Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness.

Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.

Satisfaction with local healthcare services and medical need among hypertensive patients: a nationwide study.

BACKGROUND: Investigating the factors associated with unmet medical needs is important since it can reflect access to healthcare. This study examined the relationship between the unmet medical needs of patients with hypertension and their satisfaction with the healthcare services available in their neighborhoods. METHODS: Data were from the 2021 Korean Community Health Survey. The sample included individuals aged 19 years who were diagnosed with hypertension. The main outcome measure was unmet medical need. The relationship between the outcome measure and independent variables were analyzed using multivariate logistic regressions, along with a subgroup analysis based on whether patients were currently receiving treatment for hypertension. RESULTS: Unmet medical needs were found in 4.3% of the study participants. A higher likelihood of unmet medical needs was found in individuals not satisfied with the healthcare services at proximity (adjusted OR = 1.69, 95% CI: 1.49-1.92) compared to those satisfied with services nearby. Similar tendencies were found regardless of whether individuals were currently receiving treatment for hypertension, although larger differences were found between groups in participants who were currently not receiving treatment. CONCLUSIONS: The findings infer the need to consider patient satisfaction with nearby healthcare services in implementing public health policies that address unmet medical need in patients with hypertension.

Association between Perceived Activity Restriction Due to People's Perception of Aging and Unmet Medical Needs among Middle-Aged and Elderly People: A Population-Based Study.

Background and Objectives: The older members of a population might experience unmet medical needs, despite desiring medical care due to activity limitations driven by their perception of aging. This study conducted a cross-sectional analysis of the association between perceived activity restriction (PAR) due to people's own perception of aging and unmet medical needs (UMN) in late middle-aged and older Koreans based on the Korean National Health and Nutrition Examination Survey (KNHANES). Materials and Methods: The 2016-2020 KNHANES was used to analyze a total of 2008 participants among groups aged 45 years or older by applying individual weights imposed from the raw data. The independent variable of PAR was assessed using self-reported questionnaires based on the global activity limitation indicator. Also, the dependent variable of UMN, referring to the state in which a patient's medical care or service was insufficient, inadequate, or lacking, was assessed using a single question. After excluding missing values, the data on 2008 individuals were analyzed using a chi-square test, weighted logistic regression, and a stratified analysis of gender, age, and the presence of chronic illnesses. Results: The group that experienced PAR had an OR 2.13 higher (odds ratio [OR]: 2.13; 95% confidence interval [CI]: 1.27-3.56) to present UMN than the group that did not experience PAR. Furthermore, the results of the stratified analysis indicated that, in the group of female participants with chronic illness and in the group of elderly people, experiencing PAR was associated with a higher experience of UMN. Conclusions: There was a close association between PAR and UMN. In particular, when PAR occurred in the group of female participants with chronic illness and in the group of elderly people, the incidence rate of UMN was also found to be high. This finding highlights the need for policies and institutional measures to reduce UMN within vulnerable groups with an increased risk of medical inaccessibility due to activity restriction.

A scoping review on the impact of austerity on healthcare access in the European Union: rethinking austerity for the most vulnerable.

BACKGROUND: There is consensus that the 2008 financial and economic crisis and related austerity measures adversely impacted access to healthcare. In light of the growing debt caused by the COVID-19 crisis, it is uncertain whether a period of austerity will return. OBJECTIVE: This study aims to provide a structured overview of the impact of austerity policies in the EU-28 zone, applied in response to the Great Recession, on access to health care for the adult population, using the five access dimensions by Levesque et al. (2013). METHODS: This study followed the PRISMA extension for Scoping Reviews guideline. Medline (PubMed) and Web of Science were searched between February 2021 and June 2021. Primary studies in the English language published after the 1st of January 2008 reporting on the possible change in access to the healthcare system for the adult population induced by austerity in an EU28 country were included. RESULTS: The final search strategy resulted in 525 articles, of which 75 studies were reviewed for full-text analysis, and a total of 21 studies were included. Results revealed that austerity policy has been primarily associated with a reduction in access to healthcare, described through four main categories: i) Increase in rates of reported unmet needs (86%); ii) Affordability (38%); iii) Appropriateness (38%); iv) and Availability and Accommodation (19%). Vulnerable populations were more affected by austerity measures than the general population when specific safeguards were not in place. The main affected adult vulnerable population groups were: patients with chronic diseases, elderly people, (undocumented) migrants, unemployed, economically inactive people and individuals with lower levels of education or socioeconomic status. CONCLUSION: Austerity measures have led to a deterioration in access to healthcare in the vast majority of the countries studied in the EU-28 zone. Findings should prompt policymakers to rethink the fiscal agenda across all policies in times of economic crisis and focus on the needs of the most vulnerable populations from the health perspective.

