Pediatr Drugs (2015) 17:91–95 DOI 10.1007/s40272-014-0111-3

REVIEW ARTICLE

Ethical Perspectives on Translational Pharmacogenetic Research Involving Children Parvaz Madadi

Published online: 11 December 2014 Ó Springer International Publishing Switzerland 2014

Abstract Children represent a special population characterized by dynamic changes which may affect drug safety and efficacy. The interplay of pharmacogenetics with physiological alterations that occur throughout development is an area of increasing research focus. Given the translational nature of pharmacogenetic research, it is possible that pharmacogenetic research results may possess clinically actionable information. The potential long-term implications of pharmacogenetic test results throughout the lifespan of the child, and the potential impact of the results for other members of the family need to be considered. Comprehensive counselling and communication strategies may need to be integrated as part of pharmacogenetic research studies in children.

Key Points Establishing the clinical significance of pharmacogenetic results generated as part of research studies in children may be challenging. Pharmacogenetic test results can have implications for future medications prescribed outside of the childhood research setting. Effective counselling strategies need to be employed when communicating pharmacogenetic results to children and families. This article is part of the topical collection on Ethics of Pediatric Drug Research. P. Madadi (&) Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, 555 University Avenue, Toronto M5G 1X8, Canada e-mail: [email protected]

1 Introduction Pharmacogenetic research aims to utilize genetic information in order to optimize drug safety and response. Although an individual’s genotype will remain constant throughout the course of his or her life, the interpretation of that genotype (i.e. phenotype) may change over time. In pharmacogenetics, the genotype of interest may predict the actions of enzymes, transporters, or receptors that are involved in the action and disposition of xenobiotics in the body. Yet developmental changes occurring during dynamic life stages, such as pregnancy and childhood, can in themselves mediate the pharmacokinetics and pharmacodynamics of a given medication. Therefore, pharmacogenetic research discoveries in adults cannot be extrapolated to pregnant women or children without an understanding of the interplay of pharmacogenetics with the various facets of development. There are now several institutions with a strong existing competency in translational pharmacogenetic research and discovery that are beginning to incorporate pharmacogenetics into clinical care [1–3]. Cincinnati Children’s Hospital, for example, has established a Genetic Pharmacology Service for both children and adults as part of its Clinical Laboratory Improvement Amendments (CLIA)-approved Molecular Genetics Laboratory [4, 5]. At St. Jude’s Hospital, a pharmacist-managed paediatric clinical pharmacogenetics service was established in 2009, and included the creation of automated clinical-decision-support system rules to facilitate application of pharmacogenetic information [1]. St. Jude’s has also recently initiated a new study with the goal to migrate array-based pharmacogenetic tests from the research laboratory into routine patient care, and to make the results available to prescribers pre-

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emptively [2]. These new developments have been fuelled by drug label changes and recommendations to consider pharmacogenetic testing in patients [6], widespread educational initiatives aimed to improve pharmacogenetic literacy in health care professionals, large scale foundational grants and philanthropist donations which aim to make personalized medicine a reality, and ethical considerations concerning the right for patients and research participants to know and utilize their genetic results, if desired [7]. The increasingly ‘blurring line’ between pharmacogenetic research as a discovery process and pharmacogenetic research as a clinical care optimization process presents a unique set of ethical considerations in this field. The objective of this manuscript is to discuss these ethical issues, including the return of pharmacogenetic research results and a framework for the communication of study findings, as it pertains to translational pharmacogenetic research in children.

