FDA offers guidance on clinical trial waivers for investigators at non-U.S. sites

FDA now offering Form FDA 1572 waivers

Form FDA 1572 (“Statement of Investigator”) asks an investigator to verify that they have the experience and background needed to conduct the trial. The Form 1572 also requires investigators to agree to comply with all applicable FDA regulations governing the conduct of clinical studies. Investigators must sign the 1572 above a “Warning” stating that a “willfully false statement is a criminal offense.”

If a clinical study is conducted at a non-U.S. site under an Investigational New Drug application (IND), all FDA IND regulations at 21 CFR part 312 – including the requirement to obtain a signed investigator statement – must be met unless the sponsor is granted a waiver that provides for a specific exception. See 21 CFR 312.10.

The revised draft guidance clarifies that if a non-U.S. investigator cannot or will not sign the investigator statement (e.g., because regional, national, or local laws or regulations prohibit its signing), the revised guidance clarifies that a sponsor may submit a request for a waiver of the 1572 signature requirement; alternatively, the site may operate as a non-IND site, in which case the study would be conducted as a non-IND study.

In the past, several European national competent authorities and clinical sites have been opposed to having their investigators sign the Form 1572. The position taken by both have been that the 1572 requires compliance with U.S. law, which does not apply in the EU and may conflict with EU law. For instance, German authorities qualified signatures of German investigators to 1572 forms as "impermissible.” In cases where German investigators signed the form, German GCP inspectors would identify signed 1572 forms during audits as "severe deficiency attributable to the sponsor." Following guidance of German authorities, the investigator is only permitted to sign the 1572 if a gap analysis of the differences between U.S. and EU/national law is performed by the sponsor and if the sponsor obtains waivers to those U.S. requirements on the 1572 form that deviate from the EU/national requirements. This pathway is impractical and rarely used in practice, if at all.

Regardless of whether a study is conducted under an IND, the revised guidance recommends that sponsors obtain signed, written statements from investigators acknowledging their commitment to comply with regional, national, or local laws and requirements. In addition, if a waiver is granted for any requirements in FDA’s clinical trial regulations, “the sponsor and investigator must ensure that the study is conducted in accordance with the terms of the waiver,” the revised guidance states.

FDA vs. ICH

The revised draft guidance clarifies that the good clinical practice requirements for a sponsor operating non-U.S. sites under an IND – and for the investigators at the non-U.S. sites – are the same under 21 CFR part 312 as they are under International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6(R2) Good Clinical Practice Consolidated Guidance (“ICH E6”), with three notable exceptions:

1. Institutional Review Boards. FDA requirements for IRBs (21 CFR part 56) are slightly different than ICH E6 with respect to membership and function, and thus sponsors may wish to request a specific waiver from FDA for these requirements.

2. Informed Consent. FDA requirements for informed consent (21 CFR part 50) for particular clinical trials (e.g., emergency research under 21 CFR 50.24, or clinical investigations involving pediatric subjects under subpart D) are more extensive than ICH E6 with respect to IRB responsibilities. The revised guidance notes that its “experience has not revealed that this difference has caused a conflict, but in the event of one,” the agency “would be willing to discuss a resolution with the sponsor on a case-by-case basis.”

3. Investigator Statement. ICH E6 does not require investigators to sign a Form FDA 1572. To address this issue, the sponsor can request a specific waiver of the signature requirement on Form FDA 1572.

Therefore, if none of these three issues are implicated, and the investigators at non-U.S. sites follow the recommendations in the ICH E6 guidance, then the non-U.S. investigators will be deemed to be in compliance with FDA’s IND requirements under 21 CFR part 312. However, if one of these exceptions applies, the revised draft guidance advises that the relevant party may seek a waiver for the FDA requirements.

How to request a waiver of signature on Form FDA 1572

The revised draft guidance adds a new section to the 2010 version of the guidance regarding signature waivers titled “Co-commitments, date, and signature of investigator – waiver of signature on Form FDA 1572.” This section spells out how waiver of the signature on Form FDA 1572, when granted, enables studies at non-U.S. sites to be and/or remain under an IND. In this situation, sites can remain under the IND even though the investigator at those non-U.S. sites cannot or will not sign Form FDA 1572, provided that the sponsor complies with the terms of the waiver.

When requesting a waiver, the sponsor submits to the IND a) a clear statement that the sponsor is requesting a waiver of the signature requirement on the 1572; and b) the study title, protocol number, study sites, and investigator name(s) that would be subject to the waiver. If multiple sites are identified, the submission should identify which investigator(s) is associated with each site.

The waiver request must also contain information justifying the waiver, such as the reason(s) each investigator cannot or will not sign Form FDA 1572, or the sponsor’s proposed alternative course of action to adequately satisfy the purpose of a signed Form FDA 1572. In order for a sponsor to show they have a proposed alternative course of action that adequately satisfies the purpose of a signed Form FDA 1572, the revised draft guidance provides a new appendix containing examples of sponsor and investigator commitments. For example, the revised guidance explains, the sponsor could submit each of these three items for a study in which investigators are complying with the ICH E6 guidance to show they have a proposed alternative course of action:

1. ICH compliance declaration. A declaration by the sponsor that the regional (in the case of the EU) or national regulatory authority is an ICH member and has implemented the ICH E6 guidance, along with a determination by the sponsor that an investigator’s compliance with the ICH E6 will ensure that the investigator and sponsor comply with their respective obligations under 21 CFR part 312, other than the signature requirement on Form FDA 1572;
2. Unsigned 1572s. Commitment by the sponsor to collect from each investigator for whom the signature requirement was waived a completed but unsigned Form FDA 1572 that includes all information in sections 1 through 8 and a signed statement containing commitments equivalent to the commitments specified in Section 9 of Form FDA 1572.
3. Other forms. Any templates or forms the sponsor intends to use to collect information and/or secure signed commitments from the applicable investigators.

Distinct waivers & other caveats

The revised draft guidance notes that even after a waiver request is granted, sponsors must request new waivers for any new investigator added to the IND protocol who does not sign the Form FDA 1572. In addition, the sponsor needs to wait for a waiver request to be granted before initiating or resuming study at a site, and a sponsor cannot assume that no response or a delayed response from FDA means that the request for a waiver has been granted.

The revised guidance also cautions that waiving the 1572 signature requirement does not waive the IRB requirement, and vice-versa. Further, if a request for waiver of the 1572 signature includes the use of an independent ethics committee (IEC) instead of an IRB, then the sponsor should obtain IRB waiver approval first, or submit both waiver requests in one submission. If it is one submission, which FDA recommends, the sponsor should:

1. Explicitly state, in the cover letter subject line, that it is requesting both waivers (waiver of the Form FDA 1572 signature and waiver of the IRB requirement); and
2. Ensure that both the request for waiver of the 1572 signature requirement and the request for waiver of the IRB requirement contain all information required to support each waiver request.

FDA said the revised draft guidance will be consolidated with its 2010 Form FDA 1572 Guidance when it is finalized, and issued as one comprehensive final guidance document. If you have any questions about investigator statement or IRB waivers, or about clinical trial requirements more generally, please contact any of the authors of this alert or the Hogan Lovells attorney with whom you regularly work.

Authored by Robert Church, Heidi Gertner, and Arne Thiermann