Harmonization: Regulation Goes Global
With globalization creating opportunities for companies but causing havoc for regulators, an industrywide demand for regulatory harmony has arisen. But who benefits? And how will the picture look in the years to come? We survey pharma’s global regulatory landscape.
Globalization is a hugely disruptive force. Increasing access to the world’s economies since the 1980s has created winners and losers – with recent political upheavals in the UK and US sometimes viewed as reactions against policies of free-flowing labor and capital.
But on the face of it, globalization has already happened. In almost every industry, supply chains are deeply interwoven, with products sold in one country made up of components supplied from every corner of the world. Pharma is really no different: 40 percent of drugs sold in the US are manufactured abroad, as are around 80 percent of active pharmaceutical ingredients (APIs) (1). National regulators are now no longer able to make sure the products on their markets are safe, efficacious and manufactured in accordance with prescribed quality standards, without giving thought to the wider world. As the nature of industry has evolved, the need for a global view of regulatory oversight has arisen (as former FDA Commissioner, Margaret Hamburg, discusses here).
Surveying the regulatory landscape 50 years ago, one would find a system of largely independent and divergent pharmaceutical systems, with individual countries working separately to strengthen their regulatory capacities. Today’s system is characterized by increasing levels of harmonization – from collaboration on selected topics, to Mutual Recognition Agreements (MRAs), all the way to full integration, as with the European Union. Key pillars of the new regulatory landscape are global bodies, such as the World Health Organization (WHO) and the International Council for Harmonization (ICH), which work to achieve global scientific consensus in developing regulatory guidelines.
Globalization raises many questions. Who benefits from increasing harmonization of pharma regulations? Does the industry want more? How important are the global bodies? And how will the regulatory landscape look in the coming decades?
Joel Lexchin, Professor Emeritus in the School of Health Policy and Management at York University, Canada, and an emergency physician at the University Health Network in Toronto, believes that the main driving force behind harmonization in the pharmaceutical industry is finance. “The industry isn’t interested in having to produce multiple different dossiers for each regulatory environment. Even if you don’t have to repeat trials, there’s still the cost of putting together information in different formats. Industry benefits from being able to get its marketing applications in quicker, allowing it to retain more patent life and thus return on investment.”
Whether this necessarily increases value for the patient is a separate and more complicated question, but the example of the Japanese “drug lag” is one demonstration of how regulatory divergence leads to delayed access to medicines. Pierre-Louis Lezotre, Vice President, Global Regulatory Affairs at Avanir Pharmaceuticals, points out, “It used to be the case that Japanese patients waited, on average, three years after approval in Europe or the US to have access to a new medicine.”
In the mid-2000s, the Japanese Ministry for Health, Labour and Welfare began putting in place measures to cut the time lag (2). As Lezotre explains in his book “International Cooperation, Convergence and Harmonization of Pharmaceutical Regulations: A Global Perspective,” in an effort to resolve the drug lag, the PDMA (Japan’s Pharmaceutical and Medical Devices Agency) launched its “International Strategic Plan” for bilateral, regional and global cooperation, and established an internal office in charge of international affairs. The plan involved hiring more staff and introducing an “innovation premium,” as well as establishing a special committee to review pharmaceuticals approved elsewhere in the world and to recommend fast-tracking, where appropriate, in Japan. In 2008 and for the first time, the PMDA agreed to consider data from global clinical trials in all drug applications – as long as safety studies included Japanese patients. Then, in 2011, the PMDA began offering sponsors a regulatory strategy consultation earlier in drug development. Japan also entered into a Good Manufacturing Practice (GMP) MRA with the EU in 2012, which is set to increase in scope this year (3).
Combined, these factors have helped Japan to significantly cut its drug lag (2). “We’re talking about access to life saving medicines,” says Lezotre. “Increasing that access can only be beneficial for patients.”
Another key patient benefit is more effective pharmacovigilance as a result of international cooperation. Signal detection refers to information on a possible causal relationship between an adverse event and a drug – the relationship being unknown or incompletely documented previously. Lezotre explains, “Sharing data among different countries is crucial to being able to improve signal detection and act quickly if there’s a problem. We need international agreements on rapid data sharing, as well as harmonized standards so that the various databases can talk to each other. Such activities are hugely important to keep patients safe.”
