It is just another routine day in the office and then you receive the call that your company is scheduled for a pharmacovigilance inspection. What do you do? Panic? If that is your first reaction then hopefully this article will help to put your mind at rest by providing some advice and useful tips for how to survive an European Union (EU) pharmacovigilance inspection.
Firstly, it would be useful for you to familiarise yourself with the geography of the EU. The EU is made up of 27 National Competent Authorities (NCA) who all have a legal mandate to perform pharmacovigilance inspections of Marketing Authorisation Holders (MAHs) who hold licences in their territory. The pharmacovigilance inspectorates within the EU realise the value of working together and so there are a number of initiatives in place to try to harmonise practices. However, cultural differences do exist and your experience of a MHRA inspection may be different to that of a BfArM inspection. If your only experience of pharmacovigilance inspections is those performed by the FDA then you should expect something a little different in the EU, not least being requested to provide working lunch for the inspectors.
So what should you expect? If we take the model of a MHRA pharmacovigilance inspection (who have one of the largest and longest running inspectorates in the EU) then the following key steps would usually take place:
The SPS referred to in Figure 1 is the Summary of Pharmacovigilance Systems which is a document developed by the MHRA so that an inspector has information on the MAH prior to the inspection to help to develop the inspection plan. If agreed with the inspector a MAH may be able to submit a Detailed Description of the Pharmacovigilance System (DDPS) in lieu of the SPS. If this is the case then the MAH is also likely to have to submit some supplementary information which is not contained in the DDPS.
The scope and format of the inspection itself can vary according to the type of inspection being performed. Is this the first time the MAH is being inspected? Is this a routine inspection or has it been triggered by a particular issue or concern? Is it product specific or is the whole system being reviewed? Although even if the whole system is being reviewed the inspection team will usually focus on particular products when requesting documentation. The MHRA carries out 3 main types of inspections. The most common are routine national inspections which take place within the UK. These are scheduled inspections which are undertaken on a periodic basis and are notified to the MAH in advance. ‘For cause’ national inspections are triggered as a result of, for example, safety issues, poor compliance with expedited or periodic reporting or referrals from other NCAs. Inspections of this sort may involve inspection of sites outside of the UK if, for example, major pharmacovigilance activities are performed in another country. These may not be notified to the MAH in advance or may only be notified at short notice. The final type of inspection that the MHRA carries out is CHMP-requested inspections. These can either be routine or triggered and involve MAHs who hold products authorised through the centralised procedure. Triggered CHMP-requested inspections are typically conducted at global centres for pharmacovigilance (both within and outside of the EU) and may involve teams from more than one EU NCA comprising both inspectors and assessors.
No matter what type of inspection it is the basic elements of a MHRA inspection are verbal communication (that is talking to relevant personnel to understand the work that they do) supported by written evidence. There is nothing more frustrating to an inspector that interviewees who have been ‘overcoached’ and will only respond with monosyllabic answers. Inspectors need to understand the system to make an assessment of whether it is working in compliance with relevant legislation and guidance documents and an open dialogue between the inspectors and company personnel greatly facilitates this process. Providing limited answers will only lead to further questions and could introduce confusion. Also, anything said during interview needs to be able to be supported by written documents. So if an interviewee describes a new and ‘improved’ way of working that has been introduced the week prior to the inspection this will be obvious to the inspector when documentary evidence is requested. Inspectors are aware that pharmacovigilance inspections do require significant resource and can place a strain on organisations.
Inspectors do try to minimise disruption but it is inevitable that this will occur, especially if your pharmacovigilance department consists of only 1 or 2 staff who need to be involved in all the interview sessions. Some words of advice are:
Communicate – Do not be afraid to pick up the phone and call an inspector if there are issues with the date of the inspection or the inspection plan. Inspectors will try to accommodate requests although this is not always possible. Also, don’t forget to keep communication channels open during the inspection. If you are struggling to get a document which has been requested let the inspectors know as they will understand if there are well founded reasons for the delay.
Be prepared – Inspections will require resource both pre-, during and post-inspection. For example, during an inspection a large number of documents may be requested. Can your documents be readily retrieved including those from sites outside of that being inspected? Do you have adequate printing and photocopying facilities? Do you have a system to track which documents are being provided to the inspectors? If tele- or video-conference facilities are to be used during the inspection, have you tested these to make sure they work?
Be organized – There are a number of activities involved in organising a pharmacovigilance inspection ranging from describing your entire system in the form or a SPS (or similar document) to booking rooms. It is recommended that a person (or group) is identified within the organisation who has oversight of all activities and makes sure things happen on time.
In terms of the actual (MHRA) inspection itself this will begin with a formal opening meeting during which the scope and conduct of the inspection will be described. As stated above the inspection itself consists of interviews and document review. Inspectors may also wish to review computer systems used to support pharmacovigilance activities, such as the pharmacovigilance database. Inspectors will expect to see the live system so MAHs will have to take this into account as part of their inspection preparation. Inspectors may also request to review certain areas, for example the archive facility (if on-site). The topics that inspectors cover during the inspection will depend on the scope of the inspection and the type of activities being performed by the MAH. The topics that the inspector intends to cover will be detailed in the inspection plan (which is usually agreed by all parties prior to the start of the inspection). However, additional areas may be reviewed during the inspection depending on any issues that are identified while on site. Again it is important to be organised. If the inspector asks to speak to someone who is not originally listed on the inspection plan do you know who to contact to make this happen?
