What is standing in the way of global harmonisation?

Part II: Industry Voices

What are the most urgent obstacles which need be tackled to achieve progress in regulatory affairs? We put the question to the experts.

Maria Alejandra Blanc, Director, Regulatory Affairs, Abbvie S.A.

While drug manufacturers and regulators agree, in principle, that harmonisation makes sense, it is complex to implement a set of regulation, across different markets, with different historical, political, and economic contexts.Most countries have regulations deeply rooted in the country’s legal practices and precedents; in that aspect, the introduction of a new regulatory scheme could shake the foundations of its own legal system. And, in addition to the national legal umbrella, we must consider the legal framework at the state level, that sometimes try to help the population they rule. Being medicines essential commodities, sometimes those governments create less strict regulations to assure the less benefited population will have access to them. And this enhances the complexities to introduce a harmonised position.We have here the first obstacle.In the case of developed countries, the process might prove easier to achieve than for developing countries, in which we might need to consider an additional hindrance: the pressure of the local industry. In some countries, the local pharmaceutical industry is quite powerful: they have a great deal of products which have been in the market for years, they have good reputation among prescribers and patients, and they are an important source of employment.Even when for multinational companies the global harmonisation would offer obvious benefits, for local manufacturers, harmonisation would most probably mean the need to adapt to more stringent regulations with additional, not so easy to comply with, requirements. Fulfilling them would encompass hard work and investment, they are not always willing to do.Considering this second obstacle, one of the key elements towards the success of global harmonisation initiatives is, undoubtedly, the engagement of the pharmaceutical industry in the country.The third and not less important barrier is the distrust among regulators and the battle of personal egos. One potential solution to that would be hard work towards common goals. If the objective is a common harmonised regulation, and not trying to impose my regulation over others, we could find the way.

Katrin Spaepen, Director of Vault RIM Strategy at Veeva Systems

To fully understand what’s standing in the way of global harmonisation, we need to first look at the tools and technology that regulatory professionals use to do their jobs. In order to keep up with increasingly stringent requirements, regulatory teams often stitch together a number of point solutions, which each only address a small part of the overall process. For example, they may use a document management system that’s only accessible by headquarters to author submission documents, a tool to review and approve those documents, a publishing tool to compile and publish these documents into a submission, a gateway to submit them to health authorities, and finally a variety of file shares and other insecure storage locations to archive completed submissions.

These tools are linked together through costly integrations, which become more expensive over time as companies must pay for initial development, testing, additional support staff, staggered upgrades, and long-term maintenance. In addition, working with a patchwork of integrated systems can impede visibility, create inefficiencies, and lead to a higher risk of non-compliance.If we want to reach global harmonisation, then regulatory professionals will need to standardise that technology and carve out clear roles and responsibilities within their organisations. One way to do that is by connecting team members through a unified RIM platform. Ideally, that platform will:

Include native support for data and documents so regulatory teams can have all the information they need at their fingertips

Offer a complete view of license data across the organisation, regardless of ownership

Be able to generate, submit, and store data exchange messages for seamless communication

Support external systems through an open architecture for global participation

By introducing a single platform for regulatory information, teams can simplify their IT ecosystem, streamline end-to-end business processes, and increase productivity. For example, a unified RIM solution enabled a medium-sized biopharma to automate, and in some cases eliminate, 55% of the steps in their variation management process. They also gained access to real-time reports and dashboards, which dramatically improved visibility and control.Once we reach a point where technology stops being a barrier to regulatory collaboration and starts being a facilitator then we will have a clearer path toward global harmonisation.

Barriers and Challenges for Global Harmonisation

María de la Luz Lara Méndez and Adriana Hernández Trejo, Regulatory Affairs Specialists, LATAM

Talking about global harmonisation implies that all regulatory agencies agree upon developing, implementing, and adopting the same guidelines and technical standards focused on quality, safety, and efficacy, that would be eventually applied by each Regulatory Agencies on the respective countries. Such harmonisation may generate increased effectiveness and decreased costs for every country.There are several global initiatives intended to drive harmonisation and development, such as: Asian-Pacific Economic Cooperation (APEC), International Council for Harmonisation (ICH), The International Pharmaceutical Regulators Programme (IPRP), Pan American Network for Drug Regulatory Harmonisation (PANDRH). However, their effort has not stood out as originally intended because there are different obstacles standing in the way of the global harmonisation.