2 Returning Pharmacogenetic Research Results in Paediatric Studies It is well-known that developmental changes in body size and organ function may affect drug pharmacokinetics and pharmacodynamics of medications. How pharmacogenomics interplays with developmental and aging factors has been the subject of investigation over the past decade. For the medication codeine, for example, it has been demonstrated that neonates and toddlers are particularly sensitive to the central nervous system depressive effects of this medication and may experience more severe pharmacogenetically based adverse drug reactions as compared with adults [8, 9]. In the case of warfarin, it has been determined that pharmacogenetic-based warfarin dosing algorithms in adults consistently overestimate the warfarin dose required for children [10]. Currently, numerous academic paediatric centres in North America are studying paediatric pharmacogenetic profiles, drafting clinical guidelines, and offering clinical services to optimize the use of various medications in children. Across this translational spectrum, it has been argued that the boundaries between research and clinical care are important to define, particularly as they pertain to the communication of clinically actionable pharmacogenetic research findings and the legal responsibilities associated with patient care [11]. One principle acknowledges that ‘‘standards for return practices in the research setting should not be driven purely by clinical standards’’, given the differences in the goals and procedures of research (i.e. to generate knowledge) as compared with the standards of clinical practice (i.e. to treat the patient) [11]. Internationally, there is a general consensus that (pharmaco)genetic

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research results should be communicated to individuals provided the research participant wants to receive this information and that the results are valid, actionable, and clinically significant [7, 11, 12]. Yet there is much controversy in the field of pharmacogenetics as to the evidence threshold needed to establish the clinical utility and validity of pharmacogenetic research discoveries [13–16]. Moreover, for researchers to prospectively determine whether pharmacogenetic research results generated from their particular study are valid and clinically actionable is difficult, particularly in understudied populations such as children. As such, establishing the therapeutic benefit of research findings prior to communicating individual pharmacogenetic research results is not a straightforward task. With the continuously decreasing cost of genomic sequencing, choosing the appropriate platform for pharmacogenomic research studies is a multifaceted issue. On one hand, targeted genetic testing is most manageable in terms of data analysis, translation, counselling, and keeping abreast of the latest knowledge on the issue. Conversely, a more wide-scale genome testing approach can be cost effective, and may offer prospective and preventative knowledge that may or may not be readily implementable. Conducting such genomic research studies in children adds another layer of complexity to the issue of returning individual research results, as ‘the child’s best interest’ needs to be considered [12]. While guidance documents pertaining to pharmacogenetic research are lacking, international recommendations have been formulated for sharing results from whole genome screening research in children [12]. Particularly controversial from this set of recommendations is whether adult-onset findings should be offered to paediatric research participants [11, 17]. The P3G International Paediatrics Platform recommends that such findings should generally not be returned, in order to allow the child to make his or her own decisions about receiving the results as an adult [12]. On the other hand, the American College of Medical Genetics position paper in 2013 concluded that these results should be returned to the family in a clinical setting, as the prevention of potential harm to the transmitting parent and other family members would be a benefit to the child [17, 18]. As it pertains to pharmacogenetics, genetic study results may indicate that a child may be at risk for an adverse drug reaction with a particular medication. However, that medication may not be indicated for children and/or may not be currently prescribed to the child (i.e. not readily actionable). Currently, there is no guidance for researchers as to whether they have an obligation to disclose such findings. Furthermore, there is little guidance available on the feasibility and duration of the researcher’s duty to disclose these results at a future date, and/or the optimal method for this communication. One set of consensus

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recommendations, which is not specific to paediatric research, suggests that it is most reasonable for investigators to offer to disclose genomic results within the period of study funding [11]. For pharmacogenetic research findings that may be clinically actionable at a prospective time, the approach of directly incorporating the study result into an electronic medical record system is one that is being utilized by several academic research centres [1, 5, 19, 20]. At St. Jude’s Hospital, Cincinnati Children’s Hospital, and the University of Chicago Medical Center, pharmacogenetic results are incorporated into the hospital electronic medical system. When the prescriber orders a medication for a patient who has been determined to have a high-risk genotype, a warning message appears, to remind the physician of higher than normal risks of adverse events for the patient [1, 3, 5].

