DDReg Pharma


Access to Orphan Drugs in Hereditary Angioedema

Hereditary angioedema (HAE) is considered a rare, autosomal dominant disease that is characterized by repeated episodes of swelling which can occur on the face, limbs and even the gastrointestinal and respiratory tracts leading to severe pain, vomiting, and asphyxiation. These swelling attacks may occur unexpectedly and can significantly affect a patient’s quality of life (QoL). HAE has a prevalence of between 1:10,000 to 1:150,000 according to literature, and is thus classified as a rare disease [1]. Little is known about the condition which is why it can easily be misdiagnosed leading to mortality and morbidity in some cases.
Earlier, very few treatment options existed for HAE that were associated with relatively serious side effects. However, a new era for HAE therapy began in 2008 after the US FDA approved the human plasma-derived C1 esterase inhibitor [2] followed by ecallantide, icatibant, and recombinant C1 inhibitor [3]. Access to these treatment options has alleviated HAE burden and contributed towards better QoL and reduced stress and cost on the healthcare system in terms of visiting hospitals, urgent care, and other emergency facilities.

HAE treatment options as orphan drug designations

As HAE is considered a rare disease/condition, medication such as icatibant that was intended for HAE treatment was given the ‘orphan drug’ designation by the US FDA and EMA in 2003 [4].
What is an orphan drug designation?
According to EMA, an orphan drug designation is “a status assigned to a medicine intended for use against a rare condition” and must meet a given criteria to obtain the designation. This allows the medicine some advantages including incentives such as protection from competition once authorized market approval [5].
Orphan drug policies and registration pathways have facilitated safe and effective drug development for rare diseases and making treatment options more affordable and available to the public. For example, in the EU and its Member States, incentives for research are available such as scientific advice on study protocols reduction in fees and access to EU grants; fees for marketing application approval are waived; and a 10-year exclusivity is given [6]. In 2017, 98 medicines under orphan drug designation were given market approval in the EU [7,8]
Though treatment options for rare diseases such as HAE offer multiple benefits to patients, payers raise concern on the therapies being costly for healthcare payment systems resulting in barriers that limit treatment access, formulary approval, supply, and multiple re-authorizations to name a few [9, 10, 11]. Indeed, drug development is costly and with comparatively less patients to treat for rare diseases, the cost per patient would be significantly higher in order to recover R&D expenses. For example, in the USA the median drug cost per patient in a year was $27,756 for a non-orphan disease compared to $140,443 for an orphan disease [12]. However, when looking at the bigger picture, orphan drug expenditure represented <10% of pharmaceutical expenditure and 1% of total healthcare expenditure [3].
EMA: Orphan drug regulations
EMA has supported the development and approval of orphan designated drugs facilitating timely access to affordable therapies by way of implementing comprehensive regulations [13]:
  • Regulation (EC) No 141/2000: establishes the process for orphan drug designation in the EU; defines development and market access incentives; establishes Committee for Orphan Medicinal Products (COMP)
  • Regulation (EC) No 847/2000: establishes rules for implementation; defines the essentials for Orphan Regulation application. This regulation came into force in April 2000 allowing drug sponsors to begin application submission for orphan designation to EMA
  • Regulation (EC) No 726/2004: indicated that MAs for orphan drugs should follow the centralized procedure
  • Regulation (EC) No 507/2006: this regulation was adopted in March 2006 to provide a framework for conditional marketing authorizations for orphan drugs under Regulation (EC) No 726/2004
  • Regulation (EC) No 1901/2006: established that the market exclusivity period for orphan drugs may be extended to 12 years if the submitted study results are compliant with an agreed on pediatric investigation plan at the time of MA
  • Regulation (EC) No 2049/2005: determined that scientific services and advice for orphan drugs would be provided to small and medium sized enterprises free of charge.
Support for orphan drugs with DDReg
Over last 3 years DDReg has successfully registered Icatibant in multiple countries including EU, Saudi Arab, Malaysia, Columbia and Algeria. The regulatory consulting portfolio at DDReg constitutes regulatory services for a range of medicinal products that include a number of drugs with Orphan drugs status worldwide. In the past, DDReg has also successfully filed orphan designated drugs to agencies such as EMA, UK MHRA, and Saudi FDA in line with the regulations and guidelines, thereby contributing towards making more affordable therapies available to patients for treating rare diseases.
References and Further Reading:

[1] Banerji A, Busse P, Christiansen SC, Li H, Lumry W, Davis-Lorton M, Bernstein JA, Frank M, Castaldo A, Long JF, Zuraw BL. Current state of hereditary angioedema management: a patient survey. InAllergy and Asthma Proceedings 2015 May (Vol. 36, No. 3, p. 213). OceanSide Publications.

[2] Lunn M, Santos C, Craig T. Cinryze™ as the first approved C1 inhibitor in the USA for the treatment of hereditary angioedema: approval, efficacy and safety. Journal of blood medicine. 2010 Aug 24:163-70.

[3] Lumry WR. Hereditary angioedema: the economics of treatment of an orphan disease. Frontiers in medicine. 2018 Feb 16;5:22.

[4] Icatibant Icatibant: HOE 140, JE 049, JE049 – PubMed (nih.gov)

[5] European Medicines Agency. Orphan designation: overview. 2023

[6] European Medicines Agency. Factsheet: Orphan medicines in the EU. 2023

[7] Regulation (EC) No 141/2000 of European Parliament and of the Council of 16 December 1999 on orphan medicinal products.

[8] Orphanet Report Series. List of medicinal products for rare diseases in Europe. 2021

[9] Handfield R, Feldstein J. Insurance companies’ perspectives on the orphan drug pipeline. American health & drug benefits. 2013 Nov;6(9):589.

[10] Hyde R, Dobrovolny D. Orphan drug pricing and payer management in the United States: are we approaching the tipping point?. American health & drug benefits. 2010 Jan;3(1):15.

[11] Robinson SW, Brantley K, Liow C, Teagarden JR. An early examination of access to select orphan drugs treating rare diseases in health insurance exchange plans. Journal of Managed Care Pharmacy. 2014 Oct;20(10):997-1004.

[12] Petraroli A, Squeglia V, Di Paola N, Barbarino A, Bova M, Spanò R, Marone G, Triggiani M. Home therapy with plasma-derived C1 inhibitor: a strategy to improve clinical outcomes and costs in hereditary angioedema. International archives of allergy and immunology. 2015;166(4):259-66.

[13] European Medicines Agency. Legal framework: orphan designation. 2023