Informed consent (1)

Consent to participate in clinical trials. How to make it really informed?Elena Rudneva, Weekly "Pharmacy"
Clinical research, that is, the study of new medicines with the involvement of healthy or sick people as subjects, is certainly of great importance for the progress of medicine and pharmacy.

It is on the results of carefully planned and scrupulously conducted clinical studies that "evidence-based medicine" is based, only from clinical studies can information be obtained about the effectiveness of a drug, the profile of its side effects, interaction with other drugs, etc. When conducting such studies, the ethical aspect of the doctor–patient relationship is of great importance. Questions of ethics in clinical research began to be raised relatively recently – one of the first official international documents that formulated ethical principles for conducting tests with human participation is called the Nuremberg Code (1947), while the first mention of an experiment, which today we would call a controlled clinical trial, dates back to 600 BC.E. (comparison of vegetarian and royal diets initiated by Daniel of Judea, in Ancient Babylon) [1, 2]. However, over the past 60 years, the greatest progress has been made in protecting the rights and freedoms of citizens participating in clinical trials as subjects. One of the elements of such protection is a mandatory procedure for comprehensive information and voluntary consent of the participant – the so-called informed consent.

However, in order for the historical picture to look more complete, it is necessary to mention the American physician William Beaumont, who in 1833 spoke about the need for voluntary consent of people to participate in research, and the decree of the Prussian Minister of Health in 1900, which prohibited medical interventions not aimed at diagnosis, treatment or immunization, without prior consent of the subject of such interventions, etc. The term "informed consent" itself appeared in the English-speaking environment only in 1957, and in 1960 it became widespread [3].

According to the official definition introduced by the Procedure for Conducting Clinical Trials of Medicines and Examination of Clinical Research Materials, informed consent is "a decision to participate in a clinical trial, which must be made in writing, dated and signed, taken voluntarily after proper information about the nature of the study, its significance, impact and risk, appropriately documented it is drawn up, accepted by any person who is able to give consent, or by his legal representative, in exceptional cases, if the relevant person cannot write, he can give consent orally in the presence of at least one witness" [4].

This definition is based on the interpretation of the term by the European Directive 2001/20/EC (Article 2, paragraph j) [5], which in turn is based on the interpretation of the Guidelines for Good Clinical Practice International Conference on Harmonization – "the process by which the subject voluntarily confirms his desire to participate in a particular study, after familiarizing himself with all aspects of the study that may affect the adoption of such a decision; informed consent is documented using a written signed and dated form of informed consent" [6, 7].

In addition to the definition itself, the above documents also provide more detailed recommendations regarding the content and procedure. So, in ICH GCP, a whole subsection is devoted to this issue (4.8), which, among other things, postulates the need for informed consent of the subject prior to the start of the study (clause 4.8.8), introduces the concept of an independent witness (clause 4.8.9), restricts the use of special terminology (clause 4.8.5), describes the requirements for involving subjects in non-therapeutic research (clauses 4.8.13 and 4.8.14) and in case of urgent states (clause 4.8.15), etc. Special attention should be paid to the fundamental clause 4.8.10, which contains information about the mandatory amount (20 sub-paragraphs) of information that must be communicated to the subject in writing and, accordingly, contained in a document confirming the fact of informed consent [6, 7]:

