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.

Lurbinectedin: First Approval.

The oncogenic transcription inhibitor lurbinectedin (ZEPZELCA™) is being developed by PharmaMar as a treatment for various cancers. The drug has been granted orphan drug status for the treatment of small cell lung cancer (SCLC) by regulatory authorities in multiple countries worldwide and was approved in the USA in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The US FDA and international regulators, including the Australian Therapeutic Goods Administration, are collaborating on the review of lurbinectedin under the Project Orbis initiative. Clinical investigation in other solid cancers is ongoing. This article summarizes the milestones in the development of lurbinectedin leading to this first approval for the treatment of metastatic SCLC.

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.

The impact of the Orphan Drug Act on Food and Drug Administration-approved therapies for rare skin diseases and skin-related cancers.

The Orphan Drug Act of 1983 (ODA) put in place a set of financial and marketing incentives to stimulate the development of drugs to treat rare diseases, and since its passage, more than 600 orphan drug and biologic products have been brought to market in the United States. Rapid growth in orphan drug approvals in conjunction with high orphan drug prices have triggered concern that drug makers are exploiting certain aspects of the ODA for financial gain and that some pharmaceutical drugs are receiving orphan status where it is not warranted. The landscape of approved therapies for rare skin diseases has not been well described. In this article, we provide a descriptive analysis of the United States Food and Drug Administration-approved orphan drugs for the treatment of rare dermatologic conditions and skin-related cancers since the enactment of the ODA. We discuss policy issues that emerge from the analysis and suggest areas for future research. Next, we elucidate ODA loopholes using dermatologic drugs as examples and propose potential reforms. Finally, we consider future directions for orphan drug development in the field of dermatology.

The drug lag and associated factors for orphan anticancer drugs in Japan compared to the United States.

The 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.

Orphan Drugs in Oncology.

Rare diseases represent a group of conditions affecting a very limited number of patients. Low profitability resulting from the small size of target population coupled with difficulties in conducting the research causes the lack of interest from the pharmaceutical industry. In order to promote research and development of medicines for rare diseases, a special 'orphan' legislation was introduced in a number of regions. These measures led to a significant increase in the number of approved orphan molecules. The high per patient cost of orphan drugs, as well the rapid growth of orphan drug sector, raised concerns regarding the sustainable funding of therapies for rare diseases. Rare cancers represent the majority of the current orphan drug market and are often associated with very high revenues. This chapter provides a review of orphan legislations and health technology assessment framework, analyses the position of oncology drugs on the orphan drug market and discusses future perspectives.

Regulatory and Evidence Requirements and the Changing Landscape in Regulation for Marketing Authorisation.

In this chapter, we describe the changing landscape of the EU pharmaceutical legislation concerning regulation and evidence requirements for marketing authorisation. First, we describe the legal requirements for marketing authorisation and the development of EU pharmaceutical legislation and the concept of risk-benefit balance. Second, we describe special types of authorisation, such as conditional approval and approval under exceptional circumstances, and special provisions such as incentives for orphan medicinal products and paediatric investigational plans. Lastly, we describe the available methodological guidelines focussing on choice of endpoints.

Investigating the landscape of US orphan product approvals.

BACKGROUND: The Orphan Drug Act was enacted in 1983 to encourage the development of drugs for rare diseases. Previous research has attempted to examine the impact of the Act by assessing either the number of orphan designations that have been granted or the number of new orphan drugs approved for marketing. This study provides a more in-depth understanding of the effect of the Orphan Drug Act by investigating all types of drug approvals with an orphan designation, along with multiple characteristics of the drugs, over the entire 35 years of the Act. These orphan approvals include: new molecular entities (new drugs approved first for a rare disease), secondary indications (an expansion from the first approved indication), and new formulations. RESULTS: The results show that the number of approvals for orphan indications has been increasing over time, and the upward trend is especially large in the most recent years. Much of this increase has been driven by the increase in secondary indications being approved for previously approved drugs, although there have also been increases in the number of approved new drugs. We also find that while oncology indications have been increasing significantly, there has also been an increase in other therapeutic areas. Additionally, we find that the proportion of biologic drugs being approved has increased over time. Lastly, while other parts of this drug landscape have dramatically altered over time, the proportion of orphan approvals receiving priority review has not changed. CONCLUSIONS: Our data suggest that the Orphan Drug Act appears to have stimulated significant drug development for rare diseases. Additionally, approvals of orphan indications have been increasing over time. This increasing effect has not targeted a single area of the rare disease space, rather, gains in approvals have been seen across: therapeutic areas, approval types (both new drugs and secondary indications), and for both biologics and small molecule drugs.

