greenblum & bernstein, p.l.c

NEIL F. GREENBLUM BRUCE H. BERNSTEIN JAMES L ROWLAND ARNOLD TURK MICHAEL J. FINK

LESLIE J. PAPERNER .0

WILLIAM PIEPRZ • STEPHEN M. ROYLANCE ROBERT W. MUELLER WILLIAM E. LYDDANE WILLIAM S. BOSHNICK • PAUL A. BRAIER, Ph.D. P. BRANKO PEJIC • JOHN PRETA • LINDA J. HODGE JOSHUA M. POVSNER • DANIEL B. MOON JOHN V. MAZZOLA

BRUCE H. STONER, JR. 0 ENOCH PEAVEY SEAN C. MYERS-PAYNE, Ph.D.

LAW OFFICES

GREENBLUM & BERNSTEIN, P.L.C. PATENT, COPYRIGHT AND TRADEMARK MATTERS

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February 11, 2014

JONATHAN MILLER • STEVEN B. POLLICOFF •

BARRY L HOLLANDER ()

GARY V. HARKCOM•0 JAMES P. BONNAMY JILL M. BROWNING WALTER SCHLAPKOHL, Ph.D. NAOKO OHASHI•

KEVIN R. SPIVAK•0

HARRY J. GWINNELLO STEPHEN TU• JEFFREY H. HANDELSMAN• ANNA L. VERDERAME

• ADMITTED TO A BAR OTHER THAN VA

° EUROPEAN PATENT ATTORNEY

° REGISTERED PATENT AGENT

0 OF COUNSEL

Division of Dockets Management Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, rm. 1061 Rockville, MD 20852

REDACTED COPY

Re: Doxorubicin Hydrochloride (Liposomal) Injection

CITIZEN PETITION

The undersigned submits this petition under § 505(j) of the Federal Food, Drug, and Cosmetic Act, on behalf of its client, to request the Commissioner of Food and Drugs to: (i) withdraw designation of ANDA #203263 as the Reference Listed Drug ("RLD") for doxorubicin hydrochloride (liposomal) injection; or, in the alternative (ii) require any application that refers to ANDA #203263 as the RLD to demonstrate bioequivalence with statistically enhanced confidence.

INTRODUCTION

SUN is the holder of ANDA #203263 for doxorubicin hydrochloride (liposomal) injection, which received FDA approval in February 2013 as a generic product in reference to Doxil®, a product associated with a New Drug Application filed by Johnson & Johnson ("J&J") affiliate Janssen Research and Development.

Doxorubicin is a chemotherapeutic injectable agent that is used to treat a wide variety of cancers. However, doxorubicin has serious potential side effects, even potentially lethal ones, as evidenced by the Agency's required Black Box warning. Just a few months ago, due in part these safety concerns, FDA issued a special guidance, "Draft Guidance on Doxorubicin Hydrochloride," requiring ANDA/505(b)(2) applicants to match multiple safety and efficacy parameters to demonstrate bioequivalence to Doxil, the original RLD for doxorubicin hydrochloride (liposomal) injection.

However, compliance issues in manufacturing Doxil resulted in product shortages. FDA responded by de-designating Doxil as the RLD and instead designating SUN's product as the RLD. But FDA took this action unilaterally without an opportunity for public comment or

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formal process, and without any specific findings or determinations regarding issues of safety and efficacy.

FDA's action raises serious safety issues, because proving bioequivalence to Sun's product (which was never subject to the full array of clinical trials required for NDA approval) does not demonstrate bioequivalence to Doxil (which was subjected to the full array of such clinical trials). Proving bioequivalence requires a comparison of multiple parameters between a proposed doxorubicin product and the RLD, and this high number of parameters increases the likelihood that variances will exist.

While SUN may have made every effort to match Doxil and show bioequivalence, myriad variations actually exist between Doxil and SUN's product. Variations will become more pronounced for any future ANDA/505(b)(2) applicants — basically a "copy of a copy" situation — because a proposed generic product would be evaluated in reference to SIJN's product, which was, in turn, evaluated in reference to Doxil.