Rationale for Surrogate Endpoints and Conditional Marketing Authorization of New Therapies for Kidney Transplantation.

Conditional marketing authorization (CMA) facilitates timely access to new drugs for illnesses with unmet clinical needs, such as late graft failure after kidney transplantation. Late graft failure remains a serious, burdensome, and life-threatening condition for recipients. This article has been developed from content prepared by members of a working group within the European Society for Organ Transplantation (ESOT) for a Broad Scientific Advice request, submitted by ESOT to the European Medicines Agency (EMA), and reviewed by the EMA in 2020. The article presents the rationale for using surrogate endpoints in clinical trials aiming at improving late graft failure rates, to enable novel kidney transplantation therapies to be considered for CMA and improve access to medicines. The paper also provides background data to illustrate the relationship between primary and surrogate endpoints. Developing surrogate endpoints and a CMA strategy could be particularly beneficial for studies where the use of primary endpoints would yield insufficient statistical power or insufficient indication of long-term benefit following transplantation.

Unmet Medical Need: An Introduction to Definitions and Stakeholder Perceptions.

BACKGROUND: Despite increasing informal and formal use of unmet medical need (UMN) in drug development, regulation, and assessment, there is no insight into its definitions in use. This study aims to provide insight into the current definitions in use and to provide a starting point for a multi-stakeholder discussion on alignment. METHODS: A scoping and a gray literature review were performed to locate definitions of UMN in literature and on stakeholder websites. These definitions were categorized and then discussed among the multi-stakeholder author group via semistructured group discussions and open session workshops with a broader stakeholder audience. Issues with the formation of a common definition and mechanisms for use were discussed. RESULTS: The reviews yielded 16 definitions. Differences were evident, but all included 1 or more of the following elements: (adequacy of) available treatments (16 of 16: 100%), disease severity or burden (6 of 16: 38%), and patient population size (1 of 16: 6%). The stakeholder discussions led to a suggestion for a definition including the first 2 items and, depending on context, population size. The discussions also showed that quantification of UMN is highly dependent on the scope and the value framework in which it is used based on different stakeholder preferences and responsibilities. CONCLUSION: We encourage stakeholders that want to promote alignment on the concept of UMN to prospectively discuss the scope in which they want to apply the concept, what elements they find important for consideration in each case, and how they would measure UMN within the broader regulatory or value framework applicable.

Methods for efficacy evaluations of antibacterial treatments in multiple body-site infection trials.

Unmet medical need exists for serious bacterial diseases caused by multidrug-resistant infections, necessitating an urgent need for newer therapies with greater treatment benefits to patients. For meeting this need, the usual approach has been to conduct separate clinical trials, each trial targeting infection at a single body-site, e.g., for respiratory tract, intra-abdominal site, urinary tract, or blood. However, for the unmet medical need situations, this approach seems inefficient for developing antibacterial drugs with activity against single species or against multiple species of bacteria for a broader indication. Instead, a streamlined clinical development program for such situations can benefit by considering multiple body-site infection trials. Such trials would enroll patients with infections at different body-sites, but with similar severity and comorbidity for avoiding potential treatment effect heterogeneity. Such trials, when properly designed and conducted, can be informative and can save time and resources in drug development. Goals for such trials would be to first demonstrate that there is evidence of an overall treatment effect, and then to show that the treatment effects at individual body-sites reveal consistency in contributing to the overall treatment effect, or to identify a subset of body-sites for which greater treatment effect can be supported by a specified statistical decision criterion. For this, we propose here an information-based procedure for the demonstration of treatment effect overall across all body-sites, or for a subset of body-sites, on considering two types of error rates of falsely concluding treatment effect.

