The Importance of the Subject in Informed Consent

Conduct in clinical trials involving human subjects is regulated by international, regional, and national guidance, legislation, and frameworks, which pharmaceutical companies then translate into detailed internal standard operating procedures (SOPs). Recruitment of subjects to take part in clinical research trials, at the core of which lies the informed consent process, is therefore subject to the most stringent guidelines. From the point of view of someone taking part in clinical research, however, even a fully regulator compliant set of processes and documentation is often not the most subject-friendly. In addition, high-profile media attention and negative publicity have impacted pharmaceutical companies conducting clinical trials in developing countries such as Nigeria.¹

Photography: PhotoDisc Illustration: Paul A. Belci

But it's not just trials in developing countries. Although Swedish participants had been "aware that they were taking part in a clinical trial, the quality of information understood and recalled by the participants varied, and in many cases did not meet the guidelines of the Declaration of Helsinki."² And a recent survey of 1900 subjects at 16 U.S. research institutions revealed that 53% were not even aware that they were part of a study.³

The Department of Health in the United Kingdom has initiated its own review in this area and disseminated the findings through the National Health Service.⁴ New regulations in the United States such as the HIPAA privacy regulation⁵ have impacted upon subject information in U.S. trials.

In 2002, Roche's Clinical Pharmacology Department conducted an audit of its own clinical trials' "supply chain," mapping out the processes and stakeholders involved from conception to completion of a trial. A potential risk was identified around the informed consent process. The sponsor of clinical trials is removed from this process. However, if issues were ever raised about the way informed consent had been carried out in one of its trials, as the most well-known organization in the supply chain, the damage to reputation would focus on the sponsor—although not directly responsible.

Feedback from regular investigator satisfaction surveys carried out by Roche also demonstrated the need for change. It stressed the need for more educational materials to aid subject understanding, improved paperwork, and better support for investigators and subjects.⁶ Roche began an initiative in September 2002 to explore the issues surrounding the informed consent procedure and subject information. The company commissioned an independent research organization, Article 13, to carry out a research program, initially with a UK focus.

Given the focus of the inquiry and the ultimate objectives, the research clearly fell within the realm of social research, so it was designed to be as participative as possible. Sampling involved a range of relevant stakeholders using purposive sampling where appropriate (sponsor's employees, investigators, trial subjects, and regulatory and patient advocate organizations).

Problem definition

The initial aim of the research was to define clearly the key issues around informed consent. Was a concern emerging around how informed consent was carried out and the role of the subject within the process? And were these issues relevant to the sponsor? The research started with a review of key literature^7–9 (current national, regional, and international guidance documents^10–16 ) and semistructured interviews by telephone with carefully selected key informants that included senior individuals in regulatory, government, and advocacy organizations.

Phase one key findings

This first phase, the problem definition phase, produced the following findings:

• definitions of informed consent concentrate on the giving of information by the researcher rather than on the understanding by the subject

• the whole process needs to address the subject's understanding of the information

• surveys conducted among doctors showed that many thought their patients rarely understood all of the information given to them

• the commonest cause of ethics committee deferral was the informed consent form (ICF)

• information is often too technical or pitched at a reading level too advanced for many subjects

• the understanding of subjects is not always tested

• the process does not engage subjects with what they want to know or what they think they need to know

• there is variation in how quickly or easily different subjects absorb the information given to them (e.g., some subjects need more "explaining" time)

• subject understanding (or lack of) can have an impact on the effectiveness of the trial.

The findings clearly showed that the informed consent process was too focused on a one-way flow of information and that the information was not suited to the audience.

Participatory action research

The findings were taken forward to a second phase, which used an approach called Participatory Action Research.¹⁷ The following questions were addressed:

• If there were concerns in the health sector around the informed consent process, how did the industry currently perform?

• How did the company currently perform?

• Did the company need to change its processes?

• Could action be taken at an individual company level, or did it need an industry-wide approach?

