Clinical Trials In Rare Diseases Research Articles

Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease

BackgroundClinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context.MethodsAll possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant’s response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses (“win ratio”), with ties excluded.ResultsIn the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30–4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13–3.62, p = 0.018).ConclusionThe win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Qualified placebo for trials of herbal medicine treatment in rare diseases? A cross-sectional analysis

BackgroundWhile substantial placebos have been used in herbal medicine (HM) clinical trials for rare diseases, the use and quality of reporting of HM-placebo remain unclear. We aim to describe the use of HM-placebo in clinical trials for rare diseases and determine the quality of reporting in these trials.MethodsThis is a cross-sectional study. We searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure, WanFang database, China Science and Technology Journal Database, National Institute of Informatics Support Academic Information Services, ClinicalTrials.gov and Chinese Clinical Trials Registry from their inception date to 14 February 2023 to identify registered and published trials that use placebos as a comparator in rare diseases. We collected data on placebo use reporting and the efficacy and safety of placebo. Descriptive statistics, the Chi-square test, and Binary multivariable logistic regression analysis were used to determine the placebo characteristics of the HM trial and its effect on reporting.ResultsAmong the 55 studies, we included that with a median administration time of placebo of 84 days (IQR 42–180) and a median placebo sample size of 30 (IQR 24–54). About half of the trials (27, 49.1%) did not provide their ethical approvals, and one trial had details of informed consent. None of the studies were fully reported and more than half of the items reported less than 50%. A total of 10 trials (18.2%) of placebo has active ingredients even though none of them performed pharmacological inert tests. Of the 29 studies with available data on adverse events, 5 (17.2%) trials did not show a better safety profile in the placebo group. Under the context that a relatively high-quality report is defined as a report with more than 9 items, there was a statistically significant difference between the two groups in the rate of relatively high-quality reports of the administration time (p = 0.047, OR 0.10, 95% CI 0.01 to 0.90), but the results are not representative.ConclusionThe overall situation of HM-placebo in the field of rare diseases was poor. In particular, the placebo is tied to the quality of trials, and poor placebo hinders the generation of high-quality evidence for herbal clinical trials in the field of rare diseases. We summarize the current methods of assessment involved in the use of placebos and propose various considerations for placebos in different contexts. Our study can greatly promote rare disease researchers to review the quality of their placebo and clinical trials. It is imperative to guarantee that meticulously conducted research generates clinical evidence of the highest caliber. We also expect that in the future, more rigorous relevant standards about the reporting and design of HM-placebo will be developed. High-quality clinical trials are the prerequisite for the wide clinical application of herbal medicines for rare diseases.

Study methodology and insights from the palovarotene clinical development program in fibrodysplasia ossificans progressiva

BackgroundThe design of clinical trials in rare diseases is often complicated by a lack of real-world translational knowledge. Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder characterized by skeletal malformations and progressive heterotopic ossification (HO). Palovarotene is a selective retinoic acid receptor gamma agonist. Here, we describe the methodology of three studies in the palovarotene clinical development program in FOP and discuss insights that could inform future research, including endpoint suitability and the impact of trial design.MethodsPVO-1A-001 (NCT02322255) was a prospective, protocol-specified, longitudinal FOP natural history study (NHS). PVO-1A-201 (NCT02190747) was a randomized, double-blind, placebo-controlled phase II trial; PVO-1A-202 (NCT02279095) was its open-label extension. Trial designs, including treatment regimens and imaging assessments, were refined between PVO-1A-201 and PVO-‍1A-202, and within PVO-1A-202, based on emerging data as the studies progressed. Palovarotene doses were administered using a flare-up treatment regimen (higher dose for 2/4 weeks, followed by lower dose for 4/≥8 weeks; from flare-up onset), with or without accompanying chronic (daily) treatment. Flare-up and disease progression outcomes were assessed, including incidence and volume of new HO during flare-ups and/or annually, as well as other clinical, patient-reported, and exploratory outcomes. Safety was monitored throughout all studies.ResultsOverall, 114 and 58 individuals with FOP were enrolled in the NHS and phase II trials, respectively. Results of the NHS and PVO-1A-201 were published in 2022; complete results of PVO-1A-202 will be publicly available in due course. Together the studies yielded important information on endpoint suitability, including that low-dose whole-body computed tomography was the optimum imaging modality for assessing HO progression annually and that long study durations are needed to detect substantial changes in functional and patient-reported outcomes.ConclusionsA flexible clinical development program is necessary for underexplored rare diseases to overcome the many challenges faced. Here, the NHS provided a longitudinal evaluation of FOP progression and interventional trials were based on emerging data. The studies described informed the design and endpoints implemented in the phase III MOVE trial (NCT03312634) and provide a foundation for future clinical trial development.Trial registrationNCT02322255 (registered 23/12/2014); NCT02190747 (registered 15/07/2014); NCT02279095 (registered 30/10/2014).

