Clinical Trials In Children - Legal And Ethical Aspects - Healthcare

The issue of clinical trials in children always causes a clash of opinions in the ethical and legal dimensions. However, paragraph 3 of the preamble to the Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 emphasises the need for clinical trials in children to improve the existing methods of treatment.

Indeed, it is a proven fact that children are often prescribed drugs that were tested on adults only. Thus, more than 350 clinical trials involving children under the Paediatric Exclusivity Provision of the FDA Modernization Act (passed in 1997 and becoming law under Best Pharmaceuticals for Children Act (BPCA, US) in 2002) have been conducted since 2007. According to BPCA, manufacturers are given a voluntary incentive of an additional six months of marketing exclusivity (the ability to sell the drug without competition from generic drug), if they conduct a study of drugs the FDA (US Food and Drug Administration) determines may be clinically beneficial to a child. On the basis of the results of the mentioned trials, new pediatric labelling information was included in relation to at least 159 medicinal products, which revealed the following data: one-sixth of the studied drugs were prescribed to children with wrong dosing before any prior studies; one-third of drugs were not found to be effective in children, while enhanced pediatric safety data that hadn't been known before were discovered for about 45 drugs (according to FDA).

These data confirm once again that children are not small adults. Therefore, studies which con-sider their physiological and psychological characteristics are particularly important in order to reduce the off-label use of medicines. Providing a proper legislative framework for the conduct of such clinical trials is a key prerequisite for achieving the set goals.

Against this background, proper regulation of procedures for conducting clinical trials in Ukraine is very important. However, the analysis of relevant regulatory acts gives reasons to believe that legislation in the studied area contains certain problematic terms and needs further improvement.

The main regulations governing the conduct of clinical trials in Ukraine, in particular those in children, are contained in the Ministry of Health's Order dd. September 23, 2009 No.690, which establishes the Procedure for Conducting Clinical Trials of Medicinal Products and Expert Eval-uation of Clinical Trial Materials (Procedure), and the Law of Ukraine "On Medicinal Products" dd. April 4, 1996 No.123/96-VR (Law No.123).

In relation to clinical trials in children, the mentioned acts regulate such issues as conditions for conducting studies, providing children with information about a study and obtaining their in-formed consent, limiting the participation of certain groups of children in a study, principles for conducting such studies, etc. Let us examine each of the above issues in more detail.

Conditions for Conducting Clinical Trials

According to the provisions of the Procedure and Law No.123, studies may involve children provided that:

both parents have given their written informed consent;
a child is provided with easy-to-understand written and verbal information about the clinical trial;
no rewards or incentives are used other than compensation provided in the event of health damages;
a child is expected to directly benefit from participation in a clinical trial;
the medicinal product is intended for the treatment of pediatric diseases;
the purpose of a clinical trial is to optimise the dosage and administration of a medicinal product in minors or adolescents, respectively, only provided that clinical trials of the same medicinal products in competent capable adults have been completed;
clinical trials are planned so that pain, discomfort, fear or risk are minimised, the threshold of risk and the degree of discomfort or pain being clearly defined and constantly monitored.

According to the Procedure, benefits from participation will be possible if the following conditions are met:

a clinical trial is intended to address diseases that affect minors or adolescents;
a clinical trial is necessary to confirm the data obtained during other clinical trials con-ducted in adults, or to confirm the data obtained by other research methods;
a clinical trial is specific in the way that it can be conducted only with the participation of minors and adolescents.

As we can see, some grounds for clinical trials provided under the Procedure and Law No.123 are partially overlapping. They should be evaluated comprehensively and considered when planning each particular study.

It should be noted that some of these grounds are mentioned in the so-called Paediatric Directive (laid down by Regulation No.1901/2006 of the European Parliament and of the Council of 12 December 2006), in particular, regarding benefits for children participating in a study. However, unlike the Procedure, the directive prohibits clinical trials if the relevant medicinal product provides no significant therapeutic effect as compared to existing methods used to treat children. Moreover, the said document prohibits studies in children, if the drug is likely to be ineffective or dangerous.

Significant therapeutic effect, in accordance with the provisions of EU legislation, should consist, inter alia, of the following:

expected improvement of efficacy compared to existing methods of treatment;
improved dosage or method of administration (e.g. replacement of intravenous administration by oral administration, or reduced time of administration and number of doses);
expected improvement of the child's life quality.

Categories of Participants

The Procedure identifies the following categories of children that may participate in clinical trials: minors (aged 14) and adolescents (aged 14 to 18). The above division is relevant in terms of obtaining children's assent to participate in a study. Thus, in accordance with the Procedure, a minor, if capable, shall give his/her verbal assent to participate in the study, while an adolescent patient shall personally sign and date his/her informed assent.

