product development using the

Product Development Using the NDA 505(b)(2) Pathway

Ken PhelpsCamargo Pharmaceutical Services

Trending…Combination productsTargeted delivery – Theracoat, PaciraAlternate delivery – SNBL, ChiasmaExtended release products

Oral – Tris

Legal DevelopmentsAmarin; Pacira

First amendment but ...Amarin – rescind SPAPacira – extend 2 surgical sites to any siteTakeda vs. Hikma re: colchicine

Listed drugProposed changes to combination products legislationDESI crackdown

Common MistakesFailure to correctly use listed drug – bridgingFailure to gain FDA agreement for foreign trialsInsufficient scope to PIND meetingsSkipping pre-NDA meetingNo commercial assessment

Product IdeationExisting Products

Identified Need for Improvement

Company-Specific FocusOther Criteria

CommercialNeeds, Costs, Time, rNPV

DevelopmentNeeds, Costs,

Time

Opportunities = Differentiated Products

with High ROI

The 505(b)(2) or the 510(K)

CASE STUDY: TheraCoat hydrogel technology and the connection between the regulatory path chosen and the business strategy

Thermo Reversible Hydrogel Based Solutions

Product DescriptionLiquid at low temperature

Solid at body temperature

Transition to gel is triggered by

increase in temperature

http://www.youtube.com/watch?v=EwOibueHmJk

“Freezes” when heated and “Melts” when cooled

• Special thermally triggered, biocompatible, water-soluble hydrogel

• The formulated drug is used the same way as current intravesical treatment procedure

• Adheres to the urothelial tissue and releases the embedded drug over a period of several hours

• The water-soluble hydrogel dissolves into the urine and is excreted naturally

Solidify in bladder

1

2

3

Increased drug dwell time at the tissue

Product Usage• Drug to be used is

reconstituted at bedside/pharmacy

• Catheter is inserted into the bladder

• Drug is instilled via a syringe connected to the catheter

Drug Release from TheraCoat’s GelTi

ssue

Gel/tissue direct drug diffusion Erosion of gel causes

drug release into the urine

Gel is diluted by urine, promotes gel erosion

1

2

3

The entire bladder tissue is exposed to the drug

Tiss

ue

Gel/tissue in-direct drug diffusion (via urine)4

Tactics vs. Strategy

Marketplace

Valu

e

Drug Delivery

(Medicinal)

Specialty Pharma

NCE’s

Tim

e to

mar

ket

Generics

Drug Delivery (Devices)

“syringe”

“carrier”

“excipient”

“formulation”

“molecule binding”

Borderline products, drug-delivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative

Regulatory Pathway

SECTION B. DRUG-DELIVERY PRODUCTS AND MEDICAL DEVICES INCORPORATING AS AN INTEGRAL PART, AN ANCILLARY MEDICINAL SUBSTANCE OR AN ANCILLARY HUMAN BLOOD DERIVATIVE

Regulatory Pathway

A medical device incorporates a medicinal substance as an integral part, within the meaning of Article 1 (4) MDD and Article 1 (4) AIMDD, if and only if the

device and the substance are physically or chemically combined at the time of administration (i.e., use, implantation, application, etc.) to the patient.

Regulatory Pathway

Hydrogel matrices for delayed drug release

Regulatory Pathway

Tactics vs. Strategy• Medical device category:

– Simple process for clinical validation– Simple regulatory compliance– Local IRB’s approval– Ability to diverse to other indications

(platform tech.)– Lower need for capital and resources

Lead and Follow-On Urological ConditionsUpper Tract Urothelial Carcinoma (UTUC)

Bladder Cancer (NMIBC)

Interstitial Cystitis (IC)

Overactive (OAB)

Urothelial Cancer

Urothelial Pathologies

2015 - 2019

Large Market with Recurrent Care Required

1.4 million applicable patients

Upper Tract Urothelial Cancer (UTUC)Bladder Cancer

Overactive Bladder (OAB)Interstitial Cystitis (IC)

