User:Oceanflynn/sandbox/Timeline Orphan Drugs

Timeline orphan drugs is a compilation of significant events related to legislation, research, marketing etc of orphan drugs. There are special rules for certain rare diseases ("orphan diseases") in several major drug regulatory territories. For example, diseases involving fewer than 200,000 patients in the United States, or larger populations in certain circumstances are subject to the Orphan Drug Act. Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions, fee waivers, and market exclusivity on that drug for a limited time (seven years), regardless of whether the drug is protected by patents. By 2014 orphan drugs were more lucrative than non-orphan drugs to companies in the pharmaceutical industry that focus on orphan drugs. They "offer opportunities for greater returns on investment compared to other companies, owing to factors such as the higher pricing, financial incentives, accelerated regulatory filings and smaller sales force requirements for orphan drugs." This theory was questioned in Morel et al (2014).

2015

Orphan Drugs & Rare Diseases Global Congress 2015 - Europe,

"Over 7,000 different types of rare diseases and disorders exist, with more being discovered each day, and large pharmaceutical and biotech companies are structuring to participate and leverage the growing orphan market. “Orphan drug sales will make up 19% of the total share of prescription drug sales by 2020, totaling $176 billion. And they’ll grow at an annual rate of nearly 11% per year through the end of the decade, compared with about 4% for drugs treating larger populations.”

— EvaluatePharma’s Orphan Drug Report 2014

From 1975 to 2015 many countries adopted measures to promote the commercial development of Drugs for rare diseases (DRDs) s and facilitate patient access to these treatments. Health Canada has only approved half of FDA-approved DRDs for sale in Canada. In some cases it takes six years for FDA-approved drugs to enter the Canadian market.

Various governments use different standards for Health technology assessments (HTA) regarding orphan drugs and other treatments for diseases that are not rare. Canada's Canadian Agency for Drugs and Technologies in Health (CADTH) uses the same standards for both.

2014

According to a 2014 report by Andreas Hadjivasiliou, published by Evaluate Pharma, in the last few years, the orphan drug market has become increasingly lucrative because the cost of clinical trials for orphan drugs is substantially lower than for other diseases—trial sizes are naturally much smaller than for more common diseases with larger numbers of patients— and there is a lack of alternative therapies for rare diseases. Small clinical trials and little competition place these "orphan agents" at an advantage when they come up for regulatory review. There is a further reduction to the cost of development because of the tax incentives in the Orphan Drug Act 1983. On average the cost per patient for orphan drugs is "six times that of non-orphan drugs, a clear indication of their pricing power." Partly as a result of the 1983 US Orphan Drug Act, Japan adopted it in 1993 as did the European Union in 2000. Although there are much smaller orphan disease populations are the smallest, the cost of per-patient outlays are the largest. Hadjivasiliou argues that there will be more pressure on pharmaceuticals that "represent the biggest budgetary drain" particularly as more people with rare diseases—in the United States for example—will be eligible for public subsidies through the Affordable Care Act.

"Over 7,000 different types of rare diseases and disorders exist, with more being discovered each day, and large pharmaceutical and biotech companies are structuring to participate and leverage the growing orphan market. “Orphan drug sales will make up 19% of the total share of prescription drug sales by 2020, totaling $176 billion. And they’ll grow at an annual rate of nearly 11% per year through the end of the decade, compared with about 4% for drugs treating larger populations."

— EvaluatePharma’s Orphan Drug Report 2014

According to the 2014 Orphan Drug report orphan drug designations continue to increase rapidly. There are soaring forecasts for sales of orphan drugs and the percentage of sales of total share of prescription drug sales is also increasing at a rapid rate. By 2020 the total is predicted to be $176 billion.

KuicK Research released their "Global Orphan Drug Market Outlook 2018" research report "offering comprehensive insight on recent trends, regulatory development related to US orphan drug market, Europe orphan drug market & Asia orphan drug market. The Report also gives insight on more than 600 orphan drugs in clinical pipeline and 231 marketed orphan drugs."

