BUG 8C BEA.$DSLEY, LLP 919 EIGHTEENTH STREET, N.W. SUITE C300 WASHINGTON, D.C. 2000C3-55ro OCT 22?3 '07 W$rrEa's TmmEPjKoxE 202-736-3615 TE-1-Rp$oxE 202-736-3800 FAcsnKn.R 202-736-3608 Dockets Management Branch (HFA-305) Food and Drug Administration Department of Health and Human Services 5630 Fishers Lane, Room 1061 Rockville, MD 20852 Re : Citizen Petition Requesting that FDA Not Approve an Abbreviated New Drug Application for Cefixime for Oral Suspension Unless Certain Requirements are Met _ Dear Sir or Madam : On behalf of Lupin Pharmaceuticals, Inc. (`Lupin"), a wholly owned subsidiary of Lupin Limited, which it represents, Buc & Beardsley, LLP hereby submits this Citizen Petition under sections 505(j) and 505(q) of the Federal Food, Drug, and Cosmetic Act ("FDCA" or the "Act") (21 U.S.C. 355(j) and (q)) and 21 C.F.R. 10.30 to request that the Commissioner of Food and Drugs take the following action. 1. Action Requested Lupin requests that the Commissioner not approve any abbreviated new drug application ("ANDA") for cefixime for oral suspension that relies on Suprax (cefixime) for oral suspension as the reference listed drug ("RLD") unless the ANDA meets the same standards for strength, potency, quality, impurities, stability and overage of cefixime active ingredient that Lupin was required to meet in order to obtain approval of its ANDA. 11. Statement of Grounds Lupin markets specialty pharmaceuticals and generic drugs. Among the drugs that Lupin markets is Suprax (cefixime) for oral suspension in 100 mg/5 ml and 200 mg/5 ml strengths. Suprax is an antibiotic indicated for treating urinary tract infections, otitis media, pharyngitis and tonsillitis, acute bronchitis and acute exacerbations of chronic bronchitis and uncomplicated gonorrhea caused by susceptible organisms in adults and children, including infants down to six
Page 2 months of age.' Lupin holds ANDAs 065-129 and 065-355 for the 100 mg/5 ml and 200 mg/5 ml strengths respectively. No patents are listed for, and no exclusivities apply to, Suprax. The RLD for Lupin's ANDAs was Lederle's formulation of Suprax, which has since been discontinued. The approval process for Lupin's Suprax was complex. Lupin's original ANDA for the 100 mg/5 ml strength was submitted on May 14, 2002. There was significant discussion regarding overages during the ANDA review process. Lupin was required to perform additional studies and was ultimately required to reduce the overage that it had originally proposed to match the overage in the reference listed drug. In addition, Lupin was asked to and did provide substantial additional information about impurities in its product, including a comparative analysis to the RLD, and tightened the specifications for several impurities at the request of FDA. Lupin's ANDA was approved with an overage equivalent to, and with specifications similar to, the Lederle Suprax formulation, on February 23, 2004. A supplemental application to revise certain specifications and product shelf life was subsequently submitted on August 12, 2008 and approved on April 14, 2009. Lupin's ANDA for the 200 mg/5 ml strength was submitted on September 23, 2005. Having had previous experience with FDA's views on overages and specifications, Lupin submitted the ANDA with the same percentage overage that had been previously approved in the 100 mg/5 ml strength and with similar specifications. This ANDA was approved on April 10, 2007. Lupin recently learned that another sponsor has submitted an ANDA referencing Suprax, and believes that this and future ANDA applicants may be seeking approval of a drug with an overage greater than, and impurity specifications less tight than those for Lupin's products. Because including a greater overage might allow for more degradation and because less tight specifications might allow for use of a simpler and more cost-efficient manufacturing process, Lupin believes approval of such a drug could cause it to suffer significant competitive harm. If an ANDA applicant were to represent that Lupin's product has overages higher than those approved by the FDA, Lupin believes that this representation would not be correct and would point towards an analytical method that is giving an incorrect result. 1. Suprax Prescribing Information, Indication and Usage ; Prescribing Information, Pediatric Use.
