CRP 112 Lecture 4 Flashcards
TransCelerate
-Non-profit
-Goal to improve health of people around the world by simplifying & accelerating R&D of innovative new therapies
-identify, prioritize, design
implementation of solutions for efficient, effective and high-quality delivery of new medicines worldwide
Has own cQMS (clinical quality management system) initiatives
Shared investigator platform
Clinical Research Awareness and Access
Comparator network
QMS
In pharma manufacturing
Standardized
ICH Q10: Pharmaceutical Quality System
ICH Q9: Quality Risk Management
In clinical
Fragmented
No industry wide conceptual framework for
clinical QM
ICH Q10: Pharmaceutical Quality System objectives
- Achieve product realisation
Product is delivered to meet patient needs - Establish & Maintain a State of Control
Continued suitability & capability of processes – risk mgt - Facilitate Continual Improvement
Use quality risk management
ICH Q10
-For systems supporting development & manufacture of
- Pharmaceutical drug substance (API)
- Drug products, including biotechnology & biological products
-Applies throughout product lifecycle (development, tech transfer between development and manufacturing, commercial manufacturing, product discontinuation)
ICH Q10 Management
Responsibility
Management commitment
Quality policy & quality planning
Resource management
Internal communication
Management review
Management of outsourced activities & purchased materials
Management of change in product ownership
CAPA
Change Management System
Management review of process
performance & product quality
ICH Q10 Product Quality
Monitoring
Monitoring system to ensure state of control is
maintained
Process performance & QMS
Use quality risk management (ICH Q9)
Provide tools to measure & analyze
Analyze parameters & attributes
Provide feedback on product quality
ICH Integration: Q8, Q9, Q10
Q8 Pharmaceutical Development
Q9 Quality Risk Management
Q10 Pharmaceutical Quality Systems
Together they encompass:
Quality by Design, Risk Management & Product Quality System
ICH Q9: Quality Risk Management principles
2 primary principles
Base risk evaluation on scientific knowledge & link
to patient protection
Effort, formality & documentation is based on level of risk
ICH Q9(R1): Risk Assessment
Hazard ID
Risk Analysis (likelihood and severity of consequences)
Risk Evaluation
ICH Q9(R1): Risk Control
Reduce or accept risks
Effort to reduce risk must be proportional to significance of risk
ICH Q9(R1): Risk Communication
Sharing information about risk & risk
management
Occurs at any stage of process
Output/result of quality risk management
process should be communicated AND
documented
ICH Q9(R1): Risk Review
Review output/results to take into account new knowledge and experience
Once initiated, continue for events that might impact original quality risk
management decision
Planned or unplanned events
cQMS Definition
- Currently no cQMS guidance
Integrated approach for an organization to systematically:
Define quality objectives taking into account both strategic objectives & regulatory requirements
Develop & Implement infrastructure
Advantages of a cQMS
Sites:
By focusing on “errors that matter”, it decreases burden and streamlines the processes
Sponsors:
Fewer delays due to reduced remediation associated with quality issues
Better ability to solve repetitive quality issues
Regulators:
Gives them consistent quality framework to evaluate, especially during inspections
Participants:
Increased participant safety
Focus on “errors that matter” to well being & safety of participants
Foundational aspects of a cQMS (4)
-Understanding the Context
-Leadership Commitment to Quality
-Organizational Commitment to Quality
-Continuous Improvement of clinical QMS
cQMS Understanding the Context
- Evaluate external & internal environments
- Political, economic, social, regulations,
market structures, trial designs etc. - Internal governance, organizational
structure, roles, policies, culture,
corporate knowledge etc.
cQMS Leadership Commitment to Quality
Sr. management is accountable & responsible for defining expectations for quality AND communicating the importance of quality
Each employee should understand how quality applies to them & other stakeholders
cQMS Organizational Commitment to Quality
Sr management needs to cultivate an
environment where everyone takes ownership of quality and holds themselves and others accountable for quality
Organization should empower individuals to
address quality concerns without fear of reprisal
cQMS Continuous Improvement of clinical QM
Organization monitors internal/external context for changes that might necessitate modification of the QMS
Leverage outputs from knowledge management activities
Conduct internal audits
Ensure appropriate change management is used
Elements of a cQMS (7)
-Processes
-Resources, Roles, Responsibilities
-Partnering
-Risk Management
-Issue Management
-Knowledge Management (KM)
-Documentation
cQMS Processes
Well defined and characterized
Develop clear/concise documents (e.g. SOPs)
-Instill Knowledge Management Activities (identify changes that mean re-evaluation of
processes & associated documents)
Consider burden of implementation
Determine which processes/documents mandatory, which are best practices
Training
cQMS Resources, Roles, Responsibilities
Prospectively evaluate required resources & skill-
sets to achieve clinical strategy
Ensure appropriate resources are available
Ensure clarity in roles, responsibilities &accountability
All staff to be qualified (education, training, experience)
cQMS Partnering
Co-development and outsourcing (i.e. Sponsor and CRO agreement)
Prospectively consider for all parties:
Needs
Expectations
Limitations
Risks
Ownership must be taken by each party
Prospectively document agreement on:
Expectations for how activities are conducted
Communications (including escalations)
Performance measurement
cQMS Risk Management
Types of Risk
Strategic (Licensing opportunities, partnership benefits)
Operational (IP productions)
Quality (Endpoint criteria, data credibility)
Compliance (Regulatory requirements for registrations)
“Plan Do Check Act” (PDCA) cycle
referred to in ISO 31000 – Risk Management
-policy and government
-program design
-implementation
-monitoring and review
-continual improvement
ISO 31000 – Risk Management
Helps account for unexpected when managing risk
Will identify & analyze risks in organizational context
-Active communication, process eval, oversight
Clinical trial context Significant risks
Participant safety
Data integrity
Regulatory compliance
Trust in organization
Risk Management Process
- Understanding the context
-Identify changes (Internal and External) that might create risks - Risk Assessment
-ID, analyze (level), evaluate (likelihood, impact, effectiveness of existing mititgations) - Risk Mitigation
-ID actions to address the risk (accept, avoid, transfer or reduce) - Risk Monitoring and Review
-Did actions achieve desired outcome?
