crestor citizen's petition

8/3/2019 CRESTOR Citizen's Petition

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AstraZeneca5506 4 P2 :4?

November 14, 2011

BY HAND DELIVERYDivision of Dockets ManagementFood and D rug Adm inistrationDepartm ent of Health and Human Se rvices5630 Fishers Lane, Room 1061Rockville, Maryland 20852Dear Sir or Madam:

On behalf of AstraZeneca Pharm aceuticals LP, I herewith enclose a CitizenPetition and acc om panying exhibits. I respectfully request the Food and D rugAdm inistration to direct any correspondence relating to this petition to co unsel identifiedbelow:Peter 0. SafirCovington & B urling LLP1201 Pennsylvania Avenue, NWWashington DC 20004-2401(202) 662-5162(202) 778-5162 (facsimile)[email protected]

Sincerely,

mes W . Blaset to , MD1M PH VP U.S. Strategic Developm ent

AstraZeneca LP Te l 302 886 30001800 Concord Pike PO Box 15437 Wilmington DE 19850-5437 www.astrazeneca-us.com


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Dockets Management BranchFood and D rug Adm inistration5630 Fishers Lane, Room 1061 (HFA-305)Rockville, Maryland 20852

CITIZEN PETITIONAstraZeneca P harmac euticals LP (AstraZeneca) subm its this Citizen Petitionpursuant to sections 505(j) and 505(b ) of the Federal Food, Drug, and Cosm etic Act(FDCA ) and in accordance with 21 C.F.R. 10.30, to request the Comm issioner of Foodand Drugs take the actions described below. AstraZeneca markets and distributesCREST OR (rosuvastatin calcium) Tablets (Crestor) in the United States.

I.ction RequestedAstraZeneca respectfully requests that the Food and D rug Adm inistration (FD A):1. Not approve an y rosuvastatin calcium abbreviated new drug application (AN DA ) forwhich Crestor is the reference listed drug (RLD ) if the proposed labeling for any suchAN DA drug om its the diabetes related warning and adverse reaction information thatFDA required AstraZeneca to include in Crestor's labeling whe n it approved theJUPITER primary p revention indication that is based on the results of the JUPITERtrial. The JU PITER trial is the Justification for the Use of Statins in PrimaryPrevention: An Intervention T rial Evaluating R osuvastatin.2. Not app rove any 505(b)(2) app lication for a different salt form o f rosuvastatin if theproposed labeling for such 505(b)(2) drug om its the JUPITER trial data associatedwith the diabetes related warning and adverse reaction information that FDA requiredAstraZene ca to include in Crestor's labeling when it approved the JUP ITER prim aryprevention indication that is based on the results of the JUPITER trial.

Statement of GroundsA.actual BackgroundAstraZeneca markets Crestor under FDA-approved ND A N o. 21-366. Crestor isan HM G-CoA reductase inhibitor that was initially approved on A ugust 12, 2003 (1) as

an adjunct to diet to reduce elevated total-C, LDL -C, ApoB, nonH DL -C, and TG levelsand to increase HD L-C in patients with primary h ypercholesterolemia (heterozygousfamilial and nonfam ilial) and m ixed dyslipidemia (Fredrickson Typ e IIa and fib); (2) asan adjunct to diet for the treatment of patients with elevated serum T G levels(Fredrickson Type IV); and (3) to reduce LD L-C, total-C, and A poB in patients withhom ozygous fam ilial hypercholesterolemia a s an a djunct to other lipid-loweringtreatments (e.g., LDL apheresis) or if such treatments are unavailable.Crestor is currently indicated for (1) patients with primary hyperlipidem ia andmixed dy slipidemia as an adjunct to diet to reduce elevated total-C, LD L-C, Ap oB,


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nonHD L-C, and TG levels and to increase HD L-C, (2) patients with hypertriglyceridem iaas an ad junct to diet, (3) patients with hom ozygous fam ilial hypercholesterolemia toreduce L DL -C, total-C, and Ap oB, (4) patients with primary dysbetalipoproteinemia asan adjunct to diet, (5) slowing the prog ression of atherosclerosis as part o f a treatmen tstrategy to lower total-C and L DL -C as an adjunct to diet, (6) pediatric patients 10 to 17years of age with heterozygous fam ilial hypercholesterolemia to reduce elevated total-C,LDL -C, and A poB after failing an adequate trial of diet therapy, and (7) risk reduction ofmyocardial infarction, stroke, and arterial revascularization procedures in patientswithout clinically evident co ronary h eart disease, but with m ultiple risk factors (JUPITERprimary prevention indication). Crestor is a once daily tablet that is available in 5, 10, 20,and 40 m g strengths.

The O range Bo ok (OB ) lists five patents for Crestor: U.S. Patent Nos. (i)6,316,460 (the '460 patent), which con tains drug product claims; (ii) 6,858,618 (the '618patent), which contains drug use claims; (iii) RE37 314 (the '314 patent), which containsdrug substance claims; (iv) 7,030,152 (the '152 patent), which contains drug use claims;and (v) 7,964,614 (the '614 patent), which contains drug use claims. None of thesepatents have expired.' The following O B use co de is associated with each of the '152and '614 patents: U-1032 use of rosuvastatin calcium for the primary preve ntion ofcardiovascular disease in individuals without clinically evident coronary heart disease butwith increased risk factors. The OB use code assoc iated with the '618 patent is: U-618use of rosuvastatin calcium to reduce elevated Total-C, LDL-C, Apo B, nonHD L-C or TGlevels; to increase HDL -C in adult patients with primary hyp erlipidemia or m ixeddyslipidemia; and to slow the progression of atherosclerosis.

