Subjects and informed consent

Definitions

Clinical Trials Regulation (EU) No 536/2014 (CTR) provides, among other things, definitions for:

The consent process

According to Article 29 of the CTR, informed consent shall be written and shall be dated and signed by the subject or their legally designated representative and by the person providing the information.

Where the subject is unable to write, i.e. cannot sign the consent, consent may be given and documented through appropriate alternative means in the presence of at least one impartial witness. In that case, the witness shall sign and date the informed consent.

The written information and the signed consent shall be kept at the clinical trial site, and a copy shall be given to the subject or their representative.

According to the Swedish MPA provision HSLF-FS 2021:109, the person responsible for obtaining informed consent shall also be the person who conducts the interview referred to in Article 29(2)(c) of the CTR. The basic rule is therefore that it is the responsibility of the qualified medical doctor (physician licensed by the Swedish National Board of Health and Welfare) or qualified dental practitioner (dentist licensed by the Swedish National Board of Health and Welfare) to conduct the interview and obtain consent for participation in a clinical trial on a medicinal product. If there are special reasons, the Swedish Medical Products Agency (MPA) may grant an exemption, in which case consent may be obtained by other health care professionals. For example, treatment may have to be initiated according to the trial protocol in circumstances where a licensed physician cannot be present, such as during transport by ambulance.

The procedure for obtaining consent shall be described in detail in the trial protocol. If it is proposed that a professional other than a licensed physician/dentist obtain consent, the sponsor shall justify why this is necessary.

Information for the subject – content

The information to be provided to subjects is set out in Article 29 of the CTR.

The information should enable the subject to understand:

• a description of the purpose, benefits, implications, risks and inconveniences of the clinical trial
• the subject’s rights and guarantees regarding their protection, and in particular their right to refuse to participate and the right to withdraw from the clinical trial at any time without any resulting detriment and without having to provide any justification
• a description of the conduct of the clinical trial and the expected duration of the subject’s participation
• the possible treatment alternatives, and the follow-up measures if the participation of the subject in the clinical trial is discontinued
• the right to compensation for any damage.

The EU trial number shall be specified, together with information on how this number can eventually be used to view the results of the trial in the EU database, where a summary that is comprehensible to laypersons shall be made available.

The information shall be comprehensive, concise, clear, relevant and understandable to a layperson. The information should be in writing and given to the subject or their legally designated representative. In addition to the information listed in Article 29, recommendations from the Swedish Ethical Review Authority should be taken into account.

Note that there should be signature lines for both the subject and the person obtaining consent on the consent form.

When communicating the information, particular attention shall be paid to the information needs of specific patient groups and individual subjects, and appropriate methods shall be used to communicate the information.

Cluster trials

Article 30 of the CTR describes a simplified form of obtaining consent from a group of subjects rather than from individual subjects, known as cluster trials. This procedure may only be used if it is permitted in the Member State concerned. The Medicines Act (2015:315) (in Swedish läkemedelslagen) states that it is not permitted in Sweden.

Protection of subjects and informed consent - special conditions

A clinical trial on a medicinal product may be conducted only where all the conditions set out in Article 28 of the CTR are met. In addition, the legal text specifies what conditions shall be met for the following vulnerable groups of subjects:

Clinical trials on incapacitated subjects

A clinical trial on incapacitated subjects who have not given (or have not refused to give) informed consent before the onset of their incapacity may be conducted only where all the conditions set out in Articles 28 and 31 of the CTR are met.