Page 3 A. Approving an ANDA with an Overage Greater than the Overage in the RLD Would Not Be in Accordance with Law and FDA Policy Pursuant to FDCA 505(j) and 21 C.F.R. 314.92 and 314.127, an ANDA applicant generally must demonstrate, among other things, that the strength 2 of its product is identical to that of the RLD. The legal standard incorporates the scientific presumption that if the drug covered by the ANDA has the same strength (and shares other relevant attributes enumerated by the statutory standards), it will have the same safety and efficacy as the RLD, and will be substitutable with the RLD.3 An ANDA for a different strength product than the RLD can only be received by FDA if the applicant submits, and FDA approves, a suitability petition allowing the change. 4 For these reasons, ANDA applicants are generally required to formulate a drug with the intent of providing the exact strength of the reference listed drug, no less and no more.5 In some cases, FDA may permit the use of a small "stability overage," i.e., the addition of active ingredients beyond the labeled concentration to compensate for anticipated loss of the ingredient over time. This approach can be used to extend the shelf life of products, but it is generally discouraged 6 because it may result in patients receiving "super-potent" doses of active ingredient (above the labeled strength)7 and/or drugs with concentrations of degradation impurities that exceed those that would be found if an overage was not used (also posing a potential safety issue depending on the toxicity of the impurities).g In the case of Suprax, FDA told Lupin that its 2. Strength is defined as the concentration of active ingredient in the drug and/or its potency. 21 C.F.R. 210.3(b)(16). 3. 57 Fed. Reg. 17950, 17953 (Apr. 28, 1992); Letter from Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research ("CDER"), Regarding Docket Nos. 2001 P-0323/CPI et al., 7 (Oct. 14, 2003), available at http ://www.fda.gov/ohrms/dockets/dockets/04p0231/04p- 0231-c000001-Exhibit-29-vol4.pdf; FDA Orange Book, vii (29th Ed., 2009). 4. 21 C.F.R. 314.93. A product with different strength will not be substitutable with previously approved products. 5. 21 C.F.R. 211.101(a) ; FDA/ICH Guidance for Industry : Q8(R1) Pharmaceutical Development, 5 (Rev. 1, June 2009). 6. FDA/ICH Guidance for Industry : Q8(R1) Pharmaceutical Development, 5. 7. E.g., 10/4/2006 Advisory Committee Regarding Levothyroxine, 20 (Jane Axelrad, Esq., Associate Director for Policy, CDER stating that manufacturers generally target 100% strength (i.e., with no overage) at release because it "eliminates the risk of a patient obtaining a super potent product"), available at http ://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4228tl.pdf. FDA has previously determined that a small overage of a specified amount in a cefexime for oral suspension product is safe, and an ANDA applicant is entitled to rely on that previous determination. 8. E.FDA Warning Letter to Medico Labs, Inc. (Apr. 16, 2007) (Regarding the "potential clinical concern" due to the excess degradants that could result from an overage), available at http ://www.fda.gov/iceci/enforcementactions/warningletters/2007/ucm076359.htm.
Page 4 principal concern was the excess of degradation impurities that would result from adding a substantial overage. When FDA has approved an RLD with an overage, i.e., found the RLD with the overage to be safe and effective, an ANDA applicant is permitted to include an overage in its product and match the true strength of the RLD. In that case, the ANDA drug would meet the identical strength requirement of the statute and regulations. If, however, the overage exceeds levels in the RLD, the strength of the product would be different than that of the RLD, and would raise questions about safety and substitutability of the product. In apparent recognition of this, FDA has stated that "in general, the only acceptable justification for an overage in the final [ANDA] drug product formulation is the demonstration of the same overage in the RLD."9 FDA approved Lupin's Suprax with an overage which was demonstrated to match the overage in the Lederle RLD. If FDA were to approve an ANDA referencing Suprax that permitted a higher overage, FDA would both be approving a drug of a different strength and contravening the legal requirement that the strength of ANDA and RLD products be that same (i.e., "identical"), as well as its own often stated policies.] In reviewing any ANDA that represents that Lupin's drug has an overage greater than that represented by Lupin (even given the tolerances of analytical variation), Lupin requests that FDA carefully review the analytical method used to obtain such results before concluding that the ANDA applicant is correct. B. Approving an ANDA with an Overage Greater than the Overage in the RLD Would Be Arbitrary and Capricious It is axiomatic that an agency must "treat similar cases in a similar manner unless it can provide a legitimate reason for failing to do so."' 1 "Government is at its most arbitrary when it 9. FDA Office of Generic Drugs, Question-based Review ("QbR") Frequently Asked Questions, 16 (June 4, 2007). See also, e.., FDA Guidance for Industry, Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products - Chemistry, Manufacturing, and Controls Documentation, 5 (July 2002). 10. Lupin is aware that the U.S.P. monograph, Cefixime for Oral Suspension, provides a range of 90-120% for strength measurements, and that some might argue that this specification should allow upward variation within the range. Such ranges, however, are generally adopted to take account of variability in analytical methods, not to provide a range of different active ingredient concentrations. E.g_, 10/4/2006 Advisory Committee Regarding Levothyroxine, 41 (an upper limit of 110% on levothyroxine potency is primarily intended to accommodate analytical variability in methods that are used to measure strength). 11. Independent Petroleum Ass'n of America v. Babbitt, 92 F.3d 1248, 1258 (D.C. Cir. 1996) ~ National Association of Broadcasters v. FCC, 740 F.2d 1190, 1201 (D.C. Cir. 1984) ; see also Transactive Corp. v. U.S., 91 F.3d 232, 237 (D.C. Cir. 1996) ; Doubleday Broadcasting Co. v. F.C.C., 655 F.2d 417, 423 (D.C. Cir. 1981).
