Who is responsible for obtaining informed consent from a subject in a clinical drug trial?

Informed consent is a process, not just a form signed by prospective study subjects. Documents such as the Code of Federal Regulations describe the elements of informed consent, but lack substantive direction on the process of obtaining consent.1-2 The purpose of this article is to provide guidelines for obtaining informed consent. This guide can be useful to anyone involved in clinical research, particularly newcomers to the industry.

The process of obtaining informed consent from subjects is a critical point of entry for research participants. Although the basic principles of obtaining informed consent transcend therapeutic areas and vulnerable patient populations, significant differences must be considered when research designs include individuals at increased risk. Special attention must be given to meeting the needs of vulnerable populations such as children, the critically ill, or the mentally impaired. The atmosphere for the family of a trauma patient during the first few critical hours of admission is far removed from the unhurried pace of the outpatient clinic. The focus of this article, however, is the process of obtaining consent from a population of patients who are not under duress at the time of consent.

Typically, the introduction of a potential subject to a clinical trial occurs in one of the following ways:

• The subject may have been identified as part of a recruitment campaign.

• The subject may simply be part of a patient population being studied.

• The clinical trial may be offered as a treatment option after a patient has been given the facts concerning a diagnosis and prognosis.

Although there are several ways that patients learn about clinical trial "little is known about the factors that influence decisions to participate in scientific research."3 Kuczewski and Marshall recommend adopting the approach that consent is an interactive and dynamic process and many factors can influence the study participant's willingness to sign the document. These factors include socioeconomic background, cultural traditions, literacy and language ability, and interactions with physicians and other healthcare professionals.

Bosk found "what, how, and when information is presented does make a difference to a subject's understanding of research and to subsequent enrollment."4 The investigator should carefully weigh the consequences of trying to obtain consent after the patient has just been diagnosed with a life-threatening illness. A subject's ability to make decisions may also be affected by his/her emotional state.5 Emotional stress can be a cause of failure to consent. It is recommended that the subject be given a week to accept her diagnosis before discussing enrollment in the study.

Trechan found that risk levels influence a subject's willingness to participate in clinical research.6 Furthermore, negative media attention, such as Ellen Roche's death at Johns Hopkins, may adversely affect decisions to participate.7 Getz suggests that subjects who successfully complete other clinical trials are more likely to consent again.8

Problems with the consent process

The informed consent process presents some major challenges for study participants and research staff. Several papers have addressed problems with the current process. Among them, Brady identifies the following issues:

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• Subject's hesitation to ask detailed questions

• Variable presentation of the content

• Difficulty verifying the subject's comprehension.

Additionally, a survey of 1600 respondents performed by CenterWatch in 2002 found that 14% of subjects did not read the consent before signing, and a high percentage of volunteers admitted to not fully understanding the risks and not knowing what questions to ask. The concept of "therapeutic misconception" in research is another problem that has received much attention in both legal and bioethics literature. Generally, it is important that potential subjects are aware that research is not the only therapeutic alternative for them.10-12 Lack of subject understanding and comprehension is possibly compounded by the increasing regulations that govern the performance of study personnel and the cost pressures, meaning that there is ever-decreasing time available for study personnel to spend reviewing the consent with the subject.

Setting

The informed consent process begins when a potential subject is first approached to participate in a clinical trial. Whether informed consent is obtained over the phone (remember-there may be a specific protocol for doing this at your institution), or in a doctor's office or hospital, the setting should be the same. It should be an unhurried, private atmosphere where the subject has time to review the document and ask questions. The subject should be approached in a respectful manner and the person obtaining consent should introduce themselves by name and role, stating the purpose of their communication. As already indicated, the timing of this process is very important.

The person obtaining consent must have appropriate credentials and be qualified to do so. She/he should have experience in the field of study-otherwise, how will she answer questions posed by the subject? Additionally, this person should be familiar with good clinical practice guidelines for informed consent and with his/her own institutional review board's requirements for the process.

The researcher should determine the ability of the potential subject to understand the information and give consent before proceeding further. If the subject does not read or speak English adequately, an assessment should be performed to determine the subject's needs. The researcher should then make the decision to call in an interpreter. Kuczewski and Marshall suggest that misunderstandings are more likely to occur when investigators (or coordinators) and participants speak different languages, especially when "there are no equivalent expressions for particular biomedical concepts or when the notion of informed consent is unfamiliar." They offer strategies to help minimize language barriers:

Use an effective process of translation and back-translation when an informed consent document must be translated from one language to another. This process must include adequate pretesting of the consent document to determine that it is comprehensible to individuals who will be recruited for a research project.

Enlist the help of individuals who can act as "cultural experts" on ways in which to communicate difficult scientific concepts for study populations who may be unfamiliar with the biomedical problem being investigated.

Keep the consent document as short as possible, using simple language and a format that is clear and understandable for potential research participants.

The issue of using family members when there is a language barrier is a gray area. Most subjects feel more comfortable if one or more family members are available to help them with decision-making, though this is not always the case. Additionally, excluding family or friends from the discussion may eliminate bias for or against participation; however, this must be balanced with the subject's wishes. Tailor the discussion to the subject's needs.

Discussing the research study

The informed consent process is based on complete disclosure of the facts. During this process, the study coordinator or principal investigator should endeavor to establish a rapport and trusting relationship with the potential subject.

