Feature Article

Developing a Corrective Action Plan
May 2011 Issue

Mary-Tara Roth, RN, MSN, MPH
Author has nothing to disclose with regards to commercial support.

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Introduction

Human subject research can be a complicated undertaking. During or even after the conduct of a protocol, it is not uncommon to find that, for one reason or another, the approved protocol has not been followed. These occurrences or deviations can have a range of possible impacts depending on multiple factors such as the overall risk of the study, and the nature and extent of the deviation(s). Certain deviations could cast doubt on the integrity of the data collected to support the study question; or even worse, possibly harm subjects or increase their risk of harm. Once uncovered, action must be taken to correct the problems and prevent future occurrences. This is commonly referred to as developing and implementing a “Corrective Action Plan (CAP)”. Another term that is used commonly, especially in industry, is “Corrective and Preventive Action (CAPA)”. A strong CAP/CAPA can mean the difference between a study staying open or being put on hold. It is very often the difference between FDA inspection observations that do and do not result in further regulatory action, such as warning letters or more. It’s not easy to get it right, but it’s absolutely imperative to get it right. This article will provide some background about CAPs and CAPAs, provide examples of inadequate corrective actions, and present the steps to developing a strong corrective and preventive action plan.

Some Background

The term CAPA has been around a long time, and actually comes from the manufacturing field. In this context, it’s not a one-time activity, but a systematic approach where processes are in place to review data at multiple steps in the manufacturing process for the purpose of identifying, correcting, and preventing quality issues. A CAPA process is required by the FDA device regulations 21 CFR 820.100. So …. you might ask: “I’m not making devices but conducting a research study. Why does this apply to me?” Well, you can think of the conduct of your study as a “quality system.” When you ensure there is quality at every step, and have a process in place where you identify, correct and prevent future occurrences that may impact the quality of your final “product” (i.e., your data), then the end result is that your study and data is more likely to be of high quality. The CAPA steps listed in the device regulation referenced above are pertinent to any quality system. Thus, these steps and process can be implemented in a “quality system” such as the conduct of a research study. Here at BUMC, we most often hear about CAPs when investigators are asked to submit a CAP along with deviation reports. If your study undergoes an IRB-requested audit and there are findings, you will be asked to develop a CAP. It’s important to know that the CAP you develop will be evaluated based on the steps you put in place to correct and prevent the problem in the future-- not just within your one current study, but your future studies, too. So, CAPA, corrective and preventive action, is a good way to view the process.

CAPs and FDA Warning Letters

FDA investigators are often responsible for auditing processes outside of clinical research that relate to the overall development of a drug or device. For example, they may audit the manufacturing facility of a drug maker or the labs where animal studies are done, where quality systems and CAPA are well-defined within the regulations. It follows that over time, and as the FDA has harmonized its auditing processes, the expectations for what it takes to correct a problem that has been identified on an FDA audit of a clinical study is similar to the process that is expected for these other types of audits. (For a detailed understanding of the FDA audit process for clinical research, you can take a look at the FDA’s Investigations Operations Manual and Regulatory Procedures Manual.) To understand what it takes to develop corrective actions that will satisfy the FDA, it is helpful to look at trends in FDA warning letters that are posted on-line on FDA’s website. Here are three examples of the FDA’s assessment of inadequate corrective actions and why (with bolding added):

  1. “In your response… you acknowledge that a number of procedures were not appropriately followed. You alleged that you misinterpreted the protocol procedures and that you were not given any guidance or clarification from the sponsor … In addition your response concludes with the statement that you have initiated corrective action and retraining of staff. We acknowledge your response. However we are concerned that the response is not adequate to prevent future recurrence of the violation noted above, because you failed to provide the details of your corrective actions and the staff retraining.” (from Simmons, 2/18/2011).
  2. “We acknowledge that you identified the problem and have established certain corrective actions. We also acknowledge that through your corrective actions, you identified and addressed the integrity of the investigational procedures and data in the other clinical investigations in which the terminated research nurse was involved. However, we find that you have not adequately addressed how you will improve your supervision of study staff in the future.” (from Griffin, 3/14/2011)
  3. “We acknowledge that in your written response you stated that you intend to ‘be more vigilant in documentation oversight than in the past.’ However, you did not specify the corrective actions you will take to address these violations or to prevent this type of violation from reoccurring in the future.” (from Horowitz, 3/21/2011)

In fact, a quick analysis of warning letters to clinical investigators written so far in 2011 shows the following trends in deficient plans:

  • No detail regarding the specific corrective actions to be taken to address a particular problem.
  • Insufficient detail as to the proposed corrective actions.
  • Not addressing why a specific problem occurred (and note that there may be multiple causes to some problems).
  • Not addressing the preventive measures that will be taken.
  • Not describing the extent/pervasiveness of the problem (i.e., how many subjects were affected in the current study; and did the problem extend to other studies that used the same processes).
  • Inadequate documentation of the corrective actions taken.
  • Not specifying the timeframe in which corrective actions have been or will be undertaken/completed.

