Where national and regional requirements still diverge
The requirements a regulatory writer meets still differ between countries and regions after harmonised guidance has been adopted. A national regime can adopt good clinical practice and leave the rest of the guidance unstated, a regional union can replace its members' requirements with common ones, regulators that cooperate closely still reach different decisions, and a trade agreement can aim to harmonise regulation as well.
National regimes
ICH aligns the rules of the US, the EU and Japan, and most countries outside it try to follow US or EU processes while each keeps its own particular requirements.
Switzerland is not a member of the European Union or the European Economic Area, which makes it a minor player in the global drug and device regulatory landscape. Yet it is home to some of the world's largest pharmaceutical companies and hosts the secretariats of ICH, the Council for International Organizations of Medical Sciences working group, the International Organization for Standardization and the World Health Organization. In 2013, clinical research there was governed by the Federal Law on Therapeutic Products and the Ordinance on Clinical Trials, roughly equivalent to the EU directives and the EU guidelines respectively. Both required trials to follow ICH E6 on good clinical practice, but no other ICH guideline was specifically mentioned. The ordinance also contained ambiguities that made life difficult for clinical researchers: it drew no distinction between interventional trials and non-interventional or observational studies, so both were subject to the same regulations, and it did not address some aspects of medical devices, data protection and biological samples.
In the Russian Federation, Federal Law #61 on the circulation of medicines, in force from 12 April 2010, controlled all processes related to drug circulation: manufacturing, non-clinical and clinical development, safety monitoring, and state control and registration. The national standard GOST 52379-2005, essentially a translated version of ICH good clinical practice, stipulated that all clinical studies in the country must be performed in accordance with good clinical practice.
Changes to a national base law
In 2013 a new Swiss Law on Human Research was expected to take effect and supersede the Ordinance on Clinical Trials. It would redefine the roles and duties of the local independent ethics committee and the regulator in regulating clinical trials, make the distinctions between different studies and therapeutic products clearer, and address critical issues such as research on embryos and cadavers. How this would affect regulatory medical writing was, for one writer working in Switzerland, hard to say.
In Russia, the Federal Antimonopoly Service required amendments to Law #61 to simplify the registration of orphan drugs. The changes to be implemented in 2013 included an expedited registration procedure for orphan drugs and first-to-market generics. For orphan drugs, data from pre-clinical and clinical studies conducted abroad under Good Laboratory Practice and ICH good clinical practice would become acceptable. Although there were many formal barriers to conducting clinical studies in Russia, government legislation had increased the demand for clinical studies conducted there.
China and Japan
In 2013 China had its own standalone health regulation system, with marked differences from the US and the EU in language, regulations and bureaucracy, but its pharmaceutical regulation largely adhered to ICH. In the years before 2013, Japan's Ministry of Health, Labour and Welfare made significant changes to address a downward trend in new drug applications, caused by lengthy and expensive processes for clinical studies and approvals, and to shorten the lag in drug availability compared with other developed countries. The changes included a simpler and more efficient approach to clinical studies, improved infrastructure, and the introduction of global standards such as ICH good clinical practice.
In 2013 China's regulator, the State Food and Drug Administration, reported directly to the Ministry of Health, and Japan's, the Pharmaceuticals and Medical Devices Agency, worked together with the Ministry of Health, Labour and Welfare. The functions of both were mostly similar to those of the US Food and Drug Administration, and of their differences the two most relevant to medical writing were the working language and country-specific requirements for regulatory documents. A writer working in Chinese or Japanese has to be familiar with the local regulatory requirements and also able to formulate sentences the way the local regulator expects them.
The United Kingdom's clinical trial proposals
In January 2022 the UK's MHRA set out legislative proposals for clinical trials, with consultation closing on 14 March 2022. The proposals would replace subject with participant, update the definitions of clinical study and clinical trial and add a low-intervention clinical trial, as the EU Clinical Trials Regulation does, but would keep the term substantial amendment where the EU Regulation now says substantial modification.
The Eurasian Economic Union
In 2023 the Eurasian Economic Union included Armenia, Belarus, Kazakhstan, the Kyrgyz Republic and the Russian Federation, with a combined population of 183.6 million and free movement of goods, services, capital and labour. The member states signed an agreement on common principles and rules for the circulation of medicines in December 2014. Under the Rules for Registration and Expertise of Medicinal Products issued in December 2016, registration from 1 January 2021 follows the Union's unified requirements, and clinical trials must be planned and conducted by Union procedures. Drugs already registered nationally had until 31 December 2025 to bring their dossiers into line, and the dossier structure now fully follows the Common Technical Document. Where existing clinical data are considered insufficient, new trials designed to the Union's requirements should be conducted.