"The global pharmaceutical industry has been experiencing a slow growth in recent years owing to many factors such as expiration of patents, competition from generic drugs segment, exhausting pipelines, and an increasingly stringent regulatory framework. It is most likely that many blockbuster drugs would lose their exclusivity in the next 5 year horizon. Thus, due to significant competition from generics and the current economic situation, the focus area of the pharmaceutical companies is undergoing a paradigm shift from manufacturing traditional essential medicines to investing in the new business model, which is also called orphan drugs. The returns on investment from orphan drugs are expected to help the pharma companies to overcome the impact of revenue loss due to expiry of patents of blockbuster drugs."

— Kuick Research 2014

According to a London School of Economics published a 2014 refereed article comparing the outcomes and consequences of Health Technology Assessments (HTA) processes that determine expected value for money for Orphan Drugs (ODs) among European Union (EU) member states (MS), the outcome of assessments differs significantly across the EU with consequences for access to medicines across member states (MS) [2]. Orphan drugs (ODs). For example "90% of a sample of 60 ODs" were available in "France, was found to the Netherlands and Denmark but "only one third were available in Spain, Greece and Romania [6]. Financial considerations often limit access to pharmaceuticals in many EU member states. A survey undertaken in 2014 "reported that nearly a quarter of the 22 European countries surveyed (Estonia, Latvia, Lithuania, Poland and Romania) restricted access to ODs due to budgetary constraints. Based on the same survey, only 5 countries always granted access to ODs, while several authorised access but with possible restrictions, such as prior authorisation."[7]

2013

"These 25 biotechnology firms are ranked by their market capitalization for the latest quarter that they furnished figures on their numbers of outstanding shares."