State of play
Just how harmonized are pharmaceutical regulations today? According to Lezotre, international cooperation, convergence of pharmaceutical regulations and harmonization of standards are already a reality. This phenomenon has grown in importance over the past several decades, through three main types of harmonization initiatives: bilateral, regional and global. Bilateral agreements are between two countries, or between one country and a group of countries. One good example is the EU and Israel’s Agreement on Conformity Assessment and Acceptance of Industrial Products. Here, Israel adopts and implements relevant EU law to “extend certain benefits of the internal market.”
For example, in return for adopting EU standards, Israel benefits from the EU recognizing its industrial standards as equivalent – with GMP Certificates, manufacturing and import authorizations, and certification of conformity of each batch, issued by either party being mutually recognized. This means fewer “non-tariff barriers” to pharma trade, such as divergent standards and customs checks. The agreement covers “medicinal products, active pharmaceutical ingredients, pharmaceutical excipients or mixtures thereof, for human or veterinary use [...] chemical and biological pharmaceuticals, immunologicals, radiopharmaceuticals, and herbal medicinal products” (4).
Another example of bilateral cooperation is the long history of collaboration and harmonization between the EU and the US. In April 2007, the EU and the US signed the Framework for Advancing Transatlantic Economic Integration between the two regions, which specifically called for the promotion of “administrative simplification in the application of regulation of medicinal products.” This move was followed up with a Medicines Regulation Transatlantic Administrative Simplification Action Plan, published in June 2008, which promoted cooperation in inspections, biomarkers, counterfeit medicines, risk management, scientific advice, biosimilars, pediatrics, and advances therapies (5). These initiatives have become standard practice for the EU and the US, with further collaboration on pharmacovigilance, orphan drug development, and inspections – the latter culminating in an MRA earlier this year (6).
The second type of harmonization initiative is regional. The best known example is the EU, but there are a growing number of additional groupings, including the Pan-American Network for Drug Regulatory Harmonization (PANDRH), the Gulf Cooperation Council (GCC), the Southern African Development Community (SADC), the Association of Southeast Asian Nations (ASEAN), and Asia-Pacific Economic Cooperation (APEC). If we take APEC as an example, its Life Sciences Innovation Forum has managed to coordinate multicountry clinical trials, the implementation of good clinical practices, efforts to combat counterfeit medicines, and more. By 2020, APEC is seeking to “achieve convergence on regulatory approval procedures” (7).
The final and increasingly important harmonization initiative is global – involving many organizations and countries. The two major examples are the WHO and the ICH. “The WHO is well known for its work in vaccines and combating pandemics, but it has also played a significant role in harmonization,” says Lezotre. For example, the internationally accepted classification system for drugs – Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) – was driven by the WHO, after recognizing the need for an international standard for drug utilization studies (8).
The WHO has also been instrumental in improving access to medicines in the developing world, where Drug Regulatory Authorities lack the resources and expertise to carry out all functions (9). Instead of relying on the decisions of regulators in the developed world, the WHO launched its own prequalification program, which includes a team of assessors made up of WHO staff and experts from National Regulatory Authorities (NRAs), who evaluate data presented by medicine makers. A team of inspectors then verifies the manufacturing sites for the finished pharmaceutical product and confirms its APIs comply with WHO good manufacturing practices. Once a decision is made, the medicine appears on the WHO’s list of prequalified medicines and can be purchased by international procurement agencies – for example, UNICEF, the Global Fund to Fight AIDS, Tuberculosis and Malaria, and UNITAID – for distribution in resource-limited countries. Traditionally, WHO prequalification focused on only a few diseases (in particular, HIV, malaria, and TB), with the majority of approved products being generic HIV drugs. However, in May this year, the WHO launched a new pilot project for prequalifying biosimilar medicines (10).
The WHO also works with the World Bank and NGOs to finance harmonization projects worldwide. “The World Bank manages a trust fund with money from the Gates Foundation, the UK Department for International Development, and the US Government, to finance regional harmonization projects under the African Medicines Regulatory Harmonization Initiative,” says Andreas Seiter, Senior Health Specialist at the World Bank. “We work in partnership with the WHO, NEPAD and others to help regional groups in Africa (EAC and ECOWAS) implement projects that lead to joint assessments, harmonized requirements, joint GMP inspections, and so on.”
