[Translated article] Current situation and evolution of the availability of drugs in the pediatric population in Spain.

OBJECTIVE: To analyze the characteristics of the new medicines approved in the pediatric population in the last 3 years, both those with studies only in the pediatric population and those that extend their indication in this population group, as well as the current situation in relation to their marketing and financing. METHODS: Descriptive observational study of all drugs that include an indication in the pediatric population in Spain (by extension of the indications of drugs already authorized or because they are new drugs that already include an indication in this population group), from January 2019 to March 2022. RESULTS: During the study period, 129 drugs included their indication in the pediatric population. 13.9% of them are not marketed, 46.5% are in a situation of non-financing, under study or without a request for financing, and 4.6% are financed for a specific pediatric subpopulation. 52.7% are original drugs, 4.7% are generic, 38.8% are biological, 3.8% are biosimilar, and 17.8% are orphan drugs. 57.36% of these medicines obtain the pediatric indication due to extension of the indication and 42.64% obtain it because they are new medicines that already include their studies in the pediatric population. CONCLUSIONS: Drugs with authorized indications are increasingly available in the pediatric population and the trend is to extend the indication of authorized drugs to the adult population. However, barriers in terms of financing and marketing need to be expedite and overcome to facilitate access to them.

Five-Year Sales for Newly Marketed Prescription Drugs With and Without Initial Orphan Drug Act Designation.

This study evaluates sales revenue earned in the first 5 years for newly marketed brand-name drugs with and without an initial orphan drug designation.

Pediatric Drug Development Studies for Familial Hypercholesterolemia Submitted to the US Food and Drug Administration Between 2007 and 2020.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism that leads to an increased risk of developing atherosclerosis and coronary artery disease. Hypercholesterolemia in pediatric patients is typically due to FH. Treatment of pediatric FH is achieved through lifestyle modifications, lipid-modifying pharmacotherapy, and/or apheresis. The primary objective of this review is to describe the characteristics of clinical trials conducted in pediatric patients with FH with data submitted to the US Food and Drug Administration from 2007 to 2020. Of 10 trials with 8 products in pediatric FH submitted to the Food and Drug Administration, 1 product was studied in both the heterozygous and the homozygous phenotypes, 5 were studied for heterozygous hypercholesterolemia only, and 2 were studied for homozygous familial hypercholesterolemia only. Most of the trials included pediatric patients ≥10 years of age and older. Clinical trial characteristics including the primary efficacy end points between pediatric and adult trials were mostly identical. Many lipid-lowering drugs with novel mechanisms of action have been recently approved or are currently being studied. In summary, the drug treatment of hypercholesterolemia in pediatric patients is expanding beyond the use of statins, and now involves multiple mechanisms of action involving cholesterol metabolism. As younger pediatric patients are diagnosed and treated for heterozygous familial hypercholesterolemia and homozygous familial hypercholesterolemia, optimizing the doses of these agents and safety studies specific to younger pediatric patients will be necessary.

Reforms of regulatory pathways for approval of new antineoplastic drugs in Japan from 2004 to 2019 and accompanying changes in pivotal clinical trial designs.

Background The Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was established in 2004. Since then, various pieces of legislation, notices, and guidelines have been issued, and the regulatory approval pathways for domestic drugs have been diversified. However, the effects of these measures have not been fully examined. We examined the impact of these measures on the approval of antineoplastic drugs and the design of pivotal clinical trials for efficacy assessment by the PMDA. Methods We collected data on the antineoplastic drugs approved by the PMDA in fiscal years 2004-2019. We extracted the approval review pathways and the pivotal clinical trial designs from the PMDA review reports, and analyzed them to identify patterns. Results In total, 387 indications in oncology were approved by the PMDA in fiscal years 2004-2019, or 365 indications excluding multiple regulatory pathways. The number of approved indications generally increased year on year (p < 0.001). The largest number of approved indications was under the Orphan Drug Designation (31%, 114/365) and this continues to increase (p < 0.001). In the 288 indications for which clinical trial data were submitted for review, the pivotal clinical trial designs changed significantly (p < 0.001) after the guideline on clinical evaluation for antineoplastic drugs was revised in 2006. Conclusion The number of indications in oncology approved by the PMDA has been increasing over the past 16 years, alongside changes in regulatory pathways. The 2006 guideline on clinical evaluation had a particular impact on pivotal clinical trial designs.

