An unintended consequence was that the development of medications for uncommon diseases became fiscally unattractive to the pharmaceutical industry, ie, “orphaned.” The Orphan Drug Act was enacted by Congress in 1983 to encourage development of drugs to treat less common diseases (diseases/disorders affecting fewer than 200,000 people in the U.S.) through incentives such as exclusive use approval for 7 years, reduced taxes, grants, and favorable laws. Ironically, thalidomide was designated an orphan drug on October 14, 1998 for treatment of multiple myeloma. Since its enactment in 1983, more than 400 orphan drugs and biologic products have been marketed. There may be as many as 7,000 orphan diseases to target for drug therapy, and the 17 of the 20 most expensive drugs in the world in 2013 were for rare orphan diseases.16
Paroxysmal nocturnal hemoglobinuria (PNH) is one of those rare diseases. Mutations of hematopoietic stem cells produce red blood cell membranes deficient in the glycoprotein to which signaling proteins attach (glycosyl phosphatidylinositol) and serve to inhibit complement-induced lysis. This results in intravascular hemolysis (increased LDH and decreased haptoglobin) and increased thrombosis. The FDA approved the orphan drug eculizumab for the treatment of the orphan disease PNH on March 16, 2007.
Eculizumab is a humanized mouse monoclonal antibody that gained FDA orphan drug approval (and exclusivity rights until 2019) for the treatment of aHUS on September 23, 2011, based on 2 industry-sponsored small trials of 17 and 20 patients, and it remains the primary and only known effective treatment for this disease.17-19
Eculizumab has raised many interesting questions. Its mechanism of action wets the appetite of pharmacologists and unveils more basic science questions regarding other related mechanisms of disease, recognition of foreign vs self, genetic influences, virulence of organisms, and more. National and international dilemmas have arisen because of the extreme cost of eculizumab, its position as the only effective treatment for this rare and often fatal disease, and the manufacturer’s recommendation and promotion that it be continued indefinitely. How should the price of a drug, developed in large part by government-supported research and tax incentives, and without competition, be determined and justified?
Pharmaceutical Inflation
A marketplace for pharmaceuticals is simply not analogous to other industries. Advances in pharmacotherapy, some miraculous, have come at a substantial cost. The high cost of drugs became newsworthy with the AIDS pandemic and the approval of the lifesaving azidothymidine (AZT) in 1989 (Burroughs Wellcome–also the developer of pyrimethamine [Daraprim]) and its then record price. Cancer treatment that used to cost $10,000 per year now costs $10,000 per month while the oncology community extolls a 2- or 3-month progression free survival benefit. Patients must now deal with the shock of a cancer diagnosis followed by the shock of an exorbitant copayment.
Recent media attention focused derision on Martin Shkreli, chief executive officer of Turing Pharmaceuticals, for purchasing pyrimethamine and then raising the price of the 62-year-old treatment for protozoan infection toxoplasmosis from $13.50 to $750 per pill. The debacle may also serve to highlight the complexities and ethical issues involved when profit intersects with health care. Some drug costs have dramatically increased in the U.S. because of greed, a belief that a marketplace can control costs, and the lack of regulation. The usual suspects, such as cost of research, length of development, stimulus to innovation, and return on investment, are difficult to apply to old medications whose marketing rights were acquired by purchase of another company. Can marketplace economics be applied in health situations where there is no competition, legal protections afforded manufacturers, consumers unable to make an informed decision?
While pharmacy and therapeutics committees were debating treatment of hepatitis C with either of 2 drugs approved in 2011, boceprevir (Victrelis, Merck) or telapravir (Incivek, Vertex and Johnson & Johnson), Gilead Pharmaceuticals acquired Pharmasset Inc. and its hepatitis C drug sofosbuvir (Sovaldi) for a whopping $11.2 billion in 2012. It received FDA approval April 8, 2013, under Breakthrough Therapy Designation.
While economists argued over the wisdom of such a high-cost acquisition, Gilead generated $9 billion in sales during the first 3 quarters of 2014, surpassing adalimumab (Humira), which had been the highest earning drug in 2014. Hepatitis C could now be quickly treated with truly unprecedented efficacy and without the AEs of interferon. The oft-quoted cost $1,000 per pill or about $84,000 per treatment in the U.S. drew international attention. Prior options for hepatitis C treatment, which preceded sofosbuvir by a mere couple of years, fell into pharmaceutical extinction. Telapravir succumbed to competition and ceased to be manufactured on August 12, 2014. Shortly after approval of sofosbuvir, Gilead also gained approval of its combination product for hepatitis C ledipasvir 90 mg/sofosbuvir 400 mg (Harvoni) on October 10, 2014.
