The Informed Consent Process I - The start of a Series

Today’s installment kicks off a series concerning the informed consent process. ICH-GCP defines informed consent as a process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.


Informed Consent for the purpose of Clinical Trials is something completely different than Informed Consent for the purpose of regular medical practice. Regular informed consent can be defined as a legal procedure to ensure that a patient or client knows all of the risks and costs involved in a treatment. The elements of informed consents include informing the client of the nature of the treatment, possible alternative treatments, and the potential risks and benefits of the treatment.

It is absolutely crucial to distinguish well between the two. Here is the core of the difference:

Medical practice Informed Consent is a practice to protect primarily the healthcare professional, documenting that the patient was informed of all aspects of a treatment, reducing the chance of a law suit at a later time.

Clinical Research Informed Consent is a practice to protect primarily the potential trial subject, documenting the that subject was informed of all aspects of a trial, which parts are experimental, what are the potential risks and possible benefits, etc., to enable the subject to make an informed decision on whether or not to take part in a clinical trial.

Industry representatives are likely to talk about the latter, clinical professionals are likely to think about the first, in countries where the medical practice informed consent is a very common part of practicing medicine. It is up to up all to ensure we are all talking about the same thing, when discussing Informed Consent.wow gold

ICH-GCP training of site staff

ICH-GCP says that the investigator should ensure that all persons assisting the trial are adequately informed about the protocol, the investigational product(s), and their trial related duties and functions (4.2.4). The investigator should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties (4.1.5).

If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator (PI) (1.34).
Thus, to live up to ICH-GCP, site staff, who are working under the overall responsibility of the Principal Investigator, need to be documentedly trained about the protocol, the IP and their duties and functions. It is not an absolute requirement of a study coordinator or sub-investigator to be trained on ICH-GCP.

Sit staff performing (all or a part of) the informed consent procedure make for another story. ICH-GCP says that in obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki (4.8.1). By virtue of that statement, I would expect anyone involved in the informed consent procedure to be formally trained on ICH-GCP.

That’s the guideline, and the outline of the minimum standard.

Which brings us to golden standard. Ideally, anyone playing an active role in a clinical trial site team should be appropriately trained on the international guidelines as ICH-GCP as well as the applicable regulatory requirement(s), besides the protocol, IP, duties and functions as outlined in GCP. And often they are, even if the CV does not reflect that.
An important aspect is proper training documenting. Formal ICH-GCP training, in a course which provides a certificate is one thing. Those are usually listed if attended. More often not listed are training moments which occur in the course of running trials. Sub-investigators, research nurses, study coordinators, people holding any of those kind of positions commonly attend a number of initiation meetings per year. Sometimes additionally some investigator meetings. At each of those occasions ICH-GCP training is provided. However those are most often not documented. Anyone who has not attended a full ICH-GCP training should update their CV (at least) annually to reflect attendance of those small sessions and document ICH-GCP training. Anyone who HAS attended a full ICH-GCP training should update their CV (at least) annually to reflect attendance of those small sessions as documentation of continued refresher training.

This topic came directly from the field, thanks Minal.wow gold

Source Documentation for Legally Acceptable Representative

In a trial where Legally Acceptable Representatives (LARs) are being used to obtain consent on behalf of the potential subject, it is important to maintain proper source documentation of the procedure.

To demonstrate that valid consent was obtained, the site should request and keep a copy of legal documentation to support that the LAR indeed is legally acceptable as a representative for this potential subject.

Reagan's 'Trust, But Verify' can here be adapted to 'Trust, Verify and Document'. Informed consent is too important a topic to take lightly, and consent by LAR without documentation of the legality of the representative is inadequate consent.wow gold

Legally Acceptable Representative vs Impartial Witness

ICH-GCP describes a 'Legally Acceptable Representative' as 'an individual or judicial or other body authorised under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.' (1.37)
A Legally Acceptable Representative (LAR) only consents on behalf of a prospective subject if the subject is unable to give consent. (4.8.5).
The LAR is distinctly different from an impartial witness. in 4.8.9 ICH-GCP clearly indicates that an impartial witness is used if a subject (or the LAR) is unable to read.
Sponsor companies may request the counter signature of a witness more often than ICH stipulates, and some request it as a matter of standard procedure. Doing more than the miminum standard of ICH-GCP is certainly allowed.
The easiest way to distinguish between the function/use of the Impartial Witness vs the LAR is to think about who really consents. If it is the subject himself who consents, and is able to consent, no LAR is needed. The LAR is only intended for those situations where the subject is unable to consent. For example in case of underage (not 'of the age of consent') subjects, mentally impaired subjects or trials set in emergency situations.
In all the situations where a subject is unable to consent and still included in the trial, it was foreseeable. We don't do trials including vulnerable subjects (and a subject who is unable to consent is by definition vulnerable) unless we have no alternative, and in which case the IRB/IEC has specifically approved of the use of such subjects and of the informed consent procedure used.
A witness never consents on behalf of a subject. A witness, by signing, attests that the information in the consent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's LAR and that the consent was given freely.wow gold

Declaring recruitment potential in feasibility

Cutting to the chase, feasibility is all about determining the potential for trial subject recruitment in a set time frame.

An often heard complaint from sites it that sponsors do not set realistic expectations for recruitment. Easily overlooked is that those expectations are most often determined by the data that was provided during feasibility.

When a sponsor gets an estimate of recruitment potential from an investigator, they divide that number in half to set their own expectations. An investigator declares the potential to recruit 12 patients? The expectation is that 5/6 patients can be hoped for.

Potential recruitment in feasibility is more often given as a ballpark figure, than as a true expectation, based upon a realistic assessment of the capabilities of the site. So then what does the sponsor have to calculate with? To set expectations to?

4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period.wow gold

Minimum Qualifications of an Investigator

The regulations do not specify the minimum requirements nor do the regulations specify what qualifications an investigator must have. All it states is that an investigaor should be qualified by training and experience to conduct a clinical investigation.

Sponsors have discretion in determining what qualifications, training, and experience will be needed, based on the general recognition that this would include familiarity the local law, good clinical practice (GCP) regulations (21 CFR Part 312) and standards (ICH E6) for the conduct of clinical studies.

It may well be part of a Sponsor´s SOPs to only select physicians as investigators. That certainly is within their rights. It is good, however, for sponsor staff to realise that this is a company provision, not an industry requirement.wow gold

Does an Investigator have to be a Physician?

The regulations do not require that the investigator be a physician. Sponsors are required to select only investigators qualified by training and experience as appropriate experts to investigate the drug (21 CFR 312.53(a)). In the event the clinical investigator is a non-physician, a qualified physician (or dentist, when appropriate) should be listed as a subinvestigator for the trial and should be responsible for all trial-related medical (or dental) decisions. (ICH E6 section 4.3.1) wow gold