Medical Device Link.

Originally Published IVD Technology November/December 2001

Regulations & Standards

Informed Consent for IVD Studies: The Manufacturer’s Role

Jeffrey N. Gibbs

In order to obtain FDA clearance for their products, device companies sometimes need to conduct clinical studies. Such clinical studies must be conducted in accordance with several different FDA regulations, one of which requires that study subjects provide written informed consent unless some exception applies.¹ This obligation to obtain informed consent also applies to IVD manufacturers; there is no general IVD exemption.

In this instance, as in so many others, the standard regulatory model does not fit IVDs very well. For a wide variety of other new devices—such as pacemakers and spinal implants—it has always been clear that all studies require the informed consent of study subjects. But in the past, many product-approval submissions for IVDs have contained clinical data that were gathered without subjects having given written informed consent.

There is currently some controversy over when and whether informed consent should be required from patients whose already-gathered specimens are used in clinical studies.² Manufacturers who have used such banked specimens have rarely obtained informed consent for such use. But some FDA officials have said that consent or waiver of the consent requirements may be necessary. Although companies using banked, anonymized specimens may therefore need to consider whether some type of consent is necessary, at least in some circumstances, compliance with the informed consent regulations for such uses is not de rigueur—at least for now.

For specimens obtained from identified subjects in connection with prospective clinical trials, however, the story is different. In those cases, written informed consent will generally need to be obtained unless a specific exemption applies. As more IVD companies conduct studies in which specimens are prospectively obtained from identified subjects, it will become increasingly important for the industry to understand FDA’s informed-consent regulations.

Exceptions

There are two exceptions to the general rule that informed consent must be obtained. First, in certain narrowly defined emergency settings that preclude prior informed consent, the requirement may be waived.³ Although studies involving emergency diagnosis—such as rapid testing for strokes or myocardial infarctions—could conceivably qualify, most clinical trials with IVDs would not meet these rigorous criteria. Companies that are considering using this exception should be aware that they involve significant restrictions and limitations.

The second type of exception is much broader. It covers clinical trials where the institutional review board (IRB) “finds that the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside the research context.”⁴ If an IRB finds that a proposed study meets these criteria, it may exempt the study from the need for prior written informed consent. Given that IVD trials generally do involve only minimal-risk procedures, such as collecting small samples of blood, a number of studies may qualify for this IRB-granted exemption.

However, IVD clinical studies are not automatically exempt simply because they involve only blood collection, and not all IVD trials are candidates for this exemption. For example, a study could be excluded because the diagnostic specimen is obtained through a more invasive means (e.g., as in the case of spinal fluid), because the results might play a role in diagnosing the patient, because the data could affect the subject’s insurability, because the study subjects are required to participate over a prolonged period, or because the study raises significant privacy issues. It is also important to remember that this exemption can be granted only by the IRB—it is not one where a company can self-certify that it is entitled to the exemption.

While these two exceptions apply to studies where prospective informed consent would otherwise be required, there is some confusion regarding a separate category, known as expedited review. FDA’s regulations permit an IRB to approve a study based on review and approval by a single designated individual, rather than the full IRB. Such an expedited review is permissible when a study involves no more than minimal risk; FDA has published a list of eligible studies.⁵ However, expedited IRB review is not synonymous with exemption from informed consent. Getting expedited review does not relieve the sponsor of the need to obtain informed consent using an IRB-approved form. In such instances the term expedited refers to the IRB’s review of the form; it does not mean that informed consent can be eliminated.

If the informed-consent requirement applies, it is important that the sponsor comply with FDA regulations. Failure to comply can result in FDA enforcement action or questions regarding the acceptability of the data. Increased media scrutiny of clinical studies means that inadequate consent can result in adverse publicity and other problems. And, in extreme cases, it can even lead to litigation by aggrieved subjects.