2020 in review: FDA approvals of new medicines.

Amid a global pandemic, the US Food and Drug Administration (FDA) remained relatively active, approving 55novel molecular entities (NMEs) in 2020, the third highest annual rate recorded. Orphan approvals also surged, capturing 60% of NMEs introduced during 2020, as did the number of NMEs approved using a priority review. The pandemic did appear to impact one recent trend, and in a paradoxically encouraging way. Escalating rates of consolidation slowed in 2020, with only 102 companies lost, down by two-thirds over the rate in 2019. This leaves 2000 extant clinical-stage pharmaceutical companies. When limiting this analysis to companies contributing to the research and development (R&D) of an approved drug, eight were lost, leaving 144 extant.

The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. OBJECTIVES: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. METHODS: Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. RESULTS: Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. CONCLUSION: Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

Independent Registries Are Cost-Effective Tools to Provide Mandatory Postauthorization Surveillance for Orphan Medicinal Products.

OBJECTIVES: Orphan medicinal products (OMPs) often receive market authorization under conditions imposed by regulators for ongoing postauthorization surveillance (PAS) to answer questions that remain at the time of market entry. This surveillance may be provided through industry-funded registries (IFRs). Nevertheless, data in these registries may not be of sufficient quality to answer these questions and may not always be accessible for regulatory review. We propose that a mandatory independent registry is an efficient and cost-effective tool for PAS for OMPs. METHODS: Using data from the Canadian Fabry Disease Initiative, we reviewed costs per unique patient from sites participating in both the independent national registry and IFRs for Fabry disease and compared data completeness from the Canadian Fabry Disease Initiative to that in published documents from IFRs. RESULTS: The costs of data collection through the independent registry were 17% to 36% (depending on site) lower than costs to collect data in the IFRs, and completeness of data collected through the independent registry was higher than that through the IFRs. Data from the independent registry were reviewed annually to guide indications for publicly funded Fabry disease therapy. Even when enrollment ceased to be a requirement to receive therapy, 77% of patients continued to enroll in the registry, suggesting the structure was acceptable to patients. CONCLUSIONS: Independent registries are cost-effective and efficient tools and should be mandated by regulatory agencies as the preferred tool for PAS for OMPs. Countries with publicly funded health systems should consider investment in registry infrastructure for OMPs.

Removal of the EMA orphan designation upon request of the sponsor: cui prodest?

PURPOSE: Various incentives are provided by the European Medicines Agency (EMA) to facilitate the development and marketing of orphan drugs. A 10-year period of market exclusivity is reserved to an orphan medicinal product. Sometimes, the sponsor renounces the designation before the expiration of that standard period. Our aim was to focus on these premature withdrawals. METHODS: We retrieved all the molecules included in the Community Register of Orphan Medicinal Products for Human Use from 2000 to November 2020. We considered the active substance, therapeutic indication, sponsor, year of designation, year of approval of the corresponding medicinal product, and that of the withdrawal of the orphan designation, if occurred. RESULTS: Overall, 2350 orphan designations were approved from 2000 to November 2020. Of these, 141 have been marketed. Premature withdrawal of orphan designation concerned 23 drugs (20 being antineoplastic agents), corresponding to 16 medicinal products. These withdrawals occurred after almost 2 years (range <1-7 years). CONCLUSIONS: A not negligible fraction of marketed orphan medicinal products underwent premature removal of their orphan designation. No motivation is requested by the EMA for this renouncement, although the peculiarity of the orphan medicinal products would need a greater transparency. We can only speculate about possible compensations in support of this decision, for instance in terms of commercial agreements between pharmaceutical companies, giving way to alternative products, as a couple of examples suggest. An open debate on this topic among members of academia, regulatory bodies, price and reimbursements committees, and pharmaceutical industry representatives will be welcome.

Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis.

OBJECTIVES: Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs. METHODS: Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis. RESULTS: One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001). CONCLUSIONS: Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.

FDA orphan drug designations for lysosomal storage disorders - a cross-sectional analysis.