Experts, Drs. Brij Patel and Dr. Simon Day, have submitted a report illustrating the substantial risks in the safety of new generic products by shifting the RLD designation from Doxil to SUN's product. Drs. Patel and Day conclude that changing the RLD may result in a new generic product, that is bioequivalent to SUN's product, but with 40% higher release of doxorubicin relative to Doxil. This significant difference in drug delivery would not be detected unless the new generic product were actually tested head-to-head against Doxil as the RLD. Variations in Doxil and SUN's product present substantial risks that any ANDA or 505(b)(2) application deemed bioequivalent to SUN's product would not actually be bioequivalent to Doxil for one or more critically-important safety parameters. The result could present serious safety issues for patients.

The petitioner, therefore, requests that FDA re-list Doxil as the RLD for doxorubicin hydrochloride (liposomal) injection. In the alternative, if FDA continues to list SUN's product as the RLD, we request that any ANDA or 505(b)(2) application referencing SUN's product be required to prove bioequivalence with enhanced statistical confidence to ensure that any product bioequivalent to SUN's product also will be bioequivalent to Doxil.

ANALYSIS

A. Actions Requested

1. The petitioner requests the Commissioner to withdraw designation of ANDA #203263 as Reference Listed Drug for doxorubicin (liposomal), and requests the Commissioner reject any application referring to ANDA #203263 as Reference Listed Drug.

In the alternative:

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2. The petitioner requests that for any drug application (pending or future) that references ANDA #203263 as Reference Listed Drug, the Commissioner require such application to demonstrate bioequivalence to ANDA #203263 with statistically enhanced confidence.

B. Statement of Grounds

1. Background on Doxorubicin

Doxorubicin (liposomal) is a chemotherapeutic injectable agent that is used as a treatment against a wide variety of cancers. 1 FDA has approved its use as first-line treatment against ovarian cancer, AIDS-related Kaposi's sarcoma, and multiple myeloma. 2 However, the clinical use of doxorubicin is limited due to serious, potentially life-threatening, safety concerns.

The original, non-liposomal, doxorubicin formulation was associated with severe myocardial toxicity, in some cases leading to fatal congestive heart failure (CHF). 3 The incidence of CHF in patients taking non-liposomal doxorubicin is cumulative and dose-dependent. The estimated incidence in patients at a cumulative dose of 400 mg/m 2 is as high as 5%, increasing to as much as 16% (cumulative dose 500 mg/rn 2) and 48% (cumulative dose 700 mg/m2).4'5 The incidence of myocardial toxicity and CHF have led FDA to require a detailed Black Box warning on non-liposomal doxorubicin's product label.

These serious adverse effects, among other things, motivated the development and introduction of the liposomal formulation. Therapeutically, the liposomal formulation has the advantages of prolonging drug action in the body by slowing drug release and protecting the drug from metabolic degradation, as well as reducing irritation near the injection site. 6'7

In a clinical stud_y with breast cancer patients, with cumulative doxorubicin doses between 450-500 mghn 2 or between 500-550 mghn 2, the risk of cardiotoxicity in patients treated

1 National Library of Medicine (revised January 15, 2012), (http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682221.html). 2 Doxil® label information (revised August 2013), available at http://www.doxil.corn/shared/product/doxil/prescribing-inforrnation.pdf. 3 Label information for non-liposomal doxorubicin (revision April 2012), available at http://www.accessdata.fda.gov/drugsatfda docs/labe1/2012/062921s0221bl.pdf. 4 D.D. Von Hoff et al., Risk Factors for Doxorubicin -Induced Congestive Heart Failure, Ann. Intern. Med. 91:710 -717 (1979). 5 S.M. Swain et al., Congestive Heart Failure in Patients Treated with Doxorubicin: A Retrospective Analysis of Three Trials, Cancer, 97(11):2869 -79 (2003). 6 Doxil label, supra at fn. 2. 7 Liposomal Doxorubicin label information, SUN Pharmaceutical Industries, available at http://www.accessdata.fda.gov/drugsatfda docs/labe1/2013/2032631bl.pdf.

