In examining the FDA’s clinical superiority hypothesis requirement for orphan drug designation, it’s helpful to consider the primary purpose of the Orphan Drug Act - to provide incentives for the development of promising orphan drugs that would not otherwise be developed and approved.
When a drug is the same as an already approved drug, the FDA requires that orphan drug designation requests include a plausible hypothesis of clinical superiority – regardless of whether the already approved drug has orphan drug exclusivity. [§316.20(a) and (b)(5)]
If the same drug has already been approved for the same use (with or without orphan-drug exclusivity), designation without a clinical superiority hypothesis would conflict with the primary purpose of the Orphan Drug Act – which is to encourage significant (not minor) modifications to already approved drugs that confer no meaningful benefit to patients.
A clinical superiority hypothesis is also required for the designation of a drug that is otherwise the same as an already approved drug that is already approved for the same use, whether or not the previously approved drug obtained orphan-drug designation or is eligible for orphan drug exclusivity.
Consider CSL Behring’s IDELVION. The FDA approved IDELVION (rIX-FP) for use in children and adults with congenital factor IX deficiency in March 2016. IDELVION was the first coagulation factor-albumin fusion protein product to be approved, and the second Factor IX fusion protein product approved in the U.S. that was modified to last longer in the bloodstream.
The Office of Orphan Products Development (OOPD) has designated six products for treatment of hemophilia B. Three of those products have been approved - all coagulation Factor IX. One of these approved products is a recombinant Coagulation Factor IX (BeneFIX®), approved and marketed in 1997. None of the three approved coagulation Factor IXs retain exclusivity.
Why didn’t the FDA consider IDELVION the same as BeneFIX and require a clinical superiority hypothesis for orphan drug designation?
Had it needed to, the sponsor could have argued that IDELVION was superior to other methods of extending protein half-life in vivo. In order to generate rIX-FP, FIX cDNA was connected to human albumin cDNA via a FIX derived linker sequence. The linker sequence between FIX and albumin is derived from an endogenous FIX sequence involved in normal FIX activation, enabling the cleavage of the fusion protein by the same enzymes (coagulation Factor XIa or Factor Vlla Tissue Factor) which activate FIX during the normal process of blood coagulation.
Thus, as a result of activation in vivo, in parallel active recombinant FIXa is cleaved from the albumin carrier moiety. The advantage of this technology over other methods of extending protein half-life in vivo is that it allows an unchanged human recombinant FIX to be co-expressed as a fusion to recombinant human albumin.
The clinical superiority would be based on fewer dosing administrations that the patients would have to undergo.
However, as an OOPD review stated:
“[C]linical superiority is only necessary and applicable if rlX-FP is indeed the 'same drug' as the already approved recombinant factor IX. According to CFR 3I6.20(b)(5), ‘where the sponsor of a drug that is otherwise the same drug as an already-approved orphan drug seeks orphan 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’ should be included in the request for designation.
FDA regulations also state that ‘Two protein drugs would be considered the same if the only differences in structure between them were due to posttranslational events or infidelity of translation or transcription or were minor differences in amino acid sequence; other potentially important differences, such as different glycosylation patterns or different tertiary structures, would not cause the drugs to be considered different unless the differences were shown to be clinically superior.’
It is known from the sponsor’s references that recombinant fusion protein linking coagulation factor IX with albumin with a linker peptide sequence is formed via a process in which Factor TI wild-type cDNA is cloned into an expression vector and prepared for genetic fusion with the linker and albumin cDNA. The fused genetic material is then used to produce recombinant factor IX fused with albumin.
FDA regulations state that two protein drugs would be considered the same if the only differences in structure between them were due to posttranslational events (these are not post-translational events) or infidelity of translation or transcription or were minor differences in amino acid sequence.
The DNA is not equivalent because the DNA of the FIX-albumin molecule contains the DNA of albumin (and the linker, too). Thus, the sponsor is exempt from the clinical superiority explanation requirement for orphan drug designation of rIX-FP.”
Note that clinical superiority requirements for orphan-drug designation and orphan drug exclusivity are different:
- Orphan drug designation requires a plausible hypothesis of clinical superiority
- Orphan drug exclusivity requires a demonstration of clinical superiority
If the sponsor of a subsequent drug that is otherwise the same as a previously approved drug demonstrates clinical superiority to the previously approved drug, that subsequent drug can gain marketing approval and its own orphan-drug exclusivity, despite any existing exclusivity for the previously approved drug.
It would also be eligible for exclusivity upon a showing of clinical superiority where the previously approved drug’s exclusivity period has run or never existed.