Informed consent in clinical research; Do patients understand what they have signed?

El consentimiento informado en investigación clínica; ¿Entienden los pacientes lo que firman?

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The signed Informed Consent (IC) is a key element in clinical research; and as well as a legal requirement, it is also the starting point for the application of the autonomy principle and the right of patient privacy. This means that the person chooses freely to take part in a research, and gives authorization for processing and analyzing all data collected in his/her clinical record. However, frequently the process is not easy, and represents a burden for researchers and patients. To obtain the signed Informed Consent implies that information has been provided previously, adapted to their level of understanding, about aspects which are often complex, such as the study objectives, expected benefits, rights and duties as a participant, risks, potential alternatives, or voluntary nature. These documents, moreover, have been thoroughly reviewed by an Ethics Committee for Clinical Research (ECCR), which will check that they include all requirements established by current legislation, before receiving the authorization to initiate the study¹.

The objective of the Informed Consent is to protect patients and ensure that the research is conducted according to ethical criteria; but frequently ECCRs will confirm that their contents are based on the assumption that the most information provided will be better for decision making by patients, though it is known that this is not always the case². Falagas et al.³, for example, on an IC review from 1961 to 2006, proved that only 54% of patients understood the objective of the study adequately, 50% understood what randomization meant, 47% understood the meaning of voluntary nature, 44% understood their right to withdraw from the study, 50% understood the risks accepted, and 57% of patients understood the benefits expected.

The objective of this article is to review the aspects associated with understanding the Informed Consent by patients in the setting of clinical research, its basics, legislation, and the role of Ethics Committees of Clinical Research in the preparation of said document.

In the research setting, written Informed Consent dates back to 1900, when Walter Reed requested it from patients who participated in his studies about yellow fever in Cuba⁴. Subsequently, the Nüremberg Code⁵ established in 1947 the lines for ethical conduct in clinical research, and laid the foundation for future rules in this setting. According to this document, research will be considered ethically adequate when it is based on previous experimental outcomes in animals, it must be justified by the outcomes expected, and in order to be developed, patients must have granted previously their authorization.

Informed Consent is defined as that “process through which a person confirms willingly their decision to participate in a specific clinical trial, after having been adequately informed about all the aspects of the study which are relevant for the decision to participate by the subject”¹. This term was first used in U.S.A. in 1957, in the State of California⁶; and this represented leaving for the first time the traditional medical paternalism to start giving relevance to patient’s autonomy. Californian Law developed the first IC model for clinical research, which collected the following key elements: purpose of the research, its potential consequences, potential harm, expected benefits, risks, and alternatives to the research. Knowledge of these aspects by the patient, before granting consent to participate in a clinical trial, is currently considered essential.

Later on, the Declaration of Helsinki⁷ divided research into two large groups: that conducted in patients (clinical research) and the research conducted with non-therapeutic objectives (non-clinical biological research). This declaration added new elements, such as the fact that IC must be informed as well as voluntary, and can be withdrawn at any time of the research; or that in the case of incompetent persons, their legal tutor can grant the IC. The American Congress created a National Committee with the objective of preparing a report on the protection of human beings involved in a clinical research: the Belmont Report published in 1978⁸, which collected the basic ethical principles for application in clinical research, and considered in the first place the respect for persons or autonomy principle, the practical application of which is represented by obtaining the IC. One year earlier, and also in the U.S.A., the Food and Drug Administration (FDA) published the rules for Good Clinical Practice (GCP)⁹, as an answer to the need to ensure the quality and protection of patients’ rights in clinical research. These rules were subsequently adopted in Europe, where they have been enforced since 1991¹⁰.

In our setting, the socalled Convenio de Oviedo¹¹ (Oviedo Convention) by the European Council, which was included in the Spanish legislation in the year 2000, specified the conditions necessary for conducting research in human beings. According to these, besides the lack of any alternative method with proven efficacy, it is required that risks are not out of proportion with the benefits expected, that there has been approval by a ECCR or relevant authorities, and that the candidate has been adequately informed through a Patient Information Sheet, and has granted written consent.

Informed Consent has two essential objectives: on one hand, to respect and promote patient’s autonomy, and on the other hand, to protect patients against any potential harm derived from their participation in a clinical trial. In order to achieve these objectives, it is necessary to take into account some aspects which are the basis for research in humans, such as the fact that patients generally

won’t have any medical knowledge, they have the right to decide what they do with their body and about their treatment, they must give consent after being adequately informed, and that their final decision will depend on receiving truthful and reliable information by the physician^12,13.

