Taking into account that I was recently hired for a CRA position in a new pharmaceutical company, I will need to do the next steps prior to scheduling the first monitoring visit:
- Familiarize myself with the company’s general SOPs and Sponsor’s study-specific SOPs (if applicable) relating to the clinical study initiation, conduct, and oversight;
- Carefully read the current version of the study Clinical Monitoring Plan;
- Receive internal training on protocol, study-specific procedures and monitoring;
- If no experience in a protocol-specific pathology, additional therapeutic training by Medical Monitor (or equivalent) is necessary;
- Carefully read all study-related documents, such as protocol, IB, ICF and other patient-specific documentation, protocol-specific PROs (questionnaires, scales, etc.).
Upon completion of all applicable from the listed above, it is necessary to remember that a monitoring of a clinical trial is conducted to ensure (ORCRA, n.d.):
a) ongoing review of the trial progress; b) trial data integrity, validity, completeness and conformity with the source documents; c) compliance of site’s performance with all applicable regulations/GCP/ and adherence to the protocol; d) welfare and protection of trial subjects; e) appropriate storage, allocation, accountability, and disposal of the study drug; f) assistance to LEC/IRB oversight; g) effective communication between the site and the Sponsor and informing the Sponsor of all important aspects of the study; h) the site’s preparedness for internal and external audits.
IMV process consists of (Nemours, 2006):
- Scheduling the IMV (contacting the site’s responsible person to confirm the date and staff availability, preparation and sending the confirmation letter),
- Preparation for the IMV (see below),
- Conduct of the IMV,
The following study-related information must be retrieved, carefully reviewed, and a summary of the most important aspects prepared for reference during a visit:
- All available previous site visits reports to be reviewed. It is important to read the Pre-Study Visit and Site Initiation Visit (SIV) reports, as well as the last one-two Interim Monitoring Visit (IMV) Reports (to clarify: the site’s location, site staff roles and responsibilities, the contact person at the site, the number of previous IMVs, the typical problems identified at the site, and the issues from the last IMV for follow-up).
- Check the unresolved issues that may require your actions, e.g. missing lab reports, insufficient lab/study drug supplies, missing approvals/documents in the Investigator Site File (ISF) to be brought to the visit for filing, insufficient supplies of study-specific ICFs, Questionnaires, scales, SAEs, etc.
- Confirm whether any SAEs have occurred at or since the last IMV and whether these are resolved or not/require follow-up.
- Review the Protocol Violations/Deviations Log (PVL) from the past IMVs if applicable. It is very important to confirm whether any serious protocol violations occurred at the site in the past that needed to be reported to the IRB/LEC, as well as to have a copy of this log with you during the upcoming visit to have an idea what deviations/violations are typical of the site.
- To assess the study risk profile and to understand what aspects of the study must be closely reviewed during IMVs. Though this study has a low risk profile (16%) according to the trial Risk Assessment Form and a Central Monitoring will mostly perform study overview (University of Liverpool/Laureate Online Education, 2010a), it is necessary to pay attention during possible IMVs to the following: a) continuous re-assessment of the Study Nurses’ training on identification of ADRs/AEs as this is a trial of IMP in children (and re-training during IMV if reporting of ADRs/AEs differs from other sites); b) follow-up rates of SAEs reporting (SDV during IMV if differs from other sites, re-training of PI/SN on dose modifications, SAE registration, documentation, and reporting); c) ICFs and recruitment strategies should be verified on-site for all patients if some ICFs not sent to the Clinical Trials Unit/ recruitment is too slow/ any issues are noted; d) discrepancies in reported data, pending DCFs, missing trial data; e) on-site IMV if outcomes are missing for many patients.
- To check whether there have been any regulatory updates / approvals / important communication/ newsletters since the last IMV. Copies to be filed at the site.
- To identify whether any essential documents are missing from the TMF to collect these at the IMV.
