Ensuring Quality of Regulatory Clinical Documents

Transcription

1 Ensuring Quality of Regulatory Clinical Documents Henry Li *, Kim Hanna and Steve Petteway Talecris Biotherapeutics, Research Triangle Park, North Carolina, USA Summary A large number of clinical documents are generated during the clinical stage of drug development. These documents are used to obtain regulatory permission for clinical trial initiation, to execute clinical trials, and eventually to get regulatory approval for new products or indications. The types of clinical documents required are numerous and complex and include study protocols, informed consent forms, investigator brochures, investigational new drug annual reports, and clinical study reports. In addition, clinical documents that summarize clinical study results are part of a new drug application or biological license application. Because clinical documents are critical for drug development and business, they must be of the highest quality. Towards that end, we have developed a comprehensive QC program and implemented a QC step in the clinical document preparation process. This program is process driven with an SOP for QC review and a QC step is formalized in each document-specific SOP. We also applied quality audit principles in the QC review. Independent reviewers perform each QC review using checklists to provide a consistent and objective evaluation of clinical documents. The document author addresses each QC finding and subsequent QC changes are verified. The scope of a QC review is tailored to each document. The QC review is an inherent step of the clinical document preparation process, providing necessary assurance that clinical documents generated are of the highest quality possible. Copyright r 2011 John Wiley & Sons, Ltd. Key Words: quality control; clinical documents; regulatory submission; medical writing; document review Introduction Testing an investigational product in human subjects represents a major milestone in a drug development program. Clinical studies, due to *Correspondence to: Henry Li, Talecris Biotherapeutics, PO Box , 4101 Research Commons, Research Triangle Park, North Carolina 27709, USA. henry.li@talecris.com their nature, are heavily scrutinized by regulatory agencies before their initiation and during their execution. A key aspect of a clinical development program that is often overlooked from the quality perspective is clinical documents. A large number of clinical documents are generated during clinical development to meet regulatory requirements and to guide clinical investigators to conduct clinical trials. In addition, after clinical Copyright r 2011 John Wiley & Sons, Ltd. Qual Assur J 2010; 13,

2 Ensuring Quality of Regulatory Clinical Documents 15 studies are completed, the results are analyzed and summarized in documents that form part of the regulatory submission. Regulatory approval of the investigational product determines whether the drug will become a commercial product, achieving the ultimate success of any drug development program. Because these clinical documents are critical to business, they must be of the highest quality. Ensuring the quality of clinical documents remains a challenge. In this paper, we describe our efforts in designing and implementing a clinical document QC program to ensure document quality. This program covers all regulatory clinical documents and a QC step is an inherent, formalized step in all clinical document preparation processes. We also applied key quality audit principles in QC review. The QC review of clinical documents is carried out by independent reviewers who focus on the evaluation of content validity by checking against source. The document author addresses each QC finding and subsequent QC changes are verified, providing necessary assurance that clinical documents generated are of the highest quality possible. General strategies and practices in developing and implementing a robust QC process for clinical documents are also presented. Clinical documents in new drug development Even though our QC program deals with the documents used for global submissions, for simplicity, in this paper, we use the regulatory submissions in the USA as an example. A schematic diagram depicting key clinical documents that are required from early stage of a clinical development program to the final drug approval is shown in Figure 1. These documents play an important role in moving clinical trials forward from ideas into clinical studies and final approval of a drug or a new indication. The purposes of the major clinical documents are further discussed below (Figure 1). Planning of clinical trials Sponsors usually seek regulatory consultation on a new clinical drug development program before its initiation [1]. To prepare for a pre-investigational new drug (pre-ind) meeting with a regulatory agency to obtain regulatory concurrence on a clinical program, sponsor prepares a regulatory briefing booklet, which should contain a clinical section to discuss potential clinical issues and questions. A concept clinical study protocol outlining key clinical study design and inclusion/ exclusion criteria should also be included in the pre-meeting package as a base for regulatory evaluation and discussion. Initiation of clinical trials Before a clinical trial can be initiated, regulatory approval for testing the investigational product in humans must be obtained. Sponsors Pre-IND regulatory meetings - Clinical sections of briefing booklets - Concept protocol IND Submission - IND Clinical sections - Protocol -IB - Protocol - ICF -IB - SAP NDA / BLA Submission - CTD Module 5 (CSR, ISS & ISE) - CTD Module 2 (Clinical Overview, Summaries) Planning of Clinical Trials Inititation of Clinical Trials IND Approval Execution of Clinical Trials CSRs NDA / BLA Approval - IND Annual Reports Clinical Updates Figure 1. Overview of clinical documents in new drug development. BLA, biological license application; CSR, clinical study report; CTD, common technical document; IB, investigator brochure; ICF, informed consent form; IND, investigational new drug; NDA, new drug application; ISE, integrated summary of efficacy; ISS, integrated summary of safety; SAP, statistical analysis plan Copyright r 2011 John Wiley & Sons, Ltd. Qual Assur J 2010; 13, 14 20

