Buchanan Ingersoll 1.\\ Rooney PC

1700 K Street, N.W., Suite 300 Washington, DC 20006-3807 Edward John Allera T 202 452 7900 202 452 7985 F 202 452 7989 [email protected] www.bipc.com Barbara A. Binzak Blumenfeld 202 452 7906 [email protected]

-V1 December 1, 2015

VIA HAND DELIVERY RETURN RECEIPT REQUESTED -

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

CITIZEN PETITION

On behalf of Concordia Pharmaceuticals ("Concordia" or "the Company"), sponsor of the 1 Lanoxin® (digoxin tablets) new drug application ("NDA"), the undersigned submit this Citizen Petition ("Petition") and accompanying Expert Statement2 in five parts (one original plus four copies) pursuant to § 505Gi of the Federal Food, Drug, and Cosmetic Act ("FFDCA" or "the Act") and 21 C.P.R. § 10.20, § 10.30, and Part 320. Concordia requests that the Acting Commissioner of Food and Drugs take two specific actions. First, the U.S. Food and Drug Administration ("FDA" or "the Agency") should amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's narrow therapeutic index ("NTI") drug status and recommend more appropriate bioequivalence tests and specifications. Second, FDA should change the therapeutic equivalence rating for the approved generic digoxin tablet products in the "Approved Drug Products with Therapeutic Equivalence Evaluations" ("Orange Book") from AB to BX because they do not meet appropriate bioequivalence and other requirements to be considered therapeutically equivalent and therefore substitutable.

FDA has long recognized that digoxin is an NTI drug product due to the narrow window between efficacious and toxic doses, as well as the need for therapeutic monitoring and dose adjustments. Digoxin was first marketed before 1938 and, in the 1970s, existing digoxin products were subject to FDA's batch certification program to ensure appropriate dissolution, potency, and bioavailability. Lanoxin was the first historical digoxin tablet product to receive NDA approval in 1997, and it is the reference listed drug ("RLD").

1 NDA 20-405 (approved September 30, 1997). 2 Expert Statement ofManju Beier. 3 Codified at 21 U.S. C. § 355G). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 20 15 Page2

The Agency's views on NTI drug bioequivalence have evolved in recent years in conjunction with the recommendations of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology ("AC"). These recommendations impact the design and acceptable pharmacokinetic ("PK") parameters for NTI drug bioequivalence studies. FDA agreed with these recommendations, and stated that its product-specific bioequivalence guidance documents for NTI drugs would incorporate appropriate study design and testing parameters.

A number of these product-specific guidance documents, including warfarin, incorporate some of the AC's recommendations. However, the digoxin guidance was never updated to include them. FDA should therefore amend the May 2008 digoxin guidance to reflect, at a minimum, the same bioequivalence criteria that the Agency has already recommended for other NTI drugs, including: (1) 4-way, fully-replicated crossover in vivo fasting and fed studies; and (2) a reference-scaled average bioequivalence ("RSABE") approach. Concordia also urges FDA to include the AC's other NTI drug bioequivalence recommendations in the digoxin guidance as well- specifically: (3) a 90% confidence interval ("CI") for area under the curve ("AUC'') and maximum concentration ("Cmax") of 90-111.11%; and (4) a drug substance potency range of 95.0-105.0%. These requirements are imposed on NTI drugs such as oncology drugs.

Four of the five abbreviated new drug applications ("ANDAs") for digoxin tablets were approved prior to issuance of the existing May 2008 digoxin guidance, and all five were approved before the AC's NTI drug bioequivalence recommendations from 2010 and 2011. Pursuant to the Agency's contemporary NTI standards, at least some of these drugs would not be bioequivalent to Lanoxin. Furthermore, ongoing concerns about digoxin bioavailability, content uniformity, dissolution, and potency- as well as recalls due to poor current good manufacturing practices ("cGMPs") and splitting digoxin tablets that may not be bioequivalent to Lanoxin - also raise bioequivalence questions. As a result, these generic digoxin products cannot be therapeutically equivalent to Lanoxin. Their AB ratings should be changed to BX.

Substituting a generic drug that is not therapeutically equivalent to Lanoxin may result in sub- or supra-therapeutic doses causing severe adverse events or worse. As the RLD NDA holder, Concordia is responsible for maintaining its labeling, and inappropriate drug substitution raises significant questions of product liability for the Company. Because the safety and effectiveness of digoxin is called into question by inappropriate bioequivalence standards, specification concerns, and inadequate cGMPs, FDA should adopt the AC's recommendations for NTI drug bioequivalence studies before any generic is considered therapeutically equivalent to Lanoxin.

A. Action Requested

As addressed further herein, Concordia respectfully requests that FDA take the following actions: Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 3

1. Amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's NTI status and to recommend that generic drug sponsors meet the bioequivalence criteria recommended in other NTI drug guidance documents, including:

a. Conducting a 4-way, fully-replicated crossover design for both in vivo fasting and fed studies; and

b. Using an RSABE approach.

