**4. Protection of trial subjects**

Childhood period comes with rapid growth and development and ends with puberty. Unfortunately, sometimes it is accompanied by harsh diseases like infection diseases, allergies, cancers, and psychiatric disorders. So, many advanced vaccines and medicines are needed to be developed for children and adolescents. Furthermore, some supplements are targeted for this group of population [8–10]. Hence, performing clinical trials on children and adolescents is a critical mission sometimes inevitable. Children are vulnerable population in medical research; hence, inclusion of children in clinical trials always is a matter of great concern for parents, researchers, and ethic committees. Children and adolescents who will attend in the clinical trials should be selected carefully by a qualified physician. The physician should be qualified by sufficient education, training, and experience and should be in charge for optimum health of the participants. All diagnosis should be supported by the latest clinical guidelines [11]. Furthermore, inclusion and exclusion criteria should be carefully set on the basis of study objectives and previous studies. The processes of medical care and every decisions made here should be based on evidence and guarantee the maximum safety of the patients in a way that the rights and well-being of the children would be protected. Blood sampling in children is not ethical if the benefits of the study do not exceed the harms for children. When a specific group of children directly benefit from blood sampling or blood sampling is necessary for diagnosis, the documents should be presented to the institutional ethics committee and benefits should be described to the parents or legal guardians. The subjects or his/her parent or legal guardian should be adequately informed about the processes of research, the rights and responsibilities. The aims and methods of the research should brightly be described to them. Furthermore, the subjects and their legal guardian must be aware of anticipated benefits and potential hazards of the intervention. Then, informed consent must be signed by the parents or legal guardian of the subjects below the legal age. Moreover, the subjects should ascent to participate. Then, after obtaining sufficient ethical approvals and consent forms, blood sampling could be gathered by a trained client under the guidance of existing guidelines [12, 13]. In clinical trials on pediatric psychiatry, a team-based approach involving the laboratory physician would help the quality assurance of examination, diagnosis, and reporting, as well as patient safety [14, 15].

## **5. Safety reporting**

war, two American doctors who were present in Nuremberg invented a set of research ethics principles including 10 points which are in compliance to the human rights. These principles

Later in 1964, the elected medical representatives came from all over the world, attended the 18th General Assembly of the World Medical Association in Helsinki. They decided to improve the points asserted in the Nuremberg Code and create a more formal statement of ethical principles. Its attitude was to provide detailed directions for medical science researchers to conduct the trials on human subjects with scientifically sound methods and in accordance with basic ethical principles. This statement is known as the "Declaration of Helsinki,"

Good clinical practice is an internationally accepted scientific and ethical standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials on human subjects which provides assurance that the reported results are credible and accurate; the rights, integrity, and confidentiality of trial subjects are protected [3].

The good clinical practice is a quality assurance system for the conduct of clinical trials. It is a legal requirement accepted by health systems in many countries. Hence, a new product will not be licensed by regulatory authorities if the rules of good clinical practice are not followed [5].

Patient selection for any clinical trial is a very critical point. When choosing the inclusion criteria, the researcher should think that what factors are important to the research question and include the main characteristics of target population. The researcher should be careful that excessive exclusion may degeneralize the study. The caseness of pediatric subjects should be confirmed by a pediatrician. When working on pediatric psychiatric patients, the sensitivity is much more, the eligibility of subjects must be clearly defined in the inclusion and exclusion criteria. Furthermore, the diagnosis must be confirmed by a child and adolescent psychiatrist based on the latest version of diagnostic and statistical manual of mental disorders (DSM). In psychiatry trials, documentation and history of the diagnosis are usually required [6, 7].

Childhood period comes with rapid growth and development and ends with puberty. Unfortunately, sometimes it is accompanied by harsh diseases like infection diseases, allergies, cancers, and psychiatric disorders. So, many advanced vaccines and medicines are

are known as Nuremberg Codes [2, 3].

30 Clinical Trials in Vulnerable Populations

and until now, several revisions have been released [4].

**2. Good clinical practice definition**

**3. Selection of trial subjects**

**4. Protection of trial subjects**

This history formed the basis for developing good clinical practice.

In trials with the main objective of efficacy assessment, the safety assessment is usually the secondary objective. One of the responsibilities of the researcher is to carefully monitor the adverse effects and record immediately when a participant experiences any side effect [16]. Then, the investigator should report it in a suitable way. Furthermore, in respecting the privacy, the researchers should guarantee the confidentiality of records that could identify the subject. Another duty of the researcher is to provide best possible care available and follow until complete disappearance of adverse effect. Sometimes, it is necessary to stop the trial to protect one or more subjects. Sometimes, the subjects or the legal guardian themselves decide to stop medication. In pediatric psychiatry, loss to follow-ups happens due to adverse effects of the intervention, stigma, and lack of parent's knowledge about medicinal psychotherapy [17]. So, the researcher should conduct a thorough investigation and find the exact reason of each loss to follow-up and report it. Usually, identifying the barriers and reducing them would be helpful. Educating the parents and legal guardians to help reduce the stigma of referring to psychiatrist and fear of tacking psychiatry medications may support the children health [18].

