Orphan drug designation – Europe, the USA and Japan

Abstract

Patients with rare diseases deserve the same quality, safety and efficacy in medicines as other patients with more common conditions. However, for rare diseases, the cost of developing and bringing a drug to market would not normally be recovered by expected sales. In order to encourage development and research, a supportive legislative and regulatory framework known as orphan drug designation has been adopted for medicines for rare diseases in a number of countries and regions. Although similarities exist, the criteria and processes for designation are not internationally harmonised and this editorial summarises orphan drug designation in Europe, the USA and Japan.

Keywords::

• Europe
• Japan
• orphan drug designation
• rare disease
• USA

1. Introduction

There are estimated to be between 6000 and 8000 rare diseases [1]. Although by definition each rare disease affects a relatively small number of patients, collectively rare diseases represent a considerable health burden. Patients with rare diseases are entitled to expect the same quality of treatment as other patients with more common disease. However under normal market conditions, the costs of developing medicinal products for rare diseases are not expected to be recovered by the potential sales. Therefore, a regulatory framework exists in order to encourage the research and development of medicinal products for rare diseases, so called ‘orphan drug or orphan medicinal product (OMP)'.

A supportive legislative framework for medicines for rare diseases was adopted in the USA in 1983 (the Orphan Drug Act (ODA)), Japan in 1993 (amended Pharmaceutical Affairs Law), Europe in 2000 (Regulation (EC) No 141/2000) and in other regions [2,3]. The legislation recognises ‘the expected potential' of an OMP in the treatment of a rare disease by granting a status referred to as orphan designation. A sponsor obtains orphan designation for their medicinal product by submitting an application to a designating authority, prior to applying for a marketing authorisation application (drug licensing). The criteria and process for orphan designation is not internationally harmonised and this editorial focuses on key designation features in Europe, the USA and Japan (Table 1).

Table 1. Key features of orphan designation.

Feature	Europe	USA	Japan
Key drug legislation	Regulation EC No 141/2000 Regulation EC No 847/2000	ODA	Article 77-2 of the Pharmaceutical Affairs Law
Medicinal products	Yes	Yes	Yes
Medical devices	No	HUDS	Yes
Key designation criteria	Intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition in < 5 in 10,000 Or Without incentives it is unlikely that the marketing would generate sufficient return to justify investment And There exists no satisfactory method of diagnosis, prevention or treatment of the condition or, if such a method exists, that medicinal product will be of significant benefit to those affected by the condition	Affects less than 200,000 persons in the USA Or Affects more than 200,000 in the USA and for which there is no reasonable expectation that the cost of developing and making a drug for such disease or condition will be recovered from sales in the USA	The number of patients who may use the drug should be less than 50,000 in Japan The drug should be indicated for the treatment of a serious disease, with high unmet medical need (no appropriate alternative treatment or expected higher efficacy or safety) Theoretical rationale for the use of the product for the target disease, and appropriate development plan
Review period	Maximum of 90-day procedure	Review cycle typically 90 days	None specified
Bodies involved in designation procedure	EMA – COMP EC	FDA OOPD	MHLW PAFSC PMDA
Incentives	Market exclusivity Protocol assistance Fee reductions Centralised procedure for marketing authorisation Individual Member State incentives	Market exclusivity Tax credits on clinical research Protocol assistance Orphan Products Grant Program	Subsidy payment Guidance and consultation Preferential tax treatment Priority review Extension of re-examination period
Public information	EC/EMA webpage	OOPD webpage	Government Gazette

COMP: Committee for orphan medicinal products; EC: European commission; EMA: European medicines agency; FDA: Food and drug administration; HUDS: Humanitarian use devices; MHLW: Minister of health labour and welfare; ODA: Orphan drug act; OOPD: Office of orphan products development; PAFSC: Pharmaceutical affairs and food sanitation council; PMDA: Pharmaceuticals and medical devices agency.

2. Orphan drug designation in the EU

The criteria for orphan designation are described in Regulation (EC) 141/2000 [4]. More detailed rules, guidelines and definitions are provided in Regulation (EC) No 847/2000 [5]. The criteria to be fulfilled for orphan designation are the following: the product is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 persons in the European Union (EU) at the time of submission of the designation application, or the product is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition, and without incentives would be unlikely to achieve sales that would cover the investment in its development. In addition, no satisfactory method of diagnosis, prevention or treatment of the condition concerned is authorised, or, if such method exists, the medicinal product will be of significant benefit to those affected by the condition [4].

