ithin a defined period after the initial approval of a medicinal product, many regulatory authorities require the renewal of its marketing authorization to ensure that the medicine’s safety, quality, and efficacy continue to meet the standards set by national regulations.

Typically, a renewal assessment is based on the re-evaluation of the benefit-risk balance of the product. But requirements are not globally harmonized and, in some cases, the extensive and complicated regulatory requirements for renewals can potentially risk continued timely access to these products.

This article considers the regulatory requirements of 128 jurisdictions applicable to renewals of approved small and large molecules (as of September 2023), overviews global renewal practices, and offers insights on how to reduce regulatory complexity to benefit patient access.

Most Common Renewal Approaches

Our analysis indicates that the majority of regulators (79) apply one of the following approaches to renewals:

• 36 regulators require submission of certain Common Technical Document (CTD) Module 3 (M3) information such as 3.2.P.1, 3.2.P.3.1, and 3.2.P.5.1, or country-specific Chemistry, Manufacturing, and Controls (CMC) documentation such as the 3.2.P.8.3 Addendum. In addition, these regulators request Good Manufacturing Practices certificates (cGMP), letters and declarations, artwork, and other ancillary documents.
• 43 regulators require submission of the full CTD M3, along with country-specific clinical and nonclinical documents. Information of post-approval variations may also be included in the documentation when allowed. Supporting documents required by regulators in this category may include Environmental Risk Evaluation, cGMP, etc. Some countries require a full M1-M5 dossier—the same package submitted in the initial marketing application (MA), post-approval variations and safety—for renewals. This is the most complex regulatory approach to renewals.

From the standpoint of resource utilization, the review of repeated (duplicative) information by regulators does not seem justified. Extensive, complicated renewal dossier requirements combined with limited regulatory resources create a heavy regulatory burden and duplication of work for both industry and regulators; increasing the timelines for renewals can affect the continued product supply to patients. Renewals often require a long review timeline (up to 12 months, calculated as the time between target submission date and MA expiry date) and increase the submission review backlog. Unexpected renewal delays influence global supply chain planning and management and may even impact national reimbursement processes. This potential disruption of continuous treatment can be critical for patients, especially those with life-threatening diseases.

In some countries, regulations do not allow for the simultaneous submission of applications for renewals and post-approval variations. This means that companies cannot submit any variations until the MA is renewed. As a result, the implementation of variations may be delayed, which could lead to increased supply chain complexity (i.e., companies must manage different versions of the product, as approved in each country) and shortages (i.e., when a change cannot be implemented because it is awaiting regulatory approval). This is concerning, because local delays can even impact patient access to medicines beyond that nation’s borders.

Most Efficient Approaches

Various post-marketing regulatory mechanisms have been established to ensure the quality, safety, and efficacy of medicines on the market, such as pharmacovigilance (PV) requirements (e.g., post-marketing safety reports), post-approval change (PAC) management, manufacturing inspections, etc., after initial authorization. These mechanisms ensure updates of relevant information in a timely manner. Some countries with robust and well-established local regulatory systems have implemented approaches that allow them to manage renewals of MAs much more efficiently.

In 30 of the jurisdictions we evaluated, MAs are permanent and renewals are not required, or are required only once and the MA becomes permanent thereafter. We define this approach as “unlimited MA.” In one country, renewals are solely administrative: MAs are maintained upon payment of annual retention fees and a dossier is not submitted, referred to as “autorenewal.” Finally, 18 of the evaluated jurisdictions use simple (administrative) renewals, which require MAHs to submit administrative documents such as application forms, letters and declarations, cGMP, etc.

Adopting these approaches, especially unlimited MAs or autorenewals, offers several advantages: They reduce regulatory burden, avoid duplication of work, and increase resource availability, because regulators do not re-review dossier sections that they had previously reviewed during the initial MA and post-authorization period. Regulators’ resources can be freed up to focus on core and other prioritized national activities such as pharmacovigilance, responding to cases of substandard and falsified products, developing legal and organizational frameworks, and improving publicly available information. These alternative approaches also avoid unexpected renewal delays, ensure MA continuity, and can ensure an uninterrupted supply of crucial medicines to patients at the national level. Since these approaches do not require submission of renewal applications, the risk of unexpected regulatory delays is greatly minimized. One important observation: All the regulators who have adopted these efficient practices are widely recognized as well-established and mature (historically referred to as “stringent regulatory authorities,” a concept that is being replaced by the WHO-Listed Authorities).

Considerations for Increasing Efficiency

Post-marketing regulatory mechanisms to re-evaluate the quality, safety, and efficacy of medicines beyond MA renewal have also been established. Countries should assess their local situation when optimizing their current MA renewal system to ensure a coherent regulatory framework that provides the required level of oversight and control.

Oversight of CMC post-approval changes: Some regulators may use renewal applications as a mechanism to ensure MA maintenance with CMC post-approval changes that have not yet been submitted but are allowed to be included in the renewal package. When a country has established and implemented a well-functioning post-approval change management system, and companies have a legal obligation to submit variation applications according to these local regulations and guidelines, it is not necessary to include the duplicate information (i.e., full Module 3, including variations) during the MA renewal.

Oversight of regulatory and GMP compliance of the manufacturers: GMP inspection ensures that products are produced consistently so that they meet regulatory standards for safe use. The manufacturer’s level of GMP compliance can be confirmed through periodically reviewing GMP compliance documentation or relying on GMP certificates issued by other trusted authorities.

Oversight of the benefit-risk balance of the product based on post-market surveillance and updated safety/efficacy data accumulated since the initial MA: Some regulators require extensive retrospective data during MA renewal to re-evaluate the benefit-risk balance of the product. This can be accomplished by evaluating the data accumulated through safety updates to the Product Information, Periodic Benefit-Risk Evaluation Reports (PBRERs), suspected adverse reaction reports, and additional pharmacovigilance activities throughout the tenure of the MA.

Oversight of the marketing status of a product: While some countries may use periodic renewals to monitor the marketing status of a medicinal product, it is not the most efficient way to do so. Alternative approaches, such as requiring companies to proactively notify regulators if an approved medicinal product is discontinued or not marketed (a practice already in place in Australia, the US, Canada, and the UK), can be considered. Instead of waiting for periodic renewals, these requirements enable agencies to monitor the marketing status of the approved MA more efficiently and reduce the risk of a potential drug shortage.

Current Trends and Recommendations

In several countries, regulators are considering simplifying the renewal process by implementing unlimited MA, or automatic renewals. In addition, reliance has been widely implemented to avoid duplication of work and increase efficiency. To support greater efficiency, regulators who require periodic renewal applications, especially those with complex requirements, might want to consider:

• Assessing the robustness of post-authorization approaches to make sure they are science-based and risk-based.
• Establishing an efficient post-authorization regulatory system in line with international standards, with clear procedural timelines, harmonized change classification, and use of reliance.
• Eliminating requirements for duplicative regulatory information previously submitted in dossiers, safety updates, or PBRERs (e.g., full Modules 3-5, extensive retrospective data).
• Using reliance for renewals where possible. Companies can commit to providing PBRERs and submit safety updates as well as CMC variations in a timely manner to the relying authority. In addition, companies can present to regulators evidence of continued MA validity and GMP compliance documents issued by trusted reference authorities. Regulators can leverage the evidence of MA validity from the reference authority to make informed MA renewal decisions.
• For authorities that have established an effective post-authorization regulatory system, regulators should consider implementing unlimited MAs or autorenewals.

References available upon request.