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Executive Summary
Workshop: Global Registration and Vaccine Shortage
6-10 March 2017

The objective of the workshop was to discuss the potential reasons behind vaccine shortages with particular emphasis on the impact that challenges and delays in registration could have in vaccine availability and supply.

The workshop reviewed the pathways for registration of vaccines in different countries, including the legal frameworks, legislation and regulatory bodies in United States, European Union and Japan.

It looked specifically at the Common Technical Document which represents the harmonized dossier format proposed by ICH countries. This dossier format is slowly being adopted by more and more countries at global level. While modules 2 to 5 are grossly harmonized , module 1 which is dedicated to administrative and legal information, remains mostly dis-harmonized.

A comparison of CTD module 1 from different countries with similarities and differences was presented during the workshop. A broader comparison has been done including PAHO, India, Jordan, Thailand, EU, US and Australia. The audience was extremely interested in the role that manufacturers could play in bringing to the attention of regulators the magnitude of the differences in requirements in aspects that are really irrelevant but that represent time, resources and effort by manufacturers to comply with them in different countries.

The participants considered that the comparative work initiated was worth being supported and completed through the organization of a working group of manufacturers that would meet for a few days to put together a document that would evidence the level of divergence between country requirements, even among those that are “in principle” considered as harmonized or aligned.

It was thus proposed to convene a small working group of manufacturers from companies with prequalified vaccines or with extensive experience in global registration who would help finalize the job of making a comparison between CTD modules of different countries, as well as the proposed WHO/PQ supplement to a CTD dossier submitted for PQ evaluation of vaccines. It was in principle agreed that this WG could meet in Geneva in May 2017. Based on the outcome of such work, manufacturers would propose a common list of essential documents to WHO, partners and regulatory networks.

This suggestion is put forward for consideration by the Executive Board of DCVMN.

March 18, 2017

REPORT
Workshop on proposal for alignment of regulatory requirements for vaccine registration at global level
Royal Manotel, Geneva
15 - 16 May 2017

Objectives
The workshop is aimed at drafting a proposal by vaccine manufacturers (DCVMN and IFPMA members) to be shared with WHO, regulatory networks and other relevant partners that will provide evidence of the diversity of regulatory requirements applicable to vaccine registration across countries and options to improve the level of alignment.

The proposal will focus on the following:

  • Provide background information on the current regulatory situation for vaccine registration,
  • Show similarities and differences between countries/regions in requirements for CTD submissions (modules 1-5),
  • Identify and list additional specific countries’ requirements that may negatively impact the duration of the registration process, by looking at the different regulatory pathways used
  • While meeting the requirements, suggest potential options to improve alignment, including (but not limited to) proposing a list of essential documents that could be advocated for by WHO and other partners for common use in all countries.

Participants profile:
Participants will be representatives from companies with prequalified vaccines supplied in the global market or companies very experienced in registration at global level. The selected staff from the companies should be experienced staff in regulatory affairs and exports

Expected Outcomes
1) At the end of the workshop participants will have

  • Fully developed a table comparing modules 1 to 5 of the CTDs from selected countries and identified similarities and differences,
  • Prepared a comparative table of application forms from selected countries
  • Developed a proposed list of documents that are important (“essential documents”) and common to the majority of countries,
  • Identified steps involved in the registration procedure in different countries and constructed a list of countries

2)At the end of the workshop, DCVMN Secretariat will have gathered the necessary information from regulatory affairs participants to allow for the development of a comprehensive proposal of actions needed in order to improve the alignment of requirements.

The proposal prepared as a result of the meeting will be further discussed with DCVMN and IFPMA members for consensus before being presented to WHO, regulators and other partners.

The working methodology will be working groups.


FINAL AGENDA

Day 1
ScheduleTopicSpeaker
9h00 - 9h10 Welcome Sonia Pagliusi
9h10 - 9h30 Introduction Sonia Pagliusi
9h30 - 10h00 Challenges for registration of vaccines, rationale for comparison of module 1 of CTD Nora Dellepiane
10h00 - 10h40 Discussion all
10h40 - 11h00 Coffee break
11h00 - 11h15 Organising working groups
and presenting working doc
Facilitator
11h15 - 13h00 Comparison of module 1 and listing of essential documents Working Groups 1
11h15 - 13h00 Registration procedures in different countries Working group 2
11h15 - 13h00 Comparison of application forms from different countries Working Group 3
13h00 - 14h00 Lunch
14h00 - 15h00 Continuation working groups
15h00- 15h30 Coffee break
15h30 - 17h00 Presentation by working groups
17h00 - 17h30 Conclusions and wrap up of the day all

