Earlier this month, the Food and Drug Administration (FDA) released a new Clinical Trials Guidance Document. The guidance addresses questions on informed consent elements for clinical trials, regulated under 21 CFR §50.25(c). The new regulation is on page 256, volume 76 of the Federal Register and was published on January 4, 2011.
All applicable clinical trials initiated on or after March 7, 2012, must be in compliance with the new requirement in 21 CFR § 50.25(c) and include a specific statement that refers to the trial’s description on www.ClinicalTrials.gov. For the purposes of this rule only, FDA considers “initiation” of a clinical trial to be the clearance or approval of any informed consent documents by an IRB or other ethics review committee.
The new statement on informed consent is a requirement included in Section 801 of the Food and Drug Administration Amendments Act (FDAAA). This law also provided for mandatory registration and results reporting of certain applicable clinical trials on www.ClinicalTrials.gov. The statement is the means by which the statute provided for investigators/sponsors to inform applicable clinical trial participants of the availability of the clinical trial information on the public website located at www.ClinicalTrials.gov.
FDAAA defines “applicable clinical trial” in 42 U.S.C. § 282(j)(1)(A) to generally include controlled interventional studies (with one or more arms) of drugs, biological products, or devices that are subject to FDA regulation, meaning that the trial has one or more sites in the United States, involves a drug, biologic, or device that is manufactured in the United States (or its territories), or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE). Trial sponsors and investigators have the responsibility of determining whether or not a trial is an “applicable clinical trial.” Definitions vary for applicable device and drug trials including biologics.
The trial is an “applicable clinical device trial” if: (I) the trial prospectively compares a device-based intervention subject to FDA regulation against a control in human subjects; or (II) the trial is a pediatric post-market surveillance trial. The trial is an “applicable clinical drug trial” if the trial is a controlled clinical investigation, other than a phase I clinical investigation, of a drug subject to FDA regulation.
Some trials are excluded from this definition. For devices, small feasibility trials and larger clinical trials of prototype devices with a primary measure of feasibility rather than health outcomes are not applicable clinical trials. Under current guidance contained on NIH’s website at, a device trial is not an applicable device clinical trial when the trial includes only de-identified human specimens and does not include “human subjects” (a requirement to be considered an applicable clinical trial).
For drugs, phase 1 clinical investigations (defined in 21 C.F.R. § 312.21) are not categorized as “applicable clinical trials.” 42 U.S.C. § 282(j)(1)(A)(iii). Uncontrolled clinical investigations of drugs or devices also are not considered “applicable clinical trials.”
Under new 21 CFR 50.25(c), the following statement must be reproduced word-for-word in informed consent documents for applicable clinical trials:
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”
The four required sentences fulfill the need for a standardized, specific statement concerning the availability of trial data on www.ClinicalTrials.gov for every applicable clinical trial. FDA stated that, “Requiring word-for-word reproduction of the statement avoids the need for individual analysis and determination of what is appropriate to be included. The use of the statement also avoids different statements for different trials.”
If an IRB has already approved any informed consent documents for the applicable clinical trial prior to March 7, 2012, then the trial will be considered “initiated” before the compliance date, and the new statement will not be required. If an IRB has not approved any informed consent documents for the applicable clinical trial by March 7, 2012, then all informed consent documents associated with the applicable clinical trial must in compliance with the requirement and include the new statement.
If the multi-site applicable clinical trial includes multiple IRBs or the multi-site applicable clinical trial is under one IRB, the effect is still the same. The sponsor of the trial is responsible for determining the applicable clinical trial initiation date.
There is no need to re-consent an applicable clinical trial was initiated before March 7, 2012. Subjects who consent to an applicable clinical trial via documents approved before March 7, 2012, will not need to be re-consented based solely on the new regulations.
The new requirement of including the statement has not altered the IRB approval process. However, IRBs cannot modify or delete the exact statement regarding www.ClinicalTrials.gov as stated in 21 CFR § 50.25(c). Investigators, sponsors, and IRBs are not restricted from providing additional explanation, if determined to be needed.
IRBs continue to have the responsibility to review and approve informed consent documents. Under 21 CFR §§ 50.23 and 50.24 regarding exceptions to informed consent, the statement is also required in the informed consent documents if these trials are applicable clinical trials.
The regulation does not require the new statement to be located in any particular section of the consent form. Investigators, sponsors, and IRBs have the flexibility to place the new statement wherever they believe best serves participants’ interests.
The required statement should not be included in informed consent documents or processes for clinical trials that are not applicable clinical trials. However, if investigators/sponsors independently believe that reporting data on www.ClinicalTrials.gov may influence subjects’ willingness to participate, nothing in this regulation prevents investigators/sponsors from voluntarily reporting trial data and informing trial participants in an appropriate manner.
Any applicable clinical trial, including applicable clinical trials conducted outside the United States, must comply with the new regulation and include the statement regarding www.ClinicalTrials.gov in informed consent forms. FDA accepts data from foreign clinical trials not under an IND when in compliance with 21 CFR § 312.120. The mere fact that we accept data from a foreign clinical trial in connection with a marketing application does not make it an applicable clinical trial; the foreign clinical trial constitutes an applicable clinical trial only when it meets the definitions set forth in 42 U.S.C. § 282(j)(1)(A).
Sponsors or investigators can translate the informed consent if potential participants are non-English speaking or the clinical investigator or IRB anticipates that the consent interviews will be conducted in a language other than English. FDA recommended that the IRB review, and if appropriate, approve procedures for ensuring that the translations will be prepared by a qualified individual or entity.
Parent or guardian permission, as defined in 21 CFR § 50.3(r), must include the elements of informed consent. Therefore, the parent and guardian consent forms must include the new statement word for word.
FDA has several options that enable enforcement of the new informed consent requirement. FDA has the authority to regulate the protection of human subjects and the authority to impose penalties for violations of these regulations. The Food, Drug, and Cosmetic Act (FD&C Act) prohibits the failure to establish or maintain any record or make any report required under section 505(i) and the failure or refusal to comply with any requirement under 520(g). 21 U.S.C. § 331(e) “The FD&C Act and implementing regulations allow FDA to seek administrative, civil, and criminal penalties for violations of section 301 of the FD&C Act. 21 U.S.C. § 303(a); §§ 312.44(b)(1)(ix), 312.70(a), 812.30(b)(4), 812.119(a), 56.121(b).” 76 FR 256 at 265.