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with Doxil (liposomal doxorubicin) was 11%, 8 though a study in multiple myeloma patients suggested similar risk (3%) in patients administered Doxil+bortezomib and patients taking only bortezomib. Thus, an apparent advantage of liposomal doxorubicin is its somewhat reduced myocardial toxicity compared to the non-liposomal formulation. Nevertheless, FDA maintains the requirement for a Black Box warning of myocardial toxicity on the label of liposomal doxorubicin products. 93°

Though possibly somewhat safer with regard to CHF, the liposomal formulation presents new safety issues never reported with the non-liposomal formulation. In particular, liposomal doxorubicin can cause palmar-plantar erythrodysesthesia (also known as hand-foot syndrome, or HFS), which is thought to be the result of liposomal drug distribution in the skin. HFS results in palmar-plantar skin eruptions characterized by swelling, pain, erythema, and sometimes desquamation of skin on the hands and feet." Treatment-emergent HFS can be managed by dose reduction, by treatment delay, or in severe cases, by discontinuation of doxorubicin treatment. 12

Stomatitis is another potentially treatment-limiting treatment-emergent adverse effect. A clinical study on ovarian cancer patients showed that 41.1% of patents treated with liposomal doxorubicin developed stomatitis (in contrast to just 15.3% of patients being treated with topotecan). In patients developing Grade 2 to 4 stomatitis, the Doxil label recommends responses ranging from delaying doxorubicin administration up to two weeks, through complete discontinuation of the drug. Even for patients with mild (Grade 1) stomatitis, a history of stomatitis leads to the recommendation to delay doxorubicin treatment up to two weeks, and to reduce the dose by 25%."

Liposomal doxorubicin is also associated with severe myelosuppresion. In patients with AIDS-related Kaposi's sarcoma, myelosuppression appears to be the dose-limiting adverse reaction. 14

Responding to adverse effects by dose reduction is complicated by the fact that at higher dosing (i.e., 50 mg/rn 2), liposomal doxorubicin exhibits non-linear pharrnacokinetics, such that dose adjustments may result in non-proportional greater change in plasma concentration and exposure to the drug."

As can be seen, there is a delicate balance between the risk of under-administration (reducing efficacy) and over-administration (increased potentially serious acute and chronic adverse effects).

8 Doxil label, supra at fn. 2. 9 Doxil label, sec. 5.4, supra at fn. 2. 10 SUN liposomal doxorubicin label, supra fn. 7. " Doxil label, sec. 5.4, supra at fn. 2. 12 Doxil label, sec. 2.5, table 1, supra at fn. 2. 13 Doxil label, supra at fn. 2. 14 Doxil label, sec. 5.3, supra at fn. 2. 15 Doxil label, sec. 2.5, supra at fn. 2.

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2. J&J's i6 Citizen Petition of May 6, 2009

On May 6, 2009, J&J filed citizen petition FDA-2009-P-0216 ("J&J CP"), 17 asking FDA to establish clear guidelines for demonstrating bioequivalence to Doxil. J&J requested that for this product, bioequivalence only be shown with a complex tripartite set of demonstrations—that the ANDA or 505(b)(2) applicant establish the proposed product to have:

(1) Pharmacokinetic properties equivalent to Doxil;

(2) The same physicochemical properties as Doxil; and

(3) Comparable effectiveness and safety to Doxil as demonstrated in clinical and other studies.

The J&J CP urged that similar pharmacokinetic (PK) profiles would not necessarily result in similar clinical effects at least because PK studies do not provide information on drug release at sites where toxicity may occur. The J&J CP argued that PK comparisons were not predictive of either safety or efficacy of a different liposomal doxorubicin product.

Therefore, in addition to PK comparisons, the J&J CP asked FDA to require any ANDA or 505(b)(2) application to have the same physicochemical properties as Doxil. The J&J CP proposed nine separate physicochemical properties to be compared. The J&J CP further argued that full clinical studies with effectiveness and safety endpoint also be required of all ANDAs and 505(b)(2) applications.