To date, FDA has tentatively approved A ND As filed by the following genericdrug com panies: Mylan, Aurobindo, and Teva on 5/12/2010; Par on 5/27/2010; Cobalt(now W atson) on 6/10/2010; Sandoz on 6/19/10; Sun on 9/28/2010; and Glenmark on10/14/2010. There are currently no generic versions of Crestor on the market for anyindication.Aurobindo, M ylan and Teva have each subm itted a section viii statemen tasserting that the '152 p atent is a m ethod of use patent that does not claim any indicationfor which they are seeking approval. 2 In legal filings associated with Crestor AN DAlitigation, Apotex states that its paragraph IV notice letter did not contain a certification

The '460, '618, '314, '152, and '614 patents expire 8/4/2020, 12/17 /2021, 1/8/2016, 4/2/2018 , and4/2/2018, respectively, and according to the OB each o f these patents has an additional 6 months ofpediatric exclusivity attached thereto.2 S ee Letter from K eith Webber, Ph.D., Office of Pharm. Sci. , FDA to Blessy Johns, Aurobindo Pharm aUSA , Inc., tentatively approving AND A No . 079170, Rosuvastatin Calcium Tab lets (May 12, 2010),available at http://www.accessdataida.gov/drugsatfda docs/appletter/2010/079170s0001tr.pdf; Letter fromKeith We bber, Ph.D., Office of Pharm. Sci., FDA to S . Wayne Talton, Mylan Pharm s. Inc., tentativelyapproving ANDA No. 079161, Rosuvastatin Calcium Tablets (May 12, 2010), available athttp://www.accessdata.fda.gov/drugsatfda docs/appletter/2010/079161s00 01tr.pdt and Letter from Ke ithWeb ber, Ph.D., Office of Pharm . Sci., FDA to T eva Pharm s. USA to Philip Erickson, R.Ph., Senior Dir.Regulatory Affairs, tentatively approving AN DA N o. 079166, Rosuvastatin Calcium Tab lets (May 12,2010), available at http://www.accessdataida.gov/drugsatfda docs/appletter/2010/079166s0001tr.pdf.


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as to the '152 patent; 3 Cobalt (now W atson) indicates it fi led a section v iii statem ent as tothe use claimed in the '152 pa tent; 4 Glenm ark indicates it fi led a section viii statem entom itting the use claimed b y the '152 patent; 5 Par indicates it is not seeking app roval for ause that infringes the '152 patent as co nfirmed b y its section viii statement; 6 and Sunasserts that its AN DA has been tentatively approve d solely for non-patented uses (i .e. thereduction of LDL cholesterol in patients with hom ozygous fam ilialhypercholesterolemia). 7 These tentative a pproval letters and legal filings clearly indicatethat at least som e of the generic AN DA filers are proposing rosuvastatin calcium AN DAproduct labeling that omits at least the JUPITER primary prev ention indication.

Additionally, Watson filed a 505(b)(2) application seeking FD A appro val tom arket 5, 10, 20, and 40 m g tablets of a zincrather than calcium salt form ofrosuvastatin prior to the expiry of all five of the p atents l isted in the O B for Crestor.W atson's 505(b)(2) application was tentatively approved on A ugust 4, 2011. 8 Watson's505(b)(2) ap plication provides for the use o f rosuvastatin zinc as an adjunctive therapy todiet for the treatme nt of adult patients with hypertriglyceridemia an d as an adjunctivetherapy to other l ipid-lowering treatm ents (e.g., LDL apheresis) or alone if suchtreatments are unavailable to reduce LD L-C, Total-C, and Apo B in adult patients withhomozygous familial hypercholesterolemia. 9 Although Watson's 505(b)(2) applicationseeks to m arket rosuvastatin zinc prior to expiry of all five of the Crestor O B listedpatents, it failed to subm it a Paragraph IV certification under 21 USC 355 (b)(2)(A)(iv)for the '152 patent.19

The sub ject of this petition is the JUPITER trial data associated with the diabetesrelated warning and adverse reaction information that FDA required AstraZeneca toinclude in Cre stor's label whe n it approved the JUPITER primary prev ention indication.