A series of separate workshops was conducted with key stakeholder groups. The aim was to find out what currently happened at the various stages in the informed consent process, starting from when sites were briefed through the preparation of the written material and informed consent form, to when informed consent was actually carried out with subjects. Workshops were held with the following groups:

• multifunctional staff at Roche who were involved in writing ICF and subject information, liaising with investigator sites, and overseeing quality and compliance with international guidance

• investigators who were either working or had worked with the sponsor and were directly responsible for taking consent from subjects or overseeing the process

• clinical trial subjects—separate workshops were carried out with healthy volunteers and with patients, each with a mix in terms of gender, age, and clinical trial experience.

Phase two key findings

The findings demonstrated several key disconnects in the following areas:

• in timing—when the subjects wanted information and answers to their questions and when the informed consent procedure required information to be provided

• in what information was provided for—and used for— between what the investigators and sponsor wanted and what the subjects wanted

• between new subjects and experienced subjects and what information they required.

The particular issues that surfaced for the sponsor during this second phase were:

• there is an assumption that the informed consent process is carried out consistently and transparently by all parties; however, this was not supported by evidence or an audit trail, representing a potential risk to the sponsor

• an emerging risk lies within the theme of subject understanding and the additional information subjects' desire during the trial.

Action plan

The findings from the Participatory Action Research phase were reviewed by a working group of Roche staff to assess the implications for the sponsor and recommend actions to address them. The Roche working group produced a set of guidelines (i.e., an action plan), which included:

• process recommendations setting minimum standards for what the sponsor should expect of investigator sites and ensuring increased transparency in the informed consent process

• best practice recommendations for writing user-friendly subject information

• a model ICF.

The ICF was accredited with a Crystal Mark by the Plain English Campaign, an independent UK organization¹⁸ promoting the use of clear and easy-to-read language in documents for the public.

Evaluation of changes

The new processes, guidelines, and associated training with sponsor staff were assessed to establish whether they had made a genuine difference. This evaluation consisted of questionnaires and in-depth interviews with:

• sponsor staff (email questionnaires and semistructured telephone interviews)

• investigators (email questionnaires and semistructured telephone interviews)

• subjects (freepost and questionnaire cards).

The key issues uncovered by this stage of the research evaluation centered around the subject. The responses concurred with the need for the informed consent process to focus on the subject and their requirements. The in-depth interviews also confirmed the need for the process to ensure the understanding of the information received by allowing time for volunteers to take in the information, as well as the need for methods such as active questioning of the subject.

As a result, changes were made to the training and the set of guidances. The training was built around the subject's experience of clinical trials and their need to understand and question the process. The set of guidances was amended to provide advice on producing subject-friendly written material. A model Plain English document was drafted as an example.

It was important to stress to all involved that the guidelines were not to replace regulations and guidances governing current practice. Rather, the guidelines aimed to enhance processes, to highlight the importance of subject understanding, and to improve the quality of subject information and the understanding and experience of subjects.

Implications and discussion

The initiative has been fully rolled out within Global Clinical Pharmacology and is being trialed for use in therapeutic studies. Overall, the research showed that the industry as a whole needed to take a more subject-driven approach. The first phase indicated that there were general concerns

in the health sector around informed consent, which generally had a one-way flow of information. There appeared to be no consistency in checking the level of understanding of subjects. With an increasing focus on the patient experience in the health sector, the "box-ticking" approach to informed consent was inadequate to meet the expectations of society today. The risk for subjects was that they were signing up to a trial without fully understanding what they were signing up to.

The second phase revealed examples of good practice, but also disconnects between the needs of subjects and what is provided. There was a lack of evidence and transparency about the way consent was taken at investigator sites.

The Participatory Action Research phase explored each issue and how Roche could use its position as sponsor to influence practice. This was principally through setting minimum standards of conduct at investigator sites and documenting procedures for checking that subjects had received the information. Also, the sponsor could ensure that subjects had been engaged in discussions about their involvement and tested on their understanding, as recently discussed by Jaynes.¹⁹ Additional output included guidance on writing more user-friendly ICFs, keeping the reader in mind, and aiding subject understanding. The initiative has resulted in a wider appreciation of the whole process of informed consent and the needs of the most important person: the subject participating in the trial.

