SciELO - Scientific Electronic Library Online

vol.40 issue3Cost-effectiveness analysis of apixaban compared to low-molecular-weight heparins and vitamin k antagonists for treatment and secondary prevention of venous thromboembolismPre-exposure prophylaxis for the prevention of HIV infection: a new prevention paradigm? author indexsubject indexarticles search
Home Pagealphabetic serial listing  


Services on Demand




Related links

  • On index processCited by Google
  • Have no similar articlesSimilars in SciELO
  • On index processSimilars in Google


Farmacia Hospitalaria

On-line version ISSN 2171-8695Print version ISSN 1130-6343

Farm Hosp. vol.40 n.3 Toledo May./Jun. 2016 



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

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



Elena Villamañán1, Margarita Ruano1, Enma Fernández-de Uzquiano2, Paz Lavilla2, Diana González3, Mercedes Freire1, Carmen Sobrino1 and Alicia Herrero1

1Hospital Pharmacy Unit. Hospital Universitario La Paz. IdiPaz, Madrid.
2Technical Secretary of Clinical Research Ethic Committee. Hospital Universitario La Paz, Madrid.
3Spanish Agency of Medicines and Medical Devices. Ministry of Health, Social Services and Equality. Spain.





Informed consent is an essential element of research, and signing this document is required to conduct most clinical trials. Its aim is to inform patients what their participation in the study will involve. However, increasingly, their complexity and length are making them difficult to understand, which might lead patients to give their authorization without having read them previously or without having understood what is stated. In this sense, the Ethics Committees for Clinical Research, and Pharmacists specialized in Hospital Pharmacy and Primary Care in their capacity as members of said committees, play an important and difficult role in defending the rights of patients. These Committees will review thoroughly these documents to guarantee that all legal requirements have been met and, at the same time, that they are easy to understand by the potential participants in a clinical trial.

Key words: Informed consent; Clinical research; Readability.


El consentimiento informado es una parte esencial de la investigación y su firma es imprescindible para llevar a cabo la mayor parte de los estudios clínicos. Su fin es poner en conocimiento del paciente lo que implica su participación en el estudio que se le propone. Sin embargo, cada vez más, su complejidad y extensión los hacen difícilmente comprensibles, por lo que se corre el riesgo de que el paciente dé su autorización sin haberlo leído previamente o sin haber entendido lo que en él se le expone.
En este sentido, los comités éticos de investigación clínica y los farmacéuticos, especialistas en farmacia hospitalaria y atención primaria como parte integrante de los mismos, cumplen un importante y difícil papel en la defensa de los derechos de los pacientes. En ellos se revisan exhaustivamente estos documentos para garantizar que todos los requisitos que exige la normativa estén contemplados y, al mismo tiempo, que sean de fácil comprensión para los potenciales participantes en un estudio.

Palabras clave: Consentimiento informado; Investigación clínica; Legibilidad.



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.


Background of informed consent

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 Nuremberg 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 so-called 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.


Basic principles of Informed 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 physician12,13.

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 are14:

• Objectives of the study.

• Methodology.

• Description of treatment.

• Benefits.

• Risks.

• Adverse events.

• Alternative treatments.

• Voluntary nature and possible withdrawal.

• Confidentiality.

• Economic compensation.

• Responsible researcher.


Controversies regarding the Informed Consent

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 understood17,18,19,20. 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 way for persons with education below the 2nd year of Secondary Education (12-13-year-old), and only 1.5% was understandable by a 4th level of Secondary Education (13-14-year-old). Taking into account that in countries like Spain, 46% of the adult population in the 25-to-64-year-old range has not completed a level of education above the second stage of Secondary Education24, or that in U.S.A. almost 50% of the adult population has a reading comprehension below a level equivalent to 1st year of Secondary Education (11-13-year-old)25,26, around half of the population would have important problems to understand what these documents intend to convey. It is overall accepted that the Patient Information Sheet should be written for a level of education at least three courses below the educational mean level of the 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 manner28-31. Others suggest that these can be better understood if read slowly and allowing enough time32,33 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 comprehension35,36. 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.


The role of Ethics Committees for Clinical Research in the preparation of Informed Consents

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 importance 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.



