Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints

Kakkis, Emil; O’Donovan, Mary; Cox, Gerald F.; Hayes, Mark P.; Goodsaid, Federico; Tandon, P.K.; Furlong, Pat; Boynton, Susan; M, Božić; Orfali, M; Thornton, Mark

doi:10.1186/s13023-014-0195-4

Cited by 49 publications

(38 citation statements)

References 5 publications

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“…Within the boundaries of our study, rare disease patients and their caregivers chose to adopt a realist view and attributed the highest importance to drug response potential, highlighting the importance of developing new targeted therapies, diagnostic tests and expanding the use of biomarkers [46–49] to better predict health benefit. We may also interpret this finding as a result of ‘pragmatic hope’, as discussed earlier.…”

Section: Discussionmentioning

confidence: 99%

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers

Morel

Aymé

Cassiman

et al. 2016

Orphanet J Rare Dis

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BackgroundRare disease patients and caregivers face uncommon, serious, debilitating conditions often characterised by poor prognosis and limited treatment options. This study aimed to explore what they consider of value when choosing between hypothetical therapeutic options and to quantify both their benefit-risk preferences and the influence of disease context.MethodsA mixed-methods survey with patients and caregivers was conducted in the United Kingdom across a range of rare diseases. Discrete-choice experiments that compared hypothetical treatment profiles of benefits and risks were used to measure respondent preferences across a set of seven attributes related to health outcomes, safety, and process of care. Bespoke questions on current disease management and the joint use of the 12-item WHODAS 2.0 questionnaire and of two Likert scales capturing self- and proxy-assessed disease-induced threat to life and impairment were implemented to describe disease context. Additionally, qualitative insights on the definitions of value and risk were collected from respondents.ResultsFinal study sample included 721 patients and 152 informal caregivers, across 52 rare diseases. When choosing between hypothetical novel treatments for rare diseases, respondents attributed most importance to drug response, risk of serious side effects, and the ability to conduct usual activities while on treatment. In contrast, attributes related to treatment modalities were the least important. Respondents expressed a willingness to accept risks in hopes of finding some benefit, such as a higher chance of drug response or greater health improvement potential. Increasing disease severity, impairment or disability, and the lack of effective therapeutic options were shown to raise significantly the willingness to gain benefit through increased risk.ConclusionsThis is the first study performing a quantitative discrete choice experiment amongst patients and caregivers across 52 rare conditions. It enables a more detailed understanding of the relationship between disease context, treatment attributes and the degree of risk respondents are willing to take to gain a specific degree of benefit. Researchers of novel therapeutics for rare diseases should be encouraged to invest in preference elicitation studies to generate rigorous patient evidence and specific regulatory guidance should be issued to acknowledge their importance and their use in marketing authorisations.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0444-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Quantifying benefit-risk preferences for new medicines in rare disease patients and caregivers

Morel

Aymé

Cassiman

et al. 2016

Orphanet J Rare Dis

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“…Mapping of the pathophysiologic and molecular features in Fabry-naïve and ERT groups providing the link from disease cause to final major clinical outcomes [34]. The highlighted molecular features from the meta-analysis demonstrates an opposite regulation trend in the Fabry-naïve and ERT groups.…”

Section: Figurementioning

confidence: 99%

Integrative Systems Biology Investigation of Fabry Disease

Fernandes

Husi

2016

Diseases

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Fabry disease (FD) is a rare X-linked recessive genetic disorder caused by a deficient activity of the lysosomal enzyme alpha-galactosidase A (GLA) and is characterised by intra-lysosomal accumulation of globotriaosylceramide (Gb3). We performed a meta-analysis of peer-reviewed publications including high-throughput omics technologies including naïve patients and those undergoing enzyme replacement therapy (ERT). This study describes FD on a systems level using a systems biology approach, in which molecular data sourced from multi-omics studies is extracted from the literature and integrated as a whole in order to reveal the biochemical processes and molecular pathways potentially affected by the dysregulation of differentially expressed molecules. In this way new insights are provided that describe the pathophysiology of this rare disease. Using gene ontology and pathway term clustering, FD displays the involvement of major biological processes such as the acute inflammatory response, regulation of wound healing, extracellular matrix (ECM) remodelling, regulation of peptidase activity, and cellular response to reactive oxygen species (ROS). Differential expression of acute-phase response proteins in the groups of naïve (up-regulation of ORM1, ORM2, ITIH4, SERPINA3 and FGA) and ERT (down-regulation of FGA, ORM1 and ORM2) patients could be potential hallmarks for distinction of these two patient groups.

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“…При этом 24 редких заболевания/группы болезней обеспечиваются лекарственными препаратами и лечеб-ным питанием за счет средств регионального бюджета. Их перечень утвержден Постановлением Правительства РФ от 26.04.2012 № 403 «О порядке ведения Федерального регистра лиц, страдающих жизнеугрожающими и хро-ническими прогрессирующими редкими (орфанными) заболеваниями, приводящими к сокращению продол-жительности жизни граждан или их инвалидности, и его регионального сегмента» [12]. В настоящее время в мире доступно лишь около 400 лекарственных средств для лечения 250 редких заболеваний [13,14].…”

Section: актуальностьunclassified

“…Закупка препаратов осуществляется в рамках тендера, но поскольку в 74,5% случаев закупаемое орфанное лекарственное средство поставляется производителем-монополистом, а в 75% торги не приводят к снижению цены, отдельные авторы считают эту систему избыточ-ной [54]. В этом же Постановлении изложены прави-ла ведения Федерального регистра лиц, страдающих жизнеугрожающими и хроническими прогрессирующи-ми редкими (орфанными) заболеваниями, приводящими к сокращению продолжительности жизни граждан или их инвалидности, и его регионального сегмента [12]. Наконец, в Федеральном законе от 12.04.2010 № 61-ФЗ «Об обращении лекарственных средств» закрепляется определение орфанных лекарственных средств: «лекар-ственные препараты, предназначенные исключительно для диагностики или патогенетического лечения (лече-ния, направленного на механизм развития заболевания) редких (орфанных) заболеваний», а также закрепляется возможность ускоренной экспертизы при их регистрации (продолжительностью до 80 дней).…”

Section: обзор литературыunclassified