Day 2
ScheduleTopicSpeaker
9h00 - 9h30 Rationale taken for comparison of CTD modules and presenting working doc Facilitator
9h30 – 10h30 Comparison of module 2 Working Group 1
9h30 – 10h30 Comparison of module 3 Working Group 2
9h30 – 10h30 Comparison of module 4 Working Group 3
9h30 – 10h30 Comparison of module 5 Working group 3
10h30-11h00 Coffee break
11h00 -13h00 Continuation of working groups
13h00 - 14h00 Lunch
14h00 - 15h30 Presentation by working groups
15h30 - 16h00 Coffee break
16h00 - 17h00 Ideas for proposal on potential for alignment Rapporteur
17h00 - 17h30 Conclusions and wrap up of the workshop Sonia Pagliusi

Outcomes

This was the first time that DCVMN organizes a workshop with member companies to strategize on a specific topic, in this specific case the challenges faced for the registration of vaccines in receiving countries. Furthermore, it was also the first time in which member companies from DCVMN and from IFPMA work together (working groups) to analyse the specific issues and to find possible solutions. Having identified the major problems with the CTD and other country specific requirements for registration of vaccines, the participants further investigated options that could potentially help improve the situation and strategies to communicate such options to the relevant partners.

Identification of issues

The participants were organized in three working groups, each of which included at least one IFPM member. The working groups based their analysis on the tables provided by DCVMN secretariat which reflected the comparison of CTD requirements between selected countries/ regions (ICH, PAHO, ASEAN, India, Jordan, Australia, Europe and Thailand). The groups analysed a) differences between module 1 for the said countries, b) compared the application forms imposed by some of these and other countries and c) listed specific requirements from many countries. The second part of the workshop was dedicated to the analysis of similarities and differences between countries for the other four modules of the CTD (modules 2 to 5).

Groups concluded that the tables reflected correctly the requirements imposed by the different countries and gave a good indication of similarities and differences . The tables presented to the participants highlighted requirements that were “identical”, “similar” or completely “different”. The distinction between identical and similar was based on slight differences in the headings, while the expected content was the same. It was agreed by the participants that “identical” and “similar” would be grouped together, since the contents expected under such headings were basically the same. Therefore, the comparison would include just two groups: similar and different.

The groups also noted that there were significant differences in numbering used by the different country authorities, which results in confusion. They concluded that aiming for some harmonization at the level of numbering would already represent a significant improvement with respect to the current situation.

Group 1, responsible for the review of module 1 considered that the countries included were not representative of the whole globe and added other countries, particularly to include the African region, Gulf Coast Concerns, US, and China in the analysis. The data provided by this group will be included in the table and the calculation of similarities and differences re done as well as the graphs and charts.

Group 3 performed an analysis and comparison of the application forms from Egypt, European Union, GCC, Indonesia, Iran, Iraq, Jordan and United Arab Emirates revealed a diversity of requirements. The group concluded that proposing a harmonized application form would be a worth investment.
Group 2 focused on gathering information about other country requirements for the registration process and provided a list. It was suggested to include this information as part of the paper that will be published, to show yet other differences that make the registration submissions even more complex and country specific.

Proposals

It was agreed that all the information gathered during the workshop would be put together and the analysis work completed. This information would be circulated to participants for comments and once it is agreed, the second step would be the preparation of a paper reflecting the outcomes of the workshop for publication in a peer review journal. Simultaneously with the development of the paper, a presentation in powerpoint would be prepared. Both these tools (publication and presentation) would be used as advocacy tools to explain the challenges that manufacturers face for registration of vaccines and how these constraints impact access to these products.

The group would then prepare a proposal of “options for improvement”, which would include among other suggestions

a) harmonized numbering for all CTDs
b) Model application form if adequate resources are obtained. This form would contain the list of documents that are essential and need to be provided to all countries

Steps to be completed in advance to the proposal development

1) Propose a numbering system for module 1 (Mic)
2) Revision of the first three columns of modules 3, 4 and 5 (groups 2 and 3)
3) Update the excel tables and charts (Nora)
4) Prepare a first draft of the paper (Nora) by 30 June
5) Circulate paper for comments by 30 June
6) Organize a Webinar by 11 July
7) Prepare a concrete proposal and presentation as second step (after publication of part I, which states the problems)

Proposed strategy to advocate for change

Approach the maximum number of stakeholders possible with publication and presentation to increase the awareness about the magnitude of the problem.

1) Key implementation partners
ICH, WHO, Economic Blocks, APEC, GCC, ASEAN, PANDRH, AVAREF, and other regulatory networks

2) Key advocacy partners
DIA, ICDRA, NEPAD, UNICEF, MSF, PATH, BMGF, GAVI, etc

Timelines 2018
With regards to timelines, the key milestone is ICDRA 2018 (7-8 September 2018), where we hope to have an industry session at pre-ICDRA and/or have WHO present the CTD proposal at ICDRA to the attending regulators. As such, in order to have the data in a format we can share the group must have an agreement on the first draft of the proposal by end-April, and by end-May agree on a draft aimed at sharing with WHO.

