UK and EMA Inspections Update 2019

2019年3月5日
Bart Cobert

医薬品安全監視、医薬品安全性および規制関連業務に関する執筆者・専門家

We last reviewed government inspections about 2 years ago. There have been some changes and updates making a review worthwhile now. Actually it’s always good to review your company’s inspection status and preparations periodically as a bad inspection will produce headaches for quite some time.  The gift that keeps on giving!

 

UK MHRA

Firstly we must acknowledge the “800 pound gorilla” sitting in the middle of the room: namely Brexit. The current procedure for Good PV Practice (GPvP) is based on the EU requirements. This is noted immediately on the inspection website: “MHRA inspects marketing authorisation holders (MAH) to determine that they comply with pharmacovigilance obligations established within the EU.”

If/when Brexit occurs, it is likely that the procedures will change, as the UK will no longer be subject to EU requirements unless Brexit is delayed or rescinded. Even if this occurs it is highly likely that the procedures in place now will be continued in some form for some time as the inspection process is “not broken” and has been operating satisfactorily for the MHRA for many years.

The MHRA has indicated that vigilance inspections will continue with or without a Brexit deal.  What they have not addressed (at least nothing has been said officially) is the pace of inspections and whether a full contingent of inspectors will be available. It is also unclear how the UK would do inspections in the EU if the UK does indeed leave. The EU would be a “third party” and setting up the inspection will be more complicated. Since companies with registrations (MAs) in the EU will have to register the products in the UK to continue sales in the UK, there will be a longish transition process. For UK inspections, it is likely the local UK MA holder (MAH) would be inspected by the MHRA rather than the MHRA going to the member state where the bulk of the PV work is done.

All of this needs to be worked out and it is likely that the MHRA and the UK inspectorate division will need time to work this out. For practical purposes, companies selling product or doing clinical trials in the UK should be prepared for a PV inspection at any time.

Companies should review their SOPs to be sure that the mechanism to handle an inspection is in place whether Brexit comes through soon or not. Surely, though, there will be changes after Brexit is put into place. As you will see below, the MHRA works with the EMA in preparing the schedule and in conducting the inspection.  This will surely in ways unknown as of now.

 

MHRA Inspection Website

The MHRA has updated its inspection website several times in the last couple of years. This website should be well-known and periodically reviewed by anyone handling PV in the UK and EU.

The topics are:

  • Types of Inspections

    • Routine national inspections-These will presumably continue to be risk-based though whether the MHRA will use the methodology described in the EU Module III or not remains to be seen.
    • EU inspections-This will either change or disappear as the EU will be a “third party”. This category will be replaced in some way by ex-UK inspections.
    • Triggered inspections-Also called “for cause”. These will surely continue.
    • CHMP requested inspections-This will disappear unless some sort of arrangement is set up between the MHRA and EMA. A request from the EU would presumably be handled in the same way as a request from FDA or any other third party is handled.
    • Service provider inspections-These will surely continue though if the provider is outside the UK jurisdictional issues will need to be resolved.
  • Preparing for an Inspection. This section was updated in January 2019

    • Inspections are announced quarterly and the Pharmacovigilance System Master File (PSMF) will be requested. It is highly likely the UK will continue to require this document though changes may be made in the PSMF version for the UK.  Certainly the UK specific label will need to be included.
    • Inspection location. The MHRA is flexible about this and prefers to set up face-to-face meetings but telephone inspections are possible. It is less clear what will happen after Brexit if the PV inspection must be done at a non-UK site where the PV is handled.  This will have to be arranged in any case.
    • Unannounced inspections may be done though this is difficult outside the UK even in current circumstances. Surprise inspections will surely continue within the UK though.  They are rare in Europe unlike the FDA in the US where unannounced inspections are the usual way things are done.
  • The Inspection Mechanics

    • This is largely unchanged and should be reviewed on the website.
  • Fees

  • Inspection Outcomes

    • The Critical, Major and Minor categories are unchanged.
    • Routine inspection outcomes. This is unchanged and reviews the closeout meeting and the preparation for the next steps in the inspection including the receipt by the company of a written report within 25 working days and the MAH’s requirement to respond within 25 working days after receipt.
    • Non-routine inspection outcomes. This was changed somewhat in January 2019 and you should review it.  It covers escalation to the UK groups: GPvP Compliance Management Team (CMT) and, in some cases, to the Inspection Action Group (IAG2).  There is a note that there may be additional inspection fees if this occurs.  The EU PRAC will no longer be involved.
    • Infringement notices. Such a notice may be issued to the company if serious or serious and persistent non-compliance with PV requirements have been found. This will surely continue.

 

The latest published metrics for UK pharmacovigilance inspections show that 22 PV inspections were done from April 2017 to March 2018. Presumably the MHRA relied on inspections done by other EU member states. Whether the MHRA will continue to receive and rely on these reports remains to be seen. Also whether the UK must increase the number of both domestic and ex-UK inspections remains to be seen.

Note: There is a 51 minute webinar recently loaded onto the website describing the technical IT and regulatory issues in electronic submissions to the MHRA including ICSRs and PSURs. The part about PV starts at about 40 minutes.

 

Bottom Line

As you can readily see from this blog and a review of the MHRA PV inspection website, Brexit has produced enormous uncertainty in the PV inspection system in the UK.  The UK has been doing these inspections for over 15 years and the system is well worked out. Brexit is throwing a monkey wrench/spanner (US usage/UK usage) into system.  At this point we know there will be changes but we do not know when they’ll occur or what they will be.  If there is “no deal” between the UK and EU on Brexit, expect chaos in the short and even mid-term periods.

Likely there will be additional negotiations by the MHRA with the newly-located EMA in Amsterdam though these probably won’t occur for some time since the EMA transition will take many months and possibly years. Changes in PV usually take some time to be prepared, agreed on and implemented.

 

For All Companies

As noted above, be sure your company has a system and set of SOPs in place to handle any inspection that may occur.  Coordination with your partners, subsidiaries, affiliates, agents, vendors, service providers etc. in the EU and elsewhere must be assured.  Be prepared for inspections from the EU if the EMA chooses not to rely on or work with the post-Brexit MHRA.

 

For US Companies

If you only sell or study in the US there should be no changes or issues. However, if your US company is international or has vendors or marketing/research partners abroad, particularly in the UK or EU, then they may be touched by these issues and changes. You should be in contact with them to be sure that they are ready for an inspection. If they are inspected you may, of course, be required to provide them data and assistance at short notice. Of course, you are always subject to FDA inspections so your audit and inspection readiness should always be active and in place.

 

For UK and EU Companies

It’s a new world out there. Both the MHRA and EMA are in transition and will be for at least two years as the EMA is moving into its temporary headquarters now and is due to move into its permanent site in November 2019.  As with any move and IT system change/move there will be many things to iron out. This may mean routine inspections will slow down or be delayed. Alternatively, it is probable that the UK will do non-site inspections by phone, internet, etc. Perhaps more than before. Top priority or for cause inspections will continue.  Unless arrangements are made, it is likely the EMA inspections will not include EU personnel. Similarly with the EMA, changes will have to be made as much of EMA’s work was done by the MHRA and that will stop. Inspectors may not come from the UK any longer. This may mean native English speakers will be fewer (As Malta and Ireland will be the only countries with native English speakers). What impact this will have remains to be seen.

 

So for everybody, the same bottom line: be ready for inspections come what may!

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