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1. 13. UCB

2013 Market Cap: $11.650 billion (3/31: 179.3 million shares * price €49.80 on 3/29)1,6

2012 Market Cap: $7.449 billion (3/31: 176.4 million shares * price €32.35 on 3/30)1,6

% Change: 56.4%

Position on 2012 List: #14

1. 12. Vertex Pharmaceuticals

2013 Market Cap: $17.495 billion (4/26: 221,400,864 shares * price $79.02)

2012 Market Cap: $8.151 billion (4/27: 211,061,148 shares * price $38.62)

% Change: 114.6%

Position on 2012 List: #11

1. 11. Shire

2013 Market Cap: $17.252 billion (4/29: 562,826,237 shares * price £20.17)

2012 Market Cap: $17.205 billion (4/27: 562,532,330 shares * price £20.13 on 4/26)

% Change: 0.3%

Position on 2012 List: Not on list

1. 10. Alexion

2013 Market Cap: $17.893 billion (4/23: 195,146,634 shares * price $91.69)

2012 Market Cap: $17.152 billion (4/20: 186,924,017 shares * price $91.76)

% Change: 4.3%

Position on 2012 List: #10

1. 9. Regeneron

2013 Market Cap: $20.269 billion (4/17: 95,122,401 shares * price $213.08)7

2012 Market Cap: $11.894 billion (4/11: 97,966,145 shares * price $121.41)7

% Change: 70.4%

Position on 2012 List: #12

1. 8. CSL

2013 Market Cap: $27.440 billion (6/30: A$30.042 billion) (dd)1,8

2012 Market Cap: $18.359 billion (6/30: A$20.099 billion) (dd)1,8

% Change: 49.5%

Position on 2012 List: #9

1. 7. Merck KGaA

2013 Market Cap: $33.364 billion (3/31: 217,388,939 shares * price €117.70 on 3/29)4

2012 Market Cap: $22.319 billion (3/31: 217,388,939 shares * price €78.72 on 3/30)4

% Change: 49.5%

Position on 2012 List: #8

1. 6. Teva Pharmaceutical Industries

2013 Market Cap: $33.768 billion (3/31: About 851 million shares * price $39.68 on 3/28)4,9

2012 Market Cap: $39.292 billion (3/31: About 872 million shares * price $45.06 on 3/30)4,9

% Change: -14.1%

Position on 2012 List: #5

1. 5. Biogen Idec

2013 Market Cap: $47.157 billion (4/18: 237,374,815 shares * price $198.66)

2012 Market Cap: $31.582 billion (5/1: 239,562,899 shares * price $131.83)

% Change: 49.3%

Position on 2012 List: #4

1. 4. Celgene

2013 Market Cap: $52.557 billion (4/23: 417,122,477 shares * price $126.00)

2012 Market Cap: $34.319 billion (4/25: 440,497,817 shares * price $77.91)

% Change: 53.1%

Position on 2012 List: #7

1. 3. Gilead Sciences

2013 Market Cap: $78.373 billion (4/26: 1,525,355,825 shares * price $51.38)

2012 Market Cap: $19.751 billion (4/27: 757,321,824 shares * price $26.08)

% Change: 296.8%

Position on 2012 List: #3

1. 2. Amgen

2013 Market Cap: $78.695 billion (4/24: 749,976,556 shares * price $104.93)

2012 Market Cap: $55.054 billion (4/26: 777,707,877 shares * price $70.79)

% Change: 42.9%

Position on 2012 List: #2

1. 1. Novo Nordisk

2013 Market Cap: $85.335 billion (7/2: 535.0 million shares * price DKK 911.50)1,10

2012 Market Cap: $62.809 billion (7/2: 418.0 million shares * price DKK 859.00)1,10

% Change: 35.9%

Position on 2012 List: #1

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Market cap is calculated by multiplying the number of outstanding shares by the share price. U.S. companies generally report their numbers of outstanding shares in their 10-Q quarterly or 10-K annual earnings filings with the Securities & Exchange Commission. Companies based outside the U.S. either disclose market cap directly, or their numbers of shares “in issue” or “in free issue” in half-year and full-year results disclosures. For all companies, closing share prices as of the dates of their outstanding-shares figures can be found through any of several free stock information websites. Figures of non-U.S. companies were converted to U.S. dollars from various currencies.

Notes: 1 Figures converted to U.S. dollars via www.xe.com on July 11, 2013 2 Market cap figures calculated as of March 31, the end of the company’s fiscal year, since outstanding shares figures were published in company’s annual report but not in Q1 results materials. 3 First-quarter figures for numbers of outstanding shares in Q1 2013 and Q1 2012 were rounded to the nearest tenth and furnished by the company in financial reports. 4 Prices are those at close of the trading day preceding March 31, since that day fell on a weekend during both 2013 and 2012. 5 First-quarter figures supplied by company for numbers of outstanding shares in Q1 2013 and Q1 2012 were rounded to the nearest tenth and included within press releases. 6 First-quarter figures supplied by company for numbers of weighted average shares outstanding in Q1 2013 and Q1 2012 were rounded to the nearest tenth and included within press releases. 7 2013 share count combines 95,908,088 shares of common stock and 2,058,057 shares of Class A stock; 2012 share count combines 93,032,889 shares of common stock and 2,089,512 shares of Class A stock. 8 Market capitalization figures included in the Top 40 with Market Capitalization list published July 2 by the Australian publication Biotech Daily. CSL furnishes figures on number of shares in its annual reports, the latest of which covers the 2011–12 fiscal year. 9 First-quarter figures supplied by company for numbers of outstanding shares in Q1 2013 and Q1 2012 were rounded to the nearest whole number and included within press releases. 10 Share price and number of shares data is available on the historic stock information section of company’s website, which rounds off total number of shares to the nearest whole number.

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READERS' COMMENTS

POSTED 07/28/2013 BY JAMES THORNTONIt would be helpful if you also were to list the main product line or service provided by these companies. Jim Thornton

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You must be signed in to perform this action. Click here to Login or Register for free. You will be taken back to your selected item after Login/Registration.{| class="wikitable" |+ caption ! ranking  !! company !!2013 Market Cap!! |- | 1 || Novo Nordisk ||$85.335 billion (7/2: 535.0 million shares * price DKK 911.50)1,10 |- | 2 || Amgen || $78.695 billion (4/24: 749,976,556 shares * price $104.93) |}

2012

The FDA approved NPS Pharmaceuticals’ teduglutide (trade name Gattex, for the treatment of short bowel syndrome in December 2012. In an interview with Forbes journalist at the 2012 Forbes Healthcare Summit, NPS CEO, Francois Nader, described how Dan Drucker, a University of Toronto endocrinologist discovered teduglutide.

