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Informed Consent

The informed consent form is the most important document in a clinical trial. It is the patient’s ticket to the clinical trial and by signing it, the patient becomes a subject of the clinical trial.

The concept of informed consent in a clinical trial does not only mean obtaining the patient’s signature, but also a concept called the process of obtaining informed consent. This responsibility is assigned to the appropriate person in the Delegation Log by the principal investigator and must be in accordance with local regulations (in some cases, local regulations prescribe who is allowed to carry out the informed consent process). The person obtaining consent from the patient must invest some time in order to provide the patient with information about the clinical trial, familiarize him with all the risks and benefits, as well as the obligations and rights he/she has in the clinical trial. The person obtaining consent must not in any way influence the patient and their free will to participate in the trial. Also, the sponsor must not do the same thing, i.e. “conditions” the patient for entering the study with the sentences found in the text of the Informed Consent.

It is necessary to follow all guidelines as well as the provisions of local regulations if consent is obtained from a vulnerable population.

The process of obtaining informed consent must be described in medical report from the screening visit or at other visits if a new version of the consent is signed during the course of the study. It is also the subject of all opening meetings at audit and inspections of the study team at the study site.

No procedure should be carried out before obtaining the patient’s written consent unless otherwise stated in the protocol approved by the Ethics Committee (in some countries also by the Agency).

In the context of this topic, the advantage of a site involved in clinical trials is the existence of its own procedure (SOP) for the process of obtaining informed consent.

Obtaining patient consent in Trauma studies/emergency situations

Particular attention is paid to patients who may qualify for protocols related to emergency, traumatized conditions. The usual concept applied in clinical trials when it comes to the standard process of obtaining Informed Consent – cannot be applied here.

Unless otherwise prescribed by local regulations, paragraph 30 of the Declaration of Helsinki and points 4.8.5 or 4.8.9 of the GCP guidelines apply. Of course, the sponsor must accompany this with a description in the protocol that must be approved by the Ethics Committee (in some countries, also the Agency). It would be desirable for the sponsor to also have a standard operating procedure for the above.

Paragraph 30 of the Declaration of Helsinki is below.

  1. Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious patients, may be done only if the physical or mental condition that prevents giving informed consentfrom the legally authorized representative. If no such representative is available and if the research cannot be delayed, the study may proceed without informed consent provided that the specific reasons for involving subjects with a condition that renders them unable to give informed consent have been stated in the research protocol and the study has been approved by a research ethics committee. Consent to remain in the research must be obtained as soon as possible from the subject or a legally authorized representative.

Can certain study procedures be performed before the patient’s consent is obtained?

Yes, the procedures performed during screening must be described in the protocol and must not be performed unless an Informed Consent has been signed. Then, standard medical practice procedures and the results of individual medical findings may be used during screening – this must be stated in the approved protocol.

The list of screening (Screening Log)

The Screening Log should record all patients who were assessed for inclusion. Many sponsors keep records after the patient has signed the informed consent, but this is considered a delay. Refusal to participate is a very important reason for not including a patient in the study, as it indicates the patient’s initial willingness to participate, and not being recorded in the Screening Log – can be considered a finding (or if the instructions are that only patients who have signed the Informed Consent can be recorded in the Screening Log).

Rescreening

Rescreening is generally not allowed, unless the protocol specifies under what conditions (parameters) it is allowed and in what time frames. The process cannot be implemented retrospectively. For example, the problem with rescreening may be when you have two different measurements/values ​​and then the one that best suits the center or sponsor is chosen. This is called selecting data and is usually not a good idea.

If rescreening is done outside of the protocol, it is very similar to a system of allowing patients to enter a study without meeting the eligibility criteria (waiver).

When rescreening is allowed, it must be precisely defined in the protocol. A description of rescreening explained in other documents is not acceptable (Note to File, Administrative Letters to Study Sites, Newsletters…).

If rescreening is not mentioned in the protocol and if it is performed anyway, then it is a violation of the regulations in the conduct of the study – the degree of deviation will depend on the type of parameters that are re-done.

When the sponsor “chooses” which data to take (selecting data), then such data belong to a significant finding.

