By Betsy Fallen, BAFallen Consulting LLC
As Bob Dylan sang many years ago, “For the times they are a-changin,”1 could be the motto of drug development. Regulations, requirements, and enforcement practices have changed, and industry professionals strive to maintain awareness in order to be compliant. As the number of clinical trial site locations outside of the U.S. has increased — driven by untapped populations, faster recruitment, and lower costs,2 — the challenges have added up. Regionally, the required or anticipated documentation and enforcement of those requirements has changed over time. One document that has recently garnered attention is the FDA Form 15723 and specifically its use by non-U.S. investigators.
To my surprise, this topic has recently been raised in multiple forums. I have heard questions about the form in local and international forums, and a question about it was directed at the FDA (but not addressed) at a regulatory conference. Though the audiences were mostly seasoned professionals, apparently this topic isn’t well understood.
What Is Form 1572, And What Does It Commit An Investigator To?
This form is an efficient tool to collect many details regarding a clinical site. These details include who is leading and performing the study, where it will be conducted, identifiers on the institutional review boards (IRBs), laboratories, and other commitments required by the FDA under several subsections of 21 CFR 312, investigational new drug (IND) application.4
As a template, its use has streamlined efforts and focused clinical investigators on the FDA’s expectations. The 1572 content includes information that will need to be provided to the sponsor, and, for some time, all worldwide clinical investigators were asked by sponsors to complete it. In my experience, U.S.-based clinical sites are required to provide the appropriately completed and signed form before they were considered “site-ready” to receive an investigational drug.
Centralizing information is an excellent process to ensure efficiency and compliance. But the signature panel clarifies what the investigator commits to by completing Form 1572:5
Whoa, Not So Fast!
U.S.-based clinical investigators must commit to and follow U.S. regulations, but why would investigators based outside the U.S. abide by U.S. regulations and provide a written commitment to do so?
Historically, in absence of supportive local regulation, clinical investigators in EU countries would sign the 1572. There may have been inconsistent practices before the implementation of the EU’s Clinical Trial Regulation No 536/2014.6 This regulation was intended to “simplify and harmonise the administrative provisions governing clinical trials in the Union.” This was followed by position papers published separately by the Danish (2017) and German (2018) agencies, stating they expect investigations in their countries to follow their regulations, not those of other countries.7,8 Per the German position paper, signing a 1572 confounds that understanding, and at the time of an inspection, it may become a point of contention and, if not properly documented — a point of “serious deficiency to be attributed to the sponsor.”8 Similarly, “an investigator in Denmark cannot comply with the requirements in the 1572 form.”7
Why Not Sign The FDA 1572 Form?
In order to be complaint, an investigator must meet relevant and appropriate local, national, and regional requirements. However, committing to the requirements of another region (in this case, IND regulations set by the FDA) can be difficult and require additional effort. In some locations, it may also be inappropriate to the point of a regulation infraction. In 2010, the FDA issued a guidance titled Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs: Frequently Asked Questions — Statement of Investigator (Form FDA 1572).9 This guidance offered a roadmap as to when a 1572 would be required and alternatives for other situations. Issued in 2010, it remains a relevant and frequently cited guidance.
Decisions, Decisions: Complete 1572 Or Alternate Process?
Based on the situation, there are two high-level options. The first option includes consideration of a combination of U.S. IND sites and non-U.S., non-IND sites.
In this option, the sponsor should perform a single global trial with some sites under the IND and some not. Some sponsors have created identical but separately numbered protocols, with only one under the IND, but it’s not necessary. Using two protocols, the statistical analysis plan (SAP) must be written to encompass the results of both trials.
The sponsor should collect the 1572 information from the non-IND sites. Some sponsors have created an alternate form based on the 1572 without the FDA references or IND commitments. They should also include a statement of commitment on an alternate, signed form or on the protocol signature page. The clinical investigator is expected to sign a commitment that ensures the study will be completed under ICH E3 and E6 R2 GCP, so either of these would fulfill that requirement.
The protocol should be submitted as an IND amendment (either global or U.S.-based only) and include notification that non-IND sites will also contribute data. The commitment to a single SAP should also be stated. Ensure the non-IND sites comply with 21 CFR 312.120, “Foreign Clinical Studies Not Conducted Under an IND,” which not only requires the signed GCP compliance statement but also that the FDA be able to validate the data from the trial through an on-site inspection if the FDA deems it necessary. This commitment may be made through contract or as part of the alternate information form or GCP commitment.10
The second option is a waiver for non-U.S. clinical sites performing as IND sites, and this can get tricky. Due to the simplicity of the first option, waiver requests are infrequent, except in cases where unusual circumstances prevent implementation. The FDA encourages a discussion before any waiver is submitted to ensure optimal choices are made.
In the second option, the sponsor performs a global trial including all clinical sites (U.S.- or non-U.S.-based) performed under the IND. They should request a waiver10 from the FDA to allow clinical investigators in non-U.S.-based sites to be relieved of the IND requirements as their governing local or regional law does not align with U.S. IND requirements. In the waiver, the sponsor must identify discrepancies between the IND requirements and those of the country (or countries) the IND study will be performed in.
This option should only be considered if, for some reason, the first option is not possible. Non-U.S. sites and possibly regulators should be brought into the conversation for awareness, engagement, and, optimally, endorsement.
The second option has more requirements, including more resources to ensure compliance. The potential of not meeting the requirements is a risk that needs to be considered in the sponsor’s filing strategy. Importantly, EU regulators have cited non-U.S. sites for having completed the 1572 with or without the full documentation of the discrepancies and associated waiver. In some instances, the presence of a signed 1572 is identified as a discrepancy and evidence that the trial followed regulations other than the home country’s.
At a recent conference on GCP inspection readiness, a director of clinical research and GCP inspection management shared his experiences. He was very firm that the presence of a completed Form 1572 outside of the U.S. was a cause for concern for regulatory inspectors and identified as an observation or perhaps a finding. Where this practice may not have caused concern in the past, it is a key focus now for regulators to ensure compliance, data integrity, and patient safety.
One of the keys to ensure compliance at the sponsor level is the creation, management, and enforcement of process documentation in the form of an SOP. Assigning an informed process owner charged with the accountability of keeping the SOP up to date, training affected stakeholders, and ensuring evidence of compliance is an excellent step in assuring compliance related to the use of Form 1572. The process owner would also be required to communicate with regulators and industry experts to keep apprised of new regulations, guidances, and best practices.
For now, there’s an outstanding question posed to the FDA. When I get an answer, I’ll be sure to update my readers, of course!
About The Author:
Betsy Fallen is an authority on the business processes and associated use of information technology in drug development. A passionate advocate for moving life sciences business online, Betsy is an expert on many areas of drug development. After over two decades at Merck, she now consults to support sponsors, vendors, and clinical sites in their journeys to innovation while ensuring compliance. She continues to share her knowledge in technical innovation and process efficiency and ability to assess and assure compliance in documentation, execution, and oversight. Trained as a registered nurse, Fallen is dedicated to ensuring the voice of the patient is heard as the drug development process continues to progress toward innovation and efficiency.