• According to the Swedish Medicines Act, a guardian or trustee, under Chapter 11 Section 4 or 7 of the Parental Code, with authority to take care of the individual, is the legally designated representative of a subject who is not competent to make decisions due to illness, mental disorder, weakened state of health or any other similar condition. This representative may give informed consent to a clinical trial on a medicinal product on behalf of the subject.
• The incapacitated subject shall have been informed of the trial in a way that is adequate in view of their capacity to understand. The subject shall as far as possible take part in the procedure to obtain informed consent.
• If an incapacitated subject who is capable of forming an opinion and assessing the information refuses to participate in the trial or at any time wishes to withdraw their participation, the investigator shall respect this.
• No incentives or financial inducements shall be given to the subject or their representative, except for compensation of expenses and loss of income directly related to participation in the trial.
• The trial shall be essential to the treatment of incapacitated subjects and data of comparable validity shall not be able to be obtained in clinical trials on persons able to give their own consent, or by other research methods.
• The trial shall relate directly to a medical condition from which the subject suffers.
• There shall be scientific grounds for expecting that participation in the trial by an incapacitated subject will produce:
  • a direct benefit outweighing the risks and burdens involved, or
  • some benefit for the population represented when the clinical trial relates directly to the life-threatening or debilitating medical condition from which the subject suffers and such trial will pose only minimal risk to, and will impose minimal burden on, the incapacitated subject concerned in comparison with the standard treatment of the incapacitated subject’s condition.

Clinical trials on minors

• A clinical trial on minors may be conducted only where all the conditions set out in Articles 28 and 32 of the CTR are met. Among other things, minor subjects shall be informed about the trial by the investigator or another member of the investigational team who has experience of working with children. The information should be adapted to the child’s age and mental maturity. The information shall be both oral and written.

There are also national rules to consider:

• In Sweden, a minor is a person younger than 18 years of age.
  According to the Swedish Medicines Act, guardians are the legally designated representatives who may give informed consent to a clinical trial on a medicinal product on behalf of a minor subject. Note that if there are two guardians, both must sign and date the consent form before any study-related measures are taken. However, the signing need not take place at the same time. If a guardian is located elsewhere, the consent may in urgent cases be sent by digital means (for example by e-mail), and later confirmed by original documents.

• According to the Medicines Act, a minor subject who has reached the age of 15 shall also give their own informed consent to participate in the clinical trial on a medicinal product, provided that the subject understands the implications of the trial for him or her.
• According to the Medicines Act, if a minor subject reaches the age of 15 during the course of a clinical trial, the subject’s explicit informed consent shall be obtained before that subject can continue to participate in the clinical trial.
  A subject who has reached the age of 15 and has given their consent as described above does not have to give a new consent if they reach the age of 18 during the course of the trial.

Clinical trials on pregnant or breastfeeding women

A clinical trial on pregnant or breastfeeding women may be conducted only where all the conditions set out in Articles 28 and 33 of the CTR are met.

Clinical trials in emergency situations

In a clinical trial in an emergency situation a subject may be included, and at the same time a first intervention according to the protocol may be carried out, prior to informed consent has been obtained. The trial protocol should describe the information and consent process in relation to inclusion of the subject.

The condition is that all the circumstances set out in Article 35 of the CTR apply:

• Due to a sudden life-threatening or other sudden serious medical condition, the subject is unable to give prior informed consent and to prior receive information about the clinical trial.
• There are scientific grounds to expect that the subject’s participation in the clinical trial will have the potential to produce a direct clinically relevant benefit for the subject, resulting in a measurable health-related improvement alleviating the suffering and/or improving the health of the subject or the diagnosis of their condition.
• It is not possible within the therapeutic window to provide all prior information to and obtain the consent from the subject’s legally designated representative.
• The clinical trial relates directly to the subject’s medical condition and the trial is of such a nature that it may be conducted exclusively in emergency situations.
• The clinical trial poses a minimal risk to, and imposes a minimal burden on, the subject in comparison with the standard treatment of the subject’s condition.
• After the first intervention, the investigator shall obtain informed consent for the subject to continue participation in the trial. In the case of incapacitated subjects and minors, the investigator shall inform the subject and the legally designated representative (guardian or custodian) as soon as possible and obtain the informed consent of the representative.
• In the case of other subjects, the investigator shall, as soon as possible, inform the subject or the representative, whichever is sooner. Informed consent shall be obtained from the subject or the representative, whichever is sooner. If the representative is the person giving consent, the consent shall be obtained from the subject as soon as he or she is capable to be able to continue participation in the trial.
  If the subject or, where applicable, their representative does not give consent, he or she shall be informed of their right to object to the use of the data obtained.