Signatures

At a recent presentation I was asked about whether a witness' signature is required on consent forms. The requirements on signatures are so confusing, I actually misspoke myself. That prompted me to go back to the regulations and check what they actually say about signatures on consent forms. Each of the regulations (45 CFR 46, 21 CFR 50 and ICH E6) has different requirements for signatures. Here is a summary:

46.117(a) requires that the subject sign the consent form.

50.27(a) requires that the subject sign and date the consent form.

ICH 4.8.8 requires that the subjects and "the person who conducted the informed consent discussion" sign and date the consent form.

For oral presentations, all three require a witness to be present. 46.117(b)(2) and 50.27(b)(2) requires the subject to sign the short form. The witness signs both the short form and the summary of the information presented (usually the consent form) and the "person actually obtaining the consent" signs the summary. ICH 4.8.9 requires that the subject, if capable, and the witness sign and date the consent form. Only ICH explains what the witness is attesting to: "By signing the consent form, the witness attests that the information in theconsent form and any other written information was accurately explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that informed consent was freely given by the subject or the subject’s legally acceptable representative."

Now, the question is "Which one applies?" and the answer is "It depends". 45 CFR 46 applies to most federally funded research, 21 CFR 50 applies to research regulated by the FDA. Both regulations apply when either 1) federally-funded research involves an FDA-regulated product or 2) an institution has chosen to apply 45 CFR 46 to all of its research in its FWA. ICH is only guidance, not regulation. However, most industry-sponsored clinical trials are being conducted in compliance with ICH since the industry wants to market its products internationally.

In general, when deciding which regulations to apply, it is best to apply the most stringent. With regard to signatures on consent forms, ICH is most stringent and requires both the subject and the person obtaining consent to sign and date the consent form. For oral presentations, the FDA is the most stringent, requiring the subject and the witness to sign a "short form" and the witness and person obtaining the consent to sign the consent form.

Caution on "unchecking the box"

I have to add a note of caution on my comments on "unchecking the box" to limit an FWA to federally-funded research. Before you do that, make sure that this does not affect the application of state or local laws. It was recently brought to my attention that, in New York, if the FWA doesn't apply to non-federally funded research, then the New York human subjects law (Article 24-A of the Public Health Law) would apply to that research. So, New York institutions should carefully consider whether they should "uncheck the box". My recommendation regarding only applying the Common Rule (without the subparts) still applies, though. The research would still be covered by federal regulations but not the subparts.

IRB Independence

I recently participated in a discussion on the IRBForum regarding the involvement of the Institutional Official (IO) in the policies and procedures of the IRB. This prompted me to expand on my thoughts here.

Many people believe that the IRB must be a completely autonomous body that operates without any interference from the institution. I not only believe that this is a mistaken interpretation, but it is also dangerous and puts subjects at risk. The independence required for the IRB to fulfill its mission is independence in decision making. In Sections 112 of 45 CFR 46 and 21 CFR 56 the regulations state that institutional officials cannot approve research if it has not been approved by the IRB. Thus maintaining the independence of IRB decisions, at least negative decisions. This is not saying that IRBs are completely independent from the institution. In fact, Section 112 also says that research approved by the IRB can be subject to further review by the institution. The assurance process in 45 CFR 46 gives the responsibility for establishing policies and procedures for the protection of human subjects to the institution. Therefore, it is the institution, generally through the IO, which sets policy, not the IRB. So, the belief that the IRB is completely independent is mistaken.

Why is this belief dangerous? Because a completely independent IRB runs the risk of having an adversarial relationship develop with the investigators. Without some oversight over its policies and procedures, the IRB can wind up losing sight of the burden that its requirements place on investigators. When that happens (and I have seen it develop several times as a consultant), an adversarial relationship can develop between the IRB and the investigators. This type of relationship increases the chances that investigators will not be forthcoming with the IRB or will even conduct research without IRB approval. This is when subjects are put at risk.

This is not to say that IRBs should become "rubber stamps" or that institutional polices and procedures should be lax. Rather, that the institution has the responsibility to ensure that the policies and procedures of the IRB are reasonable. As I said in the discussion on the IRBForum, the IRB needs to follow the principle of beneficence, similar to that in the Belmont Report, in its relations with investigators. It needs to make sure that the benefits of imposing requirements on investigators (primarily in terms of protecting subjects) justify the cost (in time, money, paperwork, etc.) to the investigators.

So, I do believe that the IO must be involved with the way that the IRB performs its function. The IO cannot and should not intervene in IRB decisions, but should oversee the policies and procedures that govern how the IRB functions and ensure that they balance the need to protect subjects with the needs of the investigators.