3 16 H. Li et al. are required to submit an IND application [2]. In addition to the required clinical sections in the IND submissions, several key clinical documents have to be prepared which are directly related to conduct of a clinical study: clinical study protocol, investigator brochure (IB) and informed consent form (ICF). These clinical documents must meet regulatory requirements and GCP requirements [2,3]. Execution of clinical trials Regulatory agencies require annual updates of an investigational drug development program. Sponsor prepares and submits IND annual reports that contain the updates of the progress in clinical studies [2]. If a study protocol is amended, the protocol amendment should also be submitted. After completion of clinical trials After clinical studies are completed, the results will be analyzed and summarized in clinical study reports (CSRs) [4] which provide a foundation in a New Drug Application (NDA) or Biological License Application (BLA) to demonstrate the safety and efficacy of a new drug [5,6]. New drug application or biological license application To further demonstrate safety and effectiveness of an investigational product in treatment of an indication, the results from several trials are pooled together for analysis. The results from these analyses are summarized in integrated summary of efficacy (ISE) and integrated summary of safety (ISS) [7]. Increasingly, the regulatory submissions such as NDA and BLA are prepared in the common technical document (CTD) format to allow the same set of the documents to be submitted to multiple regulatory agencies [8]. The clinical documents required by the CTD format are clinical overview and clinical summaries in CTD Module 2 and CSRs, ISE, and ISS in Module 5. Document QC program Importance of for Clinical Documents The goal of clinical documents is to report accurate and relevant data and outline clear, consistent conclusions based on these data to facilitate regulatory review. Regulatory reviewers, as a reader, often have to review a large volume of documents in a short period of time. A poor quality document will hinder regulatory review, resulting in unnecessary questions and response which in turn leads to delay in timeline and waste in resources. For example, during a review of an IND submission, a discrepancy in a definition of a key term confused a regulatory reviewer who questioned the sponsor in the regulatory response why in some places this term meant one thing while in other places, it had a totally different meaning. The sponsor had to spend time and effort to clarify the issue and convince the regulator what was really intended for this term. The content of a clinical document usually undergoes several review cycles before finalization. The specialized experts often focus only on the sections or areas that they are responsible for review. In general, these subject matter expert reviews are not intended or expected to catch every document quality deficiency. On the other hand, a QC review systematically verifies document content against source documents and/or source data to ensure that the results presented are accurate; statements are supported by references cited; and conclusions are consistent with the results. Internal consistency is verified within a document and across relevant documents in the same regulatory submission. Establishment of a clinical document QC program To ensure the quality of clinical documents, we designed and implemented a comprehensive QC program with application of key quality audit principles and approaches to ensure that

