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Minimizing Risk When Obtaining Informed Consent


Compliance with FDA regulations is only the first step in minimizing the risk associated with the informed consent process. This article provides an overview of requirements and several best practices for the sponsors of clinical trials.

In 1999, Jesse Gelsinger agreed to participate in a gene therapy trial at the University of Pennsylvania. Jesse suffered from a genetic condition that made him unable to metabolize certain substances, forcing him to maintain a strict diet and medication schedule. As part of the trial, Jesse was injected with a virus that contained human gene fragments. The virus was supposed to insert the gene fragments into Jesse’s liver cells and return them to normal genetic function. However, the injection caused a massive immune response that led to multiple organ failure. Four days after his first injection, Jesse died.

Jesse’s parents sued the University and, in the course of the litigation, learned that four previous volunteers had experienced toxic side effects from the virus. They also learned that two monkeys died during the study’s animal safety tests and that the dose of virus Jesse received was larger than that of previous patients. Jesse’s parents argued that even though Jesse signed a form in which he consented to participate in the trial, he did not give informed consent as required by law because he did not adequately understand the nature of the risks involved.

Informed Consent and the Duty to Warn

Deficiencies in informed consents are frequently alleged in lawsuits that involve clinical trial participants. Informed consent causes of action are often directed towards drug and device manufacturers in their roles as clinical trial sponsors. In products liability lawsuits that do not involve clinical trials, manufacturers can sometimes satisfy their legal duty to warn the patient of product risks by warning the learned intermediaries—the healthcare professionals who administer care to the patient. However, the experimental nature of clinical trials requires that such warnings be given directly to the patient through the informed consent process. If adequate informed consent is not obtained, the sponsor could be responsible for potentially large liabilities should something go wrong during the trial.

Informed Consent Requirements

There are international, federal, and state laws that govern the process by which a patient consents to participate in a clinical trial. International requirements regarding the informed consent process are found in paragraph 22 of the Declaration of Helsinki which states:

In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject’s freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.

FDA regulations provide more detailed guidance regarding informed consents (45 CFR 116—117; 45 CFR 46 Subpart D). They require investigators to obtain consent only under circumstances that provide the prospective subject with a sufficient opportunity to consider whether or not to participate. Such circumstances must also minimize the possibility of coercion or undue influence. Informed consent documents must be approved by an institutional review board (IRB) and must contain the following:

  • A statement that the study involves research
  • An explanation of the purposes of the research
  • A description of the procedures to be followed
  • Identification of any procedures which are experimental
  • A description of any reasonably foreseeable risks or discomforts to the subject
  • A description of any benefits to the subject or to others that may reasonably be expected from the research
  • A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject
  • A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained
  • For research involving more than minimal risk, an explanation as to whether any compensation, and an explanation as to whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained
  • An explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights and whom to contact in the event of a research-related injury to the subject
  • A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits, to which the subject is otherwise entitled (45 CFR 46.116.)
  • FDA regulations do not preempt any other laws which require additional information to be disclosed for the informed consent to be legally effective. Indeed, in court, the informed consent process is often judged against best practices of the industry. So while compliance with FDA regulations is crucial, regulatory compliance alone is not enough to protect the sponsor from liability. Most states also have common law requirements concerning the informed consent process.

    For example, in Massachusetts, it is not required that remotely possible risks be disclosed; however, physicians are required to disclose all significant medical information that they possess (or should possess) that allows the patient to make an intelligent decision about whether to undergo a proposed procedure (Harnish v. Children’s Hospital Medical Center, 439 N.E. 2d 240). If this standard had been applied to the Gelsinger case discussed previously, the Gelsingers would likely have succeeded had their case gone to trial. They would have argued that the University failed to obtain informed consent because it failed to disclose the toxic effects observed in previous subjects, the deaths of the monkeys during the animal safety study, and the increased dosage—all material facts that arguably may have changed Jesse’s mind about participating in the trial.