The sponsor must be established in the Community, and must provide documentation of the permanent address. Sponsors may apply for a designation at any stage in the development of a product (non-clinical and/or clinical), prior to a marketing authorisation application. Applications for orphan designation are reviewed by the European Medicines Agency's (EMA) Committee for Orphan Medicinal Products (COMP). COMP is composed of one representative from each member state, three patients' representatives and three members appointed by the European Commission (EC). The EMA strongly encourages sponsors to request a pre-submission meeting (normally via teleconference) prior to submitting the application (at least 2 months in advance) and to use the common EMA/FDA application form. The designation process is free of charge and the evaluation process has a fixed duration. The application should be submitted in line with the ‘Guideline for the format and content of applications for designation as orphan medicinal products' (Table 2) [6]. Sponsors should clearly substantiate claims and support statements made in the application. In particular,

Table 2. Key contents required for an orphan drug application.

Europe	USA	Japan
Application form and A1. Details of the condition A2. The proposed orphan indication A3. Medical plausibility A4. Justification of severity (life-threatening or debilitating) B1-2. Prevalence of the condition C. Return on investment D1. Existing methods of treatment D2. Justification why methods not satisfactory D3. Justification of significant benefit E1. Summary of development E2. Current regulatory status F. Bibliography	Application form and Sponsor statement Name and address of sponsor Description of rare disease or condition with indication Discussion of scientific rationale including all supportive data Description of clinical superiority, if relevant Justification of a valid subset, if relevant Summary of regulatory and development history Documentation of prevalence of < 200,000 in the USA or evidence that there is no reasonable expectation that the costs of research and development can be recovered by the sales Sponsor statement of party of interest	Application form and Data on the number of patients with objective statistical data for whom the drug will be indicated Data on medical needs Data on the disease including aetiology and symptoms Data on the current status such as availability of similar drug and treatment Data on the theoretical rationale for the use of the drugs Related data in a draft dossier of application for marketing authorisation, which is available at the time of application for orphan drug Development plan (data on the possibility of development), including outline of the development plan, current development status, expected test items, duration of the study and necessary expenses Preparation of summary of the orphan drug

• Distinct medical entities are generally considered as valid conditions. A justification of plausibility for restricting the use in a subset of a more common disease will be required.

• Medical plausibility is not an explicit orphan designation criterion. However, there must be a strong scientific rationale for the use of the product in the proposed orphan indication.

• Prevalence must be a specific number, not simply stated as less than 5 in 10,000.

• Significant benefit is defined as a clinically relevant advantage or major contribution to patient care (MC-to-PC). Assumptions should be plausible and based on sound pharmacological principles, and with regards to safety, cannot be based on theoretical risks.

From the evidence submitted by the sponsor, a short report is prepared by the EMA/COMP and following discussion at COMP, if the criteria are considered to be satisfactorily fulfilled, a positive opinion is issued. However, if there are outstanding concerns, a list of questions is sent to the sponsor. The sponsor provides a written response and is invited to attend an oral hearing to determine the final outcome. In light of a negative opinion, a sponsor can appeal or re-apply with additional data at a later date. The COMP scientific opinions are normally reached by consensus and the opinion is transmitted to the EC, which is the responsible body for issuing binding decisions. The OMP is entered in the EC register and a public assessment report is available online [7].

Sponsors with a designated orphan product benefit from incentives. A special fund from the EC is used by the EMA to grant fee reductions (i.e., applications for marketing authorisation, inspections and scientific advice). Scientific advice (called protocol assistance) helps maximise the probability of a successful outcome at the marketing authorisation stage [8]. After the granting of a marketing authorisation, OMPs benefit from 10 years of market exclusivity. Member States shall not, for a period of 10 years, accept another application for the same therapeutic indication, in respect of a similar medicinal product. During that period, directly competitive similar products (products containing a similar active substance that is intended for use for the same therapeutic indication) cannot normally be placed on the market. However, three derogations apply: i) the marketing authorisation holder (MAH) of the original application gives consent, ii) the MAH of the original application cannot supply sufficient quantities or iii) the second applicant can establish clinical superiority [9].

3. Orphan drug designation in the USA

The Food and Drug Administration (FDA), through its Office of Orphan Products Development (OOPD) administers the major provisions of the ODA [10]. The ODA is a federal law concerning rare diseases that affect less than 200,000 individuals in the USA or more than 200,000 individuals, where there is no prospect of recovering the cost of the relevant drug development and distribution through sales in the USA [11]. A sponsor may request an orphan drug designation in a previously unapproved drug, or a new orphan indication for an already marketed drug. In addition, a sponsor of a drug that is otherwise the same drug as an already approved orphan drug may seek and obtain a designation for the same rare disease or condition if they can present a plausible hypothesis that their product may be clinically superior to the first drug. Clinical superiority refers to greater effectiveness, greater safety or MC-to-PC. MC-to-PC is considered a narrow category and does not relate to minor inconveniences.

