(8) Any dose, expressed in milligrams per kilogram of body weight or other appropriate units, of the test or control item to be administered, and the method and frequency of administration. Due to their young age, as well as their limited emotional and intellectual capacities, children are considered legally incapable of giving valid informed consent; Therefore, enrolling a child in a research study requires permission from at least one parent or legal guardian (Table 3). For persons aged <18, parents or biological or adoptive guardians (legal persons and guardians) may give their consent on behalf of their child, exercising the right to vote without any form of coercion. While both mothers and married fathers have parental responsibility, unmarried parents can only exercise parental responsibility if they are named individually on the child`s birth certificate. Divorced parents also retain parental responsibility, but it is necessary to know who has awarded custody of the child [32]. In this respect, however, European laws and regulations are not harmonised and there are several divergences in each country [33]. b) Any modification or revision of an approved protocol and the reasons therefor shall be documented, signed by the study director, dated and accompanied by the protocol. (6) Review the final study report to ensure that it accurately describes the standard operating procedures and methods and that the results reported accurately reflect the raw data from the preclinical laboratory study. (b) The written SOPs required by Article 58.81(b)(11) shall specify in sufficient detail the methods, materials and schedules to be used for routine inspection, cleaning, maintenance, testing, calibration and/or standardization of equipment and, if necessary, specify corrective actions to be taken in the event of equipment failure or malfunction. Written SOPs designate the person responsible for executing each operation. a) Appointment of a study director in accordance with § 58.33 before the start of the examination. In clinical trials where the methodology used presents "less than minimal risks" to children, passive parental consent is a possible way to more easily obtain informed parental consent [34]. In addition, parents may be informed of a possible study with their children and, at the time of data collection, only the child`s consent is required.

While a child`s decision-making capacity and understanding of the research project in which they will be involved may be limited, the Medical Research Council has shown that the child may be able to make a decision and consciously participate in the research if the details of the study are provided and communicated in a clear and appropriate manner [35]. The term “consent” is coined to express the child`s willingness to participate in clinical trials despite his or her young age. “Consent” must include and respect the following key points: 1) support for the child in developing awareness of the disease; 2) explanation of the possible effects of the experimental treatment; 3) assess the child`s ability to understand and adapt to new situations or challenges; and 4) positively influence the patient`s willingness to participate in clinical trials [36]. While “consent” is not required for research that provides a direct benefit to the child, it stems from the need to respect paediatric research topics [37]. The assessment of capacity to give “consent” is based on developmental stage, intellectual ability, and life or illness experience. Typically, the age limit of 7 years is used for the start of logical thought processes and rational decision-making [38]. However, the “consent” of children aged <7 may also be required if literacy has been demonstrated [32]. Figures 1 and 22 summarize the parental and consent requirements. (d) %quot%non-clinical laboratory tests%quot% means in vivo or in vitro tests in which prospective tests are carried out prospectively in test systems under laboratory conditions in order to determine their safety. The term does not include human studies or clinical or field trials on animals. This term does not include basic exploratory studies conducted to determine whether a test object has a potential benefit or to determine the physical or chemical properties of a test tube.

Since the ability to understand the subject is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of information to the abilities of the subject. Investigators are responsible for ensuring that the subject has understood the information. While there is always an obligation to ensure that risk information is complete and reasonably understandable to subjects, when risks are more serious, this obligation increases. On occasion, it may be appropriate to conduct oral or written comprehension tests. (4) Submit regular written progress reports on each study to the study management and director, noting problems and corrective actions taken. The first condition of “impracticality” occurs when obtaining informed consent is time-consuming and economically resource-intensive or could affect the validity of the study [8]. The second condition means that while physicians are encouraged to ensure that the patient has understood the purpose of the research and the risks and/or benefits associated with participating in the study, researchers are also advised to respect the patient`s decision-making capacity, not to interfere with their decisions, and to always act in the patient`s best interests [9]. The third condition justifies waiver of consent where the clinical relevance and public health significance are potentially high [8].

(g) feed and water used for animals are tested regularly to ensure that contaminants known to interfere with the test and that can reasonably be expected to be present in the feed or in the aquatic environment are not present at concentrations above those specified in the protocol.