2017-2023: state of the art of gene therapies in rare diseases in Europe: the dynamics of clinical R&D, new approved treatments and expected therapies in the pipelines

Aim: Gene therapies have been tested over the past three decades, and after a first market authorization in 2017, the field is starting to deliver. The study aims to analyze the current development dynamics of gene therapies for rare diseases using the GENOTRIAL database®, which gathers information on gene therapy clinical trials and studies conducted between 2017 and 2023 in Europe. Methods: The study involved extracting and filtering clinical trial data from the EudraCT database. Trials with the keyword "Gene Therapy" were selected and filtered using the "Rare disease" filter. Manual verification was conducted to ensure that the selected trial only concerned gene therapy treatments authorized in Europe for rare diseases in phases I to III. A total of 300 European country-related clinical investigations representing a total of 93 European-specific clinical studies were included in the GENOTRIAL database. The trials were classified by development phases, temporal status, sponsors and investigating countries, rare diseases with their related therapeutic area, and approval regulatory information of the identified gene therapies. Results: Analysis reveals that rare diseases present a promising area for gene therapy development. On average, eight rare disease gene therapy trials are launched each year in Europe. The main sponsors of European clinical trials of gene therapies for rare diseases are from US, followed by the United Kingdom and France. The United Kingdom conducts the highest number of investigations in Europe, followed by France, Italy, Spain, and Germany. Nutritional and metabolic diseases are the most represented therapeutic area, followed by rare oncology, blood and lymphatic diseases, and ocular diseases. The analysis identifies 73 gene therapy medical products covering 35 diseases at various stages of development, with 12 new therapies approved in recent years for 8 rare diseases, while 15 other gene therapies are at an advanced stage of phase III in their development plan for 11 other rare diseases. Conclusion: Gene therapy has shown significant progress and potential in treating rare genetic diseases. Europe has emerged as a promising region for gene therapy clinical trials in rare diseases. Efforts are now required to catch up with the USA and UK regarding the number of clinical trials sponsored by European groups.

Knowledge and Attitudes of Clinical Trials among Patients with Rare Diseases and the Guardians in China.

Conducting of clinical trials for rare diseases faces multiple challenges. Patients' cognition and attitude toward clinical trials are crucial, which may affect their participation and compliance, and affect the schedule of clinical trials eventually. This study aims to explore the knowledge and attitudes of clinical trials of patients with rare diseases or patients' guardians. An anonymous cross-sectional survey was conducted from November 1, 2021, to November 30, 2021. A total of 1131 valid questionnaires were included. Among them, 417 were filled in by the patients themselves, and 714 were answered by the patients' guardians. The average score of clinical trial knowledge of the patients (8.25) was lower than that of the guardians (8.85). The willingness of the patients to participate in clinical trials was high (4.28), and the willingness of the patients' guardians was also high for patients to participate in clinical trials (4.35). The main promoting factors of clinical trial participation were the possibility of curing the disease. The main hindering factors of participation in clinical trials were lack of access to clinical trial information and concern about the safety and effectiveness of the trial drug. In conclusion, most respondents had some basic knowledge of clinical trials and high willingness to participate in clinical trials. But there were some cognitive deficiencies about clinical trials and many hindering factors to participate in clinical trials. Clinical trials of rare diseases should be patient-centered and truly meet the unmet clinical, psychological, and social needs of patients with rare diseases.

