GCP inspections and how they are conducted has evolved over the years and has had to, due to the increased complexity of trials, organisations, implementation of electronic clinical trial systems and the development of technology. No longer are trial teams based in one office with a paper trial master file (TMF). Inspections can be challenging for all involved and issues have often been encountered during the inspection conduct to do with TMF access and navigation, document request provision and sometimes simply finding the right person to answer a particular question. This can be frustrating for both parties and in some cases can lead to the extension of the inspection. It’s important to remember inspectors are only onsite for a short amount of time to understand your processes and procedures. The inspectors aren’t there to try and catch you out – it’s your opportunity to demonstrate your compliance to them. Inspectors will always be open and honest, and we expect the organisations we inspect to behave in the same way. The ultimate aim of both parties at the inspection is the same; to ensure trial participant safety and that new products are released based on robust data.
So, what should you expect from a routine statutory GCP systems inspection and what can you do to ensure the inspection goes smoothly:
You will receive an email notifying you of an upcoming GCP inspection and requesting a dossier.
DO: ensure the information provided in the dossier is as accurate as possible, that includes the clinical trial listing. If you have any questions, ask. Provide information that your organisation holds, if you do not have that information let us know. But check you have the trial ID and EudraCT number listed, if you are a contract organisation you should still have this. This is the first impression a Lead Inspector gets of your organisation, therefore a dossier and listing with lots of errors is not going to reflect well.
DON’T: spend endless hours collating information unless you are sure it is what we want i.e. if you are a CRO and don’t hold certain information requested in the clinical trial listing as you don’t need it/it doesn’t impact what you have been delegated to do then leave it blank and provide an explanatory note.
DON’T: include hundreds of pages of organograms with the entire organisation named.
Once the dossier has been received, reviewed and it has been decided by the Inspectorate to go ahead with the Inspection an Inspection team including a Lead Inspector will be allocated. The Lead Inspector will contact you to discuss inspection dates and potentially the inspection location.
DO: ask questions of the Lead Inspector if you have any. Reflect on who is going to be essential for hosting the inspection and determine which office location is going to work best. Discuss this with your Lead Inspector.
DON’T: start pestering the Lead Inspector about trial selection, this won’t get you anywhere further faster. We understand why organisations would like this information as far in advance as possible however the regulations clearly state that TMFs should be readily available. So, the more you push for this information the more it may be thought that the TMFs are not going to be inspection ready. The Lead Inspector will be working behind the scenes on trial selection and will notify you in due course and usually in advance of the inspection.
An inspection plan will be provided in advance of the inspection. The plan will detail the trial selection and may also indicate particular systems we will be concentrating on. But remember a plan is just that, Inspectors are not obligated to follow the plan and often on inspection they are not followed to the letter due to various reasons, such as if an issue has come up in a particular trial/area then more time may be allocated to this.
DO: review your TMFs and work out what electronic system access is going to be required for the inspection to ensure the Inspectors have complete and direct access. Discuss this in advance with the Lead Inspector/Inspection Team. See Electronic System Access
DON’T: allocate only senior management to the interviews who are not involved in the day to day processes and therefore are not familiar with the detail of the procedures and associated documentation, as often the detailed questions as to how it happened/worked on the trial can then not be answered. This then leads to follow-up sessions and questions being needed.
Office Based Inspection (OBI)
Your inspection (particularly if you are a large organisation) may involve an office-based inspection (OBI) prior to the on-site inspection. The OBI would be arranged with the inspection host and included on the inspection plan. We are increasingly using OBI for large organisations in advance of going on site as we have found it allows for Inspectors to make better use of the on-site time and reduces the likelihood of follow-up document review which delays the inspection report being issued. The OBI would involve pre-inspection requests having been made, it would then start with a short teleconference opening meeting and then the Inspectors would use the time to review the documents provided.
DO: ensure the document transfer system has been set up and tested (see section Document Requests).
DO: ensure there is a Host available via telephone and email to manage any further requests and queries during the day.
Inspection Facilities on-site
A main inspection room will be required for the document review to take place and if this is a large inspection with an inspection team then further rooms may be required for the interviews. If there are a team of Inspectors adequate space is needed. When conducting the document review Inspectors will want the use of the room to themselves with a method of contacting the Host as and when queries arise. If the inspection involves electronic systems such as an eTMF, then each Inspector will require a computer (including a widescreen or dual screen, keyboard and mouse etc.) to be provided for document review.
DO: ensure the inspection room is set up in advance, including the set-up of the computers and screens.
