Vulnerability of adolescents in clinical research and practice

Adolescents are considered vulnerable and exposed to different threats to health group, making it necessary discussion about ethical aspects related to their participation in research and clinical practice. The employed methodology was an integrative literature review and it was selected studies that approached the subject “bioethical matters related to vulnerability of adolescents” within the last fifteen years. Nine articles included the pre-established criteria to the study, grouped into three categories: 1) works that mentioned the psychological-cognitive comprehension of adolescent to participate in scientific research; 2) works emphasizing aspects related to medical decisions; and 3) studies approaching the issue of sexuality in adolescence. The analysis of selected studies found out it is not possible to reach a valid consensus to all situations involving adolescents in research and clinical practice.


Vulnerability of adolescents in clinical research and practice
In the development process of science, production of knowledge that contribute to improve the quality of life of people, the participation of human beings in researches generates different ethical conflicts.Some of them are related to protection against vulnerability of participants of studies and responsibility of health professionals involved in the investigation 1,2 .According to Conselho de Organizações Internacionais de Ciências Médicas (Council of International Organization of Medical Sciences), quoted at "European textbook on ethics in research", vulnerable are those relatively (or absolutely) incapable of protecting their own interests 3 .In other words, it is related to the limited capacity or reduced freedom of deciding about acts of civil life, including consenting and participating of research or adhere to treatment.Thus, discussions about this theme are made by bioethics, so that vulnerable subjects and groups are not susceptible to exploitation 4 .

Vulnerability
involves three main considerations related to the individual: Lack of competence to protect their own interests; compromising volunteerism of consent; and fragility of physical and psychological condition due to age, disease or incapacity 5 .Thus, an individual can be vulnerable for over one reason, and classify him as vulnerable simply because he belongs to a certain sub population can be a mistake.It happens in different situations with adolescents, who are often excluded from occasions that involve decision making [6][7][8][9][10][11] .Therefore, this work has the purpose of identifying, in both national and international literature, ethical aspects related to vulnerability of adolescents in clinical research and practice.

Method
To conduct this study, it was chosen the method of integrative revision of literature, being followed by some stages.The first of them intended to identify the theme and select the hypothesis or research matter, set out criteria to include and exclude studies, define sampling, outlining the type of information to be extracted from selected studies and categorize them.The second one involved assessment of studies included in integrative revision, and in the third stage the results were interpreted.Finally, the revision/synthesis of acquired knowledge was submitted 12 .To outline the study, it was searched answers to the following main matters: "How is it set out the scientific production about the theme 'bioethics aspects related to vulnerability of adolescents'?";"What is the focus given to the theme by current publications?" The bibliographic survey was made in July 2015.The searches were made in online databases Scientific Eletronic Library Online (SciELO), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs), Literatura Internacional em Ciências da Saúde (Medline), Science Direct, Web of Science and Highwire Press.The bibliography was based on integration of the following descriptors found in DeCS: "Bioethics"; "adolescent"; and "health vulnerability".The eligibility criteria to inclusion in the sample included studies that approached the proposed theme; had been published from January 2000 to July 2015; had been fully available and in Portuguese or English languages.
The search resulted in five articles at Lilacs, two at Medline, 294 references at Science Direct, one reference at Web of Science, eight articles at Highwire Press and three at SciELO.After reading, nine articles included the eligibility criteria and were selected.It was used an instrument to systematize data, containing title, year and publication type, detailing objectives, methodology, results, discussion, level of evidence and final considerations of works 13 .Nevertheless, it must be clarified that one of identified limitations in analysis of this study can be attributed to selection and combination of used terms to survey works, considering they considerably limited the set of articles published at researched databases.
In addition to such distortion related to amount and diversity of works produced in scientific literature about the matter another point that must be highlighted about the depth level of analyzed articles, as they exposed ethical aspects in a superficial way.Despite limitations, it cannot be disregarded the importance of this revision of literature, as it raises different ethical aspects related to access to health by adolescents, either on clinical practice or related to research, indicating the necessity of more discussions about the subject.

