Meeting Highlights: DIA Europe 2023
Regulatory Reliance in Action Making a Difference for Patients
Regulators and Industry Come Together to Discuss Practical Solutions
Angelika Joos
Susanne Ausborn
Reliance* is considered the hallmark of a modern, efficient regulatory framework and a 21st century regulatory tool. (See Annex 10 page 243 of this WHO report.) Yet many roadblocks still need to be removed to bring reliance into action around the world and at the same time streamline the different pathways established over the last 20 years. Senior regulatory experts representing health authorities from all around the world joined industry representatives at a DIA Europe 2023-affiliated workshop to discuss more effective and efficient information sharing to enable risk-based reliance reviews, the interpretation of product sameness, and the impact of the diverging country-specific requirements which are not necessarily justified from the point of view of modern regulatory science. This open dialogue and experience sharing increased the mutual understanding between different stakeholders and identified concrete next steps to bring reliance into more widespread practice.
*Reliance is the act whereby the regulatory authority in one jurisdiction takes into account and gives significant weight to assessments performed by another regulatory authority or trusted institution, or to any other authoritative information, in reaching its own decision. The relying authority remains independent, responsible, and accountable for the decisions taken, even when it relies on the decisions, assessments, and information of others.

Benchmarking data collected annually by CIRS shows how submission delays and long assessment timelines are delaying the availability of new medicines for patients around the globe. They demonstrate that reliance can effectively be used to focus resources and speed up approval timelines while strengthening regulatory systems. The EU network system and the EMA provide a practical example of practicing reliance for more than 25 years. In other regions, national regulatory agencies such as the Saudi FDA established reliance pathways several years ago and continuously update pertinent regulations based on stakeholders’ experience and feedback. Industry is increasingly leveraging existing reliance pathways and is exploring pilots to simplify global filings and accelerate approvals.

Continuous Dialogue is Key

These insights into different stakeholder perspectives set the baseline for identifying concrete next steps. There are still many different opinions and approaches concerning which information should be provided to other regulators (e.g., assessment reports, Q&A documents, full clinical data, approval letters, Certificates of Pharmaceutical Product [CPP], etc.) to enable reliance and who should provide them. It became obvious that this will be key to clarifying terminology and mapping the documentation currently requested by different regulators. It will be important to resist the temptation to request additional documentation or to follow a “checklist,” but to instead be very clear and thoughtful about the purpose of each document or additional piece of information requested. Continuous dialogue is key: on the one hand, through product-specific discussions between companies and regulators, for example, in submission meetings; and on the other, more frequent workshops discussing case studies and sharing experiences to optimize existing pathways or establish new reliance guidelines.

The Question of “Sameness”

One other topic heavily debated in various contexts is product sameness: How can a relying agency be assured that they receive the same product and documentation that were assessed by the reference agency? What does “the same” mean and what is the impact of any differences on the review conducted by national regulatory authorities (NRAs)? Clearly, reliance must always be science-based, and the concept of sameness must be supported and justified so that product quality is not compromised and patients around the world have access to products with the same level of quality.

Industry and regulators seem generally aligned on which characteristics must be identical or essentially the same to support product sameness, and that acceptance of differences is mostly a case-by-case approach based on justification provided by the manufacturer. It is important to highlight that reliance is not “all or nothing’’: The relying agency can still rely on the part of the file where there are no differences and use a risk-based approach to perform an abridged independent review for differences of importance in the relying agency’s national context. The list of characteristics that are identical or similar (and associated justifications) should become not just an additional checklist but a document that allows the agency to use critical thinking on specific areas. Such a document can also be leveraged during the post-approval management of the product, which should also continue to apply efficient reliance pathways.

While there are very promising examples of reliance pathways, many agencies still have country-specific requirements in their laws, regulations, and guidelines which are not necessarily justified from the perspective of modern international regulatory science. Regulators emphasized that industry must submit complete submission packages per local requirements. However, publishing national requirements and reliance approval timelines on each authority’s website, based on WHO Good Regulatory Practices related to predictability and transparency, would help industry meet this expectation. In addition, clear requirements based on a scientific and risk-based approach for standard or collaboration pathways should also be published online. In line with WHO Good Reliance Practices, additional country-specific requirements might be waived when relying on a reference country assessment using verification or abridged assessment.

The ultimate vision would be one product, from multiple manufacturing sites, in one single dossier submitted and shared for review by multiple regulatory authorities in a cloud-based system, in the proper context of data security and data protection.

Short-Term Goals Toward Long-Term Progress

Convergence and harmonization of CTD Modules 1 and 3 have been identified as an area of immediate focus. As we continue this journey, industry and regulators must jointly address several concrete action items:

  • Align and define reliance terminology to ensure common understanding. Terminology is used differently across regions (such as, for example, the Middle East and Asia Pacific) and is not fully aligned with WHO terminology. Terms such as “abridged” and “verification,” as well as product sameness, are unclear.
  • Map which documents are currently used and identify their purpose in practicing reliance.
  • Identify which information from the reference agency review is publicly available and which essential information is missing.
  • Develop a structured template to support verification of product sameness; map existing documents used to justify product sameness (CPP, Quality Information Summary, etc.); and explore potential improvements.
  • Map and assess the added value of divergent CTD Module 1 requirements based on modern regulatory science and propose a harmonized approach.
  • Globally map country-specific requirements beyond ICH standards (CTD Module 3) and assess opportunities for harmonization to enable reliance.
  • Establish key performance indicators to track the progression of convergence and effective implementation of reliance.

This workshop was a milestone on our journey to promote more collaboration among regulatory authorities and industry, and we will continue the dialogue to enhance transparency across our working practices, share reliance case study experiences, and identify shared solutions.

Workshop Participants:
Amira Younes (AbbVie), Lucia D’Apote (Amgen), Mark Pellet and Priti Shah (AstraZeneca), Céline Bourguignon (GSK), Sérgio Cavalheiro Filho (International Federation of Pharmaceutical Manufacturers and Associations [IFPMA]), Chloe Garay (Lilly), Sonia Cappellini (Menarini Ricerche S.p.A.), Isabelle Colmagne-Poulard (Merck Serono), Angelika Joos and Mic McGoldrick (MSD), Inas Chehimi (Novartis), Isil Canset Canturk (Novo Nordisk), Prisha Patel (Pfizer), Susanne Ausborn and Nevena Miletic (Roche), and Thierry Gastineau and Lyne Le Palaire (Sanofi).

Leonardo Dutra and Patricia Pereira Tagliari (Agência Nacional de Vigilância Sanitária [ANVISA], Brazil), Mariam Al Jalahma (National Health Regulatory Authority [NHRA], Bahrain), Engy El Hosary (Egyptian Drug Authority [EDA], Egypt), Martin Harvey Allchurch (European Medicines Agency [EMA]), Daisuke Koga and Junko Sato (Pharmaceuticals and Medical Devices Agency [PMDA], Japan), Maha Jaghbeer (Jordan Food and Drug Administration [JFDA], Jordan), Obaidullah Malik (Drug Regulatory Authority of Pakistan [DRAP], Pakistan), Bandar Alhammad (Saudi Food and Drug Authority [SFDA], Saudi Arabia), Fikriye Handan Öztunca (Turkish Medicines and Medical Devices Agency [TITCK], Turkiye), Miu Takahashi (Food and Drug Administration [FDA], US), and Samvel Azatyan (World Health Organization [WHO]).

Facilitators: Magda Bujar and Neil McAuslane (CIRS), and Sara Torgal (DIA).