3 S ee Brief in Support of Apo tex Corp. 's Motion to Dism iss Under Fed. R. Civ. P. 12(b) and Fed. R. Civ. P.12(b)(6) (public version) at 10, A straZeneca Pharms. LP v. A potex Corp., No. 10-cv-338 (D. D el. July 30,2010) ECF No. 17. (Exhibit A)4 S ee Reply in Support of D efendants Cobalt Pharm s. Inc. & Cob alt Labs. Inc.'s Motion to Dism iss at 5 ,AstraZeneca Pharms. LP v. Cobalt Phanns. Inc., No. 10-cv-340 (D . Del. Nov . 8, 2010) EC F No. 25.(Exhibit B)5 S ee Glenm ark Generics Inc., USA's Reply Brief in Support of Its Motion to Dism iss for Lack of SubjectMatter Jurisdiction Under Fed. R. Civ. P. 12(b)(1) and Fo r Failure to State a Claim Under Fed. R. Civ. P.12(b)(6) (public version) at 2, A straZeneca Phanns. L P v . Glenm ark Generics, Inc., No. 10-cv-341 (D. Del.Nov. 15, 2010) ECF N o. 39. (Exhibit C)6 S ee Par's Reply Brief in Support of Its Motion to Dism iss (redacted -- public version) at 7, A straZenecaPhanns. LP v. Par Pharms., Inc., No. 10-cv-343 (D. Del. Nov. 15, 2010) E CF N o. 33. (Exhibit D)7 S ee Sun's Reply B rief in Support of Its Motion to D ismiss (public version) at 2, 6, 9 A straZe neca Pharm s.LP v. Sun Pharm. Inds. LT D, No. 10-cv-345 (D. Del. Nov. 11, 2010) ECF N o. 31. (Exhibit E)8 S ee Letter from Eric Colem an, M.D., Deputy Dir., Div. of Metabolism & Endocrinology Prods., FDA, toJoyce Anne D elGuadio, Executive Dir., Regulatory Affairs, tentatively approving ND A N o. 202172,Rosuvastatin Zinc (Aug. 4, 2011), available athttp://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/202172s0001tr.pdf.9 Id. at 1.1 S ee Amended Complaint (redacted version), A straZeneca UK L td. et al. v. W atson Labs, Inc. (NV ), No.10-cv-915 (D. Del. Apr. 21, 2011) ECF No. 48. (Exhibit F)


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This trial data is protected until February 8, 20 13 by a three year marke ting exclusivityperiod that FDA g ranted to AstraZeneca on February 8, 2010 whe n it approved theJUPITER primary prevention indication. This indication has the following exclusivitycode listed in the Approv ed Drug Products with Therapeutic Equivalence Ev aluations(the Orange B ook): 1-621 primary prevention of cardiovascular disease, based on theresults of Justification for the Use o f Statins in Prim ary Preve ntion: An Intervention TrialEvaluating Rosuvastatin (JUPITER) associated therew ith.

Prior to FDA appro ving the JUPITER primary prev ention indication, an AdvisoryCom mittee Meeting was convene d on Decem ber 15, 2009 to discuss the results of theJUPITER trial and AstraZen eca's proposed indication. During that mee ting, FDA askedthe com m ittee to respond to the following com m ent/question: "In the JUPITER clinicaltrial, there was a statistically significant increase in investigator-reported diabetesme llitus in the treatment arm versus the placebo arm , 2.8% vs. 2.3%, respectively with ahazard ratio of 1.27 (95% CI 1.05, 1.53; p=0.015). Please comm ent on the significanceof this imbalance." FDA's summary of the meeting minutes indicates the committee"felt that the imbalance in the repo rts of diabetes me llitus (DM) in the presen t [JUPITER]study probably represents an authentic signal of an increase in the frequency of DM andma y be a class-effect of statin drugs." 1 2 The com mittee further noted that the "benefit ofrosuvastatin on LDL lipid values was observed in diabetic and non-diabetic subjects."13

Following this advisory com m ittee m eeting and in conjunction with subsequentlyapproving the JUPITER prim ary prevention indication, FDA required AstraZeneca toupdate the W arnings and Precautions section of the Crestor label to include a newwarning that "[i]ncreases in HbAlc and fasting serum glucose levels have b een repo rtedwith HMG-CoA reductase inhibitors, including CRESTOR." I4 Additionally, the FD Aapproved label with the JUPITER primary prev ention indication updated the AdverseReactions section of the label to include new adv erse reaction information that"[i]n JUPITER , there wa s a significantly higher frequency o f diabetesme llitus reported in patients taking rosuvastatin (2.8%) v ersus patientstaking placebo (2 .3%). Mean HbA le was significantly increased by 0.1 %in rosuvastatin-treated patients compared to placebo-treated patients. Thenum ber of patients with a HbAlc > 6.5% at the end of the trial wassignificantly higher in rosuvastatin-treated versus placebo-treated patients[see W arnings and Precautions (5.5) and Clinical Studies (14.8)]."15

1 i FDA, M eeting of the Endocrinologic and Metabolic Drugs Advisory Com mittee, Questions to AdvisoryCom mittee, Question 3 (Dec. 15, 2009)(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCo nmiittee/UCM1 94920.pdf (last visited Nov. 9,2011)).1 2 FDA, Endocrinologic and Metabolic Drugs Advisory Committee, Summary Minutes of the December15, 2009 Endocrinologic and M etabolic Drugs Advisory Com mittee Meeting, 3 (Dec. 28, 2009)(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic andMetabolicDrugsAdvisoryCommittee/UCM241503.pdf (last visited Nov. 9, 2011)).13 Id.14 Crestor Prescribing Information (Exhibit G) 5.5.1 5 Id. at 6.1.