Page 5 treats similarly situated people differently."' 2 These general principles of administrative law are as applicable to FDA in the approval context as to any other administrative action. In Bracco v. Shalala,l3 for example, FDA's decision to regulate some contrast agents as drugs and others as devices was challenged. Holding that the plaintiffs were likely to succeed on the merits of their challenge to the regulatory scheme, the court concluded that "[t]he disparate treatment of functionally indistinguishable products is the essence of the meaning of arbitrary and capricious."14 The same principle applies here. The situation that Lupin believes may exist - an ANDA that proposes an overage greater than that in the RLD - is, in all relevant respects, the same situation that Lupin faced when its ANDA was pending. Both situations involve a pending cefixime for oral suspension ANDA in which an overage higher than the overage in the RLD is proposed. When considering Lupin's ANDA, FDA refused to approve the ANDA unless the overage in Lupin's drug was no greater than the overage identified in the RLD. Lupin was therefore required to change its formulation to reduce the overage to obtain an approval. This required Lupin to reformulate and to reduce Suprax's shelf life to ensure that Suprax remains stable over the life of the product. It would be arbitrary and capricious for FDA now to approve a competitor without imposing the same requirement. Lupin recognizes that federal agencies are not precluded from changing their policies in appropriate circumstances. But they "cannot silently depart from previous policies or ignore precedent." 15 In this case, however, Lupin has no reason to think that FDA has changed its policy, or that it would want to do so. FDA's Guidance on Chemistry, Manufacturing, and Controls ("CMC") Information still states that, in general, use of an overage is not appropriate, and FDA's Question-based Review Frequently Asked Questions still provides that; in general, the only acceptable justification for an overage is a demonstration of the same overage in the RLD. Further, FDA's review of an ANDA referencing Suprax provides no reason to change the policy. No patent prevents ANDA applicants from manufacturing in the same way that Lupin does, and the experience of Lupin, and Lederle before it, demonstrates that it is possible to manufacture a cefixime for oral suspension with an overage not more than that in the original Lederle Suprax RLD, while still supporting a commercially reasonable shelf life. There is no reason to believe that another manufacturer willing to devote sufficient resources to its drug 12. Eteison v. Office of Personal Mana e~ ment, 684 F.2d 918, 926 (D.C. Cir. 1982). 13. 963 F. Supp. 20 (D.D.C. 1997). 14. Id. ; see also U.S. v. Diapulse Corp. of America, 748 F.2d 56, 62 (2d Cir. 1985). 15. Committee for Community Access v. FCC, 737 F.2d 74, 77 (D.C. Cir. 1984).
