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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CAPA Plans for Clinical Trials

February 22, 2011

GCP CAPA Plans for clinical trials

CAPA Plans: Corrective and Preventative Actions

CAPA- corrective and preventative action– Are CAPA plans for clinical trials different than a CAPA for a GMP quality system? Do GCP regulations require CAPA plans? Is a root cause analysis necessary to develop a CAPA plan? What are FDA’s expectations for CAPA plans? These are some of the questions that were asked at EXL Pharma’s conference on CAPAs in the clinical trial environment held last month in Virginia. I then had the opportunity to ask them all over again during a “for-cause” GCP audit. The results provided for some interesting insight into how sponsors, CROs, and clinical investigators can investigate errors in clinical trials and put in place a process to prevent the errors from continuing.

First we should define our terms:

Corrective Action: –Immediate action to a problem that has already occurred or has been identified.

Preventative Action= Taken to eliminate the root cause of a potential problem including the detection/identification of problems.

Root Cause Analysis: A class of problem solving methods used to identify the root causes of problems or events.

These definitions hold true for all GxP quality systems. However, there are some basic differences that set GCP CAPAs apart from the manufacturing or GLP arena:

= FDA regulations assign responsibilities to Investigators, Sponsors, & IRBs- there are NO regulatory responsibilities for human subjects participating in clinical trials

= GMPs involve a manufactured product- GCPs involve a clinical investigation, an experiment- The “products” are the integrity of the data and the protection of human subjects in clinical research.

= GMPs largely involve a manufacturing process- GCPs largely involve the interactions of People

CAPA Clinical Trials

What is the Root Cause of the Problem?

FDA has made it clear both in public presentations and in Warning Letters to sponsors and clinical investigators that they expect two responses to GCP problems once they have been identified. First, there should be an investigation regarding how widespread the problem is. In effect, conducting a root cause analysis and investigation into the problem. Next, FDA expects a description of efforts into the prevention of the problem in the future. This is essentially a plan of corrective and preventative action, a CAPA. So even though FDA’s GCP requirements don’t specify CAPA plans, if you receive a Form FDA 483, Inspectional Observations, you really need to put a CAPA plan into place. Here are two examples why:

= FDA Sponsor Warning Letter, January 2011 – “Your response is inadequate in that it does not describe your corrective and preventive actions in sufficient detail.”

= FDA NIDPOE letter to Clinical Investigator (potential disqualification warning) 2009: “…however, you failed to investigate for additional acts of falsification within the same clinical investigation or in other clinical investigations in which the study coordinator was involved.”

CAPA clinical trials

Always Look for at Least 2 Root Causes

The root cause analysis of a clinical trial problem should include an investigation into what happened. Different problems will need different levels of investigation depending on significance. In addition, the root cause analysis will need to determine if a CAPA plan is required. Not all problems or errors are both systemic and significant. You don’t want to institute a system of “Death by CAPA” by initiating a CAPA plan for each error that occurs. People make mistakes and a quality system should focus on the errors that matter. Sometimes you will see a “CAPA” that merely restates the error and then the ubiquitous note to file saying “retrained study coordinator.” This is not an appropriate CAPA plan and not an appropriate corrective action. Here are some points to include in a CAPA investigation:

= There can be multiple root causes- Always Look at Two Possible Root Causes

= “Always look at the raw data.” If you are not looking at original documents, then you are missing something of importance

= Why, why, why, why, why The “five why’s” of CAPA. Drill down to find the root cause.

= The “root cause” is not restating the error.

= PICCC: Problem, Investigate, Comparison, Clues, Cause

CAPA clinical trials

Problem Solving in Clinical Trials

PICCC is a useful tool in a root cause analysis. What does “comparison” mean? It means to compare the problem across protocols and across clinical sites. If you have the failure to follow a point in the protocol at one site, do other sites have the same problem? If that is the case, the root cause may very well be that the protocol is poorly written, it may need an amendment. The corrective action would not read, “retrained study coordinator on the importance of protocol adherence.” The CAPA plan would look in a different direction, towards the sponsor. The ubiquitous note to file may not be necessary.

There is a wealth of resources on CAPA, root cause analysis, and conducting an investigation. I am including some of those that I used for this post as well as for presentations. There is still a lot to be developed on CAPAs for clinical trials. However, it is clear that regulatory agencies want to know what you have done to investigate clinical problems and what you are doing to prevent them from recurring. In short, they want CAPA plans.

Barb Immel on CAPA Investigations

Essential Components of an Effective CAPA Plan by Jim Colyn

Root Cause Analysis by Edward Dunn, MD

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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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GxP Audit & Risk Management Congress: 20-21 October 2011, Philadelphia, PA. This conference combines both GMP and GCP tracks to maximize the opportunity for cross training, shared best practices, and networking. Two members of the GxP Perspectives LinkedIn group, Janice Wilson and Adi Lampmann, are among the faculty. The conference is sponsored by ExL Pharma and GxP Perspectives is a media partner.
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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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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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TSA Screenings: A Root Cause Analysis of Public Outrage

November 22, 2010

TSA root cause analysis

Is TSA's Lack of Training a Root Cause of Outrage?

In reading reports of the TSA full body screening and aggressive body searches I have read little about training for the transportation security officers, called TSOs. Any good QA specialist would want to conduct a root cause analysis of the outrage that the public is expressing at TSA’s tactics. I have twice been a participant to the “enhanced” screening methods, both times at Boston’s Logan Airport, and noticed that the TSOs seemed to have no training or preparation for the new screening techniques. When the TSOs bark orders at people and fail to use a normal conversational tone, then they are probably going to offend the public. The Wall Street Journal Blog, The Middle Seat Terminal, reports that TSA has been audited by the Department of Homeland Security Inspector General’s Office and cited for numerous training failures. The WSJ Blog states:

“Among the shortcomings that the inspector general found: TSA doesn’t have standard processes to use screener test results, such as “covert testing’’ where government officials try to smuggle weapons through checkpoints, to evaluate and update training programs. On-the-job training is lacking, and TSA doesn’t have uniform steps to “to ensure that officers have the tools and time necessary to complete training requirements,’’ the IG’s report said.

In addition, there aren’t standard procedures for allocating equipment, support and time needed to complete training requirements, either, the report found.”

TSA and DHS need to look into the root cause of the public outrage. Any analysis would point out the training failures. It is one significant reason why the public is expressing outrage at the new screening techniques. Politicians need to note that it isn’t just a question of public safety vs. personal liberty. TSA just isn’t doing a very good job. Those of us who travel to earn a living are seeing it each time we fly.

The Middle Seat Terminal

DHS Report on TSA Training

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Happy Thanksgiving to one and all !!!


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