Understanding the Normativity of Health Technology Assessment: Ontological, Moral, and Epistemological Commitments.

The inherent normativity of HTA can be conceptualized as a result of normative commitments, a concept that we further specify to encompass moral, epistemological and ontological commitments at play in the practice of HTA. Based on examples from literature, and an analysis of the example of assessing Non-Invasive Prenatal Testing (NIPT), we will show that inevitable normative decisions in conducting an assessment commits the HTA practitioner to moral (regarding what makes a health technology desirable), ontological (regarding which effects of health technology are conceivable), and epistemological (regarding how to obtain reliable information about health technology) norms. This highlights and supports the need for integrating normative analysis and stakeholder participation, providing guidance to HTA practitioners when making normative choices. This will foster a shared understanding between those who conduct, use, or are impacted by assessments regarding what are conceivable and desirable outcomes of using health technology, and how to collect reliable information to assess whether these outcomes are (going to be) realized. It also provides more insight into the implications of different normative choices.

Capability of Children with Hearing Devices: A Mixed Methods Study.

We investigated 34 deaf and hard-of-hearing children with hearing devices aged 8-12 years and 30 typical hearing peers. We used the capability approach to assess well-being in both groups through interviews. Capability is "the real freedom people have to do and to be what they have reason to value." Speech perception, phonology, and receptive vocabulary data of the deaf and hard-of-hearing children, that were used retrospectively, showed a large variability. The analysis of the relation between clinical quantitative outcome measures and qualitative capability interview outcomes suggests that at this age, differences in clinical performance do not appear to translate into considerable differences in capability, including capability did offer insight into the factors that appeared to ensure this equivalence of capability. We argue that capability outcomes should be used to determine the focus of (auditory) rehabilitation and support, in line with the United Nations Convention on the Rights of the Child.

Methods for Early Assessment of the Societal Value of Health Technologies: A Scoping Review and Proposal for Classification.

OBJECTIVES: Early assessments of health technologies help to better align and integrate their development and assessment. Such assessments can take many forms and serve different purposes, hampering users in their selection of the most appropriate method for a specific goal. The aim of this scoping review was to structure the large set of methods according to their specific goal. METHODS: A scoping review was conducted using PubMed and reference lists of retrieved articles, to identify review studies with a methodological focus. From the included reviews, all individual methods were listed. Based on additional literature and examples, we extracted the specific goal of each method. All goals were clustered to derive a set of subclasses and methods were grouped into these subclasses. RESULTS: Of the 404 screened, 5 reviews were included, and 1 was added when searching reference lists. The reviews described 56 methods, of which 43 (77%) were included and classified as methods to (1) explore the nature and magnitude of the problem, (2) estimate the nature and magnitude of the expected (societal) value, (3) identify conditions for the potential value to materialize, and (4) help develop and design the type of research that is needed. CONCLUSIONS: The wide range of methods for exploring the societal value of health technologies at an early stage of development can be subdivided into a limited number of classes, distinguishing methods according to their specific objective. This facilitates selection of appropriate methods, depending on the specific needs and aims.

Single-case experimental designs for bumetanide across neurodevelopmental disorders: BUDDI protocol.

BACKGROUND: Bumetanide is a selective NKCC1 chloride importer antagonist which is being repurposed as a mechanism-based treatment for neurodevelopmental disorders (NDDs). Due to their specific actions, these kinds of interventions will only be effective in particular subsets of patients. To anticipate stratified application, we recently completed three bumetanide trials each focusing on different stratification strategies with the additional objective of deriving the most optimal endpoints. Here we publish the protocol of the post-trial access combined cohort study to confirm previous effects and stratification strategies in the trial cohorts and in new participants. METHOD/DESIGN: Participants of the three previous cohorts and a new cohort will be subjected to 6 months bumetanide treatment using multiple baseline Single Case Experimental Designs. The primary outcome is the change, relative to baseline, in a set of patient reported outcome measures focused on direct and indirect effects of sensory processing difficulties. Secondary outcome measures include the conventional questionnaires 'social responsiveness scale', 'repetitive behavior scale', 'sensory profile' and 'aberrant behavior scale'. Resting-state EEG measurements will be performed at several time-points including at Tmax after the first administration. Assessment of cognitive endpoints will be conducted using the novel Emma Tool box, an in-house designed battery of computerized tests to measure neurocognitive functions in children. DISCUSSION: This study aims to replicate previously shown effects of bumetanide in NDD subpopulations, validate a recently proposed treatment prediction effect methodology and refine endpoint measurements. TRIAL REGISTRATION: EudraCT: 2020-002196-35, registered 16 November 2020, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-002196-35/NL.

