revive potential orphan drugs whose development has stalled by identifying barriers to commercialization, such as problems with formulation and bio-processing. numerous advocacy groups such as the national organization for rare disorders, global genes project, children's rare disease network, abetalipoproteinemia collaboration foundation, zellweger baby support network, and the friedreich's ataxia research alliance have been founded in order to advocate on behalf of patients with rare diseases with a particular emphasis on diseases that affect children. cost according to a 2015 report published by evaluatepharma, the economics of orphan drugs mirrors the economics of the pharmaceutical market as a whole but has a few very large differences. the market for orphan drugs is by definition very small, but while the customer base is drastically smaller the cost of research and development is very much the same as for non orphan drugs. this, the producers have claimed, causes them to charge extremely high amounts for treatment, sometimes as high as $700,000 a year, as in the case of spinraza (biogen), fda approved in december 2016 for spinal muscular atrophy, placing a large amount of stress on insurance companies and patients. an analysis of 12 orphan drugs that were approved in the us between 1990 and 2000 estimated a price reduction of on average 50% upon loss of marketing exclusivity, with a range of price reductions from 14% to 95%. governments have implemented steps to reduce high research and development cost with subsidies and other forms of financial assistance. the largest assistance are tax breaks which can be as high as 50% of research and development costs. orphan drug manufacturers are also able to take advantage of the small customer base to cut cost on clinical trials due to the small number of cases to have smaller trials which reduces cost. these smaller clinical trials also allow orphan drugs to move to market faster as the average time to receive fda approval for an orphan drug is 10 months compared to 13 months for non-orphan drugs. this is especially true in the market for cancer drugs, as a 2011 study found that between 2004 and 2010 orphan drug trials were more likely to be smaller and less randomized than their non-orphan counterparts, but still had a higher fda approval rate, with 15 orphan cancer drugs being approved, while only 12 non-orphan drugs were approved. this allows manufactures to get cost to the point that it is economically feasible to produce these treatments. the subsidies can total up to $30 million per fiscal year in the united states alone. by 2015, industry analysts and academic researchers agreed, that the sky-high price of orphan drugs, such as eculizumab, was not related to research, development and manufacturing costs. their price is arbitrary and they have become more profitable than traditional medicines.public resources went into understanding the molecular basis of the disease, public resources went into the technology to make antibodies and finally, alexion, to their credit, kind of picked up the pieces.— sachdev sidhu 2015 public funding evaluation criteria by 2007 the use of economic evaluation methods regarding public-funding of orphan drugs, using estimates of the incremental cost-effectiveness, for example, became more established internationally. the qaly has often been used in cost-utility analysis to calculate the ratio of cost to qalys saved for a particular health care intervention. by 2008 the national institute for health and care excellence (nice) in england and wales, for example, operated with a threshold range of £20,000–30,000 per quality-adjusted life year (qaly). by 2005 doubts were raised about the use of economic evaluations in orphan drugs. by 2008 most of the orphan drugs appraised had cost-effectiveness thresholds "well in excess of the 'accepted' level and would not be reimbursed according to conventional criteria". as early as 2005 mccabe et al. argued that rarity should not have a premium and orphan drugs should be treated like other pharmaceuticals in general. drummond et al. argued that the social value of health technologies should also be included in the assessment along with the estimation of the incremental cost-effectiveness ratio. abuse potential rosuvastatin (brand name crestor) is an example of a drug that received orphan drug funding but was later marketed to a large consumer base. the very large incentives given to pharmaceutical companies to produce orphan drugs have led to the impression that the financial support afforded to make these drugs possible is akin to abuse. because drugs can be used to treat multiple conditions, companies can take drugs that were filed with their government agency as orphan drugs to receive financial assistance, and then market it to a wide population to increase their profit margin. for example astrazeneca's cholesterol drug crestor was filed as a treatment for the rare disease pediatric familial hypercholesterolemia. after the drug was approved for orphan drug designation, and astrazeneca had received tax breaks and other advantages, astrazeneca later applied and received fda approval for the drug to be used to treat cholesterol in all diabetics. nice the uk's national institute for health and care excellence (nice) can pay from £100,000 to £300,000 per qaly (quality adjusted life year) for treatments of "very rare conditions". this is compared to under £20,000 for non-orphan drugs. in 2015, nice held consultations with "patient groups, the department of health, companies, learned societies, charities and researchers" regarding the appraisal of medicines and other technologies. there was a call for more research into new processes, including: the model of pharmaceutical research and development, the expectations that companies and patient groups have about how risk and reward is shared between the industry and a publicly funded nhs, and in the arrangements for commissioning expensive new treatments.— nice 2014