Results
The selected articles were mostly (67%) written by American authors, especially from the United States.About the publication year, 22% were published in 2004 and most of them were published (78%) within last five years.From selected articles, three of them (33%) came from specific journals of medical ethics, five (56%) from medical journals Vulnerability of adolescents in clinical research and practice and one (11%) from nursing journal.With regard to bioethical matters, it is observed that three of them (33%) approached vulnerability of adolescents to participate in researches, three (33%) mentioned vulnerability aspects of adolescents about medical decisions and three (33%) discussed decision making of adolescents related to sex, reproduction and genre.Thus, the publications were grouped in categories I, II and III, respectively (Table 1).The articles that are part of category I mentioned the psychological-cognitive comprehension of adolescent in participating of research, highlighting that it is a transition period that must not be simply characterized as a continuous and uniform process, requiring a multidisciplinary approach.Furthermore, it was surveyed the position of parents and responsible people within the context of research with adolescents.Thus, it was listed subjects such as informed consent, autonomy of adolescents to participate in scientific studies and vulnerability [13][14][15][16] .
In this same context, but emphasizing aspects related to medical decisions, some authors of works selected in category II claimed that the autonomy of adolescents, despite relative, is not taken into consideration in different situations.It occurs even when the adolescent is considered competent and capable of making decisions related to family routines and health situations.Moreover, in certain ethical situations involving adolescents it is not possible to make a decision following strict procedures or principles.To effectively answer many ethical dilemmas, it is required to adopt a deliberative and individualized approach [17][18][19] .Another aspect approached in works analyzed in category II considers that, among changes connected to adolescence, sexuality has a great impact, especially for being the phase of vital cycle when it is consolidated both individuality and sexual choices [20][21][22] .

Vulnerability of adolescents who participate in researches
In bioethics, children and adolescents are considered a vulnerable group because they are not usually capable of making mature decisions or are subject to authority of somebody else.Moreover, differences between children or adolescents and their parents can mask an underlying divergence, making their rights and interests become socially devaluated.They can equally have acute medical conditions that require immediate decisions, not consistent with informed knowledge or serious medical conditions that cannot be effectively treated 23 .However, when we talk about vulnerability and adolescence, few things are found and discussed in literature, considering their magnitude and relevance.The survey of publications for this revision can confirm this statement, observing the scarcity of works that approach this subject, especially when it was Brazilian studies 24 .
The agreement of child and adolescent for research, diagnosis or treatment purposes is a complex subject and without consensus in literature.The controversies include the definition of what consent is, from which age the investigators must obtain it and who must be involved in obtainment process.It equally includes ways of solving disputes between children or adolescents and their parents, the amount and quality of information that must be provided to children or adolescents and their families and what constitutes an effective, practical and realistic decision making model 25 .
Article 5 of Convention on the Rights of the Child, prepared by the United Nations, affirms that responsibilities, rights and duties of parents must be respected in a consistent way with the developing capacities of the child.Moreover, in article 12 of the same document, it is set out that child's opinions must be considered according to his/her age and maturity 26 .Pursuant to Guidelines to Research in Health of Adolescent, those with age equal or beyond 14 years old can comprehend the investigation and have cognitive capacity similar to adults to make decisions about participation in research 8 .
A revision of literature made by Hunfeld and Passchier 14 concluded that children and adolescents reasonably comprehended the purpose and risks of medical study in which they participated and that their comprehension increased with age.In this regard, some researchers defend that, before requesting the consent of child or adolescent, it is crucial that the investigator understands his/ her comprehension level.Moreover, a second relevant aspect to be considered is what the child or adolescent would wish to know, a matter not always taken into account in researches involving this audience 14,27 .It must be highlighted that in matters related to vulnerability, the potential to actual and potential benefit and damages is markedly different

Vulnerability of adolescents in clinical research and practice
when the adolescents are sick or in the hospital.In addition to that, disease has been described as a distinct and extra type of vulnerability 24 .
Ott, Rosenberger and Fortenberry 15 conducted a study that assessed the reasons that led parents to authorize the participation of their daughters in a research about sexuality and sexually transmitted diseases.They observed that most parents who considered the participation of their daughters beneficial coincides with the quantity of those who considered them vulnerable to approached situation.On the other hand, parents' authorization can be an important source of problems if those adolescents in risk situation are being systematically excluded because parents deny their participation 28 .
Chartier and collaborators 29 intended to examine the participation of adolescents in a program of depression diagnosis at school upon two different procedures to obtain parents' authorization.They found out that a significantly smaller proportion of students participated when parents' informed consent was requested.The authors deduce that it probably occurred a selection problem in this work, as female teenagers and students of public schools had more consent requests signed by third parties, which, consequently, provided them a greater representation in such study 30 .
With that in mind, Ruiz-Canela and collaborators 16 defend that waiving an active authorization of parents could be acceptable when the risk of damage is minimum; the investigation matters are related to activities to which adolescents are not legally considered children; the risk of damage or discomfort can increase if it parents' authorization is required; and when the discomfort risk is low because the questionnaire is not potentially offensive to some adolescents and/ or parents.Thus, it can be the moment to suggest a new point of view about such important matter and develop guidelines under which the parents' consent can be waived.Thus, the voluntary participation of adolescents in intervention studies must be object of a broader debate among researchers of health area.