PURPOSE: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSDs). METHODS: Assessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics. RESULTS: Between 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N = 16), Pompe disease (N = 16), Fabry disease (N = 10), MPS II (N = 10), MPS I (N = 9), and MPS IIIA (N = 9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N = 6), cystinosis (N = 5), Pompe disease (N = 3), and Fabry disease (N = 2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSDs (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N = 23) months. CONCLUSIONS: The drug development pipeline for LSDs is growing and evolving, with increased focus on diverse small-molecule targets and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included "me-too"-enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

Análisis de la evolución en el acceso a los medicamentos huérfanos en España / Analysis of the evolution in the access to orphan medicines in Spain

OBJETIVO: Evaluar el acceso al mercado de los medicamentos huérfanos en España que a fecha de 31 de diciembre de 2017 tuvieran vigente su designación, y para aquellos comercializados en España estimar los tiempos entre la asignación de código nacional (CN) por parte de la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) y la fecha de comercialización efectiva. MÉTODO: La base de datos para identificar los medicamentos huérfanos autorizados por la Agencia Europea de Medicamentos (EMA), a fecha 31 de diciembre de 2017 (n = 142), es su Registro Comunitario publicado por la Comisión Europea. La EMA publica los medicamentos huérfanos que han perdido la designación. Las fechas de asignación de CN provienen de la AEMPS, y las de comercialización, de Bot PLUS. Se llevó a cabo un análisis descriptivo de las variables de estudio. Las variables cuantitativas se describieron utilizando la media y mediana, así como la desviación estándar y su rango. Las variables cualitativas se describieron según frecuencias absolutas y relativas. La comparación de resultados se realizó mediante contrastes paramétricos y no paramétricos en función de la aplicabilidad, con un nivel de significación del 5%. RESULTADOS: Entre 2002 y 2017, la EMA autorizó (con designación vigente a 31 de diciembre de 2017) 100 medicamentos huérfanos. De ellos, 86 tienen CN asignado, y de estos, 54 se han comercializado en España (54% de los medicamentos huérfanos vigentes y 63% de aquellos con CN). Para todos los medicamentos huérfanos con fecha de comercialización (53), el tiempo (mediana) desde la asignación del CN hasta su comercialización en España es de 13,4 meses (desviación estándar: 17,0; mínimo: 2,1; máximo: 91,7). La mediana para los comercializados en 2002-2013 y 2014-2017 es de 12,4 meses y 14,0 meses, respectivamente (p = 0,46). Esta diferencia no es estadísticamente significativa, lo que cabría esperar dado el número limitado de medicamentos huérfanos en nuestra «población». CONCLUSIÓN: Numerosos factores determinan el acceso a los medicamentos huérfanos. La autorización centralizada de comercialización en Europa es un éxito; su acceso es más limitado, dadas las complejidades de evaluación de la evidencia disponible en los procesos de financiación y precio. Es necesario implementar nuevas políticas que reduzcan las desigualdades en el acceso y permitan la sostenibilidad del sistema. Para conseguir estos objetivos, podrían contemplar un proceso acelerado en la decisión de financiación y precio, y el pago por resultados con incertidumbre alta

OBJECTIVE: To assess the access to orphan medicines in Spain, focusing on those with an active "orphan" designation, as of 31st December 2017; and for those orphan medicines in the Spanish market, estimate the time between being assigned a National Code (NC) by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) and being approved for launch. METHOD: We used the European Commission's Public Register of orphan medicines to identify the orphan medicines authorised by the European Medicines Agency (EMA), as of 31 December 2017, while we sourced expired orphan indications from the EMA's website. Dates when NCs were assigned were sourced from the AEMPS, and commercialisation dates from Bot PLUS. A descriptive analysis of the study variables was done. The quantitative variables were described using means and medians, as well as standard deviations and ranges. The qualitative variables were described according to absolute and relative frequencies. The comparison of results was performed by parametric and non-parametric contrasts according to the applicability, at a 5% significance level. RESULTS: The EMA has approved 100 orphan medicines (with designation as of 31/12/2017) between 2002-2017. Eighty-six have a NC assigned by the AEMPS. Fifty-four have been launched in Spain (representing 54% of the full sample; 63% with NC). For the 53 orphan drugs with launch date in Spain, the median time between receiving its NC and its launch is 13.4 months (standard deviation: 17.0; minimum: 2.1; maximum: 91,7). The median time is 12.4 months and 14.0 months for those medicines launched in Spain between 2002-2013 and 2014-2017 respectively (p = 0.46). This difference is not statistically significant, which is what could be expected given the low numbers of orphan medicines in the "population". CONCLUSION: Complex factors determine the access to orphan drugs in Europe. The centralised procedure to obtain marketing authorisation at European level is a success. However, access is more limited, given the complexities of the evaluation of the available evidence for pricing and reimbursement decisions. It is therefore necessary to implement new policies that reduce inequalities in access and help achieve sustainable healthcare systems. To achieve this, they will need to offer the possibility of allowing earlier access, and using payment by results when there is high uncertainty

Pediatric Orphan Drug Indications: 2010-2018.

