EMEA Clinical Training

Monthly Scenarios – Communicating Study Issues

Andrew is a CRA working on a study involving the use of a new Investigational Medicinal Product
(CIMP) for the treatment of Arthritis. The PI for this study, Dr Jones, is a well renowned UK specialist
in this area, with previous research experience. The sponsor company specifically asked for this
research site to be involved and has high expectations for quick recruitment

The study start-up team handed over this site to Andrew and he initiated the site two weeks ago. As
promised by the PI, recruitment has got off to a good start, with several patients already enrolled. Andrew
had contacted the study nurse (SN) earlier in the week to schedule an interim monitoring visit (IMV) and
she confirmed that Dr Jones would be available first thing in the morning that day but had a busy
schedule and would need to leave for a meeting soon after. The nurse agreed to make sure that all the
patient records and CRFs were available for review.

During this call the study status was discussed with the SN and Andrew compared subject recruitment
data with that received via IVRS faxes in the office. All seemed to be in order and no other significant
issues were raised during the call.

In preparation for the visit, Andrew took time to update CASCADE, completing the CatS Level 1 tasks to
ensure that all subject records were created and the correct patient statuses were applied.

Part 1

On arrival at site Andrew met with the SN at the research office. All the patient hospital records and
corresponding CRFs were available for review as was the investigator site file. When asked if Dr Jones
was available, the SN said that he would hopefully be arriving shortly. The SN explained that she would
need to leave promptly due to a busy work schedule but would be available later in the afternoon to help
resolve any issues.

Andrew set about monitoring the study paperwork confirming the patient statuses and reviewing all the
consent forms before commencing review of the first patients study data.

During this visit Andrew did not have sufficient time to monitor all the patient's notes and in fact only
completed SDV for the first two patients. Andrew noted the following as a result of this review:

• Patient history for subject 976-001 SD indicated the presence of Rheumatoid Arthritis since 10
years ago with evidence of notable associated swelling. (Inclusion criteria for this study is that
the patients underlying condition should be Osteoarthritis and should be unaccompanied by the
presence of significant Rheumatoid Arthritis).

• SD for subject 976-002 indicated that the reason patient was considered for a hip replacement
was the significant discomfort experienced during long distance running. (Inclusion criteria for
this study states that patients who experience considerable discomfort during normal load
bearing day-to-day activities may be considered for the trial).

• Patient 976-001 experienced a minor fall 10 days after surgery and was admitted to hospital
overnight for observation. Fortunately, nothing untoward was discovered and the patient
returned home the next day with only minor bruises and abrasion to the surgery wound site.

Communicating Study Issues – Scenario Final V1 20 Jan 10 Page 1 of 6

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The SN arrives back later in the afternoon to review the study documentation with Andrew and
apologized for the fact that Dr Jones did not visit this morning stating that he was extremely busy and had
some important business to see to. He would not be available this day.

Questions:

1. What do you consider to be the significant issues at site?

2. What action(s) must Andrew try to take whilst still on site?

Back in the office, Andrew is quick to complete a detailed MVR report. The CTM is pleased with the
report and thanks Andrew for being concise and the report is signed off. During a TC with the sponsor the
CTM advises that there were a few issues at site but these had been resolved and that the CRA was doing
a good job! Sponsor is pleased with recruitment at this site!

Questions:

3. What follow up action should Andrew take and where else should his findings be
documented?

4. What must the PPD study team now confirm with the sponsor regarding patients already
enrolled into the study so far?

Part 2

At the next monitoring visit Andrew soon becomes aware of several more patients having been enrolled
and is quick to start SDV and verify accurate CRF completion by site.

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Andrew is not pleased with the way site have addressed previous issues and identifies some new
significant problems:

- Patient 976-001 was re-admitted to hospital with a secondary infection, likely to have been
related to the fall. No SAE report could be found in the medical records or investigator site
file.

- Of all the new patients monitored by Andrew, two of these were not eligible for the study.

Andrew made detailed notes on Monitoring Editing Notes (MENs) and updated Cascade accordingly and
was quick to review these findings with Dr Jones who was available this day. Dr Jones was surprised to
hear that his team (sub-investigators (SI) / SN) had not paid enough attention to detail but accepted that it
was ultimately his responsibility to manage the study and was apologetic. He assured that he would
personally oversee all significant study procedures from now on and confirmed that in his absence a
delegated SI would be available.

Andrew also contacted the CTM whilst on site to give an update and she contacted the sponsor
immediately to inform them. Sponsor was very concerned about these findings and were surprised not to
have been informed of similar issues identified during the first IMV. They asked for very clear and full
update and requested detailed documentation of the findings in the MVR including a clear action plan.

