FDA Enforcement: The Four Elements of Proof

April 16, 2011

The four elements of Proof FDA

FDA Enforcement:
The Four Elements
of Proof

What is FDA required to document to initiate an enforcement action? What proof is necessary to establish clear and significant violations of the regulations? What elements of noncompliance do FDA field investigators need to establish that a Warning Letter, seizure, injunction, consent degree, or prosecution is required? FDA has basic requirements that should be documented during an inspection: they are called the Four Elements of Proof. When reviewing a Form FDA 483, Inspectional Observations, it should be compared against these basic required elements for consistency, relevancy and significance. Let’s look at the Four Elements of Proof, sometimes referred to with the acronym JIVR.

FDA four elements of proof

Does FDA Have Jurisdiction?

JURISDICTION: For FDA to take an enforcement action, it needs jurisdiction. We know that FDA regulates drugs, medical devices, and biologics/vaccines. However, It isn’t always simple. There is a strict definition of “drug” in the Food, Drug & Cosmetic Act. That is the reason FDA lost at the Supreme Court with the first attempt at asserting jurisdiction over tobacco in the 1990s. It was “a question of intent,” which is also the title of former Commissioner Dr. David Kessler’s fascinating book on his time at FDA. Laws and regulations usually have a section for “definitions.” Take some time to read them. It will help you understand the way FDA interprets inspections and when to seek enforcement actions.

FDA enforcement four elements of proof

An Early FDA Inspection: Railroad Watering Points

INTERSTATE COMMERCE: One of the principal functions of the United States government is to regulate interstate commerce. Railroads were the principal means of interstate transportation when FDA was founded and an important area of FDA concern. And just try to document medical oxygen in interstate commerce. I once had a promotion delayed for three months because as a Bioresearch Monitoring investigator, I was dealing with the biopharmaceutical and medical device industries where interstate commerce is basically assumed. So I had to go out to a couple of medical gas repackers and collect DOC Samples (a DOC sample consists of paperwork, not a product) to establish that I could document interstate commerce. (See Warning Letter Below for Interstate Conveyance Sanitation.)

four elements of proof

What is the Violation?

VIOLATION: There should be a “clear and significant” violation of the regulations to put something on a 483 or Warning letter. If the laboratory normal range for the inclusion/exclusion criteria for blood glucose is 80-120 Mg/DL and the result is 121 that is a clear violation. Is it significant? I think not. Determining significance is not an easy task. It is something that may need discussion during an FDA inspection. Patient, professional discussion of the issue is usually the best approach. Your FDA field investigator may not have experience in the specific therapeutic area or technical issues of the inspection. It isn’t always easy conducting an FDA inspection and establishing the four elements of proof and the significance of the violation. And remember, You cannot determine the root cause of a problem if you don’t know what the violation is. What is the Violation? Find it in the regulations.

FDA four elements of proof

Regulations Assign Responsibility

RESPONSIBILITY: Regulations assign responsibility. In clinical trials they are assigned to sponsors, investigators, and IRBs. In GMPs and postmarket activities responsibilities are assigned to the “applicant” and the manufacturer of a regulated product. In the GLP regulations, responsibility is assigned to the testing facility. Responsibility is a Big Deal to an FDA investigator. It is just as important to ask, “Whose regulatory responsibility is it?” as it is to ask, “What is the Violation?” Without regulatory responsibility you cannot determine who should recommend the actions necessary to correct a regulatory error.

There you have it. The four elements of proof. The basic requirements for FDA enforcement.

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Interstate Conveyance Sanitation Warning Letter
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News from FDA: There is a new Proposed Rule (proposed change in regulations) from FDA on the Disqualification of Investigators. This proposed rule modernizes and harmonizes current regulations. The Final Rule will probably look quite similar.
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On the Blogroll: GxP Perspectives made the list for Top 40 Websites (and tweets) on the FDA. This comes from FDAZilla. I think it is a pretty good list.

Also: David Spero has an excellent post called The Art of Motivation on his blog. This isn’t about regulations, its about people.

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FDA Inspections: What NOT To Say & How Not To Say It

March 13, 2011

FDA inspections

"It's Not My Job"

FDA Inspections are Always stressful. How should you answer the FDA Investigator’s questions? What should you say or, more importantly, what should you NOT say? Two common answers are to tell the truth and to only answer the question asked. Both are good points. The FDA investigator is conducting a public health inspection so you should want to tell the truth. It also happens to be against the law to lie to a federal official so there are both positive and negative motivations to answer a question truthfully. It is also a good idea to give a brief, factual, and truthful answer to the question you are asked, not a question you think might be asked. And remember to use a complete sentence. Receiving a barrage of monosyllables in an interview is only going to irritate the FDA investigator. The one answer I recommend to never give to an FDA investigator is, “It’s not my job.”