6 million annual procedures

Using current practiceNo need for market education

Fast acceptance and willingness to use

>$6.5 billion drug marketAlternative to:

Systemic Drug Therapies Irrigation Therapies Surgical Procedures

U.S. data only

• Reduction in the number of filling defects (tumor locations)

• Renal pelvis is less dilated• Flow of urine via the ureter

Proof of Concept: Chemoablation of urothelial tumor in a patient using gel mixed with MMC

Post-treatmentPre-treatment

The 1st to retain chemotherapy drugs in the upper tractSafety and feasibility demonstrated

Tumor mass reduction was demonstrated

Increased Dwell Time Generates Significant Outcome

Post-treatment:

Without surgery; complete responseNo tumors were detected after the therapy

Pre-treatment:

• The gel releases the drug for several hours

• The tumors are exposed for a longer period to the drug

• Effecting the seen and unseen tumors

• Leading to complete ablation

Interim Results – Tumor Ablation With MMC Hydrogel Formulation

• Sites from Israel and EU

• Overall 34/41 patients with positive response; 23/41 complete response.

• Combination of longer dwell time at higher concentration ratio yields to improved efficacy

• 92% CR rate in the 80mg in 64cc gel group

• Ablation of ~2.5cm2 of tumor mass in average

• Despite the small n, the ablation potential of MMC when mixed with the gel is evident

Chemoablation concept via TheraCoat MMC formulation was established

40mg / 40ml (1:1); 5pts

40mg / 64ml (0.6:1); 15pts

80mg / 40ml (2:1); 9pts

80mg / 64ml (1.25:1); 12pts

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

CR PR NR

Business Strategy• What is your business model?• Reimbursement strategy?• Company position and value?• Who is your ideal partner?• How does the company offering fit with

the partner strategy?

510(K) 505(b)(2)?

Dr. Ed JuleCapsugel Dosage Form Solutions

Technology Platforms

• Spray-dried dispersions

• Hot-melt extrusions

• Lipid / liquid-based formulations - Oils, surfactants, co-solvents- SEDDS / SMEDDS

• Nano-crystal technologies

• Particle size reduction / micronization

• Multi-particulate approaches

• Matrix & osmotic approaches

• Enteric capsule delivery technology

• Colonic delivery

• Pulsatile release / dual release & fixed dose combinations

Modified & Targeted Release

• Lipid multi-particulate technology

• Inhalation formulations

• Abuse deterrence approaches

• Taste-masking expertise

• High potency API formulation and manufacturing

Specialized Applications

Bioavailability Enhancement

Dual capsule technology LFHC Soft gels

Multi-particulates Tablets

Sprinkle capsuleSachet

DPICapsules Osmotics Press-Fit /

Xpress-FitPowder, pellet,semi-solid filled

Mini-tablets

Case Study – Meeting a Narrow Absorption Window to Avoid Adverse Events

Azithromycin

The Opportunity and Challenge

Opportunity: • Azithromycin partitions into tissue (long half-life) • High doses can be given intravenously

Goal/Constraints: • High single, oral dose (2 gram)• Emesis when dosed IR orally at high

concentration• Poor absorption in the colon• Highly soluble at gastric pH

azithromycin

Time

Cum

ulat

ive

Dru

g R

elea

sed

TargetAdverse events prevalent

Poor absorption

Controlled-release technology to meet narrow target window to achieve desired performance

• Azithromycin is an azolide antibiotic which is similar in structure and function to macrolides

• Unmet need: High solid oral, single dose Rx product to be used by adults to treat acute bacterial sinusitis and community-acquired pneumonia