All this means that the IC should not be considered just a document to be signed, but a process with the ultimate end of achieving the adequate inclusion of patients in clinical research. In this process, the contents of the documents provided to patients are essential, and the basic sections that must be included are^14:

• Objectives of the study.

• Methodology.

• Description of treatment.

• Benefits.

• Risks.

• Adverse events.

• Alternative treatments.

• Voluntary nature and possible withdrawal.

• Confidentiality.

• Economic compensation.

• Responsible researcher.

As already stated, the written IC is an essential part of the requirements necessary to conduct the majority of clinical trials, and its objective is to advice patients about the study where they have been asked to participate. However, the increasing complexity and length of Patient Information Sheets have often made them difficult to understand by patients¹⁵. In many cases, these are presented like a document seen as a legal protection instrument by the institutions promoting the study, rather than the provision of understandable information for patients to decide on their voluntary participation¹⁶.

Signing the IC confirms participation in the clinical trial, and the acceptance of everything included, such as the risks involved. However, this is not always the case, and this does not ensure that the consequences of participation in the study have been understood^17,18,19,20. There are numerous articles which have analyzed the readability of Patient Information Sheets, by applying validated measure scales for reading comprehension²¹ such as the Flesch-Kincaid Index²², which is the most widely used, or the SMOG formula (Simplified Measure Of Gobbledygook)²³. Thus, in a survey conducted with participants in Oncology studies, Joffe et al.¹⁵ found that 90% of respondents were satisfied with the information received, but many of them declared they had no knowledge about the characteristics of the study they were taking part in, and the possibility of not obtaining any benefits¹⁹. Sharp et al.¹⁶, analyzed 107 Patient Information Sheets for Oncology Clinical Trials, and found that none of them was written in an understandable wayfor persons with education below the 2nd year of SecondaryEducation (12-13-year-old), and only 1.5% wasunderstandable by a 4th level of Secondary Education(13-14-year-old). Taking into account that in countrieslike Spain, 46% of the adult population in the 25-to-64-year-old range has not completed a level of educationabove the second stage of Secondary Education²⁴,or that in U.S.A. almost 50% of the adult populationhas a reading comprehension below a level equivalentto 1st year of Secondary Education (11-13-year-old)25,26,around half of the population would have importantproblems to understand what these documents intendto convey. It is overall accepted that the Patient InformationSheet should be written for a level of education atleast three courses below the educational mean level ofthe target population for the study²⁷.

Many studies have been conducted in recent years to assess how to improve the comprehension of Patient Information Sheets. Some of them have detected that these are more easily understood when written in a simple manner^28,29,30,31. Others suggest that these can be better understood if read slowly and allowing enough time^32,33 or if their length is shortened³⁴. However, unlike what should be expected, different studies have demonstrated that a text simplification to facilitate its reading won’t always entail its better comprehension^35,36. On 2003, the Eastern Cooperative Oncology Group (ECOG) conducted a study on this subject³² which confirmed that when information easy to understand was provided to oncology patients who were candidate to inclusion in a clinical trial, their anxiety was reduced and there was an improvement in their satisfaction, and this could be achieved without omitting any relevant information. However, it was not possible to demonstrate that text simplification led to its better comprehension. Davis et al.³⁶ consulted healthy people about their hypothetical participation in a clinical trial and confirmed the same that the previous study: when faced with two versions of the Patient Information Sheet (simplified and standard), even though patients preferred the simplified version, their level of understanding about what was conveyed was similar for both formats. Other authors have researched about complementary strategies that would allow to improve the comprehension of the IC. Flory et al.³⁷ found that personal interaction and feedback are the most effective way to achieve an adequate understanding of the information conveyed to the patient. Besides, it has been proved that the modification of the Patient Information Sheet in terms of more simplified and reduced contents and wording is not better for their understanding than the use of multimedia supports or the participation of a neutral educator who can spend more time with the patient.

On the other hand, a drawback also underlying the process of obtaining Informed Consent is that, generally, the patient’s physician is usually the same person who suggests their participation in the study; therefore, said physician could prompt the patient’s participation, and there could be a conflict of interests.

However, all these drawbacks should not lead to a discontinuation in the efforts to simplify Patient Information Sheets in order to improve their comprehension, for various reasons: as already mentioned, this will alleviate the anxiety generated in patients, and they will appear more satisfied with the information received, and at the same time, a simplified language will allow other persons (relatives, other healthcare professionals not involved in the study) to understand the information. As a general rule, these documents must be brief, simple and clear, so that the explanation of risks won’t generate anxiety, avoiding an alarming or threatening tone; it is also advisable to allow patient involvement, by asking multiple choice questions³⁸.