It should be noted that certain regulations lay down a broader definition of the term "child". In particular, according to the Law of Ukraine "On Protection of Childhood", a child can also be a person that, in accordance with applicable law, acquires the rights of an adult before reaching the age of 18. However, the Procedure introduces the age criterion along with the legal one, thus preventing a child's independent decision-making about his/her participation and informed assent, if he/she has acquired the rights of an adult, but has not turned 18 yet.

Providing Information about a Study and Obtaining a Child's Assent

As with other categories of participants,the Procedure requires to inform children about a clinical trial. Thus, children shall be informed within their understanding, while adolescents, as already mentioned, shall personally sign and date the informed consent form. Information should be understandable for children and available in written and verbal form.

The position of the European Medicines Agency (EMA) regarding easy-to-understand infor-mation is also worth attention. According to EMA's position, a child acquires the ability to give his/her assent having reached the age of three. However, this ability must be assessed in each case, while stable and distinct objections of a child must be taken into account.

Obtaining Informed Consent

A child's participation in a clinical trial (both therapeutic and non-therapeutic) is possible only subject to his/her parents' approval. However, unlike with such categories as incapacitated per-sons, whose participation in a study may be allowed by consent of their legal representative/close relative, a child's participation is possible only after both parents provide their written informed consent. This formulation makes the participation in a trial impossible for a child one of whose parents cannot provide his/herconsent for various reasons (e.g. when a child's father or mother is untraceably missing or dead). It should be noted that the above restriction is put into practice by the State Expert Center of MoHof Ukraine (Center). This position is quite doubtful. It can be compared to the case of children's exit from the country. Thus, in the case of departure from Ukraine a child under 16 may leave the country with one parent only, in cases where the original or a certified copy of the certificate of the other parent's death, or a court decision on the second parent's deprivation of parental rights, or a court decision recognising the other parent as missing, is provided. Of course, clinical trials potentially may carry more significant ethical risks. However, including certain exceptions into law is quite reasonable in terms of a child's rights, as children that have only a mother or a father for objective reasons should not be deprived of the right to be included in a trial if they need it.

In addition, the provisions of paragraph 3.3 of the Procedure and Article 8 of Law No.123 make it legally impossible for the following categories of children to participate in clinical trials:

children that are deprived of parental care;
adopted children;
orphans.

This restriction has repeatedly been a ground for criticism. Thus, proponents of involving the above categories of children in clinical trials argue that their participation in the study is almost the only opportunity for them to receive treatment at a high level, and sometimes their only chance of survival. For comparison, EU legislation has no such restrictions. For example, the Paediatric Directive extends to the whole child population, i.e. people aged from their birthdate to 18.

It is obvious that by setting the above limits, lawmakers were seeking to protect socially vulnerable population groups and to prevent the use of a child for selfish motives. However, it should be noted that in clinical trials involving children, no remuneration to parents of children is provided (only reasonable expenses incurred in connection with a clinical trial may be compensated). The inclusion of adopted children into the above groups raises perhaps the biggest objections. Thus, a child that was adopted after birth and was raised in a complete family will not be able to participate in a clinical trial and get the proper treatment, which actually means the child's discrimination and deprivation of the right and opportunity to get the treatment that is sometimes hardly possible to get through medical care provided by the state.

When obtaining a child's informed assent, the investigator should consider the apparent desire of a minor or adolescent to participate or not to participate in a clinical trial, or to withdraw from it at any time. At the same time, there is no requirement in the law regarding a child's non-inclusion in a trial in case of his/her refusal, i.e. decisions should be made by the investigator with consideration of such factors as, among other things, the parents' wishes, the extent to which the trial is relevant for the child's health, etc.

Informing Guardianship Agencies

In the case of clinical trials in minors and adolescents, relevant information shall be sent to guardianship agencies at the place of such persons' permanent residence according to the procedure prescribed by the central executive body that provides public policy in healthcare. This procedure was approved by MoH Order No.523 dd. 12.07.2012 (so-called amendment to Procedure). According to the Order's provisions, information about clinical trials involving minors and adolescents shall be provided in any form, but with the obligatory indication of the child's surname, name and patronymic, age, names of its parents, place of the child's residence, confirmation of obtaining of informed consent, a brief statement of the scope of the study with an obligatory confidentiality remark. The principal investigator / investigator shall send that information to the guardianship agency at the place of the child's permanent residence within one day from the date informed consent to participate in the clinical trial is obtained, in accordance with subparagraphs "a" and "b" of paragraph 3.1 Chapter IV of the Procedure (i.e. after obtaining parental consent and the child's assent).

