FDA Works Through ICH to Support Global Drug Development: Creating Harmonized Technical Standards Through Guidelines 

The International Council for Harmonisation (ICH) is a unique project that brings together regulatory authorities and pharmaceutical industry representatives to discuss scientific and technical aspects of pharmaceutical product development and registration.  

Launched in 1990 by regulatory bodies and industry associations from the United States, Europe and Japan, the ICH aims to achieve greater harmonization to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner. 

The primary areas of technical requirements harmonized by ICH include: 

1. Safety (carcinogenicity, genotoxicity, reproductive toxicology etc.)  

2. Efficacy (good clinical practices, clinical trials, evaluation by therapeutic area) 

3. Quality (stability, impurities, manufacturing, pharmaceutical development) 

4. Multidisciplinary (computational modeling and simulation, electronic standards, terminology, biopharmaceutics) 

  Key Benefits of ICH: 

• Harmonized guidelines reduce duplication of effort and enable more streamlined global drug development  
• Facilitates adoption of new improved approaches to research and development 
• Promotes public health by reducing unnecessary animal and human testing 
• Enables more efficient regulatory collaboration and exchange of information 

Composition of ICH Working Groups 

The ICH develops guidelines through an established 5-step process involving technical expert working groups. As of 2022, over 700 experts from regulatory agencies and industry are involved across 34 working groups. 

Once finalized, ICH guidelines are implemented by ICH regulatory members in their respective regions. The founding regulatory members are the U.S. FDA, European Commission, and Japan’s MHLW/PMDA. Standing regulatory members include Health Canada and Swissmedic (Switzerland). 

Role of FDA’s Center for Drug Evaluation and Research (CDER): 

CDER plays a pivotal leadership role within the ICH framework across all technical areas, this includes: 

• Proposing new topics and leading expert working groups  
• Participating actively in all stages of guideline development   
• Adopting and implementing final ICH guidelines as part of the FDA’s own guidance 
• Developing complementary training materials to facilitate implementation 
• Representing the FDA in the ICH governance structure 

Some recent major CDER contributions include leading the ICH guidelines on bioequivalence for oral solid doses (M13A), continuous manufacturing (Q13), and numerous strategic “reflection papers.” 

Expanding Participation in ICH: 

Originally focused on the U.S., Europe and Japan, the ICH underwent reforms in 2015 to promote wider global representation. New regulatory and industry members have since joined from countries like China, Saudi Arabia, Brazil and Singapore.  

The inclusion criteria require prospective members to have implemented key ICH guidelines, appointed experts to working groups, and have a legal regulatory framework for human pharmaceuticals. 

Application to Generic Drugs: 

While ICH guidelines have traditionally focused on new drug development, there are potential benefits to greater harmonization for generic drugs given their large global market share and public health importance. 

Potential areas for harmonization for generics include scientific standards for bioequivalence determination, biowaivers, global reference standards and alternatives to in vivo pharmacokinetic studies. However, key challenges remain including diverging perspectives between brand and generic sectors, and the need for extensive cross-stakeholder alignment. 

ICH Topic Areas for Multidisciplinary 

GUIDANCE ON NONCLINICAL SAFETY STUDIES FOR THE CONDUCT OF HUMAN CLINICAL TRIALS AND MARKETING AUTHORIZATION FOR PHARMACEUTICALS M3(R2)  

The purpose of this guideline is to recommend international standards for, and promote harmonisation of, the nonclinical safety studies recommended to support human clinical trials of a given scope and duration as well as marketing authorization for pharmaceuticals.  

Harmonisation of the guidance for nonclinical safety studies will help to define the current recommendations and reduce the likelihood that substantial differences will exist among regions. This guidance should facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3R (reduce/refine/replace) principles and reduce the use of other drug development resources. Although not discussed in this guidance, consideration should be given to use of new in vitro alternative methods for safety evaluation. These methods, if validated and accepted by all ICH regulatory authorities, can be used to replace current standard methods. This guidance promotes safe, ethical development and availability of new pharmaceuticals. 

This revision R2 of ICH M3 which includes further harmonisation for non-clinical safety studies will help to define current recommendations and reduce the likelihood that substantial differences will exist between regions ICHM3(R2) should facilitate timely conduct of clinical trials and reduce the unnecessary use of animals and other resources „ This should promote safe and ethical development and availability of new pharmaceutical 

ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENICRISK M7(R2) 

This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk. It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions of human use.  

