Developing and paying for medicines for orphan indications in oncology: utilitarian regulation vs equitable care?
ABSTRACT: Despite 'orphan drug' legislation, bringing new medicines for rare diseases to market and securing funding for their provision is sometimes both costly and problematic, even in the case of medicines for very rare 'ultra orphan' oncological indications. In this paper difficulties surrounding the introduction of a new treatment for osteosarcoma exemplify the challenges that innovators can face. The implications of current policy debate on 'value-based' medicines pricing in Europe, North America and elsewhere are also explored in the context of sustaining research into and facilitating cancer patient access to medicines for low-prevalence indications. Tensions exist between utilitarian strategies aimed at optimising the welfare of the majority in the society and minority-interest-focused approaches to equitable care provision. Current regulatory and pricing strategies should be revisited with the objective of facilitating fair and timely drug supply to patients without sacrificing safety or overall affordability. Failures effectively to tackle the problems considered here could undermine public interests in developing better therapies for cancer patients.
Project description:<h4>Background</h4>Life-saving orphan drugs are some of the most expensive medicines. European Union governments aim to accommodate their provision within stretched healthcare budgets but face pressure to reduce funding of such treatments. Patients struggle to retain or gain access to them as their special status is questioned, causing distress and in some cases, fears of premature death. In the UK and EU reimbursement and pricing model of drugs, and orphan drugs in particular, is being re-evaluated.<h4>Methods</h4>Using the United Kingdom as a case study we present, for the first time, legal arguments which compel governments to provide orphan medicinal products. These include (i) disability legislation, (ii) national and organisational constitutions, (iii) judicial review, (iv) tort law and (v) human rights legislation. We then address directly potential objections to our analysis and counter arguments which aim to limit provision of orphan drugs to the intended patient recipients.<h4>Results</h4>We demonstrate that a compelling case can be made that the law demands the treatment of orphan diseases.<h4>Conclusions</h4>Our legal framework will assist doctors and patients in ensuring the continued provision of treatments despite significant economic pressure to reduce funding. These legal avenues will empower stakeholders in drafting funding guidelines throughout the EU. The legal right to treatment extends beyond rare diseases and our analysis may therefore affect allocation of healthcare budgets throughout the EU.
Project description:<h4>Background</h4>Drug repurposing (i.e., finding novel uses for existing drugs) is essential for maximizing medicines' therapeutic utility, but obtaining regulatory approval for new indications is costly. Policymakers have therefore created temporary indication-specific market exclusivities to incentivize drug innovators to run new clinical investigations. The effectiveness of these exclusivities is poorly understood.<h4>Objective</h4>To determine whether generic entry impacts the probability of new indication additions.<h4>Methods</h4>For a cohort of all new small-molecule drugs approved by the FDA between July 1997 and May 2020, we tracked new indications added for the subset of drugs that experienced generic entry during the observation period and then analyzed how the probability of a new indication changed with the number of years since/to generic entry.<h4>Results</h4>Of the 197 new drugs that subsequently experienced generic entry, only 64 (32%) had at least one new indication added. The probability of a new indication addition peaked above 4% between 7 and 8 years prior to generic entry and then to dropped to near zero 15 years after FDA approval. We show that the limited duration of exclusivity reduces the number of secondary indications significantly.<h4>Conclusion</h4>Status quo for most drug innovators is creating novel one-indication products. Despite indication-specific exclusivities, the imminence of generic entry still has a detectable impact on reducing the chances of new indication additions. There is much room for improvement when it comes to incentivizing clinical investigations for new uses and unlocking existing medicines' full therapeutic potential.
Project description:OBJECTIVE:To review existing regulations and policies utilised by countries to enable patient access to orphan drugs. METHODS: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. RESULTS: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. CONCLUSIONS: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.
Project description:<h4>Background</h4>High prices of anticancer medicines have increased the economic burden for both patients and health insurance systems. Since 2017, China has implemented national price negotiations for medicines, relying on evidence from health technology assessments. We aim to assess the relation between negotiated price and value of anticancer medicines listed in China's National Reimbursement Drug List (NRDL).<h4>Methods</h4>For all price-negotiated anticancer medicines and corresponding indications listed in the latest NRDL between 2017 and 2020, we collected their clinical outcomes data, including overall survival (OS) and progression-free survival (PFS), in supporting trials. Pearson correlation coefficient was calculated to estimate the association between the daily cost and clinical benefit of each indication.<h4>Results</h4>In total, 75 indications of 46 branded anticancer medicines were included for analysis. The median daily costs for the anticancer therapies that had gone through negotiation in 2017-2020 were US$87.6, US$71.8, US$58.9, and US$39.7, respectively. For indications supported by randomized trials, no correlation between daily costs and OS and PFS benefit of the price-negotiated cancer therapies was observed (N = 41, r = -0.05, and N = 49, r = 0.04, respectively). For cancer indications newly listed in NRDL in 2020, the association between their daily cost and OS benefit was -0.78 (N = 4, p = 0.221) and 0.01 (N = 8, p = 0.986) before and after the price negotiation.<h4>Conclusion</h4>Though the negotiation policy decreased prices of anticancer medicines in China, no statistically significant correlation was observed between their daily costs and clinical benefits. A more transparent and credible pricing approach needs to be established to promote value-based anticancer medicines and healthcare system efficiency.
