EMA and Brexit Yet Again: Part 1
EMA and Brexit Yet Again: Part 1
The saga of the withdrawal (Brexit) of the United Kingdom from the European Union continues. There is enormous turbulence in the UK over this issue with the (Conservative) government in power under Prime Minister May fighting everybody to finalize a Brexit agreement. The Conservative Party is divided and in turmoil over the issue as is most everybody else in the UK and Eire (Ireland). Although there have been many discussions and negotiations between the EU and UK there remain many issues still to resolve. The details are arcane and byzantine. The costs in time lost on this from regular work as well as money are enormous.
The EMA has 2 Brexit websites:
Check them periodically as they are updated frequently. The bottom lines, though, are this:
Nobody knows yet what will happen:
- The UK leaves the EU at midnight Central European Time on March 30, 2019. This leaves only 8 months to finalize the exit agreement. In practice, this needs to be completed well beforehand to allow everyone to put the new system in place.
- Alternatively there may be some sort of agreement finally reached or they may all decide to try to “kick the can down the road” in some fashion to allow more time for everyone to figure out how to do this.
- There may not be an agreement at all which means the UK becomes a “third country” (in the EU lingo). This in turn means the UK is like any other non-member of the EU such as the US, China etc. The EU has various agreements with other countries, however, which allow these countries to have relationships for trading, services etc. in between being a third country and an EU member. Many in the UK want to do this and not be a third country but as of now there is no consensus. There appears to be more work being done now in the UK to plan for the no agreement scenario.
- In July the UK Parliament voted by 305-301 that the UK should remain part of the EMA. This is not binding on anyone however.
- If there is no agreement, then overnight (April 1, 2019) many/most of the laws in place in the UK cease to apply unless the UK passes legislation to continue their application. It is still a mess because the EU changes laws everyday in many areas and thus the UK and EU laws will diverge. Also the EU courts will no longer have jurisdiction in the UK.
The bottom line is that there is no bottom line yet!
This has major implications for the UK, the EU, Ireland (which has the only land border between the EU and UK) as well as “third countries” such as the US, Japan, China and others active in the pharma world.
To a large degree the various agencies of the EU (such as the EMA) are being left on their own to work out what will/may happen after March 30, 2019. This is a moving target and the EMA continues to issue periodic documents and announcements relating to pharma.
Several documents regarding Brexit and the EMA have been updated. Here is a summary of the key points with emphasis on PV and drug safety. Most have the new contents labeled as “NEW”.
EU Q&A from the European Commission
The EU Q&A has been updated as revision 3 on June 19, 2018.
- Question 21 notes that the UK’s withdrawal from the EU does not change the EMA’s expectation that any findings identified in inspections (GMP, GCP, GPVP) will be implemented by the companies inspected. This is not a surprise.
- There is new information on medical devices noted in questions 22 and 23.
- Question 24 notes that the marketing of a product in the same package for use in several countries (“multi-country pack”) cannot have a third country involved if there is a deviation from the SmPC that applies in all EU countries. That is, if there is a multi-country pack covering the UK. Additional wording may be included (e.g. to cover the UK) but it must conform to the EMA and SmPC authorized for use in the EU. This may involve changes in the labeling including the safety section. Careful attention should be paid to this.
- Question 25 covers the situation where the backup for the Qualified Person for PV (QPPV) is located in the EU. This will no longer be permitted as the backup must be located in the EU/EEA.
EMA Practical Guidance on Brexit
This document has also been updated as revision 2 on June 19, 2018.
- There is device information if the Notified Body for a device was in the UK. See question 2A.
- Variations that are type IA (“do and tell”) including immediate notification variations should be submitted within two months of Brexit – that is by May 30, 2019. Actual implementation must be in place before March 30, 2019. See Question 3A.
- There is a simplified method to transfer orphan designations between the same sponsor now based in the UK to a sponsor in the EU/EEA. See Question 5A.
