An elephant in the glasshouse? Trade-offs between acceleration and transformation in COVID-19 vaccine innovation policies.

Against the backdrop of a failing vaccine innovation system, innovation policy aimed at creating a COVID-19 vaccine was surprisingly fast and effective. This paper analyzes the influence of the COVID-19 landscape shock and corresponding innovation policy responses on the existing vaccine innovation system. We use document analysis and expert interviews, performed during vaccine development. We find that the sharing of responsibility between public and private actors on various geographical levels, and the focus on accelerating changes in the innovation system were instrumental in achieving fast results. Simultaneously, the acceleration exacerbated existing societal innovation barriers, such as vaccine hesitancy, health inequity, and contested privatization of earnings. Going forward, these innovation barriers may limit the legitimacy of the vaccine innovation system and reduce pandemic preparedness. Next to a focus on acceleration, transformative innovation policies for achieving sustainable pandemic preparedness are still urgently needed. Implications for mission-oriented innovation policy are discussed.

Future of the drug label: Perspectives from a multistakeholder dialogue.

Regulating drugs does not end when market access has been granted. Monitoring drugs over the life cycle has become state of the art, inherent to evolving legislation and societal need. Here, we explore how the drug label could move along in a changing playing-field and become a sustainable label for the future. A dialogue between academia, government, the pharmaceutical industry and patient/societal organizations was organized by the Regulatory Science Network Netherlands. This is their view.

Correction: A standardised framework to identify optimal animal models for efficacy assessment in drug development.

[This corrects the article DOI: 10.1371/journal.pone.0218014.].

A standardised framework to identify optimal animal models for efficacy assessment in drug development.

INTRODUCTION: Poor translation of efficacy data derived from animal models can lead to clinical trials unlikely to benefit patients-or even put them at risk-and is a potential contributor to costly and unnecessary attrition in drug development. OBJECTIVES: To develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy. DESIGN AND RESULTS: We performed a scoping review to identify the key aspects used to validate animal models. Eight domains (Epidemiology, Symptomatology and Natural History-SNH, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified. We drafted questions to evaluate the different facets of human disease simulation. We designed the Framework to Identify Models of Disease (FIMD) to include standardised instructions, a weighting and scoring system to compare models as well as factors to help interpret model similarity and evidence uncertainty. We also added a reporting quality and risk of bias assessment of drug intervention studies in the Pharmacological Validation domain. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. We conducted a pilot study of the validation in two models for Type 2 Diabetes (T2D)-the ZDF rat and db/db mouse. Finally, we present a full validation and comparison of two animal models for Duchenne Muscular Dystrophy (DMD): the mdx mouse and GRMD dog. We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human epidemiological, SNH, and histological aspects to a greater extent than the mouse despite the overall lack of published data. CONCLUSIONS: FIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful data and is more likely to generate translatable results to progress drug candidates to the clinic.

Changing standards for drug approval: A longitudinal analysis of conditional marketing authorisation in the European Union.

Drug regulatory agencies around the world increasingly implement expedited regulatory pathways allowing for approval of medicines that intend to address unmet medical needs based on lower evidentiary standards than would be conventionally required. Few studies have investigated how companies and regulators utilise these pathways. We therefore conducted a longitudinal analysis of the emergence and implementation of the conditional marketing authorisation (CMA) instrument in the European Union. Drawing on archival documents, procedural data and interviews, we show that there was substantial ambiguity among regulators and companies about how to strike a new balance between evidentiary requirements and patient needs. As ambiguities were left unresolved, parties became reluctant to use CMA and in the majority of procedures did not use the pathway in a prospectively planned fashion. Rather, CMA became an option for regulators and companies to apply when submitted data were not strong enough to justify standard approval. Particularly, incumbent companies profited from this. The results stress the challenges of realising institutional change in drug regulation by showing how interest-driven actors can act upon ambiguities in attempts to shape regulatory outcomes and stretch rule interpretations.

An analysis of marketing authorisation applications via the mutual recognition and decentralised procedures in Europe.

PURPOSE: The aim of this study is to provide a comprehensive overview of the outcomes of marketing authorisation applications via the mutual recognition and decentralised procedures (MRP/DCP) and assess determinants of licensing failure during CMDh referral procedures. METHODS: All MRP/DCP procedures to the Co-ordination group for Mutual recognition and Decentralised procedures-human (CMDh) during the period from January 2006 to December 2013 were analysed. Reasons for starting referral procedures were scored. In addition, a survey under pharmaceutical companies was performed to estimate the frequency of licensing failure prior to CMDh referrals. RESULTS: During the study period, 10392 MRP/DCP procedures were finalized. Three hundred seventy-seven (3.6%) resulted in a referral procedure, of which 70 (19%) resulted in licensing failure, defined as refusal or withdrawal of the application. The frequency of CMDh referrals decreased from 14.5% in 2006 to 1.6% in 2013. Of all referrals, 272 (72%) were resolved through consensus within the CMDh, the remaining 105 (28%) were resolved at the level of the CHMP. Most referrals were started because of objections raised about the clinical development program. Study design issues and objections about the demonstration of equivalence were most likely to result in licensing failure. An estimated 11% of all MRP/DCP procedures resulted in licensing failure prior to CMDh referral. CONCLUSION: Whereas the absolute number of MRP/DCP procedures resulting in a referral has reduced substantially over the past years, no specific time trend could be observed regarding the frequency of referrals resulting in licensing failure. Increased knowledge at the level of companies and regulators has reduced the frequency of late-stage failure of marketing applications via the MRP/DCP.

