QUALITY ASSURANCE OF CLINICAL TRIALS A culture of checks and examinations ensuring the quality of clinical trials1 Dr. Bhaswat S. Chakraborty Sr. VP & Chair, R&D Core Committee Cadila Pharmaceuticals Ltd., Ahmedabad
CONTENTS Quality Framework Understanding the critical parameters that need to be taken care of while conducting a trial Developing practical techniques to ensure the incorporation of Quality by Design (QbD) in the design trials Dealing with practical challenges in data capture and documentation design to ensure flawless execution of your clinical trials Case Studies Concluding remarks 3
GCP Good clinical practice (GCP) is a set of internationally recognized ethical and scientific standards for the following aspects of clinical trials: Design Conduct Performance Monitoring Auditing Recording Analysis, and Reporting 5
ICH GCP ◊5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). The aim: providing assurance of protection of the rights, safety and well-being of trial subject; and credibility of CT results Also applicable to CROs, vendors or other delegated service providers However, the sponsor remains responsible for the 6 quality of the trial.
KEY ELEMENTS OF THEQUALITY SYSTEM Documented procedures are developed, implemented and kept up-to-date Training of sponsor personnel as well as of the personnel in affiliates, at CROs and at trial sites Validation of computerised systems Monitoring of trial sites and technical facilities on-site or by using centralised monitoring techniques Data management and quality control Internal and external audits performed by independent auditors 7
WHAT QUALITY & AT WHATCOST? The most pragmatic definition of quality is “fitness for purpose” Simply striving for the “highest level” of quality has little practical meaning Current practices: either success at an [unnecessarily] high cost or failure also very costly A practical & cost effective paradigm: “Adequate quality of a CT should be such that the decisions made would have been no different had the quality of data and information generated been perfect” EMA reflection paper on risk based quality management in clinical trials 8
CURRENT CLINICAL TRIALS(CTS) Current CT design, implementation and oversight Expensive, outmoded and unsustainable in a global, complex trial environment Especially existing monitoring models do not optimally address the most critical risks to trial integrity They rely on frequent, on-site monitoring visits by sponsor personnel Monitoring is only one component of an overall quality framework Trial personnel agree that widespread adoption of an enlightened “quality-by-design” approach to trial planning, conduct, and oversight is needed to ensure trial quality and efficiency Such an approach would apply risk management principles 9 to the design and execution of CTs
THE CURRENT QUALITYCHALLENGE The ongoing challenge in managing the quality of clinical data is to continually monitor data collection procedures and data management practices at every level of the study. This includes: Ensuring that data generated during the study reflect what is specified in the protocol (case report form[CRF] vs. protocol) Comparing data in the CRF and data collected in source documents for accuracy (CRF vs. source documents) Ensuring that the data analyzed are the data recorded in the CRF (database vs. CRF).Quality surveillance continues after the trial has ended and plays an important role in ensuring that: Data presented in tables, listings, and graphs (TLGs) correctly match data in the database (TLGs vs. database) Data reported in the clinical study report (CSR) are the data analyzed (CSR vs. TLGs) All aspects of the data management processes are compliant with SOPs and GCPs. 10
QUALTY BY DESIGN(QBD) QbD is based on 2 basic principles:1. Clinical insight: link between the product and its safety and efficacy in humans and2. Process understanding: link between the drug product and process attributes 11
A RISK BASED QUALITYMANAGEMENT PROCESS FORCTS Initiate Risk IdentificationReview & Assessment Risk Communicatio Risk Control n Implementation 12
RISK BASED QUALITYMANAGEMENT Key idea & practice: Identify, assess, control & mitigate, communicate, and review [both risks & remedies] All risks [low, mid & high grade] associated with the clinical trial during its lifecycle RBQM facilitates better and more informed decision making and makes best use of the available resources Should be appropriately documented and integrated within existing quality systems Responsibility of all involved parties to contribute to the delivery of an effective RBQM 13
RBQM Initiate Information on Systems and Project Risk Identification and Assessment What may go wrong? Chance of occurrence? What would be in particular the impact on trial subjects’ rights/well being/safety and/or on the reliability of the trial results? Risk Control Decision made to reduce and/or accept risks Where risks are to be mitigated, the methodology adapted to conventional GCP should be defined (e.g. intensive, regular or reduced on-site monitoring and/or central monitoring, targeted SDV on primary 14 endpoint variable etc)
RBQM CONTD.. Risk Communication Documentation of Process (e.g., Risk management measures) with reviews of the measures as necessary Communication to all stake holders/decision makers Implementation Putting in place the actions identified, particularly for high risks, but conversely there may be implication on low risks Review Results and new Information (e.g. new pre-clinical data, new safety data, updated Investigator Brochure, Protocol Amendment) and ongoing review (e.g. Data Monitoring Committee Meeting Output, 15 Audit Report concerns)
QUALITY TOLERANCELIMITS Establish the acceptable variation or tolerance limits for the clinical trial procedures involved. Bearing in mind the statistical design of the trial and the potential impact of the different levels of variability on the power of the trial. a) Trial data b) Trial protocol procedures and GCP c) Trial management procedures 16
REPORTING QUALITY RBQM in clinical research revolves around the following cycle: 1. establishment of the priorities (protection of trial subjects and to its scientific objectives) 2. identification of the risks associated with the study 3. setting of the tolerance limits and the documentation of the processes for mitigation of risks associated with the priorities 4. the review of the results and data associated to the risk identified and the documentation of the actions needed A clear qualitative and quantitative way to report on the extent to which a trial has operated within the 17 tolerance limits of an acceptable level of quality
PROPOSEDAPPROACHES Regulatory Submissions and/or Publication sThe key issues of trial and protocol design, data collection, monitoringand data management (both centralised & on-site activities), dataquality tolerances, and record keeping for the study should be 18addressed.