Health technology assessment: A matter of facts and values.

The unique task and contribution of health technology assessment (HTA) is to help identify those health technologies and their uses that are most likely to preserve and restore a population's health in a way that is consonant with its values, including, for example, equity and access to high-quality care (1). Such a task is challenging for at least two reasons. First, because of the vast and constantly evolving number and diversity of health technologies and their applications. Second, because of the usual wide variety of competing views within communities and their stakeholders regarding what strategies are likely to be conducive to the goal of preserving and restoring population health. Although perhaps tempting, it would be a grave mistake to hold that the controversies that result from such competing views can be resolved by taking recourse to the facts only. For such controversies are usually fueled by different notions of health and disease and different specifications of values such as equity and individual and collective responsibility for health. For this reason, they cannot be resolved in a satisfactory way without also addressing those normative issues and their interplay with empirical analysis.

Learning and practicing more value-reflective, problem-setting health technology assessment: experiences and lessons from the VALIDATE project.

OBJECTIVES: To conduct a formative evaluation of applying the VALIDATE approach in practice by (i) assessing how students appreciated the e-learning course, (ii) exploring how, for what purposes and with what outcomes the acquired VALIDATE competences subsequently were used in internships in different institutional contexts, and how this was shaped by these contexts, and (iii) what this shows on real-world use of VALIDATE. METHODS: Comparative discussion of experiences of applying the VALIDATE approach via a semistructured survey and oral feedback from e-course students; final reports on internships in health technology assessment (HTA) practice, followed by semistructured interviews with interns and supervisors to complement and interpret results. RESULTS: All students considered the VALIDATE approach an enlightening and important addition to current HTA knowledge, especially regarding understanding the relation between empirical analysis and normative inquiry, identifying policy relevant questions and using the method of reconstructing interpretive frames for scoping. The latter appeared intellectually challenging and requiring some prior HTA knowledge. The use the VALIDATE approach in practice shows that interns productively redefined the HTA problem, based on appreciation of different stakeholders' definition of the issue; they experienced constraints from retrieving all relevant perspectives from existing literature as well as from institutional rules and routines. CONCLUSIONS: Some challenges in applying the VALIDATE approach deserve attention for its future use: currently used research approaches often assume a problem as "given"; and the data needed on different perspectives is often not reported in scientific literature. Finally, data gathering on and evaluation of value dimensions was experienced as challenging.

Integrating Empirical Analysis and Normative Inquiry in Health Technology Assessment: The Values in Doing Assessments of Health Technologies Approach.

Health technology assessment (HTA) aims, through empirical analysis, to shed light on the value of health technologies (O'Rourke et al. [2020, International Journal of Technology Assessment in Health Care 36, 187-90]). HTA is, then, where facts and values meet. But how, where, and when do facts and values meet in HTA? Currently, HTA is usually portrayed as a sequential process, starting with empirical analysis (assessment), followed by a deliberation on the implications of the findings for a judgment of a health technology's value (appraisal). In this paper, we will argue that in HTA, empirical analysis and normative inquiry are much more closely entwined. In fact, as we hope to show, normative commitments act as an indispensable guide for the collection and interpretation of empirical evidence. Drawing on policy sciences, we will suggest a concrete methodology that can help HTA practitioners to integrate empirical analysis and normative inquiry in a transparent way. The proposed methodology can be conceived as a concrete means for conducting a scoping exercise in HTA. Moreover, it offers a distinct way of giving stakeholders a structural and constructive role in HTA. This paper outlines the approach developed by the values in doing assessments of health technologies project, a project funded by the Erasmus+ program (contract number 2018-1-NL01-KA203-038960), which is the European Union's program to support education, training, youth, and sport in Europe. The project has resulted in an E-learning course, an accompanying handbook, and a consensus statement, all freely available from the project's website www.validatehta.eu.

