PREP Course 29 Managing Non-compliance with Good Corrective and Preventive Action Plan

Transcription

1 PREP Course 29 Managing Non-compliance with Good Corrective and Preventive Action Plan Presented by: Evelyn Huang & Leah Shuchter Office of Research Compliance

2 CME Disclosure Statement The North Shore LIJ Health System adheres to the ACCME s new Standards for Commercial Support. Any individuals in a position to control the content of a CME activity, including faculty, planners, and managers, are required to disclose all financial relationships with commercial interests. All identified potential conflicts of interest are thoroughly vetted by the North Shore-LIJ for fair balance and scientific objectivity and to ensure appropriateness of patient care recommendations. Course Director, Kevin Tracey, has disclosed a commercial interest in Setpoint, Inc. as the cofounder, for stock and consulting support. He has resolved his conflicts by identifying a faculty member to conduct content review of this program who has no conflicts. Evelyn and Leah have nothing to disclose

3 Today s Objective To understand how to manage noncompliance issues with good Corrective and Preventive Action Plans

4 Today s Contents What is Non-compliance? What is a CAPA? Why do we need a CAPA for managing noncompliance? How to develop a comprehensive CAPA? Case studies 4

5 Compliance with Regulatory Requirements NSLIJHS Policies Regulatory Committees (IRB/IACUC) State Best Practices Federal Researcher Protocol

6 Compliance & Non-compliance Compliance: Adherence to all the trial-related requirements, good clinical practice requirements, and the applicable regulatory requirements. (Per GCP 1.15) Non-compliance: Failure to follow regulation, institutional policies governing human subject research, or requirements or determinations of the IRB.

7 Compliance Concerns Compliance with protocol, regulations and policies requirements. Protection of subject s rights, safety and welfare. Data Integrity, reliability, and accuracy.

8 Serious / Continuing Non-compliance Serious Non-compliance: Non-compliance that creates an increase in risks to subjects, adversely affects the rights, welfare and safety of the research subjects or adversely affects the scientific integrity of the study. Willful violation of policies and/or federal regulations may also constitute serious non-compliance. Continuing Non-compliance: A pattern of noncompliance that if allowed to continue is likely to increase risk to subjects, adversely affect the rights, welfare and safety of research subjects, or adversely affect the scientific integrity of the study

9 Minor Non-compliance Minor non-compliance: it is neither serious nor continuing. Defined as any behavior, action or omission in the conduct or oversight of research involving human participants that deviates from the approved research plan, federal regulations or institutional policies but, because of its nature, the research project, or subject population ⁸, does or did not: Adversely affect subject s right, safety, and welfare Adversely affect the integrity of study data Increase any harm or immediate hazard to subject Adversely affect subject s willingness to continue participation in the study Please note that when multiple minor non-compliance issues represent a trend, it may be a sign of potential major non-compliance!

10 Non-compliance GCP Perspective¹ ICH E6, 5.20 Noncompliance States: 1. Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, should lead to prompt action by the sponsor to secure compliance 2. If the monitoring and /or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator/ institution s participation in the trial when an investigator/institution s participation is terminated because of noncompliance, the sponsor should notify the regulatory authorities promptly

11 Non-compliance FDA Perspective¹ Links to an enforceable requirement that is not or is inadequately performed by the investigator or delegate: Example: the investigator failed to adequately supervise the study per (regulatory citation, i.e.21cfr312.60). The issue becomes even more significant if: 1. It goes undetected or is not identified in a timely fashion 2. If actions to correct the deficiencies are NOT: Documented Implemented Successful to improve performance(repeat issues arise), or Measured to be effective.

12 Categories of Investigator Noncompliance¹ Based upon inspection data: Failure to follow the investigational plan: noncompliance, protocol deviations, etc Inadequate record keeping: case histories, retention, reports, etc. Inadequate control of investigational product: accountability, dispensing/administration, etc. Inadequate human subject protection: ICF, IRB approvals and reports, etc.