Amend the digoxin guidance to reflect the AC's additional NTI drug bioequivalence recommendations, including:

c. Meeting a bioequivalence range of 90-111.11% for the 90% CI for both AUC and Cmax, and require that the data "cross the one" (i.e., cross the 100% point); and

d. Meeting a drug substance potency range of95.0-105.0%.

2. Determine that approved generic digoxin oral drug products are not therapeutically equivalent to Lanoxin and should therefore be rated BX.

The bases for our requests are discussed in detail below.

B. Statement of Grounds

I. INTEREST OF CONCORDIA

A. Concordia is the Lanoxin NDA Holder and Therefore Responsible for Maintaining Product Labeling

Concordia acquired NDA 20-405 for Lanoxin oral tablets from Covis Pharma Sarl ("Covis") on April 21, 2015. As the current NDA holder, Concordia remains responsible for monitoring, collecting, and reporting adverse events associated with the drug product to FDA. The Company also remains responsible for updating its labeling based upon new safety and pharmacovigilance signals, which generic digoxin drug sponsors rely upon for their own product labeling. Concordia has a vested interest in ensuring that any generic digoxin drugs are, in fact, bioequivalent and therefore therapeutically equivalent to Lanoxin.

Approving a generic digoxin product that does not meet appropriate NTI drug bioequivalence criteria will introduce drug variability making therapeutic substitution potentially dangerous for patients. It also creates marketplace liability risks for Concordia. These labeling responsibilities and potential liability issues are discussed in greater detail in Section V.G. herein. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page4

B. The Current Petition is an Extension of Two Earlier Petitions

This current Petition is an extension of the issues raised in two prior petitions that Co vis filed in 2013. The first petition,4 filed on October 21, 2013, requested that FDA require all ANDA sponsors of digoxin 0.0625 mg and 0.1875 mg dosage strengths to conduct and pass all validation testing that FDA required Covis to perform, namely dissolution and blend uniformity. That Bioequivalence Petition also requested that FDA not grant testing waivers for these two dosage strengths.

Covis filed a second petition5 on October 21, 2013 asking FDA to confirm that the Agency had not fully approved the 0.0625 mg and 0.1875 mg Lanoxin tablets in 1997, and that the awarded three-year exclusivity for these two strengths only began running in October 2013 when FDA approved Covis' prior approval supplement ("PAS") containing the validation testing refe1Ted to above. FDA has not yet responded to this Exclusivity Petition or to the Bioequivalence Petition.

Neither petition requested amendment of the digoxin bioequivalence guidance to reflect digoxin's NTI status, and neither raised the issue of therapeutic equivalence. As a result, this current Petition is intended to complement and not duplicate those previous 2013 submissions. Because the issues are inteiTelated, Concordia requests that FDA render decisions on all of the petitions at the same time.

II. DIGOXIN BACKGROUND

A. Digoxin is an NTI Drug

Digoxin is a cardiac glycoside used to treat a number of cardiovascular conditions. Lanoxin tablets are indicated for (1) treatment of mild to moderate heart failure in adults; (2) increasing myocardial contractility in pediatric patients with heart failure; and (3) control of resting ventricular rate in patients with chronic atrial fibrillation in adults. 6 Digoxin is an NTI drug because therapeutic levels are only slightly lower than toxic levels. 7 As a result, special care and consideration is required to determine the appropriate dose, such as body weight, age,

4 Petition filed by Edward John Allera, Barbara A. Binzak Blumenfeld, and Tina Hu, Buchanan Ingersoll & Rooney PC (submitted October 21, 2013; filed November 15, 2013) (Docket FDA-P-2013-1376) (hereinafter "Bioequivalence Petition"). 5 Petition filed by Edward John Allera and Barbara A. Binzak Blumenfeld, Buchanan Ingersoll & Rooney PC (submitted October 21, 2013; filed November 15, 2013) (Docket FDA-P-2013-1377) (hereinafter "Exclusivity Petition"). 6 See Lanoxin FDA-approved labeling (revised October 2013), available at http://www .accessdata.fda.gov/drugsatfda_ docs/labe1/20 13/020405s007lbl.pdf (hereinafter "Lanoxin Tablets Labeling"). 7 Expert Statement, at ~22. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 5 use of other medications, and renal function. 8 Safe use of the product requires monitoring for the signs and symptoms of both toxicity and clinical response, and making dose adjustments based on toxicity, efficacy, and blood levels. 9

In light of these characteristics, digoxin is a prototypical NTI drug. NTI drugs have a narrow within-patient therapeutic range but a wide between-patient therapeutic range. They have a steep dose/response curve for safety and efficacy in the usual dosing interval, or small concentration differences between toxic and effective doses. These drugs also require therapeutic monitoring based on PK or pharmacodynamic ("PD") measures. FDA has long recognized digoxin's NTI status,10 even proposing at one time (prior to the approval ofLanoxin or any generic tablets) to require a patient package insert ("PPI") to raise awareness about drug­ drug interactions and potential improper administration. 11

