Characteristics of orphan drug applications that fail to achieve marketing approval in the USA

Heemstra, H; Leufkens, Hubert G. M.; Rodgers, R.P. Channing; Xu, Kui; Voordouw, Bettie; Braun, M. Miles

doi:10.1016/j.drudis.2010.11.006

Cited by 36 publications

(30 citation statements)

References 31 publications

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“…The use of these surrogate endpoints seems to have contributed significantly to the rise in numbers of new OMPs [7]. The clinical importance of those surrogate endpoints has however been questioned, as there is not always a strong relationship with clinical meaningful endpoints [5,18]. Still, obtaining marketing authorization based solely on hard endpoints is not always feasible and could jeopardize early access to the market.…”

Section: Discussionmentioning

confidence: 99%

Clinical evidence for orphan medicinal products-a cause for concern?

Picavet

Cassiman

Hollak

et al. 2013

Orphanet J Rare Dis

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BackgroundThe difficulties associated with organising clinical studies for orphan medicinal products (OMPs) are plentiful. Recent debate on the long-term effectiveness of some OMPs, led us to question whether the initial standards for clinical evidence for OMPs, set by the European Medicines Agency (EMA) at the time of marketing authorization, are too low. Therefore, the aim of this study was to quantitatively evaluate the characteristics and quality of clinical evidence that is presented for OMPs to obtain marketing authorization in Europe, using the new and validated COMPASS tool.MethodsWe quantitatively assessed the characteristics and quality of clinical evidence of the pivotal studies of 64 OMPs as described in the European Public Assessment Report and/or the Scientific Discussion document prepared by the Committee for Human Medicinal Products of the EMA.ResultsThe 64 OMPs were altogether authorized for 78 orphan indications, for which 117 studies were identified as 'pivotal’ or 'main’ studies. In approximately two thirds of the studies, the allocation was randomized (64.8%) and a control arm was used (68.5%). Half of the studies applied some type of blinding. Only a minority (26.9%) of the studies included a Quality-of-Life (QoL) related endpoint, of which a third claim an improvement in QoL. Upon analyzing the quality of reporting, we found that some aspects (i.e. the endpoints, the sampling criteria, and the interventions) are well described, whereas other items (i.e. a description of the patients and of potential biases) are not reported for all studies.ConclusionsIn conclusion, the pivotal studies that are the basis for marketing authorization of OMPs are a cause for concern, as they exhibit methodological flaws i.e. the lack of QoL-related endpoints as outcome, lack of blinding in the study design and the use of surrogate endpoints. Additionally, there are shortcomings in the reporting of those studies that complicate the interpretation. A more demanding regulatory process for OMPs is needed to guide evidence-based clinical decision-making.

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Section: Discussionmentioning

confidence: 99%

Clinical evidence for orphan medicinal products-a cause for concern?

Picavet

Cassiman

Hollak

et al. 2013

Orphanet J Rare Dis

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“…choice of endpoints and target population), experience of the sponsor, interaction with the legal authorities and disease-specific factors, i.e. the prevalence, disease class, and scientific output [26–28]. By definition, orphan drug development is challenged by small populations.…”

Section: Discussionmentioning

confidence: 99%

Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis

et al. 2016

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BackgroundEpilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations.MethodsQuantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria.ResultsWithin the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years).ConclusionOrphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.

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“…Multivariate logistic regression analysis was performed with 358 orphan drugs for which official regulatory decision (ie, approved or rejected [withdrawn]) had been confirmed. 17,18 To avoid a possible impact from censored data, we also implemented 2 survival regression analyses using 398 orphan drugs, including the 40 drugs for which a regulatory decision had not been reached by the end of our observation period. In the Cox proportional hazard analysis, approval was considered the sole event, and in the competitive risk regression analysis, approval and rejection were considered the competing events.…”

Section: Methodsmentioning

confidence: 99%

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval

Harada

Toriyabe

Ono

2019

The Journal of Clinical Pharma

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The basic components of regulatory and supporting policies for orphan drug development appear similar between the United States and Japan, but drugs designated as orphan drugs have been different between the 2 countries. The probabilities of development success (ie, marketing approval) in designated orphan drugs have also been significantly different. In this study, we analyzed recent outcomes of development for orphan drugs designated from 1993 to 2017 in Japan, considering their development and approval status in the United States. Our analysis showed that success for orphan drug development in Japan was apparently associated with prior approval status in the United States. Company size, orphan development experience, and patient enrichment were also positively associated with successful marketing approval. Although similar designations and priority review systems for orphan drugs have been enacted, economic incentives and regulatory conditions provided by the systems seem to be different between the 2 countries, which may lead to varied performance in orphan designation and approval. We need to pay close attention to the impact of industrial global development strategies when comparing the outcomes and performance of different orphan drug promotion systems.

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Characteristics of orphan drug applications that fail to achieve marketing approval in the USA

Cited by 36 publications

References 31 publications

Clinical evidence for orphan medicinal products-a cause for concern?

Clinical evidence for orphan medicinal products-a cause for concern?

Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis

Survey of Japanese Orphan Drug Program: Factors Related to Successful Marketing Approval

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