1. Experimental nature of the study;
2. The purpose of the clinical trial;
3. Types of treatment during the study and the probability of random distribution in each of the groups;
4. Research procedures, including all invasive;
5. Responsibility of the subject
6. Experimental aspects of clinical research;
7. Objectively expected risks or inconveniences for the subject, as well as (if applicable) for the embryo, fetus or infant;
8. Objectively expected benefit. If there is no expected clinical benefit for the subject, he should be notified of this;
9. Alternative procedures or treatment courses that may be available to the subject, their important potential risks and benefits;
10. Compensation and/or treatment of the subject in case of damage related to the study;
11. The expected payment to the subject, if it is assumed;
12. Expected expenses of the subject related to his participation in the clinical trial, if expected;
13. A statement that the subject's participation in a clinical trial is voluntary and that the subject can withdraw or terminate his participation at any time without any penalties or loss of privileges;
14. The statement that the monitor(s), auditor(s), independent ethical commissions and regulatory authorities will have direct access to the primary medical documentation of the subject to verify the procedures and/or clinical trial data without violating the right of the subject to confidentiality. By signing the written informed consent form, the subject or his legal representative gives permission for such access to this documentation;
15. The statement that the records allowing the identification of the subject's identity will be kept secret and will not be available to the public within the limits established by the relevant laws and regulations. When publishing the results of the study, the anonymity of the subject will be preserved;
16. The statement that the subject or his legal representative will be promptly acquainted with new information that may affect the desire of the subject to continue participating in the study;
17. To whom (with the provision of a list) to contact the subject with questions regarding the clinical trial, the rights of the subject when participating in the clinical trial, as well as in the case of damage to the subject as a result of participation in the study;
18. Possible circumstances and/or reasons why the subject's participation in the study may be terminated;
19. Expected duration of the subject's participation in the clinical trial;
20. The approximate number of subjects involved in the clinical trial.

In EU countries, in addition to the provisions of the ICH GCP and Directive 2001/20/EC, when compiling information for the subject and the informed consent form, it is necessary to follow the provisions of the Detailed Guidelines on the format of documents submitted to the ethics committee [8], as well as take into account the requirements for the protection of confidential information, in accordance with Directive 95/46/EC [9].. For example, the manual separately prescribes the need to indicate that if the subject refuses to continue participating in the study, his new medical data will not be entered into the database, and all data already collected can be withdrawn, as well as the right of the subject or his legal representative to be notified of any plans for additional, data analysis not provided for by the informed consent form (in these cases, it is necessary to request a separate consent of the subject, and he, in turn, has the right to refuse to participate in such an additional analysis). If genetic tests are to be performed during a clinical trial, the subject should be given comprehensive information about this, including a description and justification of such genetic tests, a list of planned tests and an indication of whether biological samples will be stored for additional tests in the future, as well as an indication that the patient may refuse to conduct genetic tests, but at the same time, take part in the non-genetic part of the clinical trial. The requirements of the Ukrainian legislation regarding the minimum amount of information provided to the subject generally repeat those of the ICH GCP and the European Directive.

The issue of clear and accessible presentation of information in the form of informed consent (the requirement of clause 4.8.6 of ICH GCP) deserves special attention. This is especially important in cases where people with intellectual disabilities due to age and/or diseases are planned to participate in the study (for example, patients with mild and moderate dementia, elderly and senile patients, etc.), the studied drug or research procedures have a large number of side effects that need to be described in a language accessible to the subject without using medical terms, the subjects have little time to familiarize themselves with the document and discuss all incomprehensible issues (for example, in the case of a sufficiently acute pathology, when the decision to participate in the study must be made within a few hours). However, often informed consent forms are drawn up on the basis of a clinical trial protocol written in complex medical language by specialists with special (medical) education who are familiar with most of the terms. It is difficult for them to assess the "intelligibility" of the presentation for a potential patient, and even more so to determine the average intellectual (educational) level in the target group, without having the appropriate tools and sources of information.

For the English language, so–called readability indices have been developed - measures to determine the complexity of the reader's perception of the text (at the same time, the text is usually considered "understandable" if a person has understood at least 80% of the information provided, while for informed consent it is desirable to achieve 100% understanding). Readability indices can be calculated based on several parameters: sentence length, word length, the specific number of the most frequently used and rarely used words, etc., and are evaluated as the "intelligibility" of the text for a particular part of the population (for example, text for 5th grade students, text for university graduates, etc.). In In the USA, special studies are being conducted that make it possible to correlate the numerical value of the indices with a certain population group – this makes it possible to focus on a particular numerical value of the index when compiling informed consent in clinical trials. However, due to the peculiarities of each language (the average length of sentences and the length of words, the use of articles and prepositions, ways of connecting words in a sentence, etc.), formulas for calculating indexes in one language cannot be used for another, their correction is necessary. And given the different average educational level and its distribution in the populations of different countries, it is impossible to extrapolate and estimate the numerical values of the indices obtained. Russian Russian and Ukrainian languages, unfortunately, have not developed such indexes (although there are corrected versions of English indexes for the Russian language), which, of course, makes it difficult to write and expert evaluation of information for the subjects and the form of informed consent. Despite this, in each specific case, it is necessary to look for a middle ground between the completeness of the presentation of information, its simplicity and adequate volume. In addition, when compiling an informed consent form in Russian or Ukrainian, it is necessary to remember that the overload of participial and adverbial phrases, a large number of complex sentences, a large number of definitions for one word and special terminology significantly worsen the perception of the text.

