Volker Hack

	After more than 20 years, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Harmonized Guideline was updated to ICH E6 (R2) in November 2016. The revision was implemented to modernize clinical trials and takes into consideration the evolution in technology and quality management processes that offer new opportunities to enhance efficiency, focus, and oversight on relevant activities.

 ICH E8 (R1) draft version was released in May 2019 and further supports a risk-based monitoring (RBM) strategy by providing general considerations for clinical studies.

These revised guidelines encourage implementation of improved and more efficient approaches to clinical trials, in such aspects as: trial design, conduct, oversight, documentation, and reporting to ensure human subject protection and reliability of trial results. Successful implementation of these guidance documents requires a well-orchestrated, collaborative, and cross-functionally supported effort between sponsors and their contracted vendors.

	Within ICH E6 (R2), “The sponsor should implement a system to manage quality throughout all stages of the trial process. Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial results. Quality management includes the design of efficient clinical trial protocols and tools and procedures for data collection and processing, as well as the collection of information that is essential to decisio- making.”

 While the guidance provides core recommendations, interpretation and implementation has varied greatly. ICH E6 (R2) highlights seven components necessary to manage quality through all stages of clinical trials. Those components are:

	An effective-but often overlooked-component of clinical trial oversight is risk communication. ICH E6 (R2) states, “The sponsor should communicate quality management activities to those who are involved in or affected by such activities, to facilitate risk review and continual improvement during clinical trial execution.”

 ICH E8 (R1) further supports that premise by indicating that “proactive communication of the critical to quality factors and risk mitigation activities will support understanding of priorities and resource allocation by the sponsor and investigator sites.”

	To address the possibility of overlooked risk communication, a basic set of factors relevant to ensuring study quality should be identified for each study. Emphasis should be given to those factors that stand out as critical to study quality. These critical to quality (CTQ) factors are attributes of a study whose integrity is fundamental to the protection of study subjects, the reliability and interpretability of the study results, and the decisions made based on the study results. The use of CTQ, such as critical data and processes, key performance indicators (KPIs), key risk indicators (KRIs), and quality tolerance limits (QTLs), presents an opportunity to proactively communicate CTQ factors and risk mitigation activities to support understanding of priorities and resource allocation by the sponsor and investigator sites.

	CTQ factors function as communication vehicles to ensure quality alignment across the study. In this way, CTQ, KRIs, and QTLs aligned with critical data and processes to facilitate the alignment of project teams and organizations early while supporting study and vendor oversight throughout the clinical trial life cycle. ICH E8 (R1) recommends quality measures and performance indicators be aligned with a proactive design approach. In this framework, CTQ factors are 

 is to be focused on, whereas KRIs and QTLs are 

 the CTQ factors are safeguarded to prevent or mitigate important and likely risks to investigation quality, including risks to human subject protection and data integrity.

	What follows within this article are practical methods for integrating CTQ factors within the operational execution life cycle of a clinical trial.

	Successful clinical trials begin with focus and cross-function alignment across departments and the third-party vendors that provide services, such as project management, clinical management, data management, biostatistics, medical monitoring, pharmacovigilance, and medical writing. Early risk management activities require project teams to have a strong understanding of the study endpoints and supporting CTQ factors. Those factors function as a compass to provide a common direction across the project team, helping them to focus not only on what is important, but, more notably, what is not important. Early identification of the critical risks that could affect subject safety or data integrity is paramount to driving further focus of the project team. In this way, early risk-management activities prioritize resources on the critical trial elements, impact the various functional/vendor trial plans (e.g., monitoring plan), align communication across organizations, and lay the foundation for downstream risk-based operational decisions.

	Once CTQ factors are identified, the shift from planning to execution begins. Risks that are associated to CTQ factors are assessed to determine if they can be eliminated or sufficiently reduced. For those risks that cannot be eliminated or reduced, mitigation plans are established. For example, if the primary study endpoint is associated with a laboratory sample collection, the risks associated with collection of samples cannot be eliminated. Therefore, the associated risks should be effectively managed to reduce the risk to subject safety and ensure data quality. As mitigation strategies are established, detection mechanisms are determined to quickly identify if the established mitigation strategies are effective.

