Fitting New Scientific Advances Into an Old Regulatory Paradigm: Fusion Proteins and Orphan Drug “Sameness”

FDA’s Orphan Drug Program, which traces its birth back to the January 4, 1983 enactment of the Orphan Drug Act (“ODA”) (see our previous post here), is probably one of the most successful FDA programs to date.  The success of the ODA is most apparent from the increasing number of orphan drug approvals and orphan drug designations each year (see our previous post here).  (In fact, there are so many orphan drug designation requests these days that FDA had to create an Orphan Drug Modernization Plan – here and here – “to both eliminate a backlog of existing designation requests, and to make sure that the agency can respond in a timely fashion to new applications.”)  But there are other, less visible measures of the success of the ODA, such as FDA’s ability to keep up with and address scientific advances in an aging regulatory paradigm.

Why are there so many orphan drug designation requests submitted to FDA? Well, as FDA notes in the Agency’s Orphan Drug Modernization Plan:

The uptick in designation requests reflects, among other factors, advances in science that allow researchers to target rare diseases that were previously not readily amenable to therapy. This is good news.  It is a reflection of substantial medical progress that’s allowing us to effectively target many vexing diseases.  It is also a reflection of our better understanding of the genetic basis of diseases, which unlocks our ability to define and target rare disorders.

With scientific advances, FDA is also faced with new questions about so-called orphan drug “sameness.”

By way of background, the FDC Act, as amended by the ODA, provides a 7-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug. Once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is “different” from the approved orphan drug (or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications).  In addition, FDA’s regulations provide that if the same drug has already been approved for the same orphan disease or condition, with or without orphan drug designation, a sponsor must provide “a plausible hypothesis that its drug may be clinically superior to the first drug” in order to obtain designation, and must demonstrate clinical superiority to obtain approval of a marketing application (if that application is blocked by another sponsor’s orphan drug exclusivity) and also to obtain orphan drug exclusivity.

According to FDA’s orphan drug regulations, a drug is “different” from an approved orphan drug (i.e., is not the “same drug”) if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug.  The degree of chemical or structural similarity that allows FDA to determine whether two drugs are the “same drug” depends on whether the drugs are small molecules or large molecules.  Thus, FDA’s regulations at 21 C.F.R. § 316.3(b)(14) define the term “same drug” to mean the following:

(i) If it is a drug composed of small molecules, 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.

(ii) If it is a drug composed of large molecules (macromolecules), a drug that contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug, except that, if the subsequent drug can be shown to be clinically superior, it will not be considered to be the same drug. This criterion will be applied as follows to different kinds of macromolecules:

(A) Two protein drugs would be considered the same if the only differences in structure between them were due to post-translational 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.

(B) Two polysaccharide drugs would be considered the same if they had identical saccharide repeating units, even if the number of units were to vary and even if there were postpolymerization modifications, unless the subsequent drug could be shown to be clinically superior.

(C) Two polynucleotide drugs consisting of two or more distinct nucleotides would be considered the same if they had an identical sequence of purine and pyrimidine bases (or their derivatives) bound to an identical sugar backbone (ribose, deoxyribose, or modifications of these sugars), unless the subsequent drug were shown to be clinically superior.

(D) Closely related, complex partly definable drugs with similar therapeutic intent, such as two live viral vaccines for the same indication, would be considered the same unless the subsequent drug was shown to be clinically superior.

FDA’s “same drug” definition has been in place now for decades – since FDA’s December 29, 1992 final rule became effective on January 28, 1993 – and has withstood the test of time insofar as being able to accommodate scientific advances. Today’s post is an example of a more recent scientific advance that FDA has been able to accommodate under the Agency’s decades-old “same drug” rubric: fusion proteins.