Leigh syndrome global patient registry: uniting patients and researchers worldwide

BackgroundLeigh Syndrome (LS) is a rare genetic neurometabolic disorder, that leads to the degeneration of the central nervous system and subsequently, early death. LS can be caused by over 80 mutations in mitochondrial or nuclear DNA. Patient registries are important for many reasons, such as studying the natural history of the disease, improving the quality of care, and understanding the healthcare burden. For rare diseases, patient registries are significantly important as patient numbers are small, and funding is limited. Cure Mito Foundation started a global patient registry for LS in September 2021 to identify and learn about the LS patient population, facilitate clinical trial recruitment, and unite international patients and researchers. Priorities were to allow researchers and industry partners to access data at no cost through a clear and transparent process, active patient engagement, and sharing of results back to the community.ResultsPatient registry platform, survey design, data analysis process, and patient recruitment strategies are described. Reported results include demographics, diagnostic information, symptom history, loss of milestones, disease management, healthcare utilization, quality of life, and caregiver burden for 116 participants. Results show a high disease burden, but a relatively short time to diagnosis. Despite the challenges faced by families impacted by Leigh syndrome, participants, in general, are described as having a good quality of life and caregivers are overall resilient, while also reporting a significant amount of stress.ConclusionThis registry provides a straightforward, no-cost mechanism for data sharing and contacting patients for clinical trials or research participation, which is important given the recruitment challenges for clinical trials for rare diseases. This is the first publication to present results from a global patient registry for Leigh Syndrome, with details on a variety of patient-specific and caregiver outcomes reported for the first time. Additionally, this registry is the first for any mitochondrial disease with nearly 70% of participants residing outside of the United States. Future efforts include continued publication of results and further collaboration with patients, industry partners, and researchers.

Trend of clinical trials of new drugs for rare diseases in China in recent 10 years

BackgroundRare disease is a general term for a disease that affects a small number of people but recognized as a global public health priority. Governments worldwide are paying more and more attention to the academical research and drug investment of rare diseases. The conduct of rare disease clinical trials is still difficult, despite the promotion of government policies and the awakening of social consciousness. In this article, we outlined the characteristics and obstacles of clinical trials of rare diseases in China and expected to provide reference for subsequent clinical trials in this field.ResultsIn recent years, China has made some progress in clinical trials of rare diseases in the past 10 years. There were 481 clinical trials on rare diseases in total, covering more than 10 rare diseases with high incidence. Clinical trial applications on rare diseases for a total of 481 were submitted and with an average annual growth rate of 28.2% from 2013 to 2022. The number of clinical trial application for rare diseases in 2016 dramatically increased by 80% compared to 2015 due to the policy document issued by China for clinical research in rare diseases in 2015. Besides, about 70% of applications registering for clinical trials could recruit subjects as expected. Despite this, the number of clinical trials of rare diseases in China was less compared with the United States, Europe and Japan, and the types of infant drugs were limited to biological products and chemical drugs lacking other new treatments.ConclusionsEfforts have been made in recent years to develop clinical research on rare diseases in China. The number of clinical trials for rare diseases in China was growing steadily every year, which was inseparable from the support of the country, society and rare disease patients. Still, there was a large gap between China and other developed countries in this field and this merit further investigation.

Empirical bayes approach for dynamic bayesian borrowing for clinical trials in rare diseases.

Application of Bayesian methods is one the tools that can be used to face the multiple challenges that are met when clinical trials must be conducted in rare diseases. We propose in this work to use a dynamic Bayesian borrowing approach, based on a mixture prior, to complement the control arm of a comparative trial and estimate the mixture parameter by an Empirical Bayes approach. The method is compared, using simulations, with an approach based on a pre-specified (non-adaptive) informative prior. The simulation study shows that the proposed method exhibits similar power as the non-adaptive prior and drastically reduce type I error in case of severe discrepancy between the informative prior and the study control arm data. In case of limited discrepancy between the informative prior and the study control arm data, then our proposed adaptive prior does not reduce the inflation of the type I error.

The unique challenges of clinical trials in rare disease: A regulatory writer’s perspective

Designing clinical trials in rare diseases comes with a specific set of challenges including limited knowledge around the natural history of a disease, small sample size available for trial participation, regulatory guidance that is not calibrated to the rare disease context, manufacturing and supply issues, and safety and financial risks. Here, we discuss some of these potential challenges and how, through proactive early engagement with key opinion leaders, regulatory bodies, and patient groups, a cohesive and strategic clinical development plan can be created to provide the strongest foundations when marketing approval is sought.

Direct-to-Consumer Recruitment Methods via Traditional and Social Media to Aid in Research Accrual for Clinical Trials for Rare Diseases: Comparative Analysis Study.