Consent Forms

IVD manufacturers may be tempted to leave the drafting of the consent form up to investigators. After all, they are the ones who meet the subjects and actually explain the study. However, experience has shown that this method is often unsuccessful because many investigators don’t know how to write a form that satisfies FDA regulations. Their failure to draft a proper form puts the sponsor at risk, since FDA and study subjects can ultimately hold sponsors accountable for the consent form’s noncompliance with applicable standards.

FDA’s informed-consent regulations require that the written form address a minimum of eight elements.⁶ Each of the following elements must be satisfied.

Study Participation. The form must explicitly state that the subject is participating in research and identify which procedures are considered investigational. In a surprising number of cases, the form never clearly discloses that the subject is involved in research, as distinct from standard treatment or diagnosis. This disclosure should be made at the very beginning of the form.

Study Duration. The form must describe the duration of the subject’s participation. In many IVD studies, a subject’s participation begins and ends with providing a sample. This is not always the case, though. In studies involving monitoring, the subject may be asked to participate over a prolonged period. For complicated studies, a chart showing the number and timing of tests can be helpful. Whatever the duration, the form should state it clearly.

Benefits and Risks. The form must describe the potential benefits and risks of participating in the study. The benefits may be personal to the subject (e.g., “Your participation may help in diagnosing your condition”) or impersonal (e.g., “While you will not directly benefit, your participation may help us better understand the disease”). For many IVD studies, the physical risks will be low. However, sponsors should also consider whether they need to disclose other types of risks, such as the potential impact on the insurability of a subject learning of a genetic trait that may result in illness or death. As more genetic tests are conducted, the need to carefully identify the universe of potential risks will grow.

Sponsors should also consider how to handle a related question: what will be done with the study results. If a test indicates that the subject may have an otherwise undiagnosed disease, will the physician or subject be notified? Or, if the test indicates that the diagnosis by conventional methodology may be wrong, and the patient doesn’t have the disease, who, if anyone, will be told? In many instances, the sponsor may decide that because the test is investigational, the conventional results should be accepted and neither the subject nor the investigator should be informed of the investigational results. In that situation, it may be appropriate to state for the subject on the informed-consent form that he or she will not learn the test results. The study protocol then should make it clear that the investigator and subject will not be told about the discrepancy.

Alternatives. The form must describe the alternatives to participating in the investigation. For example, if the subject could be tested by some alternate means, the form should describe that option. Sponsors should avoid describing the alternative in negative terms and thereby steering the subject toward enrolling.

Limits to Confidentiality. The form must tell the subjects that their medical records are subject to examination by FDA and other U.S. or international regulatory agencies, the sponsor, and, if applicable, the sponsor’s agent. While the form may state that the site will try to protect the subject’s medical records from disclosure to third parties, no promises should be made. Neither the sponsor nor the site can guarantee that records will not be turned over to third parties. Fully disclosing the limits on confidentiality becomes particularly important when dealing with sensitive medical information, such as the results of HIV or genetic tests.

Compensation. The form must tell subjects what compensation and medical treatment will be offered to them in the event of a research-related injury, if the research involves more than minimal risk. Few IVD clinical trials fall into this category.

Contacts. The form must tell the subjects whom to contact if they have research-related questions. This can be the investigator or a member of the investigator’s staff. The form must also tell the subject whom to contact in the event of a research-related injury. Typically, this is a member of the IRB.

Freedom to Withdraw. The form must state that the subject’s participation is voluntary and that the subject is free to withdraw from the study at any time. The form should include this statement even if the subject is giving only a single specimen—the right to withdraw consent is absolute. The form should also say that withdrawal will in no way affect the treatment of the subject.

Other disclosures may be needed depending on the circumstances. For example, it may be appropriate to describe additional costs to the subject and whether new findings during the research will be provided to the subject.⁷ If the specimen will be banked for future use, the National Bioethics Advisory Commission recommends that participants be given the opportunity to restrict or forbid the future use of their specimen for all or some potential future uses.

