Pediatr Drugs (2015) 17:55–59 DOI 10.1007/s40272-014-0114-0

CURRENT OPINION

Ethics of Pharmacological Research Involving Adolescents Eva Welisch • Luis A. Altamirano-Diaz

Published online: 19 December 2014 Ó Springer International Publishing Switzerland 2014

Abstract Pharmacological research in the adolescent population is not meeting adolescents’ needs. Medication is still frequently prescribed off label, and studies especially in sensitive areas of adolescent health care are underrepresented. Adolescents did not benefit from the new knowledge gained in cancer research, and their outcome has essentially not improved during the last two decades in comparison to younger children and adults. There are many obstacles that make it challenging to enroll adolescents in pharmacological research. Access can be difficult. Confidentiality plays an essential role for minors and may be a hindrance, notably to studying sexual and mental health matters. Pharmaceutical companies may exclude the adolescent patient because of a lack of profit and in fear of a complex study design. Research concepts should be explained to the adolescent in a comprehensive manner, and assent and consent forms should be clear and understandable. New laws and incentives have been developed to encourage pharmaceutical companies to engage adolescents in their research projects. Centralization and collaboration of all parties involved may make the whole approach to adolescent research more efficient and uniform. The mature minor doctrine has facilitated the enrollment process. Parental consent may be waived for low-risk medical trials to promote recruitment. Ethics

This article is part of the topical collection on Ethics of Pediatric Drug Research. E. Welisch (&)  L. A. Altamirano-Diaz Department of Pediatric Cardiology, Western University, LHSC, 800 Commissioners Rd. E, London, ON N6A 5W9, Canada e-mail: [email protected] L. A. Altamirano-Diaz e-mail: [email protected]

committees therefore play a major role in protecting the adolescent from harm from participating in research. In conclusion, pharmacological research in adolescents has to be encouraged. This will increase the safety of current medical treatment regimens and will allow this population to benefit from therapeutic advancements.

Key Points There is a lack of pharmacological research in the adolescent population. Enrollment of adolescents is difficult due to limited access and confidentiality issues. The mature minor doctrine facilitates participation of adolescents. The consent process has to be comprehensive, clear and easy to understand. Collaboration between centers and disciplines may heighten the yield in adolescent research.

1 Introduction In the 1930s, stimulant medication trials were performed on institutionalized minors, bypassing parental permission and surveillance. Before and during World War II, medical crimes were committed that led to the Nuremberg Code as a consequence to protect patients from unethical research [1]. However, even in the 1950s and 1960s, young patients

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were enrolled in studies that were unsafe and dangerous. This culminated in regulations to protect minors from research that might potentially inflict harm. Thereafter, little pharmacological research has been done in young patients, who are often cited as ‘‘therapeutic orphans’’. As a result, adolescents and children have lower safety standards in drug therapy, and the majority of prescribed medications in young patients are used off label [2]. Off-label use is known to have a greater risk of adverse drug reaction [2]. Today, in 2014, still more than half of the medications approved for marketing by the US Food and Drug Administration (FDA) lack evidence of safe and effective use in young patients, according to the American Academy of Pediatrics [3]. There are also differences in pharmacokinetics and other factors (e.g., body mass index, diet, etc.) in adolescents compared with adults and children that have to be taken into account and require investigation [4]. The summary of a workshop of the National Institute of Child Health and Human Development (NICHH) stated in 2012 that there are still substantial gaps in knowledge about the ontogeny of drug metabolizing enzymes and transporters, and an incomplete understanding of age-based changes in gastrointestinal, liver and kidney physiology, and of agebased intestinal permeabilities [4]. Additionally, investigators face research protocol challenges, and vulnerable patient groups like adolescents are frequently excluded from research without clear justification and are therefore under-represented in the scientific literature [5]. There are many hurdles in performing pharmacological research in young patients, including access to the study population, a possibly complex study design, required consent from parents and the adolescent, as well as often limited profit for the pharmaceutical company, which may not be keen on conducting research for a potentially limited number of ‘‘consumers’’ [6]. Research concepts are difficult for adolescents to understand, as pointed out in a recent study from 2011, and therapeutic misconception has been observed where the adolescent does not recognize that the primary purpose of clinical research is not patient-centered care but improving general knowledge [7]. Sensitive areas of adolescent health, like sexual and mental health, are in need of further investigation and have been impeded by absolute requirements for parental consents, as confidentiality plays an important role to ensure that the patient will provide complete and honest information to their health care providers [8]. The prescription of psychopharmacological medication in adolescents is on the rise despite a lack of studies examining their effectiveness and safety for the developing brain [9, 10]. The rising diagnosis of bipolar disorder and attention deficit hyperactivity disorder (ADHD) has led to a steady increase in the use of psychotropic medication in children and

