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Informed consent as an ethical requirement in clinical trials: an old, but still unresolved issue. An observational study to evaluate patient's informed consent comprehension
  1. Virginia Sanchini1,2,3,
  2. Michele Reni4,
  3. Giliola Calori5,
  4. Elisabetta Riva5,
  5. Massimo Reichlin6
  1. 1SEMM – European School of Molecular Medicine, Milan, Italy
  2. 2IEO – European Institute of Oncology, Milan, Italy
  3. 3Department of Health, University of Milan, Milian, Italy
  4. 4Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy
  5. 5Clinical Trials Office, San Raffaele Scientific Institute, Milan, Italy
  6. 6Faculty of Philosophy, Vita-Salute San Raffaele University, Milan, Italy
  1. Correspondence to Virginia Sanchini, Department of Experimental Oncology, European Institute of Oncology (IEO), IFOM-IEO Campus, Via Adamello 16, Milan 20139, Italy; virginia.sanchini{at}


We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials.

  • Autonomy
  • Informed Consent
  • Ethics Committees/Consultation
  • Research Ethics

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Clinical trials involving human beings derive part of their ethical validity from the fact that patients clearly understand the potential risks and benefits of the research study, and freely and autonomously decide to participate. The universally accepted procedure assuring the free and autonomous decision of a patient to participate in a clinical trial is obtaining informed consent (IC) prior to enrolment in the study.

Worldwide guidelines, regulatory requirements, the Declaration of Helsinki and other documents1–5 describe the structure and the requirements of the form referred to as the ‘Patient information sheet and signature form’. Furthermore, the guidelines also detail the requirements of the process of administering the IC, particularly stressing the patient's understanding of the information and his/her freedom and competence to make the decision to participate. As a consequence, the patient's signature on the IC form represents the conclusion of a process involving an in-depth physician-patient/researcher-patient discussion.

For several years, an extensive debate has been going on concerning the real value of the patient information sheet proposed by pharmaceutical companies and non-profit promoters. Considering that the majority of patients are unfamiliar with clinical trial methodology and regulatory requirements for drug registration,6 it may be suggested that an effective communication process with the physician is an important step in informing a patient's decision about which therapeutic option to choose.

The aim of the present study is to measure the understanding of the IC forms by cancer patients enrolled in clinical trials. Since the majority of the studies on this topic have been carried out in the USA, UK and France,7–10 we expanded this research to an Italian hospital enrolling cancer patients in clinical trials. The importance of this topic, as well as the need for additional studies and new modalities of intervention, were underlined by Flory and Emanuel.9

Materials and methods

We chose to study cancer patients based on the large number of oncologic trials, both worldwide and in Italy, where they represent 40% of all clinical trials carried out in the country.11 This study invited the participation of patients with colon-rectal, pancreatic or lung cancer. The invited patients had previously been enrolled after they signed a specific IC, in five different oncology randomised clinical trials at the San Raffaele Scientific Institute between March and July 2011. Their names were inserted in the Datamanager's database of the department of oncology of the San Raffaele Hospital.

Five different oncology multicenter randomised phase II or phase III clinical trials in which our institution participated were identified, and 100 of the enrolled patients were considered for participation in this study. Out of the list of the potentially eligible patients, 23 were not included (n=2 patients refused to take part in the interview; n=15 had died (mainly patients with pancreatic cancer) and n=6 were lost to follow-up). Thus, 77 patients were included in our study. Their general characteristics are reported in table 1. Most of the participants were men, with a level of education lower than a high school diploma, and with a colon-rectal malignant tumour (table 1).

Table 1

General characteristics of study participants

Patients with central nervous system impairment, or who were not Italian native speakers were ineligible. After explaining the purpose of this research, eligible patients were asked to sign a study-specific consent form. Since at our institution different medical teams deal with different diseases, we decided to consider patients eligible for the study as those affected by three different tumour types. The decision to include three types of cancers (colon-rectal, pancreatic or lung cancer) was made to facilitate patient recruitment.

All the patients interviewed in our survey were in follow-up, and the time frame of the interviews varied from 3 months to 8 months after conclusion or interruption of the trial. The time frame of the interviews was doubly motivated: (1) We wanted to eliminate the risk of any critical bias. If oncologists had known about our survey, they would probably have changed (perhaps unconsciously) the way of presenting the IC to patients, leading to biased results. (2) We wanted to avoid a possible ethical dilemma: international guidelines require that only the patients who understand what a clinical trial is and what its implications are, can be enrolled in a clinical experimentation. In other words, signing the IC form is a necessary but not a sufficient condition to make the patient eligible for a trial. Thus, if we had found (as actually occurred) that some patients were not aware of having been enrolled in a clinical trial, these should have been eventually removed from the trial for ethical reasons, in case of a negative reconsent. This would have had undesired consequences both for patient safety and for the conduct of the trial.