Differences between pre-screening and screening

“Pre-screening” is the term used to describe activities prior to obtaining informed consent (prior to enrollment) to determine initial eligibility and interest in a study. Pre-screening can be done by telephone, in person, and does not involve any study procedures.

“Screening” is the term used to describe activities performed after consent has been obtained to ensure that participants are qualified for a study. Screening activities involve interaction or intervention with potential participants to determine further eligibility that would not otherwise be done in the absence of the study.

Protocol deviations

Protocol deviations (PDs) are deviations from the protocol during the performance of study procedures. In every clinical trial, PDs occur, which, when observed/detected, need to be reported, determined what kind of PDs they are, determined their significance, kept a list of registered PDs, etc.

Certain PDs need to be reported to the sponsor, EO, Agency in accordance with applicable local regulations, indicate the deviation to the study team, retrain the team.

A potential PD may in exceptional cases appear as an occurrence that is known to occur, but the EO should be notified of this, who approves or not, and after a written decision, the EO, sponsor and site can proceed with such a process (GCP R2 4.5.2)

Transfer of a investigational product (IMP) from one site to another

According to Annex 13 of the GMP guideline, it is not allowed to transfer an investigational drug from one site to another, and accordingly, this practice should be avoided. In real life, there may be situations when this must be realized – for this, the sponsor must comply with the GMP, GCP guideline, and the statement of local regulations. All necessary documentation for the transfer of the IMP should be processed and filed at the study site.

IMP can be transferred from one site to another, but it is necessary to ensure that all documentation for logistics are in place and that the sponsor has a procedure for performing this activity.

Transfer of subjects/participants in a clinical trial from one site to another

From a GCP point of view, there is nothing to prevent the sponsor from making a transfer, but certain things must be respected. First of all, both sites must be part of the same study. It would be very useful if the documentation of the subject from the first site could be found at the second site, either directly or through the first investigator; then a complete copy of all the original data obtained in the study up to the point of transfer to the second investigator. All this would give to the second investigator a complete picture of the subject’s previous treatment. It is also important that drug supplies are properly disposed of. Of course, complete documentation of the transfer is also expected in the appropriate hospital medical records. The subject should be asked to sign a new informed consent, which includes the details of the new site and the new principal investigator.

Mandatory logs in a clinical trial

In a clinical trial, according to GCP guidelines, it is necessary to provide appropriate lists containing the data of the subjects. These are the Screening Log, Enrollment Log and Identification Log. Each list has its own purpose and accordingly it is necessary for the investigator and the study team to have access to the lists. It is necessary to take care of where each list is located and who can possess it.

The purpose of the Screening Log is to record the reason for a failed screening (screen failure, SF). The identification of patients in them must remain anonymous (only the number of patients) so that the sponsor can use this list and the information from it (reasons for SF) or possible additions required by the protocol.

The purpose of the Enrollment Log is to record the patients who are included in the study, i.e. those who have successfully completed the screening period.

The Identification Log contains all patients who received the study drug, therefore it contains all the information and identification of the subjects. The purpose of this list is patient safety, if something happens, to quickly identify a subject who is at risk. The Identification Log must not leave the site.

Sometimes a combination of these lists can be found in the investigator’s files at the study site. It is very important to know which lists, i.e. which data from which lists cannot be combined. It is necessary to look at the bigger picture and the essence, the data that is entered in the lists. It cannot be combined the Screening log and the Identification Log because these two lists contain contradictory information when viewed from a confidentiality point of view. While viewed from the perspective of patient safety, data from the Enrollment log and the Identification log can be combined, but to the extent that there are no more than two criteria that will identify the patient.

Delegation Log

The purpose of the list named above is to identify each individual who performs tasks related to the conduct of the clinical trial. Tasks that are delegated can be significant (significant tasks) and routine (routine tasks). The list can include them as common tasks (all on one list) or there can be two sets of Delegation Log:

  1. delegation of duties to individuals who make a significant contribution to the study and who are under the authority of the principal investigator
  2. identification of other personnel who are involved in the study in other ways, but do their routine work and are not under the authority of the principal investigator (pharmacy, laboratory)

It may ask where to draw the distinction between these groups of delegated tasks, but there is no right answer. It all depends on the study itself and logical thinking. By properly reconstructing things, it can be seen whether the staff is carrying out significant procedures according to the protocol and whether they are doing it in a qualified manner.