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The updated labeling also added a detailed description of the JUPITER study in theClinical Studies section of the label. 1 6 The required updates to the W arnings andPrecautions an d A dverse Reactions section of the label were agreed upo n by FD A duringlabeling negotiations following the advisory com m ittee me eting." A cop y of Crestor'scurrent label, as revised in May 2011, is attached hereto as Exhibit G.18

B.tatutory and Regulatory BackgroundSection 505 of the FD CA d escribes three types of new drug applications: (1) anapplication that contains full reports of investigations of safety and effectiveness (section505(b)(1), referred to as an N DA); (2 ) an application that contains full reports ofinvestigations of safety and effectiveness but where at least some o f the informationrequired for approval come s from studies not conducted by or for the applicant and forwhich the applicant has not obtained a right of reference (section 50 5(b)(2), referred to asa 505(b )(2) application); and (3) an ap plication that contains inform ation to show that theproposed product is identical in active ingredient, dosage form , strength, route ofadm inistration, labeling, quality, perform ance ch aracteristics, and intended use, am ongother things, to a previously approved p roduct (section 505(j), referred to as an AN DA).

1.bbreviated New Drug Applications (ANDA s)Section 505(j) of the FD CA pe rmits an AN DA ap plicant to rely on the safety andefficacy studies submitted for the RLD if the AN DA drug product has the same activeingredient, dosage form , strength, labeling, conditions of use, and rou te of adm inistrationas the RLD a nd is bioequivalent to the RL D. 1 9 The labeling of the AN DA drug productm ust be the same as the labeling for the RL D, except whe n the labeling differences arethe result of a suitability petition o r the ge neric drug is "produced or distributed b ydifferent man ufacturers." 2 Mo re specifically, FDA 's regulations provide that thelabeling for the RLD and AN DA drug product may h ave "differences in expiration date,formulation, bioavailability, or pharm acokinetics, labeling rev isions m ade to com ply with

1 6 Id. at 14.8. A version of this section of the label was first proposed by AstraZene ca when it subm ittedits sNDA for the JUPITER primary prevention indication.1 7 The proposed label AstraZeneca subm itted with its sNDA for the JUP ITER primary preve ntionindication (an excerpt of which is attached hereto as E xhibit H) did not include the information that w asadded to the W arnings and Precautions an d A dverse Reactions sections. During labeling negotiations,FDA 's January 13, 2010 pro posed label (an excerpt of which is attached hereto as Exhibit I) first added thewarning that "[i]ncreases in HbAlc and fasting serum glucose levels have b een reported w ith HIVIG-CoAreductase inhibitors, including CREST OR" to the Endocrine Effects section of the label ( 5.5) as well asrelated updates to the A dverse Reactions section of the label. After further negotiations, updated languagefor sections 5.5 and 6.1 are reflected in FDA's January 26, 2010 proposed draft label (an excerpt of whichis attached hereto as E xhibit J).1 8 Although the Crestor label has been revised since the JUPITER prim ary prevention indication wasinitially added, these subsequent label revisions did not affect the portions of the Crestor label relevant tothe JUPITER indication.19 FDCA 505(j)(2)(A).20 FDCA 505(j)(2)(A)(v) and 505(j)(4)(G).


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current FDA labeling guidelines or other guidance, or om ission of an indication or otheraspect of labeling protected by patent or accorded exclusivity."2iND A holders m ust submit to FDA for listing in the OB the relevant patents ofwhich it is aware that claim the drug co vered by the N DA or a me thod of its use and for

which a claim of patent infringem ent could reasonably be asserted if a person notlicensed by the patent owner engaged in the manufacture, use, or sale of the drug.22AN DA applicants, in turn, must submit at the time its AN DA is filed one o f the followingfour patent certifications for each O B listed patent: (I) no patent inform ation has beenlisted in the OB (paragraph I certification); (II) the listed patent has expired (paragraph IIcertification); (III) the expiry date of the listed patent and a request that FDA not approvethe AN DA until the patent expires (paragraph III certification); and (IV) the patent isinvalid, or will not be infringed by the m anufacture, use, or sale of the AN DA product forwhich app roval is sought (paragraph IV certification). 2 3If an AN DA applicant provides a paragyaph IV certification, the applicant must

notify the patent and N DA holders of the certification, so that each can, if appropriate,file an infringement suit. 24 W hen a listed patent contains only method of use claims, anAN DA applicant may try to avoid certifying as to this patent by providing a statem ent(com mo nly referred to as a "section viii statement") that the listed me thod of use p atentdoes not claim a use for w hich the applicant seeks approval. 2 5 An AN DA applican t mayalso try to om it all other protected aspects of labeling by asserting these o ther aspects areassociated w ith an indication for w hich it is not seeking appro val.As FD A explained in its response to UCB 's citizen petition regarding XY ZAL (levocetirizine dihydrochloride), perm issible labeling "differences m ay include om issionsof words or phrases from the R LD 's labeling and minor attendant changes to ensure thatthe language o f the labeling reads properly."2 6 In permitting "selective deletions . . . and

de minimis mo difications in the labeling," howeve r, FDA has no t gone so far as to perm ita generic drug 's labeling to replace "references to the protected indications" with "non-inform ative phrases" or de lete important "language . . . in its entirety."272.05(b)(2) ApplicationsSection 505(b)(2) was added to the FDCA by the Drug Price Com petition andPatent Term Restoration Act of 1984 (Hatch-Waxman Amendments). This provisionexpressly permits FDA to rely, for approval of an ND A, on data not developed by theapplicant. Specifically, a 505(b)(2) a pplication relies on one or m ore of the

