Insights from EFPIA's Reliance Webinar

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Insights from EFPIA's Reliance Webinar

04.06.24

On the 19th of March EFPIA have hosted a joint industry webinar on Reliance, providing a platform for information and discussion on use of EMA assessment outputs for use in global regulatory reliance pathways.

Spearheaded by EMA, with the participation of WHO and global regulators such as the Egypt Drug Authority and Health Sciences Agency Singapore, the webinar was well attended by 1600+ participants including regulators from 38 countries from across the timezones. international collaboration is a necessity today not a choice said Emer Cooke, Executive Director of EMA, who opened the session that had excellent content on the purpose of the various assessment document outputs and their respective usefulness for regulatory reliance by international agencies.

Watch our space for more such collaborative and open conversations with the regulators with the aim of bringing innovative medicines to a globalised world.

Watch the event recording here.

Below you can find the answers from speakers to the audience's questions.

There are health authorities that are requesting assessment reports for all variations in scope of reliance. However, the assessment reports are issued for type II variations. Is there any consideration given to issue, perhaps, abridged assessment reports for type IA, IB changes as well?

This questions was answered by EMA.

Type II and IB variations always have an assessment report that is shared with the applicant. Only minor IA notifications do not have an assessment report, but an acknowledgement of receipt is issued for all IAs describing the proposed changes. This document is always sent to the applicant and can be shared with any receiving authorities.
On which basis the AR will be released for a type II variation?

This questions was answered by EMA.

EMA issues an AR for all Type II variations. This AR is provided to Marketing Authorisation
Holders which can be submitted to other health authorities for reliance purposes. The Agency only publishes publicly the AR for Line Extensions of Approved Indications of the medicinal product.
For major Post approval changes and Type IB changes, what documents from EMA could be available to support the reliance?

This questions was answered by EMA.

EMA issues an AR for all Type II and Type IB variations. This AR is provided to Marketing Authorisation Holders. EMA also issues a CHMP Opinion (for type IIs) and Type IB Notification document. For Type IAs variations, the only document issued is the Acknowledgement of Receipt that includes the description of the approved change. These documents are not published, but provided to Marketing Authorisation holders. We always publish a line listing of all approved variations in the EPAR page of the product at EMA website. Any interested party can thus confirm that this procedure has been approved at EMA.
If a product is submitted for registration through reliance procedure but there has been PACs approved since the initial marketing authorization by EMA, should the applicant submit approvals and assessment reports for these PACs, in addition to the initial MA assessment report to the NRA for the product to be registered via reliance?

This questions was answered by the Industry.

The applicant should explain the situation and clarify the expectations with the local NRA.
Would HSA be able to elaborate on the decision process to rely on approval letters for post-approval changes, not mandating assessment reports, for certain types of approval pathways and changes, and situations where unredacted assessment reports are mandated?

This questions was answered by HSA.

The reliance on an approval letter from a reference agency for post-approval changes is acceptable if the description of the change in the approval letter is adequately detailed to verify that the proposed change is identical to that approved by the reference agency. If the accompanying approval letter lacks the required details, the application will require a standard evaluation.

For US GMP certifications where you have reliance GMP's, do you update or create an entry in EudraGMP database?

This question was answered by EMA.

GMP certificates are issued after an inspection. If there is reliance on other authorities, no EEA GMP certificate will be issued, but it might be possible that the validity date of an existing certificate is extended based on reliance.

The EudraGMP database only includes GM information from EEA authorities and some MRA partners; it does not include GMP certification status from third country authorities.

The EudraGMDP database is the Community database on manufacturing, import and wholesale-distribution authorisations, and good manufacturing-practice (GMP) and good-distribution-practice (GDP) certificates.
What does Clarifying Remarks on GMP imply? Should we consider the date on the Clarifying remark as the expiry date of the GMP?

This question was answered by EMA.

In the clarifying remarks, comments can be included on the scope of the inspection (e.g. related to a specific product or building only), but also a shorter validity can be included in there. If a shorter validity date is included, you should consider this date as the expiry date.
Can the GMP certificate after its delivery, be revoked? And in which cases?

