In May 2021, the U.S. Food and Drug Administration (FDA) published a draft guidance (Draft Guidance) addressing the requirement for all investigators involved in clinical trials conducted under a U.S. Investigational New Drug (IND) application to sign Form FDA 1572. This includes investigators in clinical trial sites outside the U.S.
By signing Form FDA 1572 (Form 1572), the investigator of a drug or biologic trial warrants that they and any listed staff have the experience and background needed to conduct the trial and agrees to comply with the protocol and all applicable U.S. regulatory provisions governing the conduct of clinical trials. From an FDA standpoint, it provides a clear basis of responsibility (and potential liability) under the applicable clinical trial regulations (21 CFR 312) for those who sign the form. It also raises questions about the extent of FDA’s extraterritorial reach over non-U.S. investigators who conduct IND studies outside of the United States.
The Draft Guidance
The Draft Guidance highlights that clinical studies conducted at sites outside the U.S. under an IND are subject to all FDA IND regulations, including the requirement to obtain a signed Form 1572. This means that the investigator must sign Form 1572 unless the sponsor requests and is granted a waiver that provides for specific exceptions. Where the foreign investigator cannot or will not sign the form due to a prohibition in regional, national, or local laws/regulations, the sponsor may request a waiver for the signature requirement under 21 CFR 312.10.
Data from “foreign studies” (i.e. ex-US studies) can be used to support FDA marketing authorization applications even if they are not performed under an IND, though sponsor-applicants must, among other requirements, collect certain information from those ex-US investigators under 21 CFR 312.20 to demonstrate to FDA that those investigators have the necessary qualifications and followed the relevant protocol and Good Clinical Practices.
While the Draft Guidance technically does not currently impose any binding rights or obligations on sponsors, researchers, or FDA, it does show FDA’s thinking and expectation in an area that has caused confusion for multinational clinical drug trials. Put simply, the Draft Guidance creates a tension between the laws of some European countries which prohibit researchers at government run institutions from submitting to FDA jurisdiction and FDA’s broad interpretation of its jurisdiction, including in its stance that Form 1572 signature waivers are not “voluntary” but rather require an affirmative sign-off from FDA.
At the moment, it is not clear when FDA will publish the final guidance document. While the comment period for the Draft Guidance closed in July, FDA allows interested parties to comment on guidance at any time, even after July. FDA will review the submitted comments and consider them preparing the final guidance.
Practical Implications and Challenges
As confirmed by the Draft Guidance, if an ex-US clinical trial site is conducting procedures and data collection under an IND, FDA is signaling that there is no alternative to the Form 1572 requirement unless a waiver is granted. In particular, FDA is not amenable to the Form 1572 being replaced by another document issued by an ex-U.S. institution as the purpose of the Form 1572 is to hold the individual researchers accountable for their individual actions and their individual compliance.
Nonetheless, a number of EU Member States do not permit investigators in clinical trials conducted on their territory to sign the Form 1572. This prohibition is based on either national law, regulatory guidance by the competent authorities and GCP inspectors or on internal institution guidelines. In some countries (e.g., Germany), investigators signing a Form 1572 is identified as an issue during GCP inspections.
In such a situation, as pointed out in the Draft Guidance and in the position paper adopted by the Clinical Development Expert Group of the European Federation of Pharmaceutical Industries and Associations, the sponsor of a clinical trial has the choice to either seek a waiver from the FDA for each investigator who does not sign Form 1572 or conduct the study in the particular clinical trial site as a non-IND study.
The request for an individual waiver for each investigation from the requirement to sign Form 1572 could be submitted to the FDA as an IND amendment and must contain at least one of the following:
- An explanation why the sponsor’s compliance with the requirement is unnecessary or cannot be achieved;
- A description of an alternative submission or course of action that satisfies the purpose of the requirement; or
- Other information justifying a waiver.
However, in contrast to a common practice in clinical trials in the past, the Draft Guidance states that, if a waiver request is submitted to the FDA, “the sponsor should not initiate the clinical study at the site in question until the waiver request is granted”. The Draft Guidance does not, however, set out a timeline for FDA to respond to the waiver request. As highlighted in the PhRMA comments to the Draft Guidance, this and other aspects of the Draft Guidance may create significant practical challenges which could delay important research from timely enrollment and completion and add additional bureaucratic workload to an already very busy FDA review division. In both cases, these challenges have the consequence of increasing potential compliance costs and business costs for sponsors. Elsewhere, FDA has adequately considered these burdens on industry by not requiring a sponsor to wait for an approval of an IND before shipping study drug and starting procedures; a sponsor is in compliance with the requirement in Part 312 if they wait 30 days. No such time limitation is spelled out for the new waiver requirement and, surprisingly, there is no indication of what sponsors with studies ongoing at the time of the Draft Guidance are to do.
In cases where the waiver is granted or the investigator is part of non-IND study, Form 1572 could be replaced with investigator commitment letter and this would comply with 21 CFR 312.20.