The coordinator or investigator should thoroughly review each section of the informed consent with the study subject. The consent form is, in essence, a teaching tool-a nontechnical, understandable document, written at an eighth-grade reading level. It is imperative that subjects understand the nature of the research study, the risks and the benefits, alternatives to research, and their rights as study subjects. Study subjects need to read (or have read to them) and comprehend the informed consent document. Ensure that they understand the nature of the study, that is, why the research is being done and why they are being asked to participate. The coordinator of the study should use whatever resources are available to promote subject understanding of the study such as, graphics, video, or even the device to be used, if possible. Care must be taken to avoid medical jargon that subjects could not possibly understand. Avoid presenting an overly positive (or negative) picture of the clinical trial for which consent is being obtained.

There is a growing body of data showing that research subjects have an unrealistic view of what their participation entails. Emphasis must be placed on the risks as well as the benefits. As has already been mentioned, subjects should understand the distinction between what is research and what is routine medical therapy.13 The idea is not to coerce but to provide the subject with the facts.

Finally, subjects should be allowed-and encouraged-to ask questions about the study. They should be able to take the document home with them if time permits.

Consent should be obtained when the investigator is available to answer questions or address concerns. The principal investigator is ultimately responsible for all aspects of conducting the research.

About HIPAA

It is incumbent upon the study team to understand how Health Insurance Portability and Accountability Act (HIPAA) regulations affect research and the informed consent process. However, with regard to HIPAA regulations, institutional practices and policies may vary significantly. HIPAA mandates "Standards for Privacy of Individually Identifiable Health Information." HIPAA applies to health information created or maintained by healthcare providers who engage in certain electronic transactions. Due to this and HIPAA's strong emphasis on confidentiality, HIPAA impacts many facets of the work we do in clinical research-specifically with the informed consent process. HIPAA requires subjects to sign an authorization. This authorization is like a consent form for HIPAA and may be a stand-alone document or may be integrated into the study consent form.

HIPAA requires that the following information be included in the authorization or consent form:14

• the information that is provided or disclosed

• who may use or disclose the information

• who may receive the information

• each purpose of the use or disclosure of the information

• expiration date or event of the consent and authorization

• individual's signature and date

• the subject's right to revoke authorization

• the subject's right to refuse to sign authorization

• the fact that subsequent disclosures by the recipient may not be protected under HIPAA.

In summary

Greg Koski, former director of the Office for Human Research Protections, recently said, "We must move beyond the culture of compliance, to move to a culture of conscience and responsibility." These are challenging times in clinical research. The coordinator has an ever-increasing load of regulations to deal with in an environment of severe time constraints. While there are many regulations governing the content of consent forms, there is very little to guide the process. With the emphasis on the patient as subject, it is easy to overlook the patient as human.

For specific tips from the Office for Protection from Research Risks go to http://ohrp.osophs.dhhs.gov/humansubjects/guidance/ictips.htm.

References

1. Code of Federal Regulations, Title 21, Part 50, (U.S. Government Printing Office, Washington, DC).

2. Code of Federal Regulations, Title 45, Part 46, (U.S. Government Printing Office, Washington, DC).

3. M.G. Kuczewski, P. Marshall, "The Decision Dynamics of Clinical Research: The Context and Process of Informed Consent," Medical Care, 40 (9 Suppl) 45-54 (2002).

4. C.L. Bosk, "Obtaining Voluntary Consent for Research in Desperately Ill Patients," Medical Care, 40 (9 Suppl) 64-8 (2002).

5. E. Wager, P.J. Tooley, M.B. Emanuel, S.F. Wood, "How To Do It. Get Patients' Consent to Enter Clinical Trials," British Medical Journal, 311 (7007) 734-737 (1995).

6. T.A. Treschan, T. Scheck, A. Kober, E. Fleischmann, B. Birkenberg, B. Petschnigg, O. Akca, F.X. Lackner, E. Jandl-Jager, D.I. Sessler, "The Influence of Protocol Pain and Risk on Patients' Willingness to Consent for Clinical Studies: A Randomized Trial," Anesthesia & Analgesia, 96 (2) 498-506 (2003).

7. M. Karigan, "Ethics in Clinical Research: The Nursing Perspective," American Journal of Nursing, 101 (9) 26-31 (2001).

8. K.A. Getz, "Informed Consent Process: A Survey of Subjects Assesses Strengths and Weaknesses," Applied Clinical Trials, November 2002, 30-36.

9. J.S. Brady, "Multimedia Delivery Can Enhance the Consent Process," Applied Clinical Trials, January 2003, 36-42.

10. S. Horng, C. Grady. "Misunderstanding in Clinical Research: Distinguishing Therapeutic Misconception, Therapeutic Misestimation, and Therapeutic Optimism," IRB: A Review of Human Subjects Research, 25 (1) 11-6 (2003).

11. E. Fried, "The Therapeutic Misconception, Beneficence, and Respect," Accountability in Research, 8 (4) 331-48 (2001).

12. P.S. Appelbaum, "Clarifying the Ethics of Clinical Research: A Path Toward Avoiding the Therapeutic Misconception," American Journal of Bioethics, 2 (2) 22-3 (2002).

13. J.P. Kahn, A.C. Mastroianni, "Moving From Compliance To Conscience: Why We Can and Should Improve on the Ethics of Clinical Research," Archives of Internal Medicine, 161 (7) 925-8 (2001).

14. Available at http://irb.mc.duke.edu Retrieved April 2003.

Acknowledgements

The author wishes to thank the following people for their help and support with this paper: Catherine Bodine, Communications Group, Duke Clinical Research Institute, Laura Duncan, IRB, Duke University Health Systems, and Sheda Moori, Site-Based Research, Duke Clinical Research Institute.

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