Project description:<b>Background and Objective</b>: Orphan drugs have been a highlight of discussions due to their higher prices than non-orphan drugs. There is currently no European consensus on the method of value assessment for orphan drugs. This study assessed the relationship between the prevalence of rare diseases and the annual treatment cost of orphan drugs in France, Germany, Italy, Norway, Spain, Sweden, and UK. <b>Methods</b>: Approved orphan drugs and prevalence data were extracted from the European Medicines Agency website. Annual treatment costs were calculated using ex-factory price. Simple regression was used to analyse the relationship between costs and prevalence. A specific bivariate analysis was performed for the rarest diseases (?1 per 10,000). <b>Results</b>: 120 drugs were analysed. Prevalence ranged from 0.001 to 5 per 10,000 (mean 1.24, median 1). Annual treatment costs per patient ranged from €755 to €1,051,956 (mean €100,000, median €39,303). Results show a statistically significant inverse correlation between annual treatment cost and disease prevalence in all countries (France: r = -0.370, <i>p </i>= 0.002; Germany: r = -0.365, <i>p </i>= 0.002; Italy: r = -0.340, <i>p </i>= 0.002; Spain: r = -0.316, <i>p </i>= 0.041; UK: r = -0.358, <i>p </i>= 0.0004; Sweden: r = -0.414, <i>p </i>= 0.014; Norway: r = -0.367, <i>p </i>= 0.002). When analysis was focused on the rarest diseases, a stronger correlation exists in all countries (France: r = -0.525, Germany: r = -0.482, Italy: r = -0.497, Spain: r = -0.531, UK: r = -0.436, Sweden: r = -0.455, Norway: r = -0.466; all <i>p </i>< 0.05 except Sweden <i>p </i>= 0.077). <b>Conclusions</b>: This study shows an inverse correlation between annual treatment cost and prevalence with high statistical significance in the studied countries. Although pricing is a complex process where different attributes are assessed, this study supports the idea that payers value rarity in pricing decisions.
Project description:<h4>Objective</h4>To determine differences in the characteristics of cancer drugs designated as orphan drugs by the Food and Drug Administration (FDA) and European Medicines Agency (EMA).<h4>Design and setting</h4>Identification of all cancer drugs (initial or supplementary indication) with orphan status approved by the FDA between 2008-2017 based on publicly accessible reports. The European public assessment reports (EPAR) was searched to determine whether these FDA-approved drugs were also approved by the EMA.<h4>Main outcome measures</h4>Extraction of active ingredient, trade name, approval date and approved indication from two FDA data sources (Orphan Drug Product Designation Database, Drugs@FDA) and comparison with the same data from EPAR.<h4>Results</h4>The FDA approved 135 cancer drugs with orphan indications that met our inclusion criteria, of which 101 (75%) were also approved by the EMA. 80/101 (79%) were first approved in the USA. Only 41/101 (41%) also received orphan designation by the EMA. 33/101 (33%) were approved for biomarker-based indications in the USA, however, only nine approved cancer drug indications by the EMA were biomarker-derived drugs. 78% (47/60) of approved cancer drugs that were only approved in the USA with orphan status were indicated for solid tumours, 22% (13/60) had indications for non-solid tumours. By contrast, out of those approved cancer drugs that received orphan designation by both agencies, 20% (8/41) were indicated for solid, and 80% (33/41) for non-solid tumours.<h4>Conclusions</h4>Orphan designation was intended to encourage drug development for rare conditions. This study shows that the FDA approves more cancer drugs with such designations compared with the EMA, especially for subgroups of more prevalent cancers. One reason for the difference could be that the European Union requires demonstration of significant benefit for drugs that target the same indication as a drug already on the market to earn the orphan designation.