	One method to monitor mitigation plans is via KPIs, KRIs, and QTLs. KRIs are metric indicators of the quality of study conduct in specific targeted areas. QTLs, introduced within ICH E6 (R2), “should be established, taking into consideration the medical and statistical characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can impact subject safety or reliability of trial results.”

 Detection of deviations from the predefined QTLs should trigger an evaluation to determine if action is needed. In this context, it is important for clinical trial teams to regularly analyze and properly align trial-specific KRIs and QTLs. These activities support continuous clinical trial quality improvement as well as driving focused decision-making communication and actions.

	A method of communication that reinforces CTQ factors is regular project team meetings. These meetings should be held in conjunction with dedicated cross-functional risk review meetings and become frequent quality check-ins for analyzing KPIs, KRIs, and QTLs to assess if established mitigation strategies remain effective and if existing or new risks are emerging (see Figure 1; click to enlarge).

	Following a continuous process improvement model, such as those of Six Sigma, Lean, and Total Quality Management, ongoing improvement is achieved through incremental and breakthrough improvements. As demonstrated within Figure 2, the more often the project team evaluates performance based upon established parameters (KPIs, KRIs, and QTLs), the greater the resulting quality becomes.

	Coinciding with continuous process improvement is documentation to recreate the environment present when key decisions were made and what specific actions were taken as a result. These activities support ICH E6 (R2) recommendations for sponsor oversight and are included within the risk management section of the clinical study report. An example of questions project teams should consider when evaluating process improvement are:

		What are the downstream actions caused by the findings?

		Does the project team have evidence of study team members changing processes?

		Can the project team demonstrate they’ve made meaningful change?

	As demonstrated within this article, KPIs, KRIs, and QTLs provide an opportunity to proactively communicate CTQ factors and risk mitigation activities to support ongoing sponsor oversight activities across vendors throughout the clinical study life cycle.

 is Director of Risk-Based Monitoring, PPD; 

is Executive Director of Centralized Services, PPD

	1. International Council for Harmonization. 2016. Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2), 

www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf

	2. General Consideration for Clinical Studies E8(R1) Draft version Endorsed on May 8.  2019, 

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/E8-R1EWG_Step2_DraftGuideline_2019_0508.pdf

Articles

Amid the recently released ICH E8 (R1) draft guidelines further supporting RBM strategies, practical methods for integrating critical-to-quality (CTQ) factors within the operational execution life cycle of a clinical trial are presented. 

Risk-Based Quality Management: The Importance of Risk Communication

Market trends are driving the need for the biopharmaceutical industry to decrease fixed costs, which leads to increased outsourcing to contract research organizations (CROs).

 CROs have reacted by forming multiple strategic alliances with the largest biopharma companies, but also by adopting their project management operating models to meet the unique needs of big pharma, as well as those of the smaller biotech or virtual organizations. In addition, CROs have invested a lot in data analytics systems and project management technologies or acquired companies to complement their service portfolio to ensure they fully realize the opportunity and are able to offer sponsors end-to-end services.

	In parallel, clinical trials have become more complex. A few facts are driving this trend. The number of protocol procedures increased by 57% from 2000 to 2011.

 Enrollment of patients is becoming more difficult, with a decrease in enrollment rate of 18% between 2002 and 2011, which has led to an increase in the number of trial sites by 58%.

 Regulatory agencies are requiring more data, especially on long-term safety or special patient populations. Payers demand more information on how drugs/biologics perform relative to products already on the market, which introduces further price pressure. Personalized medicine, companion diagnostics, adaptive design and mobile health are emerging trends that will continue to grow and add further trial complexity.

	This increased complexity places greater strategic demands on CROs and project managers (PMs).

 To ensure operational excellence and financial profitability under an ever-changing and challenging clinical trial environment, the role and profile of the PM needs to continuously evolve

 beyond the management of the “triple constraint.” The competencies of the PM in the past are not those required for today (see Table 1).