What? Most people who answer, “it’s not my job” are telling the truth! Not only that, it is not a good idea to answer for someone else who actually has that responsibility. However, you have to remember that an FDA investigator has heard that response one hundred times before. People frequently give evasive answers and avoid responsibility when being interviewed by the FDA. It gets very old, very fast.

FDA inspection

"I Know Who Has That Responsibility"

A better approach is to say, “That isn’t my job but I know whose responsibility it is and let me see if she is available.” During an FDA inspection it is important to build trust. If an FDA inspector asks a reasonable question, let’s say, “How do you ship investigational product to clinical sites?” It is in your interest to see that the right person answers the question and that you find the right person in a timely manner.

FDA has begun a program to increase the types of GCP inspections it conducts. There will be more inspections of CROs and clinical trial vendors such as clinical laboratories. In fact, they have already started. That means that many more people will need training on how to participate in an FDA inspection. GxP Perspectives will be having some Guest Commentaries on the subject and try to provide some practical solutions.

FDA Inspevtions

Frontloading Quality:
The Key to Success

The first step in successfully hosting an FDA inspection is to have a quality system in place that monitors the data or product lifecycle. You don’t want to start your quality process after you lock your database! Then, when FDA does show up, you want to give a positive impression. You want to build trust with FDA. Think back to the last time you phoned your utility company or complained about a pothole on your street. When you finally got a live person and they told you, “that’s not my job,” how did you feel? That isn’t how you want FDA to feel either.

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Here are some helpful articles and resources on FDA inspections:

Applied Clinical Trials on Mock FDA Inspections.

Ten Steps for Improving GCP Inspections by Vernette Molloy and my late colleague, Sandy Mackintosh, also in Applied Clinical Trials

FDA Inspection Guides: How the FDA conducts inspections

BioJobBlog: What’s Up With FDA Inspections Anyway?

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SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

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A new feature from FDAzilla on FDA 483s

Read the Press Release on 483s

On the Blogroll: GxP Perspectives made the list for Best 40 Blogs (and tweets) on the FDA. This comes from FDAZilla. I think it is a pretty good list.

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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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On The Blogroll: Audrey’s Network– a great way to keep up with news from the San Francisco Bay Area Life Sciences Community

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GCP Protocol Deviations & Violations: Determining the Root Cause

March 6, 2011

protocol violations and deviations GCP

GCP Protocol Violations: Determing the Root Cause

The top violation cited during FDA inspections of clinical sites has consistently been the failure to follow the investigational plan- Protocol Deviations & Violations. Coupled with recordkeeping violations the failure to follow the protocol has been the mainstay of the Form FDA 483, Inspectional Observations, issued by FDA field investigators to clinical sites for decades. However, FDA has recently been pointing out that the root cause can just as easily be poorly designed protocols as noncompliance by a clinical investigator. In the previous post on GCP CAPA plans I note that at least two root causes that should always be investigated. This is particularly true when you find systematic protocol violations. Two areas that should always be reviewed are:

Protocol Design: Frequently you will find a Note to File in a clinical site’s regulatory binder saying that the study coordinator had been “retrained” in the importance of subject compliance. However, if subjects are routinely missing visits or protocol-required procedures you need to take a look at how well designed the protocol is. Were clinical sites consulted when the protocol was written? Is the visit schedule practical? Are the tests easily performed or do they require special efforts by research staff at a busy medical practice? And just how many protocol amendments do you have anyway? It is the clinical site that will receive an FDA 483 but the root cause very well might be found at the sponsor.

GCP Violations and protocol deviations

Protocol Violations are the Top GCP Violation at Clinical Sites

Protocol Adherence: Sometimes the clinical site is the cause of the deviation. There is a significant difference between the practice of medicine and the conduct of a clinical trial. I can’t count the times that I have been told, condescendingly, that “We’ve been doing this type of medical procedure for quite some time.” That’s all well and good but have you been reading the protocol for quite some time? A clinical trial is an experiment, and frequently requires activities that are not the usual practice of medicine. You may need to order a second blood test, or change the dose of the investigational product.

In cases like this a follow-up letter from the monitor to the clinical site might not be enough. If the root cause is the failure to understand the responsibilities of a clinical investigator then the issue may need to be escalated to someone with the letters “MD” after their name. Sometimes you need a physician to explain the protocol to another physician. Seldom does the “re-education” of support staff work as an effective corrective action.

Determining the root cause of systemic protocol deviations and violations isn’t always easy. However, if you don’t follow the investigational plan you can jeopardize your application. And remember, always investigate at least two possible causes of protocol violations.

