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Compiling US Orphan Drug Designation Requests

In the United States, the Orphan Drug Act (ODA) was passed in 1983 to facilitate the development of drugs or biologics that are used for the prevention, diagnosis, or treatment of diseases or conditions affecting fewer than 200,000 persons in the US.

Before this act was passed, there was a serious lack of development for treatments of diseases found in small patient populations, due to the significant amount of funding required to prove the necessary safety and efficacy requirements to achieve FDA approval.

A product that qualifies for Orphan Drug Designation is subject to several benefits, such as:

A sponsor looking to receive orphan drug designation must submit a request with information as specified in 21 CFR 316.20-316.21. ODD is obtained prior to filing a marketing application for the product. Obtaining ODD does not diminish regulatory requirements – safety and efficacy still must be established to the usual standards before obtaining market approval. In this article, we will discuss the format and components of these submissions, and how to transmit them to the FDA.

Submission Format

Orphan Drug Designation Request submissions are not required to be built in the traditional eCTD format. Depending on the type of interaction needed, correspondence can be conducted via Telephone, can be handled via email, or can require physical documentation that must be sent by mail. The table below clarifies the mediums allowed for different types of communication.

When communicating via telephone, sponsors should call 301-796-8660. Emails should be sent to the mailbox FDA encourages sponsors to utilize read receipts to confirm that their communications are received.

Original Orphan Drug Designation requests are required to be physically submitted via mail. Sponsors have the option of submitting hard copies or Compact Discs (CDs).

Required Components

As previously discussed, these submission types do not require a specialized format such as eCTD, and therefore do not require a specialized software in order to compile. There are 3 main component types: a cover letter, the main text document, and cited literature references.

1. Cover Letter

A cover letter should be drafted to give clarity of company contacts and the intent of the A cover letter should be drafted to give clarity of sponsor contact points and the intent of the submission. If submitting your request via CD, the cover letter should be printed and included with the disc inside the shipping envelope

2. Orphan Drug Request

The main content document is where sponsors make their case for why their product should be granted Orphan Drug designation. This can be provided in the form of a completed FDA Form 4035, or a more traditional written document.

FDA Form 4035

FDA Form 4035 is an interactive form created by FDA that allows sponsors to capture all the required content for an orphan drug designation in a standardized format. The form contains detailed instructions in each section on the type of information required and provides helpful links to relevant sections of the CFR for further guidance. Sponsors can also provide attachments directly within the form to further support their claims. However, sponsors should note that only tables, charts, illustrations, and photos should be included as attachments within the form, not literature references, which will be provided separately.

1-8 Format

While FDA Form 4035 is useful resource, it is not a strict requirement for submission. Some sponsors may instead opt to self-create a document. FDA refers to this as “1-8” format, as it is preferred that the sections are numbered 1-8 to fall in line with the section numberings for content requirement in 21 CFR 316.20. This may be especially useful if a sponsor is creating content to be reused for Orphan Drug Designation requests to be submitted across Global Health Authorities. FDA has provided the guidance below to clarify the suggested length when utilizing this format.

3. References

Whether utilizing FDA Form 4035 or the 1-8 format, sponsors must include copies of each reference cited within their Orphan Drug Request. If submitting in paper, each reference should be separated out by a tabbed divider and arranged alphabetically. If submitting electronically, sponsors have the option of either providing a single PDF with all references combined or a folder containing individual PDF files for each reference.

Important Notes Regarding COVID-19

At the time of publishing this article, the agency has recognized that the COVID-19 pandemic has made the creation and submission of physical media difficult due to office building closures and social distancing practices. Therefore, they have clarified on the FAQ section on their site that submission types that are typically submitted via Mail can be submitted via email, and provide instructions on how this can be done. Sponsors can also contact with additional inquiries for their specific programs.


The Office of Orphan Products Development (OOPD) has several excellent resources on their website that give insight into creating the content of the request. The most useful links are provided below.

Designating an Orphan Product: Drugs and Biological Products

Education and Media Resources for Orphan Designation Program

Orphan Drug Designation Request Form (FDA Form 4035)

Corresponding with the OOPD Drug Designation Programs

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