We should also not forget about the high-quality printing of the information booklet for the patient and the informed consent form (these parameters should also be evaluated by the ethics commission), because the completeness of the perception of information by the subject is affected by the quality of the paper (for example, the contrast of letters on yellow paper is lower, and the coated sheet reflects light more intensively and makes it difficult to read), fat content letters and the distance between them (bold closely spaced letters can merge and make it difficult to read), the proportions and sizes of letters, the configuration and size of fonts (preferably avoid curly fonts), the length of lines, the width of the page margins, etc. Such details should be taken into account when preparing documentation in each clinical trial (employees of contract research organizations and clinical bases should understand the importance of printing informed consent and not allow poor-quality copying or printing of this document, reducing the font to save paper, using color sheets without prior approval, etc.), as well as in some cases (for example, in ophthalmological studies, it is necessary to assess the visual acuity of the target group of patients in advance and take it into account when developing an informed consent layout). Despite extensive experience in conducting clinical trials in the USA and EU countries and attention to compliance with ethical principles at all stages of preparation and conduct of research, the shortcomings of the informed consent form remain a frequent finding during regulatory inspections. For example, the table provides an exhaustive list of problems related to the content and readability of informed consents identified during FDA inspections (informed consents were approved by the sponsor of the study and the Ethics Commission) [10].

TableFrequent problems related to the content and readability of informed consent forms identified during FDA inspections

(according to [10] with abbreviations)Problem

The most ethically difficult situations that researchers and members of ethics commissions have to face are clinical studies involving children and incapacitated persons, clinical studies in emergency situations and non-therapeutic studies (that is, studies without any clinical benefit for the subjects). These issues are spelled out in the ICH GCP, the European Directive and the domestic Procedure for Conducting clinical Trials only in a framework, which sometimes makes it difficult to interpret them. Uncertainty may arise when interpreting the term "legal representative" – in this case, it is necessary to remember that the implementation of the ICH GCP principles should be based on the entire set of legislation of the country of implementation. In Ukraine, the term "legal representative" is defined in the law "On Citizenship of Ukraine" (parents, adoptive parents, foster parents, guardians, trustees, representatives of institutions that perform the duties of guardians and trustees) [11] and in the law "On Psychiatric care" (parents (adoptive parents), guardians or other persons, authorized by law to represent the interests of persons who suffer from mental disorders, including the protection of their rights, freedoms and legitimate interests in the provision of psychiatric care) [12]. It is obvious that adult children of elderly parents or children/parents of adult patients with severe psychiatric pathology, as well as their other relatives, acquaintances or neighbors are not legal representatives and cannot sign informed consent instead of the subject (except in cases of formal guardianship or guardianship).

When children are included in clinical trials, both parents must give informed consent (except in cases of officially confirmed deprivation of parental rights). Even in cases where consent to participate in the study is given by the parents or legal representatives of an incapacitated patient, the subject himself must be provided with objective information about the study, risks and adverse effects in a form accessible to him. The fundamental principle in these cases remains respect for the person (be it a child or an incapacitated adult patient). It should be taken into account that a child can and should take part in making a final decision about his participation in the study, and his refusal is an insurmountable obstacle to the inclusion of a small patient in a clinical trial. In exceptional cases, a child may be included in a clinical trial based on the consent of both parents (without the consent of the child himself) – for example, if the study does not pose an excessive risk, but offers a tangible and necessary therapeutic benefit (for example, the study of a new drug for the treatment of a pediatric oncological or hereditary disease for which there is no alternative effective treatment method). However, such a possibility should be prescribed in the protocol of the clinical trial, and the proposed procedure approved by the ethics commission.