The Union's clinical trial documents are thoroughly harmonised with the requirements of ICH, the FDA and the EMA, which makes them convenient for all parties, including those outside the Union. Clinical trials should be conducted under the Union's good clinical practice, which is harmonised with ICH E6(R1) but structured differently, with stand-alone parts covering the guideline itself, the structure and content of the clinical study report in line with ICH E3, a list of essential protocol amendments, the procedure for submitting safety information during a study, and the requirements for the safety update report. The main documents governing the planning and conduct of clinical trials are Council resolutions of 3 November 2016 on marketing authorisation and assessment, good clinical practice, bioequivalence studies, pharmacovigilance practice and research on biological products; a 2019 Board decision on preclinical safety studies; and Board recommendations on general considerations for clinical trials (2018), dose selection (2019), drug combinations (2019), the selection of non-investigational drugs (2019), quality assessment and bioequivalence for certain groups of drugs (2020) and the principles of biostatistics (2020). A common market platform in six languages, including English, carries information on the authorised drugs and the results of pharmacological inspections and state supervision, and a legal portal publishes all the regulatory documents. A unified register holds all drugs registered or re-registered under the Union's rules, but in 2023 there was not yet a unified register of clinical trials, whose information was available only on each member state's national platform.
The transition let every participant in the Union's drug market speak the same language and gave uniform approaches to clinical trials and registration consistent with international standards. For experts planning and conducting trials that involve medical writing, the universal requirements for document structure, content and trial design greatly simplified the work and eased communication between the member states' experts and companies bringing drugs to the market. But the procedure also appeared quite stressful for industry: processes had to be planned and implemented from scratch, the rules for clinical trials and registration had gaps, and the guidelines were constantly updated and hard to keep up with, which the lack of an established procedure for scientific advice to obtain timely clarification from the regulator compounded.
Convergence between the US and European regulators
The need to align regulatory practice in a global market was recognised more than 25 years before 2015, with the launch of the International Conference on Harmonisation, which has steadily driven a convergence of pharmaceutical regulations throughout the world. In the years before 2015 the US and European agencies had been working together increasingly closely, with greater information sharing and numerous staff exchange programmes. Despite this convergence, in 2015 many pharmaceutical companies were still frustrated by differences between the constituent regions of the conference, and between the US and Europe in particular.
The US and EU authorities talk to each other fairly regularly, so the EU usually knows about a drug submitted for approval in the US and may already have seen some of its submission materials before a European filing. The EU sets its filing up under slightly different rules, but the information is generally the same, only placed differently within the documents.
The agencies' cooperation
Senior leaders from the US agency, the European Commission and the European agency reviewed their cooperation at a regular bilateral meeting on 19 June 2015 and discussed strategic priorities for the following two years. Interaction was by then daily and mostly structured around scientific and regulatory working groups called clusters, with pharmacovigilance, biosimilars, paediatrics and veterinary medicines reviewed at that meeting. They decided to establish a new cluster on patient engagement to share experience and best practice on involving patients in development, evaluation and post-authorisation activities. The participants also agreed to enhance communication on their cooperation and to strengthen efforts to align core messages, and they hold in-person bilateral meetings routinely to monitor progress on the agreed priorities.
The agencies agreed to strengthen their collaboration further, which will help them increase efficiency globally and avoid duplication, and planned a focus for each area.
- Patient engagement: both agencies aim to expand patient input into the regulatory process.
- Safety monitoring: long-term collaboration in pharmacovigilance had eased the exchange of critical information and the coordination of communication to patients and healthcare professionals, and collaboration in the international pharmacovigilance cluster would be strengthened with a more strategic focus, including the assessment of everyday use of medicines.
- Biosimilars: the cluster supports global development, and the agencies are interested in aligning their scientific approaches to avoid regulatory divergence that may delay patients' access.
- Paediatric medicines: development is largely legislation-driven on both sides, and the agencies align their scientific approaches through common commentaries and development plans that help achieve a rational approach to conducting the necessary trials, with a workshop on EU and US experience possible in 2016, resources permitting.
- Rare diseases: a common template for requesting orphan designation in both regions already existed, and a joint working group, the Team of International Global Rare Disease Experts, was being established to support the development of medicines for children with rare diseases.
- Timely access: sharing information on scientific advice and evaluation to facilitate joint approaches, with the aim of minimising divergence and supporting patients' early access to new treatments.
- Veterinary medicines: framed by the One Health concept, with cooperation particularly strong on novel therapies such as stem cells, oncology products and cytokines and a focus on reducing antibiotic resistance.
- Inspections: the two were evaluating how their inspectorates and procedural frameworks compare as a prerequisite for relying on each other's findings, avoiding duplication and widening inspection coverage, and were working towards a framework for an agreement and an implementation plan.
- Data integrity: both agencies stressed it as a cornerstone of confidence in test results and agreed to work on communication and training to raise manufacturers' awareness.