The wording of the form must incorporate all these elements. At the same time, it must carefully avoid stating or implying that the subject has waived any rights. There should be no exculpatory language. Thus, for example, a form should not say that a subject can’t sue for a research-related injury or that “you hereby waive all property rights in the tissue that is collected as a result of your participation in the study.” (The form could say, however, that “You will not receive payment for any diagnostic tests that are developed as a result of your participation.”)

Finally, the informed-consent form must be intelligible. In many ways, this is the most challenging requirement, and numerous informed-consent forms fail to meet it. Indeed, many forms that have been used are hard for anyone except a healthcare professional to understand.

In response to such failures, IRBs are now applying stricter standards for reviewing intelligibility. Many IRBs use standardized reading comprehension measures. Applying numerical formulas, these tests calculate the grade reading level for the form. If a form exceeds the IRB’s cutoff, which is often eighth grade or below, then it will need to be simplified.

Therefore, when drafting informed-consent forms, sponsors should avoid complicated words, including medical terms. For most subjects, for instance, the word hematoma is meaningless. The word bruising should be used instead. Similarly, describing blood draws in milliliters provides little information; sponsors should describe measures in teaspoons instead.

Sponsors should also be wary of issues raised by special populations. For example, if a study is being conducted among subjects with senile dementia, consent may need to be obtained from an authorized representative. While it will be up to the investigators to obtain that person’s consent and ensure that the person does have the necessary legal authority, the sponsor needs to consider this situation when drafting the form. Similarly, if the study involves a pediatric population, there may need to be a separate “assent” form signed by the minor, in addition to the consent form signed by the adult. Underscoring the importance of this topic, FDA recently issued new regulations expanding the protection of minors.⁸ These types of issues will often involve state law.⁹

Finally, the sponsor may want to address two other issues. The first is that the Health Insurance Portability and Accountability Act of 1996 (HIPAA) will affect the privacy rights of subjects.¹⁰ Informed-consent forms will, in the near future, need to incorporate HIPAA’s requirements. Second, companies may want to ensure that the form affirmatively states that the sponsor may use any of the participant’s biological materials without the need for compensation to the subject, and also gain consent to perform additional testing of the specimen in the future for described purposes.

Conclusion

Informed consent should be a process, not a piece of paper. Nevertheless, drafting a suitable informed-consent form for an IVD clinical trial is a critical regulatory requirement. Fortunately, it is not an impossible task. FDA’s informed-consent regulations are fairly straightforward. Sponsors can obtain additional insights from guidance issued by FDA and the Office of Human Research Protection, an arm of the Department of Health and Human Services. Sponsors simply need to ensure that their forms contain all of the required elements, avoid exculpatory language, and can readily be understood. While that is easier said than done, it is doable—and it is required by FDA regulations.

References

1. Code of Federal Regulations, 21 CFR 50.

2. MM Moxey-Mims et al., “Informed Consent in Clinical Trials of In Vitro Diagnostic Devices: Perspectives from the FDA and Manufacturers,” Clinical Chemistry 47, no. 10 (2001): 1753–1757.

3. 21 CFR 53.23.

4. 21 CFR 56.109 (c)(1).

5. 21 CFR 56.110.

6. 21 CFR 50.25(a).

7. 21 CFR 50.25(b).

8. “Additional Safeguards for Children in Clinical Investigations of FDA-Regulated Products,” Federal Register 66, no. 79 (April 24, 2001): 20589–20600.

9. JN Gibbs, “IVDs and the States: The Other Regulatory System,” IVD Technology 6, no. 5 (2000): 30–37.

10. Health Insurance Portability and Accountability Act of 1996 (HIPAA), PL 104–191, August 21, 1996.

Jeffrey N. Gibbs is a partner in the law firm of Hyman Phelps & McNamara (Washington, DC). He can be reached via jng@hpm.com.

Copyright ©2001 IVD Technology