FDA 1572: Big Changes in FAQ Information Sheet Guidance

June 8, 2010

FAQ FDA 1572

Most Study Coordinators Belong on the FDA 1572

FDA has made some big changes in the final version of their Frequently Asked Questions (FAQ), Statement of the Investigator (Form FDA 1572) Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs (May 2010). The FAQ states that research coordinators (study coordinators) should “usually be listed in Section #6 of the 1572.” This is a significant change from the draft FAQ Information Sheet Guidance that came out in July 2008. Many clinical sites do not list study coordinators on the FDA 1572. It means that most study coordinators will need to file financial disclosure information. It will be a significant change in the way FDA inspects clinical sites. Specifically the FAQ document states:

Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the study data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.”

You can review this in Section 33, page 14 of the Final FAQ on FDA 1572s. This is a big change from the July 2008 draft FAQ:

If a research coordinator is performing critical study functions and collecting and evaluating study data, the coordinator should be listed on Block #6.

This is a very significant difference and not just because they changed “Block #6” to “Section #6.” FDA is saying that a study coordinator “generally” performs critical study functions. And FDA says that recruiting subjects is one of those functions. Obtaining informed consent, although not stated in the FAQ, is also regarding as a critical function. FDA made that clear in a Warning Letter issued October 1, 2008. The Warning Letter states:

FDA 1572 FAQ Change

FDA Makes a Clear Statement on 1572 Requirements

Study coordinators who administered the informed consent, determined subject eligibility and dispensed study drug were not listed on the Form FDA 1572, Statement of Investigator, for protocols (b)(4) and (b)(4). By performing these significant study activities, the study coordinators should have been listed on the Form FDA 1572s as subinvestigators.”

Although the 1572 FAQ, like all FDA Guidance Documents, states that it “Contains Nonbinding Recommendations,” the Warning Letter makes it crystal clear that “nonbinding” only goes so far. My advice?

Put your study coordinators on the 1572 pronto.

UPDATE: Remember that the FAQ does not need a CV for subinvestigators, just financial disclosure. It’s in the FAQ

UPDATE 6 January 2011: Two Important New GCP Documents:

There is a Draft Guidance on Electronic Source Documentation in Clinical Investigations. The comment period is for 90 day (April 4, 2011 ?)

There is a new Final Rule on required elements of Informed Consent. You can read the Federal Register Announcement here that includes FDA comments in the preamble. The exact change in 21 CFR Part 50 is:

“Sec. 50.25 Elements of informed consent.

* * * * *
(c) When seeking informed consent for applicable clinical trials,
as defined in 42 U.S.C. 282(j)(1)(A), the following statement shall be
provided to each clinical trial subject in informed consent documents
and processes. This will notify the clinical trial subject that
clinical trial information has been or will be submitted for inclusion
in the clinical trial registry databank under paragraph (j) of section
402 of the Public Health Service Act. The statement is: “A description
of this clinical trial will be available on
http:[sol][sol]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.”

Another update: Read an updated version of this article in
Applied Clinical Trials

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Comment:

For some reason WordPress isn’t showing comments for this post:

Carl,

Just discovered your blog and find it rather helpful. Our site is looking at the new 1572 guidance and will be implementing changes soon. I am not happy with the guidance for Sub-Investigators (VII, Section #6, #31) because it still leaves the interpretation wide open as to who provides “direct and significant contribution to the data.” We do oncology research and the nature of the care and treatment of these patients means that dozens of staff are involved. An auditor could intrepret that each of those staff members has a significant contribution to the “data.” I am not comfortable that Section #6, #32 protects us.

I know the Delegation of Authority log was never an official FDA document but it seemed a much more efficient means of informing Sponsors of who was conducting procedures for their studies. For me the 1572 should be reserved for those who make the decisions that a clinical trial is appropriate for given research subjects and for whom financial (or other) incentive could bias the enrollment and outcome of a trial . In our situation, that would be the physians who order the treatment for their patients. Staff assist in that process, but a study coordinator is never the one who decides that a treatment is appropriate. What brought about the need to expand the definition of who is a “sub-investigator?”

Thanks for your comment:

I basically agree with you about the study delegation log. It was in the guidance “Investigator Responsibilities” (October 2009) and I thought that it was a good vehicle for this type of situation. I do not have a clue why this has been emphasized at this time. Please make sure you look at section 32 of the FAQ where it addresses residents:

“Concerning staff residents on rotation, it may be difficult to prospectively identify those individuals who might perform specified protocol procedures or collect clinical data. Specific names of the rotational staff do not have to be listed in Section #6. Instead, to successfully address this scenario, the names of rotational individuals and the procedures they are expected to perform should be included in the clinical study records.”