4 Ensuring Quality of Regulatory Clinical Documents 17 QC review is robust and effective. The QC program has the following key features: The QC review is an inherent step of the clinical document preparation process to ensure quality and accuracy. This step is managed by the clinical department. The QC program is formalized and there are standard operating procedures (SOPs) to govern the QC practices including review and reporting. All QC reviewers are experienced in quality review of documents, familiar with regulatory clinical documents, and trained on the procedures and standards. QC reviewers are independent and objective. A QC report is prepared for each QC review to document QC findings, QC change incorporation and QC change verification. Document Planning First Draft Final Draft QC Assessment QC Reporting QC Change Incorporation QC Change Verification Planning Completion Clinical document QC process A simplified document preparation process with a detailed description of the QC step is shown in Figure 2. QC Planning At the beginning of a document preparation process, a QC review is captured in the document timeline. The QC manager should be notified on the status of the document during the document preparation process. The QC manager determines the scope of the QC review with the document author and the source documents required, which allows the planning of the necessary resources for the QC project. Since the QC step is the last step before a document becomes final, it is usually crunch time and careful planning is essential to meet the timeline. A QC review consists of multiple sub-steps to ensure all QC findings are addressed: 1. QC Assessment This step is the most time-consuming step of a QC review and is performed by an Final Document Figure 2. QC review in clinical document preparation process independent specialist (i.e. the QC reviewer is not involved in the authoring of the document). This is particularly critical, since the independence of the reviewer will allow him or her to be objective and to not assume anything during a QC review. The author should provide all necessary source documents and source data such as publications, internal reports, CSR tables, listings and figures or graphs. Validity of the results, statements, and conclusions included in a clinical document is always a top priority for a QC reviewer. Another key item is internal consistency. For instance, in a protocol, study procedures described in the protocol text body and the schedule of events table in appendix should be consistent. 2. QC Reporting The goal of this sub-step is to clearly communicate the QC findings in an effective way to the author. We intend to avoid lengthy reports; instead, we employ a parallel

5 18 H. Li et al. reporting system. First, the QC reviewer identifies all QC findings directly in the document. In the marked-up document, the QC reviewer uses several Microsoft Word tools, to highlight errors, add comments or ask questions. This way, even minor items such as missing space, misspelled words, and missed abbreviations can be identified at their exact places in the document. These errors may not be effectively captured and can also be time consuming to describe in a QC report. Second, major QC findings are documented in a QC report and require formal response from the author. To determine possible trends in document errors and improve medical writing, the QC findings are classified into different categories and tabulated for each document. 3. QC Change Incorporation The document author performs this substep. The author will carefully evaluate the QC findings, make necessary changes, and document the actions (check changes made ) in the QC report. If the author determines a QC finding is not appropriate and no change is required, the author should also document the action (check changes not made ) in the QC report with a justification or explanation why a change is not made. 4 QC Change Verification QC reviewer or a third person (not the author) verifies if the QC changes were made and the document author responded to all QC findings including the QC findings annotated in the marked-up document. The QC verification of the major QC changes is documented in the QC report. Completion To ensure all sub-steps of a QC review are conducted following the SOP, the QC manager reviews all relevant documents including completed QC report, marked-up document, revised document and, if everything is in order, signs off on the QC report. This signifies the completion of the QC project and the clinical document is finalized and ready to be submitted for publishing and subsequent submission to regulatory agencies. Application of key quality audit principles in clinical document QC review We applied several key quality audit principles and approaches to create a formalized, independent QC program (Table 1) [9]. Experience with implemented program Initial implementation The two common challenges of initial implementation of a QC program are: 1) internal resources and/or budget for external resourcing to implement QC, and 2) additional time for QC added to the back end of final document production timeline. The key is to create a culture of quality and to ensure that the value of QC in a document is fully understood - document quality outweighs the impact to resources or document production time. Our experience has shown that good planning will minimize any QC time impact given that resourcing can be pre-identified and available as the document content review process is completed. Systematic approach for QC review A QC program should be process driven and supported by multiple SOPs. The QC SOP outlines QC review steps from planning to QC completion, time required for each type of document, and QC documentation requirements. Since various clinical documents have independent SOPs governing their production (i.e. protocol, IB, etc.), QC review is also captured as a step for each clinical document in its document-specific SOP, such as the SOP for protocol preparation. These procedures ensure QC review is always an integrated step of the regulatory clinical document preparation process.

