Replies to post #532136 on NorthWest Biotherapeutics Inc (NWBO)

[pqr]

senti I believe the announced intention is to PR the “acceptance” of application, a step indicating that all required modules/submissions are complete and in apparent compliance with submission requirements.

[Magrit]

Senti - Given the attack on NWBO what are the chances they don’t PR submission?

[hyperopia]

I agree that it’s likely that Northwest Bio will announce the final submission of the application. Where are you getting this information about 29 or so modules? I think there are 5 modules in a Market Authorization Application:

Modules of a MAA

1. Administrative and Prescribing Information
* Application form
* Brief overview of Product characteristics
* Labeling text and mock-ups
* Experts’ information
* Risk assessments related to the environment
* Orphan market exclusivity information
* Description of the pharmacovigilance system
* Risk management plan

2. High Level Summaries
* Quality
* Non-clinical overview
* Non-clinical summary
* Clinical overview
* Clinical summary

3. Quality Documentation
* References
* Body of data

4. Non-Clinical Documentation
* Reports of conducted studies
* References

5. Clinical Documentation
* Tabular listing of conducted studies
* References

They are normally submitted in a Common Technical Document:

The Common Technical Document
The agreement to assemble all the Quality, Safety and Efficacy information in a common format (called CTD - Common Technical Document ) has revolutionised the regulatory review processes, led to harmonised electronic submission that, in turn, enabled implementation of good review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities.

The CTD is organised into five modules. Module 1 is region specific and Modules 2, 3, 4 and 5 are intended to be common for all regions. In July 2003, the CTD became the mandatory format for new drug applications in the EU and Japan, and the strongly recommended format of choice for NDAs submitted to FDA, United States.
https://www.ich.org/page/ctd

CTD Triangle
https://admin.ich.org/sites/default/files/2021-02/CTD_triangle_color_Proofread.pdf

It seems pretty clear that Advent has been tasked with preparing the required manufacturing information for the “quality” module of the MAA in the UK, which is also known as the CMC (Chemistry Manufacturing Controls) section of a BLA in the US, and it’s extremely extensive. For anyone that’s interested, there’s a pretty good overview of what’s required here:

ISPE Introduction to CMC Regulatory Affairs
https://www.ispeboston.org/download/educational_presentations/2016/2016-11-10-Regulatory-Symposium-BMamidipudi.pdf

And a pretty good overview of the Rolling Review route in the UK here:

Guidance for new Marketing Authorisation assessment routes in the UK following Brexit: The rolling review procedure
Nasos Kipentzoglou Published Jul 5, 2021

Rolling review procedure

Summary
The rolling review procedure is a new route for marketing authorisation (MA) applications that aim to streamline the development of novel medicines. MA applications for any new active substance, based on a “full dossier’”, including biological products, are eligible for the route. Similar biological applications, i.e., biosimilar products, are also eligible.

Timetable
Assessment of the first module will start from day 0 with the assessment cycle being completed within 60 days. Following each assessment cycle, a Module Assessment Summary (MAS) will be issued by day 60. The MAS enables the applicant to update the module, and the updated modules should be included in the final phase.
The final phase should be completed within 100 days, in two stages with a clock off period after 60 days. The MHRA may issue an RFI by day 60 and applicants will be able to discuss any issues identified in the RFI with the MHRA within 30 days. The clock then resumes on day 61 with the final decision on approvability reached by day 100. The orphan status will be determined at the time of granting the MA.

Application process
Pre-assessment of modules
Applicants should request a pre-submission meeting where the product, its intended target populations, and each module's data to be submitted are discussed. Applicants may specify MA application designations for the UK, GB only or NI only.

To apply for the pre-submission meeting, applicants should forward a copy of the completed application to [e-mail]. and the MHRA will arrange a mutually acceptable date for the meeting. Applications, including the initial module(s) to be assessed, should be submitted via the MHRA Portal.
Under the modular approach, quality, non-clinical and clinical data may be submitted (in the common technical document format) separately or jointly, depending on individual circumstances and/or data availability.

Final phase
For the final phase, a paediatric investigation plan (PIP) compliance check should be completed 60 days before the intended submission. Applicants are redirected to the MHRA’s separate guidance on Procedures for UK Paediatric Investigation Plans (PIPs) for information on the compliance check.

The guidance recommends a pre-submission meeting with the MHRA approximately 90 days before the intended submission for the final phase. At the meeting, applicants can provide a summary of the dossier and raise any special issues such as requests for consideration for an orphan or conditional MA or MA under exceptional circumstances. The pre-submission meeting may offer the opportunity for an early engagement with the NICE HTA evaluation process.
The MHRA will operate a fixed submission date to enable consultation with the CHM and publish a submission date schedule.

Appeals
Applicants can request a review of a decision not to grant an MA using the procedure set out in Schedule 5, and paragraph 11 of Schedule 11, to the Human Medicines Regulations. The MHRA decision letter will detail the appeal process and timelines. If the orphan status is not agreed upon and the company may wish to appeal this decision, the grant of a marketing authorisation will only be possible when the appeal process is completed.

Implications for manufacturers
The MHRA with Rolling review procedure will offer the chance to manufacturers applying for MA to submit increments of the eCTD rather than a consolidated full dossier submission. The rolling review will accelerate the development of novel medicines by offering periodic enhanced regulatory interaction and advice to reduce the risk of failure at the final phase. It may be integrated with the Target Development Profile (TDP) to provide a clearer pathway for the development of innovative medicines.

https://www.linkedin.com/pulse/guidance-new-marketing-authorisation-assessment-uk-nasos-kipentzoglou-2f