The consent process ICH E6(R3) requires
Under ICH E6(R3), informed consent is a process with requirements of its own: conditions it has to meet, a signature and documentation, a representative when the participant cannot consent, a witness when they cannot read, provision for emergencies, revision and re-consent as new information emerges, obligations that run to the end of participation, and consent for the use of real-world data.
Consent as a process
The informed consent process is an integral part of the conduct of interventional clinical trials. When a participant decides whether to take part, informed consent is the critical component.
Informed consent is a process, not just the form most people think of when they hear the term. It is a process of exchanging information that can include both written and visual materials, such as a graphic illustration used as a visual aid in discussions between patient and doctor, or short videos explaining the purpose of a trial or the procedures it involves. ICH E6(R3) defines informed consent as the process by which a participant or their legally acceptable representative voluntarily confirms their willingness to take part after having been informed and given the opportunity to discuss all aspects of the trial relevant to their decision. A legally acceptable representative is an individual, or a juridical or other body, authorised under applicable law to consent on behalf of a prospective participant to their participation in the trial. Informed consent is documented by a written, signed and dated consent form. The form may be on paper or electronic.
Conditions on the process
In obtaining and documenting consent, on paper or electronically, the investigator should comply with applicable regulatory requirements and adhere to GCP and to the ethical principles originating in the Declaration of Helsinki. The process should include five conditions:
- Before anyone is consented or enrolled, the investigator should have the ethics committee's documented approval or favourable opinion of the consent materials and the process.
- The information should be as clear and concise as possible, in simple language, avoiding unnecessary volume and complexity, so that the participant or representative adequately understands the objectives of the trial, alternative treatments, potential benefits and risks, burdens, their rights and what is expected of them, and can make an informed decision.
- Varied approaches, such as text, images, videos and other interactive methods, may be used in the process, including to provide information to the participant. They may also be used to support the participant's understanding of the trial. For providing information and for the discussion about the trial, they may include, for example, text in different formats, images and videos, and telephone or video conferencing with site staff. The characteristics of the potential trial population, whose members may, for example, lack familiarity with computerised systems, and the suitability of the method of obtaining consent should be taken into consideration when developing the consent materials and process. Where computerised systems are used to obtain consent, participants may be given the option of a paper-based approach.
- Obtaining consent remotely may be considered where appropriate.
- Whether the process is in person or remote, the investigator should assure themselves of the identity of the participant or representative in accordance with applicable requirements.
When consent is obtained remotely, the investigator should assure themselves of the identity of the participant or representative. This may be performed, for example, by verifying an official identification document over a video call, and the verification method and the measures safeguarding data privacy should be pre-specified. Where computerised systems support the process or consent is obtained remotely, participants may be offered a paper-based or in-person process, to the extent feasible, if they prefer it. The modalities of the consent process, such as remote or in person, should be described in the protocol.
The consent materials and process should be tailored to reflect the operational approaches, design elements and data sources incorporated in the trial, and the process, including the methods and tools for obtaining consent, should be in accordance with applicable regulatory requirements.
The consent process should be conducted by the investigator or by site staff the investigator has delegated, in accordance with applicable requirements. Neither the investigator nor site staff should coerce or unduly influence a participant to take part or to continue their participation. Before consent is obtained, the investigator or delegated site staff, in accordance with the protocol and the conditions of the ethics committee's approval or favourable opinion, should give the participant or representative ample time, unless justified, for example in an emergency, and the opportunity to enquire about the trial's details and to decide whether to take part. Their questions about the trial should be answered to their satisfaction.
Signature, documentation and copies
Before participation, the consent form should be signed and dated by the participant or their legally acceptable representative and, where appropriate, by an impartial witness and by the investigator or the delegated site staff member who conducted the discussion. By signing, the investigator or staff member attests that consent was freely given and that the information was accurately explained to and apparently understood by the participant or representative. The signature may be physical or electronic. A signature is a unique mark, symbol or entry executed, adopted or authorised by an individual in accordance with applicable requirements or practice to show expression of will and to allow authentication of the signatory, that is, to establish a high degree of certainty that the record was signed by the claimed signatory.
Before participation, the participant or representative should receive a copy, paper or electronic, of the signed and dated form and of any other consent materials provided, in accordance with applicable requirements. During the trial, they should receive copies of form updates and of any other updated materials.
Representatives, witnesses and emergencies
Where a participant cannot consent themselves, such as a minor or a patient with severely impaired decision-making capacity, their legally acceptable representative should consent on their behalf. The activities of consenting, of re-consent where applicable and, where relevant, of withdrawing consent then apply to the representative.