	In the past, PMs adhered to a simplistic but still established service triangle of time, cost and quality (i.e., triple constraint). But today that model has evolved significantly and PMs really need to sit in the driver’s seat, be fully accountable, push innovation, provide strategic leadership and drive more thorough risk analysis and management, ultimately ensuring return of R&D investments and delivery of perceived customer value (see Figure 1).

	This evolution has had significant impact on PMs. For example, PMs need to think beyond simple risk management practices, ensuring high-level quality and navigating the more demanding risk strategy described ahead while, at the same time, driving customer satisfaction and ROI.

	With TransCelerate BioPharma Inc. and regulatory authorities driving toward more quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials, risk assessment and management clearly will be an increasingly critical part of successful project management.

 PMs need not only to understand the operational risks (e.g., enrollment of subjects) of a clinical study, but need to identify those study processes and data that are critical to ensure human subject protection and the reliability of study results. PMs need to focus on key risk indicators (KRIs), which are critical predictors of unfavorable events that can adversely impact clinical studies and to detect trends early. According to the draft revision of the ICH E6 guideline, risks should be considered at the system level (e.g., facilities, standard operating procedures, computerized systems, personnel and vendors) and clinical trial level (e.g., investigational product, trial design, data collection and recording).

	In the past, PMs “only” had to manage their assigned projects because the outsourcing model was largely transactional. PMs were assigned in order to fulfill requests from clients. But now, as CROs have developed strategic relationships with some of the largest biopharma companies, PMs need to think ahead to see the bigger picture of the drug development plan and create new opportunities for the CRO and its clients.

 PMs must look at the entire lifecycle of a study-and beyond-to find opportunities to reduce cost and speed up timelines, while ensuring the highest possible quality.

	Traditionally, PMs spent much of their time looking for information. However, with the implementation of sophisticated data analytics tools, this data is now available at their fingertips. PMs need to get their arms around them and provide data analysis proficiency, turning data into information in order to enable faster decision-making and proactive identification of trends and emerging risks.

	PMs used to work with “gold standards,” but now need to be flexible and open to constant change, while always striving for better solutions. CROs are not only looking for project management-certified PMs (e.g., Project Management Institute), but also for PMs who are proficient in process improvement methodologies like lean Six Sigma to identify areas of waste in processes and projects.

 As PMs become more adaptable, they also need to overcome resistance to change in team members by leveraging their project management skills. Hence, pure project management skills, like planning and analysis, will need to be combined with change management abilities in order to achieve project success.

	Good communication always has been a core behavior for PMs in order to effectively collaborate with individuals at all levels.

 Today, however, PMs need to inspire a shared vision and empower their teams to achieve full engagement.

	PMs also need to be able to see the “big picture,” be fully aligned with their customer’s goals and objectives and understand how their decisions may significantly impact the customer’s overall development plan. This will help them to successfully manage scope, risks and their project team.

	In the past, there was an emphasis on the technical components of project management (e.g., developing a project plan, using scheduling software, etc.). Today, there is a much broader emphasis on softer skills (e.g., leadership, negotiation skills, etc.), the team dynamic components and the relationship pieces, which are really critical for the success of any PM.

	As projects became more complex, the size of the teams also has increased. For the PM, this means a larger team of specialists to manage, more departments and vendors to coordinate and more stakeholders to be accountable to.  

	More often, PMs may be working remotely from a home-based location or certainly in a location that isn’t comprised of the entire team. PMs need to be able to leverage their communication and other soft skills to effectively manage a globally diverse team. PMs will need to be good self-managers in addition to possessing the ability to successfully facilitate conditions, a trait that encourages team interaction and connection.

	As illustrated in Table 1, a successful PM today and in the future will need to be able to balance the hard and soft skills while having the ability to process complex information and embrace change.