The WHO also promotes harmonization in a number of other ways; for example, the International Pharmacopoeia (Ph.Int.) comprises a collection of quality specifications for pharmaceutical substances, which has legal status whenever a national or regional authority introduces it into appropriate legislation. The WHO has also developed standards for pharmacovigilance through its WHO Program for International Monitoring, launched a certification scheme on the quality of pharmaceutical products, and established international biological reference materials – to name but a few initiatives.
The WHO also spawned what is arguably the most important global harmonization initiative: the ICH.
In 1989, Paris hosted the WHO Conference of Drug Regulatory Authorities, where discussions took place on the possibilities for greater harmonization between the European Economic Community, Japan, and the US. Soon afterwards, the big three approached the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) to discuss a joint regulatory-industry initiative (11) – this became the ICH, which was officially born in April 1990 at a meeting hosted by the European Federation of Pharmaceutical Industries and Associations in Brussels.
David Jefferys, Senior Vice President for Global Regulatory, Healthcare Policy and Corporate Affairs for Eisai Europe, Chairman of Eisai’s Global Regulatory Council and former joint Chief Executive of the UK’s MHRA, was involved in setting up the ICH. “It’s fascinating to see how things have changed over the years, but the original idea was that it simply did not make sense to be doing things so differently across the regions – it still doesn’t,” he says.
Since 1990, the ICH has expanded to include more than the initial three regulatory and industry members, such as “standing” regulatory members from Canada and Switzerland; three additional regulatory members from Brazil, China and South Korea; as well as additional industry members (the Biotechnology Innovation Organization, the International Generic and Biosimilar Medicines Association, and the World Self-medication industry). There are also 23 observers, which include international organizations, such as the IFPMA and the WHO, regional initiatives, and several NRAs – including those from Australia and India. Regulatory members have the right to vote in assembly and appoint experts in Working Groups, and are expected to implement ICH Guidelines in accordance with the applicable “Rules of Procedures.” Observers do not have voting rights, but can nominate delegates to attend assembly meetings, and appoint experts in working groups following a positive decision of the management committee (12).
The EMA delay
The US and the EU have developed a history of collaboration and harmonization through bilaterial agreements and cooperation at ICH. Significant differences, however, remain in terms of the characteristics of the drugs approved by both agencies, as well as the speed of approval – as Enrique Seone-Vazquez (who at the time worked for Massachusetts College of Pharmacy and Health Sciences, USA) and his multidisciplinary team discovered in 2015.
The researchers looked at 100 FDA priority review new molecular entities and new therapeutic biologics that were approved by both agencies. They found that 87 percent were approved by the FDA first. They also found that the FDA’s review time was, on average, around 5 months quicker than the EMA’s. There were also differences in the kinds of drugs approved by both agencies. Those differences affected the strength (23 percent), posology (51.0 percent), indications (30.0 percent), restrictions of use (52.0 percent), limitations of use (19.0 percent), outcomes limitations (28.0 percent), and use in pediatric populations (14 percent).
Seone-Vazquez argues that international regulatory harmonization would facilitate more timely approval of innovative medicines. “The preclinical and clinical data presented to the FDA and the EMA is typically based on the same studies, but companies often decide to pursue different indications and other characteristics for the drugs approved by both agencies,” he says. “Pharmaceutical regulatory harmonization could result in reducing duplication of clinical trials and drug development and regulatory costs, and speed the approval of new drugs and the dissemination of pharmaceutical innovation.”
Socioeconomic, cultural, political and healthcare system differences are the main barriers to greater harmonization, according to Seone-Vazquez. “Additionally, pharmaceutical companies may prefer to deal with substantial differences in indications and drug characteristics, instead of abiding to a potentially more restrictive review and approval process that could be acceptable for the different regulatory agencies.”
“The ICH started with the three regions, but has evolved over the years to include more NRAs and regional groupings – becoming a big part of the global pharmaceutical harmonization scheme, and producing some highly significant standards,” says Lezotre.