There is more than 'I' in self-directed learning: An exploration of self-directed learning in teams of undergraduate students.

Preparing future professionals for highly dynamic settings require self-directed learning in authentic learning situations. Authentic learning situations imply teamwork. Therefore, designing education for future professionals requires an understanding of how self-directed learning develops in teams. We followed (bio-)medical sciences students (n = 15) during an 8-month period in which they worked on an innovation project in teams of 4-6 students. Template analysis of 39 transcripts of audio-recorded group meetings revealed three mechanisms along which group dynamics influenced self-directed learning behaviour. First, if expressions of emotions were met with an inquisitive response, this resulted in self-monitoring or feelings of responsibility. Second, openness in the group towards creativity or idea exploration stimulated critical thinking. Third, disputational talk frustrated learning, because it adversely affected group cohesion. We conclude that emotions, openness, and relatedness are important drivers of self-directed learning in teams and hence should be given explicit attention in designing collaborative learning for future professionals.

Core competencies for ethics experts in health technology assessment.

OBJECTIVES: There is no consensus on who might be qualified to conduct ethical analysis in the field of health technology assessment (HTA). Is there a specific expertise or skill set for doing this work? The aim of this article is to (i) clarify the concept of ethics expertise and, based on this, (ii) describe and specify the characteristics of ethics expertise in HTA. METHODS: Based on the current literature and experiences in conducting ethical analysis in HTA, a group of members of the Health Technology Assessment International (HTAi) Interest Group on Ethical Issues in HTA critically analyzed the collected information during two face-to-face workshops. On the basis of the analysis, working definitions of "ethics expertise" and "core competencies" of ethics experts in HTA were developed. This paper reports the output of the workshop and subsequent revisions and discussions online among the authors. RESULTS: Expertise in a domain consists of both explicit and tacit knowledge and is acquired by formal training and social learning. There is a ubiquitous ethical expertise shared by most people in society; nevertheless, some people acquire specialist ethical expertise. To become an ethics expert in the field of HTA, one needs to acquire general knowledge about ethical issues as well as specific knowledge of the ethical domain in HTA. The core competencies of ethics experts in HTA consist of three fundamental elements: knowledge, skills, and attitudes. CONCLUSIONS: The competencies described here can be used by HTA agencies and others involved in HTA to call attention to and strengthen ethical analysis in HTA.

An economic model of the cost-utility of pre-emptive genetic testing to support pharmacotherapy in patients with major depression in primary care.

The pharmacokinetics of many antidepressants (tricyclic antidepressants (TCA) or selective serotonin re-uptake inhibitors (SSRI)) are influenced by the highly polymorphic CYP2D6 enzyme. Therefore, pharmacogenetics could play an important role in the treatment of depressive patients. The potential cost-utility of screening patients is however still unknown. Therefore, a Markov model was developed to compare the strategy of screening for CYP2D6 and subsequently adjust antidepressant treatment according to a patient's metabolizer profile of poor, extensive, or ultra metabolizer, with the strategy of no screening ('one size fits all' principle). Each week a patient had a probability of side effects, which was followed by dosage titration or treatment switching. After 6 weeks treatment effect was evaluated followed by treatment adjustments if necessary, with a total time horizon of the model of 12 weeks. The analysis was performed from a societal perspective. The strategy of screening compared with no screening resulted in incremental costs of €91 (95 percentiles: €39; €152) more expensive but also more effect with 0.001 quality adjusted life years (QALYs) (95 percentiles: 0.001; 0.002) gain. The incremental cost-effectiveness ratio (ICER) was therefore €77,406 per QALY gained, but varied between €22,500 and €377,500 depending on the price of screening and productivity losses. According to our model, we cannot unequivocally conclude that screening for CYP2D6 in primary care patients using antidepressants is be cost-effective, as the results are surrounded by large uncertainty. Therefore, information from ongoing studies should be used to reduce these uncertainties.

