martes, 12 de mayo de 2015

FDA Law Blog: A Big Decision About a Small (But Significant) Change Communicated by FDA in a Small (But Not Insignificant) Way

FDA Law Blog: A Big Decision About a Small (But Significant) Change Communicated by FDA in a Small (But Not Insignificant) Way

Posted: 11 May 2015 07:25 PM PDT
By Kurt R. Karst –     

One of the things we pride ourselves on is connecting various dots – in this case, dots at the atomic level – to bring to light stories or decisions with particular significance that others may not immediately notice.  This is one of those stories . . . .

Back in February 2013, in a blog post discussing, among other things, FDA’s structure-centric interpretation of “active moiety” (rather than an activity-based interpretation) (see here), under which a drug is classified as a New Chemical Entity (“NCE”) eligible for 5-year exclusivity regardless of which portions of the active ingredient contribute to the overall therapeutic effect of the drug, we commented that “[t]his form over function approach means that relatively small changes to a molecule, such as deuterium analogues of various approved compounds (see herehere, and here), may qualify for NCE exclusivity, while more significant changes that improve the activity of a drug, but that do not change the molecule that is the active moiety, would not result in NCE exclusivity.” 

At the time of our previous post, FDA had not taken a firm position on whether or not to treat deuterated compounds as NCEs.  That’s no longer the case.  FDA’s relatively recent orphan drug designation of Auspex Pharmaceuticals, Inc.’s (“Auspex’s’”) (recently acquired by Teva Pharmaceutical Industries) deutetrabenazine (also known as d6-tetrabenazine or SD-809) for the treatment of Huntington’s Disease – in light of FDA’s previous orphan drug approval of non-deuterated XENAZINE (tetrabenazine) Tablets for the treatment of Huntington’s Disease (NDA 021894) – stands for the proposition that at least some (and perhaps all) deuterated compounds are, in fact, considered NCEs eligible for 5-year exclusivity.  (FDA subsequently designated Auspex’s deutetrabenazine for the treatment of Tourette Syndrome in the pediatric population [ages 0-16].  Tetrabenazine is also designated for the treatment of Tourette Syndrome [in school-age children, ages 5-16], but is not yet approved for this use.)

What are deuterated compounds?  Deuterium (containing one neutron, one proton, and one electron) is a non-radioactive isotope of hydrogen that is a different atom than hydrogen (containing one proton and one electron).  A deuterium atom may be covalently linked to a carbon atom and cannot be removed from the carbon or exchanged with hydrogen.  A deuterated compound can have significantly different metabolic stability and/or pharmacokinetics compared to the non-deuterated version of the compound.

The FDC Act, as amended by the Orphan Drug Act, 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 (notwithstanding the recent Depomed court decision – see our previous post here) demonstrate clinical superiority to obtain orphan drug exclusivity.

A drug is “different” from an approved orphan 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 (i.e., “micromolecules”) or macromolecules.  In the case of small molecules, “same drug” means the same active moiety.  Specifically, FDA’s orphan drug regulations (at 21 C.F.R. § 316.3(b)(13)(i)) define the term “same drug” to mean:

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.
FDA’s orphan drug regulations further define the term “active moiety” to mean:

the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.
This is the same “active moiety” definition FDA employs for purposes of awarding 5-year NCE exclusivity.  Also, it is noteworthy that in promulgating its orphan drug regulations, FDA commented (at 57 Fed. Reg. 62,076, 62,077 (Dec. 29, 1992)) that “[f]or micromolecular products, the active moiety is the whole covalently bound part of the molecule that is active.  This means that it generally consists of all of the molecule except added parts that make it a salt or ester.  Essentially, any change in covalent structure creates a new active moiety whose properties may well differ from the old active moiety.”

Initially, it appears that FDA’s Office of Orphan Products Development took the position that tetrabenazine and dutetrabenazine are the same drug.  In an August 2014 filing with the Securities and Exchange Commission (“SEC”), Auspex commented (page 26):

With respect to our application for orphan drug designation for SD-809 for the treatment of chorea associated with Huntington’s disease, we have received initial feedback from the FDA that it believes that SD-809 is the same drug as tetrabenazine, which is already approved for the treatment of this orphan indication, and that SD-809 therefore cannot be designated as an orphan drug for this indication unless we can provide a plausible hypothesis of the clinical superiority of SD-809 to tetrabenazine. . . .  The FDA has invited further discussion with us on this matter.  We have responded to the FDA with additional information to support our belief that SD-809 is not the same drug as tetrabenazine for purposes of orphan drug designation because of, among other things, the substitution of six specific hydrogen atoms in tetrabenazine with deuterium in SD-809.
The filing further discussed the possibilities of demonstrating clinical superiority if FDA was ultimately unconvinced that tetrabenazine and dutetrabenazine are not the same drug.  But just a few months later, on November 6, 2014, Auspex announcedthat FDA granted orphan drug designation of SD-809 for treatment of Huntington’s Disease.  In a subsequent SEC filing (page 29), Auspex noted:

Orphan drug marketing exclusivity generally prevents the FDA from approving another application, including a full NDA, to market the same drug for the same indication for seven years, except in limited circumstances, including if the FDA concludes that the later drug is safer, more effective or makes a major contribution to patient care.  The FDA defines “same drug” as a drug that contains the same active chemical entity and is intended for the same use as the drug in question.  A designated orphan drug may not receive orphan drug marketing exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation. . . .  In November 2014 we received orphan drug designation of SD-809 for the treatment of Huntington’s disease from the FDA.
Noticeably absent from this later filing is any discussion of plans to demonstrate clinical superiority to tetrabenazine for orphan drug designation and orphan drug approval purposes.  We’re pretty confident that the omission of any discussion of clinical superiority was intentional, because FDA ultimately determined that tetrabenazine and dutetrabenazine are not the same drug for orphan drug purposes.  That is, they are different active moieties.  Given the shared definition of “active moiety” for orphan drug and NCE exclusivity purposes, it seems pretty clear that FDA has made a reasoned and informed decision that at least some deuterated compounds are NCEs.

But when will we see FDA’s decision applied to a real-world case?  Perhaps sooner rather than later.  In December 2014, Auspex reported positive topline results from a Phase 3 clinical trial evaluating deutetrabenazine (SD-809) in chorea associated with Huntington’s Disease, “demonstrating robust efficacy, supported by significant improvements in patient global impression of change, clinical global impression of change and quality of life as well as a favorable safety and tolerability profile,” according to a company press release (here and here).

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