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Informed consent: practical considerations.

Informed consent is a legal document that summarizes what will take place in a study in a language the study subjects can understand. The role of a consent form is not only meant to describe to participants potential risks and benefits but also is the resource by which subjects are informed why a study is being done and what the particular study will contribute to what is already known and understood about the area of interest, or topic. Importantly, the informed consent has become the main document, even over and above the protocol, in our attempts to ethically conduct clinical trials.

Historically, documents meant to address the ethical treatment of human subjects and research began with the Nuremberg Code, a 1947 landmark post-Nuremberg trial document that was developed by two American physicians who worked with the prosecution. Immediately following, in 1948, the Declaration of Geneva was developed by the World Medical Association (WMA). Based on the Nuremberg Code, it was the first significant endeavor by the medical community to regulate research itself and formed the basis of most subsequent documents. Finally, the Declaration of Helsinki, written by the WMA, was the first attempt to create a specific framework for the ethical conduct of clinical trials and the treatment of participating subjects. The Helsinki document was adopted by the 18th "WMA General Assembly in Helsinki, Finland, in 1964, and has been amended many times since, last at the 59th WMA General Assembly, in Seoul, in October 2008. All of the above documents are based on the following principles.

1. There should be no unnecessary risk to the participants as they take part in clinical trials.

2. Unnecessary studies, trials that have no specific aim or benefit, hence possibly exposing patients to risks with no justifiable benefit, should not be carried out.

3. Every effort should be made to avoid scientifically unsound studies, as these would offer potentially more to harm subjects, and the final results may not be useful or applicable.

4. In the same lines as the previous point, poor planning should be avoided in all trials.

Critically important, the Declaration of Helsinki states that in medical research involving human subjects, the well-being of the individual research subject must take precedence over all other interests. The Declaration of Geneva of the WMA also binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics (adopted by the WMA in 1949 and further amended) declares that, "A physician shall act in the patient's best interest when providing medical care."

It is clear that the importance of the well-being of subjects should be foremost in the minds of physicians. Physicians should consider the ethical, legal, and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal, or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in these named documents. Medical research involving human subjects may only be conducted if the importance of the objective outweighs the inherent risks and burdens to the research subjects. These concepts must be part of any clinical study at each level, starting with the protocol and culminating in the informed consent document.

Clinical Trials

In clinical trials, the protocol is developed by the investigators, usually after extensive consultations, and is not usually seen by the subjects or discussed in detail with them. The consent form is the only opportunity for the participating study subjects to find out and read about what the study is proposing to do. The information is presented in layman's terms so patients are not confused by too much technicality and must provide a fair summary of the clinical trial. Included in this summary but not limited to it are 1. the reason for doing the study, 2. what has been done in the past as reviewed in the literature, and 3. what options patients have if they decline to participate.

The informed consent is also the right place to discuss study characteristics related to placebo use, trial duration, what would happen after the trial as far as availability (e.g., if it is a study drug), and also ramifications of early termination of the study. The most important question in the protocol, "why is this study being done?" needs to be answered in the informed consent, explaining how equipoise, that there is a 50-50 chance the intervention may work, is maintained in the study. Informed consent is not only a piece of paper that the patient needs to sign to enroll in a clinical trial, it is the document that educates the participant in what they are about to engage in.

Institutional Review Boards

A review of research protocols and informed consent documents for investigative studies has been conducted by institutional review boards (IRB) in the United States since the early 1970s. Today, IRB reviews are performed for all university-based clinical studies.

One current practical concern is the way IRBs approve protocols and informed consents. Anyone who has been involved in clinical research at one time or another has had to deal with an IRB and informed consent issues. Most, just as the current author has, likely find the process demanding, challenging, and sometimes arbitrary. A lengthy form is forced upon the researcher regardless of what type of trial is being planned, what interventions that will be used in the study, and how the data will be processed or applied. There usually is no regard to reasonable exemptions, and the appreciation of what the planned study is actually about is often obscured.

Another concern impacting the entire clinical trial approval process has been the private "for profit" IRBs. As reported recently, the U.S. Government Accountability Office (GAO) investigated private IRBs in the U.S., which mostly serve industry-funded studies, and found some disturbing practices.1 In one case, a fictitious protocol with very questionable practices was submitted to three independent IRBs. Two boards returned the protocol right away as unsuitable, but a third approved the study. Further inquiry showed that the same IRB had approved all but one of the 356 protocols it reviewed over the last 5 years. These commercial IRBs review only a small proportion of all clinical studies, yet this IRB alone had 300 active studies at the time and closer scrutiny of these boards and their companies are likely needed for the future.

Clearly, for most if not all treatment intervention trials, a strong IRB review and a long informed consent is needed. However, it is more difficult to make the same argument for observational routine care studies, where most, if not all, the measures followed in a group of patients are part of the routine care provided to the same patients each time they are seen.

