HTA criteria adopted in different models of public healthcare systems for orphan drugs: A scoping review.

Access to drugs for rare diseases constitutes a challenge to healthcare systems, especially those with public funding. This study aimed to map and summarize the criteria used by HTA agencies in different healthcare systems to evaluate reimbursement recommendations for orphan drugs. A comprehensive literature search was performed on the databases PubMed, LILACS, Scopus, and Embase and the gray literature (Google Scholar and websites of HTA agencies). Publications addressing the criteria used by HTA agencies in countries with public healthcare systems when evaluating reimbursement recommendations for orphan drugs were included. This scoping review included 23 studies published between 2014 and 2023, mostly consisting of reviews of HTA reports, guidance documents, and original articles. The criteria were mapped from 19 countries and ranked within three models of healthcare systems (National Health System, National Health Insurance, and Social Health Insurance). All models shared concerns about unmet needs and disease nature. In addition, NHS countries (e.g., United Kingdom, Sweden, and Italy) prioritized innovation and system-level impact, while SHI countries (e.g., Germany, France, the Netherlands) usually valued budget impact and employed expedited evaluation processes. This review provides a comprehensive understanding of the general tendencies of each healthcare system model in establishing differentiated criteria to address the challenges posed by the limited evidence and investment in the field of rare diseases.

[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.

Issues, Challenges and Opportunities for Economic Evaluations of Orphan Drugs in Rare Diseases: An Umbrella Review.

BACKGROUND AND OBJECTIVES: There are significant challenges when obtaining clinical and economic evidence for health technology assessments of rare diseases. Many of them have been highlighted in previous systematic reviews but they have not been summarised in a comprehensive manner. For all stakeholders working with rare diseases, it is important to be aware and understand these issues. The objective of this review is to identify the main challenges for the economic evaluation of orphan drugs in rare diseases. METHODS: An umbrella review of systematic reviews of economic studies concerned with orphan and ultra-orphan drugs was conducted. Studies that were not systematic reviews, or on advanced therapeutic medicinal products, personalised medicines or other interventions that were not considered orphan drugs were excluded. The database searches included publications from 2010 to 2023, and were conducted in MEDLINE, EMBASE and the Cochrane library using filters for systematic reviews, and economic evaluations and models. These filters were combined with search terms for rare diseases and orphan drugs. A hand search supplemented the literature searches. The findings were reported by a compliant Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. RESULTS: Two hundred and eighty-two records were identified from the literature searches, of which 64 were duplicates, whereas five reviews were identified from the hand search. A total of 36 reviews were included after screening against inclusion/exclusion criteria, 35 from literature searches and one from hand searching. Of those studies 1, 27 and 8 were low, moderate and high quality, respectively. The reviews highlight the scarcity of evidence for health economic parameters, for example, clinical effectiveness, costs, quality of life and the natural history of disease. Health economic evaluations such as cost-effectiveness and budget-impact analyses were scarce, and generally low-to-moderate quality. The causes were limited health economic parameters, together with publications bias, especially for cost-effectiveness analyses. CONCLUSIONS: The results highlighted issues around a considerable paucity of evidence for economic evaluations and few cost-effectiveness analyses, supporting the notion that a paucity of evidence makes economic evaluations of rare diseases more challenging compared with more prevalent diseases. Furthermore, we provide recommendations for more sustainable approaches in economic evaluations of rare diseases.

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.

The actual status of drug prices and adjustment factors for drug price calculation: an analysis of ultra-orphan drug development in Japan.