"In 2012 corporate America accounted for more than three-quarters of the $3.3 billion spent on lobbying in Washington, DC. General Electric was the market leader, spending $21.4m, and Google came second, with $18.2m."

According to Thomson Reuters in their 2012 publication "The Economic Power of Orphan Drugs", there has been increased investing in orphan drug Research and Development partly due to the U. S. Orphan Drug Act (ODA) 1983 and similar Acts in other regions of the world and also driven by "high-profile philanthropic funding."

By 2012,

"the revenue-generating potential of orphan drugs [was] as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success."

— Gaze and Breen 2012

2011

The period between 2001 to 2011 was the "most productive period in the history of orphan drug development, in terms of average annual orphan drug designations and orphan drug approvals." For the same decade the compound annual growth rate (CAGR) of the orphan drugs was an "impressive 25.8 percent, compared to only 20.1 percent for a matched control group of non-orphan drugs." By 2012 the market for orphan drugs was worth USD$637 million compared to the USD$638 million matched control group of non-orphan drugs, Thomson Reuters.

2010

By 2010 Idursulfase (brand name Elaprase), manufactured by Shire and used for the treatment of Hunter syndrome, was one of the most expensive drugs ever produced, costing US$375,000 per patient per year.

Montreal-based Enobia Pharma Inc. initially developed asfotase alfa (brand name Strensiq). In 2011 Alexion Pharmaceuticals acquired Enobia Pharma and therefore asfotase alfa and continued research into its usage as treatment for an enzyme replacement therapy for [[Hypophosphatasia (HPP), "an inherited and life-threatening ultra-rare metabolic disorder that leads to progressive damage to multiple vital organs, including destruction and deformity of bones." "A significant portion of the research and development" of asfotase alfa was undertaken in Canada, and "Canadian clinicians now have global expertise in the treatment of HPP." "Many analysts expect the drug to pass the "blockbuster" mark of $1 billion a year at some point and maybe reach $2 billion."

The US Patient Protection and Affordable Care Act, (PPACA), (ACA) or Obamacare, signed 23 March 2010 by President Barack Obama a significant regulatory overhaul of the U.S. healthcare system partly to decrease Medicare spending. The PPACA consisted of a combination of measures to control healthcare costs, and an expansion of coverage through public and private insurance: broader Medicaid eligibility and Medicare coverage, and subsidized, regulated private insurance. In 1989 conservative Heritage Foundation proposed an individual mandate as an alternative to single-payer health care. Conservative groups such as Heritage Action provided lobbying support for the linkage between the ACA and the government shutdown. Senate Republicans threatened to block appointments to relevant agencies, such as the Independent Payment Advisory Board and Centers for Medicare and Medicaid Services.

2009

Genzyme, a Sanofi Company undertook clinical trials starting in July 2009 comparing Eliglustat to Imiglucerase in Gaucher Disease Type 1 patients.

According to the Canadian Organization of Rare Diseases (CORD) 80% of rare diseases affect children and "more than 50% of rare disorders are inherited." Prader–Willi syndrome and Hunter syndrome were used as examples of rare diseases with no cure. By 2007 Idursulfase (brand name Elaprase), manufactured by Shire, was approved for the treatment of Hunter syndrome. By 2010 Idursulfase (brand name Elaprase), manufactured by Shireit was one of the most expensive drugs ever produced, costing US$375,000 per patient per year.

2008

By 2008 the "most common criticism of orphan-product legislation has been the very high cost of treatment with some of the 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."