B. Digoxin Regulatory History

According to the original holder of NDA 20-405 (Burroughs Wellcome), digoxin has been manufactured and marketed in the U.S. since 1934. 12 Despite its long history, this product and other digoxin products were historically marketed without approved applications. 13 In early 1970, FDA began to test marketed digoxin products, leading to dozens of recalls because of apparent potency issues. The Agency subsequently initiated a voluntary certification program to test lot samples for compliance with potency and content uniformity requirements in the United States Pharmacopeia ("USP"). Later studies demonstrated that there were bioavailability differences between digoxin products made by different manufacturers, as well as between lots made by the same company. Because of the correlation between in vivo bioavailability and in vitro dissolution, the USP digoxin monograph was amended to require a dissolution test. 14

In January 1974, FDA issued a proposed rule for marketing digoxin oral drug products. The proposed rule stated that all such products are new drugs that require an approved ANDA (including bioavailability tests) and specific product labeling. It also instituted a mandatory certification program for currently-marketed digoxin products and required recall of any

8 Lanoxin Tablets Labeling, at 2. 9 Lanoxin Tablets Labeling, at 5. 10 See, e.g., 39 Fed. Reg. 2471, 2475 (January 22, 1974) (stating in proposed 21 C.F.R. § 130.51 that there is the "potential for serious risk to cardiac patients using digoxin products which may vary in bioavailability."); see also, e.g., 65 Fed. Reg. 70573, 70574 (November 24, 2000) (noting that digoxin labeling requirements were needed "[b]ecause of the nanow margin between therapeutic and toxic levels of digoxin and the potential for serious risks to cardiac patients using digoxin products that may vary in bioavailability."). 11 45 Fed. Reg. 60785 (September 12, 1980). The Agency issued a draft guideline for a digoxin PPI, which acknowledged the chug's NTI status. However, because the regulation that established the need for PPis was later revoked, so was the digoxin PPI guideline. 47 Fed. Reg. 39249 (September 7, 1982). 12 65 Fed. Reg. 70573, 70573 (November 24, 2000). 13 41 Fed. Reg. 5339, 5340 (February 5, 1976). 14 39 Fed. Reg. 2471,2471-2472 (January 22, 1974); 65 Fed. Reg. 70573, 70573 (November 24, 2000). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 6

products not meeting the USP dissolution specifications. 15 In March 1974, the Agency stayed the time for submitting ANDAs and complying with labeling requirements pending a public meeting on digoxin labeling. 16 Labeling issues were also reviewed by the Cardiovascular and Renal Advisory Committee. 17 Labeling amendments were proposed18 and finalized19 in 1976, but the requirement for submitting an ANDA was further stayed.

0 In November 2000 (with the stay on ANDA submissions still in effece ), FDA issued two notices - one reaffirming the new drug status of digoxin and outlining the conditions for marketing, 21 and one proposing to revoke the historical conditions for marketing established as part of the batch certification process.22 Because the NDA for Lanoxin tablets had been approved in 1997, ANDAs could now be approved and the need for batch certification was eliminated. The historical regulation setting forth conditions for digoxin marketing was rescinded in June 2002.23

C. Lanoxin History

Burroughs Wellcome manufactured digoxin 0.125 mg and 0.250 mg dosage strength tablets for decades prior to submitting its NDA in September 1993. This NDA contained published studies as well as two original clinical trials. The Agency presented digoxin labeling issues to the Cardiovascular and Renal Drugs Advisory Committee for its review. That Committee also recommended that the results of a government-funded study on digoxin be submitted to the NDA and incorporated into the labeling. 24

FDA approved NDA 20-40525 on September 30, 1997, which made digoxin oral tablets eligible for ANDA approval. 26 FDA has since approved five ANDAs for the 0.125 mg and 0.250 mg dosage strengths:27

• Mylan- ANDA 40-282 (approved December 23, 1999)

15 39 Fed. Reg. 2471, 2471 (January 22, 1974). 16 39 Fed. Reg. 9184 (March 8, 1974); 39 Fed. Reg. 9219 (March 8, 1974). 17 65 Fed. Reg. 70573, 70574 (November 24, 2000). 18 41 Fed. Reg. 17755 (April28, 1976). 19 41 Fed. Reg. 43135 (September 30, 1976) (21 C.F.R. § 310.500, originally 21 C.F.R. § 130.51 prior to recodification). 20 65 Fed. Reg. 70573, 70574 (November 24, 2000). 21 65 Fed. Reg. 70573 (November 24, 2000). 22 65 Fed. Reg. 70538 (November 24, 2000). 23 67 Fed. Reg. 42992 (June 26, 2002). 24 65 Fed. Reg. 70538, 70538 (November 24, 2000); 65 Fed. Reg. 70573, 70574 (November 24, 2000). 25 65 Fed. Reg. 70573, 70575 (November 24, 2000). FDA has stated that six dosage strengths (0.0625 mg; 0.125 mg; 0.1875 mg; 0.250 mg; 0.375 mg; 0.500 mg) were approved in 1997. However, as the Exclusivity Petition argued, Covis (now Concordia) believes the Agency only fully approved the 0.125 mg and 0.250 mg dosage strengths in 1997. 26 65 Fed. Reg. 70573, 70575 (November 24, 2000). 27 Available at http://www.accessdata.fda.gov/scripts/cder/dtugsatfdalindex.cfm. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 7

• Jerome Stevens- ANDA 76-268 (approved July 26, 2002) • Sun Pharmaceuticals- ANDA 76-363 (approved January 31, 2003) • Hikma-ANDA 77-002 (approved October 30, 2007) • Impax Labs- ANDA 78-556 (approved July 20, 2009)

All five ANDAs are rated "AB" in the Orange Book. In October 2013, FDA approved a PAS for two additional Lanoxin tablet dosage strengths (0.0625 mg and 0.1875 mg).

