FDA Orphan Drug Designation Process

There are more than 7,000 rare diseases in the U.S., affecting more than 30 million people. Many of these rare diseases are life-threatening, and most have no cure. Orphan drugs (including biologics) are used to prevent, treat, and diagnose rare diseases.

The Orphan Drug Act (ODA) is the legal basis for the FDA to recognize a drug or biologic as a treatment for a rare disease or condition. The ODA was signed into law in 1983 and is designed to promote product development for rare diseases by providing financial and other incentives to developers of rare disease therapies. In this article, we provide an overview of the FDA's Orphan Drug Designation process.

Introduction of Orphan Drug Designation

The Orphan Drug Designation (ODD) process begins when a sponsor submits an ODD application to the FDA. It is important to emphasize that the office responsible for reviewing ODD applications is not the FDA's Office of Specific Products, but rather the Office of Orphan Drug Product Development (OODP).

Advantages of orphan drug designation

• Tax credits for clinical trials
• Waiver of NDA/BLA filing fees (approximately $2 million)
• The same drug will not be approved for the same indication for 7 years after the orphan drug is marketed

Main criteria for evaluating ODD

• The number of patients is less than 200,000 in the U.S.
• Promise of the drug in preventing, diagnosing, or treating a rare disease or condition
• Evidence of potential benefit from the drug, which may come from preclinical and / or clinical data

A sponsor may submit an ODD application to the regulatory agency at any point in the development process, but typically prior to the initial IND application.

ODD Application Information

(1) The applicant's administrative information

Information about the applicant, information about the main contact person, US Resident agent and related information, and information about the product.

(2) Explanation of the disease or status

Orphan drug designation is for a disease or condition rather than an indication. The applicant needs to explain the mechanism of action of the drug, the pathophysiology of the disease, the cause of the disease, the available treatments and the prognosis of the disease.

(3) Sufficient scientific evidence of the drug's potential therapeutic, preventive and other capabilities

(4) Counting the number of patients proves that the disease is rare

Estimates of the number of patients are based on prevalence and incidence. For tumors, this can be calculated using the National Cancer Institute's SEER system.

Calculating the number of people with the disease should be done using the most conservative calculation, choosing the highest incidence multiplied by the population of the United States to calculate the number of people with the disease, rather than using the average. If data are only available for one region of the United States or for a non-U.S. region, an explanation of why the data can be applied and the limitations of the data is needed to safeguard the reliability of the data.

(5) Regulatory status

Pre-IND, IND, NDA, BLA information in the U.S. and other countries, including coding and indication information, European ODD application information, and ODD information for the drug in other diseases or states.

Details can be found in 21 CFR 316.20(b). Form 4035 can help sponsors provide the required application content in a complete and concise manner.

ODD Application Pathway

For public health emergencies such as Covid-19, applications can be submitted electronically by sending an email to orphan@fda.hhs.gov.

• It is recommended to set up automatic read receipts to avoid double-checking receipts.
• It is recommended to send the request to SecureEmail@fda.hhs.gov to establish a secure email link, and to establish an encrypted transmission through an electronic certificate, for which a fee will be charged for commercial organizations.
• Usually, it is recommended to send the request in the form of a CD-ROM by mail. No other physical media can be used.

Foreign sponsors are required to have a U.S. permanent resident agent submit the orphan drug eligibility application on their behalf, as described in 21 CRF 316.22. Any organization responsible for orphan drug eligibility documentation may act as an agent. Sponsors are required to notify OOPD in the first instance if they change agents.

Prevalence of Data

Prevalence data for many rare diseases can be obtained from government or other organizations' websites. All materials on which prevalence data are estimated need to be included with the application.

The sponsor should obtain the most recent prevalence data available for the U.S. population whenever possible. If only previous years' or foreign data are available, the sponsor should provide an explanation. To reflect the most accurate data possible for the U.S. population, sponsors should use data from the U.S. Census Bureau.

• If the estimate is a range, FDA will only accept the largest estimate unless the sponsor can explain why other data are more accurate.
• If it is for the diagnosis or prevention of a rare disease, the number of people who need to take the drug each year is required
• If the disease is acute (less than one year in duration), the incidence rate can be used to estimate the number of people who will take the drug.
• If the disease is a cyclical relapsing or remitting disease, an estimated prevalence is still needed
• If claims databases or foreign data are used, it needs to be clear how these data generalize to the U.S. population and the limitations of the data

Exclusiveness of Orphan Drugs

The Orphan Drug Act encourages innovation and accelerates the development of better efficacious drugs. The statute does not want orphan drug exclusivity determinations to impede progress in rare disease treatment.

Sponsors are required to provide a credible basis to show that the new drug may have a clinical advantage over an already approved drug. Clinical advantage means being more effective, safer in a large portion of the target population, or having a Major Contribution to Patient Care (MC-to-PC).

For market exclusivity, the sponsor must demonstrate that the drug is clinically superior to previously approved drugs for the same use. This often requires Head to Head trials, where a clinical trial is conducted using the approved drug as a control, comparing the safety and efficacy.

MC-to-PC

For serious or life-threatening diseases, the main factors to consider if a drug is MC-to-PC include the following:

• Convenient location for treatment
• Treatment cycle time
• Patient comfort
• Reduced treatment burden
• Advances in the ease and comfort of drug administration
• Longer dosage intervals
• Potential for self-care

Factors that the FDA will not consider include the cost of treatment and adherence to treatment.

A sponsor may obtain orphan drug designation for a rare clinical category of a non-rare disease/condition with a reasonable and sufficient explanation. The sponsor must clearly explain to the OOPD that the drug will never be used for a disease/condition other than the corresponding rare clinical category.

Review Process for ODD

(1) The application is assigned a number, entered into the OOPD database, and a confirmation email is sent to the sponsor.

(2) The designated OOPD reviewer completes the review of the application, which may require advisory support from FDA.

(3) Review comments are forwarded to the Orphan Drug Designation Program Director for a second round of review.

(4) The Director signs the designation, release requesting additional information, or denial document and sends it to the sponsor.

Proregulations has a professional drug compliance and registration team, which has in-depth research into the process and requirements of FDA orphan drug identification and application, and can provide accurate guidance for customers. If you are interested in our services or need more details, please contact us.