Cohort and Patient Issues

There are good examples, especially in the cardiology and neurology literature, that show the act of consenting itself can lead to different baseline characteristics between a research group, or cohort, that consented and was studied, and the group that did not agree to give consent and, hence, did not participate in the trial. These baseline differences can have important impact on the final results and limit external validity of the study. (2) It may be time to look at individual studies very carefully and try to identify areas where the process can be simplified without additional risk to patients or unintentional bias regarding subject inclusion. It also would be in the best interest of patients and generally valuable if select observational studies were not impeded by unreasonable IRB and informed consent requirements.

One additional and potentially problematic issue to consider is what patients understand from the informed consent. Informed consent is not only for documenting the patient's acceptance into enrolling in a clinical trial. It currently is the patient's and the public's main source of information regarding the reasons for the planned study, what is known in the field regarding the proposed trial, and what is expected as far as efficacy and harm.

Clinical Registries

Clinical trial registries developed over the last 5 years serve as a good resource for researchers, health care providers, and patients to follow what trials are being performed. They also provide a way to be certain of the status of every trial that has been started, and that all completed trials, whether the outcome is positive or negative to expectations, is finally published, thus combating the negative trial publication bias, where only trials with positive results are published and negative ones are ignored. The concept of clinical trial registry, in other words, has been designed to disseminate knowledge about clinical trials. Currently, brief protocol summaries, including aims, primary outcomes, inclusion and exclusion criteria, duration of trial, and planned intervention, of all registered clinical trials are available on the Internet.

On the other hand, informed consent is not currently part of the clinical trial registries. The World Health Organization has developed a single international standard for the information that principal investigators of trials must disclose. The informed consent form (original or subsequent versions if the trial protocol necessitates) is not among those items listed. More recent schemes to expand registration of clinical trials also do not include full disclosure of informed consent forms. The exclusion of the content of informed consents from registries and from the literature is a serious omission in our current attempt to make clinical trials more transparent. With their inclusion, their role would be broadened and enhanced, bringing improved transparency to the entire clinical trial process.

It is worth noting that the current practice of approving clinical trial applications, including approval of the informed consent forms at IRB, does involve the input of the public. There is at least one layman member from the local community who is part of each IRB. However, this represents a very limited and short-term public access, and thus limited transparency. What needs to be done is to make this transparency and access more widespread and permanent, thus greatly enhancing the public's, peers' and patients' awareness of what is being studied and how.

Additional benefits of such transparency would be the probable cessation of "seeding trials," which characteristically attempt to introduce concepts or interventions, as opposed to testing scientific hypotheses, and may include commercial interests and "motivational" features for participation. Recent data about the ADVANTAGE (Assessment of Differences between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness) trial (3) has shown what has always been suspected by researchers--that some trials have no scientific validity but are done solely for marketing purposes. If all the components of the informed consent were fulfilled and transparent, few patients and investigators would be willing to participate in such trials and this "anti-scientific" practice may eventually stop.

Conclusion

The informed consent form was designed to educate and inform subjects before they enter into a clinical trial that there is merit to the proposed study, that they will be treated fairly and ethically, and that their well-being will not be compromised in any way by the study. Using the informed consent as a tool to further open access and provide increased transparency about clinical trials mirrors the intentions of the first declarations of ethical conduct and patient treatment in research. The inclusion of informed consents in clinical registries and published reports has the potential to advance the way clinical trials are conducted and improve public trust in the process and outcomes of clinical research.

Disclosure Statement

Yusuf Yazici, M.D., participates in the speaker bureau for Bristol-Myers Squibb (BMS) and Genentech and is a consultant to BMS, Celgene, Centocor, Genentech, Roche, and UCB.

References

(1.) Horton R. How ethical are for-profit institutional review boards? (Editorial) Lancet 2009;373:1400.

(2.) Junghans C, Feder G, Hemingway H, et al. Recruiting patients to medical research: double blind randomized trial of "opt-in" versus "opt-out" strategies. BMJ. 2005;331(7522):940.

(3.) Hill KP, Ross JS, Egilman DS, et al. The ADVANTAGE seeding trial: a review of internal documents. Ann Intern Med. 2008;149(4):251-8.

Yusuf Yazici, M.D., Assistant Professor of Medicine, New York University School of Medicine, is within the Division of Rheumatology, Department of Medicine, NYU Hospital for Joint Diseases, NYU Langone Medical Center; New York, New York; yusuf.yazici@nyumc.org.

Correspondence: Yusuf Yazici, M.D., Peter D. Seligman Center, 246 East 20th Street, New York, New York, 10003; yusuf.yazici@nyumc.org.
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Author:Yazici, Yusuf
Publication:Bulletin of the NYU Hospital for Joint Diseases
Geographic Code:1USA
Date:Apr 1, 2010
Words:2081
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