Governance of conditional reimbursement practices in The Netherlands.

When entering the market, orphan drugs are associated with substantial prices and a high degree of uncertainty regarding safety and effectiveness. This makes decision making about the reimbursement of these drugs a complex exercise. To advance on this, the Dutch government introduced a conditional reimbursement trajectory that requires a re-evaluation after four years. This article focuses on the origins, governance and outcomes of such a conditional reimbursement trajectory for orphan drugs. We find that the conditional reimbursement scheme is the result of years of discussion and returning public pressure about unequal access to expensive drugs. During the implementation of the scheme the actors involved went through a learning process about the regulation. Our analysis shows that previous collaborations or already existing organisational structures led to faster production of the required data on cost-effectiveness. However, cost-effectiveness evidence resulting from additional research seems to weigh less than political, judicial and ethical considerations in decision making on reimbursement of orphan drugs in The Netherlands.

The impact of patient advocacy: the case of innovative breast cancer drug reimbursement.

Current research into patient advocacy focuses on attempts of patient groups to mobilise resources and to influence researchers, pharmaceutical companies and policy-makers. This paper adopts a 'framing political opportunities' approach to draw attention to other kinds of advocacy strategies. In a case study of breast cancer patient advocacy of Herceptin reimbursement, it is shown how patient groups tried to gain access to policy-making by means of three different opportunity-framing strategies. Articulation aims at creating awareness through public-agenda building. Negotiation aims at frame alignment between interdependent stakeholders by arranging meetings. Politicisation is a strategy to influence the agendas of political arenas. Patient organisations succeeded in creating awareness and support, which had a considerable impact on other stakeholders. These impacts in turn aided the politicisation of the issue. However, the final impact on reimbursement procedures was only partially achieved due to depoliticising counterstrategies based on persistent ideas buttressing a particular division of responsibilities in the organisation of healthcare. According to these ideas cost control in healthcare is a medical responsibility, not a political one.

The role of patient advocacy organisations in neuromuscular disease R&D--The case of the Dutch neuromuscular disease association VSN.

This article investigates to what extent patient advocacy organisations play a role in influencing R&D and policymaking for rare neuromuscular diseases. The Dutch neuromuscular disease organisation VSN is studied in depth. A brief history of the VSN is sketched along with the international embedding of the organisation. Then, a more general perspective is provided on the reasons and extent of the involvement of patient organisations (and especially the VSN) in innovation processes. Lastly, internal mechanisms are presented that can best be applied by these organisations. The VSN adheres to a rare, long-term vision on drug innovation that requires long-term planning and policy and vision creation and steering the direction of science and technology. At the same time, other actors like scientific organisations and science policymakers and managers can benefit from these lessons to learn how to deal with patients and patient organisations in the future.

The role of users in innovation in the pharmaceutical industry.

Traditionally, innovation in the pharmaceutical industry is organised according to the linear model. Over the past two decades this model lost its meaning as a result of rising costs, increased competition, new scientific developments and better-informed, more demanding users. The linear model is not well equipped to involve these new actors and to include their feedback. Starting from a systemic approach, the involvement of actors in pharmaceutical innovation processes, more in particular users, is put central. It is discussed and illustrated with three cases why a systemic model may be more effective to cope with present developments and why users should be involved. To wind up, conclusions are drawn regarding the implications of a systemic approach for policymakers, researchers and firms.

Exploring emerging technologies using metaphors--a study of orphan drugs and pharmacogenomics.

Due to uncertainties of several aspects of emerging health technologies, there is a need to anticipate these developments early. A first step would be to gather information and develop future visions about the technology. This paper introduces metaphor analysis as a novel way to do this. Specifically, we study the future of pharmacogenomics by comparing this technology with orphan drugs, which are more established and often act as a model with comparable (economic, research organisation, etc.) characteristics. The analysis consists of describing the dominant metaphors used and structurally exploring (dis)similarities between pharmacogenomics and orphan drugs developments. This comparison leads to lessons that can be learnt for the emerging pharmacogenomics future. We carried out a comprehensive literature review, extracting metaphors in a structured way from different areas of the drug research and development pipeline. The paper argues that (1) there are many similarities between orphan drugs and pharmacogenomics, especially in terms of registration, and social and economic impacts; (2) pharmacogenomics developments are regarded both as a future 'poison' and a 'chance', whereas orphan drugs are seen as a 'gift', and at the same time as a large 'problem'; and (3) metaphor analysis proves to be a tool for creating prospective images of pharmacogenomics and other emerging technologies.