Impact of molecular point-of-care testing on clinical management and in-hospital costs of patients suspected of influenza or RSV infection: a modeling study.

BACKGROUND: At hospital admission, patients suspected of infection with influenza or respiratory syncytial virus (RSV) are placed in isolation, pending the outcome of diagnostics. In a significant number, isolated care proves unnecessary. We investigated the potential impact of molecular point-of-care (POC) diagnostics on patient management and in-hospital costs. METHOD: Prospective collection of data on resource utilization within the hospital from consecutive patients 18 years or older presenting at our university medical center with symptoms of respiratory tract infection from December 2016 to April 2017. A cost analysis was conducted using Markov modeling comparing the actual course of events (on the basis of routine diagnostic tests) with two hypothetical scenarios: when POC would impact time to diagnosis only (scenario 1) or on discharge from the hospital, too (scenario 2). RESULTS: A total of 283 patients were included, of whom 217 (76.7%) were admitted. Influenza and RSV were detected in 31% and 7% of the patients, respectively. Fifty-four percent of patients tested negative, of which 79% were kept in isolated care waiting for test results, with a median duration of 24 hours. Median length of stay was 6.0 days. Mean total in-hospital costs per patient were € 5243. Introducing POC would lower mean costs per patient to € 4904 (scenario 1) and € 4206 (scenario 2). At the hospital level, this would result in a total cost reduction of € 95 937 to € 293 471 in a single influenza season. CONCLUSIONS: Introducing POC testing for patients presenting with symptoms of viral respiratory tract infection can reduce time-to-diagnosis, hospital stay and, thereby, in-hospital costs.

Early Assessment of Proof-of-Problem to Guide Health Innovation.

BACKGROUND: Although the relevance of both push and pull factors is acknowledged in models of innovation, needs, broadly defined, are rarely considered, whereas supply-driven innovation in publicly funded health systems carries the risk that it may not match the underlying problems experienced by patients and consumers. OBJECTIVES: To explore a mixed-methods, multistakeholder approach that focuses on pertinent problems when assessing the potential value of an innovation as applied to a case of surgical innovation in meniscus surgery. METHODS: Through interviews of stakeholders (n = 11) we sought to identify current problems of meniscus surgery in the Netherlands. On the basis of the subsequent problem definitions, we used stakeholder and literature input to quantify the room for improvement and stakeholder engagement to uncover possible barriers and facilitators to the implementation of the proposed innovation. RESULTS: Despite being enthusiastic about the ingenuity of the proposed innovation and seeing some potential for cost saving, most stakeholders (n = 10) agreed that there are no major problems in current meniscus surgery meriting the innovation. They even discerned pragmatic barriers that would challenge the potential cost savings. CONCLUSIONS: By adopting a problem-oriented multistakeholder approach to early health technology assessment, we were able to estimate the potential value of an innovation in its social context, finding that, beyond the initial enthusiasm, the proposed innovation was unlikely to resolve the problems distinguished by the stakeholders. We concluded that our multistakeholder, mixed-methods approach to early health technology assessment is feasible and helps foster more demand-driven innovations.

Clinical biomarker innovation: when is it worthwhile?

Background Choosing which biomarker tests to select for further research and development is not only a matter of diagnostic accuracy, but also of the clinical and monetary benefits downstream. Early health economic modeling provides tools to assess the potential effects of biomarker innovation and support decision-making. Methods We applied early health economic modeling to the case of diagnosing primary aldosteronism in patients with resistant hypertension. We simulated a cohort of patients using a Markov cohort state-transition model. Using the headroom method, we compared the currently used aldosterone-to-renin ratio to a hypothetical new test with perfect diagnostic properties to determine the headroom based on quality-adjusted life-years (QALYs) and costs, followed by threshold analyses to determine the minimal diagnostic accuracy for a cost-effective product. Results Our model indicated that a perfect diagnostic test would yield 0.027 QALYs and increase costs by €43 per patient. At a cost-effectiveness threshold of €20,000 per QALY, the maximum price for this perfect test to be cost-effective is €498 (95% confidence interval [CI]: €275-€808). The value of the perfect test was most strongly influenced by the sensitivity of the current biomarker test. Threshold analysis showed the novel test needs a sensitivity of at least 0.9 and a specificity of at least 0.7 to be cost-effective. Conclusions Our model-based approach evaluated the added value of a clinical biomarker innovation, prior to extensive investment in development, clinical studies and implementation. We conclude that early health economic modeling can be a valuable tool when prioritizing biomarker innovations in the laboratory.