Which is the participation of the countries of America in those global initiatives?

Figure 1. Asian-Pacific Economic Cooperation (2020) https://www.apec.org/About-Us/About-APEC/Member-Economies

Figure 2. The International Pharmaceutical Regulators Programme (2020) http://www.iprp.global/members

Figure 3. International Council for Harmonisation. Members (2020) https://www.ich.org/page/members-observers

Figure 4. International Council for Harmonisation. Observers (2020) https://www.ich.org/page/members-observers

It is worth to mention that many Regulatory Agencies in America are recognised by the Pan American Health Organisation (PAHO) and the World Health Organisation (WHO) as they comply with international standards, such as the Food and Drug Administration (FDA) in the US, Health Canada, the Commission for Protection Against Sanitary Risks (COFEPRIS) in Mexico, the National Administration of Drugs, Food and Medical Technology (ANMAT) in Argentina, the National Agency of Sanitary Surveillance, Ministério da Saúde (ANVISA) in Brazil, the Institute of Public Health (ISP) in Chile, the National Institute for Drugs and Food Surveillance (INVIMA) in Colombia, and the Center for the State Control of Drug Quality, Public Health Ministry, in Cuba. Nevertheless, despite being recognised under international standards, if we compare their regulatory processes, they are far from being harmonised.So, if harmonisation initiatives exist, and the agencies look for a compliance under the same international standards and they have further adopted some guidelines in several countries, why this global harmonisation has not occurred?Several factors may be considered obstacles that represent a constraint for global harmonisation. We consider the following as the most relevant:

Political changes – A change of Federal Government brings about modifications within Regulatory Agencies, most frequently the Head of such agencies. In most Latin American countries, directive positions within the National Regulatory Agencies have become political positions instead of being of technical-scientific nature. These changes impinge on the actions taken by the former Head as new actions are proposed. This causes the delay and sometimes the termination of any global harmonisation activities previously planned.

Experience within the respective Agency – Several agencies do not have experts nor specialists in every subject. Thus, the introduction of new systems or technologies is frequently a time-consuming process, particularly in Latin American countries.

Regional regulation – Each country possesses its regulatory framework and sometimes it is not updated according to the international guidelines because global harmonisation is not contemplated by the political agenda of Presidents, Congresses, Senators, and Prime Ministers. This causes the stalling of transformation, innovation, and the capacity to improve public health.

Collaboration among Agencies – In spite the collaborative work among Regulatory Agencies aimed towards harmonisation through different initiatives, they are frequently disrupted as a connection between them is not attained. Therefore, there is no collaboration excepting such initiative.

Insufficient resources – Several regulatory agencies face resource constraints of different nature such as human, financial, and infrastructure. This lack of resources within institutions causes activity saturation resulting in reduced operative capacity for essential processes. Thus, other activities or projects different from daily activities are left aside.

Technology – Due to the aforementioned lack of resources, the implementation of new technologies is deficient within the Agencies. This generates a low availability of information for the interested parties. In turn, this also affects the prompt advancement towards regulatory, technological, and technical harmonisation for some agencies.

Socioeconomic aspects – Another aspect that should be also considered regarding harmonisation are the costs and fees established by each Agency to evaluate procedures and services. In many cases, this prompts the evaluation of unnecessary procedures causing an additional administrative load that prevents health professionals from developing and implementing optimal evaluation strategies aligned with international standards.

National Identity – Frequently, the concept of national identity may be an obstacle for global harmonisation as the acceptance of directives different from the internal initiative of the country it is often thought as an infringement or violation of the nationalist thinking. This has been caused by the lack of bilateral agreements that would allow a mutual acknowledgment.

