Evaluation, Screening and Diagnostic Testing for Determination of Clinical Trial Eligibility

 Background

Many investigators have expressed uncertainty concerning when consent should be obtained from a subject who is being evaluated for possible eligibility to participate in one or more clinical trials. The following guidance has been developed to assist investigators in making that determination.

Federal regulations governing human subjects research provide that: "no investigator may involve a human being as a subject in research . . . unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative." Such consent must be documented in a signed informed consent document approved by the IRB, except in limited circumstances where the IRB has approved a waiver. The Department of Health and Human Services' Office for Human Research Protections ("OHRP") has made clear that informed consent must be obtained prospectively and has cited institutions where investigators have "initiated" human subject research without meeting this requirement. Eligibility testing performed solely in connection with a research project (i.e., testing whose purpose is not, even in part, tied to direct clinical care or treatment decisions) is considered part of that research project. Therefore, informed consent to participate in a research study must be obtained before such testing is performed.

IRBMED Guidance

A physician performing diagnostic testing for clinical care purposes need not obtain the patient's informed consent to participate in a research study, even if the data may be used at some later time to determine eligibility for one or more studies.

Example:A patient with metastatic cancer is being evaluated. An MRI of the brain is clinically indicated to evaluate for brain metastases. The patient may be eligible for one of two protocols, depending on the results of a brain MRI. In one case, the patient is only eligible if the brain MRI is negative, in the other, only if it is positive for metastases. Should the consent to participate in a research study be obtained prior to the MRI?   

Answer: No. The MRI is clinically indicated, even if the patient doesn't go onto either protocol. No research-related consent should be obtained until after the results of the MRI are known and the specific protocol for which the patient is eligible has been identified and discussed with the patient. However, if the patient has already had a recent negative CT scan of the brain yielding results sufficient for clinical purposes, but an MRI is an absolute requirement for participation in the 'no brain mets' study, the additional scan is being ordered only for the purposes of the proposed research. The patient should sign the informed consent first - before the MRI scan - and be removed from the study and treated as clinically appropriate if the MRI finds brain metastases missed on the prior CT.

An investigator/physician performing diagnostic testing for mixed clinical care and research purposes need not obtain a protocol-specific informed consent form in advance of that testing. IRBMED recommends, however, that investigators clearly distinguish in any protocols and consent forms between those tests that have been or will be performed as part of standard clinical care and those that are necessary only in connection with a research study (whether to determine eligibility or otherwise). A consent form that lists a particular test as part of the research protocol (as opposed to part of the eligibility criteria for entry) should be signed before the test is performed.

Example:A subject is being evaluated for possible participation in a study involving a potentially cardiotoxic drug. As part of the study protocol, a pretreatment MUGA scan is required to exclude occult cardiac disease that would place the subject at excessive risk of drug-related toxicity. An ECG must also be normal prior to study entry. Should the consent to participate in a research study be obtained prior to the MUGA? 

 

Answer: Yes. The MUGA scan is clearly a part of the research project. The subject should sign the informed consent before the MUGA scan - and be removed from the study and treated as clinically appropriate if the MUGA finds cardiac disease not previously identified. Moreover, the reasons for the MUGA scan and its foreseeable risks should be described in the research protocol and the informed consent document - including the risks of radiation exposure. The consent document also should disclose whether or not the MUGA scan will be paid for by the sponsor of the research, and that the MUGA scan must be normal in order for the subject to participate further in the study.   

 

However, depending on the setting, the ECG may or may not be clinically indicated, even if the subject doesn't go onto the research protocol. Whether or not the research consent must be signed prior to the ECG would depend on whether or not the ECG is otherwise required for clinical care. In a clinical setting where it might be anticipated that an ECG will be required solely for research purposes for some subjects (for example, the younger participants), it would be appropriate to put the following statement in the informed consent document: "If you have not recently had one as part of your routine medical care, you will get an electrocardiogram (ECG) to see if you are eligible to take part in this study." If an ECG is performed for purposes of the study, the consent should be signed prior to its administration and the subject informed whether or not the ECG will be covered as part of study costs or billed to insurance (and/or the subject).