Vulnerability of adolescents and medical decisions
Adolescents are often not followed by their relatives or legal responsible people at the moment of medical decisions, which makes the appointment complex 31 .In ambulatory services, adolescents are usually instructed by health practitioners to be followed by an adult.The Ministry of Health 32 does not require the presence of a responsible person with the adolescent in health services, justifying that such presence can embarrass the adolescent and prevent the full exercise of their choices, considering his fundamental right to health and freedom.Although the absence of a responsible person is allowed in health services, the practitioner has to be aware of factors that can increase the vulnerability of this adolescent.For instance, there are situations when there is insufficient communication and bad comprehension by the adolescent, there is risk the patient feels isolated, distrustful and anxious 33 .
The article 103 of Código de Ética Médica (Medical Code of Ethics) (CEM) specifies that adolescents can decide by themselves to make appointments and exams, provided that the practitioner assesses they are able to understand their acts and conduct themselves independently, considering the principle of autonomy 34 .Consequently, the practitioners must be aware of standards that assure the rights of their patients, aiming at their best interests 35 .To Dickens and Cook 36 , if the adolescent shows maturity to decide about the problematic of his health-disease just like adults, he can enjoy the confidentiality and right to treatment according to his wishes.In assistance practice, the doctor must respect the individuality of each adolescent, keeping a nurturing posture, grounded on values of health and well-being of the youth and also respecting the principle of autonomy 37 .
If normally the legal right of consent to medical treatment and decisions is in charge of parents or legal responsible of adolescent, the literature registers that there are also many cases when adolescents can provide their own consent 35,38 .In case of sexual violence, suspected or confirmed maltreatment against children or adolescents, it is mandatory to register the violence, being required a cooperation with the Child Protective Service 32 .The laws also handle related subjects, such as duties of protecting medical confidentiality 39 , as confidentiality with adolescents can be something ethically and professionally challenging 31,40 .To Michaud and collaborators 17 , it is not possible to make decisions following strict procedures or principles, but reflection and common sense must always be present.Thus, it is evident that in clinical practice directed to this audience, there is a necessity of considering ethical aspects and particularities of each situation.

Decision making of adolescents related to sex, reproduction and gender
It is highlighted in this category the matter of gender identity disorder or transsexuality 21,22 , characterized as psychiatric disorder where the subject has a divergence of sexual identity and gender with regard to his/her biological gender, being diagnosed in any phase of life 41 .Some authors approached the requirement of advising and following up the adolescents in this circumstance.It is equally highlighted that a definitive treatment, such as sex reassignment surgery, must be postponed until adulthood (as of 18 years old), because it includes actions that impact future rights of minor and his/her life choices.It is indicated to undergo partially irreversible surgeries, such as feminization treatment (implanting breast prosthesis) or masculinization (mastectomy and hysterectomy) as of 16 years old with parents' consent 21 .
A study with the objective of exploring the matter of adolescent's capacity of consenting health care related to transsexuality was made in Colombia and the United States.The former stood out for having enacted a law that limits the inclusion of parents in medical decision making in those circumstances and the adolescent is considered an active subject of process.It occurs by obtaining qualified consent, which considers the following parameters: Requirement and urgency of procedure; risk and how intrusive the procedure is; age and autonomy degree of child/ adolescent 22 .This matter was recently approached in Brazil in ordinances of Ministry of Health.It was started with Ordinance 1.707/2008 42 , which described minimum steps to follow up and human treatment of transgender, as well as it acknowledged the requirement of regulating reassignment procedures by Sistema Único de Saúde (Unified Health System) (SUS).The Ordinance 859/2013 43 , which extended the access to health care to transgenders, allowing the beginning of hormonal therapy at 16 years old, with authorization of parents and after multidisciplinary follow up, was suspended.Nowadays it is in effect Ordinance 2.803/2013 44 , which regulates the beginning of hormonal therapy as of 18 years old and surgical procedures can be started at 21 years old, provided that there is specific indication and previous follow up for two years in specialized service.It also approached the matter of reassignment procedures on trial basis by SUS.
The Conselho Federal de Medicina (Federal Council of Medicine), upon Resolution 1.955/2010 45 , also discusses the subject and set out minimum conditions to carry out the procedure.Answering the doubt of Defensoria Pública do Estdo de São Paulo (Public Defender's Office of State of São Paulo), the Opinion 8/2013 of such body 46 is favorable to hormonal treatment of adolescents of 16 years old, in addition to support the assistance in specialist center with required resources to correct diagnosis and integral attention.Therefore, it is observed that the discussions and laws about the subject are recent in Brazil and it is identified the necessity of deepen the discussion, considering it is a complex subject that involves different points of view.The discussion has been especially intricate because it approaches two delicate topics: transsexuality and adolescents, in other words, vulnerable subjects due to psychiatric condition and age.Moreover, there is the fact that health care practitioners increasingly face situations like this and need clear guidance and grounded on specific and consistent laws.
Another item that was evident in articles that include the category discussing here was both sexual and reproductive health, specifically the confidential treatment of sexually transmitted diseases (STDs), abortion and contraception 21,22 .According to international standards of human rights, adolescents have the right to confidentiality and access to services of sexual and reproductive health, and he can consent the care or not, especially in cases of STDs and pregnancy.Nevertheless, the legislation often considers that adolescents are incapable of making decisions in an autonomous way, thinking it is appropriate the participation of parents and/or legal representatives in the process.It is observed a violation of rights to privacy and self-determination 22 .
To Romero and Reingold 22 and Beh and Pietsch 21 , there are many discussions aiming at the balance between rights of adolescents to make autonomous and confidential decisions related to their health and parents' rights.Those authors also claim that, according to clinical experiences, youths have the capacity of making decisions just like adults.But they warn that laws continue to limit their capacity in different situations related to health care.Consequently, it is identified a dichotomy related to adolescents, as it is expected they are responsible for their acts and lives, but there is no legitimacy of their rights. http://dx.doi.org/10.1590/1983-80422017251168