2 1 21 C.F.R. 314.94(a)(8)(iv).2 2 FDCA 505 (b)(1) and (c)(2).2 3 FDCA 505(j)(2)(A)(vii) .2 4 FDCA 505(j)(2)(B).2 5 FDCA 505(j)(2)(A)(viii) .2 6 Letter from Janet Woodco ck, Director, Center for Drug Evaluation and Research, FDA to R obertTrainor, UCB , Inc., denying Xyzal citizen petition (Docket No . FDA-2010 -P-0545) at 10 (Feb. 24, 2011).271d.


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investigations that "were not conducted by or for the applicant and for which theapplicant has not obtained a right of reference or use from the person by o r for whom theinvestigations were conducted." 2 8 Such reliance is perm itted "only to the e xtent theproduct seeking approval and the [RLD ] are the same" and only "to the extent suchreliance is sc ientifically justified." 2 9 The applicant mu st submit additional data to supportthe "safety and effectiveness of any differences between the [RL D] and the drugproposed in the section 505(b)(2) ap plication." 3 0 These data are referred to as "bridging"data. 3 1 The type and quan tum of required bridging data "will vary from case to case" butma y include clinical or anim al data, "as appropriate."32

Unlike a full ND A for wh ich the sponsor has conducted or obtained a right ofreference to all the data e ssential to approval, the fil ing or approval of a 505(b)(2)application may be delayed due to patent or exclusivity protections covering the RL D.Like AN DA applicants, 505(b)(2) applicants m ust also prov ide a paragraph I, II, III, orIV certification as to each patent the NDA holder has listed in the OB for the RLD.333.restor

As sum marized in the Factual Background above, after reviewing and discussingJUPITER' s clinical trial results at the advisory com m ittee m eeting, FDA insisted inconjunction w ith approving the JUPITER prim ary prevention indication that AstraZenecainclude protected diabetes related informa tion in Crestor's labeling. Indeed, theJUPITER primary prev ention indication and associated clinical trial data are protected byunexpired patent and/or m arketing exclusivity periods. As a result, an AND A and505(b)(2) applicant cannot include the protected JUPITER trial data associated w ith thediabetes related warning and ad verse reaction inform ation in any label until theassociated marketing exclusivity period expires on February 8, 2013. In order to avoidthe JUPITER related exclusivity periods, the AN DA and 505(b)(2) app licants would haveto carve the JUPITER related diabetes warning and adve rse reaction inform ation out oftheir proposed labeling. If FDA were to perm it a generic or 505(b)(2) drug product toom it such information from its labelingafter requiring its inclusion in the labeling forCrestorthe ag ency wo uld run afoul of the Adm inistrative Procedure A ct 's prohibitionon arbitrary and capricious agency action.34

2 8 FDCA 505(b)(2).2 9 S ee Letter of Janet Woodcock, M .D., Director, Center for Drug Evaluation and Research, FDA toKatherine M. Sanzo, Esq., Morgan, Lew is & B ockius, LLP; Jeffrey B. Chasnow, Esq., Pfizer.; Stephan E.Lawton, Esq., BIO; and William R. Rakoczy, Esq., Lord, Bissell & Brook LLP, Docket No. FDA-2003-P-0274 (form erly Docket 2003P-040 8) (October 14, 2003) (2003 Co nsolidated Response), at 3, 12.3 0 Id. at 14; see also 21 C .F.R. 3 14.54(a).31 FDA , Draft Guidance for Industry: Applications Covered by Section 505(b)(2) (Oct. 1999), at 8.32 2003 Co nsolidated Response, at 14.3 3 FDCA 505(b)(2)(A).3 4 Se e B racco D iagnostics, Inc. v. S halala, 963 F. Supp. 20, 28 (D .D.C. 1997) ("Under the [APA ], the FDAeither must provide a rational basis for treating" like products differently, "or it must treat all . . . similarproducts in the same way. A failure to do one of these two things is arbitrary and capricious agency actionand therefore is a violation of the A PA.").