## **6. Develop informed consent form**

Consenting is the process by which participant voluntary confirms his/her willingness to participate in the trial. The medical researchers should be careful and pay special attention when obtaining consent from vulnerable subjects, including children, the elderly, and psychiatric patients. Subjects with low perception may feel unable to make use of their right to judge the profits or hazards of the intervention and decide whether to consent or not. Child and adolescent psychiatrists should be careful about the decisional capacities of children and the role of the parents in medical decision making. Hence, obtaining informed consent form from the legal guardian of the subjects under legal age and the patients with severe psychiatric disorder is crucial. In addition, obtaining oral ascents from the subjects with low perception or children who will participate in the medical research is essential. Full procedures, rights and responsibilities, potential hazards, and benefits should be described to each participant and the legal guardian. Then, informed consent must be dated and signed by the legal guardian before the subject participates into the trial. Then, a copy of informed consent form and related information should be delivered to the parents or guardian. The original informed consent must be kept in the investigator's file [19].

The researchers must also review up-to-date information, ensure the confidentiality of the data, and provide confidentiality agreement to sponsor. Furthermore, proper facilities, location, equipment, laboratory, product storage, and archive must be provided prior to study

Good Clinical Practice in Children and Adolescents http://dx.doi.org/10.5772/intechopen.70191 33

One of the requirements of good clinical practice is that the researcher has adequate access to resources to carry out a sound clinical trial. Resources include not only sufficient budget and materials, but also the ability to recruit adequate numbers of research subjects. Furthermore, the research team members must have adequate information about their specific roles, and they should have adequate time to deal with subjects and conduct the trial. In trials being conducted in children and adolescents, at least one of the team members should be specialized or

Single-arm trials with historical controls for comparison may be biased by differences in subject characteristics (age, sex, prior therapy, phase of disorder, and supplemental care). Still, when matched controls can be selected, unknown confounding factors may be haphazardly

Designing a two-arm trial with distributing the subjects between two groups using randomization can help to minimize potential bias caused by unknown confounding factors. However, a placebo-controlled trial may be ethically defensible when the use of placebo would not add any risk or serious harm to the subjects. Sometimes, crossover design is more ethical and adheres to the principle of good clinical practice. In crossover studies, the subjects are randomly allocated to the treatment or control groups, after the first phase ends, the subjects will change the groups. In this design, all subjects receive all treatments. Of course, the

When an uneven distributed factor between groups recognized, then controlling by statistics method at the analyses level may be considered. One strategy is to stratify the variable and discuss the results at different levels of the variable. A better solution is stratification process at the time of randomization using the permuted blocked randomize allocation. In this method, randomization will be performed using different age and sex blocks. Hence, the

In a randomized clinical trial to control for the placebo effect and minimize the study bias, the subjects and researchers should be blinded using placebo, coding, and allocation concealment. In the case of a blinded trial, the protocol must declare who and in what conditions is allowed to break the codes (for example, the supervisor and in emergencies). Breaking the

trained previously to deal with the subject on this age span [24].

initiation [22, 23].

**9. Resources**

**10. Randomization**

distributed between two groups.

priority of treatments should not harm the subjects.

subjects will distribute evenly between treatment arms.

codes must be justified and must be reported [21].

## **7. Ethical approval**

The researcher should submit the sponsor-provided protocol document to the Institutional Review Board (IRB) or Research Ethics Board (REB) for approval before recruiting any case into the trial. The investigator should also submit consent forms and assessment tools, including questionnaires. During specific intervals, the researcher must report the progress of the trial and request re-approval of the research by the IRB/REB. The IRB/REB will ask for a summary of trial progress [20]. The responsibility of the ethics committee is to guarantee the protection of the rights and well-being of human subjects enrolling into clinical trials. The ethics board decisions are in line with the latest revision of the declaration of Helsinki and local pertinent regulations [21].

### **8. Quality of data**

Every research study needs to have a written protocol which includes the plan of the study as detailed as possible. The design and method of the trial should be well-thought-out, and the protocol must be well-written and approved by a faculty council. Protocol includes the trial information in detail and should consist of the trial title, the name of the main investigator, supervisor/s and sponsor/s, literature review, materials and methods, characteristics of intervention, dosage, duration, randomization, blinding, allocation concealment, inclusion criteria, exclusion criteria, project schedule (Gantt chart), and budget of the project [22].

In trials performing on children and adolescents, the investigators should be trained and interested in the scientific aspect and ensure that the study meets the needs of patient's health. The researchers must also review up-to-date information, ensure the confidentiality of the data, and provide confidentiality agreement to sponsor. Furthermore, proper facilities, location, equipment, laboratory, product storage, and archive must be provided prior to study initiation [22, 23].