Copies of the following documents and the following supplies/tools would be useful during the upcoming first visit:
- A copy of the SIV report for reference and for filing to the study-specific ISF if missing;
- A list of the unresolved issues that were identified during the previous IMV and require(d) follow-up;
- A list of missing essential documents for this site;
- Copies of initial/follow-up SAE reports if any since the last IMV;
- A copy of the PVL from the last IMV for reference;
- A copy of the protocol visits schedule separately for reference (and the latest version of the protocol itself); it may be useful to make a small binder with the schedules for all patients (with the place for notes on the reverse) and to check whether all procedures have been performed within the timelines – easy to follow-up and check what have been SDV-ed;
- A copy of the GCP for reference during discussion of issues with the site staff / re-training;
- A copy of the Visit Confirmation Letter that must be prepared and send to the site by fax/e-mail before the IMV (to be filed to the communication section of the ISF if not done by the study staff);
- Copies of any new regulatory approvals, amended documents, important communication/ newsletters to be filed to the ISF.
The following information to be included in the Site Visit Confirmation Letter:
Name of PI
Name of the protocol/study:
Dear Dr. [PI],
My name is [Name] and I will be your new CRA for the study specified above. With this letter I would like to confirm that my interim monitoring visit is scheduled on [date, time]. This was agreed with your Study Coordinator [Responsible person’s name] on [date].
The main purpose of the interim monitoring visits is to review and discuss the study conduct, to confirm that subjects’ safety and welfare is protected at your site, to review storage conditions, allocation and accountability of the investigational drug(s), to perform SDV and to ensure that trial data produced by the study sites are accurate and valid.
My visit will begin at 08:00 am and will last approximately 6 to 8 hours.
I will need to meet you personally (it will take approximately 15-20 minutes in the end of the visit to sign some study documents and to discuss study progress/findings at your site), as well as your Study Coordinator [Name], Study Nurse [Name], Pharmacist [Name], and a Sub-Investigator [Name] during the visit. Assistance of the Study Coordinator and/or Study Nurse may be required during the whole visit.
Please kindly prepare the following documents/supplies for my review during the visit:
- Informed Consent Forms (ICFs / PICs) for all enrolled patients (both randomized and screen failures),
- All source documents including originals of patients’ medical charts, completed diaries, questionnaires for all randomized patients,
- Case Report Forms (CRFs) for all randomized patients,
- Investigational Site File (please kindly amend it with all applicable new IRB/LEC correspondence, approvals, and general correspondence for your site),
- All previous or new SAEs documentation, including initial and follow-up reports,
- Original Study Logs: Screening, Enrollment/Randomization, Drug Accountability, Temperature Log,
- All documents related to study drug receipt and disposal,
- Laboratory supplies, including pregnancy tests,
- Study drug supplies, including access to your pharmacy to check storage conditions,
- Autographs, empty questionnaires and other study supplies.
I look forward to meeting with you and your study team on [date]. For the moment, please feel free to contact me at my mobile or office phone numbers [#]. In my absence please contact [Name] who is a Study Manager for this protocol at [#].
- Office of Research Compliance and Regulatory Affairs (ORCRA) (n.d.) Monitoring Guidelines and SOP Manual: Interim Monitoring Visit [Online]. Available from: http://researchcompliance.uc.edu/FDA/Documents/Monitoring%20SOP/MON%20SOP%20Mon%2004%20Interim%20Monitoring%20Visit.doc (Accessed: 08 November 2010).
- Nemours (2006) Standard Operating Procedure for Sponsor/ CRO Interim Monitoring Visits [Online]. Available from: http://www.nemours.org/filebox/research/sop304.doc (Accessed: 09 November 2010).
- University of Liverpool/Laureate Online Education (2010a) Risk Assessment Form from MCR Module 4 GOODCP, Week 2 [Online]. Available from: University of Liverpool/Laureate Online Education VLE (Accessed: 08 November 2010).
- University of Liverpool/Laureate Online Education (2010b) HA Details from MCR Module 4 GOODCP, Week 5 [Online]. Available from: University of Liverpool/Laureate Online Education VLE (Accessed: 08 November 2010).