Transnational pharmacogovernance: emergent patterns in the jazz of pharmaceutical policy convergence

Policy problems whose resolution is most readily addressed within a global context present new governance challenges. Complexities arise as states shaped by different political, economic and cultural traditions seek to harmonize regulatory standards [1, 2]. While globalization and the ascendance of capital markets have been found to hasten policy convergence, the precise causal links between the two remain underdeveloped [3]. Although case studies exploring the links between globalization and policy convergence may cast states as independent actors with the capacity to assume completely different policy instruments, the approach neglects their economic interdependence, highlighting the need for more nuanced analyses exploring the underlying strategic political dimension [4, 5]. Interdependence reflects the mutual dependency of state interests, where the national policy of one state affects those of others. Factors that affect interdependence include the symmetry of states’ economic power and influence, the type of political strategy that states pursue, and the degree to which one state depends on others [6].

Despite the underlying interdependence, state agency as manifested through domestic institutions that influence the allocation of authority, remains an important thread, as policy preferences are often artifacts of their institutional context [7, 8]. Alternate state governance orientations and the institutional constraints and opportunities they present to actors involved in the policy process affect behavior [9], and have been found to foster divergent healthcare [10, 11], chemicals [12, 13] and pharmaceutical policies [1, 14, 15]. As regulatory dissonance can create trade barriers for multinational companies, states share the burden of harmonizing their regulatory standards to forge a path for international trade and increase citizens’ access to new medicines. Even though only one in nine new drugs offer a significant therapeutic advance over current medicines [16], market interdependence nonetheless exerts pressures on states to pursue harmonization [17, 18]. Medicines regulation is a case rich in insights that shed light on how transnational networks allocate authority among state and societal actors in developing global standards that balance societal risks with the benefits of a competitive domestic industry [15, 19]. In the pharmaceuticals sector, a transnational public-private policy network, the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was formed to harmonize international regulatory standards to address the concerns of the pharmaceutical industry that different international regulatory criteria created trade barriers and increased drug development costs. Streamlined harmonized standards were further sought to reduce lengthy product reviews [17]. Originally comprised of the regulators and industry associations in the European Union (EU), Japan and the United States (US), the ICH fosters transnational cooperation in order to align regulatory standards and reduce trade barriers in response to globalization [20]. Membership was expanded in 2016 to include Canada, Switzerland, Brazil, South Korea and China, while Australia and Taiwan are observers; the first step toward membership.

Understanding how transnational networks’ delegated authority supplants state agency authority is crucial in a context in which global regulatory standards are set by public-private policy networks [21‐23]. As regulatory standard setting shifts from a solely national to a transnational concern, where the state no longer holds a monopoly in the policy process, the manner in which medicines’ benefits and harms imbued with scientific uncertainty are addressed through transnational pharmacogovernance is important to understand. Pharmacogovernance is defined as the manner in which governing structures, policy instruments and institutional authority that enable the development, implementation and enforcement of regulatory policies are managed to promote societal interests including protection of public safety [24]. The objective of this paper is to compare the pharmacogovernance framework guiding the ICH to that of six member jurisdictions (European Union, United Kingdom, France, United States, Canada and Japan) with established regulatory frameworks to allow generalizability, yet sufficient range to cover a spectrum of approaches.

Pharmacogovernance guiding the ICH was compared to that of six member jurisdictions including the European Union, United Kingdom, France, United States, Canada and Japan given their relative similarity as developed nations and regions with established regulatory frameworks to allow generalizability, yet sufficient range to cover a spectrum of regulatory approaches [36]. The research involved a review of literature, policy and technical reports (1990–2017) along with 26 semi-structured interviews with key informants in international regulatory agencies and related organizations in 2007, 2010, 2015–2017. Interviewees were engaged in pharmaceutical regulatory and policy spheres including the ICH Secretariat, the European Medicines Agency (EMA), an EMA consumer representative, US Food and Drug Administration (FDA), US Veterans Administration Center for Medication Safety, US Developing Evidence to Inform Decisions about Effectiveness research network, UK Medicines and Healthcare products Regulatory Agency (MHRA), UK National Institute for Health and Clinical Excellence (NICE), UK Drug Safety Research Unit, Haute Authorité de Santé in France, a regional pharmacovigilance center in France, an editor of La revue Prescrire the independent French drug bulletin, and Canadian provincial drug plan representatives. The FDA and Health Canada also offered written responses to interview questions. Ethics approval was attained from York University ethics certificate e2015–141.

