1. For this weekâ€™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 weekâ€™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.
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ICH GCP E6(R2)
On 15 December 2016, the International Council for Harmonistion (ICH) adopted the revised E6 guideline,
entitled â€œIntegrated Addendum to Good Clinical Practice (GCP).â€ 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 aï¬€ects the full clinical trial cycle and research enterprise. The revisions to the guideline
mainly aï¬€ect 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 diï¬€erent
markets to comply with slightly diï¬€erent regulations is
ineï¬ƒcient and unnecessarily delays bringing new drugs to
â€œLack 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 productsâ€
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 reportâ€™s critical and major ï¬ndings were mostly in relation
Cinical study reports
This was good news, in that, most critical ï¬ndings were not directly related to informed consent or human
subject safety. However, the report identiï¬ed 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
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 â€œADDENDUMâ€ 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.
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 aï¬€ect the sponsor. As seen below, the
sponsor section was the most revised. No revisions were made to IRB/IEC, Investigatorâ€™s Brochure, or the
clinical trial protocol and protocol amendment(s) sections.
ICH E6 Sections
Revisions Made To:
1.63, 1.64, 1.65
The Principles of ICH GCP
Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
4.2.5, 4.2.6, 4.9.0
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)
Essential Documents for the Conduct of a Clinical Trial
The focus of the revisions includes:
â€¢ Using a risk management approach in designing studies
â€¢ Promoting the use of risk-based and centralized monitoring in managing studies
â€¢ Addressing the reporting and follow-up of signiï¬cant noncompliance (including conducting a root
cause analysis, and creating a corrective and preventative action plan)
â€¢ Addressing technology issues (for example, specifying that electronic systems should be validated,
backed-up, and safeguarded)
â€¢ Specifying oversight responsibilities of sponsors and investigators
â€¢ Improving data integrity (for example, requiring that source data are attributable, legible,
contemporaneous, original, accurate, and complete)
â€¢ Ensuring both investigators and sponsors have access to study data and documents
The revisions aim to balance eï¬ƒciency 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 clariï¬cation.
ICH (2016) E6(R2) Revisions by Section
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 deï¬nitions to the glossary:
â€¢ Certiï¬ed copy (section 1.63)
â€¢ Monitoring plan (section 1.64)
â€¢ Validation of computerized systems (section 1.65)
Section 2 – The Principles of ICH GCP
Reï¬‚ecting modernization from paper-based documentation to electronic systems, section 2.10 includes a
minor clariï¬cation 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 veriï¬cation.
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
â€œInvestigatorâ€™s Qualiï¬cationsâ€ section and the investigator is still allowed to delegate trial-related
responsibilities. â€œAdequate Resourcesâ€ revisions specify that the investigator is responsible for supervision
(oversight) of persons with delegated tasks. Further, the investigator should ensure research staï¬€ 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 â€œRecords and Reportsâ€ also mirrors the FDA in specifying that â€œsource data should be
attributable, legible, contemporaneous, original, accurate, and completeâ€ (ICH 2016). The commonly used
acronym is ALCOAC. Records and reporting may be written or electronic.
The record identiï¬es who created or modiï¬ed the record, when
the record changed, and why it changed.
The record and dates of an entry are clear and can be interpreted
The data are recorded in real-time, the data are observed, and
records are signed (or initialed) and dated accurately.
The record is original as it is captured, collected, or is an exact
facsimile of the original.
The record is collected and recorded honestly and completely to
Up-to-date and with no omissions.
Example of â€œAttributableâ€
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 â€œContemporaneousâ€
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 â€œOriginalâ€
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 ï¬‚uid or writing over an original entry is permitted.
Section 5 – Sponsor
The most extensive changes to ICH E6 were made to the sponsorâ€™s section, beginning with a new section on
ICH E6 requires sponsors to implement a â€œquality management systemâ€ 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 identiï¬cation, risk
evaluation, risk control, risk communication, risk review, and risk reporting.
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 sponsorâ€™s contracted CRO (ICH 2016). The sponsor must plan and describe how this will
be assessed. This is typically done through the sponsorâ€™s qualiï¬cation/requaliï¬cation audit of the CRO. This
revision to ICH is a clariï¬cation of expected trial conduct to reduce misinterpretation of oversight responsibilities.