Project description:OBJECTIVE:To compare review outcome alignment between European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for medicines approved by both agencies in the time period 2014-2016. DESIGN:Using publicly available information from FDA and EMA websites, new active substances (NASs) approved by each agency from 2014 to 2016 were identified and their characteristics assessed. Divergences in regulatory outcomes for simultaneous (within 91 days) submissions to both agencies were identified and then examined for use of facilitated regulatory pathways and orphan designations; submitted versus approved indications; and approval times. RESULTS:In 2014-2016, 115 NASs were approved by EMA or FDA or both; 74/115 were new chemical entities and 41 new biological/biotechnology entities; 82/115 were approved by both agencies, 24 only by FDA and nine only by EMA. Simultaneous submission occurred for 52/115; 13/52 received expedited review by both agencies and 18 only by FDA; 8/52 received conditional approval from both agencies, 2/52 only from FDA and 1/52 only from EMA; 17/52 were designated as orphans by both agencies and 10/52 by FDA only; 31/52 indications were approved as submitted and 21 changed by EMA and 29/46 were approved as submitted (six not assessed) and 17/46 changed by FDA. Median FDA review timelines were 319 days compared with 409 days for EMA. CONCLUSIONS:There was general agreement in EMA / FDA conditional approvals. FDA used expedited pathways and orphan designation more often than EMA, suggesting stricter EMA criteria or definitions for these designations or less flexible processes. Despite consistency in submitted indications, there was lack of concordance in approved indications, which should be further investigated. FDA review times are faster because of a wider range of expedited pathways and the two-step EMA process; this may change with recent revisions to EMA accelerated assessment guidelines and the launch of Priority Medicines.
Project description:Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines.A systematic review of Pubmed, the Financial Times, the New York Times, the Wall Street Journal and the Guardian was performed to identify articles related to the pricing of medicines.Changes in drug life cycles have dramatically affected patent medicine markets, which have long been considered a self-evident and self-sustainable source of income for highly profitable drug companies. Market failure in combination with high merger and acquisition activity in the sector have allowed price increases for even off-patent drugs. With market interventions and the introduction of QALY measures in health care, governments have tried to influence drug prices, but often encounter unintended consequences. Patent reform legislation, reference pricing, outcome-based pricing and incentivizing physicians and pharmacists to prescribe low-cost drugs are among the most promising short-term policy options. Due to the lack of systematic research on the effectiveness of policy measures, an increasing number of ad hoc decisions have been made with counterproductive effects on the availability of essential drugs. Future challenges demand new policies, for which recommendations are offered.A fertile ground for high-priced drugs has been created by changes in drug life-cycle dynamics, the unintended effects of patent legislation, government policy measures and orphan drug programs. There is an urgent need for regulatory reform to curtail prices and safeguard equitable access to innovative medicines.
Project description:BACKGROUND:There are indications of staggered market entry of medicines in the national markets, with medicines being marketed first in countries with high prices. This study aimed to analyse the availability and evolution of medicine prices in the European Union (EU). METHODS:This research was performed for an illustrative sample of five medicines (abiraterone, emtricitabine/rilpivirine/tenofovir disoproxil, fingolimod, linagliptin and sofosbuvir) in 27 EU Member States. Price data at 6, 12, 18, 36 and 60 months after marketing authorisation were retrieved from national administrative price databases and registers accessible through the Pharma Price Information service. RESULTS:In the first year after marketing authorisation, price data for the selected medicines were only available in a small number of EU Member States-usually high-income countries. Availability increased over time. However, some countries, for instance Central and Eastern Europe, had price data available only several years after marketing authorisation. The average European price of the surveyed medicines decreased by at least 7.1% between 6 months and 3 years and at least 9.5% between 6 months and 5 years after marketing authorisation. Price data availability in lower-income countries at later stages, and price decreases in some countries, appear to be major reasons for the reductions in average prices. CONCLUSIONS:If policymakers aim to apply the pricing policy of external price referencing (i.e. price setting based on prices in other countries) for cost-containment purposes, they are recommended to undertake continuous price revisions over the years.
Project description:OBJECTIVES:Value-based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value-based pricing to reference cost-effectiveness thresholds (?) on individual and population-level health benefits remains uncharacterized. The current study examined the potential benefits of value-based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer-submitted price without value-based pricing. METHODS:Pan-Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (?C) and quality-adjusted life-years (?QALY) from manufacturer-submitted, pCODR lower-limit (pCODR-LL) and upper-limit (pCODR-UL) re-analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (?QALY × cases). Population QALY gain/loss in the absence of value-based pricing to reference ? was estimated by the INHB: (INHB = [?QALY - (?C/?)] × cases). RESULTS:In total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR-LL, and pCODR-UL estimates was 1851, 1617, and 1301, respectively. At a ? $100 000/QALY, funding in the absence of value-based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs. CONCLUSIONS:Despite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value-based pricing, was demonstrated. Supportive evidence exists for value-based pricing toward the promotion of health benefits for the greater population.