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How to Get Orphan Status for 505(b)(2) Drugs

2017 was a big year for orphan designations and approvals. Sixteen of the sixty-three (25%) products approved via the 505(b)(2) pathway in 2017 received orphan designation. Importantly, more than half of the approved 505(b)(2) products with orphan designation received seven years of orphan exclusivity.

That’s not bad when you consider that 505(b)(2) drugs are often not new chemical entities and therefore a Sponsor must demonstrate that the proposed orphan drug is for a different indication, or clinically superior to the previously approved drug, in order to receive seven years of orphan exclusivity. So how did they do it?

How To Get Orphan Drug Exclusivity

Usually, an orphan-designated drug will get seven years of marketing exclusivity upon approval, unless the same drug (more on the definition below) has already been approved for the same use or indication. If the same drug has already been approved, the proposed drug should be clinically superior to obtain orphan exclusivity.

However, there are exceptions, and for a brief period of time, the statute did not mirror the FDA’s interpretation that clinical superiority must be demonstrated at the time of approval. However, the Food and Drug Administration Reauthorization Act of 2017 amended the statute so the need to prove superiority has been restored.

‘Same Drug’

In the case of some 505(b)(2) products, the definition of ‘same drug’ and ‘clinically superior’ are critical.

For the purposes of orphan drug exclusivity, “same drug” for small molecules is defined as a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate, or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.

‘Clinically superior’ is defined in 21 CFR Part 316 as ‘a drug shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)‘ in one of three ways:

(1) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;

(2) greater safety in a substantial portion of the target population; or

(3) demonstration that the drug makes a major contribution to patient care.

The first two scenarios generally require data from adequate and well-controlled trials to demonstrate greater efficacy or safety. The last one is determined on a case-by-case basis by the FDA. The standard for each is high in most cases.

How Did the 2017 Approved 505(b)(2) Products Get Orphan Exclusivity?

A review of the 16 orphan products approved via the 505(b)(2) pathway in 2017 shows that 12 received orphan exclusivity. Exclusivity for four of the products was straightforward as they were new chemical entities (i.e. not the ‘same drug’ as an approved drug). The remaining eight products represented changes to the indication or intended use compared with the listed drug. No examples of clinical superiority were identified.

This is in accordance with cases of clinical superiority identified by Hyman Phelps and McNamara. Their research shows that the only case of clinical superiority in 2017 was a biologic product. The FDA’s new website for sharing cases of clinical superiority contains only the same biologic example, as of this week.

Is Orphan Drug Exclusivity Attainable for 505(b)(2) Products?


If the intended population is rare (<200,000 people in the US) and the drug is a new active moiety, orphan exclusivity is usually attainable.

If the drug is considered the ‘same drug’ as an approved drug, orphan exclusivity may be granted for a different indication, population, or intended use.

If the drug is the ‘same drug’ for the same indication/use, a justification (and demonstration) of clinical superiority will be needed.

Remember, in each of the 505(b)(2) products referred to above with orphan exclusivity, the products received seven years of marketing exclusivity and that is more than you get for new chemical entity exclusivity. Not bad for an abbreviated 505(b)(2) program!

Contact us to discuss where your product fits into the orphan drug regulations and how to make a justification for clinical superiority.


Angela Drew, PhD
Product Ideation Consultant