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DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration Rockville MD 20857

MAR 3 1 2011

David Zuchero, M.S., J.D. Chesapeake Regulatory Group, Inc. 6574 River Clyde Dr. Highland, IvLD 20777

Charles J. Raubicheck Frommer Lawrence & Haug LLP 745 Fifth Avenue New York, NY 10151

Peter 0. Safir Covington & Burling LLP 1201 Pennsylvania Ave., NW Washington, DC 20004

Re: Docket No. FDA-2004-P-0494

Dear Petitioners:

This letter responds to the following documents submitted on behalf of Watson Pharma, Inc. (Watson), a subsidiary of Watson Pharmaceuticals, Inc.:

• Chesapeake Regulatory Group's citizen petition' dated February 13, 2004 (CRG Petition),

• Frommer Lawrence & Haug's (Fromrner) citizen petition 2 dated August 17, 2004

(Frommer Petition), • Frommer's comment dated December 31, 2004 (Frommer Comment), and • Frommer's supplement dated October 4, 2006 (Frommer Supplement).

This letter also responds to Covington & Burling's comment dated August 7, 2009 (sanofi-aventis Comment) submitted on behalf of sanofi-aventis U.S. These submissions concern approval of abbreviated new drug applications (ANDAs) for a generic 3 sodium ferric gluconate complex in sucrose using Ferrlecit as the reference listed drug (RLD). Sanofi-aventis U.S. is

Th is citizen petition was originally assigned docket number 2004P-0070/CP1. The number was changed to FDA-2004-P-0494 as a result of FDA's transition to its new docketing system (Regulations.gov ) in January 2008.

This citizen petition was originally assigned docket number 2004P-0070/CP2. The number was changed to FDA-2004-P-0494 as a result of FDA's transition to its new docketing system (Regulations.gov ) in January 2008.

3 The term generic refers to a drug product for which approval is sought in an ANDA submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act).

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Docket No. 2004-P-0494

currently the new drug application (NDA) holder for Ferrlecit. Previously, Watson was the NDA holder for Ferrlecit.4

In the CRG Petition (February 2004), Watson requests that the Food and Drug Administration (FDA or the Agency) withhold approval of any ANDA for a generic version of Ferrlecit unless:

1. The process used to manufacture the generic product has been adequately demonstrated to be the same as Watson's manufacturing process 5 for Ferrlecit;

2. The physicochemical characteristics of the generic product are the same as those of Ferrlecit; and

3. The active ingredient or, in this case, the final generic product can be adequately demonstrated to be the same as that of the reference listed drug.

Watson states that if all of the above requirements cannot be met, then FDA should require that an applicant submit an NDA supported by a demonstration of equivalent safety and effectiveness based on results of appropriate preclinical and clinical studies. Watson also states that Ferrlecit is a colloidal solution (i.e., a heterogeneous mixture of ferric gluconate particles in an aqueous sucrose solution) and, as a result, presents a barrier to the granting of a waiver of in vivo bioequivalence study requirements.

In the Frommer Petition (August 2004), Watson requests that FDA refuse to receive for substantive review under 21 CFR 314.101(b) an ANDA for a generic version of Ferrlecit until FDA first establishes guidelines for determining whether a generic sodium ferric gluconate product has the same active complex6 as Ferrlecit.7

On November 22, 2004, Teva Pharmaceuticals USA (Teva) submitted a comment to the docket8 stating that (1) the petitioners raise doubt as to the possibility of the development of an

4 In its Comment, sanofi-aventis states that it owns Ferrlecit and, pursuant to a contract, licensed to Watson the right to distribute the product in the United States. Sanofi-aventis also states that, as of January 1, 2010, sanofi-aventis would become the sole owner of the Ferrlecit NDA and the sole distributor of the product in the United States (sanofi-aventis Comment at 1; see also press release dated May 18, 2009, from Watson at http://ir.watson.com/phoenix.zhtml?c-657788rol-newsArticle&I12892518chighlight=).

5 In its Comment, sanofi-aventis states that it has, at all times, been the sole manufacturer of Ferrlecit and refers to this manufacturing process as the "Sanofi-Aventis Process" (sanofi-aventis Comment at 1). In this response, we refer to this process as the Sanofi-Aventis/Watson manufacturing process.

6 The Agency interprets Watson's reference to "active complex" as a reference to Ferrlecit's "active ingredient."

7 The Frommer Petition opposes a suitability petition submitted by AAC Consulting Group dated August 6, 2004, requesting FDA to determine whether a 10-milliliter (mL)/125-milligram (mg) sodium ferric gluconate product citing Ferrlecit 5 m1/62.5 mg as a RLD is suitable for an ANDA (Docket No. 2004P-0360). Frommer's assertion that the requested change is a change in concentration is misplaced. It is not a change in concentration but rather a change in total drug content due to use of a larger vial size (Le., 10 mL vs 5 mL). FDA approved the suitability petition by letter dated March 15, 2006.

Docket No. FDA-2004-P-0494.


equivalent generic version of Ferrlecit without offering support for these claims and (2) FDA must review generic applications to make such a determination. In the Frommer Comment (December 2004), Watson responds to Teva's comment, restating the arguments from the original CRG Petition.

In the Frommer Supplement (October 2006), Watson reiterates the requests from the original CRG Petition.