BACKGROUND: Orphan drug development is crucial for children, who are disproportionately affected by rare diseases. Data are lacking on the number, nature, and benefit of recently approved pediatric orphan indications. METHODS: We classified the 402 orphan indications the US Food and Drug Administration approved between 2010 and 2018 as "pediatric" if they were approved for children only or targeted pediatric diseases. We determined the number of unique diseases targeted by pediatric orphan indications and calculated the proportion that were for (1) novel drugs, (2) non-novel drugs approved to treat ≥1 common disease, and (3) non-novel drugs approved only to treat rare diseases. Among pediatric orphan indications eligible for US Food and Drug Administration breakthrough designation (granted to drugs potentially representing major therapeutic advances), we calculated the proportion receiving this designation. RESULTS: Of the 402 orphan indications, 136 (33.8%) were pediatric. These 136 indications targeted 87 unique diseases; 21 diseases were targeted by ≥1 indication. Of the 136 pediatric orphan indications, 60 (44.1%) were for novel drugs, 45 (33.1%) were for non-novel drugs approved to treat ≥1 common disease, and 31 (22.8%) were for non-novel drugs approved only to treat rare diseases. Among 97 indications eligible for breakthrough designation, 20 (20.6%) received this designation. CONCLUSIONS: Recent orphan drug development has increased the availability of treatments for pediatric rare diseases. Most pediatric orphan indications expanded use of existing drugs, and many targeted the same disease. Some indications may represent breakthroughs, but substantial unmet need for treatments remains for most pediatric rare diseases.

The challenges of pharmacoepidemiology of orphan drugs in rare diseases.

Large electronic health records database available at a national level offer great opportunity for research in rare diseases and orphan drugs. Methods and data used in pharmacoepidemiology present a great potential for epidemiology, drug utilization studies, drug safety, drug effectiveness and pharmacoeconomics. This review presents the different sources of data in Europe, with a special focus on the French situation, with the recent implementation of SNDS (système national des données de santé [French national health data wharehouse]). Some examples are given. Development of rigorous and innovative methods must be encouraged in the future.

Orphan drug designation in Europe: A booster for the research and development of drugs in rare diseases.

The research and drug development process in rare diseases is challenging in addition to those for common diseases. To stimulate its development, the orphan drug designation (ODD) was introduced in in European Union in 2000. In the present paper, we describe the main characteristics of ODD in European Union in particular the requested criteria for ODD, the overview of the general procedure and the main incentives for Sponsors and finally the predicted factors related to successful development and marketing approval of orphan drugs after designation. In accordance with regulation, an application for ODD must be submitted to European Agency including a scientific part based on relevant scientific literature related to the condition and results on experimental studies with the specific product (and clinical studies if available). Three following criteria are a central position in this application: medical plausibility, rarity and medical significant benefit. The Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency's (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Even if pre-submission meetings are not mandatory, EMA strongly encourages sponsors to request a pre-submission meeting with the Agency prior to filing an application. Experience has shown that they have a positive impact on the success rate of the applications. The full application should be submitted in English via secure online portal. ODD makes the sponsor eligible for a number of orphan incentives including the 10-year market exclusivity and the protocol assistance by COMP. Based on literature and on the experience accumulated by our team ORPHANDEV F-CRIN-labelled platform the successful translation of rare disease research into orphan drug discovery is dependent of a clearly justified medical significant benefit, the disease class, its prevalence and the disease-specific scientific output, previous experience of the sponsor with a previous successful orphan drug to the market increased.

Innovative design and analysis for rare disease drug development.