Recruitment into clinical trials is a challenging process, with as many as 40% of studies failing to meet their target sample sizes. The principles of direct-to-consumer (DTC) advertising rely upon novel marketing strategies. The ability to reach expansive audiences in the web-based realm presents a unique opportunity for researchers to overcome various barriers to enrollment in clinical trials. Research has investigated the use of individual web-based platforms to aid in recruitment and accrual into trials; however, a gap in the literature exists, whereby multiple mass communication platforms have yet to be investigated across a range of clinical trials. There is a need to better understand how individual factors combine to collectively influence trial recruitment. We aimed to test whether DTC recruitment of potentially eligible study participants via social media platforms (eg, Facebook [Meta Platforms Inc] and Twitter [Twitter Inc]) was an effective strategy or whether this acted as an enhancement to traditional (eg, email via contact registries) recruitment strategies through established clinical research sites. This study tested multiple DTC web-based recruitment efforts (Facebook, Twitter, email, and patient advocacy group [PAG] involvement) across 6 national and international research studies from 5 rare disease consortia. Targeted social media messaging, social media management software, and individual study websites with prescreening questions were used in the Protocol for Increasing Accrual Using Social Media (PRISM). In total, 1465 PRISM website referrals occurred across all 6 studies. Organic (unpaid) Facebook posts (676/1465, 46.14%) and Rare Diseases Clinical Research Network patient contact registry emails (461/1465, 31.47%) represented the most successful forms of engagement. PRISM was successful in accumulating a 40.1% (136/339) lead generation (those who screened positive and consented to share their contact information to be contacted by a clinical site coordinator). Despite the large number of leads generated from PRISM recruitment efforts, the number of patients who were subsequently enrolled in studies was low. Across 6 studies, 3 participants were ultimately enrolled, meaning that 97.8% (133/136) of leads dropped off. The results indicate that although accrual results were low, this is consistent with previously documented challenges of studying populations with rare diseases. Targeted messaging integrated throughout the recruitment process (eg, referral, lead, and accrual) remains an area for further research. Key elements to consider include structuring the communicative workflow in such a way that PAG involvement is central to the process, with clinical site coordinators actively involved after an individual consents to share their contact information. Customized approaches are needed for each population and research study, with observational studies best suited for social media recruitment. As evidenced by lead generation, results suggest that web-based recruitment efforts, coupled with targeted messaging and PAG partnerships, have the potential to supplement clinical trial accrual.

Study design challenges and strategies in clinical trials for rare diseases: Lessons learned from pantothenate kinase-associated neurodegeneration.

Substantial challenges in study design and methodology exist during clinical trial development to examine treatment response in patients with a rare disease, especially those with predominant central nervous system involvement and heterogeneity in clinical manifestations and natural history. Here we discuss crucial decisions which may significantly impact success of the study, including patient selection and recruitment, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. We review strategies for the successful development of a clinical trial to evaluate treatment of a rare disease with a focus on inborn errors of metabolism (IEMs) that present with movement disorders. The strategies presented using pantothenate kinase-associated neurodegeneration (PKAN) as the rare disease example can be applied to other rare diseases, particularly IEMs with movement disorders (e.g., other neurodegeneration with brain iron accumulation disorders, lysosomal storage disorders). The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families. In addition to these strategies, we discuss the urgent need for a paradigm shift within the regulatory processes to help accelerate medical product development and bring new innovations and advances to patients with rare neurodegenerative diseases who need them earlier in disease progression and prior to clinical manifestations.

Power analysis for idiographic (within-subject) clinical trials: Implications for treatments of rare conditions and precision medicine.

Power analysis informs a priori planning of behavioral and medical research, including for randomized clinical trials that are nomothetic (i.e., studies designed to infer results to the general population based on interindividual variabilities). Far fewer investigations and resources are available for power analysis of clinical trials that follow an idiographic approach, which emphasizes intraindividual variabilities between baseline (control) phase versus one or more treatment phases. We tested the impact on statistical power to detect treatment outcomes of four idiographic trial design factors that are under researchers' control, assuming a multiple baseline design: sample size, number of observations per participant, proportion of observations in the baseline phase, and competing statistical models (i.e., hierarchical modeling versus piecewise regression). We also tested the impact of four factors that are largely outside of researchers' control: population size, proportion of intraindividual variability due to residual error, treatment effect size, and form of outcomes during the treatment phase (phase jump versus gradual change). Monte Carlo simulations using all combinations of the factors were sampled with replacement from finite populations of 200, 1750, and 3500 participants. Analyses characterized the unique relative impact of each factor individually and all two-factor combinations, holding all others constant. Each factor impacted power, with the greatest impact being from larger treatment effect sizes, followed respectively by more observations per participant, larger samples, less residual variance, and the unexpected improvement in power associated with assigning closer to 50% of observations to the baseline phase. This study's techniques and R package better enable a priori rigorous design of idiographic clinical trials for rare diseases, precision medicine, and other small-sample studies.