Shortly after J&J's CP was submitted, FDA released a Draft Guidance for demonstrating bioequivalence of liposomal doxorubicin formulations. 18 The Draft Guidance did not recommend in vitro safety and efficacy studies, but instead called for "sameness" to Doxil with respect to certain physicochemical parameters. With respect to in vivo PK studies, the Draft Guidance called for AUC and C. for free and liposomal doxorubicin based on a standard 90% confidence interval (CI). 19 The recent revision of the Draft Guidance also makes this recommendation. 2°

16 The citizen petition was filed under the name of Ortho-Biotech, a unit of Johnson & Johnson Pharmaceutical Research & Development, L.L.C. The holder of the Doxil NDA (NDA #050718) is Janssen Research & Development, also a unit of Johnson & Johnson. For convenience and ease of reference, these entities will be referred to herein as J&J. 17 Citizen Petition FDA-2009-P-01216. 18 a. Draft Guidance on Doxorubicin Hydrochloride, February 2010;

b. Version revised in November 2013, available at - http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformationiguidances/ucm 199635.pdf 19 Draft Guidance of February 2010, page 1. See also, Draft Guidance, revised Nov. 2013, p. 2. Supra at fn. 18. 20 Draft Guidance, revised Nov. 2013. Supra at fn. 18.

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Approximately three years later, on February 4, 2013, FDA formally responded to the J&J CP.21 FDA's response was consistent with the Draft Guidance issued three years earlier. In particular, FDA granted J&J's CP with regard to demonstrating equivalence in pharmacokinetic properties, and sameness in key physicochemical properties. However, FDA denied J&J's request to require clinical studies that demonstrate comparable effectiveness and safety.

Doxil has since been de-designated as Reference Listed Drug (RLD) for doxorubicin hydrochloride liposome injection. Even though SUN's product was designated RLD in June 2013 (discussed below), FDA's Draft Guidance revised in November 2013 still refers to Doxil as though it were the RLD. 22

3. Approval of SUN's Liposomal Doxorubicin; Shortage of J&J's Doxil

SUN submitted an ANDA for approval to market this liposomal doxorubicin formulation in the U.S. on June 16, 2011. While its ANDA was pending, shortages of Doxil arose in the U.S. after repeated compliance problems with J&J's contract manufacturer prevented J&J from providing a consistent supply of Doxil to meet the U.S. demand. Accordingly, in February 2012, FDA exercised its enforcement discretion and temporarily permitted importation of SUN's Lipodox in order to help alleviate the shortage of Doxi1. 2i FDA granted final approval to SUN's ANDA on February 4, 2013. 24 Since October 2013, SUN seems to be meeting the entire U.S. demand for the product.

Doxil is presently unavailable on the market due to supply shortages. J&J's contract manufacturer ceased its production of Doxil in October 2013. J&J has since been working with FDA to find alternative means for supplying Doxil in both the short- and long-term. 25 J&J recently announced that it has leased the same facilities previously used by its contract manufacturer to restart manufacturing Doxil under J&J's direct management, pending regulatory approval. 26 FDA's website still indicates that the marketing status of J&J's NDA #050718 for

21 FDA response dated February 4, 2013. 22 Draft Guidance, revised Nov. 2013, pages 2 and 4. Supra fn. 18b. 23 FDA announcement, last updated 2/21/2012; available at http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm292721.htm. 24 Information from Drugs@FDA for Doxorubicin Hydrochloride (Liposomal), available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (last accessed February 4, 2014). 25 Press Release, Janssen Products, Important Update- US. Supply Outage of Doxil ® (doxorubicin HC1 liposome injection) (Oct. 14, 2013), available at http://www.doxil.com/sites/default/files/DOXIL DHCP Letter.pdf?q=0. 26 Press Release, Janssen Products, J&J Strikes a Deal to Manufacture Doxil Itself at Ben Venue Plant (Dec. 19, 2013), available at http://www.fiercepharma.com/story/doxil-update-jj-strikes-deal-manufacture-doxil-itself-ben-venue-plant/2013-12-19.

