What informed consent materials must explain
A consent form informs prospective participants about a trial and obtains their consent to take part. The consent discussion and the materials given to participants explain a defined set of matters, and they carry no language through which a participant waives, or appears to waive, legal rights. ICH E6(R3) and US federal regulation each list these matters. Twenty common elements belong in most multinational forms, and some countries add requirements of their own on the form's content or on its length and layout.
The two parts of a consent form
A consent form has a dual function: to inform prospective participants about important aspects of the trial and to obtain their consent to take part. Its typical structure reflects this and commonly includes an information sheet on aspects such as the study purpose, the proposed treatment and administration schedule, eligibility and exclusion criteria, risks and benefits, and data protection provisions, and a declaration of consent to be signed by the participant or their legal representative.
Elements under ICH E6(R3)
Under ICH E6(R3), the consent discussion and the materials given to participants should explain, as applicable, the purpose of the trial; that the trial involves research, with a summary of its experimental aspects; the investigational products and the probability of random assignment to them where applicable; the trial procedures to be followed, including all invasive procedures; what is expected of the participants; the reasonably foreseeable risks or inconveniences to the participant and, where applicable, to their partner, an embryo, a foetus or a nursing infant; and the reasonably expected benefits, with the participant made aware where there is no intended clinical benefit to them.
They should also explain the alternative procedures or courses of treatment that may be available to the participant and their important potential benefits and risks; the compensation or treatment available in the event of trial-related injury; any anticipated prorated compensation for taking part; and any anticipated expenses of taking part. The ethics committee should ensure that information on payment to participants, including the methods, amounts and schedule of payment, is set out in the consent materials and in any other information given to participants.
The materials should further explain that participation is voluntary and that the participant may stop taking the investigational product or withdraw at any time without penalty or loss of benefits to which they are otherwise entitled; the follow-up procedure for participants who stop the product, withdraw or are discontinued; how the participant's data will be handled, including on withdrawal or discontinuation, in accordance with applicable requirements; and the foreseeable circumstances or reasons under which their participation may be terminated.
The materials should explain that by agreeing to take part, the participant or their representative allows direct access to source records, on the understanding that the confidentiality of the participant's medical record will be safeguarded. Direct access is permission to examine, analyse and verify records important to evaluating the trial, on site or remotely. The materials should explain that this access is limited to reviewing trial activities or reviewing or verifying data and records, by the regulatory authorities, the sponsor's representatives such as monitors or auditors and, in accordance with applicable requirements, the ethics committee. The materials should also explain that records identifying the participant will be kept confidential and, as far as applicable requirements permit, will not be made publicly available; that if the results are published the participant's identity will remain confidential; and that the trial may be registered on publicly accessible and recognised databases, as applicable requirements provide.
The consent materials should also describe what participant-related data will be collected, how the data may be used in the trial and which parties will have access to the participant's personal information, such as health records and home address, for example when trial-related activities take place at the participant's home or local healthcare centre or when data are collected remotely through digital health technologies.
They should also explain that the participant will be told in a timely manner if information becomes available that may be relevant to their willingness to continue; whom to contact for further information about the trial and about their rights, and whom to contact in the event of a suspected trial-related injury; the expected duration of their participation; the approximate number of participants in the trial; and that the trial results, and information on their own actual treatment where appropriate, will be made available to them if they want it, once the sponsor has it.
The ethics committee may ask for participants to be given more information than these elements set out when, in its judgement, the additional information would add meaningfully to the protection of their rights, safety or well-being.
Elements under US federal regulation
The US content requirements for consent include fifteen elements.
The form must state that the study involves research, explain its purposes and the expected duration of participation, describe the procedures and identify any that are experimental. Participants must know that they are not being treated with an approved product. It must describe any reasonably foreseeable risks or discomforts, and any benefits to the participant or to others that may reasonably be expected. It must disclose appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the participant. Participants are entitled to be told of less risky or other alternatives, or whether a study device has provisional approval. It must state the extent, if any, to which the confidentiality of records identifying the participant will be maintained, and note the possibility that the US Food and Drug Administration (FDA) may inspect them.
For research involving more than minimal risk, meaning risks greater in and of themselves than those ordinarily met in daily life or during routine physical or psychological examinations or tests, the form must explain whether any compensation and any medical treatment are available if injury occurs and, if so, what they consist of or where further information may be obtained. It must say whom to contact with pertinent questions about the research and participants' rights and whom to contact in the event of a research-related injury, as well as whom to contact about conflicts of interest and how to obtain further information about financial arrangements. The participant must know who is paying for the study and whether the investigator has any conflict of interest. The form must state that participation is voluntary, and that refusing to take part or stopping at any time involves no penalty or loss of benefits to which the participant is otherwise entitled.
It must also state that the treatment or procedure may involve risks that cannot currently be foreseen; the anticipated circumstances in which the investigator may end a person's participation without regard to their consent; any additional costs of taking part; the consequences of deciding to withdraw and the procedures for an orderly end to participation; that significant new findings made during the research that may bear on the participant's willingness to continue will be provided; and the approximate number of participants. That number tells a person whether they will be the only participant or one of many. Where the trial's information has been or will be submitted to the registry databank under section 402(j) of the Public Health Service Act, the form must carry a prescribed statement: that a description of the trial will be available on ClinicalTrials.gov, as US law requires, that the site will not include information that can identify the participant, that it will at most include a summary of the results, and that it can be searched at any time.