One of the most challenges for rare diseases drug development is probably the availability of subjects with the diseases under a small patient population. It is then a great concern how to conduct clinical trials with the limited number of subjects available for obtaining substantial evidence regarding effectiveness and safety for approval of the drug product under investigation. For rare diseases drug development, FDA indicated that the Agency does not have the intention to create a statutory standard for approval of orphan drugs that is different from the standard for approval of drugs in common conditions. In this case, innovative thinking and approach for obtaining substantial evidence for approval of rare diseases drug products are necessarily applied. In this article, basic considerations for rare disease drug development are discussed. The innovative thinking of demonstrating not-ineffectiveness rather than effectiveness with a limited number of subjects available is outlined. In addition, an innovative approach utilizing a two-stage adaptive seamless trial design in conjunction with the concept of real-world data and real-world evidence is proposed not only to obtain substantial evidence for approval of rare diseases drug products, but also to meet the same standard as those drug products in common conditions. Under the two-stage adaptive seamless trial design, sample size calculation for rare diseases clinical trials based on the innovative probability monitoring procedure is also discussed.

[Analysis of the evolution in the access to orphan medicines in Spain]. / Análisis de la evolución en el acceso a los medicamentos huérfanos en España.

OBJECTIVE: To assess the access to orphan medicines in Spain, focusing on those with an active "orphan" designation, as of 31st December 2017; and for those orphan medicines in the Spanish market, estimate the time between being assigned a National Code (NC) by the Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) and being approved for launch. METHOD: We used the European Commission's Public Register of orphan medicines to identify the orphan medicines authorised by the European Medicines Agency (EMA), as of 31 December 2017, while we sourced expired orphan indications from the EMA's website. Dates when NCs were assigned were sourced from the AEMPS, and commercialisation dates from Bot PLUS. A descriptive analysis of the study variables was done. The quantitative variables were described using means and medians, as well as standard deviations and ranges. The qualitative variables were described according to absolute and relative frequencies. The comparison of results was performed by parametric and non-parametric contrasts according to the applicability, at a 5% significance level. RESULTS: The EMA has approved 100 orphan medicines (with designation as of 31/12/2017) between 2002-2017. Eighty-six have a NC assigned by the AEMPS. Fifty-four have been launched in Spain (representing 54% of the full sample; 63% with NC). For the 53 orphan drugs with launch date in Spain, the median time between receiving its NC and its launch is 13.4 months (standard deviation: 17.0; minimum: 2.1; maximum: 91,7). The median time is 12.4 months and 14.0 months for those medicines launched in Spain between 2002-2013 and 2014-2017 respectively (p = 0.46). This difference is not statistically significant, which is what could be expected given the low numbers of orphan medicines in the "population". CONCLUSION: Complex factors determine the access to orphan drugs in Europe. The centralised procedure to obtain marketing authorisation at European level is a success. However, access is more limited, given the complexities of the evaluation of the available evidence for pricing and reimbursement decisions. It is therefore necessary to implement new policies that reduce inequalities in access and help achieve sustainable healthcare systems. To achieve this, they will need to offer the possibility of allowing earlier access, and using payment by results when there is high uncertainty.

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

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.

Therapies for rare diseases: therapeutic modalities, progress and challenges ahead.

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.

Variation in US private health plans' coverage of orphan drugs.

OBJECTIVES: To compare coverage of orphan and nonorphan drugs, to examine variation in orphan drug coverage across the largest US private plans, and to evaluate factors influencing coverage decisions. STUDY DESIGN: Database and regression analyses. METHODS: We analyzed a data set of private health plan coverage decisions for specialty drugs (N = 5000) in 3 ways. First, we compared the frequency with which plans applied restrictions in their decisions for orphan and nonorphan drugs. Second, we examined variation in the frequency with which 17 of the largest 20 private plans applied coverage restrictions for orphan drugs. Third, we used multivariate regression to examine factors associated with restricted orphan drug coverage. RESULTS: Health plans are less likely to restrict orphan drugs compared with nonorphan drugs. Of orphan drug decisions (n = 2168), plans did not apply coverage restrictions in 70% of cases, applied restrictions in 29%, and did not cover in 1%. In contrast, of nonorphan drug decisions (n = 2832), plans did not apply coverage restrictions in 53% of cases, applied restrictions in 41%, and did not cover in 6%. The frequency of restrictions for orphan drugs varied from 11% to 65% across plans. The attributes of orphan drugs that were more likely to be associated with restrictions than others included drugs for noncancer diseases, drugs with alternatives, self-administered drugs, drugs indicated for diseases with a higher prevalence, and drugs with higher annual costs (all P <.05). CONCLUSIONS: Health plans restrict access to orphan drugs approximately one-third of the time, and restrictions vary considerably across plans. Plans more often add restrictions for orphan drugs that are indicated for diseases with a higher prevalence and that have higher annual costs.