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In a recent FDA Warning Letter protocol violations are discussed at length.
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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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On the Blogroll: Cancer Sucks

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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SPECIAL UPDATE: 18MAR2011: FDA has released an updated version of the Compliance Program Guidance Manual 7348.810, Sponsors/Contract Research Organizations/Monitors. There are new sections on registration of clinical trials on ClinicalTrials.gov, Financial Disclosure, the Part 11 Scope & Application Guidance Document, and other issues. If you work for a sponsor, a CRO, or are a contract CRA you MUST read this document. Review Section III, Inspectional.

I am in the process of writing an analysis of this updated compliance program. Please let me know if you have questions or suggestions for points to consider. Thanks!

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New FDA Guidance Documents Planned for 2011

January 9, 2011

FDA Guidance Documents 2011

FDA Plans New Guidance Documents in 2011

FDA just issued a new draft guidance document for Electronic Source Documents in Clinical Investigations (see below) and has more in the works. In this Guest Commentary, John Avellanet, founder of Cerulean Associates LLC, takes a look at what is in store for 2011 as far as FDA Guidance Documents with a focus on new documents for postmarket surveillance. The article is excerpted from a lengthier article in John’s newsletter SmarterCompliance. John forecasts new guidance documents every year in his newsletter. There is a link to John’s website below.

Guest Commentary by John Avellanet:

FDA postmarket surveillance is the emphasis of at least six different guidance documents planned for publication in 2011. And these are in addition to the new International Conference on Harmonization (ICH) and Global Harmonization Task Force (GHTF) documents expected, including a GHTF guidance on the handling of recalls and field safety corrective actions (see below).

The list of FDA postmarket surveillance guidance documents includes:

1. Chemistry, Manufacturing, and Controls (CMC) – Postmarketing Plan
2. CMC Postapproval Changes Reportable in an Annual Report
3. Pharmaceutical Manufacturing Statistics and Trend Analyses
4. Best Practices for Conducting Pharmacovigilence Studies Using Electronic Healthcare Data (remember that since FDAAA of 2007, the term “study” explicitly means postmarket nonclinical study)
5. Medical Device Reporting for Manufacturers
6. Postmarket Surveillance and the National Competent Authority Report Exchange Criteria and Report Form
7. Types of Submissions for Postapproval Changes to Combination Products

FDA Guidance Documents

Expect New REMS Guidance from FDA

I also expect the agency to release a revised risk evaluation and mitigation strategies (REMS) guidance, at least in draft form, by year’s end. Part of this release will be the creation of a pilot program to test what a standard REMS could like as a default part of any new drug or biologic submission. This means one more step toward pushing the industry to create some type of REMS for every single new drug or biologic developed. The agency will maintain an approach to a standard REMS that will be harmonized with other regulatory member agencies in the ICH. And while such a revised draft REMS guidance may come as a separate document, I suspect the agency may take a newer tact: “guidance by FAQ.”

guidance documents

EMA is Also Releasing New Guidance & Clarifications

Both the European Medicines Agency (EMA) and the UK’s health agency (MHRA) have begun publishing clarifications and revisions to guidance documents and regulatory interpretations using question and answer formats posted on agency webpages. The FDA adopted this approach most recently in its “guidance” (for Buildings and Facilities) on avoiding moldy or musty odors in drugs. Might the agency harness the “guidance by FAQ” approach for its upcoming standardized REMS draft and pilot?

The standard REMS template – while seeming to add more requirements to drug development – will actually provide manufacturers and developers more flexibility, something already known to readers of Get to Market Now! Turn FDA Compliance into a Competitive Edge. While I do not expect the REMS guidance and template to be finalized until after the pilot program is complete, consider developing a high-level REMS as part of any late stage development today. Expect to be able to talk intelligently to FDA reviewers of your plans for a postmarket surveillance program. A high-level draft REMS strategy (you need not share the actual document with the agency) will only help.

Finally, be aware that in 2011, the HHS Office of Inspector General (OIG) will examine the FDA’s postmarket surveillance activities, with a report expected to be published in 2012. This will inevitably result in more postmarket guidance, and may give the FDA the backing it needs to make a basic REMS part of any new drug or biologic submission by 2014.

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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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SmarterCompliance Newsletter

Global Harmonization Task Force focuses on medical devices

International Conference on Harmonization focuses on drugs and biologics

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SPECIAL ANNOUNCEMENT: From the FDA Alumni Association (FDAAA): The WHO is seeking a pharmaceutical technical officer to work in China ondrug policy. The position looks very interesting. Please forward to anyone you think might be interested. Please contact WHO directly if you have questions. For info contact <a href="Florence Houn “>Florence Houn at FDAA. or view the WHO AnnouncementWHO Announcement
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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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