It is recommended, in order to achieve a better comprehension of the Informed Consent³⁹:

• To use a language and ideas familiar to patients and known by them.

• To use short words (preferably with 2 syllables), and short sentences too, if possible.

• To avoid confusing or misleading ideas.

• To apply measurement formulas for estimating the level of comprehension, according to the cultural and educational level of the patient.

• To explain clearly what the experimental treatment involves, and the standard treatment or alternatives to the Clinical Trial.

• To encourage patients to discuss it with other persons.

• To provide written information that the patient can read with time and carefully.

• To check to what extent the information provided has been understood.

In recent years, ECCRs, in their role as guarantors of patient rights, have made important efforts to improve both the quantity and quality of information provided in the Patient Information Sheets. This improvement has contributed to the fact that obtaining the IC won’t only be based on handing a written document, but that it will be considered as a process where the methodology and purpose of the study are explained adequately to the level of understanding of each patient. But ECCRs must also ensure that Patient Information Sheets collect all aspects required by the current legislation, and that patients might not be aware of, or consider irrelevant.

Frequently, when reviewing and approving clinical trials from an ethical point of view, ECCRs will find that Patient Information Sheets are faulty and need to be modified before their approval. According to a study conducted in Spain on 2007, Fernández de Uzquiano et al.⁴⁰, in a retrospective analysis of 1219 clinical trials evaluated by an ECCR, observed that these were only approved without any need for modifications or clarifications in 20% of cases, and that out of the rest, some change in contents was requested to the promoters in 59.3% of cases. In agreement with these authors, other studies conducted about ECCR activities in other countries have found similar results. In the United Kingdom, according to data from the National Research Ethics Service⁴¹, only 17% of the applications for review and approval of clinical trials will receive a favourable decision at first evaluation by the ECCRs, without any need for clarifications or modifications. The majority of these decisions are approvals depending on modifications (66%), while 8% are denied. According to this institution, the majority of non-approvals granted by the EC- CRs in a first evaluation for oncological clinical trials will be due to faults in Patient Information Sheets (96%), either by poor wording or by the use of terminology not easy to understand by patients. In 18% of cases, they understood that false expectations were offered to patients. Another reason for concern in these committees regarding Patient Information Sheets is associated with the tissue samples taken from patients and their storage, particularly in Oncological Clinical Trials⁴². At the same time, the adequate transmission of information about the potential risks accepted by patients is a frequent reason for concern by the ECCRs, including adverse effects, additional procedures, or aspects such as confidentiality.

In spite of the national and international guidelines and recommendations already mentioned, about which aspects must be included in a document for patient information, and of the actions taken by ECCRs for their enforcement, these will often differ from the information demanded by patients. In this sense, Kirby et al.⁴³, in a study about patient preferences regarding the information they want to receive when they are asked to participate in a clinical trial, observed that in first place they preferred to receive information about the study outcomes (91%), secondly about its objective (76%) or its duration (61%) and, however, assigned lower imporance to aspects thoroughly reviewed by ECCRs, such as voluntary nature (39%) or confidentiality (44%).

Therefore, when evaluating the Patient Information Sheets for clinical trials, ECCRs will often find themselves in a complicated position. On one hand, they must try to achieve that all information is easily understandable by the patient; and on the other hand, that all aspects required by the legislation are included, so that patients who have given their consent won’t be legally unprotected should any contingency occur.

As a conclusion, we will say that Informed Consent is an essential part of clinical research, and that by signing it, patients will grant freely their authorization to participate in a clinical trial. However, Patient Information Sheets are increasingly too long and difficult to understand by patients, and they seem to be more aimed to exempting the study sponsor from responsibilities than to inform. This way, there is some risk that patients will grant authorization and sign the IC without having read or understood what the physician is proposing.

In this sense, ECCRs will play an important and difficult role in the protection of patient rights, by reviewing these informative documents and ensuring that they include all requirements demanded by the legislation and, at the same time, that they are as easy to understand as possible.

The opinions expressed in this work are a responsibility of the authors for what they do not reflect necessarily the point of view of the organisms at which they are employed.

How to cite this article: Villamañán E, Ruano M, Fernández-de Uzquiano E, Lavilla P, González D, Freire M, et al. Informed consent in clinical research; Do patients understand what they have signed? Farm Hosp. 2016;40(3):209-218.