Informed consent (2)

Informed consent. A moment or a process?
Elena Rudneva, Weekly "Pharmacy"In the previous article, we talked about the basic principles of presenting information about a clinical trial and about the drug under study when involving patients or healthy volunteers in the trial.

However, every researcher who communicates with the subjects must understand that informed consent is not only a document, and not only a signature, and not only the fact of the consent of the subject. Informed consent is a process, an active dialogue between a doctor and a patient (a healthy volunteer), which begins even before the start of the study and ends significantly later than its completion, a process during which the subject gets the opportunity to make a decision about his further participation.

It is known that many patients, having voluntarily signed consent, begin to doubt the correctness of the decision made after a conversation with relatives, discussion with neighbors, or just a few days of reflection – this often happens because the subject during a conversation with a doctor could not formulate or was afraid to ask his questions and/or express concerns about the study, which means, remained insufficiently informed. The task of the researcher talking to the patient is not only to make sure that the signature on the form was put voluntarily and without coercion from relatives or medical staff, but also to find out whether the subject really understood all the information provided, including possible risks, rights and obligations, whether he asked all the questions that concern him, as well as to help the subject understand what worries him about participating in the study and give exhaustive explanations (excluding, however, psychological pressure on the patient).

The process of initially informing the patient and obtaining his consent may take several visits and require significant time and effort on the part of the research physician and his assistants. Although such a direct requirement is not contained in regulatory documents or ICH recommendations, it is considered advisable to document the process of communication with the subject in as much detail as possible in primary medical documentation, indicating the time it took for him to familiarize himself with the information.

In order to make sure that the patient (a healthy volunteer) has really read and understood the contents of the informed consent form, it may be useful to ask him a few questions – for example, "Tell us in your own words about what is written here", "Tell us what will happen during the study", "What do you expect as a result of participating in the study?", "What risks do you expect when participating in the study?", "What alternative methods of treating your disease do you know?". There were reports of the use of an online interactive consent form in several clinical trials [1] – after reading the information about the clinical trial on the web page, the subject automatically switched to checking its perception, and the subject could proceed to "signing" consent only when 100% correct answers to the test questions were reached. Despite the fact that most of the sponsoring companies, contract research organizations and ethics committees pay significant attention to the process of initial informing of the subjects, the actual state of affairs according to large-scale independent surveys of the subjects [1] is far from perfect. What can be said in this case about the problem of continuous interaction and constant informing of the subjects during the clinical trial, which is given much less attention?

The need to maintain constant information exchange with patients and healthy volunteers is indicated in the ICH Guidelines for Good Clinical Practice (clause 4.8.2.) [2,3]: "The form of written informed consent and other written information provided to subjects should be reviewed when new important information appears that may affect the consent of subjects. New versions of the form of written informed consent and written information can be used after a preliminary assessment and approval by an independent ethics committee. The subject or his legal representative must be informed in a timely manner of new information that may affect the subject's desire to continue participating in the clinical trial. The fact of providing this information must be documented." Thus, it is emphasized that the subject must re-agree to participate in the study (continue his participation in it), despite the new (often unfavorable) information received, which may relate to an increase in known risks (based on the results of periodic analysis of data on the safety of the studied drug), changes in the number of invasive procedures, an increase in the volume taken for analysis blood (as a result of changing the protocol of a clinical trial by amending it), etc., is the so–called re-consenting procedure.

When making administrative changes (for example, new contact numbers of the ethics committee), the subject must be provided with new information (which must be documented in the primary documentation, and a copy of the information sheet is stored in the researcher's file), but signing the updated form is usually not required [1].

A difficult question, of course, is the definition of a "critical mass" of new information that requires the development and implementation of a new form (it is obvious that it is not always advisable to change the form when registering each new serious side effect or suspected unforeseen side reaction). The subject should be informed about changes in the study procedures and give his consent before implementing such changes – this situation often occurs when amendments are made to the protocol of a clinical trial. If the subject refuses to accept changes to the procedure plan according to the amendment, he may be asked to refuse further participation in the clinical trial or continue participation according to the previous plan – depending on the essence of the proposed changes, the requirements of the sponsor and the recommendations of the ethics committee. Under no circumstances should the subject be forced to sign an updated consent form against his will, even if this is due to medical "expediency".

The timing of informing the subjects about new risks largely depends on the severity and probability of their occurrence. In practice, the decision to revise the informed consent form in connection with a change in the risk profile of the studied drug is most often made by the sponsor of the clinical trial, who has direct, complete and fastest access to information about the safety of the studied drug.

However, changes can be initiated by the ethics committee, which regularly receives new safety information (in the form of immediate reporting forms in case of suspected unforeseen adverse reactions and annual summary reports), or by a researcher. Only after receiving written permission from the ethics committee, an updated consent form can be provided to subjects already included in the clinical trial, or to those who are only invited to participate.

In the primary medical documentation, the process of re-informing the subject and signing the updated form must be described in the same detail as obtaining the initial consent. In some cases, the consent may be re–signed during the next scheduled visit of the patient, and in others, it is necessary to schedule an additional visit to inform the subject urgently (in accordance with the written recommendations of the sponsor or the requirements of the ethics committee in each case).