Product Development Goals

1. Target release profile– Extend drug release over 3 hours to optimize

tolerability and bioavailability

2. Stability– Retain commercial polymorph – Adequate shelf life (>2 years)

3. Manufacturability– Minimize time at high temperature– Robust operating conditions and equipment

4. Dose and final dosage form– Single 2 gram dose– Sachet, 200 µm particle for good mouth-feel

Compound Properties

Define Product Development

Strategy

Define the Performance Target

INPUTS: OUTPUTS:

Define Optimal Dosage Form Based on Target Patient

Mechanism of Release – Aqueous Pore Diffusion High loading of suspended water-soluble drug embedded within a lipid matrix that does not melt at body temperature

Release is governed by “aqueous pore diffusion” whereby dissolution of water-soluble drug and poloxamer enhances water ingress and drug release from a hydrophobic LMP matrix

Cavity formed by dissolved-away

drug crystal

Surface PoresMicrosphere Surface

Water-soluble-filled pore(connecting at point of

closest approach)

Drug crystal

30-minute soak (52% released)

60-minute soak (75% released)

50 mm

5-minute soak (15% released)Upon hydration:

Meeting the Target Release Profile

• LMP release rates can be controlled through formulation & process, without coatings

• An in-depth understanding of factors that impact release rate is essential to achieve the target release profile

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g R

elea

sed

(%)

Increased drug-particle size gives

slower release

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g R

elea

sed

(%)

Faster release due to pore formation

Impact of Excipient

Ratio

0

20

40

60

80

100

0 30 60 90 120 150 180

Time (min)

Dru

g R

elea

sed

(%)

Increased LMPparticle size gives slower

release

0

20

40

60

80

100

0 30 60 90 120 150 180Time (min)

Dru

g R

elea

sed

(%)

Slower release in gastric buffer due to reduced water uptake

Increasing % dissolution enhancer: Increasing % lipid carrier:

Changing compound particle size: Changing LMP particle size:

Impact of Particle

Size

Case Study SummaryRationale - LMPs were used to develop a new product concept to deliver

high-dose azithromycin

Performance - Release from LMPs was tailored through formulation design, without the use of coatings, to balance bioavailability against adverse events

Patient Acceptability - Good mouth-feel achieved from unique combination of small size, spherical shape and waxy materials used

Science & Engineering - Expertise applied to both design, formulation and process, enabling scale-up for commercial manufacture

Deliverable - Zmax® approved in U.S and in Japan

Zmax is a registered trademark of Pfizer , Inc.

Case Study – Taste-Masking Effective Pediatric Formulations

The Problem Statement: Taste-Masking API is a bitter-tasting anti-cancer drug approved for treatment of non-

small cell lung carcinoma

Unmet need: Pediatric population (note - adult population known to have very poor compliance, as capsule or emptied powder contents in dosing vehicle due to poor palatability)

Opportunity: • Capsule containing MP for sprinkle application• Sprinkle combination for dosing in 1) mouth, 2) dosing

spoon, 3) appropriate food / vehicle

Goal/Constraints: • No change in drug form• Less than 5% released in saliva or dosing vehicle• Taste-masked and BE to IR adult capsule• Robust process / scalable to commercial

Attribute Value Targets Proposedfor POC

Indication Oncology Adult and Pediatric PopulationsPediatric population; adult population known to have very poor compliance, as capsule or emptied powder contents in dosing vehicle due to poor palatability

Drug Small molecule, crystalline No change in form Maintain drug form, particle size reduction for enabling technology

Dosage Form HGC containing multiparticulates for sprinkle Capsule of small to modest size Uncoated #0 - #3 (depending on size) gelatin capsule

containing coated multiparticulates

Drug Product Intermediate

Small particle size taste-masked multiparticulates

Spherical, <250um median diameters, taste-masked coated multiparticulates

>40% active loaded, lipid multiparticulates; coated with non-pH or pH dependent taste-masking polymer

Dose 0.4-20 mg/m2 Common fill; dose adjusted by fill weight Identical fill material so mg/m2 dosing can be accomplished with multiple sprinkle caps