Consistency ensured test strategies for supportive evidence of treatment efficacy in noninferiority clinical trials.

Noninferiority (NI) clinical trials are designed to demonstrate that a new treatment is not unacceptably worse than an active control on a clinically meaningful endpoint. While such an endpoint can be of any type, the focus of this manuscript is on the binary-type endpoint. Examples of this endpoint can be clinical cure endpoint for patients with bacterial diseases or based on a pre-specified virological threshold for viral diseases. However, in addition to assessing such a binary endpoint for the NI comparison, the trial may also evaluate a second clinically relevant endpoint for providing additional support to the evidence of the designated primary endpoint. Specifically, if the trial is successful in demonstrating statistical significance on the first endpoint, then observing at least a positive trend in efficacy on the second endpoint may provide additional supportive evidence of efficacy. The second endpoint can be a time-to-event type endpoint, such as time-to-symptom resolution (TSR) or time to all-cause mortality for infectious disease trials, time-to-wound closure for wound healing trials, or other endpoints. We propose two consistency ensured test strategies for the two hypotheses of a trial, one associated with the binary endpoint and the other with the second endpoint, both with the objective of drawing inference regarding the efficacy of the new treatment based on findings from testing the two hypotheses. A key feature of these test strategies is that basically it does not require multiplicity adjustment of the significance levels. We conclude with general discussion of the testing methods and possible applications to unmet medical need trials.

Public Opinions Toward Diseases: Infodemiological Study on News Media Data.

BACKGROUND: Society always has limited resources to expend on health care, or anything else. What are the unmet medical needs? How do we allocate limited resources to maximize the health and welfare of the people? These challenging questions might be re-examined systematically within an infodemiological frame on a much larger scale, leveraging the latest advancement in information technology and data science. OBJECTIVE: We expanded our previous work by investigating news media data to reveal the coverage of different diseases and medical conditions, together with their sentiments and topics in news articles over three decades. We were motivated to do so since news media plays a significant role in politics and affects the public policy making. METHODS: We analyzed over 3.5 million archive news articles from Reuters media during the periods of 1996/1997, 2008 and 2016, using summary statistics, sentiment analysis, and topic modeling. Summary statistics illustrated the coverage of various diseases and medical conditions during the last 3 decades. Sentiment analysis and topic modeling helped us automatically detect the sentiments of news articles (ie, positive versus negative) and topics (ie, a series of keywords) associated with each disease over time. RESULTS: The percentages of news articles mentioning diseases and medical conditions were 0.44%, 0.57% and 0.81% in the three time periods, suggesting that news media or the public has gradually increased its interests in medicine since 1996. Certain diseases such as other malignant neoplasm (34%), other infectious diseases (20%), and influenza (11%) represented the most covered diseases. Two hundred and twenty-six diseases and medical conditions (97.8%) were found to have neutral or negative sentiments in the news articles. Using topic modeling, we identified meaningful topics on these diseases and medical conditions. For instance, the smoking theme appeared in the news articles on other malignant neoplasm only during 1996/1997. The topic phrases HIV and Zika virus were linked to other infectious diseases during 1996/1997 and 2016, respectively. CONCLUSIONS: The multi-dimensional analysis of news media data allows the discovery of focus, sentiments and topics of news media in terms of diseases and medical conditions. These infodemiological discoveries could shed light on unmet medical needs and research priorities for future and provide guidance for the decision making in public policy.

Giving priority to preclinical pain measures resistant to existing drugs for developing innovative analgesics.