	To maximize return on R&D investments, strengthen market position and maximize efficiencies, CROs and their PMs should be involved as early as possible in the product lifecycle management to align expectations and fully understand the goals and objectives of their partner sponsor’s development plan. In addition, PMs will need to use leading-edge technologies like risk-based monitoring and data analytic platforms and tools. And they will need to continuously improve standard processes and establish other innovative approaches to 

bring business value, realize cost reductions and ensure shorter clinical development cycles.

	Clearly, major change is ongoing in the biopharma industry that is driving CROs to become more innovative. That has had a significant impact on project management and the evolution of the PM profile. Managing increased complexity while taking on more project leadership continues to be a top priority for PMs. Not only do they need to embrace it, they need to help their teams embrace it. This will ensure CROs stay at the forefront of innovation-to bend the cost and time curve of drug discovery and development and, thus, enabling clients to get life-changing therapies to patients faster with higher return on their R&D investments.

 is Senior Director and Head of Project Management Standards Group, PPD; 

 is Director, Project Management Standards Group, PPD

	1. CRO Outlook & Drug Development Trends, 

	2. Getz et al. “Variability in Protocol Design Complexity by Phase and Therapeutic Area.” 

	3. Why Are Cancer Clinical Trials Increasing in Duration? Aug 31, 2015, By Moe Alsumidaie, Peter Schiemann, PhD, 

http://www.appliedclinicaltrialsonline.com/why-are-cancer-clinical-trials-increasing-duration

	4. The Changing Role of Project Managers, 

http://www.appliedclinicaltrialsonline.com/changing-role-project-managers

	5. The Evolving Role of the Clinical Project Manager, 

http://www.pharmavoice.com/article/2007-04-the-evolving-role-of-the-clinical-project-manager

	6. Five Lightweight Techniques for Improving Your Business Processes, 

, September 2015, 17 (7) 88-94, Volker Hack, Laura Bowers.

As more strategic partnerships emerge, demands on CROs have intensified-resulting in the need for next-level competencies for project managers.  

The Changing Role of the CRO: Impact on Project Management

	Market trends are driving the need for the biopharmaceutical industry to decrease fixed costs, which leads to increased outsourcing to contract research organizations (CROs).

 CROs have reacted by forming multiple strategic alliances with the largest biopharma companies, but also by adopting their project management operating models to meet the unique needs of big pharma, as well as those of the smaller biotech or virtual organizations. In addition, CROs have invested a lot in data analytics systems and project management technologies or acquired companies to complement their service portfolio to ensure they fully realize the opportunity and are able to offer sponsors end-to-end services.
	
	In parallel, clinical trials have become more complex. A few facts are driving this trend. The number of protocol procedures increased by 57% from 2000 to 2011.


	
	This increased complexity places greater strategic demands on CROs and project managers (PMs).

	This evolution has had significant impact on PMs. For example, PMs need to think beyond simple risk management practices, ensuring high-level quality and navigating the more demanding risk strategy described ahead while, at the same time, driving customer satisfaction and ROI.
	
	With TransCelerate BioPharma Inc. and regulatory authorities driving toward more quality throughout the design, conduct, recording, evaluation, reporting and archiving of clinical trials, risk assessment and management clearly will be a more and more critical part of successful project management.

 PMs need not only to understand the operational risks (e.g., enrollment of subjects) of a clinical study, but need to identify those study processes and data that are critical to ensure human subject protection and the reliability of study results. PMs need to focus on key risk indicators (KRI), which are critical predictors of unfavorable events that can adversely impact clinical studies and to detect trends early. According to the draft revision of the ICH E6 guideline, risks should be considered at the system level (e.g., facilities, standard operating procedures, computerized systems, personnel and vendors) and clinical trial level (e.g., investigational product, trial design, data collection and recording).
	
	In the past, PMs “only” had to manage their assigned projects because the outsourcing model was largely transactional. PMs were assigned in order to fulfill requests from clients. But now, as CROs have developed strategic relationships with some of the largest biopharma companies, PMs need to think ahead to see the bigger picture of the drug development plan and create new opportunities for the CRO and its clients.