Interview schema were informed by a review of the literature, agency administrative and policy documents, publicly available government documents, newspaper articles, and authors knowledge of regulatory policy. The documents containing discourse pertaining to ICH and state pharmacogovernance were read iteratively to illuminate areas for further exploration. The interview guide that was developed was modified for different groups of interviewees based on their role in drug regulation. The interview guides were continuously updated to probe additional relevant information that was uncovered during preceding key informant interviews. Although the schema was not pilot tested it was modified based on initial interviews to clarify the intent of questions.

Content analysis of transcribed interviews was conducted using Atlas.ti by two authors (KM and MW) who independently and collaboratively analyzed and organized the data into emergent themes through email discussions [37]. Data were coded and analyzed using an analytic framework. Framework domains were established a priori. A codebook (Additional file 1) was created with operational definitions for each framework domain, with illustrative examples, to guide the independent analysis by the study authors. Information from the interviews and document analysis were cross-referenced to ensure consistency between the two in order to characterize patterns in international regulatory governance and policy approaches. When there were areas of inconsistency we contacted the interviewees to confirm our interpretation of what they said, conducted additional interviews and identified additional confirmatory documentation. Key informant quotes that succinctly characterized an emergent pattern within a theme were included in the codebook to offer illustrative examples.

To elucidate patterns in state and transnational institutional governance across jurisdictions over time and clarify how regulators interact at the global level to shape transnational governance processes [38], we developed a framework to compare their regulatory authority, state-societal relations, representation and the role of legal channels [29, 39]. A comparative analysis of distinct state governance modes and approaches to risk management enabled us to clarify the conditions that foster improvisation in post-market regulatory policy, the coalitions interdependence supports, who they advantage and how they are leveraged transnationally to foster policy convergence.

Regulation is a distinctive form of policy-making and public control where the mechanisms and processes that guide the formation of regulatory standards meld political, scientific and technical dimensions [29, 127]. In advancing harmonization, transnational pharmacogovernance affords ICH members a means to leverage their interdependence to reshape international bargains including the potential to replicate their domestic rule structures through a transnational network with extensive global reach [31].

Co-regulatory governance guided the first quarter century of the ICH and orients its current decision-making [7, 45]. The success of the ICH in harmonizing pre-market regulatory standards fostered its acceptance by founding members. ICH governance involving bilateral negotiation parallels modes of state-societal relations and regulatory representation in Canada, France, the UK and Japan involving regular consultation with private members who co-develop norms and rules. The EMA is guided by Article 61 of the European Commission Regulation 726/2004 that specifies consensus-based negotiation guided by such soft law instruments as technical guidelines, parallel to ICH governance [84, 85]. With experience in harmonizing standards across the EU, the EMA held a “leadership role in promoting international regulatory cooperation” in the ICH [17]. ICH co-regulatory governance aligned with the European Commission [30, 85] and Member States, whose standards were accepted as ICH guidelines (Table 1).

European and ICH governance trajectories reveal parallels in the timing of transnational harmonization, regulatory initiatives (common technical document, risk management plans) and transparency reforms (Table 3). In France the inquiry into the AFSSAPS that highlighted the manner in which COI undermined regulatory decisions through the Mediator scandal hastened a drive for greater transparency to alleviate the appearance of and actual COI. In response, the practice of allowing a pharmaceutical trade association member to chair an ICH Working Group developing a regulatory guideline was curtailed. Parallel reforms shaped longer term governance and policy in the ICH and European regulators as well. In the ICH, industry financing was replaced by regulatory member contributions (the FDA offered $US500, 000 per year for 5 years from 2016). The US industry member noted, “The shift in the balance of power from regulated industry to regulators that the reforms will herald in is ‘appropriate’ and, if anything, the reforms should have been introduced sooner” [128]. Whether ICH governance reforms actually shift power dynamics remains to be seen as industry networks first comment on a new draft guideline and may frame it from their perspective, followed by a review by regulators. EMA’s push for transparency involved enabling the release of RCT data (that was legally contested by industry) and the potential for public hearings related to pharmacovigilance.

