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 5 New International Warning Letters

May 15, 2011

FDA international warning letters

FDA's Increased International Presence

The “Most Recent Warning Letters” section of the FDA website lists five Warning Letters to international firms. The Warning Letters were posted on May 10 and will disappear into the Warning Letter labyrinth on the website in a few days (see previous post). They are to firms in both Europe and Asia and come from four different centers: the Center for Devices and Radiological Health; the Center for Drug Evaluation and Research (Active Pharmaceutical Ingredient (API); the Center for Biologics Evaluation and Research; and the Center for Food Safety and Applied Nutrition (two Warning Letters for Seafood HACCP).

The Warning Letters do not state if the inspections were conducted by one of the FDA’s new International Resident Posts- but it is likely that the FDA’s increased global presence contributed to the enforcement actions. FDA now has offices in China, India, Belgium, and Costa Rica. This is addition to FDA’s International Inspection Cadre which is primarily drawn from FDA Field Investigators (Consumer Safety Officers) working for the 20 FDA District Offices across the country. The fact that different offices are issuing Warning Letters around the world at the same time gives a clear indication of FDA’s increased international enforcement efforts.

FDA International Resident Posts

Read the Warning Letters:

Hong Kong – Medical Devices

Spain – Active Pharmaceutical Ingredients

Sweden – Biologics cGMP

Korea – Seafood HACCP

On the Blogroll: Last week we had the FDA Lawyer’s Blog. This week I want to highlight a recent article on the FDA Law Blog on “FDA Warning Letter ‘Close Out’ Process Not Working.”

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FDA Warning Letters: How to Navigate FDA’s Website

May 10, 2011

FDA Warning Letter

One of the Many Exhibitors at the
ACRP Conference

FDA Warning Letters, and some thoughts on critical and creative thinking, conclude my reporting from the Global Conference for ACRP – the Association of Clinical Research Professionals – held last week at the Washington State Convention Center in Seattle. During the conference it became apparent that many people, including FDA employees, have a difficult time searching for Warning Letters on FDA’s website. The Warning Letter section is an absolute mess. So I thought I would provide a few simple search tips to help find Warning Letters for GCPs. Unfortunately cGMP Warning Letters are more difficult, but the tips still help. Then I would like to tell you about an interesting session I attended on critical and creative thinking.

When searching for FDA Warning Letters, the link is below, scroll down and choose to “Browse Warning Letters by SUBJECT.” You will be presented with the alphabet. Click on “C” and then scroll down past all the “cGMP” categories until you reach “Clinical Investigator” where you will find the majority of GCP Warning Letters.

FDA Warning Letters

Searching for FDA Warning Letters

They will be listed in alphabetical order. There is a “Sort by:” option. Choose “Letter issued DESC” from the drop down menu. You will then have most of the GCP Warning Letters with the most recent listed first. You can also choose as subjects: Clinical Investigator – Sponsor; Bioresearch Monitoring; IRBs; Sponsor Obligations; and “IDE….” for medical device Warning Letters. There are several ways of listing for each category. You can sort by “Letter Issued DESC” for each category. There are five GLP categories plus Good Laboratory Practices. Go figure.

FDA Warning Letters

There were a number of interesting sessions that I attended at the ACRP meeting. I wanted to tell you about Critical Thinking in a Regulated Environment, because it can be so darn difficult. Kirk Mousley described critical thinking as producing ideas and then evaluating ideas. Citing Iris Verdi he described creative thinking as original, imaginative, and uncommon. He discussed that creative thinking comes through different avenues: it is often a revisement of something that already exists (evolution); a combination of two or more ideas (synthesis); or just a different way of looking at things, asking yourself, “how else can I look at this?”

FDA Warning Letters

How Can I Look at This Differently?

Mousley also discussed the barriers to creative thinking including “not part of an approved process” (SOPs). He noted that the regulatory process itself discourages critical thinking by imposing a “process mentality.” He countered that by suggesting that you build into a process the encouragement of critical thinking. And he pointed out the myth that “every problem can only have one solution or one right answer.” One of the points that I emphasize when doing a root cause analysis of a problem identified during a CAPA process is that you should Always Look for More Than One Root Cause.

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On The Blogroll: The FDA Lawyers Blog discusses a variety of interesting issues including bioequivalence data, litigation tactics, and Victory for Embryonic Stem Cell Researchers.

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FDA Warning Letters in 2010 for GCP Failures

January 1, 2011

FDA Warning Letters GCP

FDA Maintains Pace for GCP Warning Letters
in 2010

After a significant rise in Warning Letters issued for GCP failures the past few years, FDA seems to have leveled off in the number of Warning Letters issued in 2010. I have not seen FDA metrics for Fiscal Year 2010 but my own review of Warning Letters issued to clinical investigators in 2010 doesn’t show a sharp increase, only more of the same. In particular, the primary deficiency categories are quite similar as they were 15 years ago when I attended my first FDA Bioresearch Monitoring course. Although the terminology has modernized over the years it can be summed up in four words: protocol adherence and recordkeeping.