III. BIOEQUIVALENCE REQUIREMENTS

A. In General

FDA must determine that a generic drug is bioequivalent to the RLD before the Agency will approve it.28 Bioequivalence is considered to be the absence of significant difference in rate and extent of availability of an active ingredient or active moiety in pharmaceutical equivalents29 or pharmaceutical alternatives30 when administered at the same molar dose, under similar conditions, in an appropriately-designed study.31 The generic sponsor must compare the exposure profiles of the test drug and the RLD. 32 The key measurements include AUC, a surrogate measurement for total drug exposure, and Cmax, a surrogate measurement for rate of drug absorption. The test and reference AUC and Cmax values are compared using the two one­ sided tests procedure, and the 90% CI must be entirely within the bioequivalence limits of 80- 125% (i.e., the 90% CI is between 80-125% ofthe RLD mean value).33 This historical80-125% range is based on the assumption that a 20% difference between the test and reference products is not clinically significant to the patient.34

28 21 C.F.R. § 320.21(b)(1). 29 Pharmaceutical equivalents are drug products in identical dosage forms that contain identical amounts of the identical active drug ingredient; do not necessarily contain the same inactive ingredients; and meet the identical compendia! or other appropriate standard of identity, strength, quality, purity, and potency, as well as- where applicable- content uniformity, disintegration times, and/or dissolution rates. 21 C.F.R. § 320.1(c). 30 Pharmaceutical alternatives are drug products that contain the identical therapeutic moiety (or its precursor), but not necessarily in the same amount or dosage form or as the same salt or ester; each drug product meets either the identical or its own compendia! or other appropriate standard of identity, strength, quality, purity, and potency, as well as- where applicable- content uniformity, disintegration times, and/or dissolution rates. 21 C.F.R. § 320.1(d). 31 21 C.F.R. § 320.1(e). 32 FDA, "Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -General Considerations" (March 2003), available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM070 124.pdf, at 2 (hereinafter "Bioavailability/Bioequivalence Guidance"). 33 Davit B.M. et al. Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the U.S. Food and Drug Administration. THEAAPS JOURNAL 14(4):915-924 (December 20 12). Note that, according to FDA guidance, the Agency recommends that the range values should not be rounded; the values should be 80.00 and 125.00. Bioavailability/Bioequivalence Guidance, at 23. For simplicity, we refer to "80-125%." 34 57 Fed. Reg. 17950, 17973 (April28, 1992) ("there is a presumption that most drug products show no significant difference from the rate and extent of absorption of the listed drug and that the differences are unlikely to be Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 20 15 Page 8

FDA regulations outline several methods for establishing bioequivalence/5 and the sponsor must use the "most accurate, sensitive, and reproducible approach available. "36 Based on these criteria FDA has established a list of acceptable study designs, with the Agency's preference being measurement of the in vivo concentration of the active ingredient, active moiety, or active metabolite in a biological fluid such as blood over time. 37

The regulations also address bioequivalence study design, which generally (1) is a single­ dose comparison of the proposed generic drug and the RLD in normal adults; (2) is conducted in the fasting state; (3) is a crossover design; and (4) provides for a drug elimination period that is at least three times the half-life of the active drug ingredient, therapeutic moiety, or active metabolite in blood or urine (or at least three times the half-life of acute pharmacological effect decay). 38 FDA permits deviations from these general parameters when there is a valid scientific reason to do so. For example, although non-replicate crossover studies are recommended for immediate-release ~nd modified-release oral dosage forms, FDA recognizes that replicate designs may be useful. 39 The Agency also notes that it may be pertinent to conduct the bioequivalence studies in the indicated patient population rather than in healthy individuals.40

