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Rare diseases collectively affect millions of Americans of all ages, but developing drugs and medical devices to prevent, diagnose, and treat these conditions is challenging. The Institute of Medicine (IOM) recommends implementing an integrated national strategy to promote rare diseases research and product development.

SummaryThe approval of orphan anticancer drugs in Japan has increased to meet high social demand. Drug lag, namely the approval lag of new drugs, is recognized as a social issue in Japan. We investigated the approval lag and its components, submission lag and review-time lag, between Japan and the United States (US) to reveal whether an approval lag still exists, and to identify potential factors that may contribute to reducing the approval lag. Anticancer drugs approved in Japan between April 2004 and November 2017 were investigated using publicly available information. Results showed that the median approval lag of orphan anticancer drugs in 2016–2017 was 727.0 days (interquartile range, IQR, 310.0–1054.3). The approval lag was significantly correlated with the submission lag (correlation coefficient = 1.00, P < 0.001) but not with the review-time lag (correlation coefficient = −0.16, P = 0.22). The submission lag was significantly longer for orphan anticancer drugs than non-orphan drugs (median, 712.5 days [IQR, 186.0–1448.3] vs. 387.0 days [92.8–1096.0], P = 0.023). External collaboration in drug development was associated with a longer submission lag (coefficient = 762.1, P = 0.017), while breakthrough therapy designation in the US was associated with a shorter submission lag (coefficient = −832.8, P = 0.035). In conclusion, we revealed that an approval lag for orphan anticancer drugs still existed in 2016–2017. A submission lag for orphan anticancer drugs was the main component affecting the approval lag, and was longer than that for non-orphan drugs. External collaboration in drug development may be a potential factor in reducing the submission lag for orphan anticancer drugs.

Rare diseases affect a small population of patients, resulting in low incentives for developing orphan drug products (ODPs). The United States Congress passed the Orphan Drug Act of 1983 to incentivize pharmaceutical manufacturers to develop drugs to treat rare diseases. However, ODPs generally have higher treatment costs than non‐ODP treatments. Developing generic ODPs can benefit patients by increasing market competition and providing alternate treatment options. This research aims to identify factors influencing the first submission of abbreviated new drug applications (ANDAs) for generic orphan drugs. Data were collected from the U.S. Food and Drug Administration (FDA) databases (including but not limited to the FDA Orphan Drug Designations and Approvals database, Orange Book, and the internal drug product complexity designation) and the IQVIA sales database to inform the drug product information, regulatory factors, and pharmacoeconomic factors. The Random Survival Forest (RSF) machine learning method was employed to conduct the analysis for New Chemical Entities (NCEs) and non‐NCEs. The modeling analysis was adequately assessed through both internal and external validations. For NCEs and non‐NCEs, the RSF was able to predict ANDA submission with a repeated cross‐validation C‐index of 0.675 ± 0.0261 (C‐index of full training dataset: 0.915) and 0.754 ± 0.0441 (C‐index of full training dataset: 0.838), respectively. The variables with the highest importance in the RSF model to predict ANDA submission of NCE ODPs were sales data, while for non‐NCEs, regulatory data was the most important (i.e., availability of product‐specific guidances (PSGs)). As more data becomes available in the future, the RSF methodology will likely be able to predict ANDA submissions of ODPs more effectively. The model‐informed results may be utilized in future intervention strategies to promote ANDA submissions for orphan drugs and to increase the availability of generic ODPs.

Purpose To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. Methods Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports. Results From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)’s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100–200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs. Conclusion Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs’ efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market.

The development of drugs for rare diseases — often known as orphan drugs — is attracting increasing interest and investment, catalysed in part by incentives such as those provided by the 1983 US Orphan Drug Act. This article provides the first comprehensive analysis of 25 years of data on the designation and approval of orphan drugs by the US Food and Drug Administration, with the aim of supporting and encouraging future orphan drug development and approval. The 1983 US Orphan Drug Act has stimulated the development of new therapies for rare diseases. To provide the first comprehensive overview of orphan-designated products and their indications, this article quantitatively analyses the characteristics and distribution of orphan designations and approvals by the US Food and Drug Administration from 1983 to August 2008. Of the 1,892 orphan-designated products, 326 received marketing approval, representing 247 different drugs and more than 200 different diseases. About half of the approvals had occurred by 4 years after designation was granted. The most common patient population size for orphan designations and approvals was fewer than 10,000 patients, and cancer was the most common disease area. The implications of such findings for future development and marketing of therapies for rare diseases are discussed.