Preclinical Research & Development Chronic pain is a major health and socioeconomic burden because of its high prevalence, negative influence on patients' physical and/or emotional conditions, and huge costs to society. The responses of chronic pain patients to analgesic therapies vary substantially from individual to individual, and no more than a minority of chronic pain patients with various etiologies such as neuropathy and inflammation are, in fact, successfully relieved by existing drugs including opioid analgesics, nonopioid analgesics, antiepileptics, and antidepressants. The large primary unmet medical need would therefore be the patient domain that does not respond well to existing drugs. Accordingly, the expected profile for innovative analgesics would not be efficacy in the responder patient domain, but significant efficacy in patients with existing drug-resistant chronic pain. Meanwhile, the current gold standard in preclinical pain measures for the screening of analgesic candidates is existing drug-sensitive pain measures in animal models of chronic pain. Analgesic candidates screened using such preclinical pain measures during the last decades have been far from fulfilling the expected profile for innovative analgesics. Given that it is unlikely that such existing drug-sensitive pain measures are the best approach to developing innovative analgesics, one of the other approaches would be giving priority to existing drug-resistant pain measures in preclinical research. This review introduces potentially applicable existing drug-resistant pain measures published so far and suggests that the use of them would lead to the development of innovative analgesics.

An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010-2014.

The number of elderly patients with hematologic malignancies has been steadily increasing with the aging of society. However, little research has been conducted to evaluate the prescription status of drugs for such diseases in Japan. Therefore, the aims of this study were to identify the patient population currently being prescribed drugs for hematologic malignancies in Japan and the direction of drug development. To examine the prescription pattern of drugs for the treatment of hematological malignancies in Japan from 2010-2014, we used the IMS Japan Pharmaceutical Market database and the Japanese Society of Hematology Clinical Practice Guidelines, and for drug development status, we used ClinicalTrials.gov and the University Hospital Medical Information Network Clinical Trials Registry. We found a significant upward trend in prescriptions for molecular-targeted agents, which are typically prescribed over the long term, and a significant downward trend in chemotherapeutic agents, which are usually prescribed for the short term. We also found that recent drug development in hematological malignancies has focused on molecular-targeted agents. These results suggest that drug development should be directed toward anti-tumor agents in hematological malignancies that can help maintain and improve patients' QOL.

The association between perceived unmet medical need and mental health among the Republic of Korea Armed Forces.

INTRODUCTION: We investigated the effect of unmet medical need on the mental health of Republic of Korea (ROK) Armed Forces personnel, as most of the service members work in remote areas and often experience such unmet needs. METHODS: This study used secondary data from the 2014 Military Health Survey (MHS), conducted by the ROK School of Military Medicine and designed to collect military health determinants. Descriptive statistics showed the general characteristics of the study populations by variable. We specifically compared the population after stratifying participants by suicide ideation. An analysis of variance was also carried out to compare Kessler Psychological Distress Scale 10 Scores. Additionally, dependent spouses and children of both active-duty service members and retirees are included among those entitled to Military Health System healthcare. RESULTS: Among the 4967 military personnel, 681 (13.7%) individuals reported an experience of unmet medical need within the past 12 months and gave reasons of 'no time (5.15%)', 'long office wait (2.6%)', 'no money (0.22%)', 'long distance from base (1.19%)', 'illness but not very serious (1.65%)', 'mistrust in doctors (1.95%)' and 'pressure due to performance appraisal (0.95%)'. Regression analysis revealed that unmet medical need was significantly associated with negative mental health (ß=1.753, p<0.0001) and increased suicide ideation (OR=2.649, 95% CI 1.84 to 3.82). Also, soldiers reporting unmet medical need due to 'no money', 'no time' or 'pressure due to performance appraisal' were significantly more likely to experience similar negative mental health effects. CONCLUSIONS: Our study indicates that unmet medical need is significantly associated with soldiers' mental health decline and suicide ideation, highlighting the importance of providing military personnel with timely, affordable and sufficient medical care.

Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance.

In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug-resistant Gram-negative infections, limits available treatment options . A recent CDC report, 'Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority-superiority nested trial design that is informative and allows for treatment-to-control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Strategic aspects for the commercialization of nanomedicines.

The projected growth of the nanomedicine market mirrors the increase in commercial interest and investment in the field. Yet, amidst this optimism, research efforts have often been geared towards developing innovative materials, and less on bringing these innovations to market. In this article, we present a strategic approach of 'commercialization by design' to overcome various challenges related to commercialization. This approach shifts the focus from materials-centric development to one driven by market demands, evaluating nanomedicines considering factors like reimbursement restrictions and unmet medical needs, and aiming to generate robust evidence for regulatory authorities, Health Technology Assessment bodies and Payers alike. We highlight the linkages from the market backwards to the preclinical phase, where nanomedicines are tailored to specific clinician-identified requirements. Transitioning from a technology 'push' model to one with market 'pull' will enhance the commercial success of nanomedicines.

Balancing ethical norms and duties for the introduction of new medicines through conditional marketing authorization: a research agenda.

The European Medicines Agency's conditional marketing authorization (CMA) aims to expedite patient access to medicines for unmet medical needs by shifting a part of the drug development process post-authorization. We highlight ethical issues surrounding CMA, comprising (i) the complexity of defining unmet medical need; (ii) poor understanding of CMA and its impact on informed consent; (iii) hope versus unrealistic optimism; (iv) implications of prolonged post-authorization studies and potential patient harm; (v) rights and duties of patients surrounding participation in post-authorization studies; (vi) access to previously authorized CMA medicines; and (vii) the "benefit slippage" phenomenon, defined as the gradual shift of strict criteria to less strict criteria. We propose a comprehensive research agenda to address these ethical issues, and stress the need for multi-stakeholder engagement to ensure patient-centered use of CMA.

New developments in celiac disease treatments.

Celiac disease (CeD), an autoimmune disorder triggered by gluten, affects around 1% of the global population. Standard treatment is a strict gluten-free diet (GFD), which poses significant challenges due to dietary restrictions, cross-contamination and subsequent persistent intestinal inflammation. This underscores the need for new treatment options addressing the complex pathophysiology of CeD. Recent research focuses on developing drugs that target intestinal barrier regeneration, gluten peptide modification, immune response alteration, and gut microbial ecosystem modulation. These approaches offer potential for more effective management of CeD beyond GFD. Gluten-independent treatments may be particularly relevant under the FDA's draft guidance for CeD, which emphasizes drug development as an adjunct to GFD for patients with ongoing signs and symptoms of CeD despite strict GFD.

Access to Healthcare and Health Literacy in Croatia: Empirical Investigation.

Health literacy is related to different health-related outcomes. However, the nature of the relationship between health literacy and health outcomes is not well understood. One pathway may lead from health literacy to health outcomes by means of access to healthcare. The goal of the current study is to explore the association between health literacy and the particular measure of access to healthcare-unmet medical need-for the first time in Croatia and, to the best of our knowledge, for the first time in the EU context. We use data obtained from face-to-face interviews in a large nationally representative sample of the Croatian population (n = 1000) to estimate the level of health literacy and self-reported access to care and investigate the association between health literacy and self-perceived barriers to access. Our study showed that limited and problematic health literacy is prevalent and associated with higher rates of unmet medical need. Unmet need is largely caused by long waiting lists. It is therefore essential to design health services fitting the needs of those who have limited and/or problematic health literacy as well as enhance health education with the potential of improving the access to care and health outcomes as well as design policies that reduce waiting times.

Who is the most precarious among the nonstandard workers? A comparative study of unmet medical needs among standard workers and subtypes of nonstandard workers.