In order to attain a harmonisation, we consider that it is essential the involvement of several figures participating in all health-related processes, such as the pharmaceutical industry, Universities/Academia, and the authorities. In this way, it is possible to migrate towards a confidence-based framework with scientific value and the delegation of responsibilities among all the involved parties. Consequently, the agencies may carry out collaborative work with other counties based on technical, scientific, and regulatory aspects allowing the establishment of a global framework that is possible and feasible for all probable scenarios.Finally, the questions we should be asking ourselves in this regard are why is necessary a global harmonisation? and which are the advantages for each one of the countries involved? If we wish to answer these questions, an analysis must be performed considering the needs and conditions of each country. Additionally, it is necessary to raise interest and to drive the willingness to establish directives towards a global harmonisation and to continually support this kind of initiatives.References1. “The need for global regulatory harmonization: A public health imperative,” Zerhouni, Elias and Margaret Hamburg. Science Translational Medicine. 8:338 (2016)2. Regulatory Harmonization and convergence. https://www.fda.gov/vaccines-blood-biologics/international-activities/regulatory-harmonization-and-convergence3. https://www.paho.org/hq/index.php?option=com_content&view=article&id=1615:2009-sistema-evaluacion-autoridades-reguladoras-nacionales-medicamentos&Itemid=1179&lang=es4. “Glocalization: Balancing Global and Local Concerns in Manufacturing and the Supply Chain”, Pharma´s Almanac. PAQ3 2019Maria de La Luz Lara will be leading digital training courses on regulatory affairs. Course dates are due to be announced shortly.

Figen Kabadas Oge, MSc & MBA, Head of Regulatory Affairs, Groupe Delpharm France

More than last two decades, the pharmaceutical market has undergone many significant changes and trends in terms of globalisation. Many pharmaceutical activities like manufacturing, R&D and supply chains are now global but besides all these efforts, the pharmaceutical products are mostly regulated nationally and many different local registration requirements are burden for the manufacturers. For this reason, a global regulatory harmonisation is becoming essential not only for manufacturers and other shareholders but also for the public interest as one of the aims of Universal Health Coverage (UHC) is giving the access to users high-quality and affordable health services.Even though, there is also an effort of harmonisation among regions like LATAM, CEE, CIS,ANZ, GCC, MENA and ASEAN*, many nation-by-nation regulators require pharmaceutical companies to conduct similar but distinct studies and submit different type of applications for a single product which may increase the time loss and cost affecting in result the market access. These unnecessary barriers can be overcome by greater harmonisation of drug regulations.The working on harmonisation can surely create many challenges but at the end, it will be ending by increasing efficiencies, reducing costs, enhancing R&D, and benefitting patients by improving safety, innovation and access.So, what is standing in the way of global regulatory harmonisation?The answer includes many elements but I would like to mention a few essential ones.Language barriersMany different language barriers can cause obstacles for global regulatory harmonisation.Within the scope of harmonisation, the regulations can be translated into local languages for the understanding of regulators and local manufacturers but there will be still some linguistic problems to handle. For example, translation of dossiers in local languages creates another workload for companies/sponsors. This requirement is also the reason of recreation of eCTD/NeeS files with translated leaf titles. As a result, this exercise comes out at higher cost and time loss for companies which affect the market access of products.Lack of legislations and comprehensive websites in English of non anglophone countries’ agencies is another blocking point to understand the local requirements which obliges companies to move through local experts (affiliates, distributors, consultants etc.). The absence of global harmonised regulations at these regions can make understanding of local requirements even more complicated.Another language barrier is mainly experienced during multinational clinical trials. Sometimes clinical trials conductors/patients can have some difficulties with non-native speakers of local language in any case of acute clinical situation. This hurdle could be observed during daily communication and issuing the informed consent forms.Once again, understanding is the key of effective communication which is possible by using a common language. Therefore, sharing experiences, learning from each other, constructive discussions without speaking the same language can be hurdle for global harmonisation. The difficulty for local regulatory agencies is not only about understanding global legislations but also product specific dossier review in English.