AdministrationSprinkle combination of capsule contents for dose in 1) mouth, 2) in dosing spoon with water, 3) in appropriate food/ vehicle

Drug Release Rate- Taste

<5% of dose released in dosing vehicle and simulated saliva

In vitro target + in-use stability < 1 ug/ml dissolve in 30-60 minutes in simulated saliva fluid

Drug Release Rate- BA

Immediate release in stomach

Taste-masked + bioequivalent to immediate release adult capsule formulation Immediate release in gastric

Manufacturing Scale & Process

Pediatric Ph2 study; clear scalable path to commercial Robust process; scalable path to commercial 3 step processing: melt spray congeal + fluid bed bottom

spray coating + encapsulate

Functional Excipients

GRAS or reg.-CMC acceptable in pediatric populations

GRAS or reg.-CMC acceptable in pediatric populations

Compendial excipients and/or acceptable excipient DMF (Smartseal not compendial, but have DMF, tox)

Target Product Profile

v

Multiparticulates for Taste-Masking – Approaches Maintain bioequivalence Develop an oral immediate release drug product for pediatrics that retards the release of drug prior to swallowing

Identify ‘threshold’ drug concentrations that contribute to poor palatabilityManage the safety profile of the formulation for pediatric application

Clinical Approach

API Containing MSC Cores

10wt% Smartseal® Coating

20wt% Smartseal® Coating

30wt% Opadry® II White Coating

Smartseal is a registered trademark of BASF Corporation; Opadry is a registered trademark of Colorcon, Inc.

In Vitro Dissolution of Lead Formulation Taste-Masked Beads in Saliva Simulation and Gastric Buffer

Taste/PK Study Formulations: Disso Profiles at pH 6.2

PK Taste Lot coat thickness

10.1 ± 0.9

3.9 ± 0.77.7 ± 1.3

Tast

e U

nkno

wn

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 10

10

20

30

40

50

60

70

Crizo 10% and 20% Smartseal and 30% Opadry coated mi-crosphere release profile at pH 6.2

20% Smartseal Clinical (Avg n=6)

10% Smartseal Clinical (avg n=6)

30% Opadry

Time (hr)

Diss

oved

(%)

Source: Client Tech Review, Sept. 2014

Taste-Masking Platform and Approach

• Enhanced formulations represent a key approach to 505(b)2 regulatory approvals

• Broad toolkit and formulation experience are invaluable in designing and advancing b2 product concepts

• Multiparticulates are flexible formats for crystalline and solubilized API’s in achieving BA enhancement, extended dissolution profiles and taste-masking

• Engineering capabilities and specialized / tailored equipment can facilitate efficient scale-up and manufacturability of product concepts, e.g., MSC processing

505(b)(2) Product Development Summary

Kurt Kast, J.D.Hyman, Phelps & McNamara

The Changing Landscape of 505(b)(2) and Recent Court Decisions

Kurt R. Karst, J.D.Director

Hyman, Phelps & McNamara, P.C.

November 2, 2015

Agenda

Takeda Colchicine Litigation

Veloxis Tacrolimus Litigation

Otsuka Aripiprazole Litigation

ITakeda Colchicine Litigation

Takeda Colchicine Litigation• In 2009, FDA approved (now) Takeda’s 505(b)(2)

application (NDA No. 022352) for COLCRYS (colchicine) tablets, 0.6 mg, to prevent gout, treat gout flares, and treat Familial Mediterranean Fever.

• In October 2014, Takeda filed a Complaint in the DC District Court challenging FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA No. 204820) submitted by Hikma/West-Ward for MITIGARE (colchicine) capsules, 0.6 mg, for prophylaxis of gout flares.

Takeda Colchicine Litigation• Although there are several patents listed in the Orange

Book for COLCRYS, this is the first opportunity Takeda has had to challenge MITIGARE.