UPDATE: I have posted below the BIMO FY-2010 Metrics below, courtesy of the Office of Good Clinical Practice- FDA/OC (many thanks). They are the people responsible for the Clinical Trials link on the FDA website. The metrics essentially confirm some of the conclusions of this post.

When looking at an FDA Warning Letter I am always curious about the very first charge that is listed. You will note that FDA does not use categories such as Critical, Major, or Minor as many company QA departments do. MHRA, the United Kingdom’s regulatory agency for health products, also uses a rating system, Major, Minor, and “Other.” However, FDA lists violations in the order of significance and the first item listed on either a Warning Letter or Form FDA 483, Inspectional Observations, is supposed to be the most significant. In ten Warning Letters I reviewed that were issued to clinical investigators in 2010 “failure to follow the investigational plan” was listed first on Warning Letters issued by the Center for Drugs four times. “Failure to conduct the investigation according to the signed agreement, the investigational plan, and FDA regulations was listed first in two Warning Letters issued by the Center for Devices and Radiological Health. The lesson here is that FDA pays close attention to protocol adherence.

FDA Warning Letters GCP

Keeping on Top of Records and the TMF

Recordkeeping violations were listed first on one Warning Letter but were included on eight of the ten Warning Letters I reviewed. Perhaps this is one of the reasons for the strong interest in the trial master file, the TMF. This pattern of violations has been happening a very long time. The first article I wrote after leaving FDA (six years ago) was called, “Protocol Adherence and Recordkeeping: The Twin Pillars of GCPs.” A typical Warning Letter was issued on 30 September 2010 (there is a link below). So the good news is that many researchers are paying attention to the increase in FDA Warning Letters the past few years and are instituting changes. The bad news is that there are still some people that keep repeating the same mistakes.

FDA GCP Warning Letter: 30 SEP 10

BIMO metrics – FY-2010

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A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

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Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

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In news from GxP Perspectives.

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On the Blogroll: Catalyst Biomedical – A blog that I recently discovered and that you may find of interest

Two Important New GCP Documents: 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.”

Your comments are welcome on FDA Warning Letters


FDA Warning Letters to International Companies for CAPAs & Complaints

November 28, 2010

FDA warning letter CAPA complaint

Warning Letters for CAPAs & Complaint Investigations

In the past 90 days FDA issued five Warning Letters to international firms for GMP failures to adequately investigate complaints. Whether it is GMPs, GCPs, or GLPs FDA is making the case that when things go wrong, it is a company’s responsibility to investigate and implement the necessary corrective and preventative action (CAPA), In the past, FDA was hesitant to issue Warning Letters to firms outside the United States. That clearly is changing as both the Center for Devices and Radiological Health (CDRH) and the Center for Drug Evaluation and Research (CDER) have issued Warning Letters to companies in Canada, Switzerland, China, Sweden, and India. Although the companies are from diverse locations and range from medical devices, active pharmaceutical ingredients (APIs), and finished pharmaceuticals, one issue connects them all: the failure to adequately address complaints. For the medical device Warning Letters, corrective and preventative actions (CAPAs) figured prominently.

FDA first opened international offices in 2008 in India and China and now has offices in Europe and Latin America as well. The international offices are predominantly focused on GMPs for food, drugs, and medical devices. FDA has also stepped up its inspections of clinical trials in international locations including Russia and Eastern Europe. However, there has not been the corresponding surge in Warning Letters. At least not yet. Here are charges that FDA made in the international Warning Letters:

CAPA complaint FDA warning letter

Failure to Investigate Bacterial Contamination

Claris (India): On April 15, 2010, your firm received a complaint from a U.S. distributor (Sagent Pharmaceuticals) informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a informing you that Metronidazole Injection USP IV bags (lot A090744) were contaminated with a swirling mass, which the complainant identified as the fungus Cladosporium species. There is no information in the Complaint Investigation Report to show that Claris initiated an investigation to determine the root cause and extent of the problem until April 26, 2010, when Claris received this contaminated large volume parenteral and examined it.

Storz Medical (Switzerland): Failure to establish and maintain adequate procedures for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). For example, no protocol, including acceptance criteria, was established for the validation of Change Request (b)(4). Additionally, there was no documentation showing that this change was validated. The change was implemented to fix cracked cooling pumps in the Modulith SLX-F2.

The Warning Letter goes on to say:

international complaint investigation failure FDA

Failure to Establish Procedures for Complaints

Failure to establish and maintain adequate procedures to ensure that any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall be reviewed, evaluated, and investigated unless such investigation has already been performed for a similar complaint and another investigation is not necessary, as required by 21 CFR 820.198(c).

Neoventa Medical AB (Sweden): 1. Failure to establish and maintain adequate procedures for implementing corrective and preventive action that include requirements for verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device and that all activities required under this section and their results be documented, as required by 21 CFR 820.100(a)(4) and (b).

2. Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a).

Once again the direct connection between the failure to investigate complaints and the failure of a system of CAPA.