Lack of standardisation and autonomy of local regulatory bodiesAnother reason standing in front of global regulatory harmonisation is coming from local regulatory bodies like the inconsistency in local regulatory requirements. Even in ICH follower countries, companies experience different dossier evaluation styles because of lack of standardisation for dossier review. This difference is more dominated in emerging countries which do not make assignment of specific evaluators. Even in many of these countries, a standard review time of 210 days is applied; companies still receive many questions caused by different judgments of evaluators resulting longer review timelines. Some non-written/communicated, dossier based or local requirements like additional stability studies, detailed documentation, SOPs, validation requests cause also longer approval period.Other blocking points of harmonisation are the lack of resource and knowledge of regulatory bodies. Many developing country regulatory systems are not able to review effectively of every type of submissions. Especially for New Chemical Entity (NCE) submissions, adequate regulatory scientific knowledge is needed for assessment. Because of this lack of expertise and regulation, many developing countries highly rely on prior approval or supporting regulatory decisions of other “stringent” regulatory bodies like US FDA and EMA.To overcome hurdles for global harmonisation, it is needed to gain knowledge, autonomy and enrich regulatory bodies’ organisation. Scientific skills are not always easy to gain by external trainings but by a deeper expertise with continuous learning. Even though this exercise sometimes requires having in-house and/or external experts which can add financial burden for government, it is essential to act nationally and even regionally with appropriate coordination and common will to help drug regulatory bodies having enough resource and skills.Additional regional requirementsSurely each country weighs differently key factors such as risks and benefits, region specific diseases, vulnerable populations and financial concerns which enable a one-way model regulation harmonisation.There are different needs by each country requiring some additional local studies like clinical trials or some population specific studies for neglected tropical diseases. These local requirements might be important obstacles in the design of randomised control clinical trials as the clinical pattern can vary from country to country.Based on different regional groups, even though they could adopt ICH guidelines, they have published their own regulations and guidelines including different dossier and e-submission formats. The most common example can be given between CTD and ASEAN CTD (ACTD) formats. On the other hand, the difference between ICH CTD followers and ASEAN countries are not only limited with dossier format.

Efforts of states for harmonisation and national sovereigntyRegulators cannot think and act globally if the government is in the lack of globalisation vision and negligence of its mutual benefits. Regulations are not surely cheap but the government should consider the bigger risks of non-adequate drugs and their impacts on public health which can cause more potential loss.Additional GMP audit to perform by government and follow of different pharmacopoeias can be also listed among challenging tasks of regulatory harmonisation. This kind of requirements would even be issued by some political reasons behind. For example, a requirement on additional GMP audit by local agency for import drug products could aim prioritisation of local manufacturing by technology transfers and gain manufacturing autonomy for export market with transferred “know-how” technologies. Therefore, trade war between some states could stand in front of global regulatory harmonisation.On the other hand, some governments can choose to think the benefits of their local companies/manufacturers and act according to their well-being. But at the end, it must always be remembered the most important is the patient accessibility of high quality and affordable drugs. For this reason, governmental effort is needed to support the development of local agencies, manufacturers and regulations. This will be done for sure by willingness to create effective legislations, standards, manufacturing technologies and continuous training of regulatory agencies with reorganisation. It requires many cultural, economic and governmental efforts but the reward at the end will be a game-changing development for everyone.ConclusionThe list of reasons standing in the way of global regulatory harmonisation might be very long but only a few elements are detailed above. Because of many different technical reasons and unalterable social and cultural motives, there is no “one-size-fits-all” approach for global harmonisation solution. Even though efforts by different role players are necessary, the first step should come from politicians and government. Once a common goal and mindset in mind is established, then it should be developed the capacity including reinforcement of regulatory bodies, information exchange with other regions, and constitution of regulatory standardisation. It should not be forgotten the fact that access to medicine on time for everyone is a human right rather than a luxury.* LATAM: Latin America; CEE – Central East Europe; CIS – Commonwealth of Independent States; ANZ – Australia, New Zealand; GCC -Gulf Co-operation Council; MENA – Middle East and North Africa; ASEAN - The Association of Southeast Asian Nations (ASEAN) RegionFigen Kabadas will be leading digital training courses on regulatory affairs. Course dates are due to be announced shortly.