After a scheduled follow-up visit—in most cases in the presence of a relative—patients were asked to answer a list of specific questions with the help of the interviewer. The interviewer (VS) was a philosopher with a degree in bioethics, trained by a senior psychologist with expertise in oncology. Neither had any involvement in carrying out the clinical trials. Since there are no validated questionnaires in the Italian language concerning the general comprehension of the IC form, the one we used was specifically devised for this survey by the authors with the help of the ethics committee psychologist and following a specific checklist for medical education.12 The questionnaire was conceived so as to include all the questions considered essential for the comprehension of the IC. Both the protocol and the relative questionnaire were approved by the ethics committee.

Continuous data are presented as mean±SD and range, or as median and IQR if the distribution of the variables was not Gaussian. Categorical data are presented as number and percentages in parentheses. Categorical variables were compared using the χ2 test or Fisher's exact test; continuous variables were compared using unpaired Student t test, and Mann–Whitney test, depending on their distribution. In order to test the independent relationship of the above factors with the specific confounding factors which resulted significantly correlated at univariate analysis, a multiple logistic regression model was run. Statistical significance was set at p value less than 5%. SAS statistical software V.9.2 was used for the analysis.


As far as the comprehension of the IC form is concerned, only 62% of patients answered correctly to the question ‘Are you participating in a clinical trial?’, indicating that almost 40% of them were not aware of participating, or having participated, in a clinical trial (table 2). Patients showed a better understanding of the risks related to the participation in the clinical trial, potential side effects of the pharmacological intervention, study procedures, and additional blood samples requested by the participation in the trial. However, they had more difficulties in remembering the name of the study they were enrolled in and the name of the treatment, and in understanding the potential benefits of participating in the study, the additional procedures requested by their participation in the trial, and the meaning of randomisation (table 2).

Table 2

Correct answers to questions about the comprehension of the informed consent

The primary aim of the present study was to evaluate the proportion of participants who clearly understood the information reported in the IC forms. To this purpose, not all the questions included in the questionnaire were counted to evaluate comprehension: in particular, answers to questions concerning general participation and patient satisfaction were not taken into consideration to measure comprehension.

Interestingly, the same patients who were unaware of participating in a clinical trial also reported that the time devoted by the clinician to explain the essential aspects and procedures of the clinical trial was insufficient and that the explanation they received was not exhaustive (table 3).

Table 3

Answer to questions about the participation in the clinical trial, stratified by the awareness of participating in a clinical trial

Concerning specific aspects of a clinical trial, such as the understanding of side effects and randomisation, our survey found that 40% of patients were able to report some potential side effects, whereas only 16% and 21% of patients, respectively, were able to recall study examinations and additional procedures such as blood sampling, which are more specific but less relevant aspects of the clinical trial.13 Moreover, in line with other studies, we observed that very few patients understood the randomisation procedure.10 To verify true patient comprehension, the questionnaire asked whether all subjects were receiving the same treatment: only 11% of the patients answered correctly. Furthermore, of those who understood the randomisation procedure, 79% believed they had been treated with the latest medical compound without considering the possibility that they had been selected for the control group receiving the standard treatment.10 ,14–17

To further explore the reasons for limited patient awareness, we performed an additional analysis, investigating whether the likelihood of being unaware of clinical trial participation was correlated to random attribution to the standard arm; 61% of the subjects randomised in the standard arm versus 66% of the subjects randomised in the experimental arm were aware that they had been included in a clinical trial and the difference was not statistically significant (p=0.67).

The proportions of patients who gave the correct answer to the first question were not different among the three types of cancer (Cochran Manthel Haenzel test: χ2=0.43; p=0.51). Neither did comprehension of the IC form differ between men and women (data not shown).

However, comprehension significantly decreased with the increasing age of the participants (p=0.03): median age of study participants was 65 years (IQR 57–70) for those who answered correctly to six or more questions, and 70 years (IQR 65–76) for those who provided no correct answers.

A trend and a positive correlation were observed regarding the increase in comprehension in subjects with higher education (p=0.004) (table 4), especially for questions about the name of the study they were enrolled in, the name of the treatment they were assigned to, the understanding of study procedures, the awareness that a clinical trial has different aims and requires additional procedures compared with the standard therapy, and awareness of the fact that they would have received the standard treatment if they had not participated in the trial (table 4).