In its Comment (August 2009), sanofi-aventis states that it is the successor in interest to the Ferrlecit NDA and owner of the Sanofi-Aventis/Watson manufacturing process and fully endorses the position taken in the CRG Petition and the Frommer Petition. Sanofi-aventis further requests that FDA gant the CRG Petition and the Frommer Petition regardless of any actions taken by Watson with regard to these documents in the future.

As explained below, the petitions and the supplement are granted in part with respect to the request that the physicochemical characteristics of the generic product be the same as those of Ferrlecit and that the active ingredient be adequately demonstrated to be the same as that of the RLD,9 but are denied in all other respects.

I. BACKGROUND

A. Ferrlecit

Ferrlecit (sodium ferric gluconate complex in sucrose) Injection, an iron supplement for intravenous administration, was approved for use in 1999. 113 Ferrlecit is indicated for treatment of iron deficiency anemia in adult patients and pediatric patients age 6 years and older undergoing chronic hemodialysis and receiving supplemental epoetin therapy. While other iron parenteral formulations are available, 11 the sodium ferric gluconate product ameliorates anemia yet has a low incidence of anaphylactoid reactions and other adverse effects. 12 Ferrlecit is currently the only sodium ferric gluconate product approved in the United States.

9 See section 11.0 of this response regarding FDA's concurrence with Watson's claim that Ferrlecit presents a barrier to the granting of a waiver of in vivo bioequivalence study requirements

w Product labeling for Ferrlecit, NDA 20-955; Revised September 2006.

" For example, the following parenteral iron products are approved in the United States: iron sucrose (Venofer), non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether (Feraheme), and iron dextan complexes (DexFerrum and INFed).

12 Nissenson, A.R. and Charytan, C. Controversies in iron management Kidney Int Suppl, S64-71, 2003.


Ferrlecit, like all approved parenteral iron products, is a colloid° comprised of a continuous aqueous medium and particles of carbohydrate-protected iron oxyhydroxide. 14 The active ingredient of Ferrlecit is sodium ferric gluconate complex in sucrose. 15 Each ampule of Ferrlecit contains elemental iron as the sodium salt of a ferric ion carbohydrate complex in an alkaline aqueous solution with approximately 20 percent sucrose weight/volume (w/v) in water for injection, pH 7.7 – 9.7. 1 ' The carbohydrates, gluconate and sucrose, which are bound to the iron oxyhydroxide core, serve to stabilize and protect the mineral-like iron oxyhydroxide core from hydrolysis, precipitation, and polymerization until the particle can be absorbed into the body. Benzyl alcohol is added as an inactive ingredient.17

Direct injection of unprotected inorganic iron (ferric (Fe3+)) is possible but can be extremely toxic. Studies show that the amount of iron administered in this fashion is limited to about 8 mg, the binding capacity of transferrin in the plasma. 18 In contrast, upon injection of Ferrlecit, the carbohydrate-protected iron colloid particles enter the plasma and are processed by phagocytes — immune system cells that ingest and destroy foreign particles, bacteria, and cell debris. Macrophages (a type of phagocyte present in the liver, spleen, and bone marrow) engulf and ingest colloidal iron particles in a process known as phagocytosis. Once internalized, iron particles are delivered to the lysosome, an organelle responsible for degradation of biomolecules within the cell. Iron ions from the colloid particles then become part of the intracellular labile iron pool and are available for use in biological processes. If iron is needed elsewhere in the body, the protein transferrin will bind iron ions and deliver them to their destination. If iron is not needed immediately, the cell stores it in the form of ferritin or hemosiderin.19

An important part of understanding the overall chemistry of Ferrlecit is understanding the fundamental chemistry used to form the sodium ferric gluconate complex in sucrose. Growth of an iron oxyhydroxide core begins with the hydrolysis of ferric chloride (FeC1 3)" in the presence

13 A colloid is a chemical system composed of a continuous medium (continuous phase) throughout which are distributed small particles, 1 to 1000 nanometers in size (disperse phase), that do not settle out under the influence of gravity; the particles may be in emulsion or in suspension.

14 Burgess, D. Encyclopedia of Phannaceutical Technology: Colloids and Colloid Drug Delivery Systems. Marcel

Dekker, 2000.

15 Sucrose may also exist in the unbound form in the sodium ferric gluconate product because the bond with sucrose is weak

16 Product labeling for Ferrlecit, NDA 20-955; Revised September 2006.

17 Id.

19 Danielson, B.G. and Beshara, S. Phartnacokinetics and utilization of iron sucrose. Am J Kidney Dis 42, 1104;

author reply 1104-1105, 2003.

19 Bertini, I., Gray, H.B., Steifel, E., and Valentine, J. S. Biological Inorganic Chemistry. University Science

Books, 2007.

20 This may be FeC13 or another Fe(III) species.

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of a base such as sodium carbonate (Na2003).21 The base enables the formation of iron oxyhydroxide complexes, and the core of Ferrlecit begins to form once the solution becomes saturated.22 Polymerization of the iron core is controlled through the addition of gluconate and sucrose. 23 The carboxyl group of gluconate binds to Fe3+ with high affinity, and sucrose binds through weak interactions of the hydroxyl groups. 24 As a result, sodium ferric gluconate complex in sucrose, the active ingredient in Ferrlecit, is formed. The gluconate and sucrose calbohydrate shell keeps iron oxyhydroxide core particles soluble and prevents further polymerization of the iron core, thereby rendering a stable complex.