In 2008 Health Canada provisionally licensed the Swiss company Santhera Pharmaceuticals's Idebenone (trade name Catena, Raxone, Sovrima) for treatment of Friedreich's ataxia. Durhane Wong-Rieger, President of Canadian Organization for Rare Disorders (CORD), spoke on behalf of Sanhera's Catena, arguing that it was "essential that governments, insurers and treatment centers combine their efforts and assist Friedreich's Ataxia patients in accessing this new therapeutic advancement." Idebenone was provided free of charge in Quebec, where there is a particularly high occurrence of Friedreich's Ataxia. In all the other Canadian provinces it is only provided by private insurers. Idebenone was removed from the Canadian market in 2013 due to lack of effectiveness. Idebenone was initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects and met with limited success. The .In 2012 the The Cochrane Database of Systematic Reviews on antioxidants and other pharmacological treatment in Friedreich Ataxia In July 2008 idebenone was licensed provisionally in Canada for treatment of Friedreich ataxia. Since then it has been provided free of charge in one of the ten provinces, Quebec, but in the other provinces it is only provided by private insurers. In November 2008, the European Medicines Agency refused marketing authorisation for idebenone in Europe (EMA 2009). The US Food and Drugs Administration has not authorised idebenone for use in Friedreich ataxia. According to the European Federation of Hereditary Ataxias (euro-ATAXIA) by 2012 those the cost of idebenone was high if patients had bo purchase in private pharmaceutical sales.

2007

In an effort to reduce the burden on manufacturers applying for orphan drug status, the FDA and EMA agreed in late 2007 to utilize a common application process for both agencies. However, the two agencies will continue to maintain separate approval processes.

"According to a report by the Center for Public Integrity, congressmen are outnumbered two to one by lobbyists for an industry that spends roughly $100 million a year in campaign contributions and lobbying expenses to protect its profits."

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. 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 than the estimation of the incremental cost-effectiveness ratio.

• 2006 Oldani who worked for Pfizer, Inc. as a pharmaceutical salesperson from 1989 to 1998, drew heavily on his auto-ethnographic experiences while working in the industry" for his PhD dissertation.

2005

From 1998 to 2005, the "pharmaceutical and health products industry spent more than $800 million in federal lobbying and campaign donations at the federal and state levels in the past seven years." This was more than any other industry.

2005 Maskus and Reichman co-edited International Public Goods and Transfer Technology under a Globalized Intellectual Property Regime. Grawbowski's article "Increasing R&D Incentives for Neglected Diseases: Lessons from the Orphan Drug Act.

2004

Genzyme reportedly received more than $800 million in revenue in 2004 from imiglucerase alone. Gaucher's disease affects fewer than 20,000 patients in the USA.

2003

"Drugs such as imiglucerase, an enzyme replacement therapy developed by Genzyme to treat Gaucher's disease; and other orphan blockbuster drugs have led to calls for modification of the legislation. Treatment with imiglucerase might cost as much as US$400,000 per year per adult patient.

Medicare Modernisation Act of 2003, a federal law of the United States, enacted in 2003, was the largest overhaul of Medicare in the public health program's 38-year history. It was signed by President George W. Bush. The MMA's most touted feature is the introduction of an entitlement benefit for prescription drugs, through tax breaks and subsidies. The benefit is funded in a complex way, reflecting diverse priorities of lobbyists and constituencies. As of February 2009, the projected net cost of the program over the 2006 to 2015 period was $549.2 billion. Walter Jones, R-N.C., called the vote "the ugliest night I have ever seen in 22 years." Jones claimed, "The pharmaceutical lobbyists wrote the bill," says Jones. "The bill was over 1,000 pages. And it got to the members of the House that morning, and we voted for it at about 3 a.m. in the morning." Billy Tauzin, R-La, steered the bill through the house. "In 2003 alone, the [pharmaceutical] industry spent nearly $116 million lobbying the government."

