clinical qbd best practices when outsourcing
DESCRIPTION
Implementing Quality by Design with Outsourced Partners: Challenges and SolutionsTRANSCRIPT
1
Implementing Quality
By Design with Outsourced Partners:
Challenges and
Solutions
Janis Hall [email protected]
2
● The Avoca Group and Avoca Quality Consor7um (AQC) ● AQC Quality Oversight Framework and Process Oversight ● Quality by Design Best Prac7ces Guideline and Tools ● Terminology and Defini7ons ● Implemen7ng QbD with Outsourced Partners: Challenges ● Industry Status Applying QbD Methods for Clinical Trials ● Implemen7ng QbD with Outsourced Partners: Solu7ons ● Key Messages and Conclusions ● Resources and References list
Topics
Implementing QbD with Outsourced Partners: Challenges and Solutions
3 3
Who is The Avoca Group? • The Avoca Group, Inc., founded in 1999, is a consul7ng and survey
research firm that develops and implements global rela7onship and alliance management programs for biopharmaceu7cal companies and pharmaceu7cal service providers.
The Avoca Group The Avoca Quality Consortium
What is The Avoca Quality Consor8um? • Founded in 2011. Today the Consor7um has over 35 biopharm and CRO
member companies. • Purpose: Help companies op7mize their approaches to proac7ve quality
management with an emphasis on bringing sponsors and CROs into greater alignment.
• Vision: To serve as a catalyst for the accelera7on of best prac7ces and industry standards for proac7ve quality management.
4 4
5
Quality Oversight Framework for Proactive Quality Management
Governance/ Organizational
Construct
Governance
Sourcing Models
Committee Construct
Decision Models
Ctrs of Excellence
Teams/Functions
Quality Units
Issue Escalation
Technical/ Project Oversight
Functional
Project Team
Business
Technology
Process Oversight
Delegated Processes
Shared Processes
QbD Principles
QMP
Process Development/ Improvement
Communication
Communication
Communication Plan
Escalation Plan
Oversight Leadership
Requirements
Leadership
Leadership Styles
Oversight Leadership
Characteristics
Talent Management
Metrics / Analytics /
Technology
Leading Indicators
KPIs
KQIs
Desktop On-Demand
Real Time Accuracy
Roles / Responsibilities
Sponsor Oversight
Sponsor Operations
CRO Oversight
CRO Operations
Proactive Risk / Opportunity
Management
Risk Identification
Risk Management
Opportunity Management
Quality Risk Plans
Timeline Risk Plans
Cost Risk Plans
Recovery or Transition Plans
Governance
Sourcing Models
Committee Construct
Decision Models
Ctrs of Excellence
Teams/Functions
Quality Units
Issue Escalation
Communication
Communication Plan
Escalation Plan
Leadership
Leadership Styles
Oversight Leadership
Characteristics
Talent Management
Governance
Sourcing Models
Committee Construct
Decision Models
Ctrs of Excellence
Teams/Functions
Quality Units
Issue Escalation
Technical/ Project
Oversight
Functional
Project Team
Business
Technology
Process Oversight
Delegated Processes
Shared Processes
QbD Principles
QMP
Process Development/ Improvement
Communication
Communication Plan
Escalation Plan
Leadership
Leadership Styles
Oversight Leadership
Characteristics
Talent Management
Metrics / Analytics /
Technology
Leading Indicators
KPIs
KQIs
Desktop On-Demand
Real Time Accuracy
Roles / Responsibilities
Sponsor Oversight
Sponsor Operations
CRO Oversight
CRO Operations
Proactive Risk /
Opportunity Management
Risk Identification
Risk Management
Opportunity Management
Quality Risk Plans
Timeline Risk Plans