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Doxil is active, and does not indicate that J&J has withdrawn Doxil permanently from the market (as evidenced by the "prescription" marketing status of the product). 27

4. FDA Should Withdraw Designation of SUN's Product as RLD Because the Re-Designation was Arbitrary and Capricious

FDA designated SUN's product as RLD for liposomal doxorubicin in June 2013. 28

Typically, FDA's decision to change designation of RLD is subject to public scrutiny. For example, a firm wishing to market a generic version of a listed drug that is not designated as the RLD may petition the Agency through the Citizen Petition procedure. See 21 C.F.R. §§ 10.25(a) and 10.30. If and when the Citizen Petition is approved, the second listed drug will be designated as an RLD and the petitioner may submit an ANDA citing the newly designated RLD.

Here, however, FDA re-designated the SUN ANDA product as an RLD without any formal process. FDA evidently took a unilateral action as an update to the Orange Book but did not do so in response to a public Citizen Petition (with an opportunity for comments) or announce this action in any formal or public way. In designating SUN's product to be RLD, FDA also did not announce that it had made any findings or determinations that designating SUN's product as RLD presented no risk to the public, or presented no issues of safety or efficacy for an ANDA/505(b)(2) application that cites to SUN's product as RLD.

We are not aware of any FDA regulations relating to re-designating an RLD when the originator RLD product is no longer marketed while non-RLD products remain marketed. We understand that under such circumstances, FDA typically attempts to determine the market leader among the remaining approved products, and designates that market leader as the new RLD. That is, FDA has apparently customarily used an approach that does not consider safety or efficacy when determining which product the new RLD should be. For the majority of drug products—those that are not life-saving drugs with serious adverse effects associated with under-or over-administration—FDA's customary approach might be sufficient. However, there is no reasoned basis or rationale for reflexively applying this approach to a complex drug product such as liposomal doxorubicin, for which both over- and under-administration have serious documented safety and efficacy implications.

Due to the numerous potential safety and efficacy issues discussed above regarding liposomal doxorubicin, FDA's informal approach, which fails to consider issues of safety or

27 Information from Drugs@FDA for Doxil, available at http://www.accessdatalda.gov/scripts/cder/drugsatfda/index.cfm (last accessed February 4, 2014). 28 FDA Orange Book June 2013 Changes List, available at http://www.fda.gov/downloads/drugs/informationondrugs/ucm360909.pdf.

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efficacy, involves no scientific or medical foundation, lacks proper process, and is both arbitrary and capricious.

5. FDA Should Withdraw Designation of SUN's Product as RLD Because, It Presents Substantial Risks That New Generic Products Are Bioequivalent to SUN's Product But Not to Doxil

A change in RLD is not merely an administrative formality, and should not be treated as such. It can have a profound impact on future ANDAs and 505(b)(2) applications. SUN has gone to great lengths to match Doxil as closely as possible, but even SUN's liposomal product is not identical to Doxil. FDA's Draft Guidance recites a substantial number of clinical studies, in vitro studies, and chemical/physical comparisons that must be made for "ANDAs claiming equivalence to Doxil." 29 In view of the great number of comparisons that must be made to Doxil there is a greatly diminished chance that a product that is bioequivalent to SUN's product will also be bioequivalent to the original Doxil.

This is discussed in detail in the appended expert report of Dr. Brij Patel and Dr. Simon Day ("the Patel Report"). 3° The Patel Report discusses in detail the present situation, in which Doxil (RLD-1) is no longer marketed, SUN's product is designated RLD-2, and a generic product seeks approval on the basis of comparisons to RLD-2. As discussed in the Patel Report, when multiple independent parameters are compared, the risk substantially increases that the generic product will not be bioequivalent to RLD-1 even if it is bioequivalent to RLD-2. This is referred to as "bio-drift" or "drift," as explained in the Patel report.