Scientific Development of HTA-A Proposal by the Health Technology Assessment International Scientific Development and Capacity Building Committee.

OBJECTIVES: To report from the Scientific Development and Capacity Building Committee of Health Technology Assessment International (HTAi) on activities that are being undertaken within HTAi regarding the promotion of scientific rigor in the field of health technology assessment (HTA). METHODS: Retrieval of definitions of HTA that the SDCB committee considered reflective of the current practice of HTA, followed by a narrative synthesis of the core components of HTA. RESULTS: Several definitions of HTA have been provided, all sharing the notion that HTA is the formal, systematic, and transparent inquiry into the meaning and value, broadly defined, of health technologies, when used in specific patient populations.Many frameworks and tools have been developed for assessing the quality of specific tasks that may be conducted in the context of HTA. Collating such frameworks and tools is likely to be helpful in developing standards and in providing guidance as to how the scientific quality of HTA may be secured. Two current trends in HTA were noted: a stronger health systems focus, and the need to involve stakeholders throughout the HTA process. A wider systems' perspective requires that plausible alternative scenarios are being developed, and wide consultation of various stakeholders is a prerequisite to the development of such scenarios with data from various sources. CONCLUSIONS: Current trends in HTA will lead to different demands on the HTA expert. The task of this emerging policy professional would be not just to provide technical information for problem-solving, but also to combine it with a new function of facilitating public deliberation and learning.

Methods Assessing Sociocultural Aspects of Health Technologies: Results of a Literature Review.

OBJECTIVES: Social and cultural aspects are rarely assessed in health technology assessments (HTA), despite being part of most HTA definitions. One hypothesis for the reason why they are hardly considered in HTA is that we lack relevant assessment methods. Accordingly, this review aims at providing an overview of methodological approaches to address social and cultural aspects related to health technologies in HTA. METHODS: We conducted a comprehensive literature search by searching fourteen databases and a hand-search of two pertinent journals. Additionally, we sent a query to all member agencies of the International Network of Agencies for Health Technology Assessment (INAHTA) asking them for methods they use to assess social and cultural aspects. RESULTS: A total of 125 publications met our inclusion criteria. We grouped the methodological approaches into checklists for experts, literature reviews, stakeholder participatory approaches, primary data collection methods, and combinations of methodological approaches. CONCLUSIONS: There is a wide variety of methods available for assessing social and cultural aspects of health technologies, some of which have been applied in HTA. The presented overview of the different approaches and their merits can facilitate the assessment of these aspects, and improve the knowledge regarding (potential) success and failure of the implementation of a health technology.

Optimal search strategies for identifying moderators and predictors of treatment effects in PubMed.

BACKGROUND: Treatment effects differ across patients. To guide selection of treatments for patients, it is essential to acknowledge these differences and identify moderators or predictors. Our aim was to generate optimal search strategies (commonly known as filters) for PubMed to retrieve papers identifying moderators and predictors of treatment effects. METHODS: Six journals were hand-searched for articles on moderators or predictors. Selected articles were randomly allocated to a development and validation set. Search terms were extracted from the development set and tested for their performance. Search filters were created from combinations of these terms and tested in the validation set. RESULTS: Of 4407 articles, 198 were considered to be relevant. The most sensitive filter in the development set '("Epidemiologic Methods" [MeSH] OR assign* OR control*[tiab] OR trial*[tiab]) AND therapy*[sh]' yielded in the validation set a sensitivity of 89% [88%-90%] and a specificity of 80% [79%-82%]. CONCLUSIONS: The search filters created in this study can help to efficiently retrieve evidence on moderators and predictors of treatment effect. Testing of the filters in multiple domains should reveal robustness across disciplines. These filters can facilitate the retrieval of evidence on moderators and predictors of treatment effects, helping the implementation of stratified or personalised health care.

