Social pharmaceutical innovation and alternative forms of research, development and deployment for drugs for rare diseases.

Rare diseases are associated with difficulties in addressing unmet medical needs, lack of access to treatment, high prices, evidentiary mismatch, equity, etc. While challenges facing the development of drugs for rare diseases are experienced differently globally (i.e., higher vs. lower and middle income countries), many are also expressed transnationally, which suggests systemic issues. Pharmaceutical innovation is highly regulated and institutionalized, leading to firmly established innovation pathways. While deviating from these innovation pathways is difficult, we take the position that doing so is of critical importance. The reason is that the current model of pharmaceutical innovation alone will not deliver the quantity of products needed to address the unmet needs faced by rare disease patients, nor at a price point that is sustainable for healthcare systems. In light of the problems in rare diseases, we hold that re-thinking innovation is crucial and more room should be provided for alternative innovation pathways. We already observe a significant number and variety of new types of initiatives in the rare diseases field that propose or use alternative pharmaceutical innovation pathways which have in common that they involve a diverse set of societal stakeholders, explicitly address a higher societal goal, or both. Our position is that principles of social innovation can be drawn on in the framing and articulation of such alternative pathways, which we term here social pharmaceutical innovation (SPIN), and that it should be given more room for development. As an interdisciplinary research team in the social sciences, public health and law, the cases of SPIN we investigate are spread transnationally, and include higher income as well as middle income countries. We do this to develop a better understanding of the social pharmaceutical innovation field's breadth and to advance changes ranging from the bedside to system levels. We seek collaborations with those working in such projects (e.g., patients and patient organisations, researchers in rare diseases, industry, and policy makers). We aim to add comparative and evaluative value to social pharmaceutical innovation, and we seek to ignite further interest in these initiatives, thereby actively contributing to them as a part of our work.

The Promises of Speeding Up: Changes in Requirements for Animal Studies and Alternatives during COVID-19 Vaccine Approval-A Case Study.

On 21 December 2020, the European Commission granted conditional marketing authorisation for the BNT162b2 COVID-19 vaccine 'Comirnaty', produced by Pfizer/BioNTech. This happened only twelve months after scientists first identified SARS-CoV-2. This stands in stark contrast with the usual ten years needed for vaccine development and approval. Many have suggested that the changes in required animal tests have sped up the development of Comirnaty and other vaccine candidates. However, few have provided an overview of the changes made and interviewed stakeholders on the potential of the pandemic's pressure to achieve a lasting impact. Our research question is: how have stakeholders, including regulatory agencies and pharmaceutical companies, dealt with requirements concerning in vivo animal models in the expedited approval of vaccine candidates such as 'Comirnaty'? We interviewed key stakeholders at the Dutch national and European levels (n = 11 individuals representing five stakeholder groups in eight interviews and two written statements) and analysed relevant publications, policy documents and other grey literature (n = 171 documents). Interviewees observed significant changes in regulatory procedures and requirements for the 'Comirnaty' vaccine compared to vaccine approval in non-pandemic circumstances. Specifically, the European Medicines Agency (EMA) actively promoted changes by using an accelerated assessment and rolling review procedure for fast conditional marketing authorisation, requiring a reduced number of animal studies and accepting more alternatives, allowing pre-clinical in vivo animal experiments to run in parallel with clinical trials and allowing re-use of historical data from earlier vaccine research. Pharmaceutical companies, in turn, actively anticipated these changes and contributed data from non-animal alternative sources for the development phase. After approval, they could also use in vitro methods only for all batch releases due to the thorough characterisation of the mRNA vaccine. Pharmaceutical companies were optimistic about future change because of societal concerns surrounding the use of animals, adding that, in their view, non-animal alternatives generally obtain faster, better, and cheaper results. Regulators we interviewed were more hesitant to permanently implement these changes as they feared backlash regarding safety issues and uncertainty surrounding adverse effects. Our analysis shows how the EMA shortened its approval timeline in times of crisis by reducing the number of requested animal studies and promoting alternative methods. It also highlights the readiness of pharmaceutical companies to contribute to these changes. More research is warranted to investigate these promising possibilities toward further replacement in science and regulations, contributing to faster vaccine development.

Implementing pharmaceutical track-and-trace systems: a realist review.

INTRODUCTION: One way to prevent falsified medical products from entering the regulated pharmaceutical supply chain is to implement a pharmaceutical track-and-trace system (PTTS). Such systems in the most extensive versions generally mandate a scan at every point of contact with the medical product: from the point of entry to dispensation. There have been several attempts to implement such systems; for example, a 'full' PTTS in Turkey and the more pared-down version offered by the European Union's Falsified Medicines Directive and Delegated Act. This study aims to identify facilitators and barriers to implementing (elements of) a PTTS, with the Turkish system used as a benchmark. METHODS: We conducted a 'realist' review, which synthesises literature and aims to establish how a specific technology works, for whom, under which circumstances. We searched Embase, Medline Ovid, Web of Science, Cochrane Central and Google Scholar databases, yielding 2,790 scholarly articles. We selected 21 for review. RESULTS: Implementation of PTTS elements has been attempted in different compositions in several primarily high-income and middle-income countries. Factors that affected implementation included stakeholders like the government and supply chain actors, the coordination between them, and their awareness, knowledge, and skills, as well as regulation and legislation, monetary investments, and technical and digital requirements. CONCLUSION: The interplay between contextual factors is crucial for successful PTTS implementation. Specifically, the findings indicate that aligning the incentives for all actors and allowing for adjustments in a continuous implementation process will likely facilitate implementation.

Necessity under construction - societal weighing rationality in the appraisal of health care technologies.

Health care coverage decisions may employ many different considerations, which are brought together across two phases. The assessment phase examines the available scientific evidence, such as the cost-effectiveness, of the technology. The appraisal then contextualises this evidence to arrive at an (advised) coverage decision, but little is known about how this is done.In the Netherlands, the appraisal is set up to achieve a societal weighing and is the primary place where need- and solidarity-related ('necessity') argumentations are used. To elucidate how the Dutch appraisal committee 'constructs necessity', we analysed observations and recordings of two appraisal committee meetings at the National Health Care Institute, the corresponding documents (five), and interviews with committee members and policy makers (13 interviewees in 12 interviews), with attention to specific necessity argumentations.The Dutch appraisal committee constructs necessity in four phases: (1) allowing explicit criteria to steer the process; (2) allowing patient (representative) contributions to challenge the process; (3) bringing new argumentations in from outside and weaving them together; and (4) formulating recommendations to societal stakeholders. We argue that in these ways, the appraisal committee achieves societal weighing rationality, as the committee actively uses argumentations from society and embeds the decision outcome in society.

Around the Tables - Contextual Factors in Healthcare Coverage Decisions Across Western Europe.

BACKGROUND: Across Western Europe, procedures and formalised criteria for taking decisions on the coverage (inclusion in the benefits basket or equivalent) of healthcare technologies vary substantially. In the decision documents, which display the justification of, the rationale for, these decisions, national healthcare institutes may employ 'contextual factors,' defined here as situation-specific considerations. Little is known about how the use of such contextual factors compares across countries. We describe and compare contextual factors as used in coverage decisions generally and 4 decision documents specifically in Belgium, England, Germany, and the Netherlands. METHODS: Four group interviews with 3 experts from the national healthcare institute of each country, document and web site analysis, and a workshop with 1 to 2 of these experts per country were followed by the examination of the documents of 4 specific decisions taken in each of the 4 countries, sampled to vary widely in type of technology and decision outcome. RESULTS: From the available decision documents, we conclude that in every country studied, contextual factors are established 'around the table,' ie, in deliberation. All documents examined feature contextual factors, with similar contextual factor patterns leading to similar decisions in different countries. The Dutch decisions employ the widest variety of factors, with the exception of the societal functioning of the patient, which is relatively common in Belgium, England, and Germany. Half of the final decisions were taken in another setting, with the consequence that no documentation was retrievable for 2 decisions. CONCLUSION: First, we conclude that in these countries, contextual factors are actively integrated in the decision document, and that this is achieved in deliberation. Conceptualising contextual factors as both situation-specific and actively-integrated affords insight into practices of contextualisation and provides an encouragement for exchange between decision-makers on more qualitative aspects of decisions. Second, the decisions that lacked a publicly accessible justification of the final decision document raised questions on the decisions' legitimacy. Further research could address patterning of contextual factors, elucidate why some factors may remain implicit, and how decisions without a publicly available decision document may enable or restrain decision-making practice.

The bare necessities? A realist review of necessity argumentations used in health care coverage decisions.

CONTEXT: Policy makers and insurance companies decide on coverage of care by both calculating (cost-) effectiveness and assessing the necessity of coverage. AIM: To investigate argumentations pertaining to necessity used in coverage decisions made by policy makers and insurance companies, as well as those argumentations used by patients, authors, the public and the media. METHODS: This study is designed as a realist review, adhering to the RAMESES quality standards. Embase, Medline and Web of Science were searched and 98 articles were included that detailed necessity-based argumentations. RESULTS: We identified twenty necessity-based argumentation types. Seven are only used to argue in favour of coverage, five solely for arguing against coverage, and eight are used to argue both ways. A positive decision appears to be facilitated when patients or the public set the decision on the agenda. Moreover, half the argumentation types are only used by patients, authors, the public and the media, whereas the other half is also used by policy makers and insurance companies. The latter group is more accepted and used in more different countries. CONCLUSION: The majority of necessity-based argumentation types is used for either favouring or opposing coverage, and not for both. Patients, authors, the public and the media use a broader repertoire of argumentation types than policy makers and insurance companies.