The molecular weight of Ferrlecit on gel chromatography ranges from 289,000 — 440,000 daltons.25 The distribution of molecular weights for Ferrlecit results from the sodium ferric gluconate complex in sucrose active ingredient not being a unique molecular entity, but rather molecules of various molecular weights in a continuous aqueous medium. The average molecular weight for the sodium ferric gluconate complex in sucrose is derived from the distribution of molecular weights. The sodium ferric gluconate complex in sucrose active ingredient is of various molecular weights because the iron core polymerizations are not all stopped at the exact same stage of development.26

B. Statutory and Regulatory Standards

1. Surnmaty of Legal Framework for ANDA Approval

The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Amendments) created section 505(j) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 355(j)), which established the ANDA approval process. To obtain approval, an ANDA applicant is not required to submit clinical studies to establish the safety and effectiveness of the drug product. Instead, an ANDA applicant relies on the Agency's previous finding that the RLD is safe and effective. To rely on FDA's previous finding of safety and effectiveness, an ANDA applicant must demonstrate, among other things, that the generic drug product is bioequivalent to

21 Lawrence, R. Development and comparison of iron dextran products. PDA J Pharm Sci Technol 52, 190-197,

1998.

22 Id.

23 - Yang, Y., et al. Thermodynamic stability assessment of a colloidal iron drug product: Sodium ferric gluconate. J

Pharm Sci 99, 142-153, 2010; Kudasheva, D.S., Lai, J., Ulman, A., and Cowman, M.K. Structure of carbohydrate-bound polynuclear iron oxyhyroxide nanoparticles in parenteral formulations. J Inorg Biochem 98, 1757-1769,

2004.

24 Nissenson, A.R., Lindsay, R.M., Swan S., Seligman P., and Strobos, J. Sodium Ferric Gluconate Complex in Sucrose Is Safe and Effixtive in Hemodialysis Patients: North American Clinical Trial, American Journal of Kidney

Disease 33, 471-482, 1999.

2$ Product labeling for Ferrlecit, NDA 20-955; Revised September 2006.

26 Nissenson, A.R. and Charytan, C. Controversies in iron management. Kidney Int Suppl, S64-71, 2003.


the RLD (section 505(j)(2)(A)(iv) of the Act). 27 In addition, an ANDA must contain sufficient information to show that the generic drug product has the same active ingedient(s), previously approved conditions of use, route of administration, dosage form, strength, and (with certain exceptions) labeling as the RLD (section 505(j)(2)(A) and (j)(4) of the Act). The Agency must approve the ANDA unless, among other things, the ANDA applicant has provided insufficient evidence of the foregoing, or if the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the drug are inadequate to assure and preserve its identity, strength, quality, and purity (section 505(j)(4) of the Act).

The premise underlying the Hatch-Waxman Amendments is that drug products that are (1) approved as safe and effective, (2) pharmaceutically equivalent, 28 (3) bioequivalent, (4) adequately labeled, and (5) manufactured in compliance with Current Good Manufacturing Practice regulations are therapeutically equivalent and can be substituted for each other with the "fiill expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed [RLD] product."29

2. Summary of Statutoty and Regulatory Provisions on Active Ingredient Sameness

Section 505(j)(2)(A)(ii)(I) of the Act states that, for a single active ingredient drug product, an ANDA must contain information to show that the active ingredient 3° of the generic drug product is the "same" as that of the listed drug. Under section 505(j)(4)(C)(i) of the Act, we must approve an ANDA referencing a listed drug that has only one active ingredient unless the ANDA

27 Under the Act, "[a] drug shall be considered to be bioequivalent to a listed drug if. . . . the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses." See section 505(j)(8)(B)(i); see also implementing regulations at 21 CFR part 320.

28 See 21 CFR 320.1(c) (pharmaceutical equivalents nuves, in part, drug products in identical dosage forms that contain identical amounts of the identical active ingredient and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency).

29 FDA classifies as therapeutically equivalent, and thus substitutable, those products that are (1) approved as safe and effective, (2) pharmaceutically equivalent (which means, in part, drug products in identical dosage forms that contain identical amounts of the identical active ingredient; and meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency (21 CFR 320.1(c)), (3) bioequivalent, (4) adequately labeled, and (5) manufactured in compliance with Current Good Manufacturing Practice regulations. See Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book), 301 Ed., at iv. The

terms therapeutically equivalent and substitutable are used interchangeably in this response.

