Understanding And Navigating Diverse Regulatory Environments

By Kamil Shaik and Guriqbal Singh, RegWeb

Regulatory environments comprise a wide range of regulations, laws, and standards enacted by governments and their agencies to regulate the conduct of pharmaceutical businesses and individuals. Every country has its own regulatory authority, which oversees implementing laws and regulations and establishing guidelines that govern the drug development process, licensing, registration, manufacturing, marketing, and labeling of pharmaceutical products.

The diversity of regulatory standards originates from differences in healthcare systems, cultural nuances, and socioeconomic variables. Navigating a myriad of regulations is a challenging task. This makes the approval and marketing of important and lifesaving treatments very complex. Stumbling around in these diverse regulatory environments could lead to delays in bringing medicine to people who need it.

Furthermore, given diverse rules, pharmaceutical businesses confront issues in emerging and developing countries due to noncompliance with trade-related intellectual property rights agreements, pricing limitations, and generic competition. Navigating these environments requires a strategic and informed approach.

Understanding Global And Regional Harmonization Initiatives

The global pharmaceutical market is a mosaic of regulatory frameworks, each tailored to the geopolitical environment it governs. The pharmaceutical industry's global expansion, including transnational production sites and international product marketing, has highlighted the significance of standardized quality, efficacy, and safety regulations.

Global pharmaceutical regulatory harmonization is critical for businesses, foreign consumers, and organizations. Globalization has resulted in increased regional and international collaboration, promoting trade between countries with different legislative, technological, and financial bases. As a result, national regulatory agencies from many nations are working closely together to ensure that their policies are consistent with international standards.

The international organization responsible for achieving the objective of harmonization is the International Conference for Harmonisation (ICH).

ICH is an initiative cosponsored by the drug regulatory agencies and pharmaceutical manufacturing associations of the following organizations: the EU’s EMA, the United States FDA, and Japan’s PDMA. The mission of ICH is to make recommendations for greater harmonization in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby reducing or eliminating duplication of testing conducted during the research and development of new human medicines. The common technical document provides instructions for producing trial data sets and data pieces, making evaluation easier and allowing industry to submit data to several regulatory bodies in a single format. For instance, guideline Q1A, Stability Testing of New Drug Substances and Products, specifies the temperature and humidity parameters under which a medicinal product should be stored to ensure its stability over time. If this suggestion is implemented, any of the three ICH regulatory agencies — EMA, PMDA, or FDA — will accept the test data (albeit some may require country-specific testing), as will many other regulatory organizations that have previously adopted the guidance.

Some of the regional initiatives responsible for facilitating trade among countries with diverse regulatory, technological, and financial backgrounds are:

European Harmonization

There are three types of registration in the EU: centralized, mutual recognition, and individual country procedures.

Europe was the first continent to implement regional harmonization of pharmaceutical legislation, resulting in a unified market and fostering free circulation of pharmaceuticals throughout all European member states. Pharmaceutical businesses can utilize the centralized procedure to market their products throughout the member states.

Additionally, decentralized procedures and mutual recognition agreements between the European member states are in place for manufacturers wishing to market their products in selected European countries.  It is up to the manufacturer to choose a route based on its business needs.

East African Communities Regulatory Harmonization

This initiative is being executed by the region's six national medical regulatory authorities (NMRAs). The NMRAs are the Department of Pharmacy, Medicines, and Laboratories (DPML) in Burundi, the Pharmacy and Poison Board (PPB) in Kenya, the National Drug Authority in Uganda, the Pharmacy Task Force (PFT) in Rwanda, the Tanzania Food and Drugs Authority (TFDA), and the Zanzibar Food and Drugs Board in the United Republic of Tanzania. Obtaining marketing clearance from the EAC will allow manufacturers to market their innovations in all EAC member regions.

ZAZIBONA

This is a collaboration of Botswana, Namibia, Zambia, and Zimbabwe's national medicines regulating authorities. Other Southern African Development Community members may potentially take part in this procedure. The process's goal is to create a partnership model that will make it easier to get access to high-quality medications by sharing efforts in medicine assessment and inspection of manufacturing and testing facilities. Products that pass the assessment criteria are subsequently granted marketing authorization in the participating countries.