E. Welisch, L. A. Altamirano-Diaz

adolescents [11]. This dramatic rise preceded research in this area, and not vice versa. Yet it was the impact of research on practice that showed the lack of efficacy of some medications, such as tricyclics for depression and secretin for autism [12, 13]. There remains concern about the appropriate use of psychotropic medication and the possibility of ‘‘medicalizing’’ normal variants of human behavior, considering an apparent continuity between normalcy and psychopathology for conditions such as ADHD, depression and anxiety disorders [9]. Research with adolescent cancer patients is sparse, and patients aged 15–19 years have had less progress in survival prolongation compared with younger children, which may be due to lower clinical trial enrollment [14]. The Center for Disease Control and Prevention (CDC) convened a workgroup of researchers and health care providers in the field of adolescent and young adult oncology to examine the barriers and challenges limiting participation of adolescents in clinical trials. They found low referral rates of adolescent patients with cancer to pediatric cancer centers with expertise in that field, and limited availability of clinical trials in certain cancers. In addition, there were institutional barriers impeding collaboration between pediatric and adult oncologists on clinical trials. Psychosocial barriers were identified, such as non-adherence or the fear of losing control over her or his own body. Lack of insurance coverage appears to be another obstacle. Only 3 % of those who were uninsured or underinsured enrolled in clinical trials [14]. In the 1990s, several steps were undertaken to increase research performed in the young population. The US FDA, National Institutes of Health (NIH) and US Congress developed incentives, requirements and guidelines. As a result, the Pediatric Rule requires manufacturers of certain new drugs and biological products to conduct studies in order to provide adequate pediatric labeling [15]. A similar development has taken place in Europe. The initiative ‘‘Better Medicines for Children’’ in 2002 identified enormous needs in pediatric drugs research, and consequently led to the European Pediatric Regulation in 2007 to facilitate pediatric drug development by means of incentives for pharmaceutical companies [16]. In 2003, the Society of Adolescent Medicine (SAM) statement promoted the direction that young patients could be right bearers with greater authority over themselves [8]. They stated that for research of low risk, decision-making capacity of the adolescent can be assumed, and for research involving greater risk, an individual assessment of capacity should be performed. ‘‘The overall goal in clinical practice is to deliver appropriate high-quality health care to adolescent patients while encouraging communication between adolescents and parents or other trusted adults without betraying the adolescent’s trust in the health care professional’’ [8].

Ethics of Pharmacological Research Involving Adolescents

Consequently, the mature minor doctrine has been applied, which allows adolescents to enroll in research without parental permission. The mature minor doctrine is a legal principle that grants a minor the ability to make decisions about their health and welfare if they can show that they are mature enough to make a decision on their own. It was in 1992 that the West Virginia Supreme Court defined a ‘‘mature minor’’ exception to parental consent, ‘‘according consideration to seven factors to be weighed regarding such a minor. These include age, ability, experience, education, exhibited judgment, conduct, and appreciation of relevant risks and consequences’’ [17]. Recent research of brain development has raised concerns about the decision-making capacity of mature minors. New scientific data demonstrates that when adolescents make decisions, there is greater engagement of limbic structures with less engagement of the prefrontal cortical areas in comparison to adults, as demonstrated by brain imaging (functional magnetic resonance imaging) [18–20]. They point out the differences in adolescent and adult decision-making skills and stress the fact that risktaking behavior is much more prevalent in the adolescent patient. Since 2005, the United States Supreme Court has taken the position in several judicial decisions that the scientific evidence does not support the conclusion that children under 18 years of age possess adult capacities for personal agency, rationality, and mature choice [21]. A fine line exists between protecting vulnerable patients from potentially harmful research and leaving adolescents in a state of being ‘‘therapeutic orphans’’ [9].

