FDA CDER Associate Director Speaks About Regulatory Reliance and Agility

Theresa Mullin, PhD

Director, Office of Strategic Programs

FDA

Mullin began by laying out the tragic problem of drug shortages. She cited recent shortages of life-saving cancer drugs, as well as shortages of sterile injectables and solutions following Hurricane Helene. To explain the extent of impact, she told the case of a little girl named Ava whose leukemia medication became unavailable due to a quality control issue. Ava missed four doses before she was able to resume treatment.

Next, Mullin addressed the causes of drug shortages, particularly those that regulators can help address. She presented US FDA data showing that quality issues are a leading cause of drug shortages in the US., far outpacing factors such as product discontinuation and natural disasters.

To maintain drug quality, post-approval changes are essential, said Mullin. Post-approval changes are needed to respond to everything from updates in regulatory requirements to changes in suppliers to findings during inspections.

Regulators want to encourage companies to apply new knowledge, stay up to date, and continually improve their processes. But instead, said Mullin, post-approval changes often impose complex regulatory burdens because pharmaceutical companies must go through independent regulatory processes in every country where a drug is marketed. Mullin also presented data from Pfizer on similar problems that arise with new drug approvals, showing the high query volumes Pfizer must respond to from different regulatory authorities around the world to get changes approved.

Next, Mullin explained how the COVID-19 pandemic drew urgent attention to these longstanding regulatory problems and how they contribute to drug shortages. During the pandemic, the rising need for medicines and supplies coincided with closed borders, disrupted supply chains, and travel bans that prevented regulators from visiting and inspecting facilities. Mullin also discussed climate change, a slower-moving crisis that is also creating its problems for pharmaceutical supply.

The remainder of Mullin’s talk focused on ways to meet these challenges and ensure a steady global supply of high-quality medicines. She emphasized the concept of regulatory reliance, which allows different regulatory agencies to rely on one another’s assessments. According to Mullin, factors that enable regulatory reliance include having regional laws and regulations that align with each other; ensuring that different regulatory agencies make assessments in similar ways; ensuring that assessments are available to regulators at other agencies; and protecting confidential information.

The International Coalition of Medicines Regulatory Authorities (ICMRA) addressed these issues in its vision for a Global Pharmaceutical Quality Knowledge Management (PQKM) capability. Mullin presented the International Coalition of Medicines Regulatory Authorities (ICMRA) document’s key aims, which are to improve the availability of quality medicines by enhancing regulatory reliance, agility, effectiveness and efficiency, as well as bringing assessments, inspections and data requirements into alignment.

Mullin described two pilot projects that ICMRA initiated as steps toward increasing regulatory reliance for post-approval changes. The first pilot project was the ICMRA Collaborative Assessment Pilot, which invited companies to submit applications for chemistry, manufacturing, and control-related post-approval changes to be assessed collaboratively by agencies including Anvisa in Brazil, the European Medicines Agency (EMA), US FDA, Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, Health Canada (HC) and Medicines of Healthcare products Regulatory Agency (MHRA). ICMRA received 14 applications and accepted five of them, selecting based on the potential for contributing to the supply of critical medicines and on convergent regulatory approaches. The companies submitted identical applications to the participating agencies, and all five applications were successfully completed, with different agencies approving the applications within days of each other.

Agencies invested a great deal of resources as they worked to bring their processes into alignment for the ICMRA Collaborative Assessment Pilot, said Mullin. However, a survey revealed that nearly everyone felt the effort had been worth it. Mullin presented key achievements of the project, including agreements about process, timeline, and data requirements. One of the major takeaways was the need for a shared IT platform that different regulatory authorities and companies can use to communicate and collaborate.

The second ICMRA pilot project was the Collaborative Hybrid Inspection Pilot (CHIP). Mullin explained that as part of the CHIP project, agencies worked together to inspect facilities and conditions related to post-approval changes. Only the agency located nearest to the facility had a representative on-site, while other agencies participated virtually. The participating agencies were able to agree on timelines and requirements and to reach consistent findings from the inspections. The follow-up survey and analysis for that project are still underway, but Mullin presented some lessons that have already emerged from the project, such as the need to clarify expectations about the hybrid inspection process for industry and the need to clarify when a hybrid inspection would be warranted. As with the ICMRA Collaborative Assessment Pilot, CHIP also highlighted the need for a shared IT platform.

Next, Mullin presented findings from a 2022 joint reflection paper in which ICMRA PQKMS laid out the key tasks and projects that fall under the respective umbrellas of the ICH, the International Pharmaceutical Regulators Programme (IPRP), and the PIC/S. These included an ICH effort called the PQKM Secure Multi-User IT Solution Task Force, which aims to address the need for a shared IT platform that emerged during the pilot projects.

Mullin offered additional details about the IT platform task force, which is working on legal, technical, financial and cybersecurity challenges and plans to present findings in early 2025. She also described a key project of the ICMRA PQKM Working Group (WG) to develop unique identifiers for products, substances, and facilities. This would help regulators track information and quality characteristics and ensure that they are receiving equivalent submissions.

Mullin wrapped up her talk by emphasizing the long-term and multi-stakeholder investment that will be needed to achieve regulatory reliance so that industry can work with greater agility. Those efforts are already well underway, and Mullin remarked on the novelty of so many international regulatory organizations working together toward a shared vision. The projects by organizations including ICH, PIC/S, and IPRP may have some “quick wins,” she said, but most will take long-term vision and commitment to secure patient access to medicines.