Gulf Cooperation Council (GCC)

GCC is a pharmaceutical harmonization initiative developed with the primary goal of coordinating health policies and programs across participating countries through the exchange of information, knowledge, methodologies, and expertise. Its responsibilities include pharmaceutical product registration, GMP inspection and compliance, quality control laboratory approval, and the examination of technical and post-market surveillance reports. Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, the United Arab Emirates, and Yemen participate in the GCC as members of the Health Council.

East Community Of West African States (ECOWAS)

ECOWAS's member countries are:

• Benin
• Burkina Faso
• Cape Verde
• Cote d'Ivoire
• The Gambia
• Ghana
• Guinea
• Guinea Bissau
• Liberia
• Mali
• Niger
• Nigeria
• Sierra Leone
• Senegal
• Togo.

The organization's goal is to achieve the highest possible standard of health protection for the peoples of the region by harmonizing member states' policies, pooling resources, and cooperating with one another and with others in a collective and strategic combat against the sub-region's health problems. This will allow pharmaceutical firms to gain marketing approval in all ECOWAS states using the same submission method.

Association Of Southeast Asian Nations (ASEAN)

ASEAN is a union of 10 southeast Asian countries:

• Indonesia
• Laos
• Malaysia
• Myanmar
• The Philippines
• Singapore
• Thailand
• Vietnam
• Brunei
• Cambodia.

ASEAN's goal is to establish standardized pharmaceutical regulatory rules as well as a common structure for drug registration applications, known as the ASEAN CTD.

Asia-Pacific Economic Cooperation (APEC)

APEC is a union of 21 countries, including:

• Australia
• Brunei Darussalam
• Canada
• Chile
• China
• Hong Kong
• Indonesia
• Japan
• Republic of Korea
• Malaysia
• Mexico
• New Zealand
• Papua New Guinea
• Peru
• The Philippines
• Russia
• Singapore
• Chinese Taipei
• Thailand
• United States
• Vietnam

The union’s purpose is to harmonize member-state legislation to create a unified pharmaceutical market.

APEC has worked with other international organizations to develop a number of harmonization topics, including bridging studies, stability in the APEC region's climatic zones, clinical trials, GMP, GCP, and a collaborative opportunity for common local clinical data that meets the regulatory requirements of Korea, Japan, and China.

Mutual Recognition Programs

Most of the countries have mutual recognition agreements in place that allow pharmaceutical businesses to expedite the approval process by obtaining market authorization in one country and use it as a reference market while filing an approval in other countries.

Navigating Diverse Regulatory Environments

Understanding the current regulatory landscape

It is important to have a thorough understanding of the regulatory environment before selecting a target market because different target marketplaces have distinct regulatory needs. For instance, a lot of medical device companies used to start their business in Europe and get the CE mark before applying for FDA certification.

But now that the EU Medical Devices Regulation and the In Vitro Diagnostic Regulation have changed European regulations, companies are holding off on obtaining European approval. Furthermore, companies are approaching the FDA for information on product development and future regulatory requirements, which they then apply to their development and technical files for the EU.

A company that decided to employ the traditional playbook for global regulatory strategy would be caught in a conundrum in this case, as selecting the EU as the target market may lengthen the entire timescale to commercialization.

Incorporating regulatory intelligence with an aligned approach

Your regulatory approach should be aligned with regulatory intelligence that is aligned across several markets to the greatest extent practicable. This requires an awareness of each market's regulatory standards. For example, if a company understands that a product is regulated similarly in Canada and the EU, it may easily synchronize its product development strategy to target both markets. The company may potentially consider launching in Australia, where the TGA acknowledges CE mark approvals. As a result, the product may receive several approvals at once. It is important to establish a robust regulatory intelligence system by continuously monitoring regulatory changes, industry trends, etc.

Understanding of harmonization

The ICH has developed a series of guidelines aimed at promoting international harmonization. These guidelines cover various aspects of drug development, registration, and post-approval activities. Incorporating the ICH standards during the drug life cycle will allow you to satisfy the major regulatory authorities like FDA, EMA, PDMA, Health Canada, etc., as most of these countries accept data generated by adhering to ICH guidelines.