• Hikma was able to avoid identifying COLCRYS as a listed drug in its 505(b)(2) application by virtue of relying on information not contained in (or related to) the COLCRYS NDA approval, and therefore avoid certifying to Orange Book-listed patents for COLCRYS.

Takeda Colchicine Litigation• “First, FDA acted arbitrarily and capriciously in approving Hikma’s

Section 505(b)(2) application for Mitigare without requiring the label to contain critical safety information that FDA previously stated was necessary for single-ingredient oral colchicine products.”

• “Second, FDA’s approval of Hikma’s application for Mitigare was unlawful, arbitrary and capricious because, as approved, Mitigare is not safe in light of the defects in its label.”

• “[T]hird, FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process.”

Takeda Colchicine Litigation• January 2015 DC District Court decision – Takeda Motion

for Summary Judgment denied. On appeal to the DC Circuit.

• “[T]his Court concludes that Plaintiffs are wrong to characterize FDA’s actions with respect to Mitigare as unauthorized, unsafe, or unreasoned; to the contrary, it is clear on the record presented that FDA’s approval of Mitigare was consistent with the FDCA, the regulations the agency has promulgated pursuant to the FDCA, the Citizen Petition Responses FDA has issued, and the policies and practices under which the agency operates.”

Takeda Colchicine Litigation• Do FDA’s procedural rules require West-Ward to

reference COLCRYS even though the West-Ward did not rely on COLCRYS data?

– “[T]his Court discerns no basis in law or fact for Plaintiffs’ insistence that FDA was legally required to force West-Ward to reference Colcrys and to certify to the Colcrys patents under the circumstances presented here.”

Takeda Colchicine Litigation• Does a 505(b)(2) applicant have a right to choose

which approved drug is (or is not) most appropriate or most similar to cite (or not) as a listed drug relied on for approval?

– “The bottom line is this: FDA’s prior statements confirm that, other than where duplicate drug products are involved, a Section 505(b)(2) applicant has the discretion to select a reference drug, and to make that selection in relation to the scope of the materials the applicant desires to submit.”

Takeda Colchicine Litigation• Does the FDC Act unambiguously require a

505(b)(2) applicant to certify only to patents associated with the RLD?

– “[T]his Court finds that Congress’ intent regarding the scope of a Section 505(b)(2) applicant’s patent certification obligation is clear on the face of the statute: such applicant need only certify to the product patents or the method-of-use patents that are associated with the reference listed drug (i.e., the drug product on whose investigations the 505(b)(2) applicant relies).”

IIVeloxis Tacrolimus Litigation

“Dueling” 505(b)(2)s• FDA has stated that 3-year exclusivity prevents the

Agency from approving another 505(b)(2) application (or an ANDA) “that relies on the information supporting the new conditions of approval of the first approved application.”

• One statement in the preamble to FDA’s proposed rules implementing the Hatch-Waxman Amendments, however, suggests that approval of a 505(b)(2) application with exclusivity would prevent approval of a subsequent 505(b)(2) application for 3 years even though the subsequent 505(b)(2) applicant did not rely on data in the first 505(b)(2) application.

• That statement reads as follows:– [I]f two 505(b)(2) applications are under review at the same

time and one is approved before the other, the effective date of approval of the second application to be approved will be delayed, regardless of the date of submission, if the first [505(b)(2) application] contained new clinical investigations essential for approval and thereby qualified for exclusivity.

• Does this statement, which is referred to as FDA’s “dueling 505(b)(2) application policy,” reflect current Agency policy? (FDA has not further publicly discussed the policy since stating it in 1989.)

“Dueling” 505(b)(2)s

Veloxis Tacrolimus Litigation• On October 30, 2014, FDA tentatively approved

Veloxis’s 505(b)(2) NDA 206406 for ENVARSUS XR (tacrolimus extended-release tablets), 0.75 mg, 1 mg, and 4 mg, for prophylaxis of organ rejection in kidney transplant patients.