Until relatively recently, significant differences existed between countries and regions in terms of non-clinical development regulations. “There were discrepancies in the species and number of animals required, the type of study, and so on,” says Lezotre. “If you wanted to develop a drug that could be marketed worldwide then you had to do various additional studies – with an increasing number of animals.” The ICH’s M3 (R2) guideline on non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals (together with several other key ICH non-clinical guidelines) harmonized many aspects of non-clinical development (13). These guidelines have been adopted in the EU, Japan, the US, Canada and Switzerland.
The ICH has also been instrumental in the creation of the eCTD (electronic Common Technical Document). The CTD is a set of guidelines for the submission of a regulatory dossier to obtain marketing approval for a new drug or a variation to the licensing of an existing drug. Prior to implementation of the ICH’s CTD in 2002, the EU, Japan and the US had their own set of guidelines, creating significant administrative burdens for drugmakers. Two years later, the ICH finalized an electronic version of the CTD, which was implemented in all ICH regions. “This is very important,” says Lezotre. “This additional step wasn’t about harmonizing the content of applications, but rather the structure of the information provided. The objective was to organize information electronically in the same way, using the same format. Having the same structure and terminology not only reduce delay in reformatting but also facilitate exchange of data between regulators.”
A study from 2012 surveying companies that had implemented an eCTD found that “more than three-quarters of individuals with eCTD experience were able to shorten their total time to approval, and more than 90 percent of this group was able to demonstrate cost savings relative to paper submissions, regardless of their company kind, size, or number of submissions,” according to the authors (14).
“The time savings arising from the eCTD are amplified because they are harmonized across the ICH regions,” says Jefferys. “Any measure that means you don’t have to expend additional resources is a plus.”
“The ICH has also standardized medical terminology with MedDRA, which was a key achievement,” adds Lezotre. “When you carry out a clinical study, the study report is based upon terminology. And if you want to share information internationally, you need a standardized dictionary.”
The ICH has also been instrumental in the harmonization of Good Manufacturing Practice (GMP) and pharmacovigilance activities. “The ICH now allows for common development of products. It makes it much easier for products to be accepted, with common dossiers, paperwork and reporting arrangements for pharmacovigilance, as well as guidance on inspection criteria, and so on,” says Jefferys. “The ICH has become a bedrock for the pharmaceutical industry.”
In perfect harmony
When discussing the harmonization of medicine regulations, it’s important to consider what actually happens when countries have divergent standards. Does the global standard tend to converge on the highest existing standards, the lowest standards, or somewhere in between?
Lexchin argues that, in many cases, the ICH “harmonizes to the lowest common denominator.” He refers to a 2002 study by John Abraham, which contended that the ICH’s claims about the implications of technical harmonization were not valid, and that “within the ICH, a discourse of technological innovation and scientific progress has been used by regulatory agencies and prominent parts of the transnational pharmaceutical industry to legitimize the lowering and loosening of toxicological standards for drug testing” (15).
Lexchin believes the loosening of standards reflects the influence of the ICH’s industry members, which he thinks has also manifested itself in other ways. “It’s interesting to look at the areas the ICH does not get itself involved in,” he says. “The ICH has not set standards around how patients should be recruited into clinical trials, and I don’t believe it sets a mandate for the inclusion of women or other groups in clinical trials – which might make them more expensive for companies. It also hasn’t entered into the realm of how promotion should be regulated, and I do not believe industry would want the ICH to start developing standards on promotion that are stricter than those currently imposed by national regulators.”
Lezotre disagrees. “It stands to reason that if you have the very best experts from all over the world coming together to work on a technical question, the resulting standard will be of a higher quality than if it had been developed by the best experts in a single country,” he says. “For the major critical topics, I do feel that we are harmonizing to the highest standards – you can’t say we are developing lower standards than we were 40 years ago.”
Despite this, Lezotre would like to see a number of significant changes in the global regulatory landscape, including – as Lexchin also notes – representation of all stakeholders, such as doctors and patient advocacy groups, at the ICH.
Lezotre also believes there needs to be greater coordination of global harmonization initiatives. “We need to define the role of each initiative within an overall picture,” he says. “There’s still some duplication of work between the ICH and WHO. You also have regional groupings developing standards independently of the ICH – why not involve the ICH?”