The January 1977 Federal Register preamble establishing bioequivalence requirements specifically highlighted NTI drugs, stating that "[t]he Commissioner believes that a determination of bioequivalence is most critical in a drug product that has a narrow therapeutic toxicity dosage range and requires careful patient titration and monitoring for safe and effective use."41 This same notice stated that in vivo human bioequivalence studies would be appropriate for NTI drugs, even though the Agency believed that the majority of drugs did not require in vivo human studies.42 clinically significant in patients when their absorption (AUC and CmaJ is within 20% of the listed drug in normal subjects, and the probability that the results occurred by chance is less than 5 percent (p<.05))"; FDA, Advisory Committee for Pharmaceutical Science and Clinical Pharmacology, July 26, 2011 Briefmg Information, available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dmgs/AdvisoryCommitteeforP harmaceuticalScienceandClinicalPharmacology/UCM263465.pdf (hereinafter "20 11 AC Briefmg"); Orange Book, 35th ed. (2015), at ix. 35 21 C.P.R. § 320.21(e). 36 21 C.P.R. § 320.24(a). 37 The other appropriate measurements (in descending order of Agency preference) include: (1) a human in vivo test measuring urinary excretion of the active moiety or active metabolite over time; (2) a human in vivo test measuring an appropriate acute pharmacological effect ofthe active moiety or active metabolite over time if an effect can be measured with accuracy, sensitivity, and reproducibility; (3) appropriately-designed comparative clinical trials; ( 4) an in vitro test to measure in vivo bioavailability that is acceptable to FDA; or (5) "any other approach deemed adequate by FDA to measure bioavailability or establish bioequivalence." 21 C.P.R. § 320.24(b)(1)-(6); Bioavailability/Bioequivalence Guidance, at 6-11. 38 21 C.P.R.§ 320.26(a), (b). 39 Bioavailability/Bioequivalence Guidance, at 7. 40 Bioavailability/Bioequivalence Guidance, at 8. 41 42 Fed. Reg. 1624, 1626 (January 7, 1977). 42 42 Fed. Reg. 1624, 1627 (January 7, 1977). Division of Dockets Management U.S. Food.and Drug Administration Department of Health and Human Services December 1, 2015 Page 9

FDA's bioequivalence regulations do not specifically differentiate between testing methods or preferences for NTI drugs versus non-NTI drugs. The regulations do provide that FDA will consider certain factors to identify drugs that are not bioequivalent, including drugs with a "narrow therapeutic ratio."43 At the time the Agency issued the 2003 Bioavailability/Bioequivalence Guidance, FDA recommended that the bioequivalence limits for NTI drugs should be the same as non-NTI drugs (i.e., 80-125% limit for AUC and Cmax) unless otherwise noted.44 Since 2003, however, FDA and the AC have recommended and adopted changes to the optimal way to establish bioequivalence for NTI drugs, as detailed in the next section.

B. NTIDrugs

Beginning ten years ago, FDA sought the recommendations of the AC on appropriate bioequivalence requirements for drugs with wide within-subject and narrow between-subject variability ("highly variable" drugs), as well as drugs with narrow within-subject and wide between-subject variability (NTI drugs). The preliminary discussions primarily focused on highly variable drugs, which set the basis for later addressing specific NTI drug bioequivalence recommendations.

1. AC Meetings in 2004 and 2006

In 2004 and 2006, FDA sought the AC's recommendations on existing bioequivalence measures for highly variable drug products,45 defined as having a within-patient variation 2: 30%.46 Historically FDA only required a point estimate of 80-125% without calculation of a CI. Once the Agency began requiring fed bioequivalence studies, FDA also began requiring use of a 90% CI. 47 In the case of highly variable drugs, the very large number of individuals needed for bioequivalence studies caused the AC and FDA to reconsider its requirements for these drugs. The AC suggested using a reference scaling approach and a limit on the point estimate. 48 Furthermore, AC discussions noted that "[s ]caling based on variability of the reference product both for highly variable drugs and for certain agency-defined narrow therapeutic index drugs,

43 FDA will consider"[e ]vidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2- fold difference in median lethal dose (LD50) and median effective dose (ED50) values, or have less than a 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood, and safe and effective use of the drug products requires careful dosage titration and patient monitoring." 21 C.F.R. § 320.33(c). 44 Bioavailability/Bioequivalence Guidance, at 20. 45 See generally background materials for April14, 2004 Advisory Committee meeting, available at http://www.fda.gov/ohrms/dockets/ac/cder04.html#PharmScience (hereinafter "2004 AC Background"); see also generally background materials for October 6, 2006 Advisory Committee meeting, available at http://www. fda. govI ohrms/dockets/ac/ cder06 .html#PharmScience (hereinafter "2006 AC Background"). 46 Advisory Committee Transcript (April14, 2004), at 11-12, 16 (hereinafter "2004 AC Transcript"). 47 Advisory Committee Transcript (October 6, 2006), at 0186-0188 (hereinafter "2006 AC Transcript"). 48 Advisory Commjttee Summary Minutes (April14, 2004), at 5 (hereinafter "2004 AC Minutes"). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 10

again average bioequivalence with scaling could solve this issue (emphasis added)."49 Therefore, both the AC and FDA recognized that highly variable drugs 50 as well as NTI drugs pose particular bioequivalence challenges.