1. International Conference on Harmonization. Harmonised Tripartite Guideline for Good Clinical Practice. Ginebra: IFPMA, 1996. (Consultado 11/02/2016). Disponible en: e/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdf.         [ Links ]

2. Manson NC, O'Neill O: Rethinking Informed Consent in Bioethics. United Kingdom: Cambridge University Press; 2007.         [ Links ]

3. Falagas M, Korbila I, Giannopoulou K, Kondilis B, Peppas G. Informed consent: how much and what do patients understand? Am J Surg 2009;198:420-35.         [ Links ]

4. Pierce JR. In the interest of humanity and the cause of science: the yellow fever volunteers. Mil Med 2003; 168:857-63.         [ Links ]

5. Katz J. The Nuremberg Code and the Nuremberg trial. A reappraisal. JAMA 1996;276:1662-6.         [ Links ]

6. Salgo v Leland Stanford Jr University Board of Trustees (1957). 317 P 2d 170. (California District Court of Appeal).         [ Links ]

7. World Medical Assembly. Declaration of Helsinki.Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, and amended in Tokyo in 1975, in Venice in 1993, in Hong Kong in 1989, in South Africa in 1996, and in Edinburgh, Scotland in October, 2000. (Consultado 11/09/2015). Disponible en:         [ Links ]

8. Informe Belmont. (Consultado 14/09/2015) Disponible en:         [ Links ]

9. Food and Drug Administration. Clinical investigations: Proposed establishment of regulations on obligations of sponsors and monitors. Fed Reg 1977;42:49612-30.         [ Links ]

10. CPMP Working Party of Efficacy of Medicinal Products. EEC Note for guidance: Good Clinical Practice for trials on medicinal products in the European Community. Pharmacol Toxicol 1990;67:361-72.         [ Links ]

11. Consejo de Europa. Convenio para la protección de los derechos humanos y la dignidad del ser humano con respecto a las aplicaciones de la biología y la medicina (Convenio relativo a los derechos humanos y la biomedicina), Oviedo 4 de abril de 1997. BOE n.o 251, (20 de octubre de 1999).         [ Links ]

12. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283: 2701-11.         [ Links ]

13. Canterbury v Spence (1972). 464 F 2d. (US Court of Appeals: District of Columbia).         [ Links ]

14. Galende I. Evaluación de ensayos clínicos. (Consultado 10/06/2015) Disponible en: http://www.ance         [ Links ]

15. Jefford M, Mileshkin L, Raunow H, Raunow H, O'Kane C, Cavicchiolo T, et al. Satisfaction with the decision to participate in cancer clinical trials (CCT) is high, but understanding is a problem. J Clin Oncol 2005;23:6067.         [ Links ]

16. Sharp SM. Consent documents for oncology trials: does anybody read these things? Am J Clin Oncol 2004;27:570-75.         [ Links ]

17. Cassileth BR, Zupkis RV, Sutton-Smith K, March V. Informed consent-why are its goals imperfectly realized? N Engl J Med 1980;302:896-900.         [ Links ]

18. Schaeff er MH, Krantz DS, Wichman A, Masur H, Reed E, Vinicky JK. The impact of disease severity on the informed consent process in clinical research. Am J Med 1996;100:261-68.         [ Links ]

19. Joffe S, Cook EF, Cleary PD, Clark JW, Weeks JC. Quality of informed consent in cancer clinical trials: a cross-sectional survey. Lancet 2001;358:1772-77.         [ Links ]

20. Edwards SJ, Lilford RJ, Hewison J. The ethics of randomized controlled trials from the perspectives of patients, the public, and healthcare professionals. BMJ 1998;317:1209-12.         [ Links ]

21. Ordovás JP, López E, Urbieta E, Torregrosa R, Jiménez NV. Análisis de las hojas de información al paciente para la obtención de su consentimiento informado en ensayos clínicos. Med Clin (Barc). 1999;112:90-4.         [ Links ]

22. Kincaid JP, Fishburne RP, Rogers RL, Chissom BS. Derivation of new readability formulas (Automated Readability Index, Fog Count, and Flesch Reading Ease Formula) for Navy enlisted personnel. Research Branch report 8-75. Memphis: Naval Air Station, 1975.         [ Links ]

23. Doak CC, Doak LG, Root JH. Teaching patients with low literacy skills. 2nd ed. Philadelphia: J.B. Lippincott, 1996.         [ Links ]