Elements common to multinational forms
Twenty key elements belong in most multinational consent forms, though each country may have a few elements of its own. They fall under four questions.
On why the trial is being done, the form should explain what research means and how the participant's taking part is part of it, and give the trial's objective in one sentence, such as whether it investigates safety, efficacy, a different dose or route of administration, or a new indication.
On what will happen during the trial, the form should describe in one or two sentences the investigational product, the controls and the probability of random assignment. It should identify or explain the parts, tests or procedures the protocol requires that would not be part of the participant's normal care outside the trial, such as blood samples for a pharmacokinetic study or for specific biomarkers, and questionnaires or quality-of-life surveys. Copying the procedures from the protocol can be easy, but it is important for the writer to adapt them to a participant audience, saying, for example, what a sample will be used for and when a procedure will take place. The form should also give what the participant must do to remain in the trial; the number and length of visits and procedures; the approximate number of participants and the phase of the trial; and the risks, discomforts and inconveniences, including adverse events, the potential for stopping or changing current treatments and the potential effects, and potential unintended disclosure of private information, data or trial-specific procedures. Examples of these risks, discomforts and inconveniences are the noise of magnetic resonance imaging, time off work or school, and arranging child care.
On benefits and costs, the form should explain any direct impacts or benefits to the participant, to other patients or to society at large; the standard of care and the options besides the trial, such as a surgical option not offered in it; who pays for the trial drugs, visits and procedures; and any prorated payments, reimbursements or vouchers the sponsor provides for trial-related expenses such as travel, lodging and meals. Presenting these payments as a benefit can be viewed as coercion.
On how participants will be protected, the form should state that participation is voluntary and can be refused or withdrawn at any time without penalty; what form of compensation is included for trial-related injury, which cannot include legal language telling participants the sponsor is not responsible; who will be allowed to see their medical records, such as trial staff, regulators and the ethics committee; how their personal information will be protected; how significant new findings made during the trial, such as a new treatment option or adverse events, that may affect their willingness to continue will be provided; whom to contact for trial information and trial-related injury, including the investigator, the ethics committee or institutional review board and an emergency contact; and the reasons participation may be terminated, which must be actual information, not just a general statement.
National requirements beyond the ICH guideline
Some countries add requirements of their own for the form, on its content or on its length and layout. Consent forms in China generally complied with the ICH good clinical practice requirements (ICH 4.8), whereas Japan followed the same ICH section but required more detail, for example an explanation of what a clinical trial in general is about, and actual data on adverse drug reactions from previous studies, from the package inserts of similar products and from the investigator's brochure. To make the form visually friendly to patients, Japanese forms often used tables, charts and pictures, and font and font size were carefully considered.
Some EU countries limit the length of the form by local regulation. The Czech authority allows no more than 12 pages and requires the study procedures in a single table on a single page. Spain allows at most 15 pages, in Arial or Times New Roman of at least 11 points with line spacing of at least 1.5, which would probably mean no more than 13 pages of an English master form.
The Spanish Agency of Medicines and Medical Devices (AEMPS) has also introduced requirements for the form, which medical writers may consider when working on its master version:
- Infrequent adverse events can be summarised.
- The explanation of the risks of common care procedures can be removed.
- For a marketed medicine, a set wording may be included saying that, because the drug is approved by the competent health authorities, information on its side effects is available to everyone in its information leaflet, and asking the participant to talk to the study doctor to obtain that information.
- Lengthy descriptions of study procedures should be replaced by a table, not one of the protocol's tables but one that is simpler and easier for the patient to understand.
- The same explanations need not be repeated for each visit, which lengthens the document unnecessarily, and information on common routine examinations such as blood pressure, pulse, electrocardiogram, weight and height should be left out.
- The exact activities to be carried out should be named, for example as blood sample collection; details such as the biomarkers determined or the drug levels quantified are not necessary if it has already been explained that blood will be taken for these purposes at some visits.
- Technical terms such as double-blind and randomisation should be avoided in favour of a plain description or direct explanation.
- Animal data should not be given when sufficient human data are available.
- The risks and discomforts of study tests should be described without excessive detail, but it should be made clear when visits take longer because of additional procedures the study requires, such as questionnaires or kinetic samples.
- Risks and discomforts already described with a study activity must not be repeated.
It may be helpful to bring into medical writing practice the lists of requirements for the form that local regulatory agencies such as the AEMPS have developed, with the aim of making the form as short as possible and simple for a layperson to read and understand.
Exculpatory language
Exculpatory language is wording through which a participant or their representative is made to waive, or appear to waive, legal rights, or which releases or appears to release the investigator, the sponsor, the institution or its agents from liability for negligence. The US regulation Title 45 Part 46 forbids it in any informed consent, oral or written. Under ICH E6(R3), none of the information provided to the participant or their representative during the consent process should contain language that causes the participant to waive or appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor or their service providers from liability for negligence. The FDA issued draft guidance on how to use exculpatory language, which essentially means waivers, in informed consent forms.