The Networking Issue Feature: Part 3
There are approximately 300,000 manufacturing facilities located in more than 150 countries supporting the global pharmaceutical industry.1 In the United States alone, nearly 40% of drug products and 80% of drug substances come from producers located outside of the country.2 Pharmaceutical R&D is conducted around the world, increasingly in developing markets with little experience in the regulation of clinical trials.3 Often, different pharmaceutical ingredients, drug substances and final products are manufactured in multiple countries.4
Given the extent of globalization of pharmaceutical development and manufacturing activities, it is no longer possible for individual government regulatory agencies to ensure the safety and security of the drug supply in their respective nations on their own.
Unfortunately, the multilateral strategic coordination of regulatory efforts relating to pharmacovigilance, supply-chain integrity and international health crisis management has yet to be established.1 The patchwork of regulations prevents comprehensive assurance of drug safety and creates barriers to the efficient development of novel treatments.2
Many regulatory agencies have limited resources, are lacking sufficiently skilled staff and are challenged to stay abreast of the rapid advances in new treatments and manufacturing technologies.2 This situation is particularly true for developing nations, but also applies to countries with well-established markets and regulatory infrastructure.
Meanwhile, companies are often required to conduct similar but distinct studies and submit multiple applications for a given product to agencies in different countries, increasing the time and cost it takes to bring new drugs to market.3 As a result, supply chains are often highly complex, increasing quality risks.5 Different systems are also generally employed for the monitoring of commercial drugs, driving further inefficiencies and higher costs, while limiting the sharing of vital safety information. Duplication of effort negatively impacts both manufacturers and national medical regulatory agencies (NMRAs).4
Regulatory harmonization would increase efficiencies and reduce cost by avoiding that duplication of effort.2 Drug development times and costs could be reduced and funds could be invested in new drug discovery instead of meeting different regulatory requirements.
Acceptance of inspection results and drug approvals across agencies would increase access for patients.3 It is also possible that regulatory harmonization could increase the likelihood of success for pipeline candidates.
As importantly, collaboration would lead to best practices and standards, which would improve the safety of drug products.2 Open discussions between NMRAs would also lead to the strengthening of capabilities of agencies with less experience and expertise.6 More effective pharmacovigilance through international cooperation would lead to greater understanding of the causes of adverse events and allow earlier responses to potential safety issues.7
While global harmonization of pharmaceutical regulations would be highly beneficial to regulators, drug makers and patients, there are significant hurdles that inhibit rapid movement toward this goal. Most NMRAs have limited resources to direct toward daily activities, let alone to loftier goals. Unmet medical needs vary widely from one region to another. As importantly, differences in socioeconomic, cultural, political and healthcare systems present key challenges.6
The definition of quality is not singular for any given product. Risk tolerance levels, regulatory strategies and decision-making processes (strict, rule-based vs. flexible, principle-based) differ greatly from country to country and can lead to drug approvals in some countries but not others.3 The need to demonstrate quality for specific local populations can result in regulations that are different from global standards.5
Some countries have implemented accelerated approval pathways, while others have not. Further complicating factors relate to the rapid advance of personalized medicines and the increasing use of artificial intelligence and machine learning, all of which require new regulatory approaches that could potentially vary amongst NMRAs.5
There is also a general concern that individual countries are leveraging sovereignty to delay harmonization of regulations for drugs and medical devices.8
Despite these many challenges, regulatory agencies around the world have been working slowly toward global harmonization, and noteworthy progress has been made in the last decade.
Regulatory harmonization involves the adoption of the same technical requirements, standards and guidelines for quality, safety, and efficacy by all regulatory authorities. While each NMRA has decision-making authority, in general, the same process is followed, with common documentation and alignment of legal frameworks. Collaboration and trust between different agencies are essential to enable recognition of each authority’s decisions.1 However, this goal has yet to be achieved.
Nevertheless, there has been significant regulatory convergence, with the regulatory requirements of different countries and regions becoming increasingly similar over time. This is in respect to scientific principles, practices and procedures, as reflected in the acceptance of internationally recognized technical guidance documents and implementation of regulatory mechanisms that align with them.9
One crucial example is the International Council on Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), which has been in existence for nearly 30 years. This organization develops and implements harmonized guidelines and standards for drug development and registration. It has been instrumental in the harmonization of Good Manufacturing Practice (GMP) and pharmacovigilance activities, the creation of the electronic Common Technical Document (eCTD) and standardization of medical terminology with MedDRA.6
Initially, only the European Union, the United States, Switzerland and Japan were participants, but today, China and many other countries are members, making the ICH the leading global operational and standards body.1 India is the largest nation that produces drugs and medical devices that does not participate in global regulatory harmonization efforts.
The World Health Organization (WHO) has also been involved in regulatory harmonization efforts designed to increase access to medicines in the developing world.6 Examples include development of the Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) classification system for drugs, the International Pharmacopoeia (Ph. Int.) and standards for pharmacovigilance through the WHO Program for International Monitoring; its medicines prequalification program to facilitate distribution of drugs to developing nations; and funding, in conjunction with the World Bank and NGOs, of various harmonization projects.
Other international harmonization efforts include the Pharmaceutical Inspection Convention; the Pharmaceutical Inspection Co-operation Scheme (PIC/S); the Council for International Organization of Medical Sciences (CIOMS), which largely is focused on biomedical products; the Health Level Seven International (HL7), which sets standards for the exchange, integration, sharing and retrieval of electronic health information; and the recently created International Coalition of Medicines Regulatory Authorities (ICMRA), whose members are the top health and drug regulators in 18 of the world’s most developed nations and regions. The ICMRA is focused on global strategy and coordination, including the creation of a broad, formal framework with which to enhance communication, collaboration and regulatory alignment.1,2
Regulatory convergence takes many forms, from general collaboration to more formal mutual recognition agreements (MRAs), such as the recent agreement between the European Union and the United States, to regional integration, such as within the European Union.6 Generally, these efforts focus on improving the transparency and alignment of interactions among agencies and between industry and various regulatory authorities; harmonizing inspection criteria, reports and deficiency descriptions; achieving better alignment of pharmacopoeial monographs and procedures; and harmonizing marketing authorization applications and approval timelines.5
The European Union is no longer the only region focused on harmonization of pharmaceutical regulations. Efforts are progressing in emerging regional markets.4 The African Medicines Regulatory Harmonization Initiative was launched in 2009. The Zazibona process involves cooperation between NMRAs in Zambia, Zimbabwe, Botswana and Namibia, among others. The Pan American Network for Drug Regulatory Harmonization (PANDRH) focuses on harmonization of regulations for small molecule drugs in the Americas.
Others include Mercosur (South American trade bloc), the Southern African Development Community (SADC), the East African Community (EAC), the Gulf Cooperation Council (GCC), the Association of Southeast Asian Nations (ASEAN), the Asia-Pacific Economic Cooperation (APEC) and the Eurasian Economic Union.6,7
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