Discussion
The regulatory environment is an aggregate of law, regulations and practices. A good regulatory environment is critical to support innovation systems and enable technological advancement [9]. Guidelines are an integral element of the regulatory environment. In the present study, we aimed to analyse the level of acceptance for changes suggested by stakeholders for draft EMA scientific guidelines during public consultations. Stakeholder input is a part of the process of understanding the potential impact of the guideline, intended and unintended. It facilitates predicting and anticipating causal connections between the adopted guideline and observed changes in the regulated environment. A thorough Regulatory Impact Assessment to understand costs (externalities) and benefits which are inherently associated with any regulation is an important part of building a regulatory framework [10].
The process of developing guidance is overall long, up to three years. Our results highlight that the time from the end of the consultation to adoption is generally at least half a year but can be longer, even over two years. There is a clear pacing problem with the accelerating speed of science and increasing innovativeness in the research approaches, which aim to adapt to the nature of scientific discoveries. To avoid lengthy and rather laborious guideline development processes, the EMA has also used other mechanisms, such as the publication of commentary or opinion articles in peer-reviewed journals, information days or workshops, as tools to increase clarity into how certain legislative elements are evaluated or to support emerging practices and their acceptability in medicines development [11]. These have proven as helpful measures to increase clarity particularly on the more qualitative elements in regulatory decision making. A stronger focus on regulatory science has been proposed as necessary to address the translation issue between science and future treatments. In Europe, the EMA lists many new guidelines that will be developed in their Regulatory Science Strategy to 2025 [2]. Also the Japanese regulators have suggested to include guideline development under the umbrella of regulatory science processes [12].
The OECD outlines that a successful regulatory strategy requires stakeholder support, which can be achieved through constant dialogue, publicity of the impact and consultation [10]. The results on mean scores of the stakeholder comments indicate that the current process appears to treat the stakeholders equally, with the average acceptance level being close to same for accepted and rejected comments with a mean score around 1 on a scale of 0 to 2. The differences often arise from the nature of the guideline, whether generic or procedural or focusing on an indication. Particularly the working parties are facing rapidly emerging new technological approaches (safety) or novel science (biologics) were more open for stakeholder input, which might be due to the speed of technological development being faster than development of associated regulatory frameworks with a higher appreciation of (scarce) domain expertise outside of the regulatory network. The observed differences between the EMA WPs can also be driven by elements feeding into regulatory systems, such as behavioral aspects, decision making or knowledge transfer mechanisms [13].
The gradual shift in the role of medicines regulation from gatekeeping against harmful molecules to promoting public health by offering regulatory incentives, such as additional support or faster approvals, for products that are likely to deliver the highest health gains [14] should not go unnoticed. Regulators have a very wide and useful broad general knowledge given their exposure to various products through regulatory processes but tapping onto expertise outside of their own or immediate network can be useful. We found that that the specialist knowledge is more readily accepted for indication level guideline when it comes from scientists affiliated with academia rather than industry. The opportunity cost of favoring one over the other might be to lose out on valuable contributions [15]; scientists working in medicines development and who can strengthen ability to translate scientific discoveries into therapeutics or vaccines come often from the industry side [16].
To respond to the speed of science and innovation, a better utilization of the quadruple-helix model is required to build a competitive and agile regulatory framework. Fostering a culture with aims at pooling all available expert knowledge, regardless of affiliation, is in the interest of the patient [17]. Since science is often not exact, a document-based consultation process with the focus on individual words or sentences may not capture the wealth of expertise in the ecosystem and result in the best possible outcome. A true exchange across all four stakeholder communities is likely to generate a better end result. The research shows that the stakeholders would often prefer a discussion of the results and implications, which would also be helpful for the implementation process for a guideline [6].