Increasing Clinical Trials Efficiency – The Future Is Here

Increasing clinical trial efficiency
Ahuva Koren

Ahuva Koren

CEO and Co-founder | Linkedin

鈥淒ear staff, please cease all site initiation activities. The study is put on hold until further notification鈥︹

During March 2020 we received many similar notifications from Sponsors for whom we manage their clinical trials.

The outbreak of the corona pandemic will be remembered for many years to come as a turning point, with a significant impact on how we plan, conduct and manage clinical trials.

A global crisis, like a tsunami wave, swept through an entire industry that had to deal with it as quickly as possible to find the solutions for the continuity of the clinical trials. The pandemic has hit many R&D Sponsor companies, from small to large, to the point of threatening the continuity of the clinical research development. Clinical investigators faced difficulties in recruiting patients, as well as difficulties in maintaining on-going follow-up visits due to lock-downs and/or patients鈥 fear arriving to the hospitals. Some of the medical staff were quarantined and were not available to perform tasks under their responsibility. The social distancing affected the on-site monitoring activities, as well as other activities required for the conduct and management of clinical trials. Some have predicted mourning for generations due to a significant threat to the development of new drugs and technologies.

In an attempt to ensure the continuity of the clinical trials, the regulatory authorities encouraged the move towards virtual research. Changing clinical research methods with clinical trials in progress is a challenge, especially since virtual clinical trials are not yet an industry standard.

Months ahead, when examining the recovery of the industry that was halted in March-April 2020, Sponsor and CRO companies that were able to implement before the Corona pandemic innovative processes and technologies for managing and conducting clinical trials, are the ones that recovered faster and resumed the continuity of the clinical trials.

What did the corona pandemic teach us? What could we have done differently? What needs to be done now to be prepared for the future, especially with unexpected situations?

In the next series of articles, we will review the regulatory updates, the changes the field has experienced in recent years and the new trends that are leading the clinical research industry to a new way of thinking in the planning, design, execution and management of clinical trials.

In the first article in the series, we will review the second revision of the ICH E6 document on Good Clinical Practice (GCP) which is still under implementation across the industry.

This is a last call to update your GCP systems: Are you prepared to manage the changes?

To answer the question, let鈥檚 go back for a moment to the sequence of historical events.

May 1996 is a significant date for all those involved in clinical research in humans (clinical trials). This is the date on which the International Council for Harmonization published the first version of the ICH-E6; the Good Clinical Practice (GCP) Guideline that direct all stakeholders involved with clinical research.

The document, which is largely based on the principles of the Helsinki Declaration, defines terms in the field of clinical trials, as well as the responsibilities of those involved in the conduct and management of clinical trials, to include clinical investigators, Sponsors and ethics committees. The document gives guidance for the management and conduct of clinical trials with specific reference, among other things, to aspects related to monitoring, reporting, documents鈥 retention, etc.

The ICH-GCP guideline is the gold-standard aimed to ensure:

  • the rights, safety and well-being of trial subjects are protected,
  • the clinical trial data is credible.

When the original guideline was published in May 1996, the procedures for conducting clinical trials were mostly paper-based. Since then, clinical trials have become more complex, more expensive, and global in scope. In recent years, developments in technology and methods for data analysis have made it possible to conduct clinical trials more efficiently.

To keep pace with technological development, 20-years after the publication of the original guideline, a revised guideline was published, known as ICH-GCP (E6), R2. Herein after, we will briefly name it, E6 (R2).

In E6 (R2) published in November 2016, the focus shifted from clinical trials鈥 monitoring to a data-driven approach and identification of processes important to patient safety and data integrity, while leveraging technologies to increase oversight, quality and efficiency.

Since the publication of E6 (R2), implementation by all involved is slowly advancing. For example, the Canadian Regulatory Authority implemented E6 (R2) in April 2019, the Japanize Regulatory Authority in July 2019. Not all of the Sponsor and CRO companies however implemented E6 (R2) in their internal Standard Operating Procedures (SOPs). While the industry as a whole is implementing E6 (R2), an ICH working group is already developing the next revision (R3). The first phase of R3 is scheduled for publication in December 2021.

While still busy implementing E6 (R2), we faced the outbreak of the corona pandemic. An unexpected situation that posed lockdowns and social distancing, challenged the ability to initiate new studies, continued recruitment of patients for existing studies and the ability to monitor studies in follow-up stages.

Under the Corona pandemic we have learned that not all involved in conduct and management of clinical trials are adequately equipped to adapt their processes to the risks revealed by the pandemic. We understood that rapid implementation of innovative solutions is required to protect the safety of clinical trial participants and enable continuity of the clinical trials.

