New FDA Informed Consent Requirements for Applicable Clinical Trials: Practical Approaches for Implementation

For applicable clinical trials regulated by the Food and Drug Administration initiated on or after March 7, 2012, sponsors, investigators, and institutional review boards must assure compliance with an additional informed consent requirement. ¹75 Fed. Reg. 259 (Jan. 4, 2011). A revision of FDA regulations requires investigators and sponsors of such clinical trials to include the following statement in informed consent forms:

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.
²See generally, Guidance for Sponsors, Investigators, and Institutional Review Boards: Questions and Answers on Informed Consent Elements, 21 C.F.R. §50.25(c) (Small Entity Compliance Guide), February 2012 at http://www.fda.gov/downloads/Regulatoryinformation/Guidances/UCM291085.pdf (last accessed March 12, 2012).

ClinicalTrials.gov is the National Institutes of Health website where all “applicable clinical trials” must be registered and trial results posted in accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA). ³See §801(b)(3)(A) of the FDA Amendments Act of 2007 (Pub. L. No. 110-85, Sept. 27, 2007). Registration must occur no later than 21 days after the first subject enrolls, and study results must be posted within 12 months of completion of the data collection for the primary outcome. ⁴Id. The new informed consent regulation comes on the heels of recent criticism raised by U.S. Reps. Henry Waxman (D-Calif.), Ed Markey (D-Mass.), and Diana DeGette (D-Colo.) directed to the FDA commissioner and to NIH related to alleged noncompliance with ClinicalTrials.gov registration and data posting requirements.

The discussion below addresses practical questions relating to implementation of the new regulatory requirements.

What is an ‘applicable clinical trial?’

Under the FDAAA, an “applicable clinical trial” ⁵See definition of “applicable clinical trial” at 42 U.S.C. §282(j)(1)(A). includes clinical studies on human subjects that:

• are interventional (i.e., a prospective study);

• are controlled (i.e., has one or more arms); and

• involve the use of a drug, device, or biologic being tested in the United States or its territories or is conducted under an investigational new drug application (IND) or investigational device exemption (IDE).

The definition of “applicable clinical trial” excludes phase I drug trials and device studies aimed at obtaining feasibility data as opposed to health outcomes. In addition, studies using de-identified human specimens as defined under the Health Insurance Portability and Accountability Act (HIPAA) privacy rule would not be considered “human subject research” and thus would not be considered an “applicable clinical trial.”

Can the informed consent language quoted above be modified?

No. Any deviation from the language above would be deemed to be out of compliance with requirements of the FDAAA. Additional language may be included in the consent to further explain the purpose and nature of the statement, provided that the language quoted above is not modified.

Is the requirement retroactive?

The regulations require the specified informed consent statement to be included in the consent documents for all applicable clinical trials initiated on or after March 7. A study is considered “initiated” on the date that final approval of an informed consent was granted by the reviewing institutional review board (IRB). Accordingly, if a study (including its consent form) was approved March 6, the requirement would not apply. Multicenter study consent documents that do not include the statement are not out of compliance if at least one of the study site’s informed consent documents was approved by an IRB prior to March 7.

Re-consent of subjects enrolled in clinical trials initiated prior to March 7 is not required. From a practical perspective, however, investigators and sponsors may have chosen to include the required language in consent forms for “applicable clinical trials” even if study initiation occurred prior to March 7.

Must studies outside of the United States comply with the new informed consent requirements?

Studies conducted outside of the United States should include the required statement in consent documents if study results will be used for a U.S. regulatory submission. FDA’s acceptance of data from foreign “applicable clinical trials” may be conditioned on compliance with the ClinicalTrials.gov registration and posting requirement and the new informed consent disclosure statement requirement.

Who is responsible for inclusion of the statement in the informed consent document?

The sponsor and investigator are responsible and should make the determination as to whether the clinical trial is an “applicable clinical trial” to which the new informed consent requirements would apply.

What is the IRB’s role in reviewing the informed consent language, and how does the new regulation impact the IRB’s ability to waive elements of informed consent?

The IRB’s role includes reviewing the informed consent document to assure compliance with the new informed consent requirements. Applicable law permits waiver of informed consent in very limited circumstances involving life-threatening emergency, public health emergency, and military operations (21 C.F.R. §50.23), and in emergency research (21 C.F.R. §50.24). If the IRB were to waive written consent under 21 C.F.R. §56.109(c)(1), it should be expected that the investigator and sponsor would include the required statement in the oral presentation provided to a subject in such situations.

What if the investigator determines that his/her study is an applicable clinical trial but that he/she failed to include the required statement?

The investigator could try to re-consent the subjects with an IRB-approved, amended consent form that incorporates the required statement. However, it may be difficult to re-consent subjects, this effort could cause significant time delay in reporting the study results, and it may cause the investigator, site, and/or sponsor to incur additional cost and expense.

If the investigator deliberately fails to incorporate the required statement, can FDA impose sanctions?

Yes. Any investigator who repeatedly or deliberately fails to comply with the requirements of 21 C.F.R. Part 50 may be subject to disqualification by FDA. If an investigator is disqualified, he/she is not permitted to receive investigational drugs or devices by any sponsor and therefore would be unable to participate in clinical investigations. An investigator may be reinstated only after FDA has received assurances to its satisfaction that the investigator will comply with the FDA regulations in the future. ⁶See generally, 21 C.F.R §§812.119 and 312.70.

If the investigator fails to incorporate the required statement, is there any risk to the sponsor’s marketing application?

If the investigator fails to comply with 21 C.F.R. Part 50, FDA may deem the study data to be “unreliable.” If an investigator’s data are deemed unreliable and such data are essential to a marketing application, FDA may require the submission of additional clinical data to support the marketing application or it may reject the application. In the case of an approved product, if the unreliable data are excluded and such data formed an essential portion of the approved marketing application, FDA may withdraw its approval of the product.

How can an industry sponsor adequately protect against data integrity issues related to an inadequate consent form?

The best defense is a good offense. To protect against the risk of noncompliant consents tainting research results, drug and device manufacturer sponsors should review and approve the final informed consent to be used in a clinical research study after the IRB has reviewed and approved it. While it is not optimal to go back to the IRB with changes after the IRB has approved the consent document, the potential magnitude of the harm to the integrity of the sponsor’s data would outweigh any associated burden.