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1. For this week’s writing exercise, read the attached ICH E6 guidance on good clinical practices and write a 2-4 double spaced pages essay discussing the role and responsibilities of all stakeholders involved in clinical trials for the development of medicinal products for human use.

Please note that for the first time in nearly 20 years, E6 has been revised to include additional stakeholder accountabilities. See the attached revision of the ICH E6, Revision 2, Integrated Addendum that highlights these key changes.

ICH E6(R2) Integrated Addendum

2)For this week’s writing assignment, you will be considering the BLA. Write a one or two page essay on what information is typically included in a BLA and how it differs from the information usually included in a NDA.

©2017 Biomedical Research Alliance of New York LLC
CITI Program is a division of BRANY
Overview
ICH GCP E6(R2)
Integrated
Addendum
www.citiprogram.org
Introduction
On 15 December 2016, the International Council for Harmonistion (ICH) adopted the revised E6 guideline,
entitled “Integrated Addendum to Good Clinical Practice (GCP).” Now, regulatory implementation is carried out
according to the same national/regional procedures that apply to other regulatory guidelines and
requirements (ICH 2017).
Who does the new guideline affect?
The ICH E6 addendum affects the full clinical trial cycle and research enterprise. The revisions to the guideline
mainly affect sponsors, stipulating a more proactive approach to study design, as well as risk management and
study monitoring. However, Contract Research Organizations (CROs), that often delegated trial-related tasks by
the sponsor, need to learn about the revised practice points in the guideline. Sponsor-investigators also
need to be aware of the changes and their responsibilities associated with being a sponsor. The changes
associated with being a sponsor. The changes are important to investigators, Institutional Review Board/
Independent Ethics Committee (IRB/IEC) members and administrators, study monitors, clinical research
coordinators and professionals, and institutions/sites.
Why revise the guideline?
Research has modernized in the thirty years since the original E6(R1) guideline. However, E6(R2) still has the
same goal of standardization.
Standardization ensures that marketing applications to various
regulatory agencies around the world can occur without
redundant testing. Many pharmaceutical companies conduct
multi-site international clinical trials. Repeating trials in different
markets to comply with slightly different regulations is
inefficient and unnecessarily delays bringing new drugs to
patients.
“Lack of harmonisation may not only slow
the adoption of innovative approaches to
clinical trial design, management, oversight,
conduct, documentation, and reporting,
but may also lead to inconsistency in
approaches sponsors use among the ICH
regions which could add cost and time to
the development of needed drug products”
(ICH 2014b).
The European Medicine Agency (EMA) submitted a report in 2014 summarizing 398 GCP inspections of clinical
trial sponsors, sites, and CROs from 2000-2012. The report’s critical and major findings were mostly in relation
to:
Monitoring
Data management
Cinical study reports
Source documentation
This was good news, in that, most critical findings were not directly related to informed consent or human
subject safety. However, the report identified concerns and areas for improvement in the design and conduct
of clinical trials. It was clear that the ICH E6 guidelines that originally provided a standardized framework for
harmonization needed to be modernized for the current research landscape and address these GCP inspection
findings.
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The ICH convened an expert working group to create an addendum to the existing E6 guideline. The expert
working group was consisted of ICH members from both industry and regulatory agencies, as well as
observers, to address current research topics like quality by design, quality risk management, and focus on
technological tools to ensure robust conduct, oversight, and reporting.
Format of Revised Guideline
The revised guideline uses an addendum-integrated format. This format embeds the revisions
into the current E6(R2) guideline, identifying the change as “ADDENDUM” above the new text (below the
old text) and using edge marks to show the changes.
The revised guideline also includes a document history with dates and versions of the guideline, as well as a
table that displays the current E6(R2) sections that were revised.
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What are the revisions?
The focus of the revisions is on increasing human subject protections and data integrity mainly through
better study design and conduct. Therefore, most of the changes affect the sponsor. As seen below, the
sponsor section was the most revised. No revisions were made to IRB/IEC, Investigator’s Brochure, or the
clinical trial protocol and protocol amendment(s) sections.