This question was answered by EMA.

GMP certificates can be withdrawn in case of a non-compliance statement or when a new GMP certificate is issued.
Are there GMP's that have expired / past reinspection dates that should be updated on EudraGMP database? What is EMA's plan to complete these reinspections or update the dates of such GMP's on EudraGMP database?

This question was answered by EMA.

It is possible that there are GMP certificates in the database with an inspection date >3 years ago, but as included in the footnote of the EudraGMDP database, all certificates are extended until end of 2024 unless where there is a clarifying remark included in the certificate. Once a re-inspection is performed a new certificate will be uploaded by the competent authority.
For GMP certificates that have the validity elapsed but NCA has confirmed it in the process to re-issue a new GMP certificate, would it be recommended for NCA to issue a statement to support the GMP validity so other 3rd country NCAs can stil rely on the GMP cert (especially PIC/S).

This question was answered by EMA.

There is a footnote included in the EudraGMDP database that the validity date of the GMP certificates is extended until the end of 2024, unless there is a clarifying remark included in the certificate that indicates a shorter validity date. For questions related to a specific GMP certificate, the issuing NCA should be contacted.
1) I would like to confirm if all the certificates issued by a country that is a member of the European Union, are in the EudraGMP data base.

2) Why can a site have different GMP certificates, even if it is located in the same address?

This question was answered by EMA.

1) In general, all certificates issued by an EEA member state should be included in the database. If there is a specific GMP certificate you cannot find, you can always contact the issuing authority for clarification.

2) a GMP certificate only reflects the activities in scope of a specific inspection so it is possible all authorised activities are included in different GMP certificates.
Can you comment more about the GMP Inspection Reliance Assessment Report template? is this used by EMA only or is it suggested that be used by all PIC´s members? Is it also a recommendation that all PIC´s member accept/used this report to apply the reliance?

This question was answered by EMA.

The GMP Inspection Reliance Report template can be used by all Pharmaceutical Inspection Co-operation Scheme (PIC/S) participating authorities. The template provides a recommended content and you can use this as such or as a starting point.
Thanks for highlighting the important point about OMS implications. Just to reiterate, even though the OMS statement is reflected in the eCPP segment of this session: this will impact not just the eCPPs but also other certificates, e.g., GMP certs in the future.

This question was answered by EMA.

OMS will be the data source for all the EMA systems over time. GMP certificates for CAPs are already using OMS data. It is for companies to ensure that the information contained in Module 3 and Product Information is harmonized with OMS data to avoid discrepancies.
How soon does EMA go for inspection for a site outside EU as soon as site is ready for EMA inspection?

This question was answered by EMA.

Please note that EMA itself does not perform inspections but has a coordinating role for inspections of centrally authorized products only. Pre-approval inspections are performed within the procedure timetable, but the exact timing depends on the availability of the inspectors of the national competent authorities.

European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure (europa.eu)
EMA Certificates - is renaming the certificate an authorized change?

This question was answered by EMA.

GMP certificates are issued by the EU national competent authorities. If a change is needed, the issuing authority should be contacted to verify if this is possible or not.
The GMP certificates in the EudraGMDP database are sometimes updated frequently. Do you have any recommendations to avoid scenarios where the referenced GMP certificate is no longer available in the database during the ongoing registration procedure just because a new version of the GMP certificate was uploaded to EudraGMDP?

This question was answered by EMA.

It is difficult for EMA to foresee changes in the content of the database as this content is provided by the EEA NCAs. If during MA application procedures further clarification is needed following an update, the applicant or issuing NCA shall be contacted.

Who can request an eCPP for a particular product (anyone or just the MAH)?

This question was answered by EMA.

eCPPs can only be requested by the Applicant/Marketing Authorisation Holder or a third party acting on behalf of the MAH.
Would you please share with us the link to CPP draft on OMS site?

This question was answered by WHO.

Please find the CPP information on the WHO Website.

https://www.who.int/teams/regulation-prequalification/regulation-and-safety/regulatory-convergence-networks/certification-scheme
We do not get legalization for eCPPs. In some countries this is still necessary - how can we proceed in this case? Would you send a paper CPP if this happens?

