1. Draft White Paper “Protocol Deviations”
Katharina Kurpanek
Regulatory Compliance Consultant
25th Annual
EuroMeeting
4-6 March 2013
RAI, Amsterdam
Netherlands
Good Clinical Practice and Quality Assurance Community

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3. Development of the White Paper Preliminary results Next steps
Protocol Deviations: Avoidable Problem
or Unavoidable Risk to be Managed?
Introduction
Development of the White Paper
Preliminary results
Next steps

4. Problem Statement
Noncompliance with protocol, SOPs, regulations most common finding in audits and regulatory inspections
Global inconsistency in definitions, classification, management and reporting of protocol deviations

5. Collaboration of 21 worldwide industry experts
Deviations White Paper Working Group
DIA GCP & QA Community initiated a Deviations White Paper Working Group in Jan 2012
Collaboration of 21 worldwide industry experts

6. Objective Determine a common definition for protocol deviations
Document the typical life cycle of protocol deviations from detection through reporting
Establish best practices for categorizing and managing protocol deviations
Establish best practices for managing ineligible subjects (prospectively and retrospectively)

7. Development of the White Paper Preliminary results Next steps
Protocol Deviations: Avoidable Problem
or Unavoidable Risk to be Managed?
Introduction
Development of the White Paper
Preliminary results
Next steps

8. Development of the White Paper
Working Group with 21 team members divided in 4 subgroups
Resources used: online sources, publications/ literature, in particular the SACHRP document and the Feb 29, 2012 meeting minutes, industry standards, MOH documents, and individual experience

9. Subgroup Deliverables
Definitions / Terminology
proposed consensus term and definitions
Management of ineligible subjects
background, current practice and suggested best practices
Classification / Categorization
description of alternative categorizations with rationale
Protocol deviation lifecycle
discussion of the life cycle of a PD from detection through reporting

10. Development of the White Paper Preliminary results Next steps
Protocol Deviations: Avoidable Problem
or Unavoidable Risk to be Managed?
Introduction
Development of the White Paper
Preliminary results
Next steps

11. Definitions /Terminology
A protocol deviation is any variation from
the requirements and procedures described in the study protocol and protocol amendments,
Good Clinical Practices (GCP) or other applicable Good Practices (GXPs),
legal and regulatory standards that occurs in relationship to the execution of the clinical trial.
We discourage from defining and using additional terms such as the term protocol violation
Term chosen in accordance with ICH and SACHRP recommendations

12. Protocol Deviation Lifecycle - 1
Best practices for tracking and reporting of PDs:
Creation of a protocol deviation handling plan and training personnel on it prior to the first subject into the study
Real time remote or onsite monitoring of site documents and data
Routine review of the clinical database, monitoring reports and other sources
Classification of deviations prior to database lock prior to any un-blinding
Proper and complete handling in statistical analyses and reporting of critical and major PDs in CSR
Timely reporting of PDs to IRBs/IECs, the sponsor and the regulatory authorities, as required

13. Protocol Deviation Lifecycle - 2
Five levels of detection of Protocol Deviations:
By clinical trial site personnel
By monitor, or DM (if central monitoring used)
By DM, PhV or ClinOps personnel during data validation, SAE follow-up or data review
By QA during audits, by Biostatistics during analyses or by Medical Writing during CSR preparation
By regulatory authorities during inspections

14. Protocol Deviation Lifecycle - 3
CAPA programs:
Definition of an effective CAPA program
Importance of an adequate root cause analysis
Integral part of a risk based QMS
Increasing expectations of regulatory authorities regarding corrective and preventive actions

15. Classification Critical Deviations:
those deviations that have an adverse effect on the rights, safety or well-being of the subjects and/or the quality/integrity of data are considered critical deviations.  Any fraud or misconduct at the sites, irrespective of whether a subject was harmed, is considered critical.
Major Deviations: 
those deviations that may have an adverse effect on the rights, safety or well-being of the subjects and/or the quality/integrity of data. These may include a pattern of deviations classified as minor, poor quality of the data and/or absence of source documents.  
Minor Deviations:
those deviations that do not have a reasonable effect on the rights, safety or well-being of the subjects and/or the quality/integrity of data.

16. Management of Ineligible Subjects
All subjects have to meet the protocol defined eligibility criteria, and prospective “waivers” are not acceptable
Suggested process as soon as the protocol deviation discovered: 
Assess risk level to subject (by the principal investigator, in conjunction with qualified sponsor designee, e.g. medical monitor)
Notify the subject of the deviation and inform about the risks associated with continued participation or withdrawal
Decide about continued participation or withdrawal

17. Overall conclusion
“Although protocol deviations do not appear to be something that can be avoided, it does appear that their impact can be minimized and managed with consistent definitions, adequate training, careful oversight and controls, use of appropriate technology and the implementation of a good CAPA program”

18. Development of the White Paper Preliminary results Next steps
Protocol Deviations: Avoidable Problem
or Unavoidable Risk to be Managed?
Introduction
Development of the White Paper
Preliminary results
Next steps

19. Next steps
An industry wide survey (
Global workshops at DIA meetings
Finalisation of the White Paper
Publication of the White Paper in DIA’s Journal “Therapeutic Innovation & Regulatory Science”
Our goal: White Paper as a reference document for managing (categorizing and reporting) deviations

20. Questions?
Authors:
Leslie M Sam, Eli Lilly and Company, [Corresponding Author]
Sonia Brenner, CQA Solutions, USA
Katharina Kurpanek, Regulatory Compliance Consultant, Belgium
Yvonne McCracken, Carolinas Research Associates, USA
Munish Mehra, Quantum BioPharma, USA
Maryrose Petrizzo, Boston Scientific, USA