3° FDA regulations (at 21 CFR 210.3(b)(7)) provide that"[a] cave ingredient means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect." FDA regulations (at 21 CFR 314.3(b)) also provide that "drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates use[d] in the synthesis of such ingredient"

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contains insufficient information to show that the active ingredient is the same as that of the listed drug. These statutory provisions do not describe the type or amount of information that an ANDA applicant must submit to demonstrate that the active ingredient in the generic drug product is the same as the active ingredient in the RLD, nor do these provisions describe the type or amount of information on which we may rely in determining whether the ANDA applicant has provided sufficient information to show that the active ingredient is the same. Accordingly, Congress recognized that we must have broad discretion with respect to the information we may consider in making a finding on the "sameness" of an active ingredient.31

Parallel FDA regulations implementing these statutory provisions (i.e., section 505(j)(2)(A)(ii) and (j)(4)(C)) can be found at 21 CFR 314.94(a)(5)(i) and 314.127(a)(3). FDA regulations also provide that an ANDA is suitable for consideration and approval if the generic drug product is the same as the RLD (21 CFR 314.92(a)(1)). Specifically, § 314.92(a)(1) states that the term "same as" means, among other things, "identical in active ingredient(s)." In the preamble to the final rule implementing title I of the Hatch-Waxman Amendments, we specifically rejected the suggestion that we adopt a requirement that active ingredients "exhibit the same physical and chemical characteristics, that no additional residues or impurities can result from the different manufacture or synthesis process; and that the stereochemistry characteristics and solid state forms of the drug have not been altered."32 Instead, we adopted a more flexible approach, stating that we would "consider an active ingredient [in a generic drug product] to be the same as that of

the reference listed drug if it meets the same standards for identity." 33 We further stated that, in most cases, the standards for identity are described in the U.S. Pharmacopeia (USP), although we might prescribe "additional standards that are material to the ingedient's sameness." 34 Since the standards for identity for the sodium ferric gluconate product are not in the USP, the standards are based on our evaluation of current data and other current relevant scientific information, including the characteristics of the RLD and our scientific experience and expertise. As FDA's regulations and preamble reflect, we have broad discretion in determining whether an ANDA applicant has submitted sufficient information upon which we can reasonably conclude that the generic drug product's active ingredient is the same within the meaning of Act as that of

the RLD.

3. Case Law

The U.S. Court of Appeals for the District of Columbia's decision in Serono Laboratories, Inc. v.

Shalala, 158 F.3d 1313 (D.C. Cir. 1998), supports the Agency's broad discretion in determining active ingredient "sameness." In Serono, the Court of Appeals squarely addressed the issue of active ingredient sameness within the meaning of the Act and FDA regulations.

31 See generally Serono Laboratories, Inc. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998); see also discussion in section II of this response.

32 See 57 FR 17950 at 17958-59 (April 28, 1992).

33 57 FR 17950 at 17959.

34 57 FR 17950 at 17959.

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Serono involved a legal challenge to our approval of a generic version of Pergonal, a menotropins product used to treat infertility. One of the active ingredients in the product included natural variations known as microheterogeneity. We maintained that an isoform variation in the active ingredient of the generic drug product did not preclude a finding of active ingredient "sameness" for purposes of ANDA approval. We noted in documents cited by the court that "complete chemical identification of all the carbohydrate variants in a protein product often is not possible or feasible."35

The D.C. Circuit upheld as reasonable the Agency's interpretation of the "sameness" statutory requirement, as well as the Agency's interpretation of the word "identical" in 21 CFR 3 14.92(a)(1).36 The court concluded that the statute does not unambiguously require the term "same as" to be defined as "complete chemical identity," noting that the statute says nothing at all about the type of information an applicant must submit to demonstrate "sameness" nor about the type of information upon which the FDA may rely. 37 The court characterized the sameness provision as a "broad grant of discretion" to the Agency with respect to the information it may consider and noted that the phrase "must be read in the context of the kind of drug at issue."3'

Subsequent to Serono, FDA applied this broaA gant of discretion to determine active ingredient sameness for enoxaparin, and we approved Lovenox's product 39 on the basis of this scientific discretion. Likewise, our decision here applies this broad grant of discretion to determine active ingredient sameness for sodium ferric gluconate complex in sucrose.

IL DISCUSSION

We agree that any ANDA for a sodium ferric gluconate product that references Ferrlecit as the RLD must demonstrate that it has the same active ingredient as Ferrlecit. As discussed above, FDA is statutorily required to make such a determination before it may approve an ANDA referencing Ferrlecit.

However, we disagree with the criteria you request that an ANDA applicant needs to meet to establish whether or not a generic product has the same active ingredient as Ferrlecit. First, we discuss your point regarding whether the manufacturing process used must be the same as that used to manufacture Ferrlecit. Next, we discuss our recommendations for establishing active ingredient sameness for generic sodium ferric gluconate products. Then, we discuss our recommendations for determining bioequivalence. We also discuss whether clinical investigations demonstrating safety and effectiveness are needed if the manufacturing process for a generic sodium ferric gluconate product is not the same as for Ferrlecit and if the active

35 158 F.3d at 1318.

36 Id. at 1321.

" Id. at 1319.

38 Id.

39 See Letter front Dr. Douglas Throckmorton, Deputy Director, Center for Drug Evaluation and Research, FDA, to Mr. Safir and Mr. Cunningham, Covington & Burling, re: Docket No. FDA-2003-P-0273 (July 23, 2010).

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ingedient in such a generic product is not fully characterized. Finally, we discuss your request that FDA refuse to receive an ANDA for review until it establishes guidelines for determining "sameness" for the active ingredient in Ferrlecit.