The creation of an international medicines agency is another suggestion from Lezotre. “It would not be a new EMA or FDA – obviously you wouldn’t have one agency approving all the drugs in the world. But an international agency could be at the head, facilitating cooperation between different initiatives and Drug Regulatory Agencies. It could also take on some specific projects, such as the global designation, development and regulation of orphan drugs,” he says. “Could the ICH become this body? No, the ICH does not have the right legal structure. The new global agency would rely and build on the ICH, but I would differentiate their roles. This new International Medicines Agency could be a branch of WHO that would coordinate the global pharmaceutical system and manage the day-to-day business in line with the WHO strategy. The WHO has the legal basis and mandate for such an organization and is also well structured to represent developing countries in these discussions and projects.”
Greater harmony on the horizon?
It’s difficult to predict the global regulatory landscape of coming decades. Although the forces of globalization have driven greater harmonization, the future will depend largely on politics. “Few countries and international organizations see regulatory harmonization as a priority to which they must commit funding and capital,” says Andreas Sieter. “Many regulatory agencies are inadequately staffed and funded, and lack the capacity to collaborate effectively in cross-border initiatives. Industry is also fragmented with various players benefiting from niches created by regulatory fragmentation. Some ‘weaker players’ will likely fight harmonization efforts because they tend to bring higher standards and more transparency, which benefits stronger, international manufacturers.”
Lezotre asks, “Are we going to have leaders working for more cooperation? We’ve already seen a big shift between Obama and Trump in terms of cooperation with other countries. Will APEC continue to be supported? Will the changes happening in the gulf countries affect things? The political and economic facts are key to the question of whether or not pharma will become more harmonized.”
Having said that, Lezotre does believe greater harmonization is inevitable. “Our leaders and regulatory authorities have a mandate to improve public health, and the best way to support global health is to support common high standards.”
But will this mean an end to regional and bilateral agreements as international bodies grow in importance? “No, I don’t think so,” says Lezotre. “Global initiatives like the ICH and the WHO are becoming increasingly important, but they sit upon the system of regional and bilateral agreements. You can’t have 195 countries in the room discussing the development of standards – there needs to be some organization.” Lezotre argues that regional initiatives are key to relaying information from individual countries to the global level. “You also need to consider that there are countries out there with no regulatory system in place. You can’t expect a country with one or two staff working on pharma regulation to have the capacity of the FDA; clearly, they can’t participate in all the working groups at the global level, but their needs must be taken into account – this is why bilateral and regional initiatives are so important.”
Jefferys also points to the increasing importance of regional alliances. “We’re seeing greater cooperation in Africa and South East Asia, and I think we’re going to see more mutual recognition type agreements and more workload sharing in the developing world,” he says. “I think eventually we will see an African medicines agency.”
Lexchin believes that regulatory harmonization is important, but hopes that the historical context of how different regulatory systems have developed is not lost. “In Europe, there’s a tripartite model of regulation that involves industry, medical professions and government, which isn’t the case in North America. I hope that harmonization does not override the cultural norms that have developed over the decades.”
Lexchin is also concerned about the democratic accountability of international standards bodies, such as the ICH. “To be honest, I would have preferred to see the role of the ICH taken on by the WHO, which, despite its problems, remains a nominally democratic institution,” he says. “If we are stuck with the ICH model, then I think it needs to go beyond its last reform – where all the relevant stakeholders have a voting role, including patient groups, consumer groups, professional bodies and developing countries.” He also points out that the ICH has been criticized for developing standards that are more rigorous than actually required in certain cases to exclude generic manufacturing countries, and suggests that a more inclusive ICH might help.
Jefferys is pleased with developments in the ICH towards inclusivity, with the addition of countries such as China, South Korea, and Brazil, plus the various regional groupings that have joined as observers. He also agrees with Lexchin about the involvement of patients. “I was responsible for bringing patients into the precursor to the MHRA, and I do believe we will see patients on regulatory approval bodies and international standards initiatives, such as the ICH,” he says. “How long will it take? I don’t know, but I think it has to go in that direction.
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