For example, laboratory procedures may or may not be significant, but it is known that the laboratory staff is experienced and qualified to do laboratory tests. On the other hand, the pharmacy manages the drugs and that is their obligation, i.e. job. We cannot delegate tasks to an individual who is not under our jurisdiction, therefore the principal investigator cannot delegate tasks to the staff of the pharmacy or other clinics because they are not under his jurisdiction.

  • all delegated team members should have individual contracts with the sponsor
  • reconstruct the study and verify the persons performing the study procedures, check whether they have experience and whether they are qualified and trained for the assigned tasks

Temperature excursion (IMP)

During the transport of the IMP from the sponsor to the site, it is possible that the temperature at which the drug is being transported may vary. In this case, the site must monitor the situation that has arisen – it must immediately notify the sponsor and proceed according to the procedure that the sponsor has specially prepared for such situations. All evidence and documents must be submitted to the investigator’s file at the site. The drug must be quarantined and not used until the sponsor approves. The sponsor’s approval should arrive as soon as possible and be signed by a qualified person (QP) authorized by the sponsor. If the sponsor’s verification arrives from a person belonging to the sponsor’s logistics (Supply manager…), then it is necessary to check whether that person has been delegated by the sponsor’s QP, i.e. whether he/she is authorized to issue such statements, i.e. to order the release of the drug from quarantine.

Document od self evident changes

The sponsor should define what changes can be made to the database without the prior approval of the investigator, before the study begins. This document is usually called the Document od self evident changes and is formally part of one of the sponsor’s manuals, usually the data management plan. In order for the investigator to know what changes may occur during the study, this document should be in the Investigator Site File. After the study is completed, all self-evident changes that have occurred at each site must be provided to the appropriate investigator, signed and approved by the investigator.

The above document is rare in clinical trials and is signed by the principal investigator. If signed, he/she is responsible for all changes made to the eCRF, during or at the end of the study, by the sponsor (a signed document gives the ability to sponsor to change data already entered in the eCRF during course of the study). Investigators must be aware of the fact that they must be informed of the content of the document and the significance of the consequences it brings.

Letter of acknowledgement of Investigator’s Brochure receipt

A letter of acknowledgement signed by the principal investigator is used in studies to provide the sponsor with confirmation that the investigator has received the physical Investigator’s Brochure (IB), and in auditor and inspector checklists as evidence that the safety information has been delivered to the investigator and that he/she guarantees by his/her signature that he/she is aware of the contents of the IB.

The investigator has the right to have all relevant safety information about the investigational product in order to be able to make his/her own benefit-risk assessment and in particular to look for adverse effects in his/her subjects. The sponsor is therefore responsible for providing the investigator with all relevant safety information. This information most often comes in the form of the IB, but also as safety reports (SUSARs) which can be considered as a supplement to the IB.

During an audit or inspection, it is confirmed that the investigator has received the relevant information in a timely manner, whether it is IB, safety reports or other relevant information. All this is monitored for the safety of subjects at a particular trial site. The GCP guideline discusses this in points 8.2.1 and 8.3.1, but also in 5.16.2 and 8.3.18 as well as in the entire section 7. Verification of the received IB can be done in several ways – electronically, by signing the IB, by confirmation of receipt. It does not matter how it is documented, what is more important is that the safety information was provided to the investigators in a timely manner.

Source documents (SD) and eCRF

When a study is conducted in countries where English is not the native language (which is otherwise used in documents other than the ICF or documents intended for subjects), it is completely wrong to have the attitude that the source documentation (SD) should be in English (it happens that some sponsor representatives request this). The data in the eCRF must be the same as in the SD, but not identical in the language used. Requiring the site to have the SD in English is completely wrong and irrelevant, given that the SD (medical records) are there for the benefit of the subject (patient), and not for the study and sponsor.

A patient’s SD enters his health, medical history and represents a complete “health record” of the subject as a review of the doctor’s treatment at any time and remains in that country. If there is data in the SD that does not require data entry in the eCRF, then it should simply be skipped like any working document.

Sponsors should be clear about who is who or what is more important in a clinical study – they should refer to the third principle of the ICH Declaration of Helsinki – “The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.”