Safety-Related Regulatory Actions for Orphan Drugs in the US and EU

Heemstra, H; Giezen, Thijs J.; Mantel‐Teeuwisse, Aukje K.; Vrueh, Remco L. A. de; Leufkens, Hubert G. M.

doi:10.2165/11319870-000000000-00000

Cited by 32 publications

(33 citation statements)

References 19 publications

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“…safety-related market withdrawals, post-approval black-box warnings, or written communication to healthcare professionals) is lower with orphan drugs than with non-orphan drugs [40]. In addition, clinical trials for the approved compounds were short and small.…”

Section: Discussionmentioning

confidence: 99%

“…Small sample sizes may be sufficient for registration trials especially when the size of the effect is large, such as for stiripentol in Dravet syndrome, but this may be an issue in the sensitivity of the orphan drug approach to detect less obvious safety signals. Indeed, the lower number of safety-related regulatory actions could be attributed rather to lower utilization, which is accompanied by lower chances to detect a safety issue, than indicating greater safety for orphan drugs [40]. A close follow-up of treatment outcomes is desirable because antiepileptic drugs in clinical practice are prescribed over years, which is not reflected in the design of clinical registration studies.…”

Section: Discussionmentioning

confidence: 99%

“…A close follow-up of treatment outcomes is desirable because antiepileptic drugs in clinical practice are prescribed over years, which is not reflected in the design of clinical registration studies. Orphan drugs approved in an accelerated procedure seem to have an increased risk with regards to safety-related regulatory actions which might counteracted by more intense monitoring as postmarketing obligation and consequently higher chances for detection of a safety issue [40]. As for non-orphan drugs, safety considerations are one possible reason why orphan drug designations are withdrawn before approval [41].…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…However, most applications for an orphan designation by a sponsor are done in the late preclinical or early clinical testing stage, which doesn't include extensive human safety testing. Moreover, serious adverse events with authorized orphan medicinal products have been limited until now [38]; only sitaxentan was voluntarily withdrawn from the market by Pfizer in 2010 due to new information on two cases of fatal liver injury [39]. The reason for the limited number of follow-on OMPs with significant benefit based on an assumption of a major contribution to patient care may be best explained by a current lack of interest by the pharmaceutical industry.…”

Section: Discussionmentioning

confidence: 99%

Does market exclusivity hinder the development of Follow-on Orphan Medicinal Products in Europe?

Brabers

Moors

Weely³

et al. 2011

Orphanet Journal of Rare Diseases

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BackgroundWe determined whether the market exclusivity incentive of the European Orphan Drug Regulation results in a market monopoly or that absence of another Orphan Medicinal Product (OMP) for the same rare disorder, a so-called follow-on OMP, is a matter of time or market size. In the interest of rare disorder patients better understanding of the effect of the market exclusivity incentive on follow-on OMP development is warranted.MethodsFirst, the impact of various market-, product- and disease-related characteristics on follow-on OMP development in the EU was determined by comparing rare disorders with an approved OMP and at least one follow-on OMP (N = 26), with rare disorders with an approved OMP and no follow-on OMP (N = 18). Next, we determined whether manufacturers continued development of a follow-on OMP upon approval of the first OMP for the intended rare disorder. Since in the EU significant benefit of an OMP has to be established, we determined for each follow-on OMP for which development was continued on what grounds significant benefit was assumed by the sponsor. Data were collected from the public domain only.ResultsThe likelihood of a rare disorder with an approved OMP to obtain at least one follow-on OMP development was strongly associated with disease prevalence, turnover of the first OMP, disease class, disease-specific scientific output and age of onset. Out of a total of 120 follow-on OMPs only one follow-on OMP could be identified for which development was discontinued upon approval of the first OMP for the same rare disorder. Only a substantial level of discontinuation of follow-on OMP development would have indicated the existence of a market monopoly. Moreover, sponsors that continued development of a follow-on OMP predominantly assumed that their product had an improved efficacy compared to the first approved OMP.ConclusionsThis study provides evidence that absence of follow-on OMP development is a matter of time or market size, rather than that the market exclusivity incentive of the European Orphan Drug Regulation creates a market monopoly.

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“…These medications are often intended to treat severe or chronic diseases, for which no adequate treatment is previously approved 28 .…”

Section: Design and Data Collectionmentioning

confidence: 99%

Análise de medicamentos novos registrados no Brasil na perspectiva do Sistema Único de Saúde e da carga de doença

Botelho

Martins

Reis

2018

Ciênc. saúde coletiva

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Safety-Related Regulatory Actions for Orphan Drugs in the US and EU

Cited by 32 publications

References 19 publications

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

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

Does market exclusivity hinder the development of Follow-on Orphan Medicinal Products in Europe?

Análise de medicamentos novos registrados no Brasil na perspectiva do Sistema Único de Saúde e da carga de doença

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