• FDA approved Astellas’s 505(b)(1) NDA 204096 for ASTAGRAF XL (tacrolimus extended-release capsules), 0.5 mg, 1 mg, 5 mg, on July 19, 2013 for prophylaxis of organ rejection in adult patients receiving kidney transplants, and granted a period of 3-year exclusivity that expires on July 19, 2016.

• In December 2014, Veloxis filed a Complaint and a Motion for Preliminary Injunction in the DC District Court challenging FDA’s denial of approval of the ENVARSUS XR 505(b)(2) NDA as a result of the exclusivity FDA granted to ASTAGRAF XL.


• “First, according to the unambiguous statutory language of the [FDCA], Astagraf XL was never entitled to three-year exclusivity.”

• “Second, even if Astagraf XL is eligible for three-year exclusivity (and it is not), that exclusivity, as a matter of law, cannot block approval of Envarsus XR because the Envarsus XR NDA did not rely upon any of the studies or data supporting approval of Astagraf XL.”

• “Third, even if the reliance requirement was read out of the FDCA, Envarsus XR still would not be subject to the exclusivity granted Astagraf XL because Envarsus XR does not share conditions of approval with Astagraf XL.”

• (Veloxis later alleged a fourth reason: that FDA erroneously identified an Astellas clinical study in the ASTAGRAF XL NDA – Study 158 – as a “new clinical investigation” pursuant to FDC Act § 505(c)(3)(E)(iii).)


• Should FDA have granted 3-year exclusivity for ASTAGRAF XL in the first place because it is an “old antibiotic” not subject to changes made to the FDC Act in 2008?

– “[T]he language is clear that an old antibiotic can be afforded three-year exclusivity to the extent that it was the subject of a new NDA that was submitted after October 8, 2008. . . . To the extent that Congress did not address the precise conflict presented here, i.e., the FDCA is silent as to the withdrawal and “resubmission” of an old antibiotic NDA that was pending on or before October 2008, the FDA’s interpretation of the statute to allow three-year exclusivity for an old antibiotic that is the subject of a withdrawn and resubmitted NDA is reasonable.”


• Can the Astagraf XL three-year exclusivity block approval of Envarsus XR even though Envarsus XR NDA did not rely upon any of the studies or data supporting approval of Astagraf XL?

– “The parties’ conflicting interpretations of the term ‘relied upon’ in [FDC Act § 505(c)(3)(E)(iii)] stand in stark contrast to one another. On the one hand, the plaintiff argues that the term ‘relied upon’ ‘unambiguously requires’ that the three-year exclusivity of a first-in-time 505(b) drug, i.e., the drug that is the subject of a first-in-time 505(b) NDA, can block a second-in-time 505(b)(2) drug from market entry, i.e., the drug that is the subject of a second-in-time 505(b)(2) NDA, only if the second-in-time 505(b)(2) NDA has ‘relied upon’ the first-in-time 505(b) NDA. Specifically, the plaintiff contends that there must be ‘an overlap’ between the ‘new clinical investigations’ in both NDAs. On the other hand, the FDA argues that the contested term ‘does not . . . mean that reliance is required to trigger exclusivity.’ Rather, according to the defendant, the term ‘is used only to distinguish [between] 505(b)(1) [NDAs] from 505(b)(2) [NDAs],’ because it is included in the statutory provision ‘as part of the lengthier [FDCA] definition of a 505(b)(2) [NDA].’ In other words, ‘[n]owhere in this provision does . . . [it] say that a[] [second-in-time 505(b)(2) NDA] will be blocked only if the [clinical] studies it ‘relied upon’ were . . . included in the . . . [first-in-time 505(b) NDA].’”


