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T H E R A P E U T I C S , IN C .
CITIZEN PETITION
Insys Therapeutics, Inc. (‘insys”) submits this petition under sections 505(j) and
505(q) of the Federal Food, Drug, and Cosmetic Act ("FDC Act5') and the related
regulations, 21 C.F.R. §§ 10.30-31, to request that the Commissioner of Food and
Drugs refrain from approving any Abbreviated New Drug Application (“ANDA'')
referencing its SYNDROS %(dronabinol) Oral Solution, CII approved under New Drug
Application ("NDA”) 205525, if such ANDA relies upon a waiver pursuant to 21
C.F.R. § 320.22. Insys therefore requests that the Food and Drug Administration
(“FDA”) require the submission of in vivo bioequivalence data for approval of any
generic versions of dronabinol oral solution. Insys is aware of at least two received
ANDA referencing SYNDROS and requests that FDA retroactively refuse to accept
this ANDA, as well as any other ANDA that may have been received, or refuse to
approve any ANDA unless it includes adequate in vivo bioequivalence studies.
I. ACTIONS REQUESTED
Insys is concerned that FDA has permitted and may continue to permit waivers
of bioequivalence testing for products referencing its NDA. SYNDROS has inherent
product characteristics that may affect bioequivalence. To ensure required product
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safety and efficacy, Insys requests that FDA require generic applicants to conduct and
submit in their ANDAs bioequivalence studies in both the fed and fasted state.
A. Factual Background
B. Legal Background
Under the FDC Act, an ANDA must refer to an RLD and must contain, among
other things, “information to show that the new drug is bioequivalent to the listed
drug.” 21 U.S.C. § 355(j)(2)(A)(iv). FDA regulations provide that any person
submitting an ANDA to the FDA must include either "evidence demonstrating that the
drug product that is the subject of the abbreviated new drug application is bioequivalent
to the [RLD]” or enough information showing bioequivalence to the RLD to permit
FDA to waive the submission of evidence demonstrating in vivo bioequivalence. 21
C.F.R. § 320.21(b). Two drug products will be considered bioequivalent if there is no
significant difference in the rate and extent to which the active ingredient or active
moiety becomes available at the site of drug action when administered at the same
molar dose of active moiety under similar experimental conditions. Id. § 314.3.
III. DISCUSSION
Insys requests that FDA require Par and any other ANDA applicant to submit
studies demonstrating that the potential generic is bioequivalent to Insys’ SYNDROS.
Because of the complexity of the product, as well as the directions for use with food as
outlined below in subsections A and B, Insys contends that a waiver of bioequivalence
studies under 21 C.F.R. § 320.22 is inappropriate for this drug. FDA itself has made
this determination with respect to capsule versions of the product. Draft Guidance on
Dronabinol (Feb. 2014); Insys therefore requests that FDA exercise its authority under
21 C.F.R. § 320.22(f) to require the submission of evidence of bioequivalence for oral
solution versions of SYNDROS.
A. The structure and profile of SYNDROS indicate that any
formulation changes require bioequivalence studies.
While FDA has authority to grant waivers if the waiver is ‘'compatible with the
protection of human health." dronabinol oral solution does not meet the limited criteria
that FDA cites as most appropriate for waivers. Waivers of in vivo bioequivalence
studies are typically reserved for limited instances. As noted, for a generic version of
an oral solution, FDA may grant a waiver only if it makes a preliminary assessment
that the product contains no change in formulation that may significantly affect
absorption of the active drug or no change that may significantly affect systemic
availability.
FDA guidance and precedent seems to suggest that a drug with high
permeability is likely to have high bioavailability. See e.g.U.S. Food and Drug Admin.,
Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Draft
Guidance for Industry (May 2015). Thus, high permeability, in conjunction with high
solubility and rapid dissolution, can be used as a predictor for absorption. This
assumption, however, does not hold true for dronabinol. The mean oral bioavailability
is 10-20 percent for dronabinol and its active metabolite, which is indicative of a
significant complexity of absorption, distribution, metabolism, and elimination profile
in vivo. AbbVie, Marinolf (dronabinol) Capsules Package Insert. NDA 018651
(revised Aug. 2017).