ICH E6 Sections
Revisions Made To:
Introduction
Introduction
Glossary
1.63, 1.64, 1.65
The Principles of ICH GCP
2.10, 2.13
Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
None
Investigator
4.2.5, 4.2.6, 4.9.0
Sponsor
5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4,
5.0.5, 5.0.6, 5.0.7, 5.2.2, 5.5.3 (a),
5.5.3 (b),5.5.3 (h), 5.18.3,
5.18.6 (e), 5.18.7, 5.20.1
Clinical Trial Protocol and Protocol Amendment(s)
None
Investigator’s Brochure
None
Essential Documents for the Conduct of a Clinical Trial
8.1
The focus of the revisions includes:
• Using a risk management approach in designing studies
• Promoting the use of risk-based and centralized monitoring in managing studies
• Addressing the reporting and follow-up of significant noncompliance (including conducting a root
cause analysis, and creating a corrective and preventative action plan)
• Addressing technology issues (for example, specifying that electronic systems should be validated,
backed-up, and safeguarded)
• Specifying oversight responsibilities of sponsors and investigators
• Improving data integrity (for example, requiring that source data are attributable, legible,
contemporaneous, original, accurate, and complete)
• Ensuring both investigators and sponsors have access to study data and documents
The revisions aim to balance efficiency in clinical trials while retaining human subject protections and data
integrity. Analysis of progress following implementation may provide sponsors and investigators with
insight into areas that require further clarification.
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ICH (2016) E6(R2) Revisions by Section
Introduction
The introduction section revisions explain the purpose of the revisions to the guideline, refer to other ICH
guidelines relevant to clinical trials (for example, E2A Clinical Safety Data Management and E3 Clinical Study
Reporting), and clarify that the E6(R2) addendum should replace E6(R1).
Section 1 – Glossary
ICH E6 adds the following definitions to the glossary:
• Certified copy (section 1.63)
• Monitoring plan (section 1.64)
• Validation of computerized systems (section 1.65)
Section 2 – The Principles of ICH GCP
Reflecting modernization from paper-based documentation to electronic systems, section 2.10 includes a
minor clarification to indicate that clinical trial information (irrespective of the type of media used) should be
recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
The emphasis on data integrity is seen through a minor revision to section 2.13, which added that quality
assurance systems should focus on human subject protection and reliability of trial results.
Section 3 – Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
No changes were made to this section.
Section 4 – Investigator
The investigator continues to be ultimately responsible for conducting the trial. No changes were made to the
“Investigator’s Qualifications” section and the investigator is still allowed to delegate trial-related
responsibilities. “Adequate Resources” revisions specify that the investigator is responsible for supervision
(oversight) of persons with delegated tasks. Further, the investigator should ensure research staff are
capable and trained for their assigned trial-related tasks. This is aligned with the U.S. Food and Drug
Administration (FDA) regulations (Investigational New Drug Application 2016) and FDA (2009) guidance.
The added text in “Records and Reports” also mirrors the FDA in specifying that “source data should be
attributable, legible, contemporaneous, original, accurate, and complete” (ICH 2016). The commonly used
acronym is ALCOAC. Records and reporting may be written or electronic.
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Attributable
The record identifies who created or modified the record, when
the record changed, and why it changed.
Legible
The record and dates of an entry are clear and can be interpreted
and understood.
Contemporaneous
The data are recorded in real-time, the data are observed, and
records are signed (or initialed) and dated accurately.
Original
The record is original as it is captured, collected, or is an exact
facsimile of the original.
Accurate
The record is collected and recorded honestly and completely to
demonstrate transparency.
Complete
Up-to-date and with no omissions.
Example of “Attributable”
A study team member who performed the assessment/procedure should sign his/her name/initials
when documenting the assessment/procedure that was performed. If someone else is present
during the assessment/procedure and recording on behalf of the principal investigator, that person
should also sign his/her name/initials.
Example of “Contemporaneous”
A late data entry should be noted as such. If a study team member forgets to enter data at the correct
time and must go back and do it later, the study team member should note this fact and include a date
and time when entering the data.
Example of “Original”
Study team members should not use pencil. It is important to use pen for originals. To make changes
to an original entry, draw a single line through the error, then initial and date with an explanation for
the correction. No correction fluid or writing over an original entry is permitted.