Electronic System access
Direct access will be required to all systems that make up your TMF and potentially any key clinical trial support systems for example if all of your SOPs, procedural documents and training records are held in a QMS eSystem, access will be required. Inspectors should be provided with the means to access and review all of the relevant systems, this therefore means you will be required to provide a computer with a screen (as mentioned above) for this review. If we are looking at Computerised System Validation (CSV) we'll also need access to systems that manage that system, for example, helpdesk systems. Our access to electronic systems should be read-only, but should not be otherwise limited, this includes access to audit trails which we will want to see. Audit trails may also be requested to be extracted.
DO: ensure this is all set-up well in advance, with any difficulties discussed with the Lead Inspector prior to the inspection start. Inspection time is valuable and therefore lengthy amounts of time on the first day getting system access and sitting through training sessions should be avoided.
DO: ensure as a company you know all the systems that make up your TMF and ensure you can give Inspectors direct access. Discuss this with your Lead Inspector up front to ensure access is provided as expected.
DO: anything you can to aid electronic system access, links on desktop, short crib sheet, ensure lock-out times are reasonable, minimise need for numerous passwords where possible etc. Inspectors conduct many inspections every year and each inspection may involve several electronic systems.
DO: Inspectors are happy to have training in electronic systems new to them, however do make sure the training is efficient and useful in ensuring competence in using the system, for example a system demonstration is much more useful than presenting slides which could be read through in advance of the inspection.
This will be led by the Lead Inspector who will cover the legal basis of the inspection and inspection logistics, followed by brief introductions to everyone in the opening meeting. Once this is done, we will hand over to the hosts to provide an introduction or update on their organisation.
DO: prepare and provide an introduction to the organisation, please keep it brief and pertinent to clinical trials. We won’t need to see the long organisational chart again.
DO: feel free to invite whomever you would like from your organisation to the opening and closing meetings. It can be good idea to get all those that are going to be interviewed in to at least say hello to the inspectors, it generally helps with nerves if they see we are quite human!
The TMFs are the legal basis of the inspection however additional information and documents will be requested to demonstrate supporting systems and GCP compliance. Historically document requests have been paper based and paper has been provided back to us clearly labelled with the relevant request ID. This often still works at Investigator Site inspections and single site organisations which work in paper themselves day to day. However, for large organisations we have found that electronic is becoming the preferred method for this exchange which we are happy to work with and have been changing our processes to allow for this. The method for document requests should therefore be agreed up front with the Lead Inspector. If it is decided to work electronically an electronic repository/eRoom is likely to be required (emailing multiple documents tends not to work), this again should be set-up and tested in advance. When documents/data is made available in an eRoom there needs to be a mechanism in place for notifying the Inspectors that the document is now available.
DO: discuss and agree a process for document requests in advance with the Lead Inspector.
DO: if the document requested is already available in the TMF and the Inspector has not located it, do show us the document in the TMF rather than providing a duplicate.
DON’T: provide redacted, shortened, incomplete responses. This could also be seen as impeding the inspection. This is your opportunity to demonstrate your GCP compliance so provide the complete picture, not a partial one as it will only lead to further requests which is onerous to everyone involved. Work transparently with the inspectors to ensure what is provided is provided as expected the first-time round.
DON’T: leave us waiting. If you know you don’t have something, or you have found out it will take a significant amount of time to retrieve then let us know. We may be able to shorten the request or work with you to provide an alternative document that will answer the question.
DON’T: make assumptions about what we want, if it isn’t clear then ask whomever has made the request.
DO: ensure document requests can be provided in a way that is efficient and that answers are provided in full. Avoid a lengthy document request process, we have seen on inspection huge hosting teams and document requests have to undergo so many checks and balances that it takes a significant amount of time to return the requests. This could be seen as impeding the inspection (obstructing an inspection is an offence under the regulations). We appreciate in large global organisations that a document request may not be straight forward, but hopefully you have systems in place that should support an efficient inspection process.
Interviews will be conducted throughout the inspection, as formal interviews to cover systems and as ad hoc question sessions to clarify questions and queries as they arise from the document requests. We understand that some people can be nervous, we will do our best to put people at ease, and if anyone wants to provide post interview clarifications or additional information then we welcome that too. It is preferable to perform interviews with all the interviewees present in person, however often this can’t be achieved, and interviewees need to call in. This does make the interview more challenging for all involved, particularly if the interview session is being done as a show and tell, i.e. if it is expected that the interviewees will demonstrate the documentation as they describe the processes followed.
DO: ensure those that are selected for interview can cover the full end to end processes being inspected and can demonstrate evidence of compliance within documentation available on the selected trials.