Assent is the affirmative agreement of a minor to take part, and the absence of an expression of agreement or disagreement should not be interpreted as assent. Where a minor is to be included, age-appropriate assent information should be provided and discussed with them as part of the consent process, and assent obtained as appropriate. A process for consent should be considered for a minor who reaches the age of legal consent during the trial, in accordance with applicable requirements. A participant who can be enrolled only with a representative's consent should be informed about the trial in a manner that facilitates their understanding and, if capable, should sign and date the consent or assent form as appropriate.
Where the participant or representative cannot read, an impartial witness should be present, remotely or in person, throughout the consent discussion. An impartial witness is a person independent of the trial who cannot be unfairly influenced by people involved with it, who attends the consent process when the participant or representative cannot read, and who reads the consent form and any other documented information supplied or read to the participant or representative. After the form and other information have been read and explained, and the participant or representative has orally consented and, if capable, signed and dated the form, the witness should sign and date it. The witness's signature attests that the information was accurately explained to and apparently understood by the participant or representative and that consent was freely given.
In an emergency where prior consent of the participant is not possible, the representative's consent should be requested if a representative is present. Where prior consent is not possible and no representative is available, enrolling the participant should require measures described in the protocol or elsewhere, with documented approval or favourable opinion by the ethics committee, to protect the participant's rights, safety and well-being and to ensure compliance with applicable requirements. The participant or representative should be informed about the trial as soon as possible and consent requested as appropriate.
New information and re-consent
The sponsor should aggregate, as appropriate, and review relevant safety information in a timely manner, and this may result in updates to the protocol, the investigator's brochure, the consent materials and related documents. The sponsor should review emerging safety information for new data that may affect a participant's willingness to continue, the conduct of the trial, or an approval or favourable opinion, and any such information should be communicated to participants, investigators, the ethics committee and the regulatory authorities, as applicable, in a timely manner.
The participant or representative should be informed in a timely manner if new information becomes available that may be relevant to their willingness to continue, and both the communication of that information and their confirmation of willingness to continue should be documented.
New information that could affect willingness to continue should be assessed to determine whether re-consent is needed. For example, depending on the stage of the trial, consideration should be given to whether the information is relevant only to new participants or to existing participants. Where re-consent is needed, as with emerging safety concerns, the new information should be clearly identified in the revised consent materials. Revised consent materials should have the ethics committee's approval or favourable opinion before they are used. As the trial progresses, the investigator or institution or the sponsor should provide any updates to participant information to the ethics committee, in accordance with applicable requirements.
Consent documents are routinely revised during an ongoing study when new information, such as a newly identified side effect, might affect participants' willingness to continue taking part. After being told of the new information, participants are asked to sign the new version if they agree to continue.
During the COVID-19 pandemic, it was important to communicate with participants not only about their trial but also about how the pandemic affected them and their trial, and some cases might need re-consent. For example, a participant who received medicines at home instead of at the clinic might need re-consent, because they might sometimes be in direct contact with the sponsor, or the site might have to give out their address and phone number to arrange the delivery.
Withdrawal and the end of participation
When a participant decides to stop treatment with the investigational product or withdraw, is discontinued, or reaches the routine end of the trial, the investigator should follow the protocol and related documents. For participants who did not reach the routine end, these may include instructions to avoid losing data already collected, in accordance with applicable requirements, so that the results are reliable. In general, losing already collected data may bias results and may lead, for example, to inaccurate conclusions about the safety profile of the investigational product.
A participant is not obliged to give a reason for withdrawing, but the investigator should make a reasonable effort to ascertain the reason while fully respecting the participant's rights. The investigator should consider whether a discussion with the participant or their representative is appropriate, focused on the reasons for withdrawal, to see whether the concerns can be addressed so the participant could reconsider, without unduly influencing their decision. The investigator or delegated site staff should consider explaining to the participant the value of continuing, to minimise withdrawals, and the investigator should ensure that this does not interfere with the participant's decision to refuse or withdraw at any time.
Where relevant, the investigator should inform the participant about the trial results and the treatment they received once that information is available from the sponsor after unblinding, with due respect for the participant's preference about being informed.
Consent for real-world data
Where a trial incorporates real-world data, the sponsor should, in accordance with applicable requirements, ensure that permission or approval is obtained from authorised entities such as ethics committees, or that consent is provided by the individuals whose health data or source records are used. That consent should describe the use of and access to the data and their source records by regulatory authorities and, where applicable, sponsor representatives and ethics committees. Such consent does not imply participation in an interventional trial activity.
Where the data were originally collected for purposes not specific to the trial and are subsequently incorporated into it, how consent is obtained may depend on local requirements and on the identifiability of the individual whose data are used. In some regions, consent may be obtained broadly to allow for potential future research use, and in others permission from an ethics committee may substitute for consent for secondary use. The sponsor should ensure that records of the consents or permissions are retained and available to regulatory authorities on request.