BACKGROUND: Extremely high prices facilitate drug development for ultra-rare diseases (ultra-orphan drugs). However, various problems arise in terms of healthcare financing and fairness, and the status of ultra-orphan drug pricing remains ambiguous. In this study, we investigated ultra-orphan drug prices in Japan relative to that of other drugs. We examined the relationship between annual expected drug prices and expected sales, and the expected number of patients, for 393 drugs containing new active ingredients for therapeutic use that were listed on the National Health Insurance drug price list in Japan between April 16, 2010 and August 26, 2020. In addition, we compared prices, the drug price calculation method, and price calculation adjustment factors for ultra-orphan and other drugs. RESULTS: Drug prices tended to increase as the expected number of patients to whom the drug was administered decreased; however, this trend diminished when the expected number of patients was less than 1000. On the other hand, the expected sales tended to decrease as the number of expected patients decreased, and this tendency was reinforced when the expected number of patients was less than 1000. The cost accounting method tended to be used for the price calculation of ultra-orphan drugs, but there were no price differences based on the drug price calculation method. Regarding the price calculation adjustment factors, the premium for usefulness tended to be higher for ultra-orphan drugs. The premium for marketability was higher for non-orphan drugs but did not differ from that for orphan drugs, except for ultra-orphan drugs. CONCLUSIONS: The status of drug prices and expected sales differed beyond a threshold of 1000 expected patients, indicating that recovering the development cost for ultra-orphan drugs is difficult. In addition, the higher premium for usefulness for ultra-orphan drugs reflects the largely unmet need of the associated diseases. Scarcity among orphan drugs is not considered for marketability, highlighting the need for a new framework to promote the development of ultra-orphan drugs.

Comparison of US and EU Prices for Orphan Drugs in the Perspective of the Considered US Orphan Drugs Act Modifications and Discussed Price-Regulation Mechanisms Adjustments in US and European Union.

The 2019 worldwide sales of Orphan Drugs were estimated at $136 billion USD, which constituted 16% of the global pharmaceutical prescription market and is expected to grow by 12% in the next 5 years. A better understanding of Orphan Drug pricing may contribute to on-going discussions on Orphan Drug Act (ODA) corrections in US or modifications of price setting mechanisms in EU. The objective of the study was comparison and analysis of the prices of Orphan Drugs in US and EU. All drugs with Orphan Drug status were compared in the US and EU. For the US prices, the US Department of Veterans Affairs (VA) was sourced. The EU List Prices came from six EU countries: Denmark, France, Germany, Greece, Poland, Spain. We found US prices to be higher than the six selected EU countries. The average Price Ratio was 1.64. The prices across EU countries were more homogeneous, while the number of the reimbursed and therefore available to patient medicines varied and was correlated with GDP per capita r = 0.87. Considered implementation of the External Reference Price system in US may generate significant savings in the US but may result in upward pressure on pricing of Orphan Drugs in EU. Centralization of the Orphan Drugs pricing negotiations in EU may prevent such development and offer a win-win opportunity for all involved parties.

Meeting the affordability challenges posed by orphan drugs: a survey of payers, providers, and employers.

BACKGROUND: As an increasing number of orphan drugs are FDA approved, health care payers, employers, and providers are attempting to strike a balance between patient access to innovative treatments and overall affordability. Payers and employers are evaluating how traditional specialty pharmacy management strategies and innovative models can support continued coverage of orphan drugs. OBJECTIVE: To understand how health care stakeholders are meeting the financial challenges posed by the increasing number and cost of orphan drugs and how these strategies are affecting orphan drug acquisition for providers. METHODS: A survey was conducted with payer, provider, and employer decision makers recruited from both AMCP and a proprietary database of market-access decision makers in July and August 2020. Respondents were asked about their experiences and activities in the orphan disease space, including tactics to manage affordability of drugs to treat orphan diseases. RESULTS: Reinsurance was the most commonly utilized strategy to maintain affordability of the benefit for both payers (42%) and employers (55%). Although 31% of payers have adopted gene therapy carve-outs, no employers had done so. Approximately three quarters (76%) of payers believe that limited distribution networks impede their abilities to manage orphan drugs, compared with 4% who believe limited networks improve orphan drug management. For most payers (78%), the decision to cover orphan drugs on either the medical or pharmacy benefit depends on the specific drug. Medical benefit coverage was driven primarily by site-of-care policies (55%) and the lower drug cost of average sales price pricing (50%). Pharmacy benefit coverage was driven primarily by a greater ability to manage the orphan drug (71%) and by rebates (62%). One in 3 (33%) of providers with experience treating orphan diseases acquire orphan drugs exclusively through buy and bill, whereas 10% acquire them exclusively through a specialty pharmacy provider. Buy-and-bill acquisition by providers was driven primarily by improved patient affordability (47%) and 340b pricing (47%). Specialty pharmacy provider acquisition was driven primarily by payer requirements (64%) and reduced administrative burden (64%). CONCLUSIONS: Payers and employers are adopting innovative benefit designs and strategies to cover orphan drugs while maintaining plan affordability. Cost considerations are prominent factors in determining whether orphan drugs will be covered under the pharmacy or medical benefit and how providers will acquire orphan drugs. DISCLOSURES: This research was sponsored by AMCP and PRECISIONvalue. Lopata, Terrone, and Gopalan are employees of PRECISIONvalue. Ladikos and Richardson are employees of AMPC. The authors have nothing further to disclose. This research was presented during the AMCP Partnership Forum "Preparing for and Managing Rare Diseases" held virtually September 8-10, 2020.