DON’T: flood the room with so many staff and QA that no one wants to speak up to answer the questions. Interviews for those being questioned can be stressful enough without extra observers. Inspectors expect that the organisation will want a scribe and potentially a member of QA to be present however aim to keep the number reasonable.
DO: ensure the rooms to be used for interviews are well organised i.e. if people are calling in ensure the room has been set-up to enable screen sharing etc.
Any findings and concerns will be raised with the organisation as they are found as this should ensure the organisation has opportunity to provide any further clarifications during the inspection and the organisation understands the issue and has opportunity to start to think about impact and CAPA. All findings will then be collated by the Lead Inspector and summarised at the closing meeting. Findings given at a closing meeting are as accurate as possible at that point but may be subject to slight change as there may be follow on inspections, i.e. investigator site inspections to be performed and also inspection reports undergo peer review. If potential critical findings are found the process for these will be explained including the Inspection Action Group (IAG) referral process.
DO: ensure you are clear on what the findings are and ask questions if you are unsure.
DON’T: wait until the closing meeting to challenge findings, raise concerns/clarifications etc when the finding is first raised during the inspection conduct. This is beneficial to all as at this point the Inspector/s still have time to review any follow-up clarifications/evidence. Raising at the closing meeting is just too late, and therefore the findings will be reported, and any responses will have to be in writing.
Report, responses and inspection closure
If critical findings have been found an expedited letter will be provided and responses to the critical issues required in advance of the full report. The full inspection report will be provided by the Lead Inspector within approximately 25 working days of the last date of the inspection (this could be the last outstanding paperwork to be submitted or the end of the last investigator site inspection). If there are any delays in providing the report the Lead inspector will let the organisation know. The organisation then has 25 working days to provide a written response and CAPA to all findings. Once the organisation has provided responses with CAPA they are reviewed by the Lead Inspector. The Lead Inspector will decide if each CAPA can be accepted or rejected, if they are not accepted queries will be sent back to the organisation to action. Only once the organisation and Lead Inspector have agreed upon the CAPA can an inspection statement be issued to the organisation and the inspection will closed by the Inspectorate. If quarterly update reports are required to be submitted the inspection statement will include this, the expectations for the quarterly report content should be agreed with the Lead Inspector.
DO: contact the Lead Inspector if you have any questions or concerns once you have received the report.
DO: ensure CAPA provided is proportionate, measurable, timely, fixes the root cause and is followed-up through implementation with effectiveness checks.
DON’T: provide non-committal responses and CAPA, ‘the sponsor will consider…’, ‘this is acknowledged’. As these types of responses and CAPA are likely to not be accepted by the Lead Inspector and therefore closure of the inspection will take longer. If the organisation continually provide unacceptable CAPA further action may be taken and the inspection statement will be issued reflecting this.
DO: the responses should be clearly set-out and should state what the found root cause is for each finding.
A few final points to consider;
- MHRA GCP Inspectors like to drink lots of tea.
- Please don’t accompany us to the toilets, since I started as an Inspector, I have never understood why companies do this, we have better things to do on Inspection than to start wandering around aimlessly.
- If you think the Inspection would be better to be conducted outside of the UK contact the Lead Inspector about locations. It may be more cost effective for inspectors to travel to your HQ, rather than having a large number of your staff travel to the UK.
- Be transparent, if you know of problems it is best to let us know up front and present your CAPA plan rather than waiting for us to find the issues (or hoping we don’t). Although issues may have occurred, identifying them and demonstrating what you are doing to fix the issues reflects on a much healthier culture, QMS and QA systems in comparison to hiding it or not knowing at all.
- The Inspection Host can be key to a smooth inspection, the host needs to be sufficiently senior, needs to have a thorough understanding of the organisation and the processes (to ensure they know where to get the answer to any questions) and should be an excellent organiser and communicator. A good relationship built on professional respect between the Host/s and Lead Inspector makes the Inspection process much more pleasant for all involved even if the inspection outcome involves significant findings.
- Communication is key not just with the Lead Inspector, please copy in the full inspection team on any emails. This enables the full team to keep up to date with the inspection and if the Lead Inspector is not available one of the Assisting Inspectors can help with any urgent queries.
- Post inspection if you find that the agreed CAPA requires significant change, is delayed, cannot be implemented/has been halted i.e. due to a company acquisition then the GCP Inspectorate should be notified at GCP.Inspectiondossier@mhra.gov.uk
- If you as the host organisation have any concerns about an inspection (or would like to provide positive feedback following an inspection!) please contact the MHRA GCP Operations Manager.
- Inspectors are there to work with you not against you, we are all working towards the same goal, to ensure clinical trials are conducted safely and are producing accurate and reliable data.
- We are all human, it is better to ask than assume wrongly.
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