24. Panorama de la Educación. Indicadores de la OCDE 2013. Ministerio de Educación Cultura y Deporte. (Consultado 30/01/2016). Disponible en: 0901e72b8169cc30.         [ Links ]

25. Paasche-Orlow MK, Taylor HA, Brancati FL. Readability standards for informed-consent forms as compared with actual readability. N Engl J Med 2003;348:721-26.         [ Links ]

26. Davis TC, Williams MV, Marin E. Health literacy and cancer communication. CA Cancer J Clin 2002;52:134-49.         [ Links ]

27. Jubelirer SJ, Linton JC, Magnetti SM. Reading versus comprehension: implications for patient education and consent in an outpatient oncology clinic. J Cancer Educ 1994;9:26-29.         [ Links ]

28. Young DR, Hooker DT, Freeberg FE. Informed consent documents: increasing comprehension by reducing reading level. IRB 1990;12:1-5.         [ Links ]

29. Paris A, Nogueira da Gama Chaves D, Cornu C, Maison P, Salvat-Melis M, Ribuot C, et al. Improvement of the comprehension of written information given to healthy volunteers in biomedical research: a single-blind randomized controlled study. Fundam Clin Pharmacol 2007;21:207-14.         [ Links ]

30. Beardsley E, Jeff ord M, Mileshkin L. Longer consent forms for clinical trials compromise patient understanding: so why are they lengthening? J Clin Oncol 2007;25:13-14.         [ Links ]

31. Bjorn E, Rossel P, Holm S. Can the written information to research subjects be improved? An empirical study. J Med Ethics 1999;25:263-67.         [ Links ]

32. Verheggen FW, Jonkers R, Kok G. Patients' perceptions on informed consent and the quality of information disclosure in clinical trials. Patient Educ Couns 1996;29:137-53.         [ Links ]

33. Morrow GR. How readable are subject consent forms? JAMA 1980;244:56-58.         [ Links ]

34. Silverman HJ, Luce JM, Lanken PN, Morris AH, Harabin AL, Oldmixon CF, et al. Recommendations for informed consent forms for critical care clinical trials. Crit Care Med 2005;33:867-82.         [ Links ]

35. Coyne CA, Xu R, Raich P, Plomer K, Dignan M, Wenzel LB, et al. Randomized, controlled trial of an easy-to-read informed consent statement for clinical trial participation: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 2003; 21:836-42.         [ Links ]

36. Davis TC, Holcombe RF, Berkel HJ, Pramanik S, Diver SG. Informed consent for clinical trials: a comparative study of standard versus simplified forms. J Natl Cancer Inst 1998;90:668-74.         [ Links ]

37. Flory J, Emanuel E. Interventions to improve research participants' understanding in informed consent for research: a systematic review. JAMA 2004;292:1593-601.         [ Links ]

38. Silva MC, Sorrell JM. Enhancing comprehension of information for informed consent: a review of empirical research. IRB 1988;10:1-5.         [ Links ]

39. Jefford M, Moore R. Improvement of informed consent and the quality of consent documents. The Lancet Oncology 2008;9:485-93.         [ Links ]

40. Fernández de Uzquiano. Actividad y funcionamiento de un comité ético de investigación clínica en un hospital universitario de tercer nivel de la Comunidad de Madrid. Análisis de 1219 estudios. La Neumología en la investigación clínica. Tesis Doctoral. Madrid. Facultad de Medicina. Universidad Autónoma de Madrid, 2007. (Consultado 10/06/2015). Disponible en:;jsessionid= E7698B43F9036D6962EE5F68A400A90C.         [ Links ]

41. UK NHS. Management information. UK NHS: London, 2007. (Consultado 06/07/ 2015). Disponible en: ons/publications/corporatepublications/management-information/.         [ Links ]

42. Dixon-Woods M. What do research ethics committees say about applications to do cancer trials? Vol 9 August 2008.         [ Links ]

43. Kirkby, Calvert M, Draper H, Keeley T, Wilson S. What potential research participants want to know about research: a systematic review. BMJ Open 2012;2: e000509.doi:10.1136/bm-jopen-2011-000509.         [ Links ]



Correo electrónico:
(Elena Villamañán).

Recibido el 24 de noviembre de 2015;
aceptado el 5 de marzo de 2016.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License