The 'Netflix plus model': can subscription financing improve access to medicines in low- and middle-income countries?

At present, pay for prescription models are insufficient at containing costs and improving access to medicines. Subscription financing through tenders, licensing fees and unrestricted or fixed volumes can benefit stakeholders across the supply chain. Pharmaceutical manufacturers can reduce the need for marketing expenses and gain certainty in revenue. This will decrease costs, improve predictability in budget expenditure for payers and remove price as a barrier of access from patients. Inherently, low- and middle-income countries lack the purchasing power to leverage price discounts through typical price arrangements. These markets can realise substantial savings for branded and generic medicines through subscription financing. Procuring of on-patent and off-patent drugs requires separate analysis for competition effects, the length of contract and encouraging innovation in the medicine pipeline. Prices of competitive on-patent medicines and orphan drugs can be reduced through increased competition and volume. Furthermore, pooling expertise and resources through joint procurement has the potential for greater savings. Incentivising research and development within the pharmaceutical industry is essential for sustaining a competitive market, preventing monopolies and improving access to expensive treatments. However, technical capacity, forecasting demand and the quality of generic medicines present limitations which necessitate government support and international partnerships. Ultimately, improving access requires progressive financing mechanisms with patients and cost containment in mind.

The current state of patient access to new drugs in South Korea under the positive list system: evaluation of the changes since the new review pathways.

Objective: This study aims to provide an up-to-date analysis of the current state of patient access to new drugs in South Korea, focusing on the effect of new review pathways for reimbursement. Methods: We analyzed patients' access to new drugs, listing rate and lead time until listing from marketing authorization. New pathways were defined as 'price negotiation waiver,' 'risk-sharing agreements,' and 'pharmacoeconomic evaluation exemption.' Results: The listing rate for drugs increased after the introduction of the new pathways (93.7% vs. 77.9%, p < 0.001). Before the new pathways, the median lead time for listing was 21.0 months (95% CI: 16.9-25.0), while afterward it was shortened to 10.9 months (95% CI: 10.2-11.7) (p < 0.001). Conclusion: Although it has strengthened national health insurance coverage by positively impacting the rate and lead time, the lead time for the oncology and orphan drugs is substantially longer as compared to other drugs. Expanding the eligibility criteria to include non-life-threatening but rare or intractable diseases, and resolving the system's operational issues are still necessary.

Rising Drug Costs for Neurologic Diseases.

The cost of prescription drugs in the United States is rising like never before and has led to an inflection point where clinicians must consider the potential financial damage to the patient and to society related to the more expensive drugs available. Many of the highest-priced drugs are approved as orphan drugs, a legally defined status providing additional benefits to pharmaceutical companies that is intended to incentivize therapeutic development for rare diseases. The Orphan Drug Act has been a great success since it was enacted in 1983, resulting in the development of many innovative, life-changing, and even lifesaving drugs; however, high drug prices place patients at risk for personal bankruptcy, prescription abandonment, and higher rates of hospitalization. These negative consequences have become more widespread and severe because some companies exploit pricing via the market exclusivity granted to them under the provisions of the Orphan Drug Act. As more and more companies develop these drugs, the cost to society increases as does the capacity to tolerate unjustified prices. The societal effects of drug pricing must be considered through the prism of opportunity costs; that is, what benefit is lost by choosing to spend on one thing instead of another. Clinical- and economic-based analyses from independent groups such as the Institute for Clinical and Economic Review can help physicians understand the value of drugs (ie, the benefits relative to cost). When prescribing a high-priced medication, clinicians should discuss the drug's value and the associated opportunity cost with patients and have an open discussion about patients' ability to financially tolerate the treatment.

