hile it is widely recognized that Reliance should be a fundamental part of a modern 21st century regulatory framework to efficiently use resources and avoid duplication of efforts, many open questions on how to operationalize its use on a global scale still remain. This is especially relevant for handling Post-Approval Changes (PAC), which represent the majority of regulatory submissions. Considering this, senior regulatory experts representing Health Authorities from all around the world joined industry representatives at a DIA Europe 2024 Pre-Conference Workshop to discuss the practical aspects of applying reliance approaches to PACs more widely.

Leveraging a design thinking approach in breakout groups, the experts outlined the existing concerns about the use of reliance, discussed how a science- and risk-based approach could be practically applied to accelerate approvals of PACs globally, and what’s needed to embed it as common practice.

Obtaining approval for the initial marketing authorization is just the tip of the iceberg; hidden under the water, below the surface, is the enormous iceberg of Post-Approval Changes. These constitute the majority of regulatory submissions, and pragmatic approaches must be used to manage the lifecycle of products in an efficient and sustainable manner to ensure that patients globally will benefit from medicinal products of the same level of innovation. Recent data collected by EFPIA currently in peer review demonstrates that long, unpredictable timelines are the major concern for industry, with most National Regulatory Authorities (NRAs) exhibiting different change categorizations and assessment timelines compared to EMA/WHO.

The WHO Collaborative Registration Procedure (CRP) is an established process with a focus on informed reliance. It requires the submission of a complete dossier, including safety and efficacy data, and signed confidentiality agreements. WHO facilitates the provision of assessment and inspection reports to support reliance on the reference agency’s evaluation. Currently, 68 NRAs participate in the WHO CRP. However, it is important to note that CRP can only be utilized for post-approval changes if there was an initial procedure conducted within the CRP. To efficiently use WHO’s CRP for PACs, additional resources may be required. This acknowledgment highlights the need for potential resource allocation at Regulators’ level to effectively handle and process PACs through the CRP mechanism.

Several promising initiatives are ongoing in regional settings. In addition, various pilots led by industry have been conducted to bring reliance into action by sharing relevant information from reference agencies* with participating NRAs and drive towards regulatory convergence by requesting waivers of country-specific requirements.

* A Reference Regulatory Authority is “a national or regional authority or trusted institution such as WHO prequalification (WHO PQ) whose regulatory decisions and/or regulatory work products are relied upon by another regulatory authority to inform its own regulatory decisions.”

Reliance can effectively be used to focus resources and speed up approval timelines while strengthening regulatory systems. However, so far it is only occasionally used when assessing post-approval changes. This is due to a variety of reasons, as highlighted by experts during the pre-DIA Europe 2024 Reliance Workshop. These include different requirements for change classifications and procedural guidance, as well as country-specific requirements; the lack of appropriate reliance tools for post-approval changes; legal barriers preventing application of reliance; the uncertainty about product and change “sameness” (i.e., ensuring that the change being assessed by the relying agency is the same as that evaluated by the reference agency); and the concern of losing sovereignty when relying on another NRA’s decision.

Workshop discussion of these barriers highlighted the following potential solutions:

Different requirements for change classifications and procedural guidance: It was emphasized that there are still many different country-specific requirements which go beyond common international (ICH/WHO) standards (e.g., sample requirements for local testing, request for stability data covering the full shelf life, nonacceptance of bracketing and matrixing approaches, request for internal data like chromatograms, provision of executed batch records, nonacceptance of multiple manufacturing sites under one license, administrative documents such as legalized CPP or GMP or notarization of originally signed declarations). There was agreement that it is important to increase awareness of the differences in national requirements and evaluate if they remain justified from a current scientific and regulatory perspective. The group also highlighted that harmonization and adoption of ICH and WHO standards (especially regarding risk-based categorization of PACs, procedural guidance, and documentation requirements) are considered a key enabler to reliance. It is encouraging to see that global standards developed by WHO and ICH guidelines are considered by NRAs when developing national regulations, but more needs to be done.

Lack of appropriate reliance tools for Post-Approval Changes: Assessment reports (ARs) are not yet issued by all reference agencies for major and moderate changes, and for minor changes requiring no formal approval often only acknowledgment letters are available. For as long as there are no global standards in place, it will be important to allow a certain flexibility regarding reliance tools based on the companies’ justifications, e.g., to accept declarations of what is redacted in the AR by the Marketing Authorization Holder (MAH) Q&As (i.e., personal data and commercially sensitive information or site information) instead of unredacted ARs when they are not available.

Product sameness: IFPMA recently published a template (description of differences) to be filled in by the sponsor. It is considered a “reviewer’s aid” that the applicant can submit along with the application highlighting where the reviewer can expect to find differences in the dossier between the reference and the respective NRA. The template has just been finalized and is recommended to be added as a reliance tool by all companies as part of the submission package when undertaking a reliance pathway.