The above provision has been quite recently included in the Procedure. Judging from the letter published on the website of the Center, the changes to the Procedure were due to the amendments to Article 8 of Law No.123 concerning the prohibition of clinical trials in children deprived of parental care, as well as in adopted children or orphans. Thus, the purpose of the above information is the subsequent fact-checking by a guardianship agency as to whether a child be-longs to the mentioned categories. At the same time, the procedure for a guardianship agency's further reaction is unclear, should it establish that an adopted child has been involved in a study. It is likely that a guardianship agency should inform the investigator that has provided information about a child and the fact of its adoption, and the latter would exclude the child from the study. However, one should not forget that information about adoption is confidential and the guardianship agency may not disclose it, while legislation provides for no other disclosure procedure for such information other than in court. In practice it leads to situations where guardian-ship agencies are notified of a child's involvement in a clinical trial, but they do not know how to proceed. This uncertainty confirms the lack of a thought-out mechanism and the need for improvement.

To comply with the above restrictions, sponsors and contract re

search organisations may include provisions in the form of informed consent, whereby parents are notified of the prohibition of an adopted child's participation in clinical trials and shall confirm that their child is not adopted.

Another issue that needs clarification is the requirement for a brief statement of the scope of a clinical trial. The purpose of this provision, as well as how much information should be disclosed in the notice, is not quite clear (the aforementioned letter of the Center contains no such requirement). The Procedure mentions only a summary of the protocol content (synopsis) as an information category closest in substance. However, it is believed that providing a synopsis to guardianship agencies is impractical given the nature of these agencies and the minimum degree of their involvement in the clinical aspects of trials. Therefore, we believe that sponsors and contract research organisations should instruct investigators on sending information summarising the scope of investigation in a freeform.

Liability

Article 141 of the Criminal Code of Ukraine provides for liability in the form of custodial restraint for a term of three to five years, or imprisonment for the same term, for conducting clinical trials of medicines without the written consent of the patient or his/her legal representative, or in respect of a minor or an incompetent person, if these actions have caused a patient's death or other serious consequences.

Comprehensive analysis of the above article gives reason to believe that those responsible for conducting clinical trials in children can be made liable for the following violations:

conducting a study without both parents' written informed consent, if these actions caused the patient's death or other serious consequences;
conducting a study in relation to an adolescent, if these actions caused the patient's death or other serious consequences (inflicting a severe or moderate injury).

While the occurrence of adverse effects due to conducting a study without obtaining informed consent is considered questionable, the situation with the second violation causes more concerns. If interpreted literally, the provision of the Code suggests that any person responsible for con-ducting a clinical trial (normally principal investigators / investigators appointed under an institutions' relevant orders) may be held liable in the event of a child's death or other serious consequences. However, compliance with the procedure for conducting clinical trials is not taken into account to qualify that crime. In other words, death or other serious consequences (for children under 18) is the basis for holding a person criminally liable or at least for initiating a respective investigation, even if procedure was strictly observed.

Also, we should not forget about the recently introduced Articles 321- 2 of the Criminal Code, which impose penalties for wilful violation of the established procedure for clinical trials of medicinal products, even if the violation did not lead to the onset of socially dangerous consequences. For example, non-observance of the above provisions requiring investigators to send information about a child involved in a study to a guardianship agency within one day may be regarded as a deliberate violation of the procedure for conducting clinical trials and may entail a penalty of imprisonment for up to five years.

Obviously, the provisions of these articles of the Criminal Code are imperfect, while liability is not adequate to the committed action, obviously except the cases when such actions were really meant to cause harm. Although cases of criminal charges brought against healthcare workers or even guilty verdicts against them are rare in Ukraine, there is still a potential risk of criminal charges against investigators for the aforementioned violations. This should be taken into account when planning and conducting clinical trials. In this light, we should also consider the decision recently made by the Ministry of Health willing to set up a special commission to check the widespread public information about violations of the Procedure in conducting a series of clinical trials in children. This fact confirms once again the state's concern regarding compliance issues in clinical trials and, consequently, initiatives to improve the relevant legislation are highly probable.

To Sum Up...

According to clinicaltrials.gov, 10 open investigations in children were conducted in Ukraine in 2011. This figure increased to 21 trials in 2012. As we can see, the number of studies is growing, not least thanks to the initiatives of foreign and national organisations willing to create favourable conditions and incentives for trials in children. In turn, Ukrainian legislation also goes on and develops in accordance with international documents regulating relations in the analysed area. However, not all innovations lead to positive changes. Many issues still remain unresolved, such as the process of informing competent authorities about a child's participation in a clinical trial. Restrictions in participation in clinical trials for certain categories of children also make the in-ternational community wonder, and raise concerns about the ethical side of the issue. It is also difficult to accept the penalties imposed by law for violations of procedure for clinical trials (lia-bility even without the onset of socially dangerous consequences). All these factors hamper the development of this segment of clinical trials. With this in mind, the state should make every effort to eliminate undue obstacles in conducting clinical trials in children, to improve legislation and to create favourable conditions for such studies, which will encourage the further develop-ment of new medicinal products and improve the existing methods of treatment for children.

Originally published in Journal for Clinical Studies, July 2013

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Ukraine: Clinical Trials In Children - Legal And Ethical Aspects