In a 2015 article in The Economist, the role of lobbyists in this act was criticized,

"A classic case of selfish lobbying wrapped in a cloak of selflessness was the Medicare Modernisation Act of 2003. Thanks to the pharmaceutical industry’s lobbyists, this brought new prescription-drug benefits to millions of older Americans, but without any attempt to control costs through means-testing or bulk-buying. John Friedman, an economist at Brown University, estimated that as a result the drugmakers would gain benefits of $242 billion over a ten-year period—a healthy return on the $130m the industry spent on lobbying in the year the law passed."

— The Economist 2015

2002

"From 1996 to 2001 the pharmaceutical sales force in America doubled, to a total of 90,000 reps."

1997

The European Organisation for Rare Diseases (EURORDIS), was founded in 1997 as part of patient self-advocacy and it now represents "30 million people affected by rare diseases throughout Europe."

A Wall Street Journal investigative journalist reported that one doctor alone made dozens of Rhone-Poulenc Rorer (RPR)-funded presentations openly promoting RPR's Lovenox, a blood clot medication for Off-label uses that were not approved by the FDA. RPR is "68% owned by Paris-based Rhone-Poulenc SA."

1991

Alglucerase (trade name Ceredase) was approved by the FDA in 1991 and was the first drug approved as an enzyme replacement therapy. "Acquisition cost of alglucerase is $US3.70 per unit (1994 US dollars); thus, a dosage regimen of 60 IU/kg bodyweight administered every 2 weeks for a patient weighing 70kg costs $US404,040 per year." It was withdrawn from the market due to the approval of similar drugs. By 2008 this treatment costs about US$200,000 annually for a single person and should be continued for life. The rarity of the disease means dose-finding studies have been difficult to conduct, so controversy remains over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries, meaning a government recognizes and accommodates the financial constraints that limit research into drugs that address a small population.

1990

The Brattle Group formed in 1990 to provide "consulting services and expert testimony in economics, finance, and regulation to corporations, law firms, and public agencies. It hires internationally recognized experts, and has had strong partnerships with leading academics and highly credentialed industry specialists around the world."

1983

The Orphan Drug Act (ODA) of January 1983, passed in the United States, with lobbying from the National Organization for Rare Disorders and many other organizations, is meant to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the ODA orphan drug sponsors qualify for seven-year FDA-administered market Orphan Drug Exclusivity (ODE), "tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance and and may get clinical trial tax incentives.

1981

Genzyme was started by Sheridan Snyder, George M. Whitesides and scientist Henry Blair in 1981 and is primarily devoted to finding drugs that would cure enzyme deficiency conditions that were essential to human survival and which usually afflict a very small percentage of the world’s population. Drugs used to treat such conditions are considered to be “orphan drugs.” In 1986, the company went public, raising $27 million. In February 16, 2011, Sanofi acquired Genzyme for $20.1 billion.

• 1976

Henry G. Grabowski's article "Drug Regulation and Innovation: Empirical Evidence and Policy Options" was published by the American Enterprise Institute for Public Policy Research. Grabowski Grabowski is Professor Emeritus and Director of Program in Pharmaceutical Health Economics, Duke University and a member of the National Academy of Sciences, the Institute of Medicine, the Federal Trade Commission, the General Accounting Office and the Office of Technology Assessment. *Henry G. Grabowski, Professor Emeritus and Director of Program in Pharmaceutical Health Economics, Duke University. National Academy of Sciences, the Institute of Medicine, the Federal Trade Commission, the General Accounting Office and the Office of Technology Assessment contributes regularly to the American Enterprise Institute for Public Policy Research . Grabowski

1960s

On October 10, 1962 the Kefauver-Harris Amendment became law partly as a result of the thalidomide tragedy. Kefauver's bill enhanced drug regulation by forcing pharmaceutical companies to prove to the FDA that their drugs were both safe and effective before they were introduced into the US market. The FDA received authority to regulate advertising of prescription drugs and to establish good manufacturing practices. The law required that all drugs introduced between 1938 and 1962 had to be effective. An FDA - National Academy of Sciences collaborative study showed that nearly 40 percent of these products were not effective. A similarly comprehensive study of over-the-counter products began in the 1970s.