NorthWest Biotherapeutics Inc (NWBO)

[Lykiri]

The timing of inspections and the so-called "clock-off" mechanism plays a key role in the assessment of marketing authorisation applications (MAAs). To better understand how this works in the UK during an MAA procedure, I recently contacted Julian Beach, MHRA Interim Executive Director of Healthcare Quality and Access. He has been very helpful in the past in the context of the DCVax-L application, and this time I reached out to him with a general question regarding the timing of inspections and when exactly the review clock is paused or resumed.

At the European Medicines Agency (EMA), around Day 180 of the centralised assessment process, a Request for Information (RFI) is typically issued. This phase often includes inspections of the manufacturer and other relevant parties (e.g., CROs, statisticians, database providers). During this period, the review clock is paused (“clock-off”).

The clock may be resumed on Day 181, but only if two conditions are met:

1. The final inspection report has been received by the Rapporteur and Co-Rapporteur.
2. The applicant has provided complete responses to all questions raised in the RFI.

This procedure is outlined on page 139 of the official EMA Pre-authorisation Procedural Advice for Users of the Centralised Procedure.

The MHRA confirmed in their response that they follow a similar approach:
🔹 The clock remains on during the pre-inspection phase.
🔹 If GxP-related issues arise during the assessment, the clock may be paused.
🔹 The scientific review resumes only once all inspection-related issues and other outstanding questions have been fully addressed.

The following is a chronological overview of the written correspondence with Julian Beach and the MHRA regarding this matter:

May16

Subject: Clarification on Inspection Timelines and Clock Management under UK National Procedure

Dear Mr. Beach,

I hope this message finds you well.

I’ve been reviewing the guidance related to the UK national assessment procedure for innovative medicines, including ATMPs, and I would greatly appreciate your clarification on a few points that remain somewhat unclear to me.

Specifically, in relation to the 210-day clock: once the pre-inspection phase begins—typically around one month prior to the onsite inspections—does the clock pause ("clock-off") at that point? And does it remain off until all inspections have been completed, including any follow-up documentation and responses? Or are there interim periods between inspections when the scientific assessment resumes and the clock is considered "on" again?

Additionally, could you confirm whether there is a general expectation that all inspections—covering the sponsor, CRO, independent experts (e.g., database company, statisticians), selected trial sites and their pharmacies—should be completed within a defined timeframe, for example within six months?

Thank you in advance for your time and any clarification you can provide.

Kind regards,
XXXXX

MAY 16

Dear XXXXX

Thank you for your mail.

On these sorts of request, I would appreciate you going through our Customer Centre "MHRA Customer Services" , so we can answer appropriately.

@MHRA Customer Services please can you coordinate a response here.

I hope this is acceptable.

Thank you

Julian

May 22

Our Reference: CEC XXXXXX

Dear XXXXX,

Thank you for your enquiry which we received on the 16th of May 2025.
We confirm that we are looking into your request and will come back to you. We aim to respond to all enquiries within 18 working days, though in most cases our reply will be sent prior to this.
If after further review, we consider that your enquiry will take longer than 18 working days to respond to then we will let you know.
If you need to contact us again about this request, please quote the reference number above.
Kind regards,

Haddy
MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone [phone]

June13

Our reference: CEC XXXXXX

Dear XXXXX,

Thank you for your email.

We are sorry you have not yet received a response to your enquiry. We are following this matter up and hope to respond to you as soon as we can.

We apologise for any inconvenience caused.

Kind regards,

Inemo
MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone [phone]

July 9

Our Reference: CEC XXXXXX

Dear XXXXX,

Thank you for your email. We apologise for the delay in responding to your query. We have listed out your questions, below, and added our responses beneath each.

• In relation to the 210-day clock: once the pre-inspection phase begins—typically around one month prior to the onsite inspections—does the clock pause ("clock-off") at that point?

MHRA response: No, the assessment time is not paused at this time.

• And does it remain off until all inspections have been completed, including any follow-up documentation and responses?

MHRA response: If during assessment, confirmation of GxP is required or issues relating to GxP are raised, this may be raised as a point for the applicant to address, and the clock may be turned off at this point to allow the GxP issue to be addressed.

• Or are there interim periods between inspections when the scientific assessment resumes and the clock is considered "on" again?

MHRA response: Assessment generally only takes place once all issues identified have been addressed and full responses received by the MHRA.

• Additionally, could you confirm whether there is a general expectation that all inspections—covering the sponsor, CRO, independent experts (e.g., database company, statisticians), selected trial sites and their pharmacies—should be completed within a defined timeframe, for example within six months?

MHRA response: Confirmation of GxP should be completed with the statutory timelines the MHRA works to. If this is not possible, the MHRA may not be able to conclude positively on the benefit risk of the product in relation to quality, safety and efficacy.

We hope you find the above information helpful. We apologise for any inconveniences caused by the delay in our response.

Kind regards,

Angel
MHRA Customer Experience Centre
Communications and engagement team
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, London E14 4PU
Telephone [phone]