- Question 7A addresses the change in the PSMF location from the UK to an EU/EEA member state. The EU regulation requires that the PSMF be located either at the site in the EU where the main PV activities take place or at the site in the EU where the QPPV operates. The MA holder must take this into account if the PSMF is now located in the UK.
- Question 10 covers the complex situation where an MA application has been submitted and European Commission decision on approval is expected after March 29, 2019. If the application was from a UK based company and the application cannot at this point be changed to an EU based company, it will be necessary to change it during the procedure. This is complex and whole series of documents and actions are required. There is a template supplied for this. See the Q 10 and Q 11 for full details.
- Question 12 discusses the need to update the dossier for a CHMP Scientific Opinion under Article 58 for human medicines. If this is held by a UK company it will have to be moved to a non-UK company before March 30, 2019.
- New contact points for questions related to Brexit are given as email addresses in Question 14.
- Question 15 discusses the change of Rapporteurs and Co-Rapporteurs in the EU that are being transferred to new ones in the EU/EEA. The one may take the lead in the regulatory review procedure if the approval is expected after March 29, 2019. But the new one will only take formal responsibility after March 30, 2019. A “knowledge transfer package” will be made available to the new Rapporteurs and Co-Rapporteurs starting in September 2018. The MA holder may help in the preparation of the packages.
- Question 16 addresses Brexit related changes to the Product Information (Package Leaflet) can be included as part of any other regulatory procedures affecting MA annexes such as a variation etc.
The EMA carried out a Brexit readiness survey in 2018 of over 180 MA holders for 694 centrally approved human and veterinary medications located in the UK. The results were published in July 2018.
The main findings touching safety and PV are:
- Responses were received from from MAHs on over 90% of centralised authorised products (CAPs) that were subject to the survey.
- MAHs are taking steps to make the needed changes. 400 products require a transfer of the MA to an EU/EEA member state. 94% expect to submit the transfer applications before March 29, 2019 and 6% after this date.
- 335 centrally authorized products require a change in the location of the QPPV with 84% expected to be submitted on time and 16% at a later date.
- 376 medicines for human use will require a change in the location of the PSMF with 60% expected to not be made on time.
- 88 of 694 products may not have all the steps carried out in time and this may mean the products are no longer available in the EU market. This is a major concern.
- A majority of the submissions for the required changes by the MAHs are planned for 1Q2019 when the EMA is relocating to the Netherlands. The EMA requests that such submissions be done as early as possible and before Jan 1, 2019 if possible.
In April 2018 the new Rapporteurs and Co-Rapporteurs were informed of their new duties on the 370 centrally approved products now in the UK. In September the knowledge transfer package with each product containing background knowledge on the regulatory and evaluation history of each product, including the most recent benefit-risk assessment, will be sent to the new Rapporteurs and Co-Rapporteurs.
An update to this plan with “final programming” and goals was issued in December 2017. This will be discussed briefly in the next Bart’s Corner as Part 2. The document is 153 pages long!
The next phase of this plan is due to come into effect in October 2018 to “enable staff to cover critical functions”. EMA also indicated that it will monitor the situation to see if there are higher staff loses than anticipated.
Although all the people involved in the EMA Brexit situation are working hard to make the move as well as possible, it is clear that this is, to put it kindly, a challenge and, to put it less kindly, a mess.
As implied in the statement that there might be higher staff losses than anticipated (the scuttlebutt seems to agree with this), the move of the EMA to Amsterdam is an enormous effort. It is akin to refueling a jet in the air. The key functions must continue during the transition. It is highly likely that there will be some adventures and MA holders in the EU and elsewhere must prepare plans to transition their obligations to the new EU Rapporteurs and Co-Rapporteurs, move the QPPV and backup and PSMF if necessary. Companies should also prepare for the worst-case scenario. Although there might be a last minute extension of the March 2019 deadline one cannot count on this.
For US companies with partners or CROs in the EU, you should be in close touch with them to be sure they are handling your product(s) correctly and that the needed paperwork, transfers, etc. are being done. You may want to consider an audit or gap analysis of the what is being done by your partners in the EU and UK.
Tags: brexit, ema, EU, Pharmacovigilance