MHRA inspections typically end with a closing meeting during which verbal feedback in provided on any deficiencies identified. Provisional gradings of findings will also be provided at this point. So what type of issues do MHRA inspectors come across on inspection? This does vary with time. When the MHRA first started producing metric reports of inspection findings (in 2006) MAHs were being identified who had no or little pharmacovigilance system in place. Thankfully, these type of findings have decreased over time as MAHs become more aware of the pharmacovigilance requirements in place within the EU via inspections and other means. In terms of more recent inspections, findings are now being identified in key areas such as PSUR production, compliance with Risk Management Plan commitments, signal detection and maintenance of Reference Safety Information (RSI). Examples of these are as follows:
- Cases not being presented within PSUR in an appropriate manner
- PSUR assessment report comments not being addressed in subsequent reports
- The status of Risk Management Plans (RMPs) not being discussed in PSURs
- Delays in implementing Risk Management Plan commitments • All sources of information not being included in the signal detection process
- A lack of definition regarding the actions to be taken upon signal identification and timelines for action
- Variations to the Summary of Product Characteristics not being submitted (or not submitted in a timely manner) after identification of a signal
- No assessment of the impact of a label change in one country on another country’s label.
So what happens next? Having inspectors on site is in some way only the start of the inspection process. At some point after the inspector’s visit you will be issued with a written inspection report that sets out your inspection findings and grades them depending on their severity and impact on patient safety or public health. Following issue of the inspection report the MAH will be expected to respond to any deficiencies identified and to provide the inspection team with a Corrective and Preventative Action (CAPA) plan. Some points to consider when responding to inspection findings are:
- Think outside of the box - consideration should not only be given to correcting the specific examples cited in the inspection report, but also identification and correction of the root cause of the deficiency (where appropriate).
- Be honest – do not make promises you can’t keep as any commitments made will be followed-up on re-inspection.
- It’s not just what but when – timelines should be clearly stated for each action.
- Less is more – do not provide reams of information as responses should be clear and succinct.
If you provide unclear or inadequate responses the inspector will contact you for clarifications (again and again if necessary) so it is in everyone’s interest to get it right first time.
So what are the potential consequences of your inspection? If you have findings that have been classified as ‘Major’ or ‘Other’ (‘minor’ is the terminology used for EU inspections) then you will generally agree your CAPA with the Lead Inspector following which your inspection will be closed out. The commitments you have made will then be checked on re-inspection (so it is important that you keep your promises). Within the MHRA, critical findings will be referred to a group whose members represent a number of different specialities within the Agency. Recommendations for action from this group have included early reinspection, sharing of information with other NCAs or the European Medicines Agency, sending a ‘warning letter’ to the MAH or meeting with senior MAH representatives to discuss issues and the consequences of non-compliance. However, in the most serious cases, referral for criminal prosecution may be considered.
Everyone recognises that inspections can be stressful but if you have built quality into your pharmacovigilance system you should have little to worry about. If you are operating a system that complies with the requirements then you should not need to put significant resource into such activities as reviewing all case files prior to your inspection. Remember inspections are a chance for your organisation to demonstrate regulatory compliance; MHRA inspectors are experienced pharmacovigilance professionals and will recognise a compliant system when they see one. So be open and honest, give yourself credit for the things you do well and communicate any issues that you have already been identified to the inspectors at an early stage.
So what is the future for pharmacovigilance inspections? Pharmacovigilance legislation within the EU is due to be significantly revised in the next few years, which is not only going to impact companies who hold product licenses within the EU but also inspectorates. For example, the draft legislation introduces the concept of a Pharmacovigilance System Master File which will act as a key reference document for inspectors. The legislation also introduces significant changes to a number of key pharmacovigilance areas which means that inspection methodology will have to evolve as the regulations change. A more imminent change, for the MHRA, is the introduction of a risk-based approach to national inspection planning. During this year all UK MAHs have been asked to complete a compliance questionnaire, the results of which have been used to generate a risk rating for each MAH. This will help the MHRA to determine the frequency of inspection for each MAH and also the number of inspector days needed for each inspection. In addition, as a number of companies operate on a global basis, inspectorates from around the world are looking for ways to work together so that information can be shared, practices can be harmonised and inspection resource can be used more efficiently.
Finally remember both MAHs and inspectors have the same goals – patient safety and protecting public health.
Patricia Moore is the Operations Manager for a joint Pharmacovigilance and GCP Inspectorate team at the Medicines and Healthcare products Regulatory Agency (MHRA). Patricia joined the MHRA in December 2004 and was promoted to Senior Pharmacovigilance Inspector in October 2007. Patricia still regularly performs pharmacovigilance inspections both in the UK and overseas as well as contributing to the development of the inspection programme. Patricia has an MSc in Clinical Pharmacology and has seven years experience of working in pharmacovigilance within the industry, particularly in the area of clinical safety.
This article was printed in the May/June 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 3. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.