Interdependence between the EU and Japan would appear to have contributed to regulatory convergence on risk management plans. Endorsement of industry-led post-market studies is consistent with a neo-liberal trend that engenders greater reliance on industry given its market power [61, 129]; that may lead to perceptions that safety competes with harmonization [130, 131] as pharmaco-epidemiologists advise post-market studies be conducted independently, contrary to the current trend, to guard against conflict of interest.

Transnational guidelines, developed through negotiation with private sector actors that reduce sponsors’ burden in meeting regulatory standards are framed as market-based solutions advanced by experts that balance regulation with industrial competitiveness [15, 23], support investment in new products and enhance patient access [17, 132]. As a parallel transnational regulatory network that served as a pre-ICH consultation forum for risk management plans, CIOMS is similarly guided by the techno-expert model (where pharmaceutical industry technical experts lend authority). Techno-expert models attain legitimacy through transparency, public reporting and accountability, mechanisms that increase the likelihood that policy reflects the values of democratic legislatures. The legitimacy of the techno-expert model may diminish when regulatory decisions lack public acceptance, particularly given the limited channels for incorporating societal perspectives into regulatory decisions imbued with scientific uncertainty [2, 29].

Despite growing international convergence on supranational standards that become de facto global standards as the ICH and WHO foster their adoption internationally, states retain a level of autonomy [35]. A more independent American approach to pharmacovigilance and different adverse drug event reporting standards coincided with the confluence of more extensive legislative oversight of the FDA, broader consultation with related healthcare agencies, and a culture of litigation whose cumulative effects may recalibrate risk perception and management to foster improvisation in regulatory standards. An alternate governance process in Japan with independent oversight of the regulator by the PAFSC led the Ministry to adopt a more anticipatory approach to adverse drug events. Inclusion of an independent oversight committee for the regulator such as PAFSC, combined with the managerial discretion-guided decision making within the regulator, was found to counterbalance neo-corporatist relations (Fig. 2).

In a globalized context, transnational networks increasingly replace state governance processes, where transnational sectoral autonomy dominates [21, 24, 133]. This migration of authority from state to supranational networks may shift relations of power that prompt questions of legitimacy [22]. The capacity of transnational pharmacogovernance networks to craft policy in the public interest depends on the governance process that guides the formation of formal decision rules, the incentives of the actors involved and the types of policy issues addressed. Networks’ incentives to form policies in the public interest are highest when governments impose a level of oversight that prompts accountability [134].

Representation in the transnational network’s governance framework has implications for its ability to develop standards that reflect societal interests [2]. Although medicines regulation is considered a technical non-discretionary matter, the latitude of ICH members to determine areas for harmonization and the uncertainty inherent in new product reviews [97] suggest more extensive academic research-based expertise and representation may enhance policy capacity in the public interest. A precautionary principle to COI which in practice means that rather than managing COI it should be avoided, would improve transnational and national regulatory processes.

As transnational networks become adept at responding to emerging political challenges through harmonized standards that level the international playing field, they contribute to a multinucleated global system comprised of a series of sectoral networks, that create circuits of power organized around issue areas [23]. As interdependence shapes transnational pharmacogovernance, the parallels found between ICH and member state governance, including the nature of representation and decision-making that guides ICH standard setting, reflect emergent patterns (Tables 1, 2 and 3). Although such parallels suggest a thread through which interdependence may shape transnational governance, admittedly, the factors that affect the design of transnational regulatory governance and how they contribute to regulatory convergence necessitates further analysis. Areas of policy dissonance that could be further explored in which the ICH has not been officially involved include:

In elucidating how similar variables intersect in different national contexts, such analyses may better clarify the conditions that foster policy convergence in the public interest.

While globalization and the ascendance of transnational networks may cast the state as superfluous, state capacity to determine the manner in which soft laws and technical guidelines are articulated offers a counter balance [35]. Just as an integral element of a jazz standard is the unresolved texture a dominant seventh chord introduces before its resolution, transnational policy dissonance may be integral to a resolution that enhances harmonized standards, suggesting a means for globalization to advance public policy.