Sprague and Craigmill have reported that two significant vehicle effects on the
absorption of THC (dronabinol) were observed. It was shown that treatment of mice
twice daily for 11 days with 10% propylene glycol (PG) + 1% Tween-80 in isotonic
saline impaired the elimination of a subsequently administered dose of either ethanol or
THC, because the primary route of metabolism of propylene glycol involves the
enzymes similar to those suggested to metabolize ethanol and THC. It was also found
that (2) either 6 or 11-day treatment with the propylene glycol + Tween-80 mixture
diminished the observed behavioral effect resulting from THC administration. Gary
Sprague et al.. Ethanol and delta-9-tetrahydrocannabinol: Mechanism for cross
tolerance in mice, 5 Pharmacology Biochemistry & Behavior 409 (1976).
Par's product contains ethanol and propylene glycol amounts that may lead to
variable exposure of dronabinol in patients. Therefore, in accordance with 21 C.F.R.
§ 320.22(b)(3), FDA should require bioequivalence testing to show that exposure and
absorption remains the same amongst products and that changes to excipients do not
lead to dose accumulation or any additional safety and efficacy risks.
Finally, it was observed from the Insys in vitro study that SYNDROS forms a
turbid nanoemulsion in both the fed state and fasted state in simulated gastric/intestinal
fluids. Measurement of the particle size of this nanoemulsion showed the particle size
range between 700 nm to 950 nm. It is well known that any change in the particle size
affects the rate and extent of drug absorption. Additionally, any changes to the
formulation, for example the excipients, may affeet the formation of nanosuspension,
which in turn, affects the absorption profile of dronabinol. Therefore, changes to a
formulation that affects particle size may affect bioequivalence. It is thus necessary for
any generic formulations to include traditional bioequivalence studies.
B. FDA policy requires fed and fasted state BE studies for a product
like SYNDROS.
When both test product and RED are rapidly dissolving, have
similar dissolution profiles, and contain a drug substance with
high solubility and high permeability (BCS Class I), or
11. When the DOSAGE AND ADMINISTRATION section of the
RED label states that the product should be taken only on an
empty stomach, or
iii. When the RLD label does not make any statements about the
effect of food on absorption or administration.
Id. at 3-4.
Based on these criteria, FDA should ensure the ANDA applicants demonstrate
bioequivalence under both fasted and fed conditions. The SYNDROS label makes
explicit statements about the effect of food on absorption or administration. The
approved labeling states: “Administer the first dose on an empty stomach at least 30
minutes prior to eating,’' signifying the effect of food on SYNDROS (dronabinol) oral
solution.
FDA itself has recognized the need for fed and fasting studies in dronabinol. In
the Draft Guidance on Dronabinol, FDA explicitly requires this testing for dronabinol
oral capsules. Draft Guidance on Dronabinol (Feb. 2014). Nothing about the structure
or properties of the oral solution indieates that the same considerations need not apply
in the oral solution.
For these reasons, Insys respectfully requests that FDA refuse to approve Par’s
ANDA and refuse to receive or approve any other ANDA for generic versions of
SYNDROS based on waivers of bioequivalence.
V. ENVIRONMENTAL IMPACT
I certify that, to my best knowledge and belief; (a) this petition includes all
information and views upon which the petition relies; (b) this petition includes
representative data and/or information known to the petitioner which are unfavorable to
the petition; and (c) 1 have taken reasonable steps to ensure that any representative data
and/or information which are unfavorable to the petition were disclosed to me. I further
certify that the information upon which I have based the action requested herein first
became known to the party on w'hose behalf this petition is submitted on or about the
following date: June 22, 2017. If I received or expeet to receive payments, including
cash and other forms of consideration, to file this information or its contents, I received
or expect to receive those payments from the following persons or organizations: Insys
Therapeutics Inc. I verify under penalty of perjury that the foregoing is true and correct
as of the date of the submission of this petition.
Sincerely,
Stephen Sherman
Sr. Vice President, Regulatory Affairs
Insys Therapeutics. Inc.
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