2 Liberalizing Pharmacological Research in Adolescents: Balancing Benefits and Detriments Proponents of the liberalization of research in the adolescent population argue that restrictions to research in the adolescent population may leave this patient group in the state of being ‘‘therapeutic orphans,’’ and that they are denied the benefits of knowledge gained through research. This might apply especially to high-risk young people, such as homeless youth, IV drug users, or school truants, who will lose the opportunity to participate in minimal-risk research that might be of potential benefit [22]. ‘‘Only when doubly vulnerable groups receive the appropriate research attention are the standards of their care and their quality of life enhanced’’ [5]. Adolescents may be exposed to less risk by participating in a well-designed research protocol than when receiving standard medical treatment [23]. In studies with unclear direct benefit for the participant (e.g., placebo-controlled trials), minors may gain from the experience and knowledge that they have helped others [23, 24]. The developing organism can be particularly

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sensitive to drug toxicities, and drug safety cannot be assumed based exclusively on data from adults. Psychotropics might have long-lasting effects on the developing brain by interfering with still immature neurotransmitter systems [9]. Research is therefore required to enhance knowledge about safe application of psychotropics and other medication in young patients. Many adolescents will only participate in research of sensitive health domains if their confidentiality is maintained and parental consent can be waived [8]. Emancipated adolescents (e.g., those who are pregnant, living outside family support, or married) are an example that a part of the adolescent population is able to make major decisions for themselves. Involving female adolescents in a microbicide trial without parental consent may serve as a successful example. Microbicides may prevent the spread of HIV infection in unprotected sexually active minors at high risk of HIV acquisition. Participation of mature minors in the microbicide trial may avoid delaying access to an effective product by adolescents at high risk of HIV acquisition. Sixteen- to 17-year-old participants have been enrolled in phase III studies. There were no differences of risk behavior, adherence or follow-up compared with the 18- to 19-year-old participants [25]. The requirement for parental consent may introduce a selection bias and lower response rates to research participation [20]. Opponents on the other hand are concerned that there is a significant and growing body of empirical evidence that the adolescent and teenage brain is not yet fully developed in its cognitive and affective capacities [19, 21]. There are differing views of medical versus criminal law of the mature minor doctrine. The legal culpability of adolescents is viewed as being diminished secondary to fundamental differences between juvenile and adult minds and in parts of the brain involved in behavior control. There is a difference in self-control, impulsivity, emotionality and future orientation between adults and adolescents, and adolescent patients are less likely to adhere to medical regimens. Some authors therefore believe that the mature minor doctrine should only be used in minimal-risk research when ‘‘the probability of harm or discomfort from the research is not greater than that ordinarily encountered in daily life or the performance of routine examinations or tests’’ [22]. Adolescents were significantly more willing than parents to enroll in above-minimal-risk research. Concordant views of parents and adolescents on participation in research were only present about 60 % of the time [26]. Besides, there is a positive correlation between parental involvement and authority in adolescent lives, and their future academic and social success. Involvement of parents in consenting to research may therefore be beneficial [20]. Likewise, there is very limited guidance on assessing decision-making capacities. No adequate

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instrument for assessment is available to determine precisely who is a mature minor and what criteria an adolescent has to meet [20]. Minors are in the position of being particularly vulnerable to persuasion, adverse influence and harm [20]. Placebo-controlled trials are of special concern as the participating adolescent may be randomly treated with either placebo or the active compound. The patient receiving placebo may not receive standard of care while being enrolled in the study. This may lead to exacerbation of the underlying disease process and may cause harm [27].

be provided in a straightforward and honest manner, tailored to their needs and learning styles, while ensuring that all of their questions were answered [28]. A valid shared decision-making process with parents should be developed and implemented as per adolescents’ preferences [7]. Involving adolescents and families who have previously undergone enrollment and participated in clinical trials in the education process for new patients may be beneficial [14]. Confidentiality has to be guaranteed to the adolescent, bearing in mind its limits (e.g., suspected abuse, suicide, homicide, and so on).