Alignment of their authorisation decisions
A joint analysis of 107 new medicine applications decided by both agencies between 2014 and 2016, the first by the two agencies to compare their marketing authorisation decisions, found them aligned in more than 90% of those decisions. Where outcomes diverged in the type of approval or the indication, the commonest reason was differing conclusions about efficacy and the second differences in the clinical data submitted. Some of the data differences came from timing, since more applications reached the US agency first. The European agency often reviewed applications that included additional trials or, particularly for oncology medicines, more mature data from the same trial, and in those cases it was more likely than the US agency to grant standard approval, a broader indication, or use as first-line therapy. Over the preceding decade the agencies had set up joint working groups and forums for sharing information, including clusters on special topics and therapeutic areas and parallel scientific advice and protocol assistance, bringing together experts on such matters as manufacturing and clinical site inspections, medicines for children, oncology products, biostatistics, rare diseases and vaccines. These groups are not forums for shared decisions, but the European agency reads the strong alignment in decisions as a sign that they may be contributing to alignment on regulatory science.
The Transatlantic Trade and Investment Partnership
The Transatlantic Trade and Investment Partnership under negotiation between the United States and the European Union in 2015 covered market access, specific regulation, and broader rules, principles and modes of co-operation. Its aims therefore went well beyond eliminating already-low tariffs to the harmonisation of regulations and business approaches. One report put the potential economic gain of an ambitious and comprehensive agreement at €119 billion a year, which its authors translated into up to €545 a year for an average family of four on the unlikely assumption of equal distribution. Any policy change has winners and losers, and many suspected that large corporations would benefit most, at society's expense, a suspicion strengthened by the perception that negotiations were conducted behind closed doors.
Drug development
Further convergence of drug development regulation between the US and Europe would seem potentially beneficial in some areas. Paediatric development now requires an approved plan on both sides, a Pediatric Study Plan in the US and a Paediatric Investigation Plan in Europe, and the two differ in structure and often in overall interpretation, so companies may be unable to run a single global paediatric programme. The resulting duplication is costly, potentially harmful to children unnecessarily exposed to investigational products, and may make properly powered trials harder where the patient pool is limited, particularly in indications such as multiple sclerosis where several new drugs are competing for the same patients.
Scientific advice from either agency is not binding but usually shapes the clinical development programme, and discrepant advice may generate conflicts for companies. Unification or mutual recognition of scientific advice would help remove some of the many uncertainties and duplication from drug development and free agency resources that are often stretched. Mutual recognition of good manufacturing practice inspections may also reduce duplication, and both proposals seem a natural extension of the agencies' closer cooperation.
Patent or data exclusivity on many blockbuster monoclonal antibodies had expired or was about to, so the coming years were likely to see a large growth in the number of biosimilars, with corresponding cost reductions. The agencies had been forced to develop biosimilar regulations rapidly, with some divergence between the US and Europe. Because demonstrating bioequivalence for a biosimilar is more complex and costly than the relatively small bioequivalence study a generic often needs, such divergences are likely to magnify developers' uncertainty and hinder their products' development.
Public health policy
The main concerns about the agreement arose because it would extend beyond drug development to the wider healthcare sector. Healthcare provision differs sharply across the Atlantic: European countries have universal systems, while in the US private healthcare is the norm, attempts at universal access are fiercely resisted and prescription medicines are advertised directly to consumers. The main fear of many opponents was that the agreement could give corporations too much power to guide public health policy and impose a US-style approach to it, in particular through the Investor-to-State Dispute Settlement System, which supposedly gives them the opportunity to take national governments to arbitration over legislation that leads to loss of profits, such as banning logos on cigarette packets or campaigns to reduce children's soft-drink consumption. Industry advocates deny it provides a mechanism to influence national health policy, but others argue that the threat of legal action may produce a regulatory chill in which governments are discouraged from passing health protection laws. It looked as though the European Parliament would push back on the system's full implementation in the health sector.
Transparency of the negotiations
To one commentator, measures to improve the transparency of the negotiations looked largely reactive, following high-profile leaks and protests, rather than proactive. Texts were made available to all Members of the European Parliament, and apparently were to be made available to selected individuals outside Brussels, in a reading room from which restricted material could not be removed and where members were not allowed specialist support to understand complex technical material, while negotiators had access to expert legal and technical opinion. Public consultations were held, but without transparency their influence could not be gauged. The US and European agencies, though major stakeholders, barely mentioned the negotiations on their websites. To the same commentator, the sudden embrace of transparency felt rather superficial, and the negotiators could have done much more to reassure the public that the wellbeing of European citizens was being taken into account.
Greater regulatory harmonisation could benefit pharmaceutical companies, and some of that benefit might reach patients as faster approvals and cheaper drugs if development costs fell and the savings were passed on. But the details of the deal were opaque, which made its impact hard to judge, and even with full details the complexity of the issues would make its effects hard to predict.