Options for currently submitted paper
The first paper, submitted to Vaccine as a meeting report last October, has not been published yet; issues with the ASEAN data have also been identified. As such, for the proposals paper the following options can be considered:

  • If first paper is rejected (Q1 2018): a full peer-reviewed article, combining the data from the two papers, should be the objective as it would be more impactful and to gain more traction. That would entail correcting the ASEAN data and include the proposals as well as the case studies, and resubmit as a full paper to Vaccine (or other, such as PLOS) by summer 2018. Publication would hardly be out before 2019 (assuming publication in Vaccine – could be easier with another journal). Nevertheless, we cannot resubmit as meeting report as it has been too long (May 2016).
  • If first paper is accepted and published (Q1 2018): in case the first paper is accepted conditionally (upon correction of ASEAN data), objective is to have it published as meeting report with the corrected data by Q2 2018. In parallel, we would submit the proposals paper as a full peer-reviewed article (final draft by June 2018) to Vaccine, for consistency’s sake. Publication will hardly be out before 2019.

We would then seek opportunities to amplify the publication in the following for a:

  • Press release
  • RAPS
  • Pink Sheet [1]
  • Conferences (DCVMN/IFPMA presenters)

Stakeholder Engagement

WHO
WHO has already shown high interest during an informal meeting aimed at introducing them the first paper’s results. Next objective would be to persuade them to present the data at ICDRA. Potentially we could also aim at persuading WHO to publish a guideline on the CTD, which would have the advantage of giving our proposal a “WHO stamp”, and possibly promoting its use among Gavi and Gavi-graduating countries. Main disadvantages would be that by the time we have this it will be 3-4 years, and potential loss of control over the content (e.g. WHO interprets the data in a different way and develops guidelines that do not address our concerns). Need to question whether we need a guideline, or just have WHO to organize meeting and workshops and engage regions such as ASEAN. Risk exists that enforceability of it would be even more reduced versus developing a guideline.

ICH
A better understanding of the leveraging power of ICH is needed; they could be potentially useful in interacting with ASEAN? Enforcement power would be limited though.

PAHO
PIC/S

While trying to enforce at regulator level is important, political/legislative enforcement is also needed and arguably more important as if legislation needs changing, this will not be in the scope of a NRA. Those are the stakeholders could influence this process:

  • World Bank
  • Gavi
  • BMGF
  • MSF
  • EU – influencing level is broader than just EU
  • Path

A potential selling point to those stakeholders could be cost ($$) of this problem and how much could be saved by tackling it; although we discussed it as maybe not worth it, those politicians listen to money. We could somehow paint a broad cost picture of how much this issue costs, not only in financial terms but in delays to access, morbidity and mortality.

MRP - mutual recognition procedures

  • Between and within economical Block
  • ASEAN
  • GCC
  • SAARC
  • ZaZiBoNa…

Mutual recognition between blocks of countries is more in theory but does not translate into practice. Lack of political will and other geo-political factors disallow this useful procedure. I would recommend for arguments and line of thinking to have a look at the recent EFPIA white paper on reliance and expedited pathways

Quantum leap NRA
Countries need to establish regulatory procedures, with a need for a stepwise approach, ideally with country specialization on key areas (e.g. ensuring that Good distribution practices are being followed in the in-country supply chain, ensuring that a pharmacovigilance system is in place or that there is a means to access PV data from other relevant sources).

  • Capacity building – numbers of staff – training programs
  • Capability – training – experience building on medicines AND vaccines and other product ranges
  • Realistic ambition
  • Incremental improvement –stepwise building

Workshop on Fostering regulatory convergence dialogue in ASIA 25-26 March 2019

Meeting between DCVMN Regulatory Working group and CoRE, Singapore 25 March 2019

Meeting Notes: Nora Dellepiane, 30 April 2019

This was an introductory meeting between the two organizations. There were presentations from CoRE, CEPI and DCVMN to brief the other organizations about their objectives and activities. The RWG made a presentation about the work on registration of vaccines so far. It explained that the challenges for registration had been published in Vaccine Journal and that a new paper with proposals for improvement was about to be published in Vaccine as well.