A foreign sponsor must have a US resident agent in order to file an application for orphan drug designation. The sponsor submits an application to the OOPD and the application can be submitted any time before the submission of a New Drug Application/Biologics License Application (NDA/BLA). The required information to be included in the application is found under 21 CFR 316.20(b), shown as nine items (Table 2). While all nine items are reviewed, the most important are items 4 (scientific rationale) and 8 (population prevalence). If a drug can be demonstrated as having utility in a small subset of a common disease, then it may also qualify for orphan designation (such subsets may be considered invalid according to the EU Regulation). A medically plausible subset of a more common disease is one where the characteristics of the drug limit its use in a particular subgroup. Prevalence must be a specific number, not simply stated as less than 200,000 (if a range exists, the highest estimate should be applied).

In order to determine whether a drug qualifies as an OMP, a submitted orphan drug application is reviewed by the scientific staff of the OOPD. After the receipt of the application, the assigned OOPD reviewer completes the assessment by preparing a review. This is followed by a second (OOPD team leader) and third level (OOPD Office Director) review and concurrence. The outcomes are a designation letter, a letter requesting additional information or a denial letter. Following a positive decision, the sponsors' name, name of the drug and proposed indication are published. The typical review cycle is 90 days. Sponsors that obtain an orphan designation benefit from incentives. Incentives include a 7-year period of market exclusivity following marketing authorisation, protocol assistance and tax advantages for development costs. User fees paid to the FDA for review of the sponsors' application for marketing authorisation are waived. In addition, the FDA Orphan Products Grant Program offers funding for clinical studies (safety and/or effectiveness) that will result in or substantially contribute to market approval.

4. Orphan drug designation in Japan

Medicinal products can be designated as orphan based on Article 77-2 of the Pharmaceutical Affairs Law. The Minister of Health, Labour and Welfare (MHLW) may designate orphan drugs if the following criteria are satisfied: the number of patients who may use the drug are less than 50,000 in Japan, the drug is indicated for the treatment of patients with serious diseases, including difficult-to-treat diseases and there is no appropriate alternative drug or treatment, or higher efficacy or safety is expected compared with existing products. In addition, there should be the possibility of development (theoretical rationale for the use of the product for the target disease) (Table 2) [12].

MHLW holds jurisdiction over the Pharmaceutical Affairs Law and the MHLW makes orphan designation decisions on a case-by-case basis. The decision is based on the opinion of the Pharmaceutical Affairs and Food Sanitation Council (PAFSC), who review a scientific report prepared by the Pharmaceuticals and Medical Devices Agency (PMDA). As with other regulatory submissions, Japanese data are considered to be of most value and the application for orphan designation must be in Japanese. Orphan drug designation comes with the following incentives:

• Subsidy payment through the National Institute of Biomedical Innovation (NIBIO) to reduce the financial burden of product development.

• Guidance and consultation on research and development activities.

• Preferential tax treatment.

• Priority review for marketing authorisation and categories of lower user fees.

• Extension of the re-examination period up to 10 years.

5. Conclusion

Patients suffering from rare conditions are entitled to the same quality of treatment as patients with common diseases. Orphan legislation offers important incentives to encourage the development of medicinal products for rare diseases and the success of the legislation has been demonstrated [13,14]. Although similarities exist in the designation procedures in the EU, USA and Japan, there are differences in the key criteria used to determine whether a medicinal product can be considered an ‘orphan drug'. These include the definitions of the orphan condition to be treated and the prevalence criteria. Despite these differences, numerous medicinal products designated as orphan have subsequently achieved marketing authorisation, highlighting the success of the incentive systems in encouraging development of treatments for rare diseases [3,13-15].

6. Expert opinion

The legislative and regulatory framework for orphan drugs is associated with pre- and post-marketing authorisation incentives. Access to these incentives depends on successfully demonstrating fulfilment of the criteria for orphan designation to the authorities. In order to promote success, the sponsor should consult the relevant guidance documents to ensure that the content and format of the application is optimised and the submitted references are current and relevant. All claims should be clearly supported by relevant data (in house or published). Simply stating that prevalence was quoted as ‘X' on a particular rare disease website is not normally acceptable, without further supportive analysis. The inclusion with the application of a comprehensive abbreviation list is recommended and welcomed by the reviewers. Engaging with the pre-submission process, taking on board the advice and other initiatives designed to help sponsors are important aspects of the procedure, for example, FDA/EMA Orphan Product Designation and Grant Workshop.

The ultimate aim for orphan designated products is that patients benefit through the eventual marketing authorisation. As with all medicinal products, at the time of licensure, there is a general requirement to establish the quality, safety and efficacy to the regulatory authorities. The importance of requesting and adhering to scientific advice cannot be understated [8].

Declaration of interest

The author states no conflict of interest and has received no payment in preparation of this manuscript.

Acknowledgments

The author would like to thank Maria Mavris (EURORDIS – European Organisation for Rare Diseases) for comments on the manuscript during preparation. The views expressed are those of D J O'Connor and do not necessarily reflect the official positions of the MHRA or the EMA or their respective committees.