This paragraph is at the top of page 14 in the FAQ.

Carl-

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The FDA 1572: What Belongs?

May 9, 2010

FDA 1572 What Belongs

What Belongs on a Form FDA 1572?

UPDATE: Final FAQ Guidance issued. See post, FDA 1572: Big Changes in FAQ…” published on June 8, 2010-

The Form FDA 1572, Statement of the Investigator, is a contract between the clinical investigator and FDA. The form is required by FDA regulations for clinical trials for drugs and biologics and is the Center for Drugs’ Division of Scientific Investigations (DSI) has paid particular attention of late. However, there have been divergent viewpoints about who should be listed as sub-investigators and other issues such as what laboratories should be included. FDA issued a draft guidance document on “Frequently Asked Questions” regarding the 1572 in July 2008. I recently gave an audio conference on the Trial Master File, or TMF, and had several inquiries afterwards regarding the 1572.

One inquiry was pretty basic. I was asked what I had meant by “accurate” and if a record needed to be accurate. I had discussed the guidance for good recordkeeping, “ALCOA.” This stand for Attribuatable, Legible, Contemporaneous, Original, & Accurate. I asked for an example and was told, “what if the investigator filled out the Form FDA 1572 with the wrong information?” You cannot submit false information to FDA. If the clinical investigator submits inaccurate information, then ask for a corrected 1572. It is as simple as that. We all know that the investigator does not like being corrected. However, in this case it is necessary. Getting necessary changes would be a lot easier if we didn’t ask for unnecessary changes. For example, you only need to ask an investigator for their CV once, at the beginning of the study. That’s it. There is no requirement for an annual updated, signed CV. None. There is no requirement for a PI to sign the informed consent form. None. So make things a little easier and keep to what IS required.

A trickier question is the criteria for including an individual in Section (Block) 6 on the 1572. Here is what the draft guidance on “Frequently Asked Questions” has to say:

FDA 1572  Clinical Trial

Who Should be Listed as Sub-Investigators On a Form FDA 1572?

The criteria for including an individual in Section #6 on the 1572 is to capture information about individuals who, as part of an investigative team, will assist the investigator and make a direct and significant contribution to the clinical data. The decision to list an individual in Section #6 depends on his/her level of responsibility (i.e., whether he/she is performing significant clinical investigation-related duties). In general, if an individual is directly involved in the performance of procedures required by the protocol and the collection of clinical data, that person should be listed on the 1572. For example, if the protocol notes that each subject needs to visit a specified internist who will perform a full physical to qualify subjects for the clinical investigation, that internist should be listed in Section #6.”

However, people I have spoken with are concerned because in a Warning Letter dated 01 October 2008, issued by the Center for Drug Evaluation and Research/Division of Scientific Investigations, it states:

“Study coordinators who administered the informed consent, determined subject eligibility and dispensed study drug were not listed on the Form FDA 1572, Statement of Investigator, for protocols (b)(4) and (b)(4). By performing these significant study activities, the study coordinators should have been listed on the Form FDA 1572s as subinvestigators.”

There are several protocols included in the Warning Letter and it is not clear which protocols are included for this citation. Later in the Warning Letter there is a citation that lists the following:

a. A blister card label for kit number 0582 was found identified as distributed to subject 747-002 instead of subject 747-004;
b. Three study medication labels for kit number 0495 was found identified as distributed to subject 747-003 instead of subject 747-002; and
c. Twelve study medication labels for kit number 0495 was found identified as distributed to subject 747-004 instead of subject 747-002.”

What belongs on 1572

Who Belongs on the 1572?

Although it is not possible to determine if this is the protocol cited for the 1572 violation, this investigational product appears to be packaged in a manner that would not require “significant clinical investigator-related duties.” It is not clear to me what activities necessitate inclusion on Block 6 of the Form FDA 1572. If, in fact, “direct and significant contributions to the clinical data” is the criteria for inclusion does that mean conducting an informed consent interview? Distributing blister cards? I am curious where the line is drawn.

This is not an insignificant issue, as researchers who are included on the Form FDA 1572 are required to submit a financial disclosure. It is also a source of different opinions between researchers and monitors. If you have a multi-center trial with 37 clinical sites, that could add up to a lot more documentation. My current inclination is to error on the side of caution. Warning Letters aren’t fun. Hopefully the final guidance on what belongs on the Form FDA 1572 will be out very soon.

You can review the draft guidance at this link (scroll down to the Federal Register notice for the PDF of the “Draft Guidance.”) Draft Guidance Documents for Clinical Trials.

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In Addition: FDA released its report for PDUFA IV for Fiscal Year 2008. PDUFA is the Prescription Drug User Fee Act which is now in its fourth rendition. Read the Executive Summary

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