Orphan Drug Designations in the U.S. and EU

July 8, 2022

What is an Orphan Drug Designation?

The Orphan Drug Designation (ODD) program in both the United States (U.S.) and European Union (E.U.) qualifies sponsors to receive potential incentives to develop therapies for the diagnosis, prevention, or treatment of rare diseases or conditions.

Since rare diseases affect a small portion of the population, there is less financial incentive to develop medicinal products compared to more common diseases and conditions.

Therefore, the ODD program potentiates attractive advantages, both financial and otherwise, to sponsors in order to promote the development of treatments for rare diseases.

An ODD application can be submitted to the FDA or the EMA at any stage of development, as long as it is before submission of the drug licensing application.

INCENTIVES OF U.S. ODD

Several potential advantages are afforded upon a successful ODD by the U.S. FDA including the following:

  • 25% tax credit on clinical testing expenses associated with qualifying clinical trials
  • Waiver of the Prescription Drug User Fee Act (PDUFA) application fee (~$3.1 million in 2022) that is required to be paid with NDA/BLA application submission
  • 7-year market exclusivity

Particularly, the 7-year market exclusivity (termed Orphan Exclusivity) is determined by the Office of Orphan Product Development (OOPD) upon marketing approval of the drug. This type of exclusivity bars the FDA from approving any other application for the same drug (meaning a drug with the same active pharmaceutical ingredient) for the same orphan disease or condition for 7 years from the date of approval.

INCENTIVES OF EU ODD

The EU also offers a range of incentives to encourage the development of designated orphan medicines:

  • Protocol assistance: A type of scientific advice specific for designated orphan medicines. This allows sponsors to get answers to their questions on the types of studies needed to demonstrate the medicine's quality, benefits and risks, and information on the significant benefit of the medicine.
  • 10 years of Market exclusivity. This period of protection is extended by two years for medicines that also have complied with an agreed paediatric investigation plan granted at the time of review of the orphan medicine designation.
  • Fee reductions are also available depending on the status of the sponsor and the type of service required as outlines in the table below:
Procedure or Service Sponsor Status Fee Reduction
Protocol assistance
(non-paediatric related)
Small Medium Enterprise (SME) 100%
Non-SME 75%
Protocol assistance
(paediatric related)
All sponsors 100%
Pre-authorization inspection All sponsors 100%
Initial MAA SME 100%
Non-SME 10%
Post-authorization applications and annual fee in the first year from MA SME 100%
Post-authorization inspection SME 90%

ELIGIBILITY FOR U.S. ODD

To qualify for designation in the U.S., the following criteria must be met:

  • The product must be intended for the diagnosis, prevention, or treatment in a rare disease or condition.
  • Adequate documentation or prevalence data must demonstrate that the intended condition affects less than 200,000 people in the U.S. at the time of the application (but is not expected to recover the costs of development and marketing of the new drug or biologic).

There must be a scientific rationale establishing a medically plausible basis for the use of the product for the rare disease or condition.

ELIGIBILITY FOR EU ODD

To qualify for orphan designation in the EU, a medicine must meet the following criteria:

  • The product must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating.
  • The prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development.
  • No satisfactory method of diagnosis, prevention or treatment of the condition can be authorized, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

The above information should all be included in the respective US and EU ODD applications, and relevant publications, database information, and other supporting information should be appended to the applications for review.

COMPARISON OF U.S. AND EU ODD APPLICATIONS

  • The EMA and FDA work together closely, sharing information on orphan medicines under their confidentiality arrangement. The two authorities have also developed common procedures for applying for orphan designation and for submitting annual reports on the status of development of designated orphan medicines. However, there are a number of differences between U.S. and EU ODD applications as outlined in the table below:
Items EU U.S.
Terminology Orphan medicinal product designation Orphan drug designation
Application to Committee for Orphan Medicinal Products Office of Orphan Products Development
Timetable and assessment Timetable for submission and assessment published by EMA

Option for pre-submission meeting

Procedure: 180 days, dependent on requirement for list of questions/oral explanation.

No defined timetable for submission

Procedure: 90 days

Prevalence criteria Disease or condition affects no more than 5 in 10,000 people in the EU Disease or condition affects less than 200,000 people in the U.S.
Dossier Sections A-E (ENTR/6283/00) 9 parts (21 CFR 316.20)
Key aspects of the application Medical plausibility

Prevalence

Justification of significant benefit or why other methods are not satisfactory

Scientific rationale

Prevalence

Sponsor established in territory Proof of establishment in EEA Not required
Translations Translations of product name and proposed orphan indication into all official languages of the EU plus Icelandic and Norwegian Not required
Updates at time of Licensing Submission of orphan maintenance report In cases where a clinical superiority argument is required for Orphan Exclusivity, the sponsor must demonstrate that the drug is actually clinically superior to any previously approved same drug for the same use within the marketing application