This question was answered by EMA.
We do not consider legalisation to be necessary as eCPPs and electronic signature and online validation tool guarantee the full integrity and authenticity of the document. EMA provides a letter confirming that we do not issue printed versions. EMA also replies to any query via email, but does not issue printed CPPs anymore.
Would you please mention the email I need to contact in case I need help in the verification page as you said there are some glitches that happen from time to time.

This question was answered by EMA.
All the details are on this page on the EMA website:https://www.ema.europa.eu/en/human-regulatory-overview/post-authorisation/certification-medicinal-products
What initiative or proactive approach is EMA taking to address/ align with Agencies still requiring EMA eCPPs needs to be further authenticated - i.e. legalisation, notarisation, apostilles etc?

This question was answered by EMA.

We promote the message that further authentication is not considered necessary by EMA. We have issued a letter explaining this and also flyers. EMA is available to provide clarification to any regulatory authority.

Information note on the format and validity features of electronic certificates for medicines issued by the European Medicines Agency (europa.eu)

Online verification system for electronic certificates issued by European Medicines Agency (EMA) (europa.eu)
Is it possible to do a collaboration with all embassies to start electronic legalization to save time and money?

This question was answered by EMA.

EMA does not consider necessary the need for legalisation. We consider it is a redundant procedure, considering the eCPP security features fully guarantee the integrity and authenticity of the document.
eCPP is issued for finished product but it does not reflect specific information about active substances, excipients or intermediate products. Is the approval letter in that case the best document to be used for reliance?

This question was answered by EMA.

The quantitative composition of the product can be provided and requested to be attached to the eCPP by the applicant, provided it corresponds with the approved records. It is for the NRAs to decide which type of documents should be requested for reliance.
Is the eCPP implemented across the individual NRAs in the EU/EEA or it is only implemented by EMA?

This question was answered by EMA.

EMA has been the first authority worldwide to issue eCPPs, but some National Authorities in EU member states also issue eCPPs.
Is there a letter available to explain to the destination countries that legalization isn't added evidence of authenticity?

This question was answered by EMA.

Yes, EMA has issued some letters ('To whom it may concern') explaining this. You can request a copy by email to certificate@ema.europa.eu.
Has the EMA ever been requested to verify information such as name and location address of marketing authorisation holders, manufacturers when there's discrepancy with what was submitted in other countries after WHO was introduced?

This question was answered by EMA.

We have not been approached directly by any authority regarding discrepancies in the way an address is expressed. If we receive the question, we will check the origin of the discrepancy and clarify with the receiving authority.
I´ve learned that EMA eCPP allows to include only 1 DP/DS manufacturer . Is this correct? If yes, is there any update plan to allow including of more than 1 manufacturer, if applicable.

This question was answered by EMA.

It is not correct. An EMA eCPP has to contain at least one manufacturer of finished product but more can be requested and included provided the sites have been approved in the EU.
Has every european country a website to check the CPPs documents? As EMA does.

This question was answered by EMA.

Some Authorities have implemented similar systems or are considering doing so.
Could you please share a bit of insight on EDA's position of acceptance of non-legalised documentation (especially eCPP's) and also what EDA is doing on the collaborative front for MENA and the GCC?

This question was answered by the Industry.

Kindly check this link for a webinar where EDA participated for this specific topic as a speaker https://www.ifpma.org/events/new-procedures-and-policies-for-the-electronic-certificate-of-pharmaceutical-product-ecpp/
Digital certificate, is only by Products? Or by GMP? Or by API? In our country, should we have this kind of platform?

This question was answered by the Industry.

For now, only CPPs are issued in digital format. The digital verification tool is linked to the eCPP. An eCPP is usually issued for a specific product. The use of eCPPs does not require any specific platform.
Knowing that there are manufacturers that produce products for the EU (A) and for other countries (B). How do you know that the ecpp presented corresponds to product A? How can you find out about API manufacturers?

This question was answered by the Industry.