Because an investigator performing diagnostic testing solely for research purposes must obtain the proposed subject's written informed consent prior to the testing, an investigator or group of investigators performing multiple studies that all require the same diagnostic testing for eligibility purposes may want to consider creating a master screening protocol for that testing. The informed consent document for that protocol would explain that the subject may be eligible to participate in one or more related studies; that certain evaluations and/or diagnostic testing is needed to determine which, if any, studies the subject is eligible for; and that if the investigators determine, based on the results of the testing, that the subject is eligible to participate in one or more of the studies, the subject will be provided with additional information about the studies and an opportunity to enroll, but will have to sign a separate consent.

Example:A related series of vaccine trials all require subjects to undergo HLA testing prior to entry - the specific vaccine used depends on the subject's HLA type. The investigator has funding to conduct the HLA testing, which is done on a single tube of blood. Would a master protocol be appropriate? 

 

Answer: Yes. The HLA testing is not clinically indicated, but a protocol-specific consent cannot be obtained until after the results of the testing are known and the actual protocol for which the subject is eligible has been identified and discussed with the subject. The consent document for the 'master' HLA testing protocol should include the fact that the HLA testing will be paid for by the research sponsor, not the subject or their insurance company. It should also indicate that a separate, specific consent will be required for participation in the actual vaccine trial, and that the subject is not required to participate in the vaccine trial even if the HLA testing indicates that they are eligible to do so. This consent may be short. Contact IRBMED for assistance.

The chart below summarizes the information above. Note, however, that it does not address the need (if any) for standard treatment consents.

Purpose of Test Master Evaluation/Screening Protocol Consent

Individual Protocol Consent

Determine appropriate clinical care regimen.

Not necessary

Determine appropriate clinical care regimen; may also be relevant to research .

Either is sufficient

Determine which of several protocols subject is eligible for or best suited to.

Either is sufficient

Confirm eligibility for a single protocol.

N/A

Necessary

Additional Important Considerations

Respect for Privacy

Research protocols often involve screening tests that have the potential to uncover sensitive private information. Examples include HIV testing, pregnancy testing and drug and alcohol screening (toxicology screens). As with other protocol-related interventions, when these types of tests are done as part of a research protocol, they should be clearly disclosed to the subject. Moreover, the consent document should indicate whether the results of the research screening tests will appear in the subject's non-research medical records or otherwise be shared with the subject or subject's physicians. In some cases, it may be appropriate to make arrangements for testing to be conducted in such a way as to assure that the results do not become part of the non-research medical record. Contact the IRBMED for more information about how this can be done.

Unanticipated Findings of Screening Examinations

Eligibility testing is specifically intended to identify previously unrecognized medical conditions that would affect the subject's risk of participation in research. As such, it is predictable that some otherwise healthy individuals who choose to participate in pre-study screening will be found to have previously unrecognized abnormalities. These abnormalities may be outside the primary expertise of the researchers - as, for example, in the case of a study involving psychotropic medications where a potential participant is found to have abnormal liver function tests. To the extent possible, researchers should consider in advance how such unrelated abnormalities will be handled (examples include notification of the subject and their family physician, further testing, referral to specialists, etc.) and disclose this in the informed consent document. In cases where a high-risk population is being screened, such that it is quite likely that a previously unknown problem will be discovered, consideration should be given to providing subjects with a list of physicians - including some unrelated to the research team - who can evaluate them further if desired.

Summary

Screening patients (and healthy subjects) for possible inclusion in research trials poses questions of consent, privacy, billing, and the possibility that previously unknown abnormalities will be found. Investigators should consider these issues prior to beginning a study, and obtain appropriate consent before performing any procedures or interventions solely for research purposes. For more information, contact IRBMED at irbmed@umich.edu or (734) 763-4768 or a Health System attorney at (734) 764-2178.