It s All About The RISK

Transcription

1 Session Q 2: esource Document Verification A Case for CRF Mapping Glenda Guest It s All About The RISK What are some of the realized risks that auditors are observing? Multiple sources, how to ensure consistency in resolving true source Electronic Health Record (EHR) limitations and complexity of systems Sponsor provided or site developed source document worksheets (SDW) which duplicate data in the EHR Shadow Charts Tiers of access for Source Document Verification (SDV): monitors get little or none, auditors may have greater access and Regulatory Authorities nearly always granted additional access if requested. Missed adverse events, etc. Group Reality Check SITE REPRESENTATIVES: How many different sources would you expect to need to review to identify AE and SAE information at your site? SPONSOR REPRESENTATIVES: How many different sources do you typically need to review at a single site to identify AE and SAE information for your studies? SITE REPRESENTATIVES: If blood pressure is recorded in the EMR, but has also been recorded on a Source Document Worksheet and they do not match, which is the proper data point to record? SPONSOR REPRESENTATIVES: How would you answer the same question? 2 3

2 Concerning Observations: Case Example Quality Systems Approaches to Clinical Research Large, reputable, very active East Coast University setting Cardiac Medical Device Study The ideal situation: Monitors WERE provided direct access to consented subject data in a read only format As an auditor, I was also granted such access Mental Health event discovered Site Reaction? What is your reaction? Is this new? Global Harmonization and changing expectations GCP E6(R2) now requires Sponsors implement Quality and Risk Management Systems for clinical research This is NOT new to me! We ve been advocating application of Quality System concepts to research for well over a decade. Many companies, leaders in research best practices have been working to implement Quality Systems into their clinical projects Let s talk Quality Systems Setting the Stage What is Quality in a Clinical Research Setting? 4 5 6

3 What Is Quality? (US FDA) What Quality is Not! Quality Requires Discipline: It s a take and give relationship Quality in clinical trials = the absence of errors that matter * What errors matter? those that impact: subject safety interpretation of results * FDA Presentation at DIA Latin America Conference of Clinical Research Sao Paulo, Brazil, October 22, 2013 Quality is never an accident. It is always the result of intelligent effort. John Ruskin It takes time It takes planning It takes team work It takes active oversight It saves time in the long run Some of the planning can be repurposed for other studies/programs It builds teams It improves performance 7 8 9

4 ICH E6(R2): ALL NEW! QUALITY MANAGEMENT SYSTEM REQUIRMENTS This is listed under the Sponsor responsibilities. The Quality Assurance and Quality control expectations remain, but the addition of a system, using risk based approaches is new. Encompasses all aspects: protocol and CRF, tools, procedures, data collection and processing, and collection of information essential to decision making. The document reminds us that the expectation is that risk based approaches will be implemented and that we should focus on areas with the potential to effect human subject protections and reliability of the data ICH E6(R2): SPONSOR QUALITY MANAGEMENT SYSTEM REQUIREMENTS Critical Process and Data Identification Risk identification Risk evaluation Risk control Risk communication Risk review Risk reporting What is a Quality Management System (QMS)? A QMS consists of the organizational structure, responsibilities, procedures, processes, and resources for implementing quality management NOTE: 21 CFR Part 820 is the FDA Quality System Regulation, applicable to manufacturing. However, the concepts are applicable to quality performance in clinical research as well. You may find it insightful to read this regulation and/or talk with your manufacturing colleagues about QS Management

5 Clinical Quality Management System (QMS) Who Bears the Responsibility for Quality? How is Quality Achieved? Ensure the following are in place In addition to quality management, by applying Defined organizational structure List of responsibilities and assigned persons/groups Effective procedures Documented processes Adequate resources Quality Control & Quality Assurance

6 Quality Control (QC) vs Quality Assurance (QA) Quality Control Quality Assurance Quality Control (QC): A process for maintaining proper standards (actions taken to ensure conformity of output) Quality Assurance (QA): Systematic assessment to maximize the probability that minimum standards of quality are being attained (actions taken to assess conformity and address non conformity) QC process components Include elements such as controls, job management, defined and wellmanaged processes, performance and integrity criteria, and identification of records Supports competence, such as knowledge, skills, experience, and qualifications Promotes personnel integrity, confidence, organizational culture, motivation, team spirit, and quality relationships Assessing the effectiveness of your QC activities Addressing nonconformities Examples of external QA standards Country specific regulations Accepted guidelines/standards ISO Standards ANSI /AAMI standards

7 What is Quality by Design (QbD)? What is Quality by Design (QbD)? Quality by Design (QbD) What is QbD all about? Quality by design means designing and developing a product and associated [manufacturing] processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the [manufacturing] process. FDA is embracing and encouraging implementation of Quality by Design and Risk Management into all aspects of product development, including clinical studies. International expectations moving in this direction, as we see with E6(R2) Quality by design means designing and developing a product and associated [manufacturing] processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the [manufacturing] process. FDA is embracing and encouraging implementation of Quality by Design and Risk Management into all aspects of product development, including clinical studies. Source: ICH-Q8 Pharmaceutical Development Source: ICH-Q8 Pharmaceutical Development 20 21

8 Build quality into every step; FDA Recommends (sponsors and sites) Evaluate the process at every stage in the data lifecycle; Ensure accurate, complete, and current data at every stage in the data lifecycle; and Develop and implement corrective and preventive action (CAPA) plans to ensure quality data. Elements of a Quality Clinical Study Scientifically valid and ethically sound experimental design Adequate protection of subjects rights, safety, and welfare Qualified personnel Proper monitoring Essential data current, complete, and accurate How Does This Apply to Me? Quality Data: Protocol and Data Optimization Source: Source:

9 What are Source Documents? Hospital records Accountability records Clinic and office charts Automated instrument data Laboratory reports Microfilm or magnetic Memoranda media Subjects diaries X rays Evaluation checklists Subject files Informed Consent documentation The Elements of Quality Data Whether your data are paper or electronic, the FDA ALCOA and ICH ALCOA + C principle applies: Attributable Legible Contemporaneous Original Accurate E6(R2) adds Complete FDA Suggestions for a Quality Study: Regulations and Beyond * Select qualified investigators Assure protocol & data requirements optimized Provide adequate training Stress importance of informed consent process Ensure proper monitoring Ensure investigator compliance Ensure all contracted 3 rd parties comply with the appropriate regulations NOTE: ICH E6(R2) requires Sponsors to oversee the Vendors provided via their CROs *Building Quality Into Clinical Trials: An FDA Perspective, Jean Toth Allen, SQA Conference, May 3,

10 Optimizing the Protocol Appropriate investigator input prior to finalization Inclusion/exclusion criteria appropriate and not unnecessarily restrictive Timing of procedures clinically appropriate Testing, initially and at follow up visits, appropriate to the study endpoints INTERACTIONS UP FRONT CAN AVOID COSTLY PROTOCOL DEVIATIONS Optimizing the Dataset Errors happen! minimize impact by collecting only essential data relevant and critical to safety and effectiveness endpoints meet all guidance recommendations, where applicable captured via checklists, limited to numbers, and/or to a few descriptive words less can be more avoid duplicate copies dialogue with FDA review division where appropriate Resources for this discussion ICH E6(R2) FDA Guidance: esource in Clinical Investigations European Union Reflection Paper: Expectations for esource Data CDISC Paper: Electronic Source Data These references are available along with this presentation on the Meeting website. Source: Source:

11 Map the CRF to your existing sources Ideas About Optimizing Source Data Identify study specific data that is NOT routinely captured in your sources Create Source Data Worksheets ONLY FOR DATA NOT ROUTINELY CAPTURED IN YOUR SOURCE Don t duplicate / transcribe data more than necessary If you use sites with EMRs that cannot appropriately provide monitors/auditors/regulatory authorities direct access, you should have a procedure that can be verified as reliable in order to expect anyone to accept your copies instead of the true source. Why is CDISC Part of This Discussion? FDA (specifically CDRH) is moving to require implementation of Data Standards, and CDISC is a major player. CDRH encourages manufacturers to use data and terminology standards in pre market submissions and post market reports for medical devices. The FDA can review and analyze data and information more quickly when manufacturers and user facilities have used our standards. Definitions and links to additional resources for using the FDA s data and terminology standards for the preparation of pre and post market submissions is available here: Process Validation: Certified Copies ICH E6(R2) could have stated it more strongly, but only hints at the need 1.63 Certified Copy A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original

12 Process Validation: Certified Copies The European Medicines Agency (EMA) is more clear: Accurate and complete copies for certification should include the meaning of the data (e.g. date formats, context, layout, electronic signature and authorisations), as well as the full audit trail. The investigator site should have the ability of reviewing the data and generate copies. Where certified copies are made the process for certification should be described, including the process for ensuring that the copy is complete and accurate and for identifying the certifying party and their authority for making that copy. The process of making a certified copy needs to be validated. PROCESS for Creating Copies of EMR? Simply having someone sign/date that a copy is certified is insufficient assurance of the acceptability of a copy when direct access to source cannot be granted. FDA representatives have encouraged adoption of Quality Management Approaches to this challenge. There should be a written procedure Individuals should be trained to the procedure (retain documentation of this training) Sponsor should verify the process results in reliable output If not, sponsor should not accept copies of the source GREAT! First Hurdle Passed We have access more reliable source. BUT: we still have issues with multiple source, restrictions on certain sensitive areas of EHRs, and the like.what is one to do?

13 CRF Mapping May be Beneficial DATA Standards and FDA True esource and Mapping for CDISC/CDASH Performed EARLY Requires a good near final version of the CRF Requires TIME up front Tell me some of the benefits you can see from this approach Clearly defined procedures (permits training, enhances performance) Consistency (CRA/CRC changes, multiple source management, change control) Potentially SAVES time ($$$) at the back end Clinical Trial Data: CDRH does not require the use of a specific format for clinical trial data. CDRH accepts clinical trial data in any format, including the following standardized formats. These formats were developed by the Clinical Data Interchange Standards Consortium (CDISC): Clinical Data Acquisition Standards Harmonization (CDASH) Provides standardized fields to aid data collection at clinical investigative sites. Study Data Tabulation Model (SDTM) Provides a standardized model for clinical study data tabulations. Analysis Dataset Model (ADaM) Provides a standardized model for dataset analysis. In order to realize the benefits of big data and standardization of terminology mapping will be needed for validation purposes What do I mean by that? Automated population of study databases Global safety oversight improvements Others? So, mapping will be necessary. Why continue to accept what the sites provide rather than taking control of the process, planning collaboratively and standardizing for im0roved quality control and assurance?

14 In Summary Quality requires planning and oversight We ALL play a critical role, even when no one is looking Global expectations for Quality Systems and Risk Management are harmonizing Optimizing the Data Set and Source Data should help improve quality data ALCOA +C is expected for source documents, whether hard copy or electronic CRF Mapping may contribute to higher quality data, and more efficient data related operations (SDV, queries, re work, process documentation) Glenda Guest, CCRA, RQAP-GCP Vice President Norwich Clinical Research Associates (NCRA) GMG@NCRA.COM Contact Information: