Introduction.

Background & Legal Framework.

A rare disease is any disease that affects a small percentage of the population, although the exact definition varies across jurisdictions. While each disease is rare, collectively, these disorders affect 6–7% of the population in the developed world1. This represents 400 million people worldwide, of which 30 million Europeans and 25 million Americans, and that makes the diseases and finding treatments for them a serious public health concern2. There are between 5000 and 8000 rare diseases2; however only approximately 130 in the EU3, and 500 in the US4 have approved treatments. As such, there is a significant need to develop therapies for these patients. Historically, rare disease drug development was often limited by the prohibitive cost of the pharmaceutical program and the perceived low probability of successfully recouping the drug development costs. The recognition of this by competent authorities has led to the creation of new regulations and policies to encourage and incentivise orphan drug research and development, including licensing, pricing and reimbursement.

In the EU, Regulation (EC) No 141/2000 (the Orphan Regulation), defines the procedure for designation of orphan medicinal products, and defines the incentives for development and marketing of orphan designated medicines. The Orphan Regulation also established the Committee for Orphan Medicinal Products (COMP), which is responsible for evaluating applications, and recommending orphan designation. The final decisions on orphan designation are issued by the European Commission (EC), who also publish a register of designated orphan medicinal products.

Since the end of the Brexit transition period on 1st January 2021, Great Britain (GB) has its own orphan designation procedure which mirrors that outlined in Regulation (EC) No 141/2000. However, in contrast to the EU, the MHRA will not review applications for orphan designation until the time of a marketing authorisation application (MAA) submission; there will be no pre-marketing authorisation orphan designation. All medicines that gain a GB orphan marketing authorisation will be listed on the Great Britain Orphan Register.

In the US, the Orphan Drug Act, codified in 21 CFR Part 316 provides procedures to encourage and facilitate the development of drugs for rare diseases, including the process for requesting orphan drug designation. The FDA’s Office of Orphan Products Development (OOPD) is responsible for evaluating requests for orphan drug designation as well as other duties related to the development of products for the diagnosis and/or treatment of rare diseases. OOPD also maintains a database of products with orphan drug designation.

Eligibility.

The definition of a rare disease varies across jurisdictions. In the EU, as stated in Article 3 of Regulation (EC) No 141/2000 on orphan medicinal products, the criteria for orphan drug designation are as follows:

a) that it 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 Community when the application is made,

or,

that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the Community and that without incentives it is unlikely that the marketing of the medicinal product in the Community would generate sufficient return to justify the necessary investment;

and

b) that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorised in the Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.

The sponsor must establish that each of the above criteria are met, as well as demonstrate establishment in the EU.

Eligibility requirements in GB are the same as the EU, but with a focus on GB for prevalence calculations and existing approved treatments. 

As defined in 21 CFR 316.21(a), in the US, a drug can be considered for orphan designation if it is intended to treat a rare disease or condition affecting fewer than 200,000 people in the United States, or if the sponsor is not expected to recover development costs plus reasonable profit within 7 years following FDA approval.

Prevalence.

There are a number of definitions that can be used to estimate the number of people with the condition. In the US, prevalence is defined as the number of persons who have been diagnosed as having the disease or condition at the time of the submission of the orphan drug designation application. In the EU and GB, prevalence is reported as a proportion (further details in the COMP guideline ‘Points to consider on the estimation and reporting on the prevalence of a condition for the purpose of orphan designation’, EMA/COMP/436/01). 

Point prevalence is the proportion of a population that is alive and affected by the specific condition at a specific point in time, typically the time of application. Complete prevalence represents the number of previously diagnosed persons alive at the specific point in time regardless of how long ago the diagnosis was, or if the patients may now be considered cured or may need treatment. Partial prevalence limits the number of patients to those diagnosed during a fixed time in the past, e.g., 5 years.

The choice of epidemiological parameter used in the orphan application should reflect the nature of the condition. For example, complete prevalence should be used for chronic diseases, where a patient previously diagnosed may be considered always “affected by” that condition until the time of death. Whereas partial prevalence may be appropriate for non-chronic diseases.

The duration of the condition may also be relevant to the population estimate. The functional relationship between point prevalence (P), incidence (I) and mean duration (D) is commonly expressed as P = I x D. As such, for acute conditions with a duration of less than 1 year, incidence rates (defined as the annual number of new cases of the disease or condition) may be used.

Data used to support the prevalence estimate should ideally be based on the relevant geographical region. If only foreign data are available, applicants should justify why the data can be generalised to the region of interest, and explain the limitations of such data. Furthermore, the most recent available data should be used, and the validity of the data should be assessed. It is also important to not average out multiple prevalence or incidence rates but to use the highest rate available, resulting in the most conservative prevalence estimate.

In addition to disease prevalence there are a number of other elements that an applicant must consider in order to be eligible for orphan drug designation; these are discussed in more detail below.

Distinct Medical Entity.

In the EU, the Orphan Regulation and “Guideline on the format and content of applications for designation as orphan medicinal products” stipulates the requirement for the condition to be a recognised medical entity in terms of characteristics such as pathophysiology, histopathology or clinical characteristics. The characteristics defining a distinct condition should determine a group of patients in whom development of a medicinal product is plausible, based on the pathogenesis of the condition and pharmacodynamic evidence and assumptions. Different degrees of severity or stages of a disease are not generally considered as distinct conditions. The fact that a subset of patients exists in whom the medicinal product is expected to show a favourable benefit/risk (as defined in the proposed therapeutic indication) would generally not be sufficient to define a distinct condition. 

A subset of a condition which, when considered as a whole, has a prevalence greater than 5 in 10,000, could be considered a valid condition if patients in that subset present distinct and unique evaluable characteristic(s) with a plausible link to the condition and if such characteristics are essential for the medicinal product to carry out its action. In particular, the pathophysiological characteristics associated with this subset should be closely linked to the pharmacological action of the medicinal product in such a way that the absence of these characteristics will render the product ineffective in the rest of the population suffering from the condition.

Details of the condition that the medicinal product is intended to diagnose, prevent or treat should be provided; this information should supply a clear description of the disease or condition in question and should be based on published references. Details of the causes and symptoms should be provided. When applicable, this section should refer to the condition according to international disease classification systems such as the WHO’s International Classification of Disease (ICD), the Medical Dictionary for Regulatory Activities (MedDRA) or other well recognised systems.

This requirement is less stringent in the US, however 21 CFR 316.20 in relation to the “Content and Format of a Request for Orphan-Drug Designation” does indicate that the application must include “a statement that the sponsor requests orphan-drug designation for a rare disease or condition, which shall be identified with specificity.” 

As described in 21 CFR 316.3(b)(13) and FDA’s Frequently Asked Questions (FAQ) About Designating an Orphan Product, Sponsors can receive orphan drug designation for the use of a drug in an orphan subset of a non-rare disease or condition when they can explain based on a characteristic or feature of the drug (e.g., mechanism of action, toxicity profile, prior clinical experience) why the drug will be limited to use in the subset of question. An orphan subset is not based on an unmet need, or how a sponsor may wish to study or indicate a drug. 

The explanation for the orphan subset must make it clear to the FDA’s Office of Orphan Products Development (OOPD) that the drug could never be used in the disease or condition outside of the subset.

For example, it might not be appropriate to treat all persons with a non-rare disease or condition with a drug that is highly toxic; however, those patients who are refractory to, or intolerant of, other less toxic drugs might be reasonable candidates for treatment with the drug. Therefore, those patients who are refractory to, or intolerant of, other less toxic drugs may be considered an appropriate orphan subset for purposes of orphan drug designation of the highly toxic drug. FDA also indicates that characteristics of the drug that have been demonstrated through previous clinical experiences may be used to identify an appropriate orphan subset.

Serious Condition/Unmet Need.

Orphan conditions must be serious conditions where the drug has the potential to address an unmet medical need. 

For applications submitted in accordance with the first paragraph of Article 3(1)(a) of the Orphan Regulation, a statement justifying the life-threatening or chronically debilitating nature of the condition supported by scientific or medical references should be provided. Furthermore, existing medicinal products approved for the target indication should be described, and if applicable, a justification of why the existing standard of care is not satisfactory should be provided. In the US, the Applicant must provide an overview of the proposed use of the drug, and the reasons why such therapy is needed for orphan drug designation.

Medical Plausibility & Potential for Significant Benefit.

A crucial element for orphan designation is data to demonstrate the scientific rationale for use of the drug in the orphan condition. The medical plausibility is best supported by clinical data of the drug in the rare disease; however, in absence of human data, non-clinical data may be sufficient.

The EMA’s Recommendation on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation (EMA/COMP/15893/2009) describes the importance of discussing the relevance of in vitro or in vivo non-clinical models in the context of the condition. If available, established in vivo models for the global condition should be used. If only in vitro evidence is available at the time of the application, the relevance of the findings should be discussed in the context of the proposed condition.

Similarly, the FDA’s Frequently Asked Questions (FAQ) About Designating an Orphan Product states that the scientific rationale portion of the designation request must include enough information to establish a medically plausible basis for expecting the drug to be effective in the rare disease. This is best supported by clinical trials of the drug in the rare disease or condition. However, in absence of human data, the request for orphan drug designation may be satisfactorily supported with non-clinical data that uses the active moiety or principal molecular structure of the proposed orphan drug in a relevant animal model for the rare human disease.

In addition to data demonstrating medical plausibility, in the EU and GB, when existing treatment methods exist for the orphan indication, the applicant must also demonstrate the potential of the drug to offer a significant benefit over the current treatment methods. Comparative data to demonstrate the significant benefit is the preference. Significant benefit can be based on an assumption of improved efficacy, improved safety or major contribution to patient care.

Because comparative data is often not available at the early stage, many applicants apply for orphan designation, a critical review comparing authorised treatments and the proposed orphan medicinal product and justifying the assumption of significant benefit should be provided. This review should be based not only on the limitations and risks of the authorised products but also on the benefit expected with the proposed product. At the time of marketing authorisation, orphan designations based on the significant benefit criterion will be reviewed. At this stage, the COMP will require a higher level of evidence than at the time of designation for the orphan destination to be maintained.

Application Procedure.

The application procedure in the EU is conducted to a defined timeline, with specific dates for submission and evaluation by the COMP. The date-specific submission deadlines for documentation submission, validation/start of procedure and COMP decision are summarised on the EMA website. The total length of the procedure (accounting for the presubmission meeting [PSM] phase) is between 6 and 7 months, depending on the requirement for an oral explanation meeting.

The PSM is an optional element in the procedure. These meetings are conducted via teleconference with the procedure administrator assigned to the Company’s procedure but may also involve members of the COMP (depending on availability and the requirement for their input). The procedure timeline is unaffected by the inclusion of a PSM, and valuable input on the presentation of information for the purposes of validation can be obtained. While the meeting does not offer a pre-assessment and is administrative by nature, applicants may obtain a strong sense of the likelihood of success as well as helpful scientific input on the content of the application.

The MHRA’s advisory committee, the Commission on Human Medicines (CHM) is responsible for the assessment of applications for GB orphan designation. A decision on fulfilment of the orphan criteria runs in parallel with the assessment of the marketing authorisation procedure. A decision on orphan status will be made at the time of the decision on approval of the marketing authorisation. Any questions concerning the fulfilment of the orphan designation criteria will be raised with the company during the evaluation of the MAA.

21 CFR 316.20 describes the content and format of an orphan drug request in the US. FDA Form 4035 should be completed with the required information. The application includes administrative information, a description of the condition, the scientific rationale, information on the drug’s regulatory status, and the population estimate.

Following receipt of the application, OOPD aims to complete its review within 90 days. Following the review, either the designation is confirmed, or the Applicant will receive a response letter outlining the reasons why OOPD was unable to grant the request. In case of the latter, the Applicant has 1 year to submit the additional information. 

Following successful designation in the EU or US, the Sponsor must comply with annual reporting requirements. Annual updates regarding the stage of development of the drug should be submitted with 14 months of the designation, and annually thereafter. 

Updates at Time of Licensing.

In the EU, the Sponsor must submit an application a report on maintenance of the orphan designation at the time of marketing authorisation, in order to be eligible for the ten-year market exclusivity incentive. The maintenance report should be submitted after the Sponsor receives confirmation that validation of the application for marketing authorisation has been completed. The Sponsor’s report includes data on: 

• the current prevalence of the condition to be diagnosed, prevented or treated, or the potential return on investment;

• the current life-threatening or debilitating nature of the condition;

• the current existence of other methods for the diagnosis, prevention or treatment of the condition;

• if applicable, a justification of the medicine’s significant benefit.

The COMP reviews the report independently of, but in parallel to the evaluation of the marketing authorisation application by the Committee for Medicinal Products for Human Use (CHMP). The COMP will adopt an opinion orphan designation maintenance following the CHMP positive opinion on the marketing authorisation application.

As the request for orphan designation in GB is submitted with the MAA, the orphan criteria must be met at this time.

In the US, once FDA grants an orphan drug designation, it can only be revoked if the application is found to contain false data or if material were omitted. The designation cannot be revoked if the prevalence at time of licensing exceeds the original estimate.

Incentives.

Orphan drug designation in the EU is associated with significant fee reductions and exemptions for various regulatory activities (summarised in Table 1). 

Table 1: Fee reductions for designated orphan medicinal products

In addition to EMA fee-related incentives, companies developing Orphan Medicinal Products are incentivised by the potential for market exclusivity following marketing authorisation. This is widely regarded as the foremost benefit of orphan drug designation in the EU, and provides 10 years of market exclusivity following approval, protecting the product from market competition from similar medicines with the same indication. This period of protection is extended by two years for medicines that also have complied with an agreed PIP granted at the time of review of the orphan medicine designation.

Article 3 of Regulation (EC) No 847/2000 defines a similar medicinal product as a medicinal product containing a similar active substance or substances as contained in a currently authorised orphan medicinal product, and which is intended for the same therapeutic indication.

It also defines similar active substance as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular features) and which acts via the same mechanism. 

Thus, all Sponsors submitting an MAA are advised to check the Community register of orphan medicinal products for information on medicinal products designated as orphan which are under market exclusivity protection. If any of the designated orphan medicinal products has been granted an MA in the EU, and a period of market exclusivity is in force, a Sponsor should include a similarity report in the MAA addressing the possible similarity between new medicinal products and the orphan medicinal product(s) which have received a marketing authorisation.

Following Brexit, the market exclusivity incentive is the same for orphan designated products in GB. However, as there is no pre-marketing authorisation orphan designation, no fee incentives apply.

In the US, orphan designated drugs are exempt from uses fees, including Application Fees and Product and Establishment Fees. Other incentives associated with orphan drug designation include the following: 

• Seven years of exclusive marketing rights for the designated indication once the drug receives FDA marketing approval.

• A tax credit for up to 50% of qualified clinical research expenses incurred in developing a designated orphan product (from the date of designation). No credit is allowed for clinical testing conducted outside the US, unless there is an insufficient patient population available for testing within the US.

• Paediatric Research Equity Act (PREA) requirements exemption.

• Eligibility to apply for orphan drug grants.

Incentives.

There are a number of incentives available to encourage the development of drugs for rare diseases, and orphan drug designation is associated with significant benefits. However, there are specific data requirements to obtain orphan drug designation. These vary according to the geographical region as well the drug and condition. 

Scendea’s expert consulting team has experience of obtaining orphan drug status in the EU, GB and US in a variety of challenging circumstances, and can advise companies on the data requirements, how best to position the available data, and how to use available data from the literature to support an application.