Modifying the Criteria for Granting Orphan Drug Market Exclusivity.

OBJECTIVES: To examine policy options to deny orphan drug exclusivity after drugs exceed a target population of 200 000 across all orphan indications (combined prevalence threshold) or once drugs receive a nonorphan approval (market approval threshold). METHODS: Retrospective analysis of drugs with 2 or more orphan approvals from 1983 to July 01, 2017 examining prevalence of orphan indications and approval years of orphan and nonorphan indications. Characteristics of drugs crossing either threshold are described. A budget impact analysis of Medicare and Marketscan® claims databases estimated potential savings from generic or biosimilar entry as a result of foregone market exclusivity periods determined by these policies. RESULTS: Out of 86 drugs with 2 or more orphan approvals, 21 drugs would be denied orphan drug exclusivity periods under the prevalence threshold and 18 drugs would be denied orphan drug exclusivity periods under the market approval threshold. Drugs with orphan approvals after 2010 were more likely to be denied orphan drug exclusivity. In 2017, Medicare could have saved about $2 billion on 8 drugs under the prevalence threshold policy and $1.3 billion on 12 drugs under the market approval threshold policy). Private insurers could have saved $814 and $919 million, respectively. Over half of the savings would come from 9 drugs that first entered the market for a nonorphan indication. CONCLUSIONS: Modifying the criteria for granting orphan drug exclusivity would affect a small number of orphan drugs but could generate large savings through increased competition. Other incentives such as grants or tax credits for clinical trials could be explored to incentivize research for new orphan indications for drugs that crossed either threshold.

Ensayos clínicos en enfermedades raras financiados por los participantes / Participant-funded clinical trials on rare diseases

El desarrollo de medicamentos para ciertas enfermedades raras puede verse truncado por la falta de financiación. En estos casos, en ocasiones, los propios pacientes -o sus familiares- financian el ensayo clínico en el que recibirán el medicamento experimental. Hay 3modelos de autofinanciación: 2de ellos, «pagar por probar» y «pagar por participar», ya se han puesto en práctica; el tercero, el modelo «plutocrático», que ha sido recientemente planteado, es, hasta la fecha, un modelo teórico. En este trabajo se repasan los beneficios y riesgos científicos, sociales y éticos de los 2modelos de investigación clínica: «pagar por participar» y el modelo «plutocrático». Una manera frecuente de poder autofinanciar estos ensayos clínicos es la obtención de fondos por micromecenazgo. Los aspectos más controvertidos de esta modalidad de financiación también son abordados en este trabajo desde diversas perspectivas. Por último, se plantea un escenario futuro que permitiera en nuestro país la puesta en marcha de estos ensayos clínicos autofinanciados mediante el modelo plutocrático

The development of medicines for certain rare diseases can be frustrated by lack of funding. In certain cases the patients themselves, or their relatives, occasionally fund the clinical trial in which they will be treated with the investigational medicine. There are 3models of self-funded research: 2of them, "pay to try" and "pay to participate", have already been put into practice. The third, the "plutocratic" proposal, which has been recently put forward is still a theoretical model. In this work the scientific, social and ethical benefits and risks of the 2clinical research models, "pay to participate" and the "plutocratic" proposal, are reviewed. Patient-funded clinical trials are frequently performed through crowdfunding. The most controversial aspects of this funding modality are also addressed in this article from several perspectives. Finally, a future scenario that would allow the launching of self-funded clinical trials in Spain by the "plutocratic" proposal is proposed

One drug to treat many diseases: unlocking the economic trap of rare diseases.

There are two major problems with the development of therapies for rare diseases. First, among over 7000 such diseases, the vast majority are caused by genetic defects and/or include neurodegeneration, making them very difficult to treat. Second, drugs for rare diseases, so-called orphan drugs, are extremely expensive, as only a small number of patients are interested in purchasing them. This results in the appearance of a specific economic trap of rare diseases; namely, despite high biomedical, pharmaceutical and technological potential, the development of new orphan drugs is blocked by the economic reality. The purpose of this work was to find a potential solution that might resolve this economic trap of rare diseases. A literature review was conducted, and a hypothesis was formulated assuming that the use of one drug for the treatment of many rare diseases might overcome the economic trap. We provide examples showing that finding such drugs is possible. Thus, a possible solution for the problem of developing orphan drugs is presented. Further preclinical and clinical studies, although neither easy nor inexpensive, should verify whether the hypothesis regarding the possibility of unlocking the economic trap of rare diseases is valid.