Multi-national innovative companies usually produce products under the same QMS (Quality Management System) regardless of manufacturing site.

Only for Biological products, API manufacturers are listed in the Annex II of the Product Information and that Annex can be attached to the eCPP upon request of the MAH.
What practical steps can be done to encourage the HA that still request for authentication / legalisation of eCPP to reconsider this requirement? is there an open forum between agencies like EMA and the likes of WHO to address this with the referring agencies?

This question was answered by the Industry.

More education and advocacy is necessary to ensure HAs are familiar with the EMA authentication tool. Specific outreach and education discussions with those countries could perhaps be helpful.

Our HA has asked for day 80 unredacted reports. Is this a common request?

This question was answered by the Industry.

This is not a common request. Day 80 reports contain only the preliminary assessment from the rapporteur which has not undergone any peer review or other discussion among the EU regulators. It does not contain the full benefit/risk assessment or final conclusion.
Can all the manufacturers submit their product assessment reports when an NRA request them?

This question was answered by EMA.

Manufacturers are able to share assessment and inspection reports with other regulators. In case of EMA assessments and inspections, manufacturers are required to ensure they comply with EU personal data protection requirements.

Marketing Authorisation Holders (MAH) or applicants for centrally authorised products (CAPs) may share EMA assessment or inspection documents for their products with regulators outside the EU. It should be noted that only the final assessment report represents the final scientific discussion and conclusion(s) of the respective EMA Committee. When sharing EMA assessment or inspection documents, the MAH/applicant should ensure compliance with the Union legislation on the protection of personal data, including Regulation (EU) 2016/679 and Regulation (EU) 2018/1725. The MAH/applicant assumes any and all liabilities related to any disclosure, particularly with regard to the need to redact certain references in the documents where appropriate or legally needed (e.g. personal data of the assessor/inspector, quality and manufacturing commercial information). The MAH/applicant should always ensure that the EMA is recognised as the source of the original document.

European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure (europa.eu)
What is the standard timeline for publishing EPAR or other EMA documents at EMA website?

This question was answered by EMA.

EMA will publish the EPAR on an initial marketing authorisation within 15 days after the Comission Decision is issued. However, information is published at the time of submission and other time points as explained in the link below:

https://www.ema.europa.eu/en/documents/other/guide-information-human-medicines-evaluated-european-medicines-agency-what-agency-publishes-and-when_en.pdf

For post-authorization procedures, the EPAR is updated usually within 2 weeks of the opinion (can be longer in case of linguistic review) or 15 days of the Commission Decision.
Can ARs be downloaded by anyone (i.e. is it a public database) or only by the MAH?

This question was answered by EMA.

EPARs (European public assessment reports) are freely available and downloadable from the EMA website. The full assessment reports are shared with applicant companies only.

European public assessment reports: background and context | European Medicines Agency (europa.eu)
Is it preferable for you to share the report directly to the NRA or to the sponsor who will then share with the NRA?

This question was answered by EMA.

Our preference is to encourage sponsors to share, since this also encourages dialogue and openness between sponsors and NRAs. We do, however, expect them to comply with any personal data protection obligations, provide the entire document (not just extracts) and acknowledge the source of the document.
Is it possible for a NRA to rely on more than 1 assessment report (for eg: one from EMA, one from FDA) at the same time in their assessment process?

This question was answered by EMA.

An NRA can choose how it wants to practice reliance. Indeed, some NRAs have procedures that accelerate approval timelines based on both EMA + FDA approvals. So yes, it is possible.

This question was answered by Industry.

We just heard about HSA verification pathway which is as such. However abridged is most used as FDA full assessment reports are not easily / timely available.
May I know what is the timeline for EMA to share the full assessment report with applicant companies after CHMP positive opinion?

This question was answered by EMA.

EMA will share it on the same day of its adoption (at the latest the day after if the meeting finishes late).
We had experience where the redaction of assessor's information (under GDPR) caused the NRA to reject the assessment report because full, unredacted AR is required. What is your advice to all the NRAs which have this requirement?

This question was answered by EMA.