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Section 5 – Sponsor
The most extensive changes to ICH E6 were made to the sponsor’s section, beginning with a new section on
quality management.
Quality Management
ICH E6 requires sponsors to implement a “quality management system” from trial design to trial conduct to
close-out. A well-designed protocol is the most important tool for ensuring human subject protection and
high-quality data (FDA 2011). The addendum adds that the sponsor should use a risk-based approach to
develop the protocol and study materials. This process is outlined in section 5.0 as risk identification, risk
evaluation, risk control, risk communication, risk review, and risk reporting.
Active Oversight
As stated in the previous guideline, the sponsor is still permitted to delegate trial-related responsibilities to
others (for example, contractors and vendors), but the sponsor is ultimately responsible for the quality and
integrity of the trial data. The revised guideline adds, in section 5.2.2, that the sponsor should ensure oversight
of trial-related duties and functions carried out on its behalf, even for those responsibilities subcontracted to
another party by the sponsor’s contracted CRO (ICH 2016). The sponsor must plan and describe how this will
be assessed. This is typically done through the sponsor’s qualification/requalification audit of the CRO. This
revision to ICH is a clarification of expected trial conduct to reduce misinterpretation of oversight responsibilities.
Electronic Systems
ICH E6 recognizes that sponsors routinely use electronic systems for trial data. Further changes were added in
section 5.5, “Trial Management, Data Handling, and Record Keeping,” to include
that the sponsor should use a risk assessment in validating electronic trial
data handling and/or remote trial data systems. As before, the
guideline requires the sponsor to maintain standard operating
procedures (SOPs) for using these electronic data systems. The addendum
adds specific requirements that the SOPs must include system setup, installation, use, validation and functionality
testing, data backup, recovery, and training for users. The addendum also clearly puts the responsibility for
reliable data on the sponsor, requiring in section 5.5.3(h) that the sponsor ensure the integrity of the data, even
when making changes to the computerized systems (such as, software upgrades or migration of data) (ICH 2016).
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Monitoring
Effective monitoring is critical to ensuring both subject protections and high quality trial data. Monitoring
continues to be the sponsor’s responsibility. By far, the most substantial changes to ICH E6 are related to study
monitoring. The addendum incorporates elements from the FDA’s (2013) risk-based monitoring guidance,
which supports alternative approaches (specifically, risk-based and combination activities) to monitoring.
The revised ICH E6 requires that the sponsor develop:
A systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the
extent and nature of monitoring described in this section is intended to permit varied approaches
that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site
monitoring, a combination of on-site and centralized (off-site) monitoring, or, where justified,
centralized monitoring (only). The sponsor should document the rationale for the chosen monitoring
strategy (e.g., in the monitoring plan).
The ICH E6 addendum defines centralized monitoring and
distinguishes it from on-site monitoring. Centralized monitoring allows the real-time review of accumulating trial data,
which helps to identify missing or inconsistent data, examine
trends, identify data errors, analyze sites/investigators, and/or
select sites for targeted on-site monitoring.
Note: If the sponsor is planning to
perform off-site reviews of source
documents (centralized monitoring),
this should be established and
agreed to by the site, well before
study initiation. Centralized monitoring
may be more time-consuming for
sites than typical on-site visits.
Per section 5.18.6(e), “monitoring reports,” including both centralized reports and on-site monitoring visit
reports, are now required to be provided to the sponsor (including appropriate sponsor management
and CRO staff) by the monitor in a timely manner and with sufficient detail to allow sponsors to
follow up, if needed. This allows and requires the sponsor to follow-up on
identified serious noncompliance. In section 5.20, the addendum adds the
sponsor should perform a root cause analysis and implement appropriate
corrective and preventive actions (for example, a corrective and preventative
action plan) if noncompliance is or may be serious.
Finally, each study now requires a study-specific monitoring plan. The plan should take into consideration
potential risks of harm to human subjects and data integrity. The monitoring plan should not only include how
the study will be monitored, but a rationale. Additionally, the monitoring plan should also emphasize the
monitoring of critical data and processes, especially those that are not routine clinical practice and require
extra training (ICH 2016).