2. AC Meetings in 2010 and 2011

In April201051 and July 2011/2 the AC specifically discussed NTI drug bioequivalence issues. The Agency asked the AC to consider whether: (1) NTI drugs are a distinct group of products, how they should be defined, and if FDA should prepare a list; (2) the existing bioequivalence standards are sufficient for NTI drugs or how they should be revised; and (3) the assay potency standard for NTI drugs should be tightened.

a. Recommended NTI Drug Definition and Creation of a List

In 2010, the AC considered whether "critical dose drugs" (i.e., NTI drugs) are unique products and how they should be defined. FDA presented the AC with a list of preliminary defining criteria, including the need for therapeutic drug concentration or PD monitoring due to the ability of small dose or concentration differences to cause serious therapeutic failures or serious drug reactions. 53 Because of the narrow range of within-patient variability, the need for blood level monitoring during NTI drug use is critical to safety and ensuring that an efficacious dose does not become toxic. The AC unanimously voted (with one abstention) that NTI drugs are in fact a distinct group of products and that FDA should prepare a formal definition of these drugs for further review. 5

The AC also unanimously voted that FDA should develop a publicly-available list ofNTI drugs with information about how products are added and removed from the list. 55 The AC acknowledged the difficulty but importance of creating such a list and not merely relying on

49 2004 AC Transcript, at 66. 50 Haidar S.H. eta!. Evaluation of a Scaling Approach for the Bioequivalence of Highly Variable Drugs. THE AAPS JOURNAL 10(3):450-454 (September 2008), at 451. 51 See generally background materials for April13, 2010 Advisory Committee meeting, available at http://www.fda.gov/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ AdvisoryCommitteeforPharmaceutic alScienceandClinica1Pharmacology/ucm20 1700.htm (hereinafter "20 10 AC Background"). 52 See generally background materials for July 26, 2011 Advisory Committee meeting, available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmaceutic alScienceandClinica1Pharmacology/ucm240583.htm (hereinafter "2011 AC Background"). 53 Advisory Committee Transcript (Aprill3, 2010), at 41-42 (hereinafter "2010 AC Transcript"); Gary Buehler, FDA, "History ofBioequivalence for Critical Dose Drugs" (slides presented at Aprill3, 2010 meeting) (hereinafter "2010 AC Buehler Slides"). 54 FDA, Advisory Committee Summary Minutes (Aprill3, 2010), at 4 (hereinafter "2010 AC Minutes"). The Advisory Committee preferred the term "NTI drug" in lieu of"critical dose drug" because "critical" can have different meanings for different individuals. 55 2010 AC Minutes, at 4. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 11 historical examples of well-recognized NTI drugs. 56 The AC observed that such a list would have to be monitored and continuously updated, particularly as more is learned about a drug when it is used in the general population after its approval. 57

In July 2011, FDA proposed a more formal definition of "NTI drugs" as those products "where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions. Serious events are those which are persistent, irreversible, slowly reversible, or life-threatening." FDA recognized that NTI drugs are generally characterized by (1) a steep dose/response curve for safety and efficacy in the usual dosing interval, or small differences in concentrations between effective doses and toxic doses; (2) the need for therapeutic monitoring based on PK or PD measures; and (3) small within-subject variability. 58 The AC again voted unanimously (with two abstentions) that this proposed definition was reasonable and appropriate, even though the AC made several recommendations for future revisions, such as making the definition more quantitative and addressing sources of variability attributed to individual patients, batches, and manufacturers. 59 As will be shown herein, digoxin is an NTI drug.

b. Recommended NTI Drug Bioeguivalence Standards

FDA also asked the ACto consider whether the existing bioequivalence testing standards were sufficient for NTI drugs. The AC discussed whether the historic 90% CI range of 80-125% for both AUC and Cmax measurements was appropriate, and how study design changes could improve reliability ofbioequivalence assessments for these products.

(i.) Narrowing Bioequivalence Limits to 90-111.11%

Because NTI drugs are characterized by narrow within-patient variability, both FDA and the AC were concerned that the traditional bioequivalence limits of 80-125% would not ensure safe product substitution. At the 2010 AC meeting, the Agency presented a hypothetical situation in which one generic drug has a bioequivalence range of 85-90% and another generic drug has a range of 115-120%. In this case, even though both drugs fall within the historical 80-

56 2010 AC Transcript, at 158-159 (Dr. Jerry Collins, National Cancer Institute: "I think it would be helpful to have [a list], but not the 20-year-old list of our old favorites. I would not underestimate the amount of work that's necessary to compile a list like this. No one has ever sat down and done it, other than a group of folks sitting around just thinking of older drugs."). 57 2010 AC Transcript, at 160 (Dr. Tway, industry representative: "So for those drugs that are narrow therapeutic index, then post-marketing surveillance as the drugs are approved and moved on, you may fmd that there are drugs that could come off the list or need to be added to the list."). 58 Lawrence Yu, FDA, "Approaches to Demonstrate Bioequivalence of Critical Dose Drugs" (slides presented at Aprill3, 2010 meeting) (hereinafter "2010 AC Yu Slides"). 59 FDA, AC Summary Minutes (July 26, 2011 ), at 4-5 (hereinafter "20 11 AC Minutes"). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 12

125% limits, there could be therapeutic problems for a patient if one drug is substituted for the other. 60