Cost Risk Plans
Recovery or Transition Plans
Governance/ Organizational
Construct
Governance
Sourcing Models
Committee Construct
Decision Models
Ctrs of Excellence
Teams/Functions
Quality Units
Issue Escalation
Communi-cation
Communication
Communication Plan
Escalation Plan
Oversight Leadership
Requirements
Leadership
Leadership Styles
Oversight Leadership
Characteristics
Talent Management
Completed In Development Planned for 2014
Process Selection
6
Best Practices for Proactive Quality Management and Quality Oversight
Process Oversight Guideline • Process Tool-‐1-‐ Elements of Process Oversight • Process Tool-‐4-‐ Quality by Design Principles
• Process Tool-‐1a-‐ Task Ownership Matrix • Process Tool-‐4a-‐ QbD for Pharma GMP Ac8vi8es
• Process Tool-‐1b-‐ Template Task Ownership Matrix • Process Tool-‐4b-‐ QbD for Pharma GCP Ac8vi8es
• Process Tool-‐2-‐ Transfer of Regulatory Obliga8ons • Process Tool-‐4c-‐ Opera8onalizing QbD for Clinical Trials
• Process Tool-‐2a-‐ Template Transfer of Regulatory Obliga8ons • Process Tool-‐4d-‐ QbD Template CTQ Table
• Process Tool-‐3-‐ Process Document Control • Process Tool-‐4e-‐ QbD Template IMP Interven8on Risk
• Process Tool-‐3a-‐ Process Tracking Table • Process Tool-‐4f-‐ QbD Template Design and Methods Risk
• Process Tool-‐3b-‐ Joint Process Development • Process Tool-‐4g-‐ QbD Template FMEA
• Process Tool-‐3c-‐ Six Sigma SIPOC Tool • Process Tool-‐4h-‐ QbD Best Prac8ces when Outsourcing • Process Tool-‐3d-‐ Six Sigma Swim Lane Tool • Process Tool-‐4i-‐ QbD Supplier Risk Assessment • Process Tool-‐3e-‐ Template for Joint Process Documenta8on • Process Tool-‐5-‐ Joint Quality Management Plan
• Process Tool-‐3f-‐ Process Improvement • Process Tool-‐5a-‐ Supplier Assessment Report Template
• Process Tool-‐3g-‐ Lean and Kaizen Events • Process Tool-‐5b-‐ Central Supplier Assessment Tracking Table
• Process Tool-‐3h-‐Root Cause Analysis • Process Tool-‐5c-‐ Project Supplier Tracking
• Process Tool-‐3i-‐Template RCA Fishbone Diagram • Process Tool 5d-‐ Approved Supplier List
• Process Tool-‐3j-‐Sta8s8cal Process Control-‐ Control Chart • Process Tool-‐6-‐ Change Management Best Prac8ces
• Process Tool-‐3k-‐Process Mapping Instruc8ons • Process Tool 6a-‐ Change Management Plan Template
Focus for Presenta7on
Quality by Design Best Prac7ces
7
Quality by Design Terms and Definitions
QbD-‐ is an approach to development that begins with predefined objec7ves and emphasizes product and process understanding and process control, based on sound science and quality risk management (ICH 2009)
Design space-‐ the mul7dimensional combina7on and interac7on of input variables and process parameters that have been demonstrated to provide assurance of quality; when defining a design space, the applicant should keep in mind the type of opera7onal flexibility desired. (ICH Q8 R1)
Cri8cal-‐to-‐Quality (CTQ) is an aXribute of a product or process that has a direct and significant impact on its actual or perceived quality and should be within an appropriate limit, range, or distribu7on to ensure the desired quality (derived from ICH Q8 R1)
8
Quality by Design- Terms and Definitions
RBM (Risk-‐Based Monitoring)-‐ (FDA Aug 2013 Guidance) “monitoring” refers to the methods used by sponsors (or CROs) to oversee the conduct of and repor7ng of data from clinical inves7ga7ons, including appropriate clinical inves7gator supervision of study site staff and third party contractors.