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Page 8C.rgument35For the reasons set forth below, FDA should not finally approve an A ND A forrosuvastatin calcium or a 505(b)(2) application for a different salt form of rosuvastatinthat omits from its labeling the warning and adverse reaction language that accom panied

the approval of the JUPITER primary preve ntion indication. Such agency action wouldarbitrarily allow a ro suvastatin drug product to be marke ted without the warning andadverse reaction information that FD A re quired AstraZeneca to include in its labeling.For A ND A applicants, omitting this warning and adv erse reaction information wouldconflict with FDA 's same labeling requirem ent.1.DA Shou ld Not Approve an ANDA for R osuvastatin Calciumor a 5 05(b)(2) Application for a Different Salt Form ofRosuvastatin that Om its the Protected Diabetes RelatedW arning and Adverse Reaction Information From Its Label

a)mitting Diabetes Related Warning and AdverseReaction Information From an AN DA's RosuvastatinCalcium Label Conflicts W ith FDA's Same La belingRequirementThe exclusivity code for the m arketing exclusivity period associated with theJUPITER prim ary prevention indication is 1-621, "primary preven tion of cardiovasculardisease, based on the results of Justification for the U se of S tatins in Primary Prevention:An Intervention Trial Evaluating Rosuvastatin (JUPITER)." Any proposed labelingcarve o ut that seeks to om it the JUPITER trial data associated w ith the diabetes relatedwarning and adverse re action inform ation would ne cessitate the e xcision of substantial,protected portions from the W arnings and Precautions, A dverse R eactions, and Clinical

Studies sections of Crestor's label. Such labeling om issions w ould involve extensivenot m inordeletions of important language in its entirety, and would result in an AN DAproduct label that does not mee t FDA's "same labeling" requiremen t. The JUPITERprimary prevention indication and associated clinical trial data are protected by unexpiredpatent and/or mark eting exclusivity periods. As a result, an AN DA applicant cannotinclude this protected information in its labeling until the associated marketingexclusivity period expires on February 8, 2 013, and if included requires the A ND Aapplicant to subm it patent certifications for each of the '152 and '614 patents.Following the Decem ber 15, 2009 advisory comm ittee mee ting and inconjunction w ith approving the JUPITER primary prev ention indication, FDA insisted

AstraZeneca include the warnings about increases in HbA l c and serum glucose levels inCrestor's labeling. It was during labeling negotiations that Crestor's label was updated to

35 In addition to the arguments set forth herein below , the decision of how to label a generic rosuvastatincalcium product highlights another concern. Beyon d potential confusion about therapeutic effects thatwould likely arise from labels that differ as described herein, emerging case law suggests that som e courtsmay even be inclined to ho ld an innovator liable for personal injury claims arising from the use of a gene ricproduct. This further complicates any decision regarding which label to impose for the ge neric product.


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include the JUPITER related diabetes warning and adverse reaction information.3 6 As aresult, in view o f the JUPITER trial results and at FD A's insistence, AstraZeneca updatedthe W arnings and Precautions section o f Crestor's label to include a warning in S ection5.5, Endocrine Effects, that "[i]ncreases in H bAlc and fasting serum glucose levels havebeen reported with HM G-CoA re ductase inhibitors, including CRE STOR [(see AdverseReactions (6.1)]."37 Additionally, in view of the JUPITER trial results and followinglabeling negotiations with FDA, A straZeneca updated the "Adverse R eactions" section ofthe label to include new adverse reaction inform ation in Section 6.1 that states

"[i]n JUPITER, there was a significantly higher frequency o f diabetesm ellitus reported in patients taking rosuvastatin (2.8% ) ve rsus patientstaking placebo (2.3%). M ean Hb Alc was significantly increased by 0.1 %in rosuvastatin-treated patients compared to placebo-treated patients. Thenum ber of patients with a Hb Alc > 6.5% at the end of the trial wassignificantly higher in rosuvastatin-treated versus placebo-treatedpatients[see W arnings and Precautions (5.5) and Clinical Studies(14.8)].38The diabetes related warning and adv erse reaction information added to sections 5and 6 each contain cross-references to other sections of the label where additionalinformation associated with this diabetes related labeling upd ate can b e found. Inparticular, section 5.5 points to section 6.1; section 6.1, in turn, points to section 5.5 andsection 14.8. Findings from JUPITER are specifically referenced in section 6.1 and adetailed description of the JUPITER trial is set forth in S ection 14.8.3 9 In fact, Section14.8 is the only section of Crestor's label that actually describes the study population andstudy parameters of the JUPITER trial. For example, neither Section 5.5, nor Section 6.1describe any of the characteristics of the patients studied in the JUPITER trial, includingthe fact that all JUPITER p articipants had h sCRP levels > 2 m g/L. Clearly, sections 5.5,

6.1 and 14.8 of the CRE STOR label are inextricably intertwined and e ach section shouldbe read in conjunction w ith the others to give a full appreciation of the diabetes warningand adverse reaction information included in the FDA app roved label. In order to avoidthe patent and marke ting exclusivity periods associated with the JUP ITER indicationand/or the JUPITER trial data, an AN DA filer will have to carve all three of theseintertwined sections ou t of its label.As am ply illustrated above , the diabetes related w arning and adverse re actioninformation set forth in Sections 5.5, 6.1, and 14.8 are inextricably interwoven with eachother m aking each of these sections an integral part of the labeling. As a result, allowingan AN DA filer to omit any of these sections from its AN DA p roduct labeling would

conflict with FDA's sam e labeling requirement.

3 6 As discussed in note 17, supra, FDA highlighted its proposed label changes in draft labels, excerpts ofwhich are attached hereto as Exhibit I and Exhibit J.3 7 Crestor Prescribing Information (Exhibit G) 5.5.3 8 Id . at 6.1.3 9 Id . at 14.8.