What is the connection between the implementation of E6 (R2) and coping with the corona crisis?

E6 (R2) sets out new principles for research planning and design and has significant implications on research sites, Sponsor companies, and their interaction with each other. Companies that were able to assimilate the principles of E6 (R2) had the tools to manage the crisis properly and recover in a short period of time.

What are the major changes in E6 (R2)?

The document adopted by the regulatory authorities, such as the FDA, EMA, PMDA and others, highlights 3 main issues:

Risk based approach to quality monitoring (RBQM)

Oversight

Technology

The document focuses on a proactive approach according to which one should think in advance about the expected variability in conducting the study, and focus on defining the data and the important procedures for maintaining patient safety and data reliability.

The document clarifies the expectation from the RBQM methods, and reinforces the need for risk planning and centralized monitoring, to include statistical data monitoring.

Companies are required to test their readiness to implement:

  • Quality by Design (QbD) approach, and
  • Risk-Based Quality Management Systems (RBQM)

The document clearly defines the oversight responsibility required to ensure quality:

  • By Sponsor companies on CROs they contract with.
  • By research site/investigators on the ones they have delegated tasks to.

Thanks to technology, any concern about patient safety and / or data reliability can be proactively evaluated and addressed early in the clinical research life cycle.

The technology enable implementation of RBQM approach, as well as the oversight, by:

  • Real-time data aggregation and monitoring.
  • Trend assessment and analysis.

Oversight

The document clearly defines the oversight responsibility required to ensure quality:

  • By Sponsor companies on CROs they contract with.
  • By research site/investigators on the ones they have delegated tasks to.

Risk based approach to quality monitoring (RBQM)

The document focuses on a proactive approach according to which one should think in advance about the expected variability in conducting the study, and focus on defining the data and the important procedures for maintaining patient safety and data reliability.

The document clarifies the expectation from the RBQM methods, and reinforces the need for risk planning and centralized monitoring, to include statistical data monitoring.

Companies are required to test their readiness to implement:

  • Quality by Design (QbD) approach, and
  • Risk-Based Quality Management Systems (RBQM)

Technology

Thanks to technology, any concern about patient safety and / or data reliability can be proactively evaluated and addressed early in the clinical research life cycle.

The technology enable implementation of RBQM approach, as well as the oversight, by:

  • Real-time data aggregation and monitoring.
  • Trend assessment and analysis.

How do changes in E6 (R2) affect the interaction between the Sponsor companies and the CROs?

Historically, the Sponsor companies would have contracted with the CRO companies only after the Sponsor had a final protocol or at least a synopsis, while delegating to the CRO responsibilities for the operational (practical) management of the clinical trial.

Following the second revision of E6, an engagement between the parties is gradually seen.

The engagement starts at protocol development stages, and sometimes even during the planning and design stages of the study, stages in which one could optimize the processes required to meet the study end points, with an emphasis on risk assessment.

In the risk assessment process, during the planning and design stages of the study protocol, it is important to conduct a joint brainstorming session in which the Sponsor will share, among other things, the knowledge he has gained about the investigational product from previous studies, including preclinical studies. The goal is to think together what might go wrong? The risks in the specific study for which the protocol is now being developed together need to be defined so action to mitigate them can be taken. Such process is part of Quality by Design (QbD) approach, as advised in the revised ICH guideline.

Together with the clinical protocol development, the Sponsor and the CRO are required to work together in the research planning stages to develop a monitoring plan that will address the risk assessment. The Sponsor should develop a risk management process themselves, or alternatively, be very clear about responsibilities鈥 delegation for risk management development to the CRO.

There are Sponsors who are very involved in the management of the clinical trial by the CRO, others (smaller, with limited resources), rely more on the CRO in the planning and management of the clinical trial.

Under the new collaborative environment where we focus on data, critical procedures, and delegated responsibilities for risk management, Sponsors need to think about how they systematically oversee tasks they perform themselves and tasks they have delegated to the CRO.

In the past, it was industry common practice for the Sponsor to not significantly interfere with the CRO subcontracting arrangement, as the contract is between the CRO and its subcontractors. Hence, most Sponsors have minimized the oversight to auditing their CROs to ensure that CROs have orderly procedures for evaluating and certifying their subcontractors. This level of oversight is no longer sufficient under E6 (R2). Now, the sole responsibility for oversight lies with the Sponsors who have to oversee services the CRO receives from subcontractors.

