Training, Site Selection and
Human Subject Protection:
Factors to Consider When
Developing a Monitoring
Plan
Cynthia F. Kleppinger, M.D. Senior Medical Officer
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
US Food and Drug Administration
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2
Objectives
• Describe the monitor and staff training
requirements, site selection criteria and
human subject protection practices reported
by CTTI survey respondents
• Discuss strategies to address these factors
in a monitoring plan
3
ICH E6: Monitoring
• The determination of the
extent and nature of
monitoring should be based
on considerations such as
the objective, purpose,
design, complexity, blinding,
size, and endpoints of the
trial.
And E6 says…
• In general there is a need for on-site monitoring,
before, during, and after the trial; however, in
exceptional circumstances the sponsor may
determine that central monitoring in conjunction
with procedures such as investigators’ training
and meetings, and extensive written guidance
can assure appropriate conduct of the trial in
accordance with GCP. Statistically controlled
sampling may be an acceptable method for
selecting the data to be verified.
Survey Results: Training
Assess study staff's understanding
of the trial protocol and procedures
Reality
http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/Clinical+Trial+Insights/The-Heavy-Burden-of-Protocol-Design/ArticleStandard/Article/detail/513703
Verify, in an ongoing manner, the
adequacy of site staff (resources
and training)?
What does ICH E6 say?
• Each investigator should be qualified by
training and experience and should have
adequate resources
• Verifying that the investigator has
adequate qualifications and resources and
these remain adequate throughout the trial
period
Minimum level of education
monitors are required to have
Require that monitors have a
minimum amount of experience
Require that monitors have
continuing education in clinical
research/monitoring
What does ICH E6 say?
• Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately.
• Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
Survey Results: Site Selection
What are the most important
factors impacting site quality? • Quality of training of the research coordinator in GCP,
quality of study-specific training provided by sponsor
• Presence of a qualified clinical coordinator with sufficient time to perform the trial related duties, qualified staff, site staff turnover and capacity
• Design of the protocol, simplicity of the study, complexity of protocol and procedures, clarity of protocol
• Investigator: qualification and experience, dedication, motivation, oversight, commitment to excellence, time
• Monitoring staff quality and experience, quality and availability of the monitor, early engagement of the monitor at the site, company staff experience/knowledge
Rationale for conducting
evaluation of site facilities
• Regulatory/GCP requirements, SOPs
• Facilities & equipment can directly impact trial
conduct quality
• To ensure they are qualified to conduct the study
at their site (appropriate staff/equipment to
conduct study procedures, availability of suitable
patients to enroll in the study, knowledge of
GCP, etc.)
• Commensurate with high study risk
Selection of qualified investigators
who have experience with
intervention or condition
Required documentation is obtained
from participating investigators (e.g.
CV, financial disclosure, regulatory
documentation)
Clinical investigator and staff are
appropriately trained on protocol
or investigational plan
Verify, in an ongoing manner, the
adequacy of protocol-required
facilities and equipment
Factor geographic location of sites
Survey Results: Human
Subjects Protection
Adequate Protection of the
Rights of Human Subjects
Assuring the Protection of
Subject Safety
Assure subjects adequately
informed about the trial
Assure ability to obtain
informed, written consent
Assure ability to maintain ongoing
communication with participants
Require evidence of subjects’
identification verification (e.g.
photo ID)?
Assess Understanding of IC
If so, is it formal testing?
Rationale for Assessment of Consent
• If it is an IRB requirement
• Under-resourced to observe consent process
and assess participant understanding
• Have not found a scalable way to have sites
(willingly) test trial participant understanding of
consents
• Unreliable tools have been problem as has been
translation/cultural barriers to assessing patient
understanding of information
Back-translation of IC
Good News
• Does your organization confirm site
informed consent forms are
updated/modified when necessary:
Always 91%
Conduct an assessment of risk
prior to developing a monitoring
plan for each protocol
Mapping Thoughts to Actions
• Evaluate critically monitor selection. Is it
rationale. Is it consistent. What went
wrong in the hiring of a poorly performing
monitor?
– Is that monitor really qualified and well-versed
on the protocol to be the only
resource/teacher to site staff?
– How is GCP training at the site evaluated by
the monitor?
Oversight of Monitors
• Are the staff truly qualified to critically read
and assess the monitoring reports?
• Is anyone cross-checking the reports?
• Are you critically looking at poorly written
reports to assess the reason?
• Are there on-site evaluations by
supervisors and are they consistently
done?
Site Selection
• Who is really making that decision and
does the rationale map to your quality
expectations?
• Have you critically reviewed a wrong site
selection and corrected the reasons why it
got selected?
• Are you reviewing the quality of the site
staff? Are you re-assessing?
Human Subjects Protection
• Are your values being reflected in your
actions?
• Are you really addressing the issues that
come with the globalization of clinical
research?
Final Thoughts
• A risk-based approach can only occur if
the foundation is solid.
• Quote by EU inspector on a conference
call “Risk assessment is not the same as
gambling”.
Thank you
for your
attention.
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