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


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).

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.

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, 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.

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.

Informed Consent: Questions on New FDA Requirement

February 13, 2011

FDA Requirements Informed Consent Questions

FDA Has New Requirements for Informed Consent

FDA has implemented a new informed consent requirement by updating their informed consent regulations (21 CFR Part 50). The principle of informed consent has been a central ethical factor for efforts to protect participants in clinical trials since the aftermath of World War II. This Guest Commentary by Steven Steinbrueck discusses the new FDA requirement and asks some basic questions about informed consent. I think they are questions well worth asking. What works and what doesn’t work in the informed consent process? Are informed consent forms understandable? Do research participants understand the concepts of the research? Are the right questions being asked? The new FDA regulation is copied at the bottom of Steven’s commentary.

Guest Commentary by Steven Steinbrueck

I was prompted to write by two things—a nice invitation from Carl and the soon to be implemented change to the informed consent regulations. As most of us are aware, there will be a new element required for those clinical studies subject to 21 CFR 50.25; notification that results of the trial will be published in

Although I have very little against this requirement, I do find it interesting that the first substantial change in informed consent regulations in quite some time, while logical and required by FDAAA 2007, adds little to help potential research subjects make an informed risk assessment regarding the advisability of participating in a clinical trial.

I think we should stop and think about what we believe, and what we know, about informed consent.

Fundamentally, we believe that human research requires voluntary consent by the participant and that this consent may only be legitimately sought following the provision of required information. Without such consent, human research is thought to be unethical. We can all point to multiple publicized instances where this widely accepted tenet has been ignored.

informed consent questions

The Nuremberg Code was Adopted After the World War II Nuremberg Trials

More than 60 years ago, the Nuremburg Code began with the exhortation that “…voluntary consent is absolutely essential;” the guilt of the physicians on trial began with consent issues. We find similar and more detailed guidance in Belmont, Helsinki and ICH. Most countries have codified their requirements in multiple laws and regulation. In the US, these requirements are primarily found in 21 CFR 50.25 and 45 CFR 46, the so-called Common Rule.

I doubt that we have much argument about the fundamental requirement for truly informed consent, or even its major topics. So, what am I even talking about?

But, what do we know? Essentially, that a large portion of research participants do not understand one or more important concepts about the research they are involved in. Many researchers have documented what has been called therapeutic misconception, therapeutic optimism, and even therapeutic nihilism on the part of both participants and researchers. Although percentages vary between 40 and 70+%, we are aware that we have not fulfilled the obligation to ensure that the information provided is not only complete, that it contains all elements required by regulation or guidance, but also that the volunteer comprehends the information provided—prior to their participation.

Although compliance is necessary, it is insufficient. We must do something about the incomprehensibility of many consent forms. They must be shorter and the time between presentation of the information and consent must be longer. Additional information, including HIPAA authorizations and lengthy explanations of alternative treatments and non-experimental procedures must be provided in separate documents. And finally, we must routinely assess understanding before and during the trial. For, to enroll someone who does not understand, is to enroll someone who has not truly been given the opportunity “to decide what shall o r shall not happen to them.” And that is simply against our collective beliefs.

Steven Steinbrueck, MPH
Stonebridge Consulting


“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, 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.”


MHRA and Clinical Trials– Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

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DTC Drug Ads: A Common Sense Solution

February 10, 2011

DTC drug ads common sense approach

Should Congress Pass New Legislation on DTC Drug Ads?

One of the most controversial developments in the pharmaceutical industry in recent years was the approval of direct-to-consumer (DTC) ads that began popping up in 1997. Multi-colored butterflies helping promote sleeping pills didn’t seem to many to be in the best interests of public health. Drug companies have responded by saying that the DTC drug ads helped with patient education. Critics such as Marcia Angell, the former editor of the New England Journal of Medicine, has sharply disputed the drug companies claim about DTC ads. Her book, “The Truth About Drug Companies” is a must read for people interested in the pharmaceutical industry.

In todays New York Times we have an op-ed article that proposes what to me is a common sense solution. Ian D. Spatz, a former pharmaceutical company executive, writes that DTC ads also hurt drug companies and a solution to the issue is necessary. He proposes that Congress pass legislation that would alter the content and intent of DTC drug ads:

A more effective way to limit the ads would be for Congress to pass legislation that would allow drug companies to cooperate with one another, and with physician and patient organizations, to develop joint ad campaigns that are specific to certain diseases and conditions but not to any particular drug. These ads would inform consumers about the disease; its treatment options, including pharmaceuticals; and how to gain further information not biased toward any particular brand.”

An interesting approach and one, that I think, should be considered.

NY Times: Better Drug Ads, Fewer Side Effects

The Truth About Drug Companies, by Marcia Angell


On the Blogroll: Diabetes Self Management, well organized and informative


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MHRA and Clinical Trials– Read about the Academy of Medical Research Report by Nick Taylor in Outsourcing-Pharma

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