The EMA is obliged to follow EU rules on personal data protection, and it is not something that we can waive. However, the redaction of personal data will not impact any information relevant for the assessment or needed for reliance purposes.

European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure (europa.eu)
Do you share to other NRAs the quality assessment of products being applied for registration in EMA, regardless if it is for approval or disapproval? If so, do you share the final quality assessment, but with highlighted points and its justification?

This question was answered by the Industry.

The final quality assessment is part of the CHMP final assessment report which is shared with applicants, regardless of the outcome being positive or negative.
Based on the EMA team explanation for differences between the Assessment report and the EPAR, can EPAR be used for full reliance case by Reliant authorities?

This question was answered by the Industry.

Yes, as presented by EMA, the EPAR includes the information on the benefit/risk assessment and can be used for reliance.
Would EPAR be sufficient for utilizing in reliance country decision? Should the full (unredacted) AR be necessary for all applications?

This question was answered by the Industry.

The EPAR is a public document that provides very comprehensive information from the assessment and can be easily retrieved and shared. The EPAR reflects the scientific conclusions of the relevant committee at the end of the assessment process, providing the grounds for the committee opinion on whether or not to approve an application.

WHO guideline encourages the use of the public assessment report for reliance purposes to the greatest extent (see Good reliance practices &6.3). If additional information is required for the regulatory decision making, this should be detailed by the relying agency and can be provided.

trs1033_annex10-good-reliance-practices.pdf (who.int)
In reference to Brexit & Windsor framework for centralized registered products, can sponsers share with MHRA unredacted assessment reports during 2024 as Northen Ireland is still a member state in the centralized proceedure?

This question was answered by the Industry.

Assessment reports of Centralized procedures are being shared with MHRA as part of the Brexit agreements in relation to the territory of UK(NI). This practice will stop once Regulation (EU) 2023/1182 implementing the Windsor framework agreement becomes applicable, since the MHRA will become the only competent authority.

But as detailed in question 34, Manufacturers are able to share assessment and inspection reports with other regulators.

We would like to learn more about EMA participation in WHO Collaborative Procedure, will this be part of today's discussion?

This question was answered by EMA.

You can also find information at this link on EMA website:

https://www.ema.europa.eu/en/partners-networks/international-activities/multilateral-coalitions-and-initiatives/world-health-organization-who
To submit the relevant WHO annexes (QIS) to EMA for endorsement, does applicant connect to EMA directly or WHO will connect the applicant to EMA?

This question was answered by EMA.

This goes through WHO, which then asks EMA to verify the QIS.
What should be our approach to get an important drug approved in global markets in say less than 2 years (being ambitious). What should be the right way to start and what would be your tips to get this done?

This question was answered by EMA.

One route could be to have an EU centralised approval, and then use the WHO SRA-CRP procedure. An important element is to align regulatory submissions to make sure that regulators have the same dossier at the same time. EMA also operates the 'OPEN Pathway' with Australia, Brazil, Canada, Japan, Switzerland and WHO.

In any case, MAHs are responsible to choose the appropriate regulatory pathways depending on the type of product and commercial strategy.
While accessing reports from EMA has been effective, it’s not the case for other reference agencies. What is the WHO doing to encourage support of this process by other reference agencies?
This question was answered by WHO.

In the context of the Stringent Regulatory Authority - Collaborative Registration Procedure (SRA-CRP) we are approaching new SRAs to encourage them to join the scheme. In addition, WHO advocates for transparency and information sharing as per the WHO Good Regulatory Practices and WHO Good Reliance Practices.
1) Typically it takes how long from the date of submission to WHO to the QIS endorsement by EMA.

2) Will applicant be updated on the progress of the CRP (for example status of QIS, any questions from EMA on QIS).

This question was answered by the Industry.

The validation of the QIS is very fast, especially if there are no clarifications/amendments needed. When errors are spotted or clarifications needed, the EMA will contact the MAH for an amended QIS until EMA can endorse it as alligned to the EU dossier.