Vulnerability of adolescents in clinical research and practice
Recently, it has been observed an effort by Brazilian government in developing policies that consider them subjects of rights, citizens capable of making responsible decisions in this field.However, it is also identified inconsistency in legislation 47 .Pursuant to Brazilian Civil Code, the adolescent is of age at 18 years old, an age that is discrepant with the permission to vote as of 16 years old 48 .The national guidelines of Integral Attention to Health of Adolescents and Youths are grounded on human rights, being children and adolescents acknowledged in those documents as social subjects, bearing their own rights and guarantees, regardless of parents and/or relatives 49 .
There is also controversy with regard to sexuality.The Estatuto da Criança e do Adolescente (Child and Adolescent Statute) 10 claims that basic rights of health and freedom prevail over any other that may prejudice them.The doctor is allowed to define with the adolescent contraception methods, including emergency contraception, if there are no evidences of sexual abuse.It is also grounded on CEM, when it mentioned that it is the right of patient (...) to freely decide about contraceptive method 50 .Pursuant to Código Penal Brasileiro (Brazilian Penal Code) 51 , to have a sexual intercourse with minors of 14 years old is a crime of rape, being the violence related to age and, especially, to vulnerability of victim.However, this is discrepant with current social reality, as most adolescents start their sexual activity before this age 47 .Thus, it is observed that there are discrepancies between legal premises and social practices.Considering such disparity, it is crucial that matters related to adolescent sexuality are equated and solved considering the bioethics principles (beneficence, not maleficence), aiming at pleasurable and safe sexuality, respect and confidentiality, provided that it does not cause harm.Finally, another complex and specific theme approached in this category was implanting oocytes and collecting ovarian tissue, intending to restore fertility of adolescents with cancer who underwent different treatments that often culminate in infertility.Some mentioned ethical considerations were related to safety of procedure.The medications used to stimulate oocytes can increase the seriousness of tumor and postpone chemotherapy and storing oocytes entails risk of chromosomal abnormalities.On the other hand, the risks are justified by benefits of positive psychological effect to the adolescent, who sees, with this technique, a possibility of resurgence of fertility.
It is evident the necessity of more researches and creating policies that approach future rights of patient, about availability of gametes and actions related to it, such as the procedure in case of death 20 .Technical matters, such as feasibility of procedures to preserve fertility, are approached in literature 52,53 to the detriment of ethical matters.This can be justified by incipience of subject, being many techniques related to it still being tested.Nevertheless, upon discussing ethical aspects related to the subject, this study intends to contribute with the state of art and indicate the necessity of intensifying discussions about it.