To meet current regulatory requirements, the Sponsor will be required to pre-approve all CRO subcontractors. Sponsors will expect to receive further details on the competency evaluation results performed by CROs on their subcontractors. In addition, Sponsors will require evidence that CROs actively manage their subcontractors throughout the study.

Furthermore, it is likely that Sponsors will include in the service agreement with the CROs clauses regarding third party suppliers/ subcontractors in order to allow themselves direct oversight capabilities of these subcontractors and their functioning throughout the study.

What about the impact on research sites and Investigators?

doctor talking patient while holding tablet

E6 (R2) places a greater burden on research sites, in the collection and remotely sharing of regulatory documents by technological means.

Some tasks previously performed by the Sponsor or CRO are now moved to the responsibility of the research sites.

In accordance with E6 (R2), investigators are required to demonstrate active oversight of role holders they have delegated responsibilities to. Therefore, it is recommended and worthwhile, among other things, to save correspondence between the Principal Investigator and his research staff, summaries of meetings and telephone conversations as well as to document training activities.

In addition, new monitoring strategies have an impact on research sites. In the past, the CRA visited the research site frequently, according to a dictated schedule- for example, once every 6-8 weeks, in order to check, among other things, the reliability of the data.

Today, according to many monitoring plans, on-site monitoring activities are combined with remote (off-site) monitoring operations. CRAs perform many operative actions through telephone calls, and visit research sites less frequently. Moreover, the monitoring activities are different from what the research sites are previously accustomed to. The CRA examines in depth, details pertaining to work processes. The CRAs will validate the procedures performed by the research site staff and ask questions such as, how a particular device is calibrated, to ensure that data is collected uniformly across all research sites.

The research sites must be prepared with skilled and experienced personnel to meet requirements, ensure compliance with the requirements and ensure they continue to be聽 聽聽attractive for the Sponsors. It is advisable for research sites to have written working procedures (SOPs) or clear guidance documents for the tasks they are responsible for. Written procedures mark the quality of the research site and if until today they were a recommendation, over time they have become more significant and important to maintain.

Will E6 (R2) affect the patients participating in the studies?

portrait male doctor patient

In the past, the focus was on “what is important for patients in accordance with investigators鈥 view”. E6 (R2) helps us to consider “what is important to the patient”.

  • What are the critical data and procedures important for maintaining patient safety and data reliability?
  • How to make the study accessible to the patient?
  • How to reduce the patient’s burden as a result of his participation in the study?

There is a lot of innovation around this topic. It is important to incorporate these considerations in the early stages of protocol development, in order to make the right decisions about the information to be collected, and how it will be collected.

The issue of patient centricity has certainly been a significant consideration in recent years and a new approach of Decentralized Clinical Trials (DCT) has developed around it.

Are we expected to cease 100% SDV?

Over the years we have defined Source Data Verification (SDV) as confirmation of the聽data聽presented in the Case Report Form (CRF) with聽the, patient’s medical records (source data) This action was implemented by a conservative industry, and was not dictated by the regulatory authorities. Reading the original version of the ICH-GCP guideline, in section 5.18.3 it is stated that a statistically controlled sample may be an accepted method for selecting the data to be verified.

E6 (R2) moves away from 100% SDV on the understanding that human errors associated with transcribing are few, and if there are errors, their impact on data quality is negligible. What is important is that processes dictated by the study protocol are indeed carried out uniformly by the various research sites participating in the study, a process called Source Data Review (SDR). This is a valuable process to make sure accurate scientific data is collected where it really matters.

Let鈥檚 take for example, measuring blood pressure. A uniform standard of measurement can be determined in the study protocol. All medical centers participating in the study will receive the same device for measurement. The Sponsor or CRO will be required to check that the operators at site know how to operate the device to ensure that the device is operated uniformly, to document when the blood pressure measurement was performed (day, time), and how. Alternatively, it can be stated in the study protocol that the blood pressure can be measured by any device and it is important to ensure that the measurement itself takes place uniformly, that it is performed twice, in sequence, once lying down and once sitting. In this case, the Sponsor or CRO will be required to check that the process is indeed carried out uniformly at the various centers.

In both cases described, verifying how the process required to measure blood pressure is the most important one and not the act of verifying the copying of the blood pressure measurement data from the medical record to the CRF.

Beyond SDR, central monitoring can be added to examine the trends of the data arriving from the centers. To check the trends of blood pressure indicators at study level, and when deviated results are obtained from one of the centers, compared to the mean, the CRA will be required to check how the clinical trial is conducted at that center and specifically the deviated data.