Cost-Effectiveness Analysis of Genotype-Guided Treatment Allocation in Patients with Alcohol Use Disorders Using Naltrexone or Acamprosate, Using a Modeling Approach.

Alcohol use disorders (AUD) are a major contributor to the global burden of disease, and have huge societal impact. Some studies show that AUD patients carrying the G-allele of the OPRM1 variant c.118A>G respond better to naltrexone, resulting in reduced relapse rates compared to carriers of the AA genotype. Genotype-guided treatment allocation of these patients carrying a G-allele to naltrexone could potentially improve the treatment outcome. However, cost-effectiveness of this strategy should be investigated before considering clinical implementation. We, therefore, evaluated costs and Quality-Adjusted Life-Years (QALYs), using a modelling approach, from an European perspective, of genotype-guided treatment allocation (G-allele carriers receiving naltrexone; AA homozygotes acamprosate or naltrexone) compared to standard care (random treatment allocation to acamprosate or naltrexone), by using a Markov model. Genotype-guided treatment allocation resulted in incremental costs of EUR 66 (95% CI -28 to 149) and incremental effects of 0.005 QALYs (95% CI 0.000-0.011) per patient (incremental cost-effectiveness ratio of EUR 13,350 per QALY). Sensitivity analyses showed that the risk ratio to relapse after treatment allocation had the largest impact on the cost-effectiveness. Depending on the willingness to pay for a gain of one QALY, probabilities that the intervention is cost-effective varies between 6 and 79%. In conclusion, pharmacogenetic treatment allocation of AUD patients to naltrexone, based on OPRM1 genotype, can be a cost-effective strategy, and could have potential individual and societal benefits. However, more evidence on the impact of genotype-guided treatment allocation on relapse is needed to substantiate these conclusions, as there is contradictory evidence about the effectiveness of OPRM1 genotyping.

ON IMPACT AND IMPACT FACTORS.

The International Journal of Technology Assessment in Health Care (IJTAHC) is part of the so-called Cambridge Core, the "home of academic content" (1). As such, not surprisingly, it is judged by standard scientific standards such as the Journal's Impact Factor (IF). Although on the rise, there is still significant room for improvement (2). In this Editorial, I will discuss the relevance of the IF to the Journal and offer some suggestions as to how it might be given new impetus. I will conclude by briefly discussing some challenges associated with assessing impact in the context of health technology assessment (HTA).

THE GAP BETWEEN ECONOMIC EVALUATIONS AND CLINICAL PRACTICE: A SYSTEMATIC REVIEW OF ECONOMIC EVALUATIONS ON DABIGATRAN FOR ATRIAL FIBRILLATION.

OBJECTIVES: As model-based economic evaluations (MBEEs) are widely used to make decisions in the context of policy, it is imperative that they represent clinical practice. Here, we assess the relevance of MBEEs on dabigatran for the prevention of stroke in patients with atrial fibrillation (AF). METHODS: We performed a systematic review on the basis of a developed questionnaire, tailored to oral anticoagulation in patients with AF. Included studies had a full body text in English, compared dabigatran with a vitamin K antagonist, were not dedicated to one or more subgroup(s), and yielded an incremental cost-effectiveness ratio. The relevance of all MBEEs was assessed on the basis of ten context-independent factors, which encompassed clinical outcomes and treatment duration. The MBEEs performed for the United States were assessed on the basis of seventeen context-dependent factors, which were related to the country's target population and clinical environment. RESULTS: The search yielded twenty-nine MBEEs, of which six were performed for the United States. On average, 54 percent of the context-independent factors were included per study, and 37 percent of the seventeen context-dependent factors in the U.S. STUDIES: The share of relevant factors per study did not increase over time. CONCLUSIONS: MBEEs on dabigatran leave out several relevant factors, limiting their usefulness to decision makers. We strongly urge health economic researchers to improve the relevance of their MBEEs by including context-independent relevance factors, and modeling context-dependent factors befitting the decision context concerned.

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases. Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.