Table 4

Comprehension of the informed consent stratified by education attainment

A significant correlation was observed between comprehension and tumour type. Patients with pancreatic tumour answered correctly to significantly more questions about treatment name, potential risks and adverse events, alternative therapies, study procedures and additional procedures, number of blood samples to be collected, and randomisation procedure, compared with patients with the other tumour types. Comprehension of type of treatment (p=0.022), knowledge of benefits (p=0.046), alternative treatments (p=0.038) and additional procedures (p=0.007) remained statistically different among types of cancer even when adjusted for age and educational attainment (table 5).

Table 5

Comprehension of the informed consent stratified by type of cancer


The IC form has an important role in the assessment of the ethical justifiability of a clinical trial.1–5 Several studies have been carried out to evaluate patient comprehension of the IC form. Although international guidelines and bioethical work on clinical experimentation focus on the importance of adequate information and voluntary choice of the participants, studies on patient comprehension7–10 have identified common problems and underlined the ineffectiveness of the measures undertaken to solve them. Notably, the data obtained in the present survey are still in line with those described in the earliest papers, despite the fact that the first study on this topic was published more than 30 years ago.18

Difficulties in assessing comprehension

Despite the apparent consensus in the literature concerning the patients’ lack of comprehension of the essential aspects and features of being enrolled in a clinical trial, what ‘patient comprehension’ actually refers to may vary substantially between studies, as shown in recent papers.7 ,8 According to these studies, this confusion is mainly due to two related factors: (1) a variety of terms has been used—comprehension, understanding, recall—to define what the specific study aims at measuring; (2) different criteria have been considered for assessing comprehension. Both components make the comparison between different studies problematic.8

We believe that our study escapes these difficulties. Although our survey aims at measuring patient comprehension, this is assessed through a list of very basic questions (table 2) concerning elements that cannot be forgotten in a short period of time. It thus avoids time-related factors that are used to distinguish between different terms. In particular, the definitional dichotomy between comprehension/understanding (defined as short-time comprehension) and recall/memory (defined as long-time comprehension) is not relevant in our case, since we did not ask for detailed information that can easily be forgotten.

Moreover, our survey asked for specific aspects that strictly related to the clinical trial itself. These aspects assessed dimensions of comprehension that should be seen as basic to aspects of comprehension, regardless of which criteria for comprehension are accepted. For instance, if a person does not know he or she is in a clinical trial, then it is clear that he or she did not comprehend the consent forms. As a result, our conclusions may be relevant to a range of studies that make use of different criteria for comprehension.

The role of studies of comprehension

The emphasis on patient comprehension has been subjected to several objections, mainly by Sreenivasan.19 Based on the consideration that individuals involved in a clinical trial are not the best judges of their own interests, he proposed an alternative view based on the ‘duty to obtain a prospective participant's consent’,19 where the patient's comprehension is reduced to the signature on the IC form, thus increasing the power of ethics committees in the choice of treatments. As it stands, however, guidelines emphasise the importance of patient comprehension as a morally relevant aspect of IC.

Implications of and explanations for results

We can hypothesise that the correlation observed between comprehension and tumour type could be partially due to the fact that patients with different types of cancer were followed by different teams of investigators. Consequently, different levels of communication skills and levels of comprehension might be assumed, indicating that communication between physicians and patients probably plays a major role in patient understanding. This observation is in line with the patients’ requests that physicians and medical staff devote more time to them, discussing the study procedure and, more generally, the patient medical conditions.20–23

It was also observed that both age and educational level were associated with a higher level of comprehension.13 This may suggest a need for greater care in explaining clinical trials to the elderly.

The finding that 62% of the patients in our sample were aware of being enrolled in a clinical trial is a particularly thought-provoking result. Only some of the patients were aware of having been previously enrolled in a clinical trial, whereas most of them had some understanding of the secondary aspects of the trial (study examinations and blood sampling). On some interpretations of the classical regulatory documents concerning clinical experimentation on human subjects,1–5 it may be acceptable to give up knowledge of some minor elements of clinical experimentation. However, a lack of understanding of the fundamental aspects of the research is more problematic and controversial. While lack of understanding of minor practical procedures may not be of great significance, the awareness of possible side effects is more important, and unawareness of one's enrolment in a clinical trial could be regarded as morally unacceptable, as it may amount to violating both psychological integrity and personal dignity.