THE MOST DIFFICULT PARTS

Adequate Data

Many ODD applications are submitted early in the development of a drug. Clinical data are not required to be submitted with an ODD request if no studies in humans have been conducted with the proposed drug in the rare disease or condition. The Agency will accept in vitro or animal data that clearly shows that the drug is plausibly effective in treating the rare disease or condition. However, particularly for animal studies, the animal used must be recognized as an adequate model for the rare disease or condition in humans, and supporting documentation (literature publication, database, etc.) should be submitted to reference the adequacy of the animal model. Some diseases or conditions do not have an established animal model, and applicants may need to be creative to justify the use of a non-human model for the disease or condition and the mechanism of action of the drug. To establish a medically plausible basis for the use of the drug for the rare disease or condition, all in vitro studies, animal studies, and clinical experience should be provided for review whether positive, negative, or inconclusive.

Prevalence/Incidence

The prevalence estimate1 for an ODD request should show that, based on the most conservative estimates found in literature, databases, and other resources, the disease or condition that is the subject of the request is currently present in less than 200,000 people in the U.S. or not more than 5 in 10,000 people in the EU For example, if five peer-reviewed literature articles give five different estimates of a disease prevalence, the highest prevalence estimate would be considered the most conservative. Importantly, prevalence is not the same as incidence; the latter is the number of new cases of a disease or condition, whereas the agencies are looking for the number of people in the U.S or EU that currently have the disease or condition, known as the prevalence.

Many sources of information that estimate a disease prevalence from publicly available literature or health databases are estimated from a previous year or even previous decade. With ever-growing populations in the U.S., the estimated number of people with a rare disease or condition inevitably also increases. A calculation should be provided in a US ODD request that converts the prevalence of a disease in a previous year to the prevalence based on the current U.S. population size .

Furthermore, supporting sources of prevalence estimates must be within the U.S. population for a US ODD request or within the EU population for an EU ODD request. Often, data related to the prevalence of a rare disease is lacking, and sponsor may need to be creative in constructing an adequate prevalence estimate.

Clinical Superiority

As explained above, where the sponsor of a drug that is otherwise the same drug (i.e., the same active moiety) as an already approved drug seeks orphan drug designation for the subsequent drug for the same rare disease or condition, an explanation of why the proposed variation may be clinically superior to the first drug. “Clinically superior” means that the drug shows a significant advantage over and above that of the approved drug by exhibiting greater efficacy, greater safety in a substantial portion of the target population (i.e., the drug causes fewer and/or less severe adverse events than the approved drug) or provides a major contribution to patient care (e.g., an oral dosage form is less invasive than an intravenous route of administration).

Also noted above, once a sponsor has been granted an ODD, Orphan Exclusivity (U.S) or maintenance of the orphan designation (EU) is requested in the marketing application. Oftentimes the FDA will require a direct comparison study between approved drug(s) and the proposed orphan drug to confirm clinical superiority in order to grant the 7-year Orphan Exclusivity in the US.

NEXT STEPS AFTER SUCCESSFUL ODD

After a U.S. ODD has been granted to a sponsor, the sponsor must submit annual reports within 14 months after the date of approval. The annual report is intended to update OOPD on the status of the designated orphan drug development, including a review and status of ongoing clinical studies, a description of the investigation plan for the coming year, any anticipated or current problems in the process, difficulties in testing, and any potential changes that may impact the product's designation as an orphan product.

Similarly, in the EU, the COMP requests annual updates on the status of product development after within 14 months of designation. The FDA and the EMA will accept the submission of a single annual report from sponsors of orphan products designated for both the U.S. and the EU.

Sponsors are encouraged to continue to develop the candidate drug, and upon readiness of a marketing application, a request for Orphan Exclusivity (for the U.S.) or a maintenance of the orphan designation (for the EU) should be included in the marketing application. During the marketing application review period, the respective agencies will determine if the disease still meets the requirements outlined above for an orphan drug, and ultimately decide whether to grant the incentives of Orphan Exclusivity to the drug.

CONCLUSIONS

The cost to develop drugs is extreme. Since rare diseases affect a small number of individuals, the likelihood of recovering the costs of traditional drug development is slim. Therefore, the international orphan designation programs provide a gateway for sponsors to develop drugs for rare diseases that otherwise may not be attractive candidates for financial reasons. The incentives of tax breaks, application fee waivers, and marketing exclusivity satisfy the overall mission: To identify and designate products as promising for rare diseases and to further advance scientific development of such promising medical products. To make the most of these incentives, early engagement with the FDA and/or EMA is suggested. ProPharma group offers expert guidance on orphan drug development.

1The OOPD will allow sponsors to use an incidence estimate for acute diseases with a duration of less than one year provided that they are curable and do not recur. Relapsing or remitting diseases such as cancer typically require a prevalence estimate. The National Cancer Institute’s Surveillance, Epidemiology and End Results or SEER Program website is OOPD’s standard source for cancer statistics in the United States.

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