Page 6 development could not obtain the same result as manufacturers before it. for another manufacturer makes little sense. 16 Relaxing the standard C. FDA May Not Approve an ANDA for a Drug Without Rigorous Scrutiny of the Impurities in the Drug, Especially as Compared to the Impurities in the RLD FDA cannot approve an ANDA if its CMC "are inadequate to assure and preserve its identity, strength, uali, and puritx."i7 The presence of impurities in an ANDA drug which are different than those found in the RLD, or at a higher concentrations than those found in the RLD, can raise questions about whether this standard is met, and relatedly, the safety of the product. j g The different impurities, or impurities at higher concentrations, generally must be "qualified," (i.e., potential safety issues assessed) prior to ANDA approval using data from existing sources (e.g_, literature), if available, or by conducting studies (e.g_, toxicity studies), if such data are not available. 19 In addition, because concentrations of certain impurities (namely, degradants) can change over time, it is crucial that qualifications, and limits, on impurities take into consideration the drug product's changing composition over its shelf life.2 FDA rigorously applied these standards when it reviewed Lupin's original ANDAs and supplements for Suprax, requiring Lupin to reduce the levels of certain impurities, qualify others with extensive toxicology testing, conduct its impurity evaluations over the entire shelf life proposed for its product, and conduct comparative analyses to the RLD. Any ANDA following Lupin's must be held to the same high standards by the agency, to ensure the quality, purity, and 16. An applicant's inability to make a product that matches the Lupin overage also raises questions about the adequacy of CMCs. Like NDAs, ANDAs are required to have CMCs that are "adequate to ensure... the strength" of the product, and allow it to perform as labeled. FDCA, 505(j)(4) ; Letter from Randall W. Lulter, Ph.D., Acting Associate Commissioner of Policy and Planning Regarding Docket Nos. 2004P-0206/CPI et al., 19-20 (Feb. 22, 2006), available _at http ://www.regulations.gov/search/regs/home.html#documentdetail? R=0900006480475c1I. 17. FDCA 505(j)(4)(A) ; 21 C.F.R. 314.127(a)(1) (emphasis added). 18. See e.g., Letter from Janet Woodcock, M.D., Director, CDER, Regarding FDA 2005-P-0367 (Nov, 17, 2008), available at http ://www.regulations.gov/search/regs/home.html# documentdetail?r=09000064807b06cd. 19. FDA Draft Guidance for Industry : ANDAs : Impurities in Drug Products, 5-6 (Rev. 1, Aug. 2005). 20. FDA/ICH Guidance for Industry : Q3B(R2) Impurities in New Drug Products, 5 (Rev. 2, July 2006).
Page 7 safety, of the product, and for the agency to fulfill its legal obligation to treat similarly situated products in a similar fashion, as discussed above. 21 To relax the standard to which Lupin's products were held for another generic applicant could result in a commercial disadvantage for Lupin if, as Lupin believes based on its own experiences with manufacturing processes for Suprax and other similar products, such an applicant would be able to use a process that would not require as much control over impurities, and therefore, be more commercially efficient. III. Environmental Impact Petitioner claims a categorical exclusion under 21 C.F.R. 25.30 and 25.31(a). IV. Economic Impact Petitioner will submit economic information upon request of the Commissioner. 21. FDA's Draft Guidance for Industry : ANDAs : Impurities in Drug Products 3-4, provides that, in establishing degradation product acceptance criteria, ANDA should look first to U.S.P. specifications, and, if there are none, to levels observed in the approved human drug product. The U.S.P. monograph, Cefixime for Oral Suspension, contains no impurity specification.
Page 8 V. Certification I certify that, to my best knowledge and belief : (a) this petition includes all information and views upon which the petition relies ; (b) this petition includes representative data and/or information known to the petitioner which are unfavorable to the petition ; and (c) I have taken reasonable steps to ensure that any representative data and/or information which are unfavorable to the petition were disclosed to me. I further certify that the information upon which I have based the action requested herein first became known to the party on whose behalf this petition is submitted in the last two months. 22 If I received or expect to receive payments, including cash and other forms of consideration, to file this information or its contents, I received or expect to receive those payments from the following persons or organizations : Lupin Limited. I verify under penalty of perjury that the foregoing is true and correct as of the date of the submission of this petition. Respectfully submitted, G Lea.c,d s ~nw G. a :,~- Kate C. Beardsley James A. Boiani Buc & Beardsley, LLP 919 18th St., NW Suite 600 Washington, DC. 20006 Phone : (202) 736-3615 22. The specific information that became known within the last two months was that another ANDA for a cefixime oral suspension product had been submitted to the agency. This information, and a concern that FDA might relax its application of the standards for approval to cefixime ANDAs, prompted this petition.