Policy Recommendations to Promote Prescription Drug Competition: A Position Paper From the American College of Physicians.

The prescription drug market in the United States relies on competition to keep prices reasonable. Although many policies have been implemented to spur competition and decrease costs for patients, these policies may be outdated and should be redesigned and updated to achieve success in the current prescription drug market. In this paper, the American College of Physicians (ACP) proposes that new policies should be implemented to prevent market manipulation, help lower-cost alternatives make it to the market faster, and ensure a robust and competitive market for generic and biosimilar drugs. The ACP believes these changes will have a meaningful effect on patients without shifting costs to other areas of the health care system.

[Orphan drugs and drug pirates]. / Weesgeneesmiddelen en medicijnkapers.

The European Orphan Medicines Regulation, which came into effect in 2000, stimulates the development of medicines for rare diseases. The number of registered orphan medicines has increased from eight in 2000 to 169 in 2019; 38% of these are available in the Netherlands. The costs for orphan medicines in the Netherlands are increasing by 9% every year, and now amount to €272 million annually. There is, however, still no effective medication for thousands of rare diseases. The Orphan Regulation was intended for new orphan medicines, but some companies also use it for 'repurposing' of old agents, for which they also get 10 years exclusive market rights in the EU. The improper use of legislation has led to concern among patients, doctors, and medical insurance companies. The Netherlands Council for Public Health and Society and MPs in the lower house of the Netherlands parliament have proposed measures for tackling the high prices of medicines and Mr. Bruins, the former Minister of Health, wanted to propose legislative change in the EU. The EU 'pharmaceutical incentive review' offers the possibility to revise the current rules.

A crisis in US drug pricing: Consequences for patients with neuromuscular diseases, physicians and society, part 1.

Drug prices in the United States have reached astounding heights, negatively impacting patients and society. The vast majority of prescription drug spending is on brand name drugs, which are protected from typical market pressures by FDA exclusivity and intellectual property patents. Drugs to treat "orphan" diseases, of particular relevance to neuromuscular clinicians, are some of the most expensive in all of medicine. The Orphan Drug Act's original intent was to incentivize the creation of drugs that would otherwise provide little economic payoff. While it has facilitated incredible, life-changing drugs for our patients, it has also become a source of abuse. Many expensive drugs approved under the Orphan Drug Act were previously available for compassionate use or for another indication at much lower prices. As patients increasingly face high drug prices, it is important for clinicians to understand a drug's risk for inducing financial toxicity, as the financial and emotional consequences of an overpriced low-value drug may outweigh its intended benefit.

Regulatory approval and public drug plan listing of new drugs for rare disorders in Canada and New Zealand.

A previous assessment of the alignment of health technology assessments and price negotiations for new drugs for rare disorders in Canada completed between 2014 and 2018 demonstrated that it is working for governments but has yet to lead to improved access in a timely manner for all appropriate patients in all provinces. In this analysis, drugs for rare and ultra-rare disorders with a completed price negotiation or no negotiation between 2014 and 2018 in Canada, and their reimbursement recommendations and listings in Canadian public drug programs are compared with their regulatory approval in New Zealand and listing in the New Zealand National Formulary. The results show that pharmaceutical manufacturers generally seek regulatory approval for rare disorder drugs in Canada before New Zealand, and fewer rare disorder medicines receive regulatory approval in New Zealand. One reason for this difference might be New Zealand's smaller population. However, another reason is likely the restrictive drug formulary in New Zealand. Drugs not given coverage in New Zealand are frequently made unavailable by the manufacturer. Planned changes to Canada's pricing regulations and guidelines will significantly diminish the country's attractiveness as a place in which pharmaceutical companies want to do business, which has the potential to negatively impact the health of all Canadians irrespective of whether they have private or public drug coverage.