Presentation prepared for MSc Bioprocess Engineering Module - \'Regulatory Affairs Science for Biotech Products\'

1. Regulatory Affairs Science for Biotech Products – Oral Presentation Orphan Drugs

2. The term ‘Rare Disorder’ refers to those diseases with low prevalence, and often times, no treatment There is no single definition for what constitutes a ‘Rare Disorder’ The WHO defines an incidence of 0.65-1/1000 as ‘rare’ The EU defines 5/10,000 as ‘rare’ The US defines <200,000 patients as ‘rare’ Japan defines <50,000 patients as ‘rare’ Australia defines <2000 patients as ‘rare’ In the EU and USA, more than 55 million people suffer from a rare disease{{241 Heemstra,Harald E. 2008}} Appx. 10% of human disease is classed as Rare Estimates vary on the no. of rare diseases – thought to be between 5000 and 8000 80% of these are thought to have genetic origins Rare Disorders Rare diseases are becoming less rare due to our increasing understanding of pathophysiology, resulting in the separation of broad iseasecategories into smaller and more well defined disease entities. about 250 new rare diseases are described each year {{250 Wastfelt,M. 2006}}

3. Article 25.1 of the Universal Declaration of Human Rights states: “everyone has the right to health and well being and especially to medical care and social services” The ethical implications of this are clear – it is incumbent upon governments to intervene in the drugs market to ensure the provision of life-saving treatments to even small patient populations The Right to Health Protection

4. Orphan Drugs are those drugs which are developed for the treatment of rare disorders The lack of economic feasibility leads to a lack of even preliminary research into these disorders Due to the economic reality, it is necessary for Governments and Regulatory bodies to provide a framework and incentive for companies to develop Orphan Drugs Drugs for higher prevalence disorders which may still be unprofitable for companies to develop treatments for can also come under the Orphan designation – for example Tropical Diseases, or AIDS, which had Orphan designation in the 1990s What are Orphan Drugs? AIDS had the most designations and the second largest number of approvals…the ODA can provide key early impetus to the development of interventions for a major epidemic disease {{245 Braun,M.Miles 2010}}

5. Important Dates in the History of Orphan Drug Regulation

6. Some Examples of Rare Disorders…

7. …and Orphan Drugs Oncology drugs have been by far the most common to receive Orphan status, with appx. 33% of all designations

8. With the objective of stimulating rare disease research as well as the development of pharmaceutical agents for the treatment of rare conditions, President Ronald Reagan signed the ODA into law in 1983 The ODA is recognized as one of the most successful legislation actions of the US in recent history Incentives in the US include: 7 year market exclusivity for orphan drugs; Tax credits totalling half of development costs; Research and development grants; fast-track development and approval; Access to Investigational New Drug Program and preapproval; Waived drug application fees. Orphan drug status is granted through the FDA and is independent of the patent system. In addition, orphan drug market exclusivity periods come into effect at the date of market approval and are not expended during product development Non-economic advantages as a company’s ethical profile may benefit from the association to a rare disease Half of the biotechnological products approved in the USA in the period 1982–2002 were designated orphan drugs …one of the key factors that has stimulated the US biotech industry in its growth Orphan Drugs in the US In the 8–10 years before the Act, only ten drugs for rare diseases received FDA marketing approval, compared with more than 300 orphan drug approvals in the 25 years following the Act{{245 Braun,M.Miles 2010}} orphan exclusivity is often considered to be a greater incentive than a patent (which requires that a drug is novel and its production ‘nonobvious’); drugs that would ordinarily not be eligible for patent protection might be eligible for orphan exclusivity {{250 Wastfelt,M. 2006}}

9. The EU Orphan Drug system has been deemed to be less successful less than 50 orphan drugs on the European market by the end of 2008 This has been partially attributed to the high number of designated products failing the approval process only 7.1% of the EU designated potential orphan drugs were approved for marketing; are the incentives enough? EU Incentives: A market exclusivity of 10 years Direct access to the centralised procedure for European marketing authorisation 50% fee reductions for regulatory procedures Free scientific advice during the development process It has been argued that the US ODA is successful because of tax grants, which are not available in Europe Orphan Drugs in the EU

10. Experience of a company in obtaining authorisation for orphan drugs is the most important predictor of market authorisation. Companies that have successfully brought an orphan drug to the market increase their odds of obtaining market authorisation for consecutive orphan drugs more than 17- fold The incentives in place are deemed to be effective – the industry’s status in Europe is the major issue: Several of the world’s largest, US-based biotech companies had an orphan drug as their first product The industry in the EU must grow from the SME sector, and acquire expertise in getting approval, as happened in the US in the past; the relative maturity of the industry is the major difference and cause of the differing success of Orphan Drug legislation in the two areas to date Barriers to Success of EU Orphan Drug Legislation

11. 5 indicators have been cited as influential in a companies decision to develop an Orphan Drug: Incentives are introduced to this end: EU and US incentives are broadly the same, differences being US offers Tax Incentives EU offers 10 year exclusivity vs7 years in the US The Incentivisation of Orphan Drug Development

12. The nature of Orphan Drugs can create a difference in the amount of safety information at time of approval limited number of patients in clinical trials quality of the clinical trials special approval procedures The probability of obtaining a first safety-related event to be 3.5% after 3 years and 20.3% after 8 years for all orphan drugs Orphan Drugs and Safety Considerations Given the severe nature of many of the diseases for which these drugs are indicated, the number of safety-related regulatory actions is relatively low (Risk vs. Benefit) – However, greater vigilance is required from health professionals in respect of Orphan Drugs where information is limited

13. For the last 60 years, a growing conflict has existed between economic considerations in healthcare provision, and the ‘medical ethic’ In the case of Orphan Drugs, the economic argument for collective efficiency in drug development (i.e. direct efforts towards profitable, large population diseases) is in contravention of the principles of Hippocratic medicine, which emphasises the importance of each individual As effector of economic order, and guarantor of public health, it is for the government or other sovereign entity of a nation to mediate this conflict for the ‘common-good’ The Medicine-Economy Conflict

14. There is an argument that Orphan Drug legislation has created the opportunity for commercial and ethical abuse The existence of 30 blockbuster drugs with at least one Orphan Designation would appear to indicate that companies can make unreasonable profits from subsidised developments 43 brand name drugs with global annual sales of greater than a billion US$ have orphan designations The EU has a mechanism for recouping monies from drugs which are ‘ substantially profitable’ This is poorly defined, and has never been actioned Investment seems to concentrate in lucrative fields (i.e. Oncology) to the detriment of other previously unaddressed or under-addressed rare diseases. The definition used for rare diseases is in question here Drugs such as interferon and somatropincan have up to 33 orphan designations. Orphan drugs, intended to treat small patient populations, become drugs which treat large populations Hence, initially unprofitable orphan drugs potentially reach blockbuster status due to multiplication and extension of indications. Social, Economic and Ethical Issues with Orphan Drugs “All cancers but four are considered to be rare diseases” -Abbey S. Meyers, executive director for the National Organisation of Rare Diseases

15. Patients could be paying twice for the same drug as public funds finance orphan drug R&D , while the patient also pays for the product It is possible that orphan drug incentives be used to develop non-orphan drugs. Alternatively, an already profitable product can later obtain orphan designation On the other hand, stimulating rare disease research can often lead to scientific breakthroughs applicable to common conditions as was the case with the study of homozygous familial hypercholesterolaemia which lead to the development of statins Social, Economic and Ethical Issues with Orphan Drugs

16. Extraordinary Price increases (i.e. > 100%) have been an issue with Orphan Drugs due to market exclusivity Cosmegonat $16.79/ dose, raised to $593.75/dose – a 3,436% per drug dose increase Actharat $1,650 a vial to $23,000 per vial, a 1,310% price increase Experts in Health Policy and Corporate Social Responsibility have questioned the morality of such a system While market restrictions have been suggested, it is also noted that access to these drugs in developed countries is not significantly effected by varying price decisions in different countries – the argument that the price the market will bear can still meet the common interest is strong Social, Economic and Ethical Issues with Orphan Drugs

17. Suggestions for reform include: Adopt a policy similar to the Japanese, wherein a 1% tax is paid on any orphan drug generating large revenues (100m Yen) Redefinition of the concepts Orphan Drug and Rare Disorder in the context of increasingly personalised medicine Subsidy Paybacks International Harmonisation of Orphan Drug Policy Regulated pricing for all pharmaceuticals Particularly with regard to extraordinary price increases Reform of Orphan Drug Legislation

18. Braun, M.M., Farag-El-Massah, S., Xu, K. and Cote, T.R. 2010. Emergence of orphan drugs in the United States: a quantitative assessment of the first 25 years. Nature Reviews Drug Discovery, 9(7), pp.519-522. Denis, A., Mergaert, L., Fostier, C., Cleemput, I. and Simoens, S. 2010. A comparative study of European rare disease and orphan drug markets. Health Policy, 97(2-3), pp.173-179. Heemstra, H.E., de Vrueh, R.L., van Weely, S., Bueller, H.A. and Leufkens, H.G.M. 2008a. Predictors of orphan drug approval in the European Union. European Journal of Clinical Pharmacology, 64(5), pp.545-552. Heemstra, H.E., de Vrueh, R.L.A., van Weely, S., Buller, H.A. and Leufkens, H.G.M. 2008b. Orphan drug development across Europe: bottlenecks and opportunities. Drug Discovery Today, 13(15-16), pp.670-676. Hemphill, T.A. 2010. Extraordinary Pricing of Orphan Drugs: Is it a Socially Responsible Strategy for the US Pharmaceutical Industry? Journal of Business Ethics, 94(2), pp.225-242. Lavandeira, A. 2002. Orphan drugs: legal aspects, current situation. Haemophilia, 8(3), pp.194-198. Moors, E.H.M. and Faber, J. 2007. Orphan drugs: Unmet societal need for non-profitable privately supplied new products. Research Policy, 36(3), pp.336-354. Seoane-Vazquez, E., Rodriguez-Monguio, R., Szeinbach, S.L. and Visaria, J. 2008. Incentives for orphan drug research and development in the United States. Orphanet Journal of Rare Diseases, 3pp.33. Tambuyzer, E. 2010. Rare diseases, orphan drugs and their regulation: questions and misconceptions. Nature Reviews Drug Discovery, 9(12), pp.921-929. Wastfelt, M., Fadeel, B. and Henter, J.I. 2006. A journey of hope: lessons learned from studies on rare diseases and orphan drugs. Journal of Internal Medicine, 260(1), pp.1-10. Wellman-Labadie, O. and Zhou, Y. 2010. The US Orphan Drug Act: Rare disease research stimulator or commercial opportunity? Health Policy, 95(2-3), pp.216-228. References