To ensure reliance, continuous license maintenance, and consistent supply during the lifecycle management (LCM) of a product, several factors need to be considered:

• Transparency of information between industry and NRAs is crucial in fostering trust and facilitating reliance.
• Management of all stakeholders’ resources at all levels needs the establishment of a smart system.
• Sharing experience among regulators on how to conduct a reliance-based review and, specifically, identifying which documents must be considered will help to operationalize reliance more broadly.
• A global broker to facilitate the sharing of information might be necessary. Organizations like WHO or ICMRA could play a leading role in guiding and facilitating more global exchanges.
• Clarifying the information needed for risk-based decision making and use of reliance to achieve a commonly accepted submission package is important to streamline processes and reduce discrepancies when applying reliance.
• Differences in regulatory frameworks, particularly in initial and post-approval stages, pose challenges and should be addressed to simplify reliance for users. In this context, the gradual removal of country-specific requirements and the streamlining of local procedures can help avoid complexities and backlogs.
• Abandoning the periodic license renewal procedures to focus resources on variations might be an option.
• It will be important to evaluate the lessons learned, develop some best practices to standardize the approaches, and, at the same time, develop metrics to measure the effect of their implementation.

Continuous dialogue between industry and regulators and stronger collaboration between regulators discussing practical aspects of reliance-based real case examples is of particular importance.

Some concrete next steps were identified at the Workshop:

• Industry is encouraged to submit more pilots and/or leverage regional platforms to foster alignment among all global stakeholders and drive regulatory convergence.
• Industry is encouraged to establish a repository for reliance case studies to share with WHO.
• Industry (EFPIA/IFPMA) will map the most critical country-specific requirements beyond ICH standards (CTD Module 3) for Post-Approval Changes globally and assess opportunities for harmonization to enable reliance.
• Industry should review the existing World Bank/IFPMA training on Post-Approval Changes to ensure it is fit for purpose and addresses reliance sufficiently.
• Regulators are encouraged to share the learnings from pilots more broadly, to conduct and respond to surveys and publish its results.
• Regulators are recommended to investigate updating variations/PAC guidelines to align with international standards and include the principles of reliance.
• Explore cloud-based systems for information sharing to allow both industry and regulators to align and define the critical business needs.
• All stakeholders should develop and refine a common glossary for reliance.

The workshop marked a significant achievement in the ongoing efforts to foster stronger collaboration between regulatory authorities and industry, particularly regarding post-approval changes. It is truly inspiring to witness that we have moved beyond discussing the reasons for implementing reliance (the why) and are now focused on the practical aspects of its implementation (the how). All stakeholders involved in the workshop from industry and regulatory agencies (listed below) are committed to maintaining an open dialogue to improve transparency in the working practices and to share experiences through reliance case studies. This will help identify any potential challenges and work together to find effective solutions.

The authors are grateful to all the participants for their active engagement and for contributing to the constructive and productive discussions during the workshop.

Workshop Participants:

Alison Bond and Lucia D’Apote (Amgen), Mark Pellet and Priti Shah (AstraZeneca), Michael Cunha (Bayer), Vera Wardhana (Boehringer Ingelheim), Hugo Ta and Michelle Czajkowski (Gilead), Andrew Deavin and David Rush (GSK), Sérgio Cavalheiro Filho (International Federation of Pharmaceutical Manufacturers and Associations [IFPMA]), Ginny Beakes-Read and Greg Jordinson (Johnson & Johnson [J&J]), Chloé Garay (Lilly), Sonia Cappellini (Menarini Ricerche S.p.A.), Isabelle Colmagne-Poulard and Wan-Li Liao (Merck Serono), Angelika Joos and Mic McGoldrick (MSD), Inas Chehimi (Novartis), Jacob Larsen (Novo Nordisk), Aine Kane and Anjana Patel (Pfizer), Melly Lin and Susanne Ausborn (Roche), Corinne Chabassol and Lyne Le Palaire (Sanofi), and Anna Czwarno (Vaccines Europe).

Chimwemwe Chamdimba (African Union Development Agency [AUDA-NEPAD]), Biljana Tubić (Agency for Medicinal Products and Medical Devices of Bosnia and Herzegovina [ALMBiH], Bosnia and Herzegovina), Elkiane Rama and Nelio Cézar de Aquino (Agência Nacional de Vigilância Sanitária [ANVISA], Brazil), Jiaqi Lu, Tao Wang, and Xiangyu Wang (National Medical Products Administration [NMPA], China), Sabina Uzeirbegović (Agency for Medicinal Products and Medical Devices [HALMED], Croatia), Hamada Gamal (Egyptian Drug Authority [EDA], Egypt), Martin Harvey Allchurch (European Medicines Agency [EMA]), Reem Al-Naimat (Jordan Food and Drug Administration [JFDA], Jordan), Ahmed Hussein Babiker (Ministry of Public Health [MOPH], Qatar), Bandar Alhammad (Saudi Food and Drug Authority [SFDA], Saudi Arabia), Marko Erić and Mladen Bogdanović (Medicines and Medical Devices Agency of Serbia [ALIMS], Serbia), Fikriye Handan Öztunca and Musa İlker Durak (Turkish Medicines and Medical Devices Agency [TITCK], Turkiye), Sybil Ossei-Agyeman-Yeboah (West African Health Organization [WAHO]), Marie Valentin and Samvel Azatyan (World Health Organization [WHO]), and Gugu Mahlangu (ex-Medicines Control Authority of Zimbabwe [MCAZ], Zimbabwe).

Facilitators: Magda Bujar (CIRS), and Sara Torgal and Tamei Elliott (DIA).