The age limits within which children can or should give separate consent to participate in the study are not prescribed in the ICH GCP (only the statement that it is necessary to provide information in an accessible form and take into account explicit disagreement), but are determined by the legislation of each specific country (or state). In fact, this age is determined based on the psychophysiological characteristics of each age group, may differ depending on the study and in each case must be approved by the Ethics Commission (having a sufficient level of competence in pediatrics). In training materials and some articles, the following "framework" recommendations sometimes sound (for the USA): up to 7 years of age, written consent of the child is not required, written consent of the parents is sufficient; from 7 to 13 years of age, in addition to parental consent, written consent is required in an abbreviated, age-adapted form; from 14 to 17 years of age, a teenager puts his signature on the full form, next to the signatures of the parents.

Ukrainian legislation also does not clearly define the age limits for each of these options for obtaining informed consent to participate in clinical trials, however, the peculiarity is that both parents must be informed and consent; it is also necessary to take into account the obvious unwillingness of the child to participate in the study (regardless of his age). All features of informing patients and their parents in pediatric research should be clearly and in detail spelled out in the protocol, reviewed and approved by the ethics Commission and strictly carried out when conducting research on clinical bases.

Another important and not fully understood question is the interpretation of the concept of "independent witness" – who can be an independent witness and in which cases his participation is necessary. ICH GCP defines an independent witness as a person independent of clinical research who is not subject to unscrupulous influence of members of the research team, is present when informing the subject if he cannot read, and reads the information set out in the informed consent to the subject (clause 1.26). Clause 4.8.9 ICH GCP indicates that by signing the informed consent form, an independent witness confirms that the information from the form was fully explained to the subject and understood by him, and that the subject voluntarily agreed to participate in the clinical trial. The detailed European guidelines [8] also recommend that the subject be informed of the justification for the participation of a witness, information about the method of choosing a witness and the procedure for obtaining consent. In Ukrainian legislation, an independent witness is mentioned only in the Manual 42-7.0:2005 [7] – in the same wording as in the ICH GCP. However, in reports and training sessions, representatives of regulatory authorities recommend that an independent witness be involved in signing informed consents only if such a procedure (and the justification for its application) is described in the protocol and approved by the ethics commission – otherwise, abuse and violations of the rights of the subjects cannot be excluded. The choice of a witness is also quite difficult, since it is necessary to guarantee its "independence". Thus, it is not recommended to involve members of the research team for this role; employees of the clinical base who are not involved in the study can be witnesses only if they are not under the direct influence of the researcher (for example, if the researcher is the chief physician); relatives of the subject may have a conflict of interest and not act in his interests, therefore they are also not quite "independent" [10].

The procedure for informing the patient and obtaining informed consent in case of emergency conditions should be clearly spelled out in the protocol of the clinical trial and carefully evaluated by the ethics commission during the examination of materials in order to exclude the possibility of violation of the rights of the subjects.

(To be continued)list of literature

1. The Old Testament.

The Book of Daniel, chapter 1:11-15.
2. Gulyaev D.V. The first scientific and practical school of neurologists "Carpathian readings", October 2007.
3. Are you truly informed about informed consent? Lisa Golec – Monitor, Fall 2004.
4. The order of carrying out the klinichnih viprobuvan likarskikh zasobiv ta expertize the material of the klinichnih viprobuvan, hardening by the order of the Ministry of Health of Ukraine vid 13.02.2006 p. No. 66.
5. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001.
6. ICH Harmonized Tripartie Guideline. Guideline for Good Clinical Practice (E6). – Jan 1997.
7. Nastanova z klinichnih doslizhen "Nalezhna klinichna praktika" 42-7.0:2005.
8. Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006, Revision 1.
9. Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995, as amended by Regulation (EC) No 1882/2003.
10. Good Clinical Practice: Question&Answer Reference Guide/Edited by M.P. Mathieu – Barnett International – May 2007.
11. The Law of Ukraine "About the Greatness of Ukraine", 2001.
12. The Law of Ukraine "About psychiatric assistance", 2000.
13. The foundations of the legislation of Ukraine about the protection of health, 1996.

Portal "Eternal youth" www.vechnayamolodost.ru20.05.2008