A. Manufacturing Process

Watson requests that no generic equivalent of Ferrlecit be approved unless the process used to manufacture the generic product has been adequately demonstrated to be the "same as" the Sanofi-Aventis/Watson manufacturing process (CRG Petition at 1,4 to 5, and 9). Watson explains that the manufacturing process is extremely complicated to reproduce and creates a distinct chemical structure unique to Ferrlecit (CRG Petition at 4; Frommer Supplement at 2; Frommer Comment at 1). Watson claims that the manufacturing process is a multistep process involving numerous individual ingredients that must be combined in a specific order, at specific rates, and under specific conditions for the reaction to proceed correctly (CRG Petition at 4). Watson further specifies that variations in reaction temperatures, pH, filtration, and stirring and flow rates could result in critical changes to the final product (CRG Petition at 4).

Watson provides anecdotal evidence that other processes have failed (CRG Petition at 5). Watson states that in the mid-1990s, a change in the source of one of the raw materials used in the manufacture of Ferrlecit caused a marked increase in adverse event reports in Italy and Germany, which resulted in a dramatic change in the safety profile of the final product. Watson also claims that a preservative-free version of Ferrlecit was manufactured for use in a clinical study and that when this version of the drug was used, an unusually high number of adverse events occurred. Watson alleges that although the events cannot be definitely attributed to the change in Ferrlecit formulation, it is reasonable to suspect that it was a contributing factor.

While we agree that any ANDA using Ferrlecit as the RLD must contain the same active ingredient, we disagree with the claim in your citizen petition that the manufacturing process must also be the same. Based upon the fundamental chemistry of iron colloids containing carbohydrate ligands, it is anticipated that an ANDA applicant wishing to manufacture the sodium ferric gluconate complex in sucrose active ingredient will employ the same underlying chemistry in its manufacturing process as is used for Ferrlecit. 4° Thus, it is generally expected that ANDA manufacturers will generate the polynuclear iron oxyhydroxide core of the generic sodium ferric gluconate product via hydrolysis of FeC1341 in the presence of a base such as

Na2CO3 .42 The iron oxyhydroxide core will be stabilized by the addition of gluconate and sucrose to produce the generic sodium ferric gluconate product.43

Yang et al. and Kudasheva et al.

41 This may be FeC13 or another Fe(111) species.

42 Yang et al. and Kudasheva et al.

43 Yang et al.


It is widely recognized in the scientific literature that, given the nature of the molecule in Ferrlecit, the fundamental chemistry will drive the manufacturing process. 44 So, while the manufacturing process of the generic sodium ferric gluconate product will be based upon the same fundamental chemistry as the RLD, the actual method used to manufacture the product45 does not have to be identical. Indeed, a recent study suggests that variations in the manufacturing process used to produce sodium ferric gluconate complex in sucrose have not resulted in an active ingredient with a different molecular weight. 46 In this study, three different procedures (varying the order of the carbohydrate components introduced under general manufacturing conditions) were used to synthesize the sodium ferric gluconate complex in sucrose and the average molecular weights of the final products were comparable to one another and to Ferrlecit.

With regard to the anecdotal evidence provided by Watson that other processes failed, Watson did not provide evidence to substantiate the claim that the Sanofi-Aventis/Watson manufacturing process is the only process capable of producing an active ingredient that can be demonstrated to be the same as that in Ferrlecit. Specifically, supportive data regarding the changes cited by Watson (i.e., change in source of one of the raw materials, use of preservative-free version of Ferrlecit) were not provided, nor were data provided regarding how the changes affected the safety and efficacy characteristics of Ferrlecit. FDA would not approve a generic version of Ferrlecit without assurance that all components used for the product's manufacture meet the standards of identity, strength, quality, and purity so as to assure the safety and efficacy of the generic product.'" ANDA applicants must submit, with one exception not relevant here, the same type of chemistry, manufacturing, and control (CMC) information as required in an NDA.48 The required CMC information includes, among other things, "...a description of the manufacturing and packaging procedures and in-process controls for the drug product" and "the specifications necessary to ensure the identity, strength, quality, [and] purity...of the drug product. . . ."49

Furthermore, an ANDA may be submitted for a generic sodium ferric gluconate product that is free of preservative or contains a preservative other than benzyl alcohol, which is the preservative used for Ferrlecit. However, in such a case, the ANDA must contain appropriate

44 Ellison, H.L. and Hazel, F. Influence of concentration and age on some colloidal properties of ferric chloride solutions. Chemical Reviews 18, 829-835, 1934; Whitehead, T.H. The complex compound theory of colloidal oxides. Chemical Reviews 21, 113-128, 1937; Schneider, W. and Schwyn, B. The hydrolysis of iron in synthetic, biological and aquatic media. In: W. Stumm, Editor, Aquatic Sutface Chemistry, Wiley, New York, pp. 167-194,

1987.

45 Yang et al. and Kudasheva et al.

46 Yang et al.

47 21 CFR 314.127(a)(1); section 505(j)(4)(A) of the Act.

48 21 CFR 314.94(a)(9)(i).

49 21 CFR 314.50(d)(1)(ii)(a), 314.94(a)(9).

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data showing that the differences in formulation will not adversely affect the safety and effectiveness of the proposed drug product."

B. Physicochemical Properties

In the CRG Petition, Watson states that the physicochemical differences resulting from different methods of production could have a negative impact on the safety and effectiveness of a generic product (CRO Petition at 5). Watson requests that FDA not approve any generic version of Ferrlecit unless the "physicochemical characteristics of the generic product are the same as those of Ferrlecit" (CRG Petition at 1 and 9; Frommer Supplement at 2).