Jane Fiona Cumming,* MBA, is the co-founder of Article 13, Bradley House, 26 St Albans Lane, London, NW11 7QE, UK. Anureet Ritu Sahni, MD, is a clinical pharmacology operations project manager for Roche Products Limited, and Graham Ralph McClelland, PhD, is global head of clinical pharmacology operations for Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, London, AL7 1TW, UK.

*To whom all correspondence should be sent.

References

1. J. Stephens, "Suit Accuses Pfizer of Rights Violations," Washington Post, 30 August 2001.

2. N. Lynoe, M. Sandlund, L. Jacobsson, "Informed Consent in Two Swedish Prisons: Study of Quality of Information Given to Participants in a Clinical Trial," Medical Law, 20, 515–523 (2001).

3. N.M. Goldfarb, "Readable Informed Consent Forms Are Not Optional," Journal of Clinical Research Best Practice, 1 (9) (September 2005).

4. Department of Health, "Good Practice in Consent: Achieving the NHS Plan Commitment to Patient-centred Consent Practice," HSC 2001/023, London (2003).

5. The HIPAA Privacy Regulation (Standards of Privacy of Individually Identifiable Health Information) Implementations Implement the Requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).

6. K. Irvine and E. Hilton "Ensuring a HIPAA-Compliant Informed Consent Process," CenterWatch Inc. (1 February 2003).

7. G.R. McClelland, J.L. Siegel, M.K.M. Goddard, "Measuring Investigator Satisfaction: A Global Survey Identifies Strengths and Improvement Opportunities," Applied Clinical Trials, 11 (6), 70–82 (2002).

8. S.J.L. Edwards, R.J. Lilford, J. Hewison, "The Ethics of RCTs from the Perspectives of Patients, the Public and Health Care Professionals," British Medical Journal, 317, 1209–1212 (1998).

9. P.R. Ferguson, "Patients' Perceptions of Information Provided in Clinical Trials," Journal of Medical Ethics, 28, 45–48 (2002).

10. F. Verheggen and F. Van Wijmen, "Informed Consent in Clinical Trials," Health Policy, 36, 131–153 (1996).

11. Food and Drug Administration, Guidance for Industry–E6 Good Clinical Practice: Consolidated Guidance ICH, FDA, Rockville, MD (1996).

12. Medical Research Council, MRC Guidelines for Good Clinical Practice in Clinical Trials, MRC, London (1998).

13. Food and Drug Administration, Guidance for Institutional Review Boards and Clinical Investigators, 1998 Update, FDA, Rockville, MD (1999).

14. D. Hutchinson, The Trial Investigator's GCP Handbook, Brookwood Publications (1997).

15. Department of Health and Medicines Control Agency, EU Directive on Good Clinical Practice in Clinical Trials, DH and MCA Briefing Note, DH and MCA (2002).

16. Royal Free Hospital (1990), A Guide to Consent for Examination or Treatment (Pond Street, London, NW3 2QG).

17. R. O'Brien, "An Overview of the Methodological Approach of Action Research," online version available at: http://www.web.net/~robrien/papers/arfinal.html (1998).

18. The Plain English Campaign Web site: www.plainenglish.co.uk.

19. T. Jaynes, "Informed Consent: Imparting Knowledge or Signing a Form?" Applied Clinical Trials, 14, 104–106 (2005).

Acknowledgment

Key informants consulted for this initiative included senior representatives from the following organizations: Central Office for Research Ethics Committees (COREC), www.corec.org.uk; Consumers for Ethics in Research (CERES), www.ceres.org.uk; Medical Defence Union (MDU), www.the-mdu.com; British Medical Association (BMA), www.bma.org.uk; and Roche Clinical Pharmacology Unit.