    Informed Consent Best Practices

    Lawsuits involving clinical trial subjects often involve scrutinizing the adequacy of the informed consent. There are a number of risk management practices a sponsor can implement in order to ensure that clinical trial participants are participating voluntarily and with full knowledge of the risks associated with the trial. The following suggestions are by no means an exhaustive list, but are intended to provide some general guidelines for sponsors who are interested in increasing the effectiveness and minimizing the risk of their informed consents

  • Understand that obtaining informed consent is a process. While obtaining the signature of a participant on an informed consent form is an essential part of the informed consent process, the process should involve more than just having the participant read and sign a consent form. It is not unusual for an informed consent form to be thirteen to fifteen pages long, raising serious questions as to how much subjects actually understand if they just read and sign the consent. In other words, a signed consent form is not a substitute for the required disclosure by a physician or healthcare professional. It is more or less evidence that patient consent was obtained, but it is not conclusive. A patient may sign an informed consent form but still be said to not have truly given consent if other parts of the informed consent process were lacking.

  • Obtaining an adequate informed consent involves explaining the risks and benefits in such a way that the participant fully understands the potential consequences of participating in the study. When discussing the nature of the trial and the associated risks with potential participants, healthcare professionals should be clear, taking care to cover all important details, and avoiding overly technical terminology. They should answer any questions the potential participant has and make notes to memorialize the process and any significant issues discussed. They should also make sure that the oral explanation provided is congruent with the information provided in the consent form. Throughout the consenting process, healthcare professionals should also be mindful of differences in culture, education, race, or religion that may affect how information is communicated and received. The goal is to minimize confusion and present the information in a way that allows the potential participant to make a reasoned decision as to whether or not to participate in the trial.
  • Make sure the patient is able to understand the risks. There are a variety of circumstances that can impair or diminish a patient’s capacity to understand the nature of a trial, its associated risks, and alternative treatments. For example, if the patient is unable to speak or understand English, a trusted translator will be necessary in order to ensure that the proper information is disclosed. Clinical trial investigators should also refrain from enrolling individuals who have a physical condition that adversely affects his or her reasoning capacities. Other circumstances that might impair a patient’s capacity to understand include mental illness, senility, or medication that prevents comprehension.
  • Consult with a products liability attorney. Clinical trial sponsors should consult an attorney who specializes in products liability law and can provide a perspective to their informed consent process and forms that reflect what courts and juries have previously found problematic. For example, FDA regulations may not require certain information in a consent form, such as the regulatory status of the device being tested, but an experienced attorney may advise a sponsor to include it to avoid future litigation over the issue. Consulting with a products liability attorney on an informed consent form may ultimately save the sponsor money if the consent ends up being an issue in litigation.
  • Make sure your consent forms are current. Informed consent forms must be approved by the trial’s IRB. IRBs exist to protect the rights and interests of the patient, and they review informed consent forms during the trial’s application and renewal process. (See Medmarc’s article, “The Ethical Oversight of Clinical Trials,” in Rx for Risk volume 3, issue 1, for further information on the role of IRBs.) They may request that changes be made to the language of the form. Sometimes, these changes are requested after the trial has commenced, resulting in multiple versions of the consent forms. Clinical trial sponsors should ensure that new enrollees are reviewing and signing the most current form. This helps avoid potential allegations that the patient did not receive adequate informed consent because the form was outdated.
  • Do not ignore the dates. There have been several cases in which plaintiffs alleged that the informed consent had not been adequately obtained because the date in which the consent was signed was after the date in which the subject began participating in the trial. In a similar vein, other plaintiffs have argued that the lack of a date on an informed consent raised doubt as to whether it was properly and timely obtained. Do not allow the adequacy of the informed consent to be called into question by these types of hasty or careless mistakes.
  • Keep the language simple and comprehensible. The FDA requires that the informed consent process be in language that is understandable to the prospective subjects; however, this is helpful from a liability standpoint as well. Subjects are unlikely to be well-versed in the technical terms and phrases that are common to healthcare practitioners. For example, state that the participant can take the test medication by “swallowing a pill” as opposed to “through gastrointestinal absorption.” The use of such technical terminology could easily be viewed as overly complicated and potentially misleading. Remember the audience and write clearly and simply so lay participants can understand.
  • Conclusion

    The choice to participate in a clinical trial cannot be adequately exercised without information regarding the purpose of the trial and its potential risks and benefits. Following the aforementioned suggestions in addition to complying with FDA regulations can help a clinical sponsor reduce the risk of liability and ensure that the informed consent process is the best that it can be.

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