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Page 10(1) The Wholesale Deletion of Sections 5.5, 6.1 and14.8 is Not a "M inor Attendant Change" to the

LabelOm itting the JUPITER related diabetes warning and ad verse reaction information

from an ANDA drug product label would involve extensivenot minordeletions ofimportant language in its entirety, and would result in an AN DA drug product label thatdoes not me et FDA's "same labeling" requirem ent.The situation at ha nd is vastly different from that described in FDA 's responses tothe LYR ICA and XY ZAL citizen petitions. In both of those responses, FDA prov idedexam ples of how generic com panies could make "selective deletions and de minimismo difications" to labeling without disclosing the patent-protected indication. FDA citedseveral exam ples of m odifications to the labeling that would eliminate any reference s tothe patent-protected indication w hile remaining, in the ag ency's view, consistent with the"same labeling" requirem ents. In the LYR ICA pe tition, FDA illustrated its point by

providing the following exam ple of how LY RICA 's labeling could be modified so thatgeneric pregabalin labeling could "adequately ensure the ne cessary safety information isconvey ed without disclosing the patent-protected indication:40(LYR ICA label): "Antiepileptic drugs (AE Ds), including LY RICA, increase therisk of suicidal thoughts or be havior in patients taking these drug s for anyindication. Mon itor patients treated with any A ED for any indication for theem ergence o r worsening of depression, suicidal thoughts or behavior, and/or anyunusual changes in m ood o r behavior."(Proposed generic label): "Pregabalin increases the risk of suicidal thoughts orbehavior in patients taking the drug for any indication. Monitor patients treatedwith pregabalin for any indication for the em ergence o r worsening of depression,suicidal thoughts or behavior, and/or any unusual changes in moo d or behav ior."Unlike LYRICA and XYZAL, however, the warning and adverse reactioninformation interwoven througho ut sections 5.5, 6.1 and 14.8 of C restor's label cannot bepreserved through the "om ission of wo rds or phrases . . . and m inor attendant changes."Instead, these sections would have to be de leted in their entirety because the very purposeof these sectionsin particular Sections 6.1 and 14 .8is to describe the JUPITER trialand related data from w hich the diabetes related warning and adverse re actioninformation emanates. 4 1 Unlike the above changes to the LYRICA label, which FDAconsidered to be m inor labeling tweaks, rem oving all references to the JUPITER

protected information wou ld necessitate either remo val of all three of these sections intheir entirety or a com plete and com prehensive re-writing of these sections which, by anyestimation, far exceeds the de minimis mo difications FDA deem ed acceptable inLYRICA and XYZAL.4 0 I d .4 1 It would not be possible to keep the warning and adverse reaction information in sections 5.5 and 6.1 andexclude the information about JUPITE R in section 14.8. Such labeling would be incom plete becausesection 14.8 provides the origin of the data and necessary context regarding why FDA insisted on includingthe new w arning and adverse reaction information.


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Furthermo re, if in conjunction with approving the JUPITER primary prev entionindication FDA considered the JUP ITER trial data associated w ith the diabetes relatedwarning and adverse re action information important enoug h to insist that it be included inthese interwoven sections of Crestor's label for all Crestor patient populations, FDAcannot now rationally find that this information m ay be om itted from the labeling of anAN DA drug produ ct. Such a finding would involve the arbitrary application of differentstandards to the labeling of innovator an d generic drug pro ducts.

b) The Diabetes Related Warning and Ad verse ReactionInformation Contained in C restor's Labeling IsApplicable to All ANDA and 5 05(b)(2) PatientPopulations and IndicationsImportantly, in FD A's view, the new information described in Section 5.5 and 6.1regarding increases in HbAl c and fasting serum glucose levels as well as higherfrequency of diabetes mellitus are not limited to, nor specifically directed at, anyparticular patient population. In fact, when FD A's Endocrinologic and M etabolic DrugsAdvisory Committee met to discuss AstraZeneca's supplemental NDA for the JUPITERprimary prevention indication, several comm ittee m em bers urged FDA to requireCrestor's label to include a wa rning about diabetes so that ph ysicians knew to carefullymo nitor HbAl c and serum glucose levels.4 2 These m emb ers did not suggest such awarning should be limited to the JUPITE R patient population. In fact, FDA 's summ aryof the m eeting minutes indicates the com mittee "felt that the imbalance in the repo rts ofdiabetes mellitus (DM ) in the present [JUPITER] study probab ly represents an authenticsignal of an increase in the frequency of DM and may be a class-effect of statin drugs."43The com mittee further noted that the "benefit of rosuvastatin on L DL lipid values wasobserved in diabetic and non -diabetic subjects."4 4 More over, additional evidence thatFDA considers the diabetes related w arning and adverse re action inform ation to app ly toall rosuvastatin approved indications can be found in the sem i-annual Periodic SafetyUpdate Re ports that FDA, based on the JUP ITER trial results, now requires AstraZenecato provide and which m ust include analyses of post-m arket reports of diabetes m ellitusand diabetes-related adverse e vents for all patients no t just those taking rosuvastatinfor the JUPITER p rimary prev ention indication.45

c) It Would Be A rbitrary and Capricious for FDA toApprove a R osuvastatin ANDA or 505 (b)(2)