John Lim, is a former SHA staff with extensive regulatory experience, Neo Cherng Yeu is an associate Director at CoRE. The discussions were very fruitful, the main points highlighted for the attention of the RWG are as follows:

  1. A general recommendation was to work through regulatory networks for the implementation of Module 1. SEARN was mentioned as one possible network to work with.
  2. For modules 2 to 5 CoRE agreed with the WHO recommendation to work it out through ICH.
  3. A general comment was that if we manage to get a few regulators to change, others would follow
  4. The International Pharmaceuticals Regulators Program (IPRP) was mentioned as a good forum to approach to discuss with regulators. The Program members include individual countries but also groups such as APEC, ASEAN, PANDRH, EAC and GHC and EDQM and WHO as observers. Canada and Brazil are currently the Chair and Co-Chair of the Program.
  5. They advised to check whether the changes that the RWG proposes apply only to vaccines or include small molecules. It would be important to explore which countries have a vaccine specific registration system different from that for small molecules.
  6. They advised to check countries’ legislation to see which of the proposed changes would require changes in legislation and where. Countries could be divided in groups for implementation depending on legal considerations and scope of product categories to be covered.
  7. For reliance, WHO had suggested that some of the proposals could be captured in TRS documents, this would make them accessible and usable by all countries willing to do so.
  8. The reliance package could also be segregated according to NRA degree of development in countries. Different countries, might require different strategies. Countries with a developing registration system could choose to rely and give waivers, while those with registration system could choose what they would want to review and what they could rely upon
  9. Listing of authorities by WHO would guide reliance, procurement and PQ itself.
  10. Advised to consider what would be the incentives to regulators to introduce such changes and to work on those as part of the implementation process (e.g. access, cost reduction, helping own industry, ability to react to emergencies, etc.)
  11. Advised to consider whether messages to regulators, evaluators and health authorities in general should be different or not.

Based on these comments/recommendations the group decided to form two sub-groups that would work in the following areas:

  • Access messages : Prashant, Sebastian, Norbert and Shubhangi
  • Opportunity countries to target harmonization (Pharm/Vaccine CTD alignment, Use of CTD already, Legal considerations): Mic, Monique, Nirav, Ida, and Jacqueline
  • Further clarify which countries in ASEAN would accept the ICH CTD in addition to the ASEAN CTD: BioFarma
  • Follow up with CoRE on the appropriate person to address in Malaysia (chair of the PPWG of ASEAN) to bring the topic for discussion in ASEAN

Deadline for completion of a) to e) 30th April 2019

Meeting of the Regulatory Working group on variations, Singapore 26 March 2019

Mic summarized the outcome of the meeting with CoRE and helped define the action points stated above

There were presentations by different members of the RWG as follows:

  • Objectives of the meeting and expected outcomes: Nora
  • Experience with WHO CRP for vaccines: Mic
  • Experience on vaccines variations management in LATAM: Sebastián
  • Experience on vaccines variation management in ROW: Shubhangi
  • IFPMA experience with variations (brochure and position paper): Norbert

Based on the outcome of the previous day meeting and the presentations a) to e) the group took the following decisions:

  • CRP is not working for vaccines so far, and it may not be worth investing energy right now in pushing implementation since WHO seems not to have the necessary resources. This decision applies of course both to registration and variations. If WHO would decide to pilot CRP in some countries, the RWG would be willing to assist.
  • The WHO guidance on variations published on TRS 993 should be used by the maximum number of countries possible
  • The value of developing and publishing a paper on variations would be decided at a later stage (mid-May) based on the findings from the group and the additional case studies developed.

The following are examples of issues provided during the meeting.

Case Studies
1.0 Differences in categorization of variations & approval timelines.
The different NRAs have different categories (for same change) ranging from minor (immediate implementation), moderate (faster approval) and major (long lead time for the approval). Once the changes are approved, few NRA mandate the implementation in stipulated time, different approval lead time creates supply disruption.

Possible Solutions:
1.1 The variation categorization shall be harmonized with WHO guidelines.
1.2 Solution can be country specific dialogue or group specific engagement (to be constructed based on similarity trends amongst the countries – regional approach possibilities can be explored)
2.0 Inconsistency in data requirements for same change.

ASEAN, WHO and other international guidelines require limited stability data to be submitted at the time of submission maximum up to 12 months. For regulatory agencies like those of Sri Lanka and Sudan, complete shelf life is required to submit the variations. Philippines demands new dossier submission if more than one change is done (independently from the magnitude of the change). An example was given of one agency with an inconsistent approach to variations’ classification (i.e. classifying a similar variation in different ways for different submissions).
There are countries where minor changes shall be reported annually (USA, EU, India etc.) and no formal approval is required. There are few regulatory agencies which demand proof of approval of the change by other NRAs.

Possible Solutions
2.1 Harmonization in line with WHO guidelines or recognition of WHO publications. Training and workshops as collaborative program between industry and regulatory agencies.
2.2 Charts and matrix correlating countries with reference to mutual referencing, recognition can be worked out.

Next steps regarding work on variations:
The whole group would consider possible case studies describing challenges for the review and approval of variations in countries to complement those given in the IFPMA brochure and position paper, in order to decide whether it is worth preparing a paper for publication on this topic. Case studies should be provided latest by mid-May 2019 so that a decision about the way forward can be made.

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