We agree that the physicochemical properties of tbe generic product must be equivalent to those of Ferrlecit. Data showing equivalence of physicochemical properties between the generic product and Ferrlecit provide important evidence that the active ingredient in the final generic product is the same as that of the RLD. FDA will only approve a generic sodium ferric gluconate product that references Ferrlecit as the RLD if the physicochemical properties are determined to be equivalent to those of Ferrlecit.51

Sodium ferric gluconate complex in sucrose can be characterized and compared to the RLD, Ferrlecit, by using several characterization techniques. For example, techniques that assess the structure of Ferrlecit through various complementary approaches, such as Mössbauer spectroscopy, X-ray diffraction, polarography (voltammetry), UV/vis spectroscopy, electron spin resonance, and elemental analysis, among other techniques, can be used to provide evidence of equivalence of the iron core. In addition, equivalence of the particles that make up the overall complex for sodium ferric gluconate complex in sucrose can be demonstrated using characterization tools such as size-exclusion chromatography, analytical ultracentrifugation, and dynamic light scattering, among other means. Taken together, these characterization techniques may be used to demonstrate equivalence in terms of physicochemical characteristics of the active ingredient in the generic sodium ferric gluconate product to that contained in Ferrlecit. Equivalence of physicochemical properties demonstrates sameness of sodium ferric gluconate complex in sucrose.52

Watson raises some specific issues in the CRG Petition pertaining to physicochemical characterization of generic versions of Ferrlecit that we address below.

1. Characterization of Sodium Ferric Gluconate Complex in Sucrose

Watson emphasizes the uniqueness and complexity of the Ferrlecit macromolecule and claims that its structure has yet to be determined and can only be partially inferred from

" 21 CFR 314.94(a)(9)(iii).

51 Indeed, the fundamental chemistry used to manufacture the generic sodium ferric gluconate complex in sucrose is anticipated to be the same as that used to manufacture Ferrlecit (i.e., polynuclear iron oxyhydroxide synthesis and addition of carbohydrate/gluconate). See sections I.A and ILA of this response.

52 The physicochemical parameters of the generic product would have to fall within the variability of the physicochemical parameters of the RLD, Ferrlecit, to be equivalent to the RLD.

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physicochemical testing (CRG Petition at 6-7). Watson claims that until the exact structure of the Ferrlecit macromolecule is established and until the drug product is fully characterized, it is not possible to determine if a generic product is the "same as" Ferrlecit (CRG Petition at 6).

We disagree with Watson. Based on our evaluation of all the relevant data and other current relevant scientific information, our experience, expertise, agency precedent, and applicable law, we find that the sodium ferric gluconate complex in sucrose has been adequately characterized for the purposes of ANDA approval; thus we conclude that an ANDA applicant for a generic sodium ferric gluconate product can demonstrate active ingredient sameness by meeting the criteria described in this response.

We also disagree that Ferrlecit is a uniquely complex product. Parenteral iron colloid complexes such as the sodium ferric gluconate product are produced via well-known chemistry involving iron oxyhydroxide synthesis, neutralization, and addition of carbohydrate/gluconate (see section I.A of this response). Thus, sodium ferric gluconate complex in sucrose is actually a relatively straightforward structure composed of an iron oxyhydroxide core with carbohydrate/gluconate forming a shell that binds to and solubilizes the complex.

The distribution of molecule weights in Ferrlecit means that its active ingredient is not a unique molecular entity.53 Thus, the Agency would need to determine whether an ANDA applicant has submitted sufficient information upon which we can reasonably conclude that the generic drug product's active ingredient is the "same" as that of the RLD. Taken together, the tests previously described in this section provide a sufficient scientific basis for demonstrating that a generic sodium ferric gluconate product is physicochemically equivalent to the RLD and demonstrates sameness of sodium ferric gluconate complex in sucrose.

2. Molecular Weight

Watson states that if the molecular weight of a generic product differs significantly from the molecular weight of Ferrlecit, FDA should require clinical studies to demonstrate equivalent safety and efficacy (CRG Petition at 7). Watson claims that in the past, FDA had raised concerns about the comparability of iron dextran products with different molecular weights (Dexferrun and INFeD) and required an applicant to perform additional clinical studies to demonstrate that the products were equivalent (CRG Petition at 7-8). Watson alleges that even though the additional studies indicated that these products appeared equivalent based on measures of therapeutic equivalence (pharmacokinetics and iron utilization), there was no attempt to prove them comparable with respect to safety and the differences in molecular weight could have an effect on their safety profiles (CRG Petition at 8). Watson provides data from a retrospective study published in 2001 that reported that there were eight times more adverse events in patients receiving Dexferrum than in patients receiving INFeD (CRG Petition at 8). Watson claims that these data illustrate that iron complexes are unique compounds that may not behave in the body as do conventional drugs (CRG Petition at 8). Watson further alleges that even though two iron compounds have been shown to be therapeutically equivalent, it does not

S3 See section I.A of this document.

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ensure that they will have the same safety profile, especially when they are physicochemically different (CRG Petition at 8).