3 Possible Strategies to Implement Safe and Meaningful Research

3.3 Overcoming Psychosocial Barriers

3.1 General Principles Research should be scientifically sound and should address key scientific questions. A risk–benefit analysis of participating in research should be established. Where appropriate, studies should have been conducted first on animals and adult humans, and conducting research with vulnerable individuals should only be undertaken when the researcher has determined that the risk to benefit ratio is low or when no other option exists [20]. Placebo use in clinical trials should be reserved to situations when alternative scientific designs like ‘‘add on’’ or ’’crossover’’ studies will not give sufficient answers [27]. The site of investigation should be experienced in performing studies in the adolescent population. Research should be designed to limit the number and volume of blood samples required [6]. This could be achieved by the utilization of population kinetics, new drug assay techniques from non-blood samples and new developments in analytical methodology. 3.2 Improving the Consent Process In adolescents, the consent and assent process should not be coercive or persuasive. The protocol design should be age appropriate without unrealistic restrictive inclusion/ exclusion criteria with regard to diet, the need to be off medication or unrealistic study requirements (during school time or on weekends) [23]. Suggestions from adolescents for a successful consent process in oncology trials have been analyzed [28]. Adolescents prefer obtaining more specific information about the trial, and they wanted more time for decision-making (e.g., providing information in advance, explaining the study multiple times and planning two meetings). They proposed using different methods to deliver information (e.g., audio and visual methods like graphs, figures, videos, DVDs) and stressed the importance of the physical environment (e.g., a comfortable space). Adolescents preferred that information should

The researcher should be aware of external factors that might limit participation, such as inaccessible research site, public transportation costs, and time. Monetary compensation should be considered. The uninsured adolescent may benefit from free treatment whilst being enrolled in a trial. Age-appropriate internet sites with information about research, and the usage of social media outlets (e.g., Facebook, Twitter, or YouTube) might be helpful [14]. Hard to reach populations may only be accessed if working together with informal gatekeepers such as key members of a support group, or an informal network of individuals with similar vulnerabilities [5]. 3.4 Increasing Collaboration and Centralizing the Process Research infrastructure for conducting clinical trials of medication in adolescents should be developed and extended, like networks, collaborations and partnerships, especially between pediatric and adult institutions. This may facilitate the referral of an adolescent to specialized centers that offer best care and conduct clinical trials [8]. Interdisciplinary collaborations should be developed that integrate expertise from different disciplines, such as genetics, brain imaging, preclinical and clinical pharmacology, clinical trial and services research to accomplish translation of (neuro)science discoveries into clinical applications. Centralization of institutional review boards (IRBs) processes (e.g., Central IRB) can make the approval procedure more uniform and may facilitate implementation [14]. 3.5 Simplification of the Regulation Process and Assurance of Adolescent Protection A risk-adapted approach by the supervisory agencies (e.g., FDA or European Medicines Agency) to the governance of clinical trials could reduce the regulatory burden. Adverse event monitoring could be modified in the light of available

Ethics of Pharmacological Research Involving Adolescents

safety data about the project. For example, low-risk trials that investigate off-label medications well established in clinical practice might need only minimal surveillance, whereas trials with markedly higher risk of not yet licensed products will require full regulatory and safety monitoring [29]. Ethics committees may allow adolescents to participate in minimal-risk research without parental consent and without formal mature minor assessment [22]. In research involving more than minimal risk, ethics committees have a central role in deciding the level of protection required and the necessary level of involvement of adolescents and their parents in providing consent to participate.

4 Conclusion Given the lack of pharmacological research in the adolescent population, safe and meaningful research has to be promoted. Research ethics committees have an important role to assure the safety of adolescent patients and their access to research, but ‘‘it is paramount that ethical issues unique to children are not forgotten and that children do not become a commodity in the clinical trial economy’’ [23]. Acknowledgments E. Welisch and L.A. Altamirano-Diaz declare no relevant conflicts of interest. No sources of funding were used to support the writing of this manuscript.

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Ethics of pharmacological research involving adolescents.

Pharmacological research in the adolescent population is not meeting adolescents' needs. Medication is still frequently prescribed off label, and stud...
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