Muscle Channelopathies

This article describes the clinical features, diagnosis, pathophysiology, and management of nondystrophic myotonia and periodic paralysis. An increasing awareness exists about the genotype-phenotype overlap in skeletal muscle channelopathies, and thus genetic testing is needed to make a definitive diagnosis. Electrodiagnostic testing in channelopathies is highly specialized with significant overlap in various mutation subtypes. Randomized clinical trials have now been conducted in these disorders with expanded treatment options for patients with muscle channelopathies. Skeletal muscle channelopathies are rare heterogeneous conditions characterized by lifelong symptoms that require a comprehensive management plan that includes pharmacologic and nonpharmacologic interventions. The significant variability in biophysical features of various mutations, coupled with the difficulties of performing clinical trials in rare diseases, makes it challenging to design and implement treatment trials for muscle channelopathies.

Acesso a medicamentos para doenças raras no pós-estudo: revisão integrativa

Abstract This study is an integrative literature review to analyze the scientific production about post-trial drug access by participants of clinical trials for rare diseases. The search was carried out in the Virtual Health Library, Embase, PubMed, SciELO, Scopus and Web of Science databases, covering 21 studies. Two categories emerged from the analysis: clinical research with orphan drugs and market regulation; and access to orphan drugs: background, globalization and the right to health. The first analyzes issues related to the number of patients with rare diseases, the efficacy and safety of these studies and the cost and price of medications. The second addresses the historical background of post-trial access, the globalization of clinical trials and the difficulties to ensure the right to post-trial access to orphan drugs. Few articles addressed post-trial drug access by participants with rare diseases as a central issue, which points to the importance of further studies on this subject.

Cerebrospinal Fluid Proteomics in Friedreich Ataxia Reveals Markers of Neurodegeneration and Neuroinflammation

Clinical trials in rare diseases as Friedreich ataxia (FRDA) offer special challenges, particularly when multiple treatments become ready for clinical testing. Regulatory health authorities have developed specific pathways for “orphan” drugs allowing the use of a validated biomarker for initial approval. This study aimed to identify changes in cerebrospinal fluid (CSF) proteins occurring in FRDA patients that may be potential biomarkers in therapeutic trials. CSF was obtained from 5 FRDA patients (4 females, 1 male) from the Brussels site of the European Friedreich Ataxia Consortium for Translational Studies (EFACTS). Two patients were ambulatory, three used a wheelchair. Residual CSF samples from 19 patients who had had a lumbar puncture as part of a diagnostic workup were used as controls. All CSF samples had normal cells, total protein and glucose levels. Proteins were identified by label-free data-dependent acquisition mass spectrometry (MS) coupled to micro-high performance liquid chromatography. We found 172 differentially expressed proteins (DEPs) (92 up, 80 down) between FRDA patients and controls at P < 0.05, 34 DEPs (28 up, 6 down) at P < 0.0001. Remarkably, there was no overlap between FRDA patients and controls for seven upregulated and six downregulated DEPs. Represented pathways included extracellular matrix organization, signaling, the complement cascade, adhesion molecules, synaptic proteins, neurexins and neuroligins. This study supports the hypothesis that the quantitative analysis CSF proteins may provide robust biomarkers for clinical trials as well as shed light on pathogenic mechanisms. Interestingly, DEPs in FA patients CSF point to neurodegeneration and neuroinflammation processes that may respond to treatment.

Use of funded multicenter prospective longitudinal databases to inform clinical trials in rare diseases-Examination of cholestatic liver disease in Alagille syndrome.

The conduct of long‐term conventional randomized clinical trials in rare diseases is very difficult, making evidenced‐based drug development problematic. As a result, real‐world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2‐year prospective follow‐up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (−1.43 [0.28] −1.99, −0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (−65.2 [16.2] −98.3, −32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real‐world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

Randomized Controlled Trial Data for New Drug Application for Rare Diseases in Japan.

High-quality evidence is often not obtained in the clinical trials of rare diseases because these trials tend to be smaller in size and non-controlled. We investigated the potential factors associated with the need for randomized controlled trials (RCTs) in the clinical data package for new drug applications for rare diseases in Japan. This study focused on 130 drugs with orphan drug designation approved in Japan between April 2004 and March 2020. Multivariable regression analysis showed that the prevalence (odds ratio [OR] 3.21, 95% confidence interval [CI] 1.18-8.6) and the type of primary endpoint (OR 6.66, 95% CI 2.41-18.37) were associated with the need for RCTs in the clinical data package in Japan. Our findings highlight the importance of adequate understanding of the target disease in new drug development for rare diseases.