We expect the average molecular weight and the molecular weight distribution 54 of a generic product using Ferrlecit as the RLD to be within the variability of the RLD in order to meet the sameness requirement. An ANDA applicant for a generic sodium ferric gluconate product will be expected to perform comparative physicochemical studies demonstrating that the average molecular weight and molecular weight distribution of the generic product and RLD are equivalent. An ANDA for a generic product with an average molecular weight or molecular weight distribution that is different from that of the RLD would not be considered to possess the same active ingredient as Ferrlecit.

Further, your statement that FDA found the iron dextran products, Dexferrum and PNFed, to be therapeutically equivalent is incotrect. Dexferrum and INFeD were not deemed therapeutically equivalent by the FDA and, instead, are BP rated in the Orange Book. 55 In addition, the average molecular weights and molecular weight distributions for Dexferrum and INFed were different. Watson acknowledges this fact earlier in the CRG Petition when comparing Dexferrum and INFed (CRG Petition at 2): "These two iron dextrans are not exactly the same; the iron complexes in INFeD have a significantly lower average molecular weight than those in Dexferrum, but both are considered to be iron dextrans. None of the iron dextran products are rated as therapeutically equivalent to one another." Accordingly, FDA would not approve an ANDA for a generic sodium ferric gluconate product if its average molecular weight or molecular weight distribution were different from that of the RLD.

C. Bioequivalence Studies

Watson states that Ferrlecit is not a true solution, but rather "a colloidal solution, i.e., a heterogeneous mixture of ferric gluconate particles in an aqueous sucrose solution" similar to other "parenteral colloidal solutions [that] are considered by the Division of Bioequivalence to be a problem and waivers of in vivo bioequivalence studies are not granted on them" (CRG Petition at 8-9). Watson claims that this presents the same barrier for granting a waiver of in vivo bioequivalence requirements for a generic sodium ferric gluconate product (CRG Petition at 9).

In this case, because iron colloid injection products are not solutions and may differ in rate and extent of iron availability, in vivo bioequivalence studies will be required as FDA's Office of Generic Drugs (OGD) routinely does for other nonsolution parenteral products. Due to the nature of parenteral iron complexes, a two-pronged approach of in vitro and in vivo studies in humans comparing the generic drug product and the RLD will be needed to demonstrate that the

" See section I.A of this document.

" A BP rating is a rating for active ingredients and dosage forms with potential bioequivalence problems. As explained in the Orange Book Preface, injectable suspensions containing an active ingredient suspended in an aqueous or oleaginous vehicle are coded BP unless there is adequate evidence of bioequivalence. http://www.fda.gov/drugs/developmentapprovalprocess/ucm079068.htm

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rate and extent of iron absorption of the generic sodium ferric gluconate product do not show a significant difference from the rate and extent of absorption of the RLD. These studies are described in further detail below.

We agree that a waiver of this in vivo bioequivalence requirement for a generic sodium ferric gluconate product is not appropriate. Under 21 CFR 320.22, any person submitting an ANDA may request a waiver of a requirement for submission of evidence demonstrating in vivo bioequivalence of the drug product. Under § 320.22(a), FDA must waive the requirement if the drug product meets any of the provisions in § 320.22(b), (c), or (d). Section 320.22(b)(1) concerns parenteral solutions and provides that in vivo bioequivalence of the drug product may be considered self-evident if the drug product is a parenteral solution intended solely for administration by injection and contains the same active and inactive ingredients in the same concentration as a drug product that is the subject of an approved full NDA. Because iron colloid injection products are not solutions, they do not fall within § 320.22(b)(1).

1. In Vitro Bioequivalence Studies

As an in vitro measure of bioequivalence, FDA recommends that the proposed generic sodium ferric gluconate product be compared to the RLD based upon their particle morphologies and particle size. 56 The comparison of particle morphology may be achieved by the use of electron microscopy and atomic force microscopy, among other techniques. Additionally, given that particle size has the potential to affect the rate and extent of drug absorption, FDA also recommends that the proposed generic sodium ferric gluconate product be compared to the RLD based upon particle size distribution, using methods such as dynamic light scattering. The particle size distribution results may be analyzed by using the population bioequivalence (PBE) method described in the draft guidance for industry on Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action and Statistical Information from the June 1999 Draft Guidance and Statistical Information for In Vitro Bioequivalence Data. 57' 58

There are, however, limitations to these in vitro methods for demonstrating bioequivalence because it is difficult to characterize surface properties of the carbohydrate shell surrounding the iron mineral core. The effect of the shell surface on iron uptake, including the effect on phagocytosis, has not been reported in the literature.

2. In Vivo Bioequivalence Studies

56 These would be considered in vitro bioequivalence studies, rather than CMC studies, because in vitro bioequivalence studies are intended to meet formal statistical equivalence criteria between the test and reference products. CMC studies, on the other hand, are evaluated based on a quality standard with respect to the test product only, or as part of an evaluation of active ingredient sameness.

57 We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance Web page at hUp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm under

Biopharmaceutics.

58 This guidance on locally acting dmgs is cited here because the analysis (population bioequivalence (PBE) method) is the same for both injection and inhalation formulations.