Centralized vs. On-‐site vs. Off-‐site (remote) site monitoring ● Centralized monitoring-‐ A “remote evalua7on carried out by sponsor personnel or representa7ves (e.g. Data Manager, Sta7s7cian, or Monitor)” (FDA Guidance).
● On-‐site Monitoring-‐ An in-‐person evalua7on carried out by sponsor personnel or representa7ve(s) at the site(s) at which the clinical inves7ga7on is being conducted” (FDA Guidance).
● Off-‐site Monitoring-‐ Monitoring ac7vi7es as defined either within process documents or in the monitoring plan that occur away from the study site loca7on (TransCelerate)
9
Quality by Design Terms and Definitions
Source Data Verifica8on (SDV) vs. Source Data Review (SDR) (TransCelerate)
SDV-‐ data within the CRF (or other data collec7on systems) are compared to the original source to confirm that the data were transcribed accurately (i.e. source data vs. data in the CRF)
SDR*-‐ review source documenta7on to check quality of source, review protocol compliance, ensure the Cri7cal Processes and source documenta7on (e.g. accurate, legible, complete, 7mely, dated) are adequate, to ascertain Inves7gator involvement and appropriate delega7on, and assess compliance to other areas (e.g. SOPs, GCP). . . not a comparison of source data against CRF data. . . . necessary to evaluate areas that do not have an associated data field in the CRF or system available for more 7mely remote review.
*Requires cri8cal thinking skills and judgment
10
Implementing QbD with Outsourced Partners: Challenges (1)
New, evolving thinking • Concepts are new and developing • Not established as standard prac7ces • Imbalance of knowledge, experience and acceptance • Concepts not equally mature across clinical trial process • High profile and poten7al for high expecta7ons beyond capabili7es
Stakeholders Engagement/Understanding/Capabili7es • Not all stakeholders are engaged • Sponsor/Supplier/Inves7gators
• Unequal understanding/commitment/involvement with methods development
• Func7onal area and geographic imbalance of understanding
11
Implementing QbD with Outsourced Partners: Challenges (2)
Culture, behaviors and resources • Tradi7onal risk averse behavior-‐ Paradigm shif-‐focus on high risk factors • Staff challenges
• “Hard-‐wired” • Reluctant, unwilling or unable to change • Func7onal area imbalance of knowledge • Poten7al reassignment or removal of resources to fit new needs
• Sponsors/CROs • “Walk the talk” • Demonstrate tolerance of low risk events • Reinforce/reward/recognize adop7on
Contracts • Transparency • Complexity vs. tradi7onal • Flexibility
12
How would you rate your current understanding of QbD processes, as applied to clinical development?
Only approximately half of the respondents stated that they had at least a “good understanding” of QbD processes, as applied to clinical development.
10%
14%
40%
43%
43%
39%
7%
4%
0% 20% 40% 60% 80% 100%
Sponsors
CROs
Very strong understanding Good understanding Fair understanding Poor understanding
N
235
153
Data from 2014 Interim AQC Research
13
How would you rate your company’s current application of QbD principles in clinical development?
CRO respondents were more likely than sponsor respondents to report frequent or consistent application of QbD principles in clinical development, but sponsors
don’t appear to be very aware of CRO’s application of these approaches.
9%
2%
19%
31%
22%
38%
48%
55%
38%
12%
20%
4%
0% 20% 40% 60% 80% 100%
Sponsors re own
companies
Sponsors re their clinical
service providers
CROs
Consistent application Frequent application Inconsistent application Little application
N
228
228
144
Data from 2014 Interim AQC Research
14
On average, how satisfied are you with your own company’s or your counterpart’s implementation of these key practices of quality and
risk management?