At the 2010 meeting, the AC reviewed FDA simulations of various bioe~uivalence approaches for NTI drugs, 61 and considered how other countries treat such products.6 The AC voted 11-2 that the current bioequivalence standards were not sufficient for NTI drugs. The AC specifically addressed a narrowed bioequivalence range of 90-111.11% (including the 100% or 1.0 point), even though some members were concerned that FDA had not Eresented enough data to demonstrate that this particular range should be adopted for NTI drugs. 3 Although there was no formal2010 AC vote on a new 90% CI range of 90-111.11%, FDA nonetheless voiced its support for this recommendation at the July 2011 meeting. This narrowed 90-111.11% range was "adopted" for discussions during the 2011 meeting without FDA asking for a vote. 64

(ii.) Study Design

In 2011, the AC considered two different aspects of NTI drug bioequivalence study design. First, it recommended (by a 12-1 vote) that the bioequivalence testing consist of a 2- treatment, 4-period, fully-replicated crossover design. 65 A 4-period design allows replicated testing of both the test and reference products to obtain separate estimates of their variance. This approach provides an assessment of the pharmaceutical quality of each formulation, 66 and this design was viewed as providing valuable information about the test and reference drugs. Second, the AC voted unanimously (with one abstention) to adopt a RSABE approach. 67 Products with both high and low within-subject variability can be tested using reference scaling, which adJusts the bioequivalence limits by scaling to within-subject variability of the reference product.6 The RSABE, which FDA first developed in 2004, 69 permits within-patient variations

60 2010 AC Yu Slides. 61 Donald J. Schulmann, FDA, "Evaluation of Scaling Approaches to Demonstrate BE ofNTI Drugs- OGD Simulation Efforts" (slides presented at July 26, 2011 meeting) (hereinafter "20 11 AC Schulmann Slides"). 62 Barbara M. Davit, FDA, "FDA Proposal for Bioequivalence of Generic Narrow Therapeutic Index Drugs" (slides presented at July 26, 2011 meeting) (hereinafter "20 11 AC Davit Slides"). 63 2010 AC Minutes, at 5. 64 FDA, AC Transcript (July 26, 2011), at 245 (Dr. Yu, FDA: "[L]ast year, you already proposed a bioequivalence limit of 90 to 111.111 percent. We thought it was a good approach. So, therefore, we didn't ask you for additional deliberation and the vote here.") (hereinafter "2011 AC Transcript"). 65 2011 AC Minutes, at 5. 66 Kamal K. Midha, University of Saskatchewan College of Pharmacy and Nutrition, "Narrow Therapeutic Index Drugs: An Approach to Bioequivalence and Interchangeability" (slides presented at July 26, 2011 meeting) (hereinafter "20 11 AC Midha Slides"). 67 2011 AC Minutes, at 5. 68 Davit B. and Conner D. Reference-Scaled Average Bioequivalence Approach, in Kaufer I. and Shargel L., eds., Generic Drug Product Development- International Regulatmy Requirements for Bioequivalence. New York, NY: Informa Healthcare, 2010: 271-272.; Davit B.M. et al. Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration. THEAAPS JOURNAL 14(4):915-924 (December 2012); Desai J. and Jain P. Reference Scaled Average Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 20 15 Page 13

to be considered during product testing and has supported several FDA approvals of highly­ variable generic drugs as well. 70

c. Assay Potency Standard for NTI Drugs

Finally, the AC considered whether the typical active pharmaceutical ingredient ("API") content variation of 90-110% should be narrowed for NTI drugs. The AC unanimously voted to narrow the potency standard for NTI drugs to 95.0-105.0%. This range had been discussed for NTI chugs in the past (e.g., levothyroxinef1 and is consistent with the potency standards in other countries of the world. However, the AC noted that other issues affecting potency should be addressed, including stability, content uniformity, and variability.72

3. Current Status ofNTI Drugs in the US.

The bioequivalence regulations do not at this time differentiate between NTI and non­ NTI drug products, although they do specify that FDA will consider factors such as "narrow therapeutic ratio" to identify drugs that are not bioequivalent. 73 This regulation, promulgated in 1977 and amended in 1992, was issued far in advance ofthe 2010 and 2011 AC meetings. The AC concluded that NTI drugs do have unique characteristics that must be considered when designing and evaluating bioequivalence studies. Although FDA has never formally amended its regulations to establish NTI drug bioequivalence standards through notice-and-comment rulemaking, in practice the Agency has already adopted the AC's recommendations.74

For example, a 2011 FDA presentation to drug manufacturers noted that "[t]he FDA's new quality and bioequivalence standards for NT! drugs will bring the US into harmony with other regulatory agencies 75 and improve public confidence in quality and switchability of generic drugs."76 FDA also stated during that presentation that it would "[p]ublish the draft FDA's

