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.