The National Cancer Institute defines a “fusion protein” as:

A protein made from a fusion gene, which is created by joining parts of two different genes. Fusion genes may occur naturally in the body by transfer of DNA between chromosomes. For example, the BCR-ABL gene found in some types of leukemia is a fusion gene that makes the BCR-ABL fusion protein.  Fusion genes and proteins can also be made in the laboratory by combining genes or parts of genes from the same or different organisms.

A more expansive definition from Wikipedia says:

Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this fusion gene results in a single or multiple polypeptides with functional properties derived from each of the original proteins.  Recombinant fusion proteins are created artificially by recombinant DNA technology for use in biological research or therapeutics. Chimeric or chimera usually designate hybrid proteins made of polypeptides having different functions or physico-chemical patterns.  Chimeric mutant proteins occur naturally when a complex mutation, such as a chromosomal translocation, tandem duplication, or retrotransposition creates a novel coding sequence containing parts of the coding sequences from two different genes.

A search of FDA’s Orphan Drug Designations and Approvals Database shows that the Agency has designated several fusion protein products. Thus far, we are aware of two fusion protein BLA licenses issued by FDA.  Both products raised questions about orphan drug “sameness” at FDA, and have helped to solidify FDA’s position on when two products, one of which is a fusion protein, is considered the “same drug” as the “naked” (i.e., non-fused) product.  Specifically, FDA’s position is that a post-translational fusing of amino acids to the drug results in a “same drug” determination, while a pre-translational fusing of amino acids to the drug results in a “different drug” determination.

The “sameness” analysis above is apparent in FDA’s decision to grant a period of orphan drug exclusivity for ALPROLIX [Coagulation Factor IX (Recombinant), Fc Fusion Protein], which FDA licensed on April 28, 2014 under BLA 125444 for use in adults and children with Hemophilia B for control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes. In an April 2014 email memorandum documenting the decision to grant orphan drug exclusivity for ALPROLIX, FDA commented:

[T]he Office of Blood and Blood products in CBER was contacted to discuss exclusivity for Coagulation factor IX, Fc fusion protein. It was noted that the protein that is fused to factor IX is a dimer.  One monomer of the dimer is manufactured fused to factor IX pretranslationally.  The second monomer is then a post-translational modification.  Therefore, the changes in structure to the factor IX protein do involve pre-trnaslational [sic] modification. It was agreed that this was a different product than recombinant factor IX and is thus eligible for orphan drug exclusivity. [(emphasis added)]

Another example of FDA’s application of the Agency’s “same drug” rubric in the context of a fusion protein is IDELVION [Coagulation Factor IX (Recombinant), Albumin Fusion Protein], which FDA licensed on March 4, 2016 under BLA 125582 for the (1) on-demand control and prevention of bleeding episodes, (2) perioperative management of bleeding, and (3) routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Although the sponsor of IDELVION initially thought that FDA might consider its product to be the same as another Coagulation Factor IX product, BeneFIX (BLA 103677), and thus require a plausible hypothesis of clinical superiority in order to obtain orphan drug designation, FDA determined otherwise. According to a March 2012 Memorandum from FDA’s Office of Orphan Product Development:

The sponsor has provided an adequate scientific rationale to support orphan designation. The sponsor presented two studies in FIX knock out mice and one study in a dog model of hemophilia B.  All three studies compared the effects of rIX-FP to the approved coagulant factor IX, BeneFIXfi. The sponsor contends that these animal studies demonstrated that rIX-FP displays an extended half-life as compared to BeneFIX, and thereby clinical superiority to the presently available therapy.  The sponsor stated that the clinical superiority would be based on fewer dosing administrations that the patients would have to undergo.

However, clinical superiority is only necessary and applicable if rIX-FP is indeed the “same drug” as the already approved recombinant factor IX. That is, according to CFR 316.20(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 IX 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 post-translational 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.  [(emphasis added)]

So what might be up next on FDA’s orphan drug “sameness” plate? With FDA on the verge of licensing the first gene therapy product, we think that gene therapy “sameness” might be the next hot topic.  But we’ll leave a discussion of that issue for another day.