In the scenario addressed in the Patel Report, where RLD-2 differs from RLD-1 in only one parameter (by 10%), the chance that a successive generic that is bioequivalent to RLD-2 is also bioequivalent to RLD-1 is about 75%• 31 Where two independent parameters are involved, the likelihood drops to 56%. 32 With only three independent parameters, the chance that such a generic is bioequivalent to RLD-1 drops to only 42%—that is, it becomes most likely (58%) that the successive generic is not bioequivalent to RLD-1. 33

Redacted

29 Draft Guidance of February 2010, page 4; supra, fn. 18a. 313 Expert Report of Dr. Brij Patel and Dr. Simon Day (submitted in redacted form). 31 Patel Report, section 1.13; supra, fn. 30. 32 Patel Report, section 1.16; supra, fn. 30. 33 Patel Report, section 1.16; supra, fn. 30. 34 Patel Report, section 1.14; supra, fn. 30.

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As discussed above, liposomal doxorubicin has unique and severe risks associated with both over-administration, and under-administration. Over-administration is associated with both acute and chronic risks, such as congestive heart failure, infusion reactions, hand-foot syndrome, and myelosuppression. The obvious risk associated with under-administration is that the patient receives a less effective dose, or a sub-effective dose of the drug, such that the cancer is either treated insufficiently, or not at all.

FDA's Draft Guidance further require any liposomal doxorubicin to demonstrate chemical and physical characteristics equivalent to the RLD. 35 But liposomal doxorubicin is particularly difficult to manufacture to specification. 36 For example, J&J's contract manufacturer had problems meeting the FDA's compliance regulations in manufacturing Doxil since at least 2011 . 37 The unique challenges in manufacturing liposomal doxorubicin render stricter standards necessary to ensure differences in manufacturing do not affect safety and efficacy.

We are not requesting that FDA perform a scientifically- and medically-based analysis in each and every instance where a brand-name product ceases to be marketed. Where the drug is simple and there are relatively few parameters to compare to establish bioequivalence, and where over- or under-administration are not associated with life-threatening implications, FDA's traditional approach of simply selecting the market leader as new RLD may be adequate. However, for the reasons explained above, this is not the situation that applies to liposomal doxorubicin.

For at least the reasons discussed above, and as discussed in the Patel Report, we submit that FDA's action designating SUN's product as RLD without making any scientific or medical analysis was an abuse of discretion, and was arbitrary and capricious. This is exacerbated by the fact that Doxil remains approved with an active marketing status, and is not a discontinued product. Thus, FDA should immediately rescind RLD status of SUN's product.

6. If RLD Status of SUN's Product is Maintained, FDA Should Require that Bioequivalence to SUN's product be Demonstrated with Statistically Enhanced Confidence

If FDA decides to maintain the status of SUN's product as RLD (which we maintain would be incorrect), we offer an alternate proposal. Specifically, in order to reduce the likelihood of bio-drift, should an ANDA or 505(b)(2) application refer to SUN's product as RLD, we propose that FDA request that the second generic demonstrate bioequivalence with statistically enhanced confidence.

35 Draft Guidance, revised Nov. 2013, page 4. Supra fn. 18. 36 Complaint at ¶J 18- 19, Alza Corp. v. Boehringer Ingelheim USA Corp., No. 8877 -CS (Del. Ch. 2013). 37 Press Release, U.S. Supply Outage of Doxil; supra, fn. 25.

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More specifically, the Patel Report demonstrates that when a generic compares bioequivalence to RLD-2 instead of RLD-1, the likelihood that the generic will not be bioequivalent to RLD-1 increases rapidly with an increase in the number of independent parameters required for the bioequivalence comparison. For example, as discussed above, in the case of 10% difference between RLD-1 and RLD-2, a 1-parameter comparison results in a 25% chance that the subsequent generic bioequivalent to RLD-2 is not bioequivalent to RLD-1. 38 However, in a 2-parameter comparison, the likelihood that the subsequent generic bioequivalent to RLD2 is not bioequivalent to RLD-1 surges to 44%: 39

137 5

125

110

100

88

80

Two Parameters

BE to RLD-2

44% bioequivalent to RLD-2 but not to

RLD-1

BE to RLD-1

56% bioequivalent to both RLD-2 and

RLD-1

Products bioequivalent to RLD-1 that will

never be submitted

80 88 100 110

125 137 5

With an increase to just three independent parameters (e.g., liposome size, PEG content at surface, and in vitro release), the likelihood that the generic is not bioequivalent to RLD-1 increases to 58%,4° making it niore likely than not that the subsequent generic would not be bioequivalent to Doxil.