Collaboration with regulatory authorities

Understanding the regional disparities before adopting a regulatory approach is crucial as there are differences in pharmaceutical regulations across regions or other specific in-country requirements. Collaboration with regulatory authorities will provide ample opportunity to understand the regulatory requirements and ease the approval process.

Adopting global compliance standards

Ensure compliance and quality by adhering to good manufacturing practices, implementing quality by design principles, and adopting robust post-marketing surveillance programs.

Collaboration with stakeholders

Collaboration among cross-functional teams will allow greater compliance at every stage of drug development.

For Further Reading:

Lakkis MM. Global and Regional Drug Regulatory Harmonization Initiatives. Drug Information Journal. 2010;44(3):289-297. doi:10.1177/009286151004400311

Chong, S.S.F., Kim, M., Limoli, M. et al. Measuring Progress of Regulatory Convergence and Cooperation Among Asia–Pacific Economic Cooperation (APEC) Member Economies in the Context of the COVID-19 Pandemic. Ther Innov Regul Sci 55, 786–798 (2021). https://doi.org/10.1007/s43441-021-00285-w

Ms. Noxolo Luthuli, and Mr. Wilberto Robles. Africa Medicines Regulatory Harmonization Initiatives. https://catalystglobal.org/wp-content/uploads/2022/01/White-Paper-on-Africa-Harmonization-Initiatives-FINAL-041817-1.pdf

Forum on Drug Discovery, Development, and Translation; Board on Health Sciences Policy; Institute of Medicine (IOM); Weisfeld V, Lustig TA, editors. International Regulatory Harmonization Amid Globalization of Drug Development: Workshop Summary. Washington (DC): National Academies Press (US); 2013 Oct 24. 3, Overview of the Current Global Regulatory Landscape. Available from: https://www.ncbi.nlm.nih.gov/books/NBK174229/

Premier Research. Current Challenges (and Solutions) in Global Regulatory Harmonization. https://premier-research.com/blog-global-regulatory-harmonization-current-challenges/

Ndomondo-Sigonda M, Azatyan S, Doerr P, Agaba C, Harper KN (2023) Best practices in the African Medicines Regulatory Harmonization initiative: Perspectives of regulators and medicines manufacturers. PLOS Glob Public Health 3(4): e0001651. https://doi.org/10.1371/journal.pgph.0001651

Guidance for the Preparation of Applications in the Common Technical Document (CTD) Format. Registration Of Pharmaceutical Products for Human Use In The Economic Community Of West African States. https://wahooas.org/web-ooas/sites/default/files/publications/1991/ctdenguidance-preparation-applications.pdf

Sithole T, Mahlangu G, Salek S, Walker S. Evaluating the Success of ZaZiBoNa, the Southern African Development Community Collaborative Medicines Registration Initiative. Ther Innov Regul Sci. 2020 Nov;54(6):1319-1329. doi: 10.1007/s43441-020-00154-y. Epub 2020 Apr 29. PMID: 33258094; PMCID: PMC7704514.

About the Authors:

Kamil Shaik is a regulatory affairs specialist at RegWeb Consulting Services Inc. Canada. He holds a master’s degree in regulatory affairs and has experience in the pharmaceutical industry. His expertise spans CMC, regulatory intelligence, and project management. Reach him at kamil.shaik@regweb.ca.

Guriqbal Singh is the founder and director of RegWeb, a regulatory consulting firm in Ontario, Canada. He has been working in the pharmaceutical industry since 2006 with experience in international regulatory, CMC, and regulatory intelligence. He has experience in the project management of regulatory maintenance activities for global markets involving initial MAA, variations, renewals, and responses to questions. He has conducted conformance reviews on regulatory dossiers and reviews of pre- and post-approval documentation for regulatory submissions. He is a subject-matter expert for registration requirements in emerging markets with a special focus on ASEAN, APAC, GCC, and Africa. Reach him at guriqbal.singh@regweb.ca or 1-647-673-1718.