ICH M7(R2) has revised the format of M7 into two linked separate documents:

• First document is the core guideline including a table of all monographs, that are included in the addendum and hyperlinked to the second document.
• Second document is the addendum containing all monographs of mutagenic impurities assessed by the EWG.

BIOPHARMACEUTICS CLASSIFICATION SYSTEM-BASED BIOWAIVERS M9 

This guidance provides recommendations to support the biopharmaceutics classification of drug substances and the BCS-based biowaiver of bioequivalence studies for drug products. The BCS-based biowaiver principles may be applied to bioequivalence purposes not explicitly specified in the guideline, provided they can be supported by a thorough scientific rationale. 

The BCS-based biowaiver approach is intended to reduce in vivo bioequivalence studies. This Guideline – provides recommendations on the biopharmaceutics classification of drug substances, and to support BCS-based biowaivers for drug products. Aims to harmonise current regional guidance, reduces in vivo bioequivalence studies, and support streamlined global drug development. 

DRUG INTERACTION STUDIES M12 

This guideline provides recommendation to promote a consistent approach in designing, conducting, and interpreting enzyme- or transporter-mediated in vitro and clinical drug-drug interaction (DDI) studies during the development of a therapeutic product. A consistent approach will reduce uncertainty for pharmaceutical industry to meet the requirement of multiple regulatory agencies and lead to more efficient utilization of resources. 

Main objectives and scope of the Guideline:

• To develop recommendations that promote a consistent approach in designing, conducting, and interpreting in vitro and clinical DDI studies during the development of a therapeutic product.
• The Guideline is limited to pharmacokinetic interactions, with a focus on enzyme- and transporter-mediated interactions.
• Covers small molecules and biologics (monoclonal antibodies and antibody-drug conjugates).
• Covers metabolite-mediated interactions, model-based data evaluation (mechanistic static model and physiologically based pharmacokinetic (PBPK) modeling) and DDI predictions.
• Out of Scope: Pharmacodynamic interactions and other types of pharmacokinetic interactions due to gastric pH change, formation of complexes or chelates, food effects, etc. 

BIOEQUIVALENCE FOR IMMEDIATE RELEASE SOLID ORAL DOSAGE FORMS M13A 

This guideline is intended to provide recommendations on conducting bioequivalence (BE) studies during both development and post approval phases for orally administered immediate-release (IR) solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/powders for oral suspension. Deviations from the recommendations in this guideline may be acceptable if appropriate scientific justification is provided. Applicants are encouraged to consult the regulatory authority(ies) when an alternate approach is proposed or taken. 

Guideline Objectives:

• This BE guideline is intended to reduce the need for multiple different sets of data and information from duplicative BE studies to support marketing authorisation in more than one jurisdiction.
• This guideline will provide recommendations on BE study design and standards for IR solid oral dosage forms.
• This guideline will result in the harmonisation of current regional guidelines/guidances, reduce the need for additional in vivo BE studies, and support streamlined global drug development. 

ICH MODEL-INFORMED DRUG DEVELOPMENT (MIDD) DISCUSSION GROUP (DG) 2021 

MIDD has been shown to enhance the efficiency of drug development and regulatory decision making thereby optimising both time and resources used in the early “learning” phases and informing the “confirmatory” phases of development. MIDD Discussion Group 31 March 2022.

Although MIDD has been defined in slightly different ways across industry groups, academia and regulatory agencies, the central concepts of these definitions include:

1. Integrating data from multiple sources in the form of mathematical and statistical models based on the understanding of physiology, pharmacology, and disease processes.
2. Applying these models to inform drug development decision making and registration interactions, especially with respect to optimization of the design of future clinical studies, dose regimen optimization and individualization.

Many regulatory agencies expect to receive, and currently accept model-based analyses as part of dossier submissions. However, the level of integration of MIDD into regulatory decision making can vary between regulatory agencies, from application to application, and within agencies for similar submissions.

The lack of common documentation standards, consistency in model assessment expectations and understanding of terminology hinders efficient assessment of model-based submissions, including quality of the data used, the robustness of the analysis, vis-à-vis the modelling impact and credibility with respect to its intended applications.

The lack of harmonisation results in the underutilization of MIDD approaches in drug development and regulatory decision making. This has led to missed opportunities to fully leverage the learning from available data to optimize designs, enhance the interpretation of subsequent confirmatory studies, and reduce reliance on traditional approaches to answering drug development questions.

In summary, the ICH has been a vital force for international harmonization of pharmaceutical technical guidelines over the past 30 years. With its expanded global membership and strategic orientation, it is well-positioned to continue facilitating regulatory convergence and enable more efficient development of innovative and generic medicines for global public health.