Questions:

5. In addition to the PI who else crucially should Andrew meet with?

6. In relation to the site staff, what essential documentation should Andrew specifically
review with Dr Jones?

Part 3

At the next IMV the situation had not improved sufficiently with Andrew identifying several potential
SAEs not having being reported. He immediately informed the CTM and the PPD study team promptly
notified the Sponsor and expressed a serious concern about how this investigator was handling the study.
On PPD's recommendation the Sponsor finally agreed that site recruitment be put on hold until the issues
were properly resolved and took advice from the MHRA (UK Competent Authority) on the situation. The
MHRA advised that this should be reported as a Serious Breach of GCP.

PPD / Sponsor contacted the Hospital Trust directly to inform them of the situation. The R&D
department were astounded that they had not been notified previously and expressed their disapproval for
not having been informed sooner – as per the contract.

A significant degree of cooperation was required by all parties to get this site back on track.

Communicating Study Issues – Scenario Final V1 20 Jan 10 Page 3 of 6

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Questions:

7. As a monitor, Andrew was efficient at keeping the CTM informed. However, what else
could he have done to help avoid this situation arising in the first place?

8. Informing the PI of study issues via a follow-up letter is a GCP / PPD requirement. Do you
think it likely that Dr Jones was in receipt of this crucial information forwarded in this
way? How could the efficiency of this process be improved?

9. Do you think the CTM could have communicated more efficiently with the Client?

10. Now that the Sponsor has been informed should, what other parties should PPD / Sponsor
consider notifying?

11. Would it be a reasonable for PPD / Sponsor to notify the R&D department
without the prior consent of the PI?

Communicating Study Issues – Scenario Final V1 20 Jan 10 Page 4 of 6

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References

ICH / GCP

4.0 INVESTIGATOR.

4.1.3 The investigator should be aware of and comply with GCP and the applicable regulatory
requirements. (Section 4.1 Investigator’s Qualifications and Agreements)

4.2.3 The Investigator should have available and adequate number of qualified staff and adequate
facilities for the foreseen duration of the trial to conduct the trial properly and safely.

4.2.4 The Investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the
investigational product(s) and their trial related duties.

4.5 Compliance with the protocol

4.10.2 The investigator should promptly provide written reports to the Sponsor, IEC and where
required by applicable regulatory requirements, the Institution, on any changes affecting the
conduct of the trial and / or increasing the risks to subjects. (Section 4.10 Progress Reports)

UK ABPI SOA (CONTRACT) TEMPLATE:

4.14.1 The Trust shall permit the Trial Monitor and any Auditor or Inspector access to all relevant
clinical data of Clinical Trial Subjects for monitoring and source data verification, such access to
be arranged at mutually convenient times and on reasonable notice. Such monitoring may take
such form as the Sponsor or CRO reasonably thing appropriate including the right to inspect any
facility being used for the conduct of the Clinical Trial and to examine any procedures or records
relating to the Clinical Trial, in accordance with the provisions of clause 6.2 of the
Agreement.‘The CRO will alert the R&D Office of the Trust promptly to significant issues
(in the opinion of the Sponsor or CRO) relating to the conduct of the Clinical Trial.

GLOBAL WPD-CL-36 Site Initiation Visits

7.0 Conducting a Site Initiation Visit

• Thoroughly reviews study specifics, ICH GCP and regulatory requirements with the investigator
and key site personnel, as applicable to the role in the study

7.1.2 Protocol and Study Design

• Monitor to discuss with PI, amongst other things:

12. Protocol and Compliance

13. Accountability / delegation of tasks
14. Subject Safety and reporting
15. Medical Care / oversight of subjects during study

8.0 Completing Post-Visit Activities

Communicating Study Issues – Scenario Final V1 20 Jan 10 Page 5 of 6

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• CTM to notify the PM and/or the Client Company of significant issues and discusses with the
PM the need to escalate issues to other individuals (e.g. PPD Clinical Quality Assurance, PPD
Senior Management) in accordance with the project-specific communication plan

GLOBAL WPD-CL-37 Interim Monitoring Visits

7.0 Conducting an Interim Monitoring Visit

• Notifies the Project Manager and/or Client Company (as described in the project communication
plan) of any significant issues requiring immediate intervention.

8.0 Completing the Post-Visit Activities

• Notifies the Project Manager and/or Client Company of significant issues and discusses with the
Project Manager the need to escalate issues to other individuals (e.g., PPD Clinical Quality
Assurance, PPD senior management) in accordance with the project-
specific communication plan.

Communicating Study Issues – Scenario Final V1 20 Jan 10 Page 6 of 6

EMEA Clinical Training
LMS Code CLN1-05198