 PMs must look at the entire lifecycle of a study-and beyond-to find opportunities to reduce cost and speed up timelines, while ensuring the highest possible quality.
	
	Traditionally, PMs spent much of their time looking for information. However, with the implementation of sophisticated data analytics tools, this data is now available at their fingertips. PMs need to get their arms around them and provide data analysis proficiency, turning data into information in order to enable faster decision-making and proactive identification of trends and emerging risks.


	
	PMs used to work with “gold standards,” but now need to be flexible and open to constant change, while always striving for better solutions. CROs are not only looking for project management-certified PMs (e.g., Project Management Institute), but also for PMs who are proficient in process improvement methodologies like lean Six Sigma to identify areas of waste in processes and projects.

 As PMs become more adaptable, they also need to overcome resistance to change in team members by leveraging their project management skills. Hence, pure project management skills, like planning and analysis, will need to be combined with change management abilities in order to achieve project success.
	
	Good communication always has been a core behavior for PMs in order to effectively collaborate with individuals at all levels.

 Today, however, PMs need to inspire a shared vision and empower their teams to achieve full engagement.
	
	PMs also need to be able to see the “big picture,” be fully aligned with their customer’s goals and objectives and understand how their decisions may significantly impact the customer’s overall development plan. This will help them to successfully manage scope, risks and their project team.
	
	In the past, there was an emphasis on the technical components of project management (e.g., developing a project plan, using scheduling software, etc.). Today, there is a much broader emphasis on softer skills (e.g., leadership, negotiation skills, etc.), the team dynamic components and the relationship pieces, which are really critical for the success of any PM.


	
	As projects became more complex, the size of the teams also has increased. For the PM, this means a larger team of specialists to manage, more departments and vendors to coordinate and more stakeholders to be accountable to.  
	
	More often, PMs may be working remotely from a home-based location or certainly in a location that isn’t comprised of the entire team. PMs need to be able to leverage their communication and other soft skills to effectively manage a globally diverse team. PMs will need to be good self-managers in addition to possessing the ability to successfully facilitate conditions, a trait that encourages team interaction and connection.
	
	As illustrated in Table 1, a successful PM today and in the future will need to be able to balance the hard and soft skills while having the ability to process complex information and embrace change.
	
	


	
	To maximize return on R&D investments, strengthen market position and maximize efficiencies, CROs and their PMs should be involved as early as possible in the product lifecycle management to align expectations and fully understand the goals and objectives of their client’s development plan. In addition, PMs will need to use leading-edge technologies like risk-based monitoring and data analytic platforms. And they will need to continuously improve standard processes and establish other innovative approaches to bring business value, realize cost reductions and ensure shorter development cycles.
	
	Clearly, a lot of change is ongoing in the biopharma industry that is driving CROs to become more innovative. That has had a significant impact on project management and the evolution of the PM profile. Managing increased complexity while taking on more project leadership continues to be a top priority for PMs. Not only do they need to embrace it, they need to help their teams embrace it. This will ensure CROs stay at the forefront of innovation-to bend the cost and time curve of drug discovery and development and, thus, enabling clients to get life-changing therapies to patients faster with higher return on their R&D investments.
	
	

		CRO Outlook & Drug Development Trends, 

		Getz et al. “Variability in Protocol Design Complexity by Phase and Therapeutic Area.” 

		Why Are Cancer Clinical Trials Increasing in Duration? Aug 31, 2015, By Moe Alsumidaie, Peter Schiemann, PhD, 

		The Changing Role of Project Managers, 

		The Evolving Role of the Clinical Project Manager, 

		Five Lightweight Techniques for Improving Your Business Processes, 

Market trends are driving the need for biopharma to decrease fixed costs, leading to increased outsourcing to CROs. To meet greater demand, the role and profile of Project Managers needs to continuously adapt to an ever changing clinical trial environment.

Volker Hack

Articles

Risk-Based Quality Management: The Importance of Risk Communication

The Changing Role of the CRO: Impact on Project Management

The Changing Role of the CRO and its Effect on Project Management