The observed lack of patient understanding of the fundamental aspects of a clinical experimentation (together with a better comprehension of its minor aspects) may suggest that the distinction between clinical care and clinical research is unclear to the patients. As a consequence, patients seem to consider clinical trial steps and procedures as part of the current clinical practice. The present research suggests that a much larger effort should be devoted to the explanation of the difference between ordinary clinical practice and the carrying out of a clinical trial. In particular, it should be clarified that the aim of clinical care—to cure patients—strictly differs from the aim of clinical research—to extend generalisable knowledge. However, the two practices may be easily confused. This may happen when, as in the trials we investigated, so-called ‘therapeutic research’ is concerned.24 Some authors speak of therapeutic research as that kind of research with possible therapeutic outcomes. This results from a partial overlap between the aims of clinical care and clinical research, as exemplified in the case of late-phase trials (IIb and III).

Additionally, the confusion between the clinical care and clinical research may occur when—as was the case in the trials we investigated—the responsible physician is also the experimental investigator recruiting his/her patients for a clinical trial. Doubtless, this situation increases the possibility of therapeutic misconception. One way of addressing this issue is to give greater power to ethics committees, as suggested by Sreenivasan, thus reducing the emphasis on patient understanding. Alternative solutions are to burden physicians with a very strict obligation to explain the different aims of a clinical trial or to identify a different professional agent who may act as a bridge between research investigator and research subject.

Practical suggestions

The oncology department of our hospital—of which one of the authors is a member—agreed to conduct this research because of the importance it attaches to the appropriate modalities of the patient involvement in clinical trials, and in order to improve the procedures aimed at guaranteeing adequate information to participants. Although some, such as Sreenivasan19 play down the importance of patient understanding, the hospital regards greater comprehension as an important step towards realising the core value of respect for patients in human experiments.

What follows is a list of concrete suggestions to make the patient more aware of his/her participation in a clinical trial. Based on the results of our study, our intent is to propose and apply these concrete measures in the oncology department of our hospital and, possibly, to extend them to other oncology departments.

  1. Basic courses of clinical methodology in the hospital for patients. Our proposal is to explain to patients what a clinical trial is before they are invited to participate. Regular general courses on basic clinical trial methodology should be implemented so as to educate patients at an early stage of their contact with the hospital. Any patient identified as potentially eligible for a trial should be directed by physicians to such a methodology course to ensure awareness and understanding of clinical trials when participation in a specific study is offered. In this way, the IC procedure extends beyond the IC form, and the value of IC is also furthered in the recruitment phase.

  2. Use of televisions in wards to show interviews to patients enrolled in clinical trials. An introduction to clinical trials, from patient enrolment to study preparation, including the aim of clinical studies, could be shown on an internal hospital channel. In such programmes, adequate space should be devoted to the procedures used to obtain IC, explaining the patients’ right to information necessary for a clear understanding of the trial, with the information preferably reported by a former patient.

  3. Presence of relevant material in hospital wards. Documentation (leaflets, booklets etc) concerning clinical trials should be made available for patients, possibly distributed by volunteers and prepared by the ethics committee members together with cancer patients associations.

Since the exchange of information and the time devoted to the communication process appears to play a decisive role in patient comprehension,10 two further measures can be implemented.

  1. Training of medical staff. Specific training of medical staff is clearly needed. Schools of medicine should also be invited to include specific courses on communication skills in their curricula.

  2. Involving bioethicists in clinical trials. The role of bioethicists in the hospital setting is becoming more important, and their increased interaction with patients may prove very helpful. Since the role of bioethicists in the ethics committee is mainly that of evaluating the IC forms, it would be useful for the same person to act as a bridge between patient and physician/researcher, verifying the patient's understanding of the meaning of the trial in which he/she is participating and, if necessary, clarifying issues the patient has not fully understood.

As suggested by Flory and Emanuel,9 direct human contact, rather than videos or paper forms, tends to be more successful in improving understanding. Since the time devoted by physicians to examinations is scheduled and therefore necessarily limited, the introduction of an expert specifically trained and dedicated to increasing comprehension represents a promising solution.

Our proposals would certainly require additional institutional resources and, perhaps, cause a slight reduction in patient participation in clinical research.25 These, however, are prices worth paying in order to make an attitude of respect for the patients the overriding value in human experimentation.


The authors wish to acknowledge Ilaria Carretta for her suggestions in the preparation of the questionnaire and Marina Scavini, Laura Cremonesi and Christopher Wareham for their valuable help in revising the manuscript.



  • Contributors VS has contributed in planning, conducting the study, writing and reviewing the paper. MR has contributed in planning, selecting clinical trials for the study, reviewing the paper. GC has contributed in planning, analysing the data and writing the results. ER has contributed in planning, reviewing the paper. MR has contributed in planning, reviewing the paper in its ethical aspects.

  • Competing interests None.

  • Ethics approval Study approval was obtained and signed by Ethics Committee of San Raffaele Scientific Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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