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Section 6 – Clinical Trial Protocol and Protocol Amendment(s)
No changes were made to this section.
Section 7 – Investigator’s Brochure
No changes were made to this section.
Section 8 – Essential Documents for the Conduct of a Clinical Trial
ICH E6(R2) adds in the introduction section a requirement to specify that both the sponsor and investigator/
institution (site) conducting the trial should maintain their respective essential documents in a system that
provides processes for locating the document, as well as providing for document identification, version history,
search, and retrieval.
ICH E6(R2) adds more about document control, specifying that the sponsor should not have exclusive
control of case report form (CRF) data submitted by the investigator, and that the investigator/institution
should have control of all their own essential documents before, during, and after the trial. ICH E6(R2)
clarifies that the sponsor should ensure that the investigator has continuous access to the CRF data
reported to the sponsor (ICH 2016). Also, ICH E6(R2) states that copies used to replace original documents
must meet the definition of certified copies.
Law or guidance?
The FDA adopted ICH E6(R1) and subsequently ICH E6(R2) as guidance. Therefore,
the ICH E6 guidelines do not have the force of law in the U.S. and are not regulations.
In the Federal Register Notice, FDA stated that the ICH E6 guideline “does not
create or confer any rights for or on any person and does not operate to bind FDA
or the public. An alternative approach may be used if such approach satisfies the
requirements of the applicable statutes, regulations, or both” (FDA 2018, 8882-3).
Health Canada implemented ICH E6(R1) in 1997. The revised ICH E6(R2) has not
yet been implemented by Health Canada. Health Canada did advise of its intent to
implement with a target date of 1 April 2019.
The European Commission adopted ICH E6(R2) on 15 December 2016 and has set
an effective date of 14 June 2017.
Summary
The ICH E6 (R2) guideline continues to provide practical standardization for the conduct of clinical trials. The
revisions reflect a modernizing and evolving research landscape and do not
change the core of the guideline. Sponsors, investigators, and others in the
research enterprise should be aware of the integrated addendum and new
procedures in order to continue to design and conduct clinical trials that
protect human subjects and ensure data integrity.
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References
• European Medicines Agency (EMA). 2014. “Classification and analysis of the GCP inspection findings of
GCP inspections conducted at the request of the CHMP.” Accessed January 20, 2017.
• International Council for Harmonisation (ICH). 2014. “Final Business Plan Addendum for ICH E6: Guideline
for Good Clinical Practice.” Accessed June 6, 2017.
• International Council for Harmonisation (ICH). 2015. “Addendum to ICH E6(R2) presentation.” Accessed
January 20, 2017.
• International Council for Harmonisation (ICH). 2016. “Integrated Addendum to ICH E6(R1): Guideline for
Good Clinical Practice E6 (R2).” Accessed January 20, 2017.
• International Council for Harmonisation (ICH). 2017. “Formal ICH Procedure.” Accessed January 20.
• Investigational New Drug Application, 21 CFR § 312 (2016).
• U.S. Food and Drug Administration (FDA). 2009. “Guidance for Industry: Investigator Responsibilities —
Protecting the Rights, Safety, and Welfare of Study Subjects.” Accessed January 20, 2017.
• U.S. Food and Drug Administration (FDA). 2011. “Oversight of Clinical Investigations: A Risk-Based
Approach to Monitoring (Draft Guidance).” Accessed January 20, 2017.
• U.S. Food and Drug Administration (FDA). 2013. “Guidance for Industry: Oversight of Clinical Investigations
— A Risk-Based Approach to Monitoring.” Accessed January 20, 2017.
• U.S. Food and Drug Administration (FDA). 2018. “E6(R2) Good Clinical Practice: Integrated Addendum
to E6(R1); International Council for Harmonisation; Guidance for Industry.” Federal Register 41(83):8882-3.
Additional Resources
• International Council for Harmonisation (ICH). 2014. “Final Concept Paper Addendum for ICH E6: Guide
line for Good Clinical Practice.” Accessed June 6, 2017.
• International Council for Harmonisation (ICH). 2015. “Addendum to ICH E6 (R2) presentation.” Accessed
January 20, 2017.
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