Background The aim of this study was to review and compare types of reimbursement recommendations for orphan drugs issued by eight European health technology assessment (HTA) agencies and the reimbursement status of these drugs in the corresponding countries. Separate calculations were also performed for three sub-groups: ultra-orphan drugs, oncology orphan drugs and other (non-ultra, non-oncology) orphan drugs. Results We reviewed drugs authorized by the European Medicine Agency (EMA) between 1 November 2002 and 30 September 2015. Among these, we identified 101 orphan drugs. Seventy-nine of them were assessed by eight European HTA agencies. The average rates of positive, conditional and negative reimbursement recommendations issued by these agencies were 55.7 %, 15.3 % and 29.0 %, respectively. On average, 21.2 % of EMA-authorized orphan drugs were reimbursed in the eight European countries studied: 49.0 % of those with positive, 53.6 % of those with conditional, and 16.0 % of those with negative reimbursement recommendations. In addition, 5.4 % of orphan drugs that had not been assessed by any of the eight HTA agencies were also reimbursed. The shares of oncology, ultra, and other orphan drugs that were assessed by HTA agencies were similar, with the lowest share observed in ultra-orphan drugs (72 %) and the highest in other orphan drugs (80 %). In terms of reimbursement, 20 % of oncology orphan drugs, 25 % of ultra-orphan drugs and 21 % of other orphan drugs were reimbursed. Conclusions Reimbursement of orphan drugs does not always correspond to the type of HTA recommendation. While the highest rate of reimbursement is observed (unsurprisingly) among drugs with positive or conditional recommendation, a high rate of reimbursement (11 %) is also observed among ultra-orphan drugs that had never been assessed by any HTA agency.

Background The Orphan Drug Act is an important piece of legislation that uses financial incentives to encourage the development of drugs that treat rare diseases. This analysis studies the effects of a portion of the Orphan Drug Act, the orphan drug designation. Specifically, it studies the value that investors place on the orphan drug designation, by investigating how investors react to companies’ announcing that their product has received the designation. Results The results, on average, show that the stock price of a company increases by 3.36% after the announcement of the designation, increasing the value of the company. The results are more pronounced for oncology drugs, and drugs being developed by the smallest companies. Conclusion The orphan designation appears to be successful at generating positive value for companies, as seen by the positive and significant average increases in stock price.

[...]the diseases, not the drugs, are the orphans because all drugs are very expensive,3 having marrying this success story (table). [...]in some cases, several OMPs are available for the same disease; for example, three drugs are licensed for treatment of Gaucher's disease (imiglucerase, velaglucerase alfa, and taliglucerase alfa).15 No evidence favours any one product over the other, and each drug costs about US$200 000 per patient per year. In a landmark departure from previous practice in 2014, the US Senate requested information on developmental costs and numerous other details for sofosbuvir, a drug for radical treatment of hepatitis C virus infection.19 Individual EU member state governments have since increasingly been requesting that industry disclose information about costs incurred during drug development that justify drug prices, but without legal obligations, these requests have largely been evaded. First synthesised in 1869, hydroxyurea has been used for decades in patients with myeloproliferative disorders and is now also indicated for sickle-cell disease.22,23 In the 2017 issue of the British National Formulary, one type of hydroxyurea for myeloproliferative disorders is listed at £0·24 per g, and another type of hydroxyurea for sickle-cell disease is listed at £16·7 per g. Common sense suggests that something must be wrong here.

Orphan drugs designed to treat rare diseases are often overpriced per patient. Novel treatments are sometimes even more expensive for patients with ultra-rare diseases, in part due to the limited number of patients. Pharmaceutical companies that develop a patented life-saving drug are in a position to charge a very high price, which, at best, may enable these companies to further develop drugs for use in rare disease. However, is there a limit to how much a life-saving drug should cost annually per patient? Government interventions and regulations may opt to withhold a life-saving drug solely due to its high price and cost-effectiveness. Processes related to drug pricing, reimbursement, and thereby availability, vary between countries, thus having implications on patient care. These processes are discussed, with specific focus on three drugs used in pediatric nephrology: agalsidase beta (for Fabry disease), eculizumab (for atypical hemolytic uremic syndrome), and cysteamine bitartrate (for cystinosis). Access to and costs of orphan drugs have most profound implications for patients, but also for their physicians, hospitals, insurance policies, and society at large, particularly from financial and ethical standpoints.

To review existing regulations and policies utilised by countries to enable patient access to orphan drugs. A review of the literature (1998 to 2014) was performed to identify relevant, peer-reviewed articles. Using content analysis, we synthesised regulations and policies for access to orphan drugs by type and by country. Fifty seven articles and 35 countries were included in this review. Six broad categories of regulation and policy instruments were identified: national orphan drug policies, orphan drug designation, marketing authorization, incentives, marketing exclusivity, and pricing and reimbursement. The availability of orphan drugs depends on individual country's legislation and regulations including national orphan drug policies, orphan drug designation, marketing authorization, marketing exclusivity and incentives such as tax credits to ensure research, development and marketing. The majority of countries (27/35) had in place orphan drug legislation. Access to orphan drugs depends on individual country's pricing and reimbursement policies, which varied widely between countries. High prices and insufficient evidence often limit orphan drugs from meeting the traditional health technology assessment criteria, especially cost-effectiveness, which may influence access. Overall many countries have implemented a combination of legislations, regulations and policies for orphan drugs in the last two decades. While these may enable the availability and access to orphan drugs, there are critical differences between countries in terms of range and types of legislations, regulations and policies implemented. Importantly, China and India, two of the largest countries by population size, both lack national legislation for orphan medicines and rare diseases, which could have substantial negative impacts on their patient populations with rare diseases.