Prioritization and risk mitigation approaches across several dimensions: Protection of trials subjects - Rights and Integrity, Safety Credibility of data and results Stratified according to knowledge of product (MA status) Customized approach depending on: Protocolcomplexity Therapeutic indication and nature of endpoints, including population and co-medications Administration of the product, dose, formulation Complexity of study procedures and measurement, including the nature of the intervention Vulnerability of the study population 19
OPERATIONAL DELIVERABLESOF RBQM Overall QC plan Sampling plan to be used (if applicable) Data source to be used for QC at each operational stage Metrics to be documented Acceptable quality levels Management of compliance with the protocol, SOPs, and GCPs Resolution of system problems prior to the end of the study Reduction of data queries Identification of ways to reduce cycle times for various processes Ensuring data integrity throughout the studys course and that the data collected are the data required by the protocol Ensuring the accuracy and consistency of data from entry into the CRF to final datasets reported in the final CSR Dealing with instances of nonconformity while carrying out clinical trials 20 Delivering an accurate and complete report (final CSR) …
CASE STUDIES 21
CS 1: ASCEND-HF, STUDY DESIGN RCT, Double Blind, in acute Heart Failure (HF) patients 3500 Nesiritide, 3500 Placebo Randomize <48 hours from hospitalization, <24 hours from IV RX for HF Co-Primary Endpoint Dyspnea index at 6/24hrs Co-Primary Endpoint 30-day Death/HF rehospitalization and secondary endpoints All-cause Mortality at 180 days 22
CS 1: ASCEND-HF, BUILDING & DEFININGQUALITY Building Building Establish principles for quality operations/data before trial begins Integrate principles throughout trial operations Communicate expectations to sites and trial teams Implement surveillance plans and provide feedback Adhere to pragmatic principles Efficient, effective (& hopefully economical) Defining Enrolled the right participants according to the protocol with adequate consent? Did participants receive the assigned treatment and did they stay on the treatment? Was there complete ascertainment of primary and secondary efficacy data? Was there complete ascertainment of primary and secondary safety data? 23 Were there any major GCP related issues? Source: Hernandez and Reist (2011), CTTI Workshop Presentation
CS 2: GLOBAL STUDY – BOEHRINGERINGLEHEIM, DESIGN RCT, Double Blind, Outcome trial in respiratory area Total17,000 patients At1,200 sites At 50 countries Over ~3 ½ years duration 1 yr recruitment 2.5 yr follow-up 28 Source: Andy Lawton (2011), CTTI Workshop Presentation
CS 2: GLOBAL STUDY – RBQM Early detection of risks or non-compliance Leads to earlier implementation of actions → Increase quality of trial Structured overview of trial risks on multiple levels Trial / Country / Site Optimised monitoring process Optimised audit strategy Weekly risk report Initially based on “Recruitment” phase factors Now updated for “ongoing” (follow-up) phase Some items dropped / score reduced Essential to form quality feedback loops for issues Use the information that is already available or simple to get 29 Utilize your Meta data!! Source: Andy Lawton (2011), CTTI Workshop Presentation
CONCLUDING REMARKS1. If quality is defined as the absence of errors that matter, the definition needs to be specified for a given trial.2. However, general principles about what really matters in clinical trials can and should be developed.3. A shift to a QbD and RM-based approach across the clinical research enterprise are being promoted.4. Harmonization both within and across regulatory agencies is highly desired.5. Addition of processes on top of existing ones would be regressive rather QbD should transform how things are done in the first place.6. Quality and regulations should act as enablers and not 31 obstacles to innovation.