ICH E6 recognizes that sponsors routinely use electronic systems for trial data. Further changes were added in
section 5.5, â€œTrial Management, Data Handling, and Record Keeping,â€ 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 speciï¬c 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).
Eï¬€ective monitoring is critical to ensuring both subject protections and high quality trial data. Monitoring
continues to be the sponsorâ€™s responsibility. By far, the most substantial changes to ICH E6 are related to study
monitoring. The addendum incorporates elements from the FDAâ€™s (2013) risk-based monitoring guidance,
which supports alternative approaches (speciï¬cally, 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 ï¬‚exibility in the
extent and nature of monitoring described in this section is intended to permit varied approaches
that improve the eï¬€ectiveness and eï¬ƒciency of monitoring. The sponsor may choose on-site
monitoring, a combination of on-site and centralized (oï¬€-site) monitoring, or, where justiï¬ed,
centralized monitoring (only). The sponsor should document the rationale for the chosen monitoring
strategy (e.g., in the monitoring plan).
The ICH E6 addendum deï¬nes 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 oï¬€-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 staï¬€) by the monitor in a timely manner and with suï¬ƒcient detail to allow sponsors to
follow up, if needed. This allows and requires the sponsor to follow-up on
identiï¬ed 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-speciï¬c 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).
Section 6 – Clinical Trial Protocol and Protocol Amendment(s)
No changes were made to this section.
Section 7 – Investigatorâ€™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 identiï¬cation, 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)
clariï¬es 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 deï¬nition of certiï¬ed 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 satisï¬es 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 eï¬€ective date of 14 June 2017.
The ICH E6 (R2) guideline continues to provide practical standardization for the conduct of clinical trials. The
revisions reï¬‚ect 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.
â€¢ European Medicines Agency (EMA). 2014. â€œClassiï¬cation and analysis of the GCP inspection ï¬ndings of
GCP inspections conducted at the request of the CHMP.â€ Accessed January 20, 2017.
â€¢ International Council for Harmonisation (ICH). 2014. â€œFinal Business Plan Addendum for ICH E6: Guideline
for Good Clinical Practice.â€ Accessed June 6, 2017.
â€¢ International Council for Harmonisation (ICH). 2015. â€œAddendum to ICH E6(R2) presentation.â€ Accessed
January 20, 2017.
â€¢ International Council for Harmonisation (ICH). 2016. â€œIntegrated Addendum to ICH E6(R1): Guideline for
Good Clinical Practice E6 (R2).â€ Accessed January 20, 2017.
â€¢ International Council for Harmonisation (ICH). 2017. â€œFormal ICH Procedure.â€ Accessed January 20.
â€¢ Investigational New Drug Application, 21 CFR Â§ 312 (2016).
â€¢ U.S. Food and Drug Administration (FDA). 2009. â€œGuidance for Industry: Investigator Responsibilities â€”
Protecting the Rights, Safety, and Welfare of Study Subjects.â€ Accessed January 20, 2017.
â€¢ U.S. Food and Drug Administration (FDA). 2011. â€œOversight of Clinical Investigations: A Risk-Based
Approach to Monitoring (Draft Guidance).â€ Accessed January 20, 2017.
â€¢ U.S. Food and Drug Administration (FDA). 2013. â€œGuidance for Industry: Oversight of Clinical Investigations
â€” A Risk-Based Approach to Monitoring.â€ Accessed January 20, 2017.
â€¢ U.S. Food and Drug Administration (FDA). 2018. â€œE6(R2) Good Clinical Practice: Integrated Addendum
to E6(R1); International Council for Harmonisation; Guidance for Industry.â€ Federal Register 41(83):8882-3.
â€¢ International Council for Harmonisation (ICH). 2014. â€œFinal Concept Paper Addendum for ICH E6: Guide
line for Good Clinical Practice.â€ Accessed June 6, 2017.
â€¢ International Council for Harmonisation (ICH). 2015. â€œAddendum to ICH E6 (R2) presentation.â€ Accessed
January 20, 2017.
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