is limited data on the utility of PGx information to guide paediatric care outside of large academic centres. The Canadian Paediatric Society has recently released a position statement addressing this knowledge gap, outlining the urgent call for paediatric specific guidance on gene-based drug dosing. The statement’s respective recommendations highlight the growing need to improve medication safety for children and adolescents using a gene-based approach, while ensuring health care professionals, such as paediatricians and pharmacists, stay up to date with this rapidly evolving field.

Increased knowledge about PGx guidance in paediatrics has led to the creation of paediatric specific PGx knowledge bases, such as PharmGKB Paediatric (https://pediatric.pharmgkb.org/). This has further created an opportunity to explore inter-individual variability in medication responses in the paediatric population. Although this precision medicine approach promises improved medication safety for children and adolescents, health care professionals are faced with many challenges in clinical implementation. This is due in part by a lack of training in how to interpret PGx test results. A 2022 survey of Canadian paediatric psychiatrists and paediatricians showed that although respondents agreed PGx testing has the potential to reduce the risk of ADRs, nearly half of those surveyed reported low familiarity with PGx or were not aware that integrational PGx guidelines are available (4). Moreover, parents are overall very receptive to PGx testing when implications are thoroughly explained, with a major concern being that their physicians may not know how to interpret results (5). Health care professionals need access to high-quality interprofessional education and resources about PGx to close the gap between research and clinical care (6). This can be achieved through continuing professional development via professional societies, or workplace education opportunities that are hosted by subject matter experts. Ensuring that PGx test results are evident to clinicians long after the test was run is also a significant challenge. Integration of genomic data into the electronic health record (EHR) ensures high visibility, maximizes the usage and facilitates long-term future use of this data. It is essential that the inclusion of PGx data in the EHR is supported by best practice alerts. These informatics tools are valuable resources to guide health care professionals toward the proper utilization of PGx within their clinical practice. A major barrier is that PGx testing is not currently funded by provincial health care plans, and financial coverage is significantly variable among private health insurance companies (7). As a result, access to testing is generally limited to pilot programs in large academic centres or is restricted to indications such as TPMT genotyping in paediatric childhood acute lymphoblastic leukemia, although not routinely practiced in all Canadian provinces (8).

A position statement issued by the Canadian Paediatric Society calls for the radical expansion of access to timely and clinically validated PGx testing for children and adolescents. Given that a variety of medications are prescribed across all paediatric specialities and patients with chronic medical conditions often require treatment with multiple medications, monitoring the efficacy and safety of prescribed medications is of great priority (9). PGx results will often change clinical practice given that 95% of the population is estimated to carry one or more genetic variant that would warrant deviation from standard dosing guidelines (10). A 2021 study in a limited paediatric population has supported this data, showing 40% of patients who received point-of-care testing for targeted medications received PGx test results suggesting deviation from standard treatment regimens (11). Additionally, 80% of patients who underwent pre-emptive PGx testing for a broader range of medications benefited from this proactive approach to guide potential future therapy (11). These results emphasize how enhanced knowledge of a patient’s PGx profile can support decision-making and informed rationales for medication selection and dosing.

As we are entering an era of precision medicine, this position statement demonstrates potential to collaborate with health agencies to leverage current regulatory systems to fit within a precision medicine framework. In Canada, paediatric patients are currently underserved by drug approval regulations in that numerous medications prescribed to children are used off label without an age-appropriate formulation (12). As Health Canada’s Regulatory Review of Drugs and Devices (R2D2) initiative is underway, this is an opportune time to focus on gene-based drug dosing within this vulnerable population. Under this initiative, increased collaboration is being called upon between organizations that play a role in medication access within Canada to improve the efficiency of their regulatory systems. To date, there are 14 projects under the R2D2 initiative, all of which intend on improving access to medications. The field of PGx presents as a powerful opportunity to leverage the current R2D2 initiative toward reform that includes gene-based drug dosing as part of a regulatory framework for paediatric medications in Canada.

In additional efforts to promote the movement toward precision medicine, direct to consumer genetic testing services have presented themselves as an opportunity to provide patients with a wide range of personal genetic data, including PGx (13). These services have played a significant role in increasing awareness around genetics and serve as a tool to empower individuals in gaining insights about their health and ancestry through genetic data. One set back regarding direct-to-consumer PGx testing lies in the lack of a regulatory entity that monitors testing and guides data dissemination. Although published drug–gene associations exist, not all have been translated into clinical recommendations by professional entities due to lack of clinical evidence. Therefore, the evidence that links genetic variants to functional outcomes, and the clinical utility of genotypes for specific genes, varies dramatically from test to test (13). With an absence of high level regulation on clinical PGx practices, instances of conflicting guidelines and recommendations may occur resulting in data that cannot be accurately applied in a clinical setting to guide patient care. Although much potential lies ahead, genomics, ancestry and medicine are inextricably connected within a fraught history.

Clinical decision-making must be approached through an inclusive and equitable lens to ensure that all communities are able to benefit from this science. There is increased scrutiny around race-based diagnosis and treatment as it reflects flawed social, biological, and genetic assumptions (14). These flawed assumptions disproportionately affect minorities and vulnerable groups, causing disparities in access to both health care and educational resources among the Canadian population. PGx testing programs that are limited to large academic centres are largely left inaccessible, further impeding widely available testing opportunities. On a clinical scale, PGx results often invoke ethnic background as variation in genetic ancestry may elucidate differences in therapeutic efficacy for commonly used medications (14). PGx decision-making should be addressed in the context of an ethnically heterogenous population to warrant diversity and inclusion across genomic research efforts. Leading genomic research efforts in diverse populations is also critical in ensuring that genomic advancements do not exacerbate health disparities by fostering discoveries that will solely benefit more well-represented groups (15). In order for PGx to lead to meaningful clinical outcomes, the science must connect closely to equitable, barrier-free efforts to allow for the translation from bench to bedside.

FUNDING

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POTENTIAL CONFLICTS OF INTEREST

All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.