Designing clinical trials for rare diseases: unique challenges and opportunities.

Orphan drug development is a rapidly expanding field. Nevertheless, clinical trials for rare diseases can present inherent challenges. Optimal study design and partnerships between academia and industry are therefore required for the successful development, delivery and clinical approval of effective therapies in this group of disorders.

A preliminary application of a haemophilia value framework to emerging therapies in haemophilia.

Emergence of new therapies are anticipated to improve clinical outcomes and quality of life of persons with haemophilia. Challenges in conducting randomized clinical trials in rare diseases have resulted in a lack of direct head-to-head comparisons to support value-based decision-making between different treatments. We conducted a literature review for new and emerging haemophilia A and B therapies (extended half-life [EHL] replacement factor, non-replacement therapies [NRT], and gene therapies [GT]) to identify differentiating patient-centred outcomes defined previously in a haemophilia value framework. Since the literature included all publication types (e.g., surveys, modelling studies, commentaries/reviews), collected data were assigned level of evidence scores. Across different classes of therapies, bleeding was determined as the most frequently reported differentiating outcome, with EHL, NRT, and GT each demonstrating an advantage over comparator replacement therapies. EHL therapies for haemophilia A and B and NRT for haemophilia A showed good representation across Tier 1 outcomes (health status achieved/retained), while more publications were identified with Tier 2 (process of recovery) outcomes for NRT than EHL or GT. In Tier 3 (sustainability of health), frequency of breakthrough bleeds represented a differentiating outcome for EHL (both haemophilia A and B), NRT (haemophilia A only), and GT (haemophilia B only), whereas sustained good health was differentiating for most comparisons. We demonstrate the utility of the haemophilia value framework as a common core outcome set for effectively comparing therapies. Application of this framework will serve as a useful decision-making tool for patients, clinicians, and within health technology assessments. With the emergence of high-cost, paradigm changing treatments across multiple areas of medicine, we, the haemophilia community, need to be equipped to meet the growing demands for more rigorous evidence-based value assessments using the tools expected by assessors. The traditional access toolbox needs to evolve to meet the paradigm shift in treatment options. Value can no longer be defined by annualized bleed rates alone. To realize the full impact of new therapies, we need to utilize tools, such as a value framework, to organize evidence, identify data gaps, and assess patient-defined, meaningful outcomes across a multi-faceted dimension. The haemophilia value framework is an effective tool for organizing the available evidence and identifying gaps in the evidence. This can be used for assessing the value of emerging therapies in haemophilia utilizing data generated through randomized clinical trials and real world evidence generation. This is a call for incorporating the Value Framework into official submissions to authorities, as it captures a broader range of outcomes, including patient meaningful outcomes, in ways that better assess the potential benefits of new therapies.

Natural History Studies in NCL and Their Expanding Role in Drug Development: Experiences From CLN2 Disease and Relevance for Clinical Trials.

Conducting clinical trials in rare diseases is challenging. In trials that aim to use natural history control cohorts for evaluation of efficacy, lack of data on natural history of disease prolongs development of future therapies significantly. Therefore, collection of valid natural history data in clinical settings is needed to advance drug development. These data need to fulfill requirements on type of collection, quantifiable measures on the course of disease, verification and monitoring as well as compliance to strict data protection and sharing policies. Disease registries can be a source for patient data. Late-infantile CLN2 disease is characterized by rapid psychomotor decline and epilepsy. Natural-history data of 140 genotype-confirmed CLN2 patients from two independent, international cohorts were analyzed in a natural history study. Both datasets included quantitative ratings with disease-specific clinical scores. Among 41 patients for whom longitudinal assessments spanning an extended disease course were available within the DEM-CHILD DB (an international NCL disease patient database, NCT04613089), a rapid loss of motor and language abilities was documented in quantitative detail. Data showed that the course of disease in late-infantile CLN2 disease is highly predictable with regard to the loss of language and motor function and that the results were homogeneous across multiple and international sites. These data were accepted by EMA and FDA as valid natural-history controls for the evaluation of efficacy in experimental therapies for CLN2 disease and led to an expedited approval of intracerebroventricular enzyme replacement therapy with cerliponase alpha in May 2017.