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Although it is unlikely that differences in the gluconate/sucrose shell of these iron particles for the proposed generic sodium ferric gluconate product and the RLD will have a significant effect on drug uptake by the reticuloendothelial system (RES) (such as through phagocytosis by macrophages), as a conservative measure, a test of in vivo pharmacokinetics in humans should be used to complement in vitro bioequivalence data. For the in vivo bioequivalence study, a single dose pharmacokinetics study in humans comparing the proposed generic sodium ferric gluconate product and the RLD is recommended. Total iron and transferrin bound iron in serum should be measured in such a study. Transferrin-bound iron can be measured by chemical methods, 59 by running serum through an alumina column to remove drug-bound iron, 6° or by other approaches. When the amount of transferrin-bound iron is subtracted from total iron, the amount of drug-bound iron in the serum can be calculated. The pharmacokinetic parameters, &ea-under-the-concentration-time curve (AUC) and maximum serum drug concentration (Cmax), of drug-bound iron are used to establish bioequivalence. These pharmacokinetic measurements are useful in ruling out the possibility that generic sodium ferric gluconate product and the RLD have different RES uptake.

Taken together, equivalence of these in vivo pharmacokinetic measurements along with in vitro evidence of comparability of drug particle morphology and equivalence in drug particle size distribution provide information that can support a determination of bioequivalence.

D. Conduct of Clinical Investigations Demonstrating Safety and Effectiveness

Watson claims that if the manufacturing process for the generic sodium ferric gluconate product is not the same as for Ferrlecit and if these generic products are not fully characterized, then FDA should require applicants of generic sodium ferric gluconate products to submit an NDA supported by a demonstration of equivalent safety and effectiveness based on results of appropriate preclinical and clinical studies (CRG Petition at 1 and 9). Watson states that, in this unique situation, the same regulatory approval standards should be required of generics as was required of Watson for Ferrlecit (Frommer Supplement at 2). Watson alleges that it is insufficient for these generic applicants to obtain approval simply by virtue of bioequivalence data (Frommer Supplement at 2).

We disagree that it is necessary to require that applicants for generic sodium ferric gluconate products submit an NDA and conduct preclinical and clinical studies to be able to market their product. Rather, physicochemical characterization of a generic sodium ferric gluconate product provides sufficient information to demonstrate active ingredient sameness to the RLD, Ferrlecit, and thus allow an applicant to seek approval via the ANDA process. In addition, as explained above (section II.C), equivalence of in vivo phannacokinetic measurements along with in vitro evidence of comparability of drug particle morphology and equivalence in drug particle size provide information that can support a determination of bioequivalence. As discussed in section

59 Seligman, P.A. and Schleicher, R.B. Comparison of methods used to measure serum iron in the presence of iron gluconate or iron dextran. Clin Chem 45, 898-901, 1999.

60 Van Wyck, D., Anderson, J. and Johnson, K. Labile iron in parenteral iron formulations: a quantitative and comparative study. Nephrol Dial Transplant 19, 561-565, 2004.

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Sincerely,

oodcock, M.D. Director Center for Drug Evaluation and Research

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I.B of this response, once we conclude that an ANDA for a sodium ferric gluconate product meets the requirements for approval, the generic sodium ferric gluconate product and Ferrlecit can be substituted with the full expectation that generic sodium ferric gluconate product will have the same clinical effect and safety profile as Ferrlecit. We do not see a scientific justification in your request for what we would consider duplicative studies to demonstrate safety and effectiveness of a generic sodium ferric gluconate product Therefore, we deny your request for preclinical and clinical studies to demonstrate the safety and effectiveness of generic sodium ferric gluconate products.

E. Establishing Guidelines as a Prerequisite for FDA to Receive an ANDA

Watson asks FDA to refuse to receive for substantive review, under § 314.101(b), an ANDA for generic formulations of Ferrlecit until FDA establishes guidelines for determining what support is necessary to demonstrate that generic sodium ferric gluconate products contain the same active ingredient as Ferrlecit (Fromther Petition at 1; Frommer Comment at 2-3). Watson claims that Ferrlecit's structurally-dependent manufacturing process and lack of full characterization require that FDA establish these guidelines (Frommer Petition at 2).

FDA does not intend to delay review or deny approval to an ANDA or a NDA on the grounds that FDA has not published guidelines for determining active ingredient sameness. FDA decides whether to approve an ANDA based on evaluation of the scientific information provided in the application for the proposed generic drug product If the applicant complies with all applicable statutory and regulatory requirements, FDA will approve the application regardless of whether it has published applicable guidelines for determining active ingredient sameness. 6t Accordingly, to the extent that your petition contends that FDA must publish such guidelines, or that FDA cannot approve any ANDAs referencing these products before publishing these recommendations, FDA disagrees and denies these requests. We note, however, that we may issue product-specific recommendations for this product in the future should we determine that it would be appropriate to do so.

III. CONCLUSION

We are confident that any FDA-approved generic version of Ferrlecit will have the same active ingredient as, and will betherapeutically equivalent to, Ferrlecit Therefore, for the reasons discussed above, the petitions and supplement are granted in part with respect to the request that the physicochemical characteristics and active ingredient of the generic product be the same as those of Ferrlecit, but denied in all other respects.

61 See section 505(j) of the Act.

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sow% · 2019. 4. 11. · 7 The Frommer Petition opposes a suitability petition submitted by AAC...

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