-Periodically assess changes in internal or external context - Communication and Consultation
-Include all stakeholders
-Include regulatory authorities when applicable
-Occurs at all stages of process
cQMS Issue Management
Issues that Matter
Supports effective CAPA process
Issue documentation & investigation
Trending and Analytics
cQMS Knowledge Management (KM)
Getting right information to right people at the right time
Ensure key prior knowledge is accessible to entire team
Types of knowledge:
Explicit
Visible – easily recognized,
shared, documented & assessed
Tacit
Experience of team members
Goal is to collaborate and communicate – exchange
and maintain knowledge
cQMS Documentation
Level of documentation Commensurate with risk level, significance of activity and meeting stakeholder requirements
-Supports the achievement of Quality
ACRO QMS
-building on TransCelerate
-Sourcing models: Fully Outsourced, Internalized Model (Sponsor has direct visibility into activities), or Hybrid Approach (Shared environment aka Functional Service Provider (FSP) Relationship)
Greater visibility into risk management
process & observations
Removal of emotional decisions
Data driven decisions instead!
Pro-active, collaborative oversight model
ACRO QMS Components
Knowledge Management
Risk Management
ID & mitigate risks that impact the 2 things+1!
Participant safety
Data quality & integrity
Plus regulatory compliance
Issue Management, Focus on Issues that Matter
Roles & Responsibilities
Technology
Quality Metrics (Key Risk Indicators (KRIs), Quality Tolerant Limits (QTLs), Key Performance Indicators (KPIs))
Policies/Procedures for CRO
Building Quality into Clinical Trials
Quality cannot be monitored, audited, or inspected
retrospectively
At the trial level, the protocol – or
investigational plan - is the blueprint for quality
ICH
International Council for Harmonisation
ICH E6(R3)
Designing quality in clinical trials
Stakeholder engagement
Trial design
Proportionate trial management
Focus on factors critical to quality
of trials
-new study designs, conduct, technologies and data sources
ICH E8(R1) - designing quality into clinical studies
ICH E6(R3) Step 3 Stages
Stage I - Regional regulatory consultation
Stage II - Discussion of regional consultation comments
Stage III - Finalisation of Step 3 Experts Draft Guideline
ICH E6(R3) Principles
Guideline is intended to be media neutral to enable use of
different technologies
- encourages thoughtful consideration & planning to address aspects of CTs to ensure trial quality
-Digital health technologies
-variety of relevant data sources
-Keep clinical trial conduct in line with advancing science &
technological developments
-Adapt use of technology to fit participant characteristics &
particular trial design
-Quality should be built into scientific &
operational design/conduct of CTs
Prospectively manage risks to Critical to Quality
-Computerised systems must be Fit
for Purpose addressing factors Critical to Quality
-Transparency by registration & public posting of results.
ICH E6 (R2) – Quality Risk Management
Quality management includes:
efficient design of clinical trial protocols
data collection & processing tools & procedures
collection of information essential to decision making
Quality management system should use a risk-based approach
Sponsor: Quality Management
Sponsor should implement a system to
manage quality throughout all stages of the trial process, focus on participant protection and reliability of trial results
Quality management includes:
efficient design of clinical trial protocols
data collection & processing tools & procedures
collection of information essential to decision making
-all aspects of trial are
operationally feasible
-Protocols, CRFs, & other operational documents should be clear, concise & consistent
-Quality management system should use a risk-based approach
Risk based approach (7)
-ID critcal processes and data
-ID risks
-risk eval
-risk control
-risk communication
-risk review
-risk reporting
Critical process and data identification
During protocol development, sponsor should
identify those processes & data that are:
critical to assure human participant protection & reliability of study results
Risk identification
Risks should be considered at both:
system level (e.g. standard operating procedures,
computerized systems, personnel) &
clinical trial level (e.g. trial design, data collection &
informed consent process)
Risk evaluation
Identified risks should be evaluated vs.
existing risk controls by considering:
Likelihood of errors occurring
Extent to which such errors would be detect
Impact of errors on human participant protection &
reliability of trial results
Risk control
Sponsor should decide which risks to:
Reduce and/or accept
Approach used to reduce risk to an
acceptable level should be proportionate to significance of risk
Predefined quality tolerance limits should be established
Detection of deviations from predefined quality tolerance limits should trigger an evaluation to determine if action is needed
Risk communication
QM activities should be documented &
communicated to those involved or
affected
facilitate:
risk review & continual improvement during clinical trial execution
Risk review
Sponsor should periodically review risk
control measures to ascertain whether
implemented quality management activities remain effective and relevant
Take into account emerging knowledge & experience
Risk reporting
Sponsor should
-describe quality management approach implemented in trial
- summarize important deviations from predefined quality tolerance limits and remedial actions taken
TransCelerate Risk Assessment and Categorization Tool (RACT)
Provides categories of risk, questions for discussion & considerations specific to risk categories (i.e phase, complexity, population, tech, CRF source, endpoints, IP etc)
RACT considerations
Impact (1-3)
Data integrity, participant safety, GCP compliance
Probability of occurring (1-3)
High, medium or low probability
Detectability (3-1)
Higher detectability is lower risk (easy to detect =1)