What will the regulatory authorities expect to see in future inspections?

It is likely that for studies initiated after the publication E6 (R2) there will be an expectation of the implementation of the revised guideline. Authorities will seek affirmation for using a risk-based approach to streamline research and development activities. Inspectors from the regulatory authority may request to review the risk management plan of the clinical study under review, as well as the quality management system documentation and procedures. Implementation of 100% Source Data Verification (SDV) may signal to regulatory authorities that a risk-based approach has not been adopted and may lead to a possible inspection by the Regulatory Authority.

In an executive roundtable workshop entitled 鈥淚mproving the Implementation of Risk-Based Monitoring Approaches of Clinical Investigations鈥, organized on July 2019 by the FDA and Duke Margolis Center for Health Policy, David Burrow, Director of the FDA鈥檚 Office of Scientific Investigations stated; 鈥淲e鈥檙e not saying not to do any source data verification any more, but it should be done with intent, when it鈥檚 indicated for the right purpose.鈥

Two other areas in which the authorities might seek implementation of ICH-GCP R2 are fulfilment of the requirements for active and documented oversight and study documentation management.

Per ICH GCP (R2) guideline, clinical documentation must be filed on a regular basis. In the past, when managing paper Trial Master File (TMF), inspectors would never know if documents were filed on an ongoing basis or only before the inspection. Today when TMFs are moving towards electronic systems, inspectors, e.g. from MHRA, are requiring direct access to the eTMF. With such direct access to Sponsor鈥檚/CRO鈥檚 eTMF, one can no longer 鈥渉ide鈥. With electronic systems that captures all audit trails, inspectors can see when the system was activated, and when the documents were uploaded. Whether you are a big, small, pharma or device company, inspectors will expect filling of the documentation in the eTMF to be on time and complete. Delays in filing increases the likelihood of quality issues. You do not want to be in a position that due to bad eTMF management your Investigational Product will not be approved.

As we move forward, what steps are Sponsors and CRO companies required to take to ensure readiness?

The first step begins at management level, understanding that a change is needed, that new assessments are required and analyzing what is required to implement it, both at the level of technology, and at training and procedures level. Role-players who previously focused on performing tasks are now evolving to manage tasks that require critical thinking. To understand;

  • What is a risk?
  • What are the components of a risk?
  • How to assess risks correctly?
  • How to mitigate them?
  • How to analyse the root cause analysis when something goes wrong? and more.

Deciding on the steps required to implement E6 (R2) guidelines:

What is required for the development and management of these changes at the level of technology, procedures, and skills of the team. Exploring the required changes in relation to current way of operation and in terms of risk management

The updated principles of E6 (R2) add a tier to the original document. New concepts have entered our content world. We are required to adopt and implement them into clear working procedures, alongside the technology.

There are many technologies designed to maintain both the RBQM approach as well as the required oversight. Most give an answer to one area of need but not to the other. For example; EDC, CTMS, eTMF, ePRO, e-Consent. It is essential connecting them all to meet the overarching goals dictated by E6 (R2)

The team needs to understand; why and how to perform, and what is important.

We are required to develop skills to implement E6 (R2)

Is streamlining worthwhile compared to expected costs?

Streamlining the management and conduction of clinical trials means investing in:

  • Change management.
  • The time required to adapt and implement new procedures as well as the time for staff training.
  • Purchase new technologies.

On the other hand, as part of the RBQM activities, a significant part of the monitoring operations can be performed remotely, thus reducing the cost involved with on-site monitoring visits to the centers.

Above all, streamlining will increase the quality of research conduct and management as well as will shorten timelines.

In summary:

While the revised ICH-GCP (E6) guideline presents a number of challenges, it provides the Sponsors, CROs and investigators with an opportunity for significant change for the benefit of an industry that is facing increasing complexity and high costs of clinical trials.

Many of us do not like changes. Our industry is known for implementing changes at a slow pace, but as time goes on and we get used to the new way of thinking, we will understand that we need innovation to save ourselves unnecessary tasks and focus on tasks and processes that matter for the patients鈥 safety and data reliability.

Implementing the revised guideline promotes a different and more efficient management of the future clinical trials, stimulates innovation in the industry and enables significant growth.

In this article, we focused on what needs to be done to implement the changes. Now the question arises, how to implement the changes? It is advisable to consult with relevant experts who will guide you in the implementation of the change.

GCP is a leading CRO for more than 19-years. Advising, planning and managing clinical trials for local and global companies.
We will be happy to take part on your journey to success.

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