For the convenience of the subjects, especially in the case of providing voluminous information or a large number of changes being made, we can recommend [4] the additional use of special forms reflecting the changes made (Table 1) – such forms must also receive preliminary approval of the ethics committee along with the updated informed consent form.

Table 1. Example of a form reflecting the changes made to the updated informed consent form compared to the original one (according to [4] with changes)Randomized study of ABC monotherapy versus combination of ABC and XYZ

Another difficult issue is the need to inform about the changes of those subjects to whom these changes essentially do not apply. An example is the subjects of the control group of an open clinical trial with a change in the risk profile of the studied drug – the patient is well aware of the type of treatment he receives and understands that changes in the risk profile in this case do not concern him. Another example is the change in the research procedures provided for by the plan at the second visit – the subjects who will come to the third, fourth, etc. visits, these changes will not affect. More complicated is the question of the "activity" of participation – is it necessary to additionally inform the subjects and request their re-consent when they no longer receive the drug under study, and monitoring is conducted by phone, for example? In the information sheets of the US Food and Drug Administration (FDA), it is reported that the administration does not require the repeated consent of subjects who have completed their active participation in the study [1], however, if changes in the risk profile concern, for example, delayed adverse reactions, all subjects should be informed (information can be provided at the next scheduled visit or sent by mail). Neither ICH GCP nor Ukrainian legislation provides clear recommendations for the cases described above. The researcher should make a decision depending on the essence of the changes, as well as be guided by the requirements of the sponsor and the ethics committees, which in turn are based on standard operating procedures.

However, there are clinical studies during which neither the risk profile of the studied drug nor the research procedures change. Does this mean that the initial consent of the subject will be valid for all months or years of his participation in the study? In this case, the concept of ongoing consent includes informal, regular and often undocumented communication between the subject and the staff of the clinical base, the result of which (expression of consent) is continued participation in a clinical trial. After all, one way or another, the subject expresses his consent or disagreement to participate in a clinical trial at every communication with the staff of the research center, whether it is another visit to receive the studied drug or examination, a telephone conversation to clarify the well-being and complaints of the subject, etc. Examples of interaction with subjects, which are elements of the continuous consent process, proposed by Ames P.D. ([4], with changes), are presented below:

• During the initial process of informing the subject, discuss methods for providing new information
• Every time you meet with a subject, find out if they have any questions about the clinical trial – this way you will develop the habit of asking questions and strengthen their trust.
• Discuss any questions of the subjects as significant and important, even if they seem to you untimely and insufficiently substantiated
• Note for yourself the types of questions that the subject asks – this will help you determine what exactly is bothering him
• Always answer the question asked
• Note in the medical documentation that the patient wants to continue his participation in the clinical trial
• Have educational brochures for patients ready and recommend the subjects to read them (we are talking about general educational brochures such as "Becoming a volunteer in a clinical trial is your decision", "Is it right to participate in a clinical trial?", etc., which exist in abundance, for example, in the USA, and have not yet been developed in our country).

Thus, each interaction between the subject and a member of the research team is an opportunity for the subject to learn and gives him new information that may affect the desire to continue participating in the study. At the same time, the description in the primary medical documentation of each communication, which can be regarded as part of the continuous consent process, although not directly required by regulatory legal acts or special guidelines, is part of the "good documentation practice". For example, a subject called a research doctor and complained about the development of some undesirable phenomenon, during this telephone conversation, the researcher told the subject how often such an undesirable phenomenon occurs and with what probability to expect it in the future. Obviously, such information is not new in itself – it was certainly contained in the form of informed consent, however, obtained under new conditions (against the background of the development of an undesirable phenomenon), it may affect the desire of the subject to participate in a clinical trial. A brief record of the conversation that took place (and not just about the complaints that appeared) will later help to more fully and clearly restore the course of interaction with the subject. Some authors [4] recommend that during each visit of the subject to indicate in the medical documentation the fact that he agrees to continue his participation in the study – this helps to form the ethical basis of clinical research and maintain trust in this process. Proper and effective interaction with the patient (that is, ensuring continuous information and consent) is an important element for the retention of the patient in a clinical trial [5].

Thus, the informed consent of the subjects to participate in a clinical trial is a complex continuous process of interaction with members of the research team and continues throughout the trial. The importance of continuous consent is due to the fundamental ethical principle of respect for a person – it is an integral element of respecting the rights of patients during a clinical trial and optimizing its conduct from the point of view of the organizers.

List of literature1. Good Clinical Practice: Question&Answer Reference Guide/Edited by M.P. Mathieu – Barnett International – May 2007.

2. ICH Harmonized Tripartie Guideline. Guideline for Good Clinical Practice (E6). – Jan 1997.
3. Nastanova z klinichnih doslizhen "Nalezhna klinichna praktika" 42-7.0:2005.
4. The ongoing process of Informed Consent. Patricia D. Ames – Monitor, February 2006.
5. Tried and True Techniques for Motivating and Retaining Patients in Clinical Trials. K.Williams, N.Hook-Seid – Monitor, June 2007.

Portal "Eternal youth" http://vechnayamolodost.ru/24.06.2008