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 FDA issued a draft guidance document on “Frequently Asked Questions” regarding the 1572 in July 2008.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 Here is what the draft guidance on “Frequently Asked Questions” has to say: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.


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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FDA Warns Pfizer After Children Receive Overdoses in Clinical Trial

April 20, 2010

FDA Pfizer Warning Letter

FDA Warns Pfizer

FDA took on the largest pharmaceutical company in the world, Pfizer, after FDA documented that as many as 13 children were overdosed with the drug Geodon, being studied to treat bipolar disorder. In a one month inspection an FDA field investigator, accompanied by a physician from the Center for Drugs, Division of Scientific Investigations (DSI), reviewed Pfizer’s conduct. It took FDA 11 months to write the Warning Letter, dated April 13, a delay that would not have been permitted a few years ago. However, in the past three years FDA has cited three of the largest pharmaceutical companies for failures as a sponsor of clinical trials.

All three were cited for the failure to monitor the progress of the investigation, an activity that is more likely than not contracted out to CROs- Contract Research Organizations. The other two large sponsors, Sanofi-Aventis and Johnson & Johnson, used CROs to monitor their studies. It is not clear from the Warning Letter if Pfizer used a CRO for the audited studies. There were other dosing errors of concern to FDA in the Warning Letter. Pfizer was also cited for informed consent issues and failure to have cardiologists available to read safety ECGs.

FDA had this to say about Pfizer’s conduct on monitoring:

FDA regulations require that sponsors ensure proper monitoring of clinical investigations. Our investigation found that Pfizer failed to properly ensure monitoring of the study referenced above. As a result of inadequate monitoring, widespread overdosing of study subjects at multiple study sites was neither detected nor corrected in timely manner.”

Pfizer responded to FDA as reported by the Associated Press, in an article by Matthew Perrone.

Pfizer Warning Letter

Pfizer Responds

Pfizer spokeswoman Kristen Neese said many of the problems cited by the FDA were first pointed out by the company itself more than four years ago.

‘Pfizer has communicated with the FDA about our conduct of clinical trials and, over the next two weeks, will provide an outline of new and existing processes for preventing similar issues with Pfizer clinical trials,’ Neese said in a statement.”

It is important to note that FDA had cited Pfizer in the past regarding the failure to monitor clinical trials. Repeat violations are more likely to result in an enforcement action. However, all three of these sponsor Warning Letters indicate that if something goes wrong at a clinical site, such as overdosing children, then the sponsor will be held responsible.

In Pfizer’s defense, it should be noted that Pfizer is the organization that caught the overdosing. The Warning Letter cites Pfizer for not determining that the subjects received incorrect dosages of study drug through their monitoring of the site. However, Pfizer data managers determined the overdose occurred. It seems that Pfizer may have been “monitoring the progress of the investigation” in more than one way, through monitoring visits AND through review of the data by their data management department. It seems harsh to me to cite a sponsor for violations that the sponsor found themselves. Something to think about.

This is the first Warning Letter that Pfizer has received for clinical or other research. They have received Warning Letters in the past for labeling or promotional claims, most recently in 2008.

Read the Warning Letter here:


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Clinical Trial GCP Failures Spark FDA Warning Letter

March 11, 2010

FDA issued a new Warning Letter for the most common GCP failures: Informed consent; recordkeeping; and protocol adherence. The 24 February letter to a clinical investigator in Meridian, MS is a textbook case on how not to conduct a clinical trial. First, the investigator failed to recruit eligible subjects and it went downhill from there. This was not a case of Good Clinical Practice (GCP).

FDA GCP Warning Letter

Study Eligibility is a Major FDA Concern

The problem is that this is a psychiatric study and the subjects need to be diagnosed with bipolar disorder in order to participate. Protecting research subjects who may have diminished autonomy is a primary concern for FDA. Thee of six subjects randomized in the study did not meeting the eligibility criteria of having Bipolar I Disorder. FDA considers this “placed at risk for injury from participation in the study,” a serious GCP violation.

FDA has paid closer attention to meeting eligibility requirements of a protocol listed in the inclusion/exclusion criteria. It has been showing up on more Warning Letters in the past two years. And the problems continued from there. One subject was dosed three days before baseline. Not good.

Recordkeeping Errors:

FDA cited the investigator for numerous recordkeeping errors noting:

The records for Subject 1004 contained numerous errors in subject number, protocol number, and date or identity of study visit. For example:

i. Numerous records reflect that subject number 1002 was used instead of the correct subject number 1004.

ii. Forms marked “Screening Visit,” “Week 1 Visit,” and “Week 4 Visit” all are dated October 31, 2006.

iii. There are two forms marked “Week 1 Visit” documenting the Children’s Depression Rating Scale Revised (CDRS-R) evaluation with two different dates, October 31, 2006 and November 8, 2006.

Informed Consent:

FDA Clinical Trial

FDA Approval Requires Sound Data

The Warning Letter goes on to list informed consent violations and failure to inform the IRB of changes in research activity, something I believe you will be seeing more of. None of these violations involve fraud, the topic in the previous two posts. However, they seriously jeopardize the quality of the research data and fully deserve FDA’s attention. The Division of Scientific Investigations (DSI) in the Center for Drug Evaluation & Research issued the Warning Letter.

Read the Warning Letter here:



Special Notice: The Blog was published in the Journal of Diabetes Science & Technology on the topic of Supervisory Responsibilities of Investigators with my colleagues Ann Berenbaum and Patti Young.

Access the Abstract Here


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