The possibility of obtaining marketing authorization of orphan pharmaceutical compounding preparations: 3,4-DAP for Lambert-Eaton Myasthenic Syndrome.

BACKGROUND: Pharmaceutical compounding preparations, produced by (hospital) pharmacies, usually do not have marketing authorization. As a consequence, some of these pharmaceutical compounding preparations can be picked-up by a pharmaceutical company to obtain marketing authorization, often leading to price increases. An example is the 3,4-diaminopyridine slow release (3,4-DAP SR) tablets for Lambert-Eaton Myasthenic Syndrome (LEMS). In 2009 marketing authorization was given for the commercial immediate release phosphate salt of the drug, including a fifty-fold price increase compared to the pharmaceutical compounding preparation. Obtaining marketing authorization for 3,4-DAP SR by academia might have been a solution to prevent this price increase. To determine whether the available data of a pharmaceutical compounding preparation with long-term experience in regular care are adequate to obtain marketing authorization, 3,4-DAP SR is used as a case study. METHODS: A retrospective qualitative case-study was performed. Initially, document analysis was executed by collecting the required data for marketing authorization in general and whether data of Firdapse® and 3,4-DAP SR met these requirements. Secondly, the (non-) available data of the two formulations were compared with each other to determine the differences in availability. RESULTS: At the time of approval, almost all data were available for both Firdapse® and 3,4-DAP SR. Conversely, much of the data used for the approval of Firdapse® originated from the 3,4-DAP immediate release (3,4-DAP IR) formulation. Only two bioequivalence studies and one pharmacology safety study was performed with Firdapse® before marketing authorization application. CONCLUSIONS: In conclusion, at time Firdapse® obtained approval, the data available did not differ substantially from 3,4-DAP SR, indicating that approval with 3,4-DAP SR would have been possible. We make a plea for approval of orphan medicinal products developed and manufactured by academic institutions as to keep utilization of these products affordable.

Orphan Drug Regulation: A missed opportunity for children and adolescents with cancer.

BACKGROUND: Oncology represents a major sector in the field of orphan drug development in Europe. The objective was to evaluate whether children and adolescents with cancer benefited from the Orphan Drug Regulation. METHODS: Data on orphan drug designations (ODDs) and registered orphan drugs from 8th August 2000 to 10th September 2016 were collected from the Community Register of medicinal products for human use. Assessment history, product information and existence of paediatric investigation plans were searched and retrieved from the European Medicine Agency website. RESULTS: Over 16 years, 272 of 657 oncology ODDs (41%) concerned a malignant condition occurring both in adults and children. The five most common were acute myeloid leukaemia, high-grade glioma, acute lymphoblastic leukaemia, graft-versus-host disease and soft-tissue sarcomas. 74% of 31 marketing authorisations (MAs) for an indication both in adults and children (26 medicines) had no information for paediatric use in their Summary of Product Characteristics (SmPC) at the time of the first MA. Furthermore, 68% still have no paediatric information in their most recently updated SmPC, at a median of 7 years after. Only 15 ODDs (2%) pertained to a malignancy occurring specifically in children and only two drugs received an MA: Unituxin for high-risk neuroblastoma and Votubia for sub-ependymal giant-cell astrocytoma. CONCLUSION: The Orphan Drug Regulation failed to promote the development of innovative therapies for malignancies occurring in children. Major delays and waivers occurred through the application of the Paediatric Medicines Regulation. The European regulatory environment needs to be improved to accelerate innovation for children and adolescents dying of cancer.

