FDA Warning Letter Cites Repeat Violations

August 28, 2011

FDA Warning Letter Repeat Violations

FDA Cites Repeat Violations on Reporting Adverse Events

A recent FDA Warning Letter to a clinical investigator shows the importance of implementing the corrective actions promised from previous inspections. FDA states; “Given that you have not implemented the corrective actions promised in response to the August 2008 inspectional observations, we have concerns about whether the corrective actions that you have currently outlined will be properly implemented and executed in a manner that will prevent the recurrence of this and similar types of violations in the future.” In this case the previous inspection had cited the clinical investigator for the failure to report adverse events and serious adverse events, the same violations that the 2011 inspection documented. The violations, combined with the failure to implement corrective actions from the previous inspection, earned the investigator a Warning Letter.

It is important to remember how an FDA investigator prepares for an inspection. First, they receive an assignment from the Center for Drugs, The Center for Devices, or the Center for Biologics to conduct the inspection. Then there is a review of the file that includes the previous inspection reports. Each inspection report notes the violations at the previous inspection, or if it is the initial inspection, and if the violations are ongoing or resolved. The fastest way from a Form FDA 483, Inspectional Observations, to a Warning Letter is if there are ongoing violations from the previous inspection.

repeat violations

Review of Previous Inspection Reports

Promising corrective actions is all well and good. However, it is important to note that FDA will actually check up on your proposed corrections the next time they conduct an inspection, even if the inspection is three years later.

The Warning Letter has an interesting feature as it is signed by “Leslie K. Ball, M.D., Acting Director, Office of Scientific Investigations, Office of Compliance, Center for Drug Evaluation and Research.” Up until recently this had been the Division of Scientific Investigations. At FDA an Office is a higher organizational unit than a Division (all emphasis by GxP Perspectives). Evidently there has been some form of reorganization. However, this hasn’t been reflected on CDER organizational charts. The most recent “CDER Key Officials List,” dated August 22, 2011, listss the following:

Division of Scientific Investigations (DSI)

Leslie Ball, M.D., Director
Joseph Salewski, Deputy Director
CT Viswanathan, Ph.D., Associate Director
Chris Howard, Project Management Officer (Acting) (co-located)
Tanya Clayton, Project Management Officer (co-located)
Kevin Prohaska, Human Subject Protection Team (Acting)
Alex Gorovets, International Policy Team (Acting)
Constance Lewin, M.D., Good Clinical Practice Branch I
Sherbet Samuels, Good Clinical Practice Team I (Acting)
Tejashri Purohit-Sheth, Good Clinical Practice Branch II
Jean Mulinde, Good Clinical Practice Team II (Acting)
Sam Haidar, Good Laboratory Practice and Bioequivalence Investigations Branch (Acting)
Martin Yau, Bioequivalence Team (Acting)
Jackie O’’Shaughnessy, Good Laboratory Practice Team (Acting)
Thomas N. Moreno, Information and Informatics Team (Acting)

Evidently there are some significant changes taking place. Perhaps we will learn more later.

Read the Warning Letter

Also: Read the recent Warning Letter from CBER to a Clinical Trial Sponsor

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On The Blogroll: Applied Clinical Trials Blog discusses Facebook.

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FDA warning letter

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FDA Issues Draft Guidance on Medical Device Clinical Trials

August 15, 2011

FDA clinical trial medical device

FDA Seeks Comment on Draft Guidance Document

FDA has issued two new draft guidance documents on medical device clinical trials to support a Pre-Market Approval application (PMA). Approximately 30% of FDA regulated clinical trials are for medical devices and are regulated by the IDE regulations (21 CFR 812). The remaining 70% are for drugs and biologics and are regulated by the IND regulations (21 CFR 312). The majority of guidance documents, including ICH E6 for good clinical practice, and the majority of clinical trial vendors address drug products, not medical devices. Although Good Clinical Practice is relevant to all clinical trials there are unique aspects for device studies as opposed to drug studies. This is one reason that FDA issued a device-specific guidance document.

The draft guidance document, Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff – Design Considerations for Pivotal Clinical Investigations for Medical Devices (August 15, 2011), addresses therapeutic and aesthetic devices and diagnostic devices. Areas the document address include; Regulatory Framework for Level of Evidence and Study Design, The Importance of Exploratory Studies in Pivotal Study Design, Clinical Outcome Studies, Diagnostic Clinical Performance Studies, and Sustaining the Level of Evidence of Clinical Studies. The guidance states that its scope is:

clinical trials FDA medical device

Design Considerations for Pivotal Studies

“This guidance describes principles that should be followed for the design of premarket clinical studies1 that are pivotal in establishing the safety and effectiveness of a medical device. Practical issues and pitfalls in pivotal clinical study design are discussed, along with their effects on the conclusions that can be drawn from the studies concerning safety and effectiveness.”

The Agency also released the draft guidance document; Draft Guidance for Industry and Food and Drug Administration Staff – Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review (August 15, 2011). The Agency states:

FDA clinical trial medical device

Benefit-Risk Determination

“This guidance document explains the factors that FDA considers when making benefit-risk determinations in the premarket review of certain medical devices. The processes discussed in this guidance are applicable to devices subject to premarket approval (PMA) applications and, in limited cases, devices subject to premarket notification (510(k)) requirements. This guidance applies to both diagnostic devices and therapeutic devices.

Although guidance is not binding, the concepts and factors described herein generally capture how benefit-risk determinations are made by FDA during the premarket review process.”

Read the Guidance Document on Design Considerations

Read the Guidance Document on Benefit/Risk Determinations

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ALSO of interest: FDA is currently accepting comments on the IVD Draft Guidance Document on In Vitro Companion Diagnostic Devices.

The draft guidance was issued 14 July, Bastille Day. I wish that I could explain it to you as well as Jamie K. Wolszon at the FDA Law Blog, but I can’t so I recommend taking a look over there:

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FDA Law Blog on IVD Companion Devices

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You can help out GxP Perspectives! Please let your colleagues and friends know about GxP Perspectives. I also encourage you to get an email subscription (on the sidebar to your right) or join the LinkedIn group (below).

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Required Summer Reading: Essex IRB Warning Letter. Earlier this year FDA warned of a fictitious submission to central IRBs. Essex took the bait and approved the fictitious submission.

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On The Blogroll: On Biostatistics and Clinical Trials– Finally a blog on biostatistics that I can almost read:) It is written by Dr. Deng, 邓春勤 A Medical Doctor turned into Biostatistician in Clinical Trial and Drug Development Industry

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FDA warning letter

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