38 Patel Report, e.g., section 1.13; supra, fn. 30. 39 Patel Report, e.g., section 1.16; supra, fn. 30. 40 Id

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The current version of the Draft Guidance was designed as, and is suitable for, a guide to demonstrating bioequivalence of a product (such as SUN's product) to the original RLD, Doxil. However, the Draft Guidance was not designed to address bio-drift and its potential safety and efficacy issues, and so is not applicable to the present situation—where bioequivalence comparisons would be made not to Doxil, but to another product. It would be arbitrary and capricious, and an abuse of discretion, if FDA were to automatically apply the bioequivalence comparisons to Doxil called for in the Draft Guidance to bioequivalence comparisons to SUN's product.

Given the risks of over- and under-administration of liposomal doxorubicin, the highly increased risk of bio-drift should an ANDA/505(b)(2) application be permitted to use SUN's product as RLD, and the inapplicability of the Draft Guidance for use with an RLD other than Doxil, FDA is requested to require that any subsequent ANDA/505(b)(2) application using SUN's product as RLD demonstrate bioequivalence to SUN's product with increased confidence than called for in the current Draft Guidance.

As a matter within FDA's expertise, we request that FDA develop a well-reasoned set of requirements, based on scientific and medical principles, for a subsequent ANDA/505(b)(2) application to demonstrate bioequivalence to SUN's product with enhanced confidence, while simultaneously minimizing bio-drift from Doxil.

C. Environmental Impact

Under 21 C.F.R. §§ 25.30 and 25.31, the present petition is categorically excluded from filing an environmental assessment or environmental impact statement.

D. Economic Impact

Petitioner believes that an economic impact statement is not required in this case, but agrees to provide such an analysis if requested by the Commissioner.

E. Certification

The undersigned certifies, to the best knowledge and belief of the undersigned, that this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition.

az6,)A2(

Paul A. Braier, Ph.D., Esq. Greenblum & Bernstein, P.L.C. 1950 Roland Clarke Place Reston, Virginia 20191 (703) 716-1191

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List of Exhibits

The attached Exhibits are numbered according to the first footnote in the Citizen Petition that cites to the Exhibit:

1. Doxorubicin Information, National Library of Medicine (revised January 15, 2012).

2. Doxil® label information (revised August 2013).

3. Label information for non-liposomal doxorubicin (revision April 2012).

4. D.D. Von Hoff et al., Risk Factors for Doxorubicin-Induced Congestive Heart Failure, Ann. Intern. Med. 91, 710-717, 1979.

5. S.M. Swain et al., Congestive Heart Failure in Patients Treated with Doxorubicin: A Retrospective Analysis of Three Trials, Cancer, 97(11) 2869-2879 (2003).

7. Liposomal Doxorubicin label information, SUN Pharmaceutical Industries.

17. J&J's Citizen Petition FDA-2009-P-01216.

18a. Draft Guidance on Doxorubicin Hydrochloride, February 2010.

18b. Draft Guidance on Doxorubicin Hydrochloride, Revised November 2013.

21. FDA response to J&J's citizen petition (February 4, 2013).

23. FDA announcement permitting Lipodox importation, last updated 2/21/2012.

24. Doxorubicin Liposomal marketing Information from Drugs@FDA.

25. Press Release, Janssen Products, Important Update- US. Supply Outage of Doxil ® (doxorubicin HC1 liposome injection) (Oct. 14, 2013).

26. Press Release, Janssen Products, J&J Strikes a Deal to Manufacture Doxil Itself at Ben Venue Plant (Dec. 19, 2013).

27. Doxil marketing Information from Drugs@FDA.

28. FDA Orange Book June 2013 Changes List.

30. Expert Report of Dr. Brij Patel and Dr. Simon Day.

36. Complaint, Alza Corp. v. Boehringer Ingelheim USA Corp., No. 8877-CS (Del. Ch. 2013).

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