3 Communicating Pharmacogenetic Research Findings to Families Another important consideration when conducting pharmacogenetic research in children is the concept of a tripartite relationship between the child, parent(s) and researcher [21]. While there is an ethical duty on the part of researchers and parents to act in the best interest of the child, to respect the autonomy of the child, and to ensure that their right to an open future has not been infringed, parental decisions may potentially infringe on a child’s future right to self-determination. For example, parents may be more willing to enrol their children in research studies that may reveal potentially life-threatening inherited conditions than to enrol themselves in such studies [21, 22]. It is therefore important that researchers and participants fully explore the potential implications of study findings for an entire family during the consenting process. While such considerations have been relatively wellestablished in adult genetic research paradigms investigating serious inherited diseases, these parameters are often not incorporated as part of pharmacogenetic research programmes in general, let alone in research in which the study participant is a child. This may be partially attributed to the notion that pharmacogenetic testing is less impactful for an individual than testing for genetic disorders because of the underlying objective of the testing in the first place. Yet there are instances in which pharmacogenetic test results may reveal an individual’s propensity for a potentially life-threatening adverse drug reaction, such as carbamazepine-induced Steven Johnson’s syndrome. In the case of one family in which the death of an infant son was related in part to a pharmacogenetic test result, extended family members and subsequent children all underwent pharmacogenetic testing and counselling [23].

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As a general framework for communicating pharmacogenetic research results to study subjects, it has been suggested that three types of information need to be discussed in order to facilitate comprehension while minimizing potential psychological/behavioural harm: (1) description of the actual test result, (2) significance of the result for medications that the participant is currently being prescribed, and (3) a discussion that the results may also be important for future medications that the patient may receive [24, 25]. In children, an additional consideration may include the notion that the significance of a pharmacogenetic finding may change over the course of maturity and development. Specialized counselling services should also be considered for pharmacogenetic studies involving pregnant women, who may be motivated to participate in research to inform medication decisions for current and future pregnancies [26, 27]. Although pharmacogenetic studies may focus on maternal drug safety and efficacy, foetal safety, including teratogenic risk, will also need to be discussed, especially as teratogenic risk perception related to medications may be unrealistically high in some pregnant women [28]. Currently, little is known about the impact that the communication of pharmacogenetic research results has on health care decision making and parental perceptions of medication risks in children. Given the dynamic and multi-factorial components that may contribute to drug safety and efficacy throughout an individual’s lifetime and the differing impact of results for different medications prescribed over time, the question of who is ideally suited to communicate pharmacogenetic research information and what support infrastructures are in place to facilitate the long-term implications of study findings as a child transitions throughout the health care system has not been delineated. Moreover, given the massive amount of genetic data that is being generated and studied, (pharmaco)genetic findings are being interpreted and re-interpreted within a rapidly changing knowledge base [29]. This changing context of study findings raises potential obligations on the part of researchers to keep abreast of relevant findings and potentially re-contact study participants who may be affected by new information [29]. On the other hand, it has been suggested that investigators should not be obligated to search for actionable genomic variants beyond those identified in the course of their research [11], and that the consenting process should clarify the circumstances in which participants might be contacted in the future, and whether the participants consent to contact if new findings are found [11]. Outside of academic research laboratories, only a few institutions offer accredited clinical pharmacogenetic testing services, and as such, there may be considerable cost and lack of follow-up resources for research participants and families to receive the support that they need. Research

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participants may also turn to primary health care providers for guidance on pharmacogenetic study results. They may also have expectations that these results will be used for current or future medical decisions. However, while patients and the public expect a high level of information and effective communication from their health care professionals in the area of pharmacogenetics and adverse drug reactions [30–32], a gap exists between patients’ expectations and health care professionals’ knowledge in this field [31, 33–35].

4 Conclusion There is an emerging need for the development of pharmacogenetic counselling and communication expertise across the health care profession. Despite the prevalence of pharmacogenetic research studies in children, little is known on how the disclosure of pharmacogenetic information may affect parental perceptions of medication risk and future health care decisions for the child. How to communicate pharmacogenetic research findings in a manner that will minimize potential harms has not been well-delineated when it comes to pharmacogenetic research studies involving children. Conflict of interest I have no conflicts of interest to disclose. There was no funding received for this work.

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Ethical perspectives on translational pharmacogenetic research involving children.

Children represent a special population characterized by dynamic changes which may affect drug safety and efficacy. The interplay of pharmacogenetics ...
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