Does orphan drug legislation really answer the needs of patients?
Marlene E Haffner, Josep Torrent-Farnell, Paul D Maher
Lancet 2008; 371: 2041–44
Orphan-drug legislation (panel) (1) was intended to make drugs for rare diseases sufficiently profitable to bring to the market. Legislation in both the USA and in the European Union has been effective in meeting that goal. Since the passage of the US Orphan Drug Act in 1983, more than 300 products for rare diseases have received market approval from the US Food and Drug Administration (FDA). (2) This number compares with only ten products approved to market in the preceding decade. (3) But does this mean that the legislation has met patients’ needs? Although the number of marketed orphan products has increased, there has also been a steady increase in the time (4) and expense (5) needed for product development; yet the overall number of products approved to market has decreased (6) In this essay, we will consider criticism from interested parties in both the USA and European Union. (7–9)
The most common criticism of the orphan-product legislation has been the very high cost of treatment with some of the drugs. 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 modifi cation of the legislation. Treatment with imiglucerase might cost as much as US$400 000 per year for an adult patient. (10) Although Gaucher’s disease affects fewer than 20 000 patients in the USA, (11) Genzyme reportedly received more than $800 million in revenue in 2004 from this product alone. (12) Some would like to see a cap placed on revenues from orphan drugs, shortening of exclusivity provisions, or review of exclusivity provisions when profi table. (13)
Orphan blockbuster drugs such as epoetin alfa (Epogen) and recombinant human-growth hormone (Genotropin, Humatrope, Nutropin) have been criticised because much of their post-market revenue has come from off -label use. Such outcomes are rare; however, orphan-product exclusivity does not preclude off-label use for highly prevalent diseases. Orphan legislation considers the relevant population for an orphan drug on the basis of the action of the drug. From the perspective of the patient with a rare disease, whether a drug is also effective in treating a more prevalent disorder is irrelevant. Of more importance to these patients is the knowledge that the product is safe and eff ective for their treatment.
The development of any new medication is a long, risky, and costly undertaking, and drug companies are naturally impatient to recover their investment once the drug is marketed. However, despite the highly publicised cases above, there are many examples of orphan drugs that provide valuable treatment, but which have little prospect of commercial return (eg, zinc acetate for Wilson’s disease). Although every eff ort should be made to prevent any unfair advantage from orphan-product legislation, changes that might stifl e essential enthusiasm for development of rare-disease products should be avoided. Without the well considered incentives of the Orphan Drug Act, development of drugs for many rare diseases might well not have taken place. For example, the public service orphan drug human botulism immune globulin would not exist for the treatment of infant botulism without the US Orphan Drug Act and the orphan product grant for a clinical trial. Use of this product has reportedly resulted in more than 30 years of avoided hospital stay and more than $50 million of avoided hospital costs. (14)
Orphan-product exclusivity (ie, exclusive marketing rights for an extended period) is important for the development of older drugs, such as thalidomide, for rare disorders. Thalidomide was approved in the USA in 1992 as treatment for erythema nodosum leprosum (15) and more recently for multiple myeloma.16 Similarly, companies associated with the development of recombinant biotechnology products have often commented on the importance of orphan-product exclusivity. Any product in development during the entire 17 years of patent-based exclusivity might benefit from the provision of orphan-product exclusivity, since this exclusivity begins only when the FDA and European Union give market approval. Biotechnology companies such as Amgen, Genzyme, and Genentech had orphan products as their fi rst marketed products.
Others have argued that orphan-drug legislation, especially in Europe, is not generating sufficient interest and is proceeding too slowly. (17) Although there have been fewer European marketing approvals than in the USA, the early European experience is best compared with the first years of the US Orphan Drug Act. From 1983 to 1988, the US Orphan Products Program awarded 255 orphan-product designations, and the FDA approved 37 marketing approvals for designated orphan products. During the fi rst 5 years of orphan-product legislation in Europe (2000–05), the European Commission granted 369 orphan-product designations and approved marketing for 21 orphan products. By the end of 2006, the FDA Offi ce of Orphan Products Development (OOPD) had awarded 1713 orphan-product designations and 304 designated orphan products had received market approval. At the same time, the European Union had 443 designated orphan products, and 31 orphan products with positive market decision.