Final considerations
This study identified, by means of analysis of scientific literature, three categories about bioethics aspects related to vulnerability of adolescents: With regard to participation in researches, medical decisions and decision making related to sex, reproduction and gender.
In this first category, it was evident the necessity of considering the psychologicalcognitive comprehension of adolescent and his autonomy to participate in researches.
In the second one, most studies discussed that adolescents, although considered competent and capable of making decisions related to routines in family and health situations, do not have autonomy in situations related to medical decisions.Finally, in the category related to decision making about sex, reproduction and gender, it was identified matters related to gender identity disorder or transsexuality; discrepancies between legal premises and social practices related to sexuality; and aspects related to decision making about different procedures aiming at maintenance of fertility in adolescents with cancer.
It is also observed a lack of consensus and definitive laws that set out accurate criteria about participation of adolescents in research and clinical practice.Each individual and situation is different and require a contextualized approach.Consequently, the health care practitioners, in addition to managers of right, teachers, pedagogues and society in general must encourage the discussion about different aspects related to reflection between respect to autonomy and protection against vulnerability of adolescents, aiming at assuring their rights and strengthen their citizenship.Category I Qualitative study

Attachment
A survey among parents of adolescents about their conception of benefits of participation of their children or legal dependents in a study about sexuality.The parents reported as main benefit the scientific relevance, familiarity relationships with the team (connection) and autonomy of adolescent.Other reasons included altruism and payments.

Literature revision
The authors intended to critically assess different factors that could be taken into account in decision making about waiving the active authorization of parents in observational investigation with adolescents.They defend that waiving an active authorization of parents could be acceptable when the risk of damage is minimum; the investigation matters are related to activities to which adolescents are not legally considered children; the risk of damage or discomfort can increase if it parents' authorization is required; and when the discomfort risk is low because the questionnaire is not potentially offensive to some adolescents and/or parents.

Michaud and collaborators; 2010 17
Category II

Literature revision
The concepts outlined in the article show that in ethical situations involving adolescents it is not possible to make a decision following strict procedures or principles, but reflection and common sense must always be present.Each person and situation is different and it is required a deliberative approach to face ethical dilemmas in health care of adolescents.The deliberative approach is a contextualized and prudent process that prevent anyone from immediately go to "obvious answers and conclusions", very based on personal, emotional and biased opinions.Instead, it is the careful assessment of role of all moral values and their relative priorities that are incorporated in each term of decision, especially in situations when there is a great conflict between different values.
Bluebond-Langner and collaborators; 2010 18 Category II Experience report Basic premise in involvement of individuals in decision making related to health care is that they must comprehend risks, benefits and likely results.If the involved people are children, the matter is if they get to understand the options.Some practitioners use the age and development stage of child as criteria, but the development of individuals does not occur in a uniform way and age does not necessarily predict the knowledge degree of a child.Their experiences with disease have a more important role in their comprehension.Another important factor is the interaction between adults and children.The expectations of one often interfere in those of the other one, such as when children believe they must continue with the treatment because they do not want to disappoint their parents.Another point in focus is that children are not autonomous beings, in other words, any approach that involve the perspective of children in decision making must take into account the perspective of parents, as they have both legal and moral responsibility to take care of their children.But it is important to involve children in decision making about their care, allowing them to speak and listening to them.Category II

Literature revision
The article questions that in many jurisdictions adolescents have the right of consenting the clinical treatment, but do not have the right to refuse.Thus, there is an asymmetry between consent and refusal.The asymmetry exists because, in some cases, the refusal of treatment represents a serious risk, even of death.Therefore, some scholars have been in favor of requiring a greater competence level than the one set out when the risks are low.
Dudzinski; 2004 20 Category II Normative ethic analysis The article considers that implanting oocytes and collecting ovarian tissue, intending to restore fertility of adolescents who survive cancer is promising.However, it is discussed the necessity of more researches before adolescents being enrolled in clinical tests in an ethic way.It reflects it must be assured that the intervention does not harm the patient, does not delay the treatment of cancer and assure the informed consent of adolescent patients and informed consent of their parents or tutors.It also discusses the necessity of developing policies about future rights of patient to protect their gametes and policies that aim at the disposal of those gametes in case of death.Furthermore, it claims the necessity of policies that protect the patient from harm and assure their right to self-determination.

Literature revision
The article discusses the existence of conflicts between interests of children and parents or responsible people, of community or society in different aspects, being controversial, especially when it handles sex, reproduction and gender.Thus, the practitioner must always analyze the necessity of judicial approval or consider cases when the interest of State and child can replace the authority of parents.

Literature revision
The article discusses the slowness of Courts of Colombia and the United States in enacting legislations that explicitly protect the decisions of transsexual adolescents, about aspects related to their sexuality.The author highlights the decision of courts in Colombia, where the jurisprudence limits the capacity of parents to make medical decisions related to gender in the name of their transgender children.

Table 1 .
Characteristics of studies included in revision about vulnerability of adolescents related to research, medical decisions and decision making related to sex, reproduction and gender.

80422017251168 Research Vulnerability of adolescents in clinical research and practice Author, year, category and study outline Results/considerations
http://dx.doi.org/10.1590/1983-