Someone already mentioned 'product sameness' - well, that is crucial for majority of non-EU HA in order to accept reliance concept due to different set of dossier (EU vs non-EU) and some release sites and other. Question is... would EMA issue any guide or public statement regarding product sameness with goal 'how to proof, convince and explain HA' that we do not speak about different quality, efficacy and safety?

This question was answered by EMA and WHO.

Product sameness is an issue led by WHO, and EMA follows the WHO guidance on product assessment. The WHO works with a range of NRAs on this topic through the IPRP forum.
More information on sameness in the IPRP Questions and Answers: https://www.iprp.global/news/iprp-questions-and-answers-document-reliance-now-published
Could you point us to the template on sameness referred to in the chat just now please?

This question was answered by WHO.

Under the WHO Collaborative Registration Procedure (CRP), we use the Quality Information Summary, please see QIS under
https://www.who.int/publications/i/item/WHO_TRS_1019

The QIS (or QIS-CRP) represents the final, agreed upon key information from the PQ (or SRA-CRP) dossier review, adopted from WHO TRS 970_Annex 4.WHO good practices of NRAs in implementing the collaborative registration procedures

To facilitate reliance activities, IFPMA has developed a template that provides a transparent overview and description of any differences between the documentation submitted for marketing authorization or post-approval changes in the relying and the reference National Regulatory Agency (NRA).

Description of differences_IFPMA template

Will the EMA recognise or rely on other countries assessment for MA?

This question was answered by EMA.

The EMA is already a reliance system, with reliance between the 30 European Union (EU) + European Economic Area (EEA) countries. We do also have many collaborative assessment initiatives (e.g OPEN) with other regulators (including the International Coalition of Medicines Regulatory Authorities, ICMRA) and also reliance on inspections by other regulators.
Which external partners (Slide 13-14) were you referring to that are involved in assessments.

This question was answered by EMA.

Through the clusters, EMA discusses often our assessments with international partners, like FDA, PMDA, Health Canada or Swiss Medic. They are not involved in our assessment, but we might share key issues or discuss important points in our own assessment. This often occurs if submissions are made in parallel in different regions.
In the near future would the EMA adopt a guideline for the regulatory reliance for its harmonisation worldwide?

This question was answered by EMA.

Interesting proposal, but actually I think the most important guidance on Good Reliance Practices is the WHO document:

TRS 1033 - Annex 10: Good reliance practices in the regulation of medical products: high level principles and considerations (who.int)
Is EMA open to provide more training or share best practices with NRA in the future. I believe more engagement from EMA and other SRA are needed to raise awareness on reliance. Is EMA considering collaboration with academia in LMIC/LIC to include reliance in academia curricula.

This question was answered by EMA.

EMA cooperates with regulators in many regions, but one important forum is the WHO Annual Collaborative Registration Procedure (CRP) Conference. The next one will be in November 2024.
Past experience has shown that e.g. far east markets still rely heavily on legalizations. Has this improved with the situation during the pandemic? Thank you for confirming.

This question was answered by the Industry.

No. More advocacy & education is needed.
For collaboration engagements with other health authorities, does EMA lead this or is it expected to be driven by health authorities themselves?

This question was answered by the Industry.

Heath authorities interested in collaboration with EMA should contact the EMA international office.
Could you please detail the centralized registration procedure for Biosimilars.

This question was answered by EMA.

The centralised registration procedure is the same procedure for all medicine assessments, including biosimilars.
How can I find more detail and updates about mutual recognition of reliance procedure with FDA?

This question was answered by EMA.

More information on Mutual Recognition Agreements can be found on the following EMA webpage:

Mutual recognition agreements (MRA) | European Medicines Agency (europa.eu)
For Non-Centralised authorised medicinal products what are potential regulatory reliance tools that we can use?

This question was answered by the Industry.

CRP can also be used for non-centralised medicineal products.
If the template for the differences in M3 is available for use, where could it be found?

This question was answered by the Industry.

To facilitate reliance activities, IFPMA has developed a template that provides a transparent overview and description of any differences between the documentation submitted for marketing authorization or post-approval changes in the relying and the reference National Regulatory Agency (NRA).

Description of differences_IFPMA template