13 What is a Corrective and Preventative Action (CAPA)? A system of quality procedures required to eliminate the causes of an existing noncompliance and to prevent recurrence of noncompliance and other quality problems. 13

14 When is a Comprehensive CAPA Needed For Non-compliance Issues? When serious and/or continuing noncompliance issues occur When multiple minor non-compliance issues indicate/represent a trend

15 Why do We Need a CAPA for Managing Non-Compliance issues? A comprehensive CAPA is the evaluation, investigation, and documentation of any investigator performance that does not meet regulatory requirements It is an important piece of the program quality assurance elements, not a simple action plan or report The CAPA plan is the shared responsibilities of the investigator and the relevant parities when applicable (sponsor, IRB, monitors, etc)¹ So, in managing investigator noncompliance, there is far more to be done than simply reporting a protocol deviation.

16 Formal Corrective/Preventive Action(CAPA)¹ Communication and Documentation are the KEYs for each step! Identify Noncompliance Issue Evaluate the Effectiveness Identify the Root Cause Propose and Implement the Preventive Actions Implement Corrective Actions

17 Step One Identify and Recognize Noncompliance Issue Identify a discrepancy or problem in the conduct of the clinical research study: Through internal quality assurance review conducted by investigator s site/department Through institutional quality assurance review Through external review: sponsor, regulatory agencies, etc. Through subject s complaints Through study service provider s complaints

18 Identifying Non-compliance Issues - Case Linda is a research nurse for quite a few Pediatric Oncology trials(10 active trials in total). She is always busy with interviewing study subjects in the treatment area when they come in for the scheduled study treatments. One day, she has a chance to sit down and review a study s new protocol which was approved by the IRB 1 month ago. She found that the new amendment requests new additional safety lab tests before each study treatment. In the past one month, 5 subjects came in for study treatments without getting the new safety lab tests.

19 Step Two Identify the Root Cause Root cause analysis is an important and difficult process used in CAPA to dig down to the root of the identified issue.¹ Which tool would be helpful for the analysis? The Five Why s

20 The Five Why s⁴ The 5 Why s is a technique used in the Analyze phase of the Six Sigma DMAIC (Define, Measure, Analyze, Improve, Control) methodology. By repeatedly asking the question Why, you can peel away the layers of symptoms which can lead to the root cause of a problem. When is 5 why s most useful? When problems involve human factors or interactions. In day-to-day business life; can be used within or without a Six Sigma project.

21 How to Complete the Five Why s State the identified issue Ask Why five times to get to the root of the issue/problem How to complete the 5 why s?⁴ 1. Write down the specific issue. This helps you formalize and describe it completely. It also helps a team focus on the same issue. 2. Ask questions focused on the specific issues, why the issue happens and write the answer down below the issue. Avoid yes /no questions. Also ask about actions and behaviors actually taken in the past can be most helpful. 3. If the answer you just provided doesn t identify the root cause of the issue that you wrote down in Step 1, ask Why again and write that answer down. 4. Loop back to step 3 until the team is in agreement that the issue s root cause is identified. Again, this may take fewer or more times than five Whys.

22 The Five Why s - Example Why are new safety labs missing for those 5 subjects? Why were the lab staff not aware? Why was the lab order unclear? Why did the research nurse write the uncompleted order? Why was the new protocol requirement for the safety labs not explained to the research nurse?

23 Sample Questions to Consider for Root Cause Analysis Are there adequate and simple guides/tools for the study requirements?¹ Is there adequate resources for the study conduct, such as space, staffing, time, funding, training, and education, etc? Do the PI and his/her research team clearly understand their responsibilities of study conduct? Do the PI and his/her research team receive adequate and appropriate support and guidance from the institution, sponsor and /or monitors?

24 Step Three Implement the Corrective Actions Corrective Actions: Immediate reactive actions to correct/eliminate an issue that has already occurred or has been identified. The actions need to address the identified root cause effectively and timely. Process of the implementation: Propose the action plans and identify the objectives Identify the appropriate responsible personnel for the actions Identify the necessary resources to support the actions (staffing, funding, education, training, etc) Plan a timeframe for the implementation Again, communication and documentation are the keys!

25 Corrective Actions - Case Before the subject s new cycle of chemotherapy, his new safety lab tests were not done. These tests are required per the new approved protocol amendment. What would be your corrective actions plan?

