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505(b)(2) Orphan Drug Approval with only a BE study?

A reader recently inquired about Orphan drugs and asked me if I thought an Orphan drug developed under 505(b)(2) could be approved based on just a Phase 1 study – a pharmacokinetic or pharmacodynamic comparison to the RLD.

At first I thought I couldn’t think of an example.  Generally, an Orphan drug fulfills an unmet need in 200,000 or fewer people in the U.S. and requires a clinical study for approval.  In return, among other benefits, the drug is given 7 years exclusivity – except, and here is a potential answer to the subject question:

If the new drug is shown to be different from the approved orphan drug because the new drug is “clinically superior” (e.g., shows greater efficacy,safety or contribution to patient care).

Thus, for example, you might find that a revised formulation significantly reduced adverse events.  An Orphan injectable formulation is changed to reduce the injection site reactions, for instance.  In this case, it is likely that only a Phase 1 study would be needed.  We would recommend a pre-IND meeting with FDA to assure that FDA would consider the change ‘clinically superior’.  The FDA has indicated that it would decide these matters on a case-by-case basis ( 57 Fed Reg 62079 – see particularly comment 27).