Sponsors re own
company
CROs re sponsors
CROs re own company
Sponsors re CROs
N= 231 136 150 218
Quality planning overall 3.5 3.3 3.8 3.0
Quality control overall 3.6 3.4 3.8 3.1
Quality improvement overall 3.5 3.2 3.8 3.0
Use of Failure Mode Effects Analysis (FMEA) methodology 3.1 2.9 3.1 2.7
Proactive risk assessment overall 3.3 3.1 3.7 2.7
Design of training materials, monitoring plan, audit plan, data management plan, taking into account identified risks
3.5 3.3 3.8 3.2
Adaptation of safety monitoring plan according to trial-specific risks 3.6 3.4 3.7 3.3
Adjustment of conventional GCP methods to identified risks (e.g. on-site vs. central monitoring; targeted source document verification)
3.4 3.2 3.7 3.1
Proactive risk mitigation overall 3.3 3.2 3.6 2.8
For QbD-related practices, mean ratings among sponsor and CRO respondents were generally in the neutral to satisfied range, with each group feeling more
positively about its own practices than about its partners’ practices.
Data from 2014 Interim AQC Research
15
Industry Status in Applying QbD Methods
Broad use 15%
New user 19%
Pilot one trial 10%
Establishing infrastructure
29%
No plans to use 8%
Unsure/Don't know 19%
Is your organiza8on applying QbD methods for clinical research and if so, to what degree?
(select one) N=52
Survey data gathered March 21 and 26, 2014 during an Avoca Quality Consor7um Quarterly Webinar: QbD Best Prac7ces
16
Industry Status in Applying QbD Methods
Yes 44%
No 23%
Unsure/Don't know 33%
Has your organiza8on used QbD approaches for assessing protocol risk? (select one) N=48
Survey data gathered March 21 and 26, 2014 during an Avoca Quality Consor7um Quarterly Webinar: QbD Best Prac7ces
17
Industry Status in Applying QbD Methods
0%
10%
20%
30%
40%
50%
60%
70%
80%
Clinical program planning
Protocol design Data collec7on Site monitoring Pharmacovigilance Other Not applying methods yet
Is your organiza8on applying QbD methods to any of these areas? (Check all that apply) N=43
Survey data gathered March 21 and 26, 2014 during an Avoca Quality Consor7um Quarterly Webinar: QbD Best Prac7ces
18
Industry Status in Applying QbD Methods
Internal – culture (risk averse)
10%
Internal-‐ infrastructure (tools/systems)
24%
Internal-‐ skills (right resources/training)
19%
Internal-‐ other 2%
External-‐ inves7gator/site (capabili7es/
knowledge) 5%
External-‐ suppliers (capabili7es/knowledge)
14%
External-‐ other 2%
Not applying QbD methods yet
24%
As a sponsor or CRO organiza8on, when it comes to applying QbD methods, what is your greatest challenge? (select one) N=42
Survey data gathered March 21 and 26, 2014 during an Avoca Quality Consor7um Quarterly Webinar: QbD Best Prac7ces
19
Implementing QbD Approaches with Outsourced Partners
CROs and Sponsors should
1. Assess suppliers for knowledge, experience and exper7se implemen7ng QbD methods
2. Deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
3. Joint collabora7on with partners to ensure appropriate implementa7on of QbD processes
4. Build QbD methodologies into vendor contracts
20
Solutions when Outsourcing: Supplier Expertise Assessment (1)
● Need for transparency since this is a rapidly evolving space
● Balance of knowledge ● CRO has more experience than sponsor ● Sponsor has more experience than CRO ● Level set knowledge and expecta7ons before commiong to working together
1. Assess suppliers for knowledge, experience, exper7se implemen7ng QbD methods
21
Solutions when Outsourcing: Supplier Expertise Assessment (2)
How to assess knowledge, experience, exper7se implemen7ng QbD methods?