6 Ensuring Quality of Regulatory Clinical Documents 19 Table 1. Applying quality audit principles in a QC program Steps Planning Conduct Quality Audit Principles Audit plan developed and audit scope determined before audit initiation Formalized procedures for the quality audit process Independent examination and evaluation of production Verification of practice and conduct against standards Reporting Documentation and communication of audit findings Corrective Action Follow-up with corrective actions Resource utilization QC QC review with prespecified QC review scope is planned as a step of the clinical document preparation process SOPs are established for the QC review QC reviewers are independent of document authors and provide objective assessments of documents QC reviewers verify validity and accuracy of document content against source documents, source data, standards, references and style guides with a focus on result verification and internal consistency All errors are identified in the document. Major QC findings are summarized in the QC report. Both are submitted to the document author. Corrections and responses from authors to all QC findings are verified before a QC project can be closed. All external (contractual) QC support requires selection of well qualified, experienced and technically competent staff. In our setting, we generally utilize contract QC reviewers to perform large QC projects and employ internal resources for small QC review projects that usually take no more than a day to complete. This arrangement provides, in our case, the best efficiency in document turn round time and cost saving. All QC projects are centrally managed by a QC manager where decisions on internal versus external support are planned. Some companies rely on external resources completely. Other companies have their own internal QC groups. Regardless of the established resource pool, it is critical to achieve consistency and efficiencies across QC projects by following procedures and standard checklists. A comprehensive QC checklist is an integral part of our QC SOP to ensure the QC reviews are both consistent and robust. The QC manager reviews the QC reports to ensure that the consistency and quality of QC project(s) is maintained. Where possible, the QC manager attempts to leverage prior knowledge of a program so the QC projects can be performed more efficiently. For example, if multiple documents are created from portions of a CSR, it may be value added to employ the same QC reviewer who reviewed the CSR across all documents since this QC reviewer is already familiar with the study source documents (tables and listings). Timeline management QC review is often the last step of a document timeline. Sometimes, there are multiple QC review projects ongoing at the same time all with demanding timelines. The key to success is good planning between authors and QC manager to ensure QC resources are available at the right time. Utilization of non-medical writer authors When non-medical writer team members are involved in authoring a clinical document, they may require guidance and assistance on the QC requirements and procedures. As part of clinical document preparation team, the QC program should contain standard communication plan for the QC component and provide necessary coordination in order to implement a timely QC review and completion.

7 20 H. Li et al. Conclusion We have established a comprehensive QC program for regulatory clinical documents that are submitted to regulatory agencies worldwide to obtain approvals for clinical trial initiation or for marketing new drugs. A QC review provides a detailed, independent, objective review of clinical documents, identifying errors and deficiencies in clinical documents and verifying QC change implementation. The QC program consists of formalized procedures so a QC review is an inherent document preparation step for each regulatory clinical document, which provides necessary assurance that the clinical documents generated are of the highest quality possible. References 1. Guidance for Industry IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information. IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information. ww.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm pdf [26 June, 2010]. 2. FDA Code of Federal Regulation Part 312 Investigational New Drug Application. 3. ICH Harmonised Tripartite Guideline E6(R1) Guideline for Good Clinical Practice. 10 June 1996: [26 June, 2010]. 4. ICH Topic E 3 Structure and Content of Clinical Study Reports. ich/013795en.pdf [26 June, 2010]. 5. FDA Code of Federal Regulation Part 314 Applications for FDA Approval to Market a New Drug. 6. FDA Code of Federal Regulation Part 601 Biologics Licensing. 7. Guidance for Industry Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document. Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm pdf [26 June, 2010]. 8. Guidance for Industry M4: Organization of the CTD. Guidances/UCM pdf [26 June, 2010]. 9. Russell, J.P. (ed.). The ASQ Auditing Handbook third edition. American Society for Quality, Quality Press, Milwaukee, 2005.