OBJECTIVE: Nonstandard workers might have a relatively higher risk of unmet medical needs than standard workers. This study subdivided nonstandard workers to investigate the effects of nonstandard employment on unmet medical needs. METHODS: We used the Korea Health Panel 2011-2018 data. The independent variable, employment contract, was defined using the nonstandard form described by the ILO: Temporary workers, Part-time workers, and Temporary agent workers. The analytical method used in this study was a panel logit model that accounted for repeated measured participants. By controlling for time-invariant individual-fixed effects, we investigate the relationship between subdivided nonstandard work and the risk of unmet medical needs with reference to standard work. RESULTS: The results of the analysis clearly showed that compared with standard workers, temporary agency workers had a significantly higher risk of unmet medical needs (Odds ratio = 1.182, 95% CI = 1.016-1.374). The main cause of this phenomenon was economic reasons in this group. CONCLUSIONS: This study found that temporary agency workers in the general Korean population have a significantly higher risk of unmet healthcare needs. The result of this study implies that financial hardship might be a fundamental health hazard among workers with nonstandard employment.

The role of drug regulatory authorities and health technology assessment agencies in shaping incentives for antibiotic R&D: a qualitative study.

BACKGROUND: Few antibiotics have entered the market in recent years despite the need for new treatment options. Some of the challenges of bringing new antibiotics to market are linked to the marketing authorization and health technology assessment (HTA) processes. Research shows great variation in geographic availability of new antibiotics, suggesting that market introduction of new antibiotics is unpredictable. We aimed to investigate regulatory authorities' and HTA agencies' role in developing non-financial incentives to stimulate antibiotic research and development (R&D). METHODS: We conducted individual, semi-structured, stakeholder interviews. Participants were recruited from regulatory authorities (EMA and FDA) and HTA agencies in Europe. Participants had to be experienced with assessment of antibiotics. The data were analyzed using a deductive and inductive approach to develop codes and identify key themes. Data were analyzed using thematic analysis including the constant comparison method to define concepts, and rival thinking to identify alternative explanations. RESULTS: We found that (1) interpretation of key concepts guiding the understanding of what type of antibiotics are needed vary (2) lack of a shared approach on how to deal with limited clinical data in the marketing authorization and HTA processes is causing barriers to getting new antibiotics to market (3) necessary adaptations to the marketing authorization process causes uncertainties that transmit to other key stakeholders involved in delivering antibiotics to patients. CONCLUSIONS: A shared understanding of limited clinical data and how to deal with this issue is needed amongst stakeholders involved in antibiotic R&D, marketing authorization, and market introduction to ensure antibiotics reach the market before resistance levels are out of control. Regulatory authorities and HTA agencies could play an active role in aligning the view of what constitutes an unmet medical need, and direct new economic models towards stimulating greater diversity in the antibiotic armamentarium.

Meeting the Need for a Discussion of Unmet Medical Need.

As Europe and the world continue to battle against COVID, the customary complacency of society over future threats is clearly on display. Just 30 months ago, such a massive disruption to global lives, livelihoods and quality of life seemed unimaginable. Some remedial European Union action is now emerging, and more is proposed, including in relation to tackling "unmet medical need" (UMN). This initiative-directing attention to the future of treating disease and contemplating incentives to stimulate research and development-is welcome in principle. But the current approach being considered by EU officials merits further discussion, because it may prove counter-productive, impeding rather than promoting innovation. This paper aims to feed into these ongoing policy discussions, and rather than presenting research in the classical sense, it discusses the key elements from a multistakeholder perspective. Its central concern is over the risk that the envisaged support will fail to generate valuable new treatments if the legislation is phrased in a rigidly linear manner that does not reflect the serpentine realities of the innovation process, or if the definition placed on unmet medical need is too restrictive. It cautions that such an approach presumes that "unmet need" can be precisely and comprehensively defined in advance on the basis of the past. It cautions that such an approach can reinforce the comfortable delusion that the future is totally predictable-the delusion that left the world as easy prey to COVID. Instead, the paper urges reflection on how the legislation that will shortly enter the pipeline can be phrased so as to allow for the flourishing of a culture capable of rapid adaptation to the unexpected.