Bioequivalence: Scaling Approach for the Highly Variable Drugs. INTERNATIONAL J. PHARMACEUTICAL RESEARCH AND INNOVATION 4:20-21 (2011). 69 Davit 2012, at 921. 70 Davit 2012, at 920-921 (noting that FDA had fully approved four (and tentatively approved one) highly-variable drugs using the RSABE approach). 71 2011 AC Transcript, at 338-339. 72 2011 AC Minutes, at 5-6. 73 FDA will consider"[e ]vidence that the drug products exhibit a narrow therapeutic ratio, e.g., there is less than a 2- fold difference in median lethal dose (LD50) and median effective dose (ED 50) values, or have less than a 2-fold difference in the minimmn toxic concentrations and minimum effective concentrations in the blood, and safe and effective use of the drug products requires careful dosage titration and patient monitoring." (21 C.F.R. § 320.33(c)). 74 Davit B. et al. International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences. THE AAPS JOURNAL 15(4):974-990 (October 2013), at 985 ("In 2011, FDA presented a proposal on BE requirements for generic NTI drugs before its Advisory Committee; the Committee agreed with the proposal summarized below, which is still under development."). 75 These NTI drug bioequivalence standards in other parts of the world are discussed in Section IV.C., infi'a. 76 Lawrence Yu, FDA, "Quality and Bioequivalence Standards for Narrow Therapeutic Index Drugs" (slides presented at GPhA 2011 Fall Technical Workshop), available at Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 14

approach for NTI drugs (warfarin etc) at the FDA individual product bioequivalence guidance."77 As discussed in Section IV.A. herein, FDA has in fact included several of the AC's NTI drug bioequivalence recommendations, such as the 4-way crossover study design and the RSABE approach, in a number of product-specific guidance documents.

Furthermore, in 2013 the U.S. Department of Health and Human Services ("DHHS") issued a funding opportunity announcement to assist FDA with its efforts to develop a list ofNTI drugs and "implement the NTI policy." The purpose of the project was to gather patient data on therapeutic monitoring and drug dose adjustments to assist in preparing such a list. The funding announcement noted that, in 2011, the Agency "proposed tighter quality and bioequivalence (BE) standards for NTI drugs."78

Finally, the Agency recently denied a citizen petition requesting NTI drug status recognition for dalfampridine. In doing to, it is apparent that FDA is applying these AC recommendations in practice. The petition79 asserted that dalfampridine is an NTI drug, and thus generics must meet specific bioequivalence criteria. FDA's May 2015 denial80 of that petition rejected the purported NTI drug status of dalfampridine, differentiating its characteristics from those of warfarin. 81 FDA also rejected the argument that the bioequivalence interval for this product should be 90-111% because the drug is not an NTI drug. 82 Finally, the Agency determined that a fully-replicated, 4-way, crossover study is not necessary for generic dalfampridine approval, even though "[t]his design is often used to assess the bioequivalence of NTI drugs."83 FDA concluded that "standard BE acceptance criteria and study design" are appropriate for dalfampridine bioequivalence studies. 8 This Agency response is further evidence that FDA has accepted and applies the NTI drug bioequivalence criteria when appropriate.

Despite FDA's acceptance of the AC's recommended NTI drug bioequivalence criteria, the Agency has not amended the digoxin guidance. The existing digoxin AND As were approved before these NTI drug policies evolved, and even before the issuance of the current (2008) digoxin guidance. Not only should the digoxin guidance be revised to incorporate the AC's recommendations, but FDA should also re-examine the basis on which the generic digoxin

http://www.fda.gov/downloads/dmgs/developmentapprovalprocess/howdrugsaredevelopedandapprovedlapprovalap plications/abbreviatednewdrugapplicationandagenerics/ucm292676.pdf (hereinafter "20 11 GPhA Yu Slides"). 77 2011 GPhA Yu Slides. 78 DHHS, Funding Opportunity Announcement Number RFA-FD-13-020, available at http://grants.nih.gov/guide/rfa- files/RF A-FD-13-020 .html. 79 Citizen Petition filed by Acorda Therapeutics, Inc. (December 12, 2014). 80 Petition Denial from Janet Woodcock, FDA, to Acorda Therapeutics, Inc. (May 14, 2015) (Docket No. FDA- 2014-P-2193) (hereinafter "Dalfampridine Petition Denial"). 81 Dalfampridine Petition Denial, at 7. 82 Dalfampridine Petition Denial, at 8-9. 83 Dalfampridine Petition Denial, at 9. 84 Dalfampridine Petition Denial, at 11. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 15

products were approved. Based on available evidence, the Agency should conclude that these drugs are not bioequivalent, and therefore not therapeutically equivalent, to Lanoxin.

IV. FIRST ARGUMENT: THE DIGOXIN BIOEQUIVALENCE GUIDANCE SHOULD BE AMENDED TO INCLUDE THE AC's NTI DRUG BIOEQUIVALENCE RECOMMENDATIONS

A. FDA Has Already Drafted or Revised Other NTI Drug-Specific Guidance

As the regulatory history illustrates, the Agency clearly recognizes that digoxin is an NTI drug. Yet, unlike other NTI drugs, the digoxin bioequivalence guidance does not incorporate any of the AC's recommendations. FDA should therefore amend the guidance to include the NTI drug bioequivalence criteria recommendations, including at a minimum those criteria already included in other NTI drug guidance documents: (1) conducting a 4-period, fully­ replicated crossover design for both in vivo fasting and fed studies; and (2) using an RSABE approach. The digoxin guidance should also be amended to include the other AC recommendations discussed above as well