● Capabili7es presenta7ons ● Case studies ● Technology ● Training/Resource assignments ● Tools/templates ● Integra7on into their infrastructure
● Expert group par7cipa7on ● Publica7ons/white papers ● Speaking at conferences
1. Assess suppliers for knowledge, experience, exper7se implemen7ng QbD methods
22
Solutions when Outsourcing: Supplier Risk Assessments (1)
2. Sponsors and CROs should deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
Derived from M. Fields, Seaqle Gene7cs presenta7on on protocol complexity Aug
2011-‐ Clinical Quality Oversight Conference
23
Solutions when Outsourcing: Supplier Risk Assessments (2)
2. Sponsors and CROs should deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
iiDerived from K. Sprenger, Pfizer, Oct 2013 CTTI Presenta7on
24
Solutions when Outsourcing: Supplier Risk Assessments (2)
2. Sponsors and CROs should deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
25
Solutions when Outsourcing: Supplier Risk Assessments (2)
2. Sponsors and CROs should deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
26
Solutions when Outsourcing: Supplier Risk Assessments (2)
2. Sponsors and CROs should deploy best prac7ces for conduc7ng supplier risk assessments for outsourced services
27
Solutions when Outsourcing: Joint Collaboration for Implementation (1)
Joint collabora7on with partners to ensure implementa7on of QbD processes ● Seong Expecta7ons ● QbD Roles and Responsibili7es ● QbD across Clinical Trial Process
● Clinical Program ● Study Design/Protocol Development (Process Tools 4e/4f) ● Study Execu7on ● Data Management ● Sta7s7cal Analysis and Repor7ng ● Medical Wri7ng
3. Joint collabora7on with partners to ensure appropriate implementa7on of QbD processes
28
Solutions when Outsourcing: Joint Collaboration for Implementation (2)
Joint collabora7on with partners to ensure implementa7on of QbD processes ● Seong Expecta7ons ● QbD Roles and Responsibili7es ● QbD across Clinical Trial Process
● Clinical Program ● Study Design/Protocol Development (Process Tools 4e/4f) ● Study Execu7on ● Data Management ● Sta7s7cal Analysis and Repor7ng ● Medical Wri7ng
3. Joint collabora7on with partners to ensure appropriate implementa7on of QbD processes
29
Solutions when Outsourcing: Joint Collaboration for Implementation (3)
Joint collabora7on with partners to ensure implementa7on of QbD processes ● Seong Expecta7ons ● QbD Roles and Responsibili7es ● QbD across Clinical Trial Process
● Clinical Program ● Study Design/Protocol Development (Process Tools 4e/4f) ● Study Execu7on ● Data Management ● Sta7s7cal Analysis and Repor7ng ● Medical Wri7ng
3. Joint collabora7on with partners to ensure appropriate implementa7on of QbD processes
30
Solutions when Outsourcing: Build QbD into Contracts (1)
CROs and Sponsors should build QbD methodologies into vendor contracts
● Transparency, complexity, flexibility-‐ document it
● Task ownership matrix
● Statement of Work
● Contract
4. CROs and Sponsors should build QbD methodologies into vendor contracts
31
Solutions when Outsourcing: Build QbD into Contracts (2)
CROs and Sponsors should build QbD methodologies into vendor contracts
● Transparency, complexity, flexibility-‐ document it
● Task ownership matrix (Process Tools 1a/1b)
● Statement of Work
● Contract
4. CROs and Sponsors should build QbD methodologies into vendor contracts
32
Implementing QbD Approaches with Outsourced Partners
CROs and Sponsors should 1. Assess suppliers for knowledge, experience and
exper7se implemen7ng QbD methods 2. Deploy best prac7ces for conduc7ng supplier risk
assessments for outsourced services 3. Joint collabora7on with partners to ensure appropriate
implementa7on of QbD processes 4. Build QbD methodologies into vendor contracts
33
QbD Best Practices: Key Messages ● Paradigm shif ● Fit for GCP ac7vi7es/clinical trials ● Health authori7es accept/expect risk-‐based approaches to be applied ● Industry is developing methods and tools ● This new approach is a BIG WIN:
● Prac7cal and sustainable ● Cost containment ● Improve quality ● Increase safety ● Improve data integrity ● Drive more quality submissions ● Drive more product approvals-‐ WHICH IS WHAT WE DO
34