Another concern about orphan legislation is whether development actually takes place for the truly rare diseases, or only for the more common ones. This question was explored in depth during a 2001 review of the implementation of the Orphan Drug Act by the US Department of Health and Human Services.(18) The report showed that in no year was the average patient population for designated products more than 90,000 whereas in general the prevalence for designated products was between 50,000 and 70,000. (18) Just as importantly, perhaps, are the many examples of orphan products to treat diseases with populations of less than a few thousand and even less than 100. Approved drugs such as pegademase (19) (also supported with an orphan grant) for the treatment of severe combined immunodefi ciency associated with a defi ciency of adenosine deaminase (SCID-ADA), and nitisinone, (20) for the treatment of tyrosinaemia type I, show that the Orphan Drug Act is supporting development for some of the rarest diseases. In the USA, tyrosinaemia type I is estimated to aff ect about 2500 patients, (21) whereas SCID-ADA is thought to aff ect as few as 40. (22)
One might argue that the increased interest in orphan products is merely an indication of the rise of biotechnology. Many of the pricing criticisms aimed at orphan drugs relate to biotechnology drugs and show, at least in part, a larger issue of the expensiveness of their One might argue that the increased interest in orphan products is merely an indication of the rise of biotechnology. Many of the pricing criticisms aimed at orphan drugs relate to biotechnology drugs and show, at least in part, a larger issue of the expensiveness of their One might argue that the increased interest in orphan products is merely an indication of the rise of biotechnology. Many of the pricing criticisms aimed at orphan drugs relate to biotechnology drugs and show, at least in part, a larger issue of the expensiveness of their One might argue that the increased interest in orphan products is merely an indication of the rise of biotechnology. Many of the pricing criticisms aimed at orphan drugs relate to biotechnology drugs and show, at least in part, a larger issue of the expensiveness of their One might argue that the increased interest in orphan products is merely an indication of the rise of biotechnology. Many of the pricing criticisms aimed at orphan drugs relate to biotechnology drugs and show, at least in part, a larger issue of the expensiveness of their
research and development. (23) Clearly, advances in genomics and proteomics have led to increasingly precise disease definitions, and the development of innovative pharmacogenomic approaches to treatment. (24) To what extent interest in orphan diseases is a consequence of these scientifi c trends, and not of the underlying eff ect of the legislation, is diffi cult to answer. No controlled trial can resolve such a question; however, the difficulty of drug development for rare diseases seems to be an economic one, because of economies of scale, and one that would exist independent of any advances in the scientifi c front. In an environment in which medicine is increasingly adapted to the needs of patients, the incentives of the Orphan Drug Act could arguably take on even greater importance.
One unexpected consequence of orphan legislation has been the realisation that many infectious diseases that are highly prevalent in developing areas of the world qualify for incentives to develop orphan drugs in developed countries, such as in the USA. Tuberculosis and malaria, two of the top fi ve infectious disease killers in the world,25 qualify as rare diseases in developed nations. Although orphan status has been awarded to some drugs to treat these diseases, most notably for rifampicin (26,27) and rifapentine (28) in the treatment of tuberculosis, and halofantrine, (29) mefloquine, (30) and quinine sulphate, (31) for the treatment of malaria, this decision is an aspect of orphan-drug legislation that might benefit from more vocal dissemination.(32,33)
Much of the value of orphan-product legislation is probably very difficult to quantify concisely. What is the value of studies that have not led to product approvals? Hundreds of articles have been published in peer-reviewed journals, describing appropriate uses of products to treat rare diseases. What is the value of a negative clinical study? Although such a study is a loss to sponsors and a disappointment to patients, if it prevents side-eff ects of ineff ective remedies or leads to insights necessary for a cure, it is both valuable and necessary.
Many of the drugs reviewed by OOPD and the European Union Committee on Orphan Medicinal Drugs are at the cutting edge of medical advancement. Pegademase was the first instance of an enzyme-replacement therapy for a metabolic disease. (34) After pegademase, five enzymereplacement therapies were developed to treat Gaucher’s disease, Fabry’s disease, and enzyme deficiencies of the urea cycle. (35) Pegademase also involved the fi rst use of a polyethylene glycol delivery system to increase the half-life of a drug and decrease immunogenicity.(22) This approach has had more widespread applicability in Pegasys, a pegylated interferon subsequently approved for the treatment of hepatitis C.(36) From monoclonal antibodies such as rituximab, to conjugated monoclonal antibodies such as tositumomab, to small molecules such as imatinib mesylate, it is apparent that orphan legislation is not just supporting me-too products derived from advances in more prevalent disorders, but rather development of orphan products has been and is part of the discovery of innovative treatments. Approved orphan-product designations for development of treatments in RNA interference, antisense therapies, new gene therapy vectors, and others suggest that this association is unlikely to change.
Panel:
Comparison of incentives for various orphan legislations (1)
USA
• 7 years’ marketing exclusivity
• Tax credit for 50% of clinical trial costs
• Protocol assistance
• Food and Drug Administration fee waiver
• Orphan grants programme
Japan
• 10 years’ marketing exclusivity
• Tax credit of 6% on any kind of studies, limited to 10% of the company’s taxes
• Funding possible for up to 50% of R&D costs
European Union
• 10 years’ marketing exclusivity
• Protocol assistance
• European Medicines Agency fee waiver
• European Union and national incentives to foster orphan development
Australia
• 5 years’ marketing exclusivity
• Fee waiver possible
• R&D not supported by grants or tax incentives
R&D=research and development.
Office of Orphan Products Development
Food and Drug Administration
Rockville, MD, USA (J Torrent-Farnell MD, P D Maher MD);
and Amgen, Washington, DC, USA (M E Haffner MD)
Correspondence to:
Dr Marlene E Haffner, Amgen
555 13th Street NW, Suite 600 West
The Myelin Project wishes to thank Dr. Astrid James and the publishers of The Lancet for granting us permission to post this article.
References1 NORD. Letter to FDA Commisioner: Mark McClellan. Medicare program. Competitive acquisition of outpatient drugs and biologicals under part B interim rule. Sept 6, 2005. http://www.rarediseases.org/news/policy/policy (accessed April 3, 2006).
2 Office of Orphan Products Development. List of orphan designations and approvals. http://www.fda.gov/orphan/designat/list.htm. (accessed Jan 18, 2007).
3 Rados C. Orphan products: hope for people with rare diseases. FDA Consumer Mag, 2003; 37: 10–15.
4 Milne CP. Orphan products: pain relief for clinical development headaches. Nature Biotechnol 2002; 20: 780–84.
5 The Tufts Center for the Study of Drug Development. Pegs cost of a ew prescription medicine at $802 million. 2001. http://csdd.tufts.edu/NewsEvents/RecentNews.asp?newsid=6 (accessed April 24, 2006).
6 FDA. Challenge and opportunity on the critical path to new medical products. White paper. March 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html (accessed April 1, 2006).
7 Loughnot D. Potential interactions of the Orphan Drug Act and pharmacogenomics: a fl ood of orphan drugs and abuses? Am J Law Med 2005; 31: 365–80.
8 Love J. Brief note on the abuse of orphan drug programs in creating monopolies, January 5th 1999. http://www.cptech.org/ip/health/orphan/#Brief%20note%20on%20the%20abuse%20 of %20Orphan%20Drug%20programs%20in%20creating%20monopolies (accessed April 3, 2006).
9 Maeder T. The orphan drug backlash. Sci Am 2003; 288: 80–88.
10 Anand G. Why Genzyme can charge so much for Cerezyme. Wall Street J Nov 16, 2005.
11 Futerman AH, Sussman JL, Horowitz M, Silman I, Ziniran A. New directions in the treatment of Gaucher disease. Trends Pharmacol Sci 2004; 25: 147–45.
12 Smith A. From orphan to blockbuster? Biotechs lead the way in getting orphan drugs to market, and sometimes they actually make money. http://money.cnn.com/2005/07/08/news/midcaps/orphan/ index.htm (accessed April 3, 2006).
13 Cheung RY, Cohen JC, Illingworth P. Orphan drug policies: implications for the United States, Canada and developing countries. Health Law J 2004; 12: 183–200.
14 Arnon SS. Creation and development of the public service orphan drug human botulism immune globuli. Pediatrics 2007; 119: 785–89.
15 FDA. NDA 20-785 FDA: approval letter, July 16, 1998. http://www.fda.gov/cder/foi/appletter/1998/20785ltr.pdf (accessed May, 2007).
16 International Myeloma Foundation. The International Myeloma Foundation applauds FDA approval of thalomid for myeloma patients. 2006. http://www.myeloma.org/main.jsp?source=link&source_link_id=2185&type=article&tabid=1&menu_id=0&id=1831 (accessed May 20, 2008).
17 Joppi R, Bertele V, Garatinni S. Orphan drug development is progressing too slowly. B J Clin Pathol 2006; 61: 355–60.
18 Department of Health and Human Services. The Orphan Drug Act: implementation and impact. San Francisco, CA: Offi ce of Inspector General, Department of Health and Human Services, 2001.
19 Center for Drug Evaluation and Research, FDA. Electronic orange book, application 019818, pegademase, approved March 21,1990. ttp://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=019818&TABLE1=OB_Rx (accessed April 12, 2006).
20 Center for Drug Evaluation and Research, FDA. Approval letter for application nember 21-232, Orfadin, Jan 18, 2002. www.fda.gov/cder/foi/nda/2002/21-232_ORFADIN_Approv.pdf (accessed Jan 25, 2007).
21 Scott CR. The genetic tyrosinemias. Am J Med Genet Part C Semin Med Genet 142C: 121–26.
22 Hershfi eld MS, Buckley RH, Greenberg ML. Treatment of adenosine demainase defi ciency with polyethylene glycol modifi ed adenosine deaminase. N Engl J Med 1987; 316: 589–96.
23 Anand G. As biotech drug prices surge, US is hunting for a is hunting for a solution. Wall Street J Dec 28, 2005: A1.
|
OPML |
Search This Site |
Home
•
del.icio.us
digg
facebook