- “[T]he FDA may not approve a second-in-time NDA that shares ‘conditions of approval’ with the first-in-time 505(b) drug. Moreover, the FDA is prohibited only from approving a second-in-time NDA that is a 505(b)(2) NDA, as [FDC Act § 355(c)(3)(E)(iii)] does not speak to a second-in-time 505(b)(1) NDA. . . . Exclusivity under [FDC Act § 355(c)(3)(E)(iii)] is triggered by an overlap in the conditions of approval between the first-in-time 505(b) drug and the second-in-time 505(b)(2) NDA and not an overlap between the ‘new clinical investigations’ supporting the first-in-time 505(b) NDA and second-in-time 505(b)(2) NDA. Indeed, it would frustrate Congress’s intent to incentivize new drug development through, among other means, marketing exclusivities, if a second-in-time 505(b)(2) NDA could escape the reach of the three-year exclusivity by simply relying on a 505(b) NDA different than the first-in-time 505(b) NDA. That result would reduce the incentive of the sponsor of the first-in-time 505(b) NDA to research and develop new drugs.”


• Even if the reliance requirement was read out of the FDC Act, would Envarsus XR still be subject to the exclusivity granted Astagraf XL, because Envarsus XR does not share conditions of approval with Astagraf XL?

– “The scope of Astagraf XL’s three-year exclusivity can only be as broad as the conditions of approval that were based upon the new clinical investigations identified in the Astagraf XL NDA. . . . The plaintiff makes much of the fact that despite the similarities between Astagraf XL and Envarsus XR—that is, they are both once-daily, extended release tacrolimus formulations—there are many other ‘clinically meaningful’ differences between Astagraf XL and Envarsus XR. But that is beside the point. The effect of marketing exclusivity in [FDC Act § 505(c)(3)(E)(iii)] turns on whether a second-in-time 505(b)(2) NDA shares any conditions of approval with the first-in-time 505(b) drug granted exclusivity.”


IIIOtsuka Aripiprazole Litigation

Otsuka Aripiprazole Litigation• In mid-October, Otsuka filed a Complaint in the DC District Court

challenging FDA’s October 5, 2015 denial of a Citizen Petition (Docket No. FDA-2015-P-2482) and approval of Alkermes’ 505(b)(2) NDA 207533 for ARISTADA (aripiprazole lauroxil) Extended-release Injectable Suspension in light of unexpired 3-year new clinical investigation applicable to Otsuka’s ABILIFY MAINTENA (aripiprazole) for Extended-release Injectable Suspension, for Intramuscular Injection 300 mg/vial and 400 mg/vial, approved under NDA 202971.

• ARISTADA is a prodrug of N-hydroxymethyl aripiprazole (and which N-hydroxymethyl aripiprazole is a prodrug of aripiprazole) that FDA approved for the treatment of schizophrenia (the same use for which ABILIFY is approved).

• Otsuka alleges in its Complaint that FDA violated the FDC Act’s 3-year exclusivity provisions (FDC Act § 505(c)(3)E)(iii) and (iv)), the Agency’s regulation governing 3-year exclusivity (21 C.F.R. § 314.108), and the Administrative Procedure Act in approving ARISTADA.

– “The FDA decisions challenged in this case undermine a fundamental aspect of the [FDCA]. . . . Here, FDA disregarded the text and purpose of the exclusivity provisions and, in their place, created a wholly unauthorized new scheme to deny Otsuka exclusivity rights it earned and to approve a so-called new drug that undeniably is not a medical advance; provides no new or additional therapeutic benefit; and, as its own manufacturer has boasted repeatedly, operates in the body exactly as does Otsuka’s drug. Rather than incentivize innovation and new drug development to benefit public health, FDA’s action punishes the innovator and unlawfully rewards a follow-on copycat company that proposes to bring to market a drug that provides no new or additional public health benefit. FDA’s decision inverts the intent of the FDCA by denying Otsuka the protection to which it is legally entitled and rewarding what is, at best, an imitative competitor’s facially clever, but substantively meaningless, chemical trick. Neither law nor sound policy supports this outcome. FDA’s decision should not stand.”

Otsuka Aripiprazole Litigation

product development using the

Documents