Corrective Actions and OHRP

In addition to knowing how the FDA handles deviations and assesses corrective actions, there is OHRP guidance that also underscores the importance of ensuring that a plan should be developed so that such problems are prevented in the future. OHRP’s “Guidance on Reporting Incidents to OHRP”, May 27, 2005, (see section IV) states: “When reviewing a report of an unanticipated problem, OHRP assesses most closely the adequacy of the actions taken by the institution to address the problem. …. In particular, OHRP assesses whether or not the corrective actions will help ensure that the incident will not happen again, either with the investigator or protocol in question, or with any other investigator or protocol….”

7 Steps to a Successful CAP

In the event that problems are identified in a protocol that you are conducting, either through your own internal quality reviews or via an external audit, you should act on the following steps as soon as you become aware of the problem. These steps comprise your CAP/CAPA, and following them can help you avoid the problems noted above regarding inadequate CAPs:

  1. Report the problem to the IRB, sponsor and to other entities as applicable.
    • Depending on the extent of the problem(s) and their potential to impact the overall risk of the study, your protocol reporting requirements, and your reporting requirements to to the BUMC IRB, you may also need to report to various entities such as the industry sponsor, your NIH institute/center, and/or the FDA (if you are the investigator-sponsor and the study is operating under an IND or IDE that you hold).
    • This may be a process that occurs over time where you update the IRB once you have more information; however, your reporting should happen right away. Don’t wait until you have developed a full CAP to inform the IRB and the sponsor. Per the BUMC IRB policy, deviations should be reported as soon as the PI becomes aware of the deviation. You can report it once you know of the problem, and let the IRB know in your report that your CAP is in development. You can also describe any immediate measures you have taken to address the problem.
  2. Evaluate the extent of the problem.
    • How many subjects does it impact? Was anyone harmed? Was there potential for harm? Could the problem possibly exist in other protocols that use the same processes and staff?
  3. Determine the cause(s) of the problem.
    • Note that especially for systemic problems, there may be multiple levels of causes. It may be relevant to perform a root cause analysis so that appropriate corrective actions can be implemented to address the various contributing causes. Some causes may require involvement of the institution if they lie outside your direct oversight.
  4. If possible, correct the problem as it relates to current subjects.
  5. Develop processes to ensure that the problem is prevented in the future.
    • It helps to document these processes and then, of course, to show through your documentation that your staff has been trained on the processes.
  6. Train staff and others (as applicable) on the new processes.
    • It’s imperative to document the training you have done to correct any deficiencies.
  7. Follow up to ensure that all steps of the CAP are successful.

And don’t forget…

There are a few aspects of CAPS that are commonly missed, but that are ESSENTIAL. One is to adequately document each of the steps you take in your plan. For example, you may have had a great training program to update staff on important (sometimes new) processes, but if you don’t note who attended the training and when it occurred, any future audit of your protocol would likely find your corrective action plan deficient. Your documentation should provide evidence to any future auditor (and to your future staff) as to what processes have been developed or amended, who has been trained and when, and that you have performed quality checks (internal audits) to ensure the plan has been successful. Another important commonly missed aspect of a successful plan is specifying a timeframe on completion of your corrective actions. For example, it’s not enough to state that you will provide training for your staff. You should specify at what point the training of your staff will be completed. Last, adhere to your promises and make sure you do what you say you are going to do! The last thing you want is for a re-audit of your study to take place, only to find that there are steps that haven’t been done which you had promised to put in place to ensure compliance and protections.

Moving forward

Diligent oversight and on-going review and assessment of your own adherence to the protocol will go a long way to preventing problems that can have impacts on your data integrity and subject safety. If such problems are uncovered, it is important to know how to address them and prevent such problems in the future.

If you need to create a CAP, the CRRO can help. Also, the CRRO has specific customizable templates to assist you in documenting staff training and in performing self-assessments in common problem areas (consent, eligibility, protocol compliance).

Quiz

There are no quiz questions this month. Take a few minutes and check where you stand with quizzes that count towards Recertification. You need at least 48 correct answers in your My Account to be recertified to continue doing clinical research at BUMC. Click here for an explanation of who needs to be recertified and how to meet the requirements. If you still have questions, please send them to crtimes@bu.edu.

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