4 2 Transcript of FDA, Endocrinologic and Metabolic Drugs Advisory Com mittee Meeting (Dec. 15, 2009)(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Endocrinologic andMetabolicDrugsAdvisoryCommittee/UCM200611.pdf (last visited Nov. 9, 2011)).43 FDA, Endocrinologic and Metabolic Drugs Advisory Committee, Summary Minutes of the December15, 2009 Endocrinologic and Metabolic Drugs Advisory Com mittee Meeting, 3 (Dec. 28, 2009)(http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM241503.pdf (last visited Nov. 9, 2011)).44 Id.4 5 NDA 21366/S-016 Approval Letter, February 8, 2010, available athttp ://www.accessdata. fda.gov/drugsatfda_docs/appletter/2010/021366s0161tr.pdf.


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Application W ith Labeling that Omits the DiabetesRelated Warn ing and Adverse Reaction InformationIf FDA pe rmits either an AND A applicant for a generic rosuvastatin calcium drugproduct or a 505(b)(2) applicant for a different salt form of rosuvastatin to om it the

diabetes related warning and adverse reaction information from its labelingafterrequiring its inclusion in Crestor's labelingthe agency will be applying differentstandards across these rosuvastatin drug products, thereby running afoul of theAdm inistrative Procedure Act 's prohibition on arbitrary and capricious agen cy action.46It is not rational for FDA to approve an AN DA for a generic version of Crestor withoutthe diabetes related warnings and adverse reaction inform ation it insisted A straZenecainclude in Crestor's labeling in conjunction with approving the JU PITER primaryprevention indication. To do so, w ould allow applicants to adopt a pre -JUPITER v ersionof Cre stor's label, thereby ignoring the diabetes related warning an d adve rse reactioninformation that FDA re quired AstraZeneca to include in its labeling and which FD Aitself and the advisory com mittee m em bers consider to be applicable across all patientpopulations and to all indications. Indeed, allowing either an A ND A or a 505(b)(2)applicant to om it the diabetes related warning and ad verse reaction information from itslabeling would constitute disparate treatment of functionally indistinguishable productsand strike at the heart of arb itrary and capricious agency action.47

2.onclusionFor the foreg oing reasons, FDA should not finally approve (i) any rosuv astatincalcium AN DA for which Crestor is the RLD if the proposed labeling for any suchAN DA d rug om its the diabetes related warning and adverse reaction inform ation thatFDA required AstraZeneca to include in Crestor's labeling whe n it approved theJUPITER primary prev ention indication that is based on the results of the JUPITER trial,or (i i) any 505(b )(2) application for a different salt form of rosuvastatin if the pro posedlabeling for such 50 5(b)(2) drug o mits the diabetes related warning and adverse reactioninformation that FDA required AstraZeneca to include in Crestor's labeling whe n itapproved the JUPITER primary prev ention indication that is based on the results of theJUPITER trial.III. Environmental Impact

This petition is categorically exem pt from the requiremen t for an environm entalassessment or an e nvironme ntal im pact statem ent pursuant to 21 C.F.R. 25.30 and25.31.IV . Economic Impact

Information on the econo mic impact of the petition will be provided upon request.

4 6 Se e B racco D iagnostics, Inc. v. Sh alala, 963 F.Supp. 20, 28 (D.D.C. 1997) ("Under the [APA ], the FDA... must provide a rational basis for [not] . . . treating similar products in the same way.")4 7 Id. at 28.


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Jatvfies W. B lasetto, MD, M PHVP U.S. Strategic Developm ent

Page 13

V.ertificationPursuant to 21 C.F.R. 10.30(b), the undersigned certifies that, to the bestknowledge an d belief of the undersigned, this petition includes all information and viewson which the petition relies, and that it includes representative data and informationknown to the petitioner which are unfav orable to the petition. Pursuant to 21 U .S.C. 355(q)(1)(H), I certify that, to my best knowledge and belief: (a) this petition includesall information and views upon which the petition relies; (b) this petition includesrepresentative data and/or inform ation known to the p etitioner which are unfavorable tothe petition; and (c) I have taken reasonab le steps to ensure that any representative dataand/or informa tion which are unfavora ble to the petition were disclosed to me . I furthercertify that the inform ation upon w hich I have based the a ction requested herein firstbecam e known to the party on w hose behalf this petition is submitted on o r about thefollowing dates: May 12 , 2010 (when F DA granted tentative approval to the Aurobindo,Mylan, and Teva A ND As, each of which included a statement under 50 5(j)(2)(A)(viii),carving out the JUPITER primary preven tion indication that was added to Crestor's labelon February 8, 2010) and A ugust 4, 2011 (when FDA granted tentative approval toW atson's NDA for rosuvastatin zinc 5, 10, 20, and 40 m g tablets, subm itted pursuant tosection 505(b)(2) of the FD CA ). If I received or expect to receive pay me nts, includingcash and other forms of consideration, to file this information or its contents, I receivedor expect to receive those paym ents from the following persons or organ izations: Regularsalary received from A straZeneca L P. I verify under pena lty of perjury that the foregoingis true and correct as of the date of the submission of this petition.

Respectfully submitted,

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crestor citizen's petition

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