26 Step Four Propose and Implement the Preventive Actions Plan⁵ Preventive Actions: proactive actions taken to eliminate the root cause of a potential issue including the detection/identification of problems. They are actions taken to achieve the long term outcome. It is used when something could go wrong and these are actions taken to stop it from happening, or to stop it from becoming too severe. In order to identify risks that need preventive action, adequate monitoring and controls must be in place in the quality system to assure that potential problems are identified and eliminated before they happen. If something in the quality system indicates that a possible problem may develop, a preventive action must be implemented to avert it and then eliminate the potential situation.

27 Process of Preventive Action Plan Implementation Preventive actions implementation include: Document and record how and why it is identified as a potential issue Propose the future actions Identify and obtain the necessary recourses to support the action plan Identify and delegate the personnel that will be responsible for investigating the issue, taking the actions, and reviewing the implementations Plan the timeframe for the completion of the plan implementation Please note: The records you keep on preventive actions you ve taken, provide evidence that an effective quality system has been implemented and that it is able to anticipate, identify and eliminate potential problems.³

28 Preventive Actions - Case What is the potential issue that you can see from the previous protocol new required safety lab issue? What preventive actions would you propose?

29 The Differences Between the Corrective Actions and Preventive Actions A corrective action is a reaction to a problem that has already occurred. A preventive action is initiated to stop a potential problem from occurring.

30 Step Five Evaluate the Effectiveness⁷ One of the most fundamental steps in the CAPA process is the evaluation and verification of the actions that were taken effectively to address the identified issues. Several key elements for this step: Who is delegated to perform this evaluation and verification and what is the time frame? Have all of the objectives of this CAPA been met? (Did the actions correct or prevent the issue and are there assurances that the same situation will not happen again?) Have all recommended changes been completed and verified. Has appropriate communications and training been implemented to assure that all relevant research personnel understand the issue and actions that have been implemented? Is there any chance that the actions taken may have had any additional adverse effect on the issue, or any possible actions may have addressed the issue more appropriately or effectively?

31 Evaluate Effectiveness - Case Regarding the previous discussed protocol new required safety lab test issue, what is your plan for evaluating the effectiveness of corrective and preventive actions?

32 Guidelines for CAPA Please go to the ORC website and download the CAPA guidelines and template. 32

33 Case study FDA warning letter to a PI managing an IDE study at an academic medical center May 2012 noted: 1. Failure to ensure that informed consent was obtained in accordance with 21 CFR Part 50 [21 CFR 50.25(a)(2) and ]. In your February 2012, response letter, pg. 2, Corrective action for Observation 1a, you stated that, despite obtaining IRB approval for these changes to the ICD, the study coordinator failed to use the updated versions when consenting subjects. You indicated that you will consent subjects enrolled in the future with the correct version of the ICD. Your response is inadequate in that you do not fully explain your procedure for ensuring that site staff will access the correct ICD version in future situations. Please provide a description of this procedure and documentation of staff training on the procedure. 33

34 Case study 2. Failure to maintain accurate, complete, and current records relating to each subject s case history and all relevant observations, including records showing the dates and reasons for each deviation from the protocol [21 CFR (a)(3) and (a)(4)]. Using inaccurate or incomplete screening data to enroll subjects and failing to receive approval from personal physicians prior to subjects study participation may prevent you from making informed decisions regarding the appropriate inclusion of study subjects. These practices may also jeopardize study completion and the safe participation of subjects. Furthermore, failure to maintain accurate, complete, and current records, including the rationale for the protocol deviations, could jeopardize the integrity and reliability of study data. 34

35 Tips: 1. Follow the 5 steps 2. Use the CAPA template Case Study What does FDA expect in Corrective Action Plans? ⁶ Evaluation of the extent of the problem Assessment of the root cause Any corrective actions: plan to correct, implementation detail, training etc. Supporting documentation Preventive actions to prevent recurrence Assessment of the correction

36 Thank You! Contact Us for Questions Research Compliance General: (516) Website: 36

37 References: 1. Karen Gilbert, Root cause analysis and CAPA planning at investigating sites, clinical monitoring summit, Boston, June, Dianne Gobin, 20 Ideas for Managing CAPA and the Inspectional Process, 6 th annual FDA inspection summits, Bethesda, October, FDA CAPA guidance, Tonya White-Salters, Corrective and preventive actions a five steps approach, Avicia 7. Preventive / corrective ations (CAPA) guidelines, R.M. Baldwin, INC,