Do investors value the FDA orphan drug designation?

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.

Evolving prevalence of haematological malignancies in orphan designation procedures in the European Union.

The Committee for Orphan Medicinal Products (COMP) evaluates prevalence of rare conditions as one of the criteria for granting an orphan designation with a prevalence threshold of 5 in 10.000. At the time of Marketing Authorisation (MA) these criteria are reassessed to ensure they are still met. The COMP has noted discordance between the prevalence of certain haematological malignancies at the time of Orphan Designation and at the time of Marketing Authorisation. Consequently, we conducted a retrospective assessment of Chronic Lymphocytic Lymphoma and Multiple Myeloma/Plasma cell Myeloma as well as several other haematological rare aetiologies frequently subject of orphan designation. These were: Diffuse large B-Cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Cutaneous T-Cell Lymphoma (CTCL), Mantle Cell Lymphoma (MCL) and Chronic Myeloid Leukaemia (CML). The review used submissions as well as recent publications and results from external and EMA databases. As a first step in the analysis, an increase over time in the number of people affected was evident for four conditions in the COMP designation documents, whereas for DLBCL, FL, CTCL and MCL there had been no significant change, since the introduction of the Regulation in 2000. Specifically, the prevalence estimates increased from 1.2 to 3.6 per 10,000 for multiple myeloma, from 0.4 to 1.7 in acute lymphoblastic leukaemia, and from 2.7 to 4.85 for chronic lymphocytic leukaemia/small lymphocytic leukaemia and 1 to 2 in 10,000 for chronic myeloid leukaemia. The reasons for the changes in the prevalence of these four haematological conditions over the last 15 years were not assessed but recent publications have alluded to better outcomes due to new treatments being made available. In addition, many orphan diseases have a median age of onset over 60 years so that also the aging of the population may be a relevant contributing factor.

Orphan drug policies and use in pediatric nephrology.

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.

The correlation between HTA recommendations and reimbursement status of orphan drugs in Europe.

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.

Trends In Orphan New Molecular Entities, 1983-2014: Half Were First In Class, And Rare Cancers Were The Most Frequent Target.

The Orphan Drug Act was enacted in 1983 to stimulate drug development for rare diseases. How well this law has accomplished that goal is an important public health question. This study examined the characteristics of the 209 orphan drugs approved as new molecular entities in the period 1983-2014. As a whole, these drugs were highly innovative and provided substantial gains in reducing unmet medical needs for rare diseases: Over 50 percent of the drugs were first in class, and 78 percent received a priority review. Drugs approved as either therapeutic or supportive therapies for rare cancers represented the highest proportion of these drugs (35 percent). Additionally, in 2010-14 large companies became a strong presence in developing orphan new molecular entities for oncology indications. Overall, new orphan drugs appeared to be highly innovative and provided important advances in care for patients with rare diseases.

The Orphan Drug Act: Restoring the Mission to Rare Diseases.

The Orphan Drug Act has fostered drug development for patients with rare cancers and other diseases; however, current data suggest that companies are gaming the system to use the law for mainstream drugs. We identify a pattern of pharmaceutical companies submitting drugs to the Food and Drug Administration (FDA) as orphan drugs but once approved, the drugs are used broadly off-label with the lucrative orphan drug protections and exclusivity benefits. Since the law was passed, the proportion of new FDA-approved drugs that were submitted as orphan drugs has increased with a peak last year of 41% of all FDA-approved drugs approved as orphan drugs. On the basis of the current data, we suggest that patients with rare cancers and other diseases may suffer due to dilution of the incentives and benefits. We propose reform to increase submission scrutiny, decrease benefits based on off-label use, and increase price transparency.