FDA Warning Letters CAPA

Chinese API Manufacturer Hit with FDA Warning Letter

Yunnan Hande (China): Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

Pega Medical (Canada): Failure to establish and maintain the requirements, including quality requirements, that must be met by suppliers, contractors, and consultants, as required by 21 CFR 820.50(a)… For example, Complaint NCR No. (b)(4) reported…”

Read the Warning Letters:

Storz Medical, AG Warning Letter

Yunnan Hande Biotech Warning Letter

Claris India Warning Letter

Pega Medical Warning Letter

Neoventa Medical AB

FDA International Resident Posts

And What About Clinical Trials?

At a recent FDANews conference FDA representative Ann Meeker-O’Connell, M.S., Division of Scientific Investigations, Office of Compliance CDER/FDA, said,

FDA warning letter international complaint investigations

Clinical Trial CAPAs Face Different Challenges

“But, clinical trials are inherently variable systems with a goal of producing reliable data for regulatory decision-making . . . How can this be reconciled with a quality system framework originating in mass manufacturing?”

That is a very good question and one that many of us have been wrestling with. However, it is clear that FDA has been taking on the question of the international nature of the drug and device industry, including manufacturing and clinical trials.

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Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

UPDATE: There is a very interesting Important Notice to IRBs that is on the FDA website. Sort of a Coast IRB redux.

Public Comment Period is Open for New FDA Draft Guidance:
FDA Draft Guidance on Electronic Source Data in Clinical Investigations

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Visit the TMF Page at the Top Right of the Blog! I am trying to assemble resources for those of us concerned with the Trial Master File. I welcome any contributions you might have of interesting articles and resource documents.

On FDA’s Website there are Two New Warning Letters from FDA to Clinical Investigators that show the need to effectively respond to a Form FDA 483, Inspectional Observations, with a well thought out CAPA Plan.


FDA Sends J & J a Warning Letter For Internet Marketing- Forest Labs Agrees to Pay $300 Million for Violating FDA Laws

August 30, 2010

website FDA Warning Letter J&J

internet Marketing Cited in FDA Warning Letter

Johnson and Johnson subsidiary, DePuy Orthopedics, received an FDA Warning Letter for marketing violations. The Warning Letter cites DePuy for internet marketing of their products without FDA approval. The Warning Letter is one more headache for J&J that is discussed in the post from 19 August on J&J’s Quality Control Headaches. The Warning Letter states:

“The Office of Compliance (OC) in the Center for Devices and Radiological Health (CDRH) reviewed your website, http://www.depuyorthopaedics.com. for the TruMatch™ Personalized Solutions System and the Corail® Hip System.”

Read the Warning Letter to DePuy

View J&J’s Current Webpage on Hip Replacements

UPDATE: J&J is not the only company in hot water with FDA for marketing. Forest Laboratories has agreed to a $300 Million settlement for the following: “Forest Pharmaceuticals, Inc. entered into a plea agreement in which the company accepted responsibility for criminal actions including distribution of an unapproved new drug, distribution of a misbranded drug, and obstruction of an FDA inspection.”

FDA Press Release on Forest Labs

Read “J&J’s Quality Control Headaches”

On The Blogroll: Again, I would like to highlight some of the blogs found on the blogroll to the right. This blog focuses on public health, The Pump Handle.

Save The Date: On 4-5 November 2010 the Pacific Regional Chapter of the Society for Quality Assurance (PRCSQA) and the Organization of Regulatory and Clinical Associates (ORCA), a Pacific Northwest based organization, will co-sponsor a Fall Training on regulatory compliance topics in Seattle, WA.

The PRCSQA LinkedIn Group will update the agenda for the training. PRCSQA Fall Training workshops have traditionally been “at cost” and are an affordable training opportunity. The sessions will cover both GCPs and GLPs with speakers lined up on vendor management, quality systems, and GLP updates.

In news from GxP Perspectives read the updated article on the Form FDA 1572 in:

Applied Clinical Trials “Closing Thought” on FDA 1572

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FDA Warning Letter on Eligibility and Informed Consent

July 30, 2010

FDA informed consent and study eligibility

FDA Warns on Informed Consent and Study Eligibility

Once again, FDA has issued a Warning Letter to a clinical investigator on the informed consent process and enrolling subjects who did not meet study eligibility criteria. The Warning Letter also cited serious record-keeping violations. This Warning Letter was issued by the Center for Biologics Evaluation and Research, which handles approximately 10% of the FDA’s Bioresearch Monitoring inspections. FDA Warning Letters in the past few years have frequently cited study eligibility and informed consent issues. They are two of the most critical areas of FDA concern. In this case 7 of 17 subjects were enrolled who did not meet inclusion/exclusion criteria. That’s pretty significant.

Seven subjects did not sign an informed consent form required by a protocol amendment and two others signed a consent form meant for HIV positive subjects. These subjects were not HIV positive. These are not minor dating errors or forgetting to get initials on page 7 of 12. They are major informed consent violations. The investigator also could not produce electronic records that were important source documents because of computer problems. Another reason to take a look at the previous Guest Commentary on Part 11 (scroll down). This is another good reason for sponsors and clinical site staff to review study eligibility and informed consent requirements. They are among the first places FDA will look.

Read The Warning Letter

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This just in: Request for Comments- Exculpatory Language Used in Informed Consent, a joint FDA and OHRP draft guidance document (September 2011)


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