International regulatory harmonization is increasingly important given the complex, global and diverse nature of pharmaceutical industry operations. Different regulatory authorities often have different scientific and regulatory requirements that drug developers need to meet for product approval. This can lead to duplication of effort, increased costs and time for the developer to bring the product to market, and slower patient access. To address this challenge, FDA engages with other regulatory and industry stakeholders worldwide to harmonize regulatory requirements across regions.

A major part of FDA’s regulatory harmonization effort is undertaken through our work as a Founding Regulatory Member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

In this CDER Conversation, Theresa Mullin, PhD, Associate Center Director for CDER’s Strategic Initiatives, talks about CDER’s important work in ICH, providing leadership of key committees and expert working groups, developing harmonized guidelines and related training, and providing expert feedback on guideline development. 

What is international harmonization and why is it important?

Put simply, international regulatory harmonization is when regulatory authorities in different regions align their technical requirements for drug development and evaluation as much as possible within national and regional legal frameworks.  The resulting harmonized guidelines are developed by a process of scientific consensus with regulatory and industry experts working side-by-side. The commitment of regulators to then implement the final guidelines is key to ultimately achieving the public health benefit of harmonization.

International harmonization of technical requirements can help give the pharmaceutical industry clarity on the data and evidence needed to support regulatory submissions and meet regulatory expectations. This enables more streamlined global drug development for industry by reducing unnecessary duplication of clinical trials in humans and unnecessary animal testing and enabling use of the same standards for manufacturing quality and risk management in global operations. Patients benefit by having faster access to safe, effective, and high-quality drugs in many more countries.

Harmonization of requirements for drug sponsors or applicants can also enable more efficient regulatory review and information exchange, for example, through use of the electronic common technical document for regulatory submissions. Convening pharmaceutical regulatory authorities and industry stakeholders in one venue offers the opportunity for harmonized guidelines to have both a strong scientific and operational foundation and allows both regulators and industry to learn more about the range of considerations and perspectives from their global counterparts. 

What is CDER’s role in ICH guidelines?

ICH guidelines are our primary way to achieve international harmonization. CDER plays a significant role in the development of each ICH guideline, which we then adopt and issue as our own guidance for industry. ICH guidelines cover scientific and technical aspects of pre-clinical and clinical research, manufacturing, a range of multidisciplinary topics, and electronic data standards for reporting and regulatory submissions for drug regulatory review and approval. The ICH guidelines are organized into four basic categories: Safety, Efficacy, Quality, and Multidisciplinary topics.

ICH Expert Working Groups (EWGs) are formed to develop each guideline and are comprised of technical experts from ICH Members and Observers. Each EWG works to develop a harmonized guideline through a 5-step process that includes scientific consensus building (Step 1), developing a draft guideline (Step 2), seeking public feedback on the draft guideline (Step 3), developing and approving a final guideline (Step 4), and ultimately, implementing the final guideline (Step 5). 

CDER offices can propose new topics for harmonization. If adopted by ICH for new guideline development, a CDER subject matter expert (SME) will typically serve as the Rapporteur (lead for the EWG) for that FDA CDER-proposed topic, and a CDER SME will also participate as a technical expert (e.g., as topic lead or deputy topic lead) to the EWG.

For each of the 4 topic categories addressed by ICH, CDER has a named “caucus lead,” who provides support to CDER experts participating in EWGs and oversight of guidelines in development. Within CDER’s Office of the Center Director, I serve as the CDER representative to the ICH Management Committee and Assembly and lead the FDA delegation to ICH.  In addition, I serve as the Chair of the ICH Management Committee. CDER also works closely in ICH with our counterparts in FDA’s Center for Biologics Evaluation and Research, since ICH guidelines also generally apply to products they regulate.

During the Step 3 public consultation process, we publish a notice in the Federal Register, the official daily publication of Federal agency regulations, announcing the availability of the draft guidance for public comment. We may also host free webinars to provide information to increase awareness of the opportunity to comment on certain guidances.

All ICH regulatory members are committed to implementing finalized guidelines in their country or region (e.g., the European Union). To facilitate this process, FDA, in collaboration with the other ICH members, develops training materials. CDER may also update or issue its own complementary guidances based on ICH activities.

What role did CDER play in recent ICH guidelines?

The following is a just a sampling of the important guideline work being led by CDER SMEs.

ICH M13A Bioequivalence for Immediate - Release Solid Oral Dosage Forms

Generic drugs supply a significant portion of the global pharmaceutical market. Harmonization in this area presents opportunities for market competition, cost savings, and greater supply, thereby increasing patient access to high-quality generic drugs. ICH M13A, a draft guideline published in December 2022, serves as the first in the series of M13 guidelines to describe the scientific and technical aspects of study design and data analysis to support bioequivalence (BE) assessment for orally administered immediate-release (IR) solid oral dosage forms.

CDER SMEs from the Office of Generic Drugs (OGD) served as rapporteur and participated in the ICH M13 EWG, relying on their experience in reviewing and approving generic drug applications. CDER hosted a free webinar to provide an in-depth look into the draft guideline and provide clarification on FDA’s planning on the implementation of ICH M13A. The ICH M13 EWG has begun to address comments received through the public consultation process, including those received through the FDA’s public docket. 

The development of the M13A guideline has spurred OGD to update its existing draft BE guidance for BE studies with pharmacokinetic endpoints to support abbreviated new drug applications (ANDAs) and CDER plans to update relevant product-specific guidances when M13A is ready for implementation. 

ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products

FDA published ICH Q13 as a final guidance in March 2023 to implement this guideline providing global harmonization of regulatory approaches for continuous manufacturing for drug substances and drug products and encouraging broader adoption of advanced manufacturing technologies. Greater product and process understanding that may be associated with industry use of these advanced technologies will also support better pharmaceutical manufacturing quality management and help reduce the risk of quality-related drug shortages.

CDER will work with other regulators and industry members from the EWG to develop training materials to facilitate consistent implementation of Q13. Training will also help ensure awareness as regulators develop new policies or revise existing ones when appropriate. SMEs from CDER’s Office of Pharmaceutical Quality OPQ have served as rapporteur, and as members of the EWG that developed ICH Q13. Those experts will continue in their roles as part of the implementation working group that will develop the training materials. 

Reflection Papers

CDER has also been instrumental in the development and adoption of ICH Reflection Papers that outline areas of strategic importance for future guideline work. Some more recent CDER-led reflection papers include Good Clinical Practice Renovation, which led to work currently under way on E6(R3) Good Clinical Practices. The Patient Focused Drug Development paper has led to the approved new topic on patient preference studies to begin in January 2024.

What is next for CDER and ICH?

CDER will continue to play an important leadership role in ICH, helping set the strategic direction for guideline work to enable pharmaceutical innovation, help regulators and industry quickly adapt and respond to public health challenges and ultimately ensure access to medicines for patients around the world.

To read more about the full range of ICH guidelines and reports from the latest meetings of the ICH Assembly and the EWGs, please visit the ICH website. We also collaborate with colleagues from Health Canada to hold a virtual “ICH North American region” meeting to provide more in-depth presentations on guidelines reaching Step 2 and Step 4 harmonization milestones, with assistance from the CDER Small Business & Industry Assistance SBIA program.  These meetings can be viewed in real-time or on YouTube.