Do we need authorized orphan drugs when compounded medications are available?

Authors


Dr S. Simoens, Research Centre for Pharmaceutical Care and Pharmaco-economics, KU Leuven, Onderwijs en Navorsing 2 bus 521, Herestraat 49, 3000 Leuven, Belgium. Tel.: +32 (0)16 323 465; fax: +32 (0)16 323 468; e-mail: steven.simoens@pharm.kuleuven.be

Summary

What is known and Objective:  Orphan drugs are used to diagnose, prevent or treat a rare disease. This Commentary aims to present a number of case studies questioning the need for designating compounded medications with a long history of effective use, which is well-supported by published clinical evidence.

Comment:  Prior to the market introduction of orphan drugs, medication compounding was done in our hospital pharmacy for several rare diseases. Examples include amifampridine for the treatment of Lambert–Eaton myasthenic syndrome (Firdapse®), ibuprofen for the treatment of neonatal patent ductus arteriosus (Pedea®) and zinc acetate for the treatment of Wilson’s disease (Wilzin®). Several ‘non-orphan’ pharmaceutical products, used off-label for the treatment of rare diseases, that became orphan medicinal products include Hydrea® for the treatment of sickle-cell syndrome (Siklos®) and Viagra® for the treatment of pulmonary arterial hypertension (Revatio®).

What is new and Conclusion:  In our opinion, as indicated by our examples, a better balance should be struck between the development of orphan drugs along the recently established regulatory pathways and the pragmatic use of pharmacy-compounded products and evidence-based off-label use of already available commercial products. Societal needs would be best met by focusing orphan drug development on rare diseases for which there is a high unmet medical need.

What is known and Objective

In the European Union, rare diseases are defined as life-threatening or chronically debilitating conditions that affect no more than five in 10 000 of its people. As the pharmaceutical industry has little interest, under normal market conditions, in developing and marketing medicines intended for such small numbers of patients, the EU offers a range of incentives to encourage the development of these medicines, also called orphan drugs.1 The aim of this Commentary is to argue through a number of case studies that when alternatives such as hospital product-compounding and cheaper evidence-based products are available, the authorization of orphan drugs is not cost-effective.

Comment

From 2000 to 2009, 18 patients were hospitalized at University Hospitals Leuven with the diagnosis of Wilson’s disease. The estimated prevalence of Wilson’s disease is six in 100 000 EU citizens. All these patients were treated, according to the international guidelines, with capsules containing penicillamine or zinc sulphate, compounded in the hospital pharmacy. On 31 July 2001, Orphan Europe declared zinc acetate (synthesized in 1912) as a ‘designated orphan drug’ and on 13 October 2004 as an ‘authorized orphan drug’ (under the brand name of Wilzin®) for the treatment of this rare disorder. The US Food and Drug Administration (FDA) gave designated orphan status to zinc acetate on 11 June 1985. The first publication on the clinical effectiveness of zinc acetate appeared in 1992. The Belgian National Institute for Health and Disability (i.e. the third-party payer) refused to grant reimbursement to Wilzin® as the branded pharmaceutical product was five times more expensive than the existing compounded medication.2

During the same period, 126 patients were diagnosed with sickle-cell disease. The estimated prevalence of this disease is 11 in 100 000 EU citizens. On 9 July 2003, Addmedica’s hydroxyurea (synthesized in 1869) became a ‘designated orphan drug’ and on 29 June 2007, an ‘authorized orphan drug’ (under the brand name of Siklos®) in Europe for the treatment of sickle-cell syndrome. The FDA gave designated orphan status to hydroxyurea on 15 April 2005. The first publication on hydroxyurea’s clinical effectiveness appeared in 1987. The Belgian National Institute for Health and Disability refused reimbursement for Siklos® because the same active ingredient was already on the market in the same form, as Hydrea®, at a much lower price for the treatment of chronic myeloid leukaemia and was fully reimbursed since 1964.

During the same period, 1324 patients were diagnosed with high-grade dysplasia in Barrett’s oesophagus. The estimated prevalence of this disease is 20 in 100 000 EU citizens. On 6 March 2002, Pinnacle Biologics obtained ‘designated orphan drug’ for porfimer sodium (synthesized in 1993), and on 25 March 2004, the drug became an ‘authorized orphan drug’ (under the brand name of Photobarr®) in Europe for the treatment of high-grade dysplasia in Barrett’s oesophagus. The FDA gave designated orphan status to porfimer on 19 October 2001. The first publication on the drug’s clinical effectiveness appeared in 1993. The Belgian National Institute for Health and Disability did not grant reimbursement for Photobarr® based on a negative health technology assessment of the product.

We believe that a dialogue between decision-makers, academic investigators and the industry must be initiated to find the right balance between public policy incentives to develop orphan drugs and medical needs. A company planning to start a development programme for an active ingredient with the same intended use can, through this dialogue, avoid heavy development costs for an orphan drug that is subsequently not approved for reimbursement because it competes with the compounded preparation or acceptable off-label use of an existing product. For example, the sponsors soliciting orphan designation for oxybutynin in patients with spina bifida, beta-carotene for erythropoietic protoporphyria and bi-myconase for congenital sucrose isomaltase deficiency must be aware that these products are already compounded for evidence-based clinical use and therefore may not be reimbursable.

A second example relates to off-label use, that is, the use of a registered product outside the conditions specified in the Summary of Product Characteristics. Since 1987, hydroxyurea (Hydrea®) has been used off-label for the treatment of sickle-cell disease. If the Summary of Product Characteristics was revised to reflect the available clinical evidence, there would probably never have been an initiative to develop the product as an ‘orphan medicinal product’ for the treatment of sickle-cell disease.

European legislation defines an ‘orphan medicinal product’ as one intended for a condition for which there exists no authorized satisfactory method of diagnosis, prevention or treatment or, if so, that it will be of significant benefit to those affected by the condition. Unfortunately, it is not clear whether existing method includes compounded products (as for Wilson’s disease), off-label use (as for sickle-cell disease) or other interventions (as for high-grade dysplasia in Barrett’s oesophagus). Before market access of several orphan drugs, compounding was done in our hospital pharmacy for products intended for several rare diseases, including amifampridine for the treatment of Lambert–Eaton myasthenic syndrome (Firdapse®), 5-aminolevulinic acid for the intra-operative photodynamic diagnosis of residual glioma (Gliolan®), arsenic trioxide for the treatment of acute promyelocytic leukaemia (Trisenox®), betaine for the treatment of homocystinuria (Cystadane®), busulfan for conditioning prior to haematopoietic progenitor cell transplantation (Busilvex®), caffeine citrate for the treatment of primary apnoea in neonates (Peyona®), cholic acid for the treatment of inborn errors in bile acid synthesis (Orphacol®), histamine for the treatment of acute myeloid leukaemia (Ceplene®), ibuprofen for the treatment of neonatal patent ductus arteriosus (Pedea®) and zinc acetate for the treatment of Wilson’s disease (Wilzin®). Also, several ‘non-orphan’ pharmaceutical products were used off-label for the treatment of rare indications that afterwards became orphan medicinal products. These included Azactam® for the treatment of chronic pulmonary infections in patients with cystic fibrosis (Cayston®), Hydrea® for the treatment of sickle-cell syndrome (Siklos®), Ledertepa® for conditioning prior to haematopoietic progenitor cell transplantation (Tepadina®), Onsenal® for the treatment of familial adenomatous polyposis (Celebrex®) and Viagra® for the treatment of pulmonary arterial hypertension (Revatio®).

What is New and Conclusion

Because the cost of treatment of a rare disorder with an orphan drug is too high to be affordable by the average household, reimbursement by the EU Member State is crucial. French and Portuguese healthcare systems reimburse all orphan drugs, and patient organizations generally approve of this approach. However, in our opinion, as indicated by our examples, a better balance should be struck between the development of orphan drugs along the recently established regulatory pathways and the pragmatic use of pharmacy-compounded products and evidence-based off-label use of already available commercial products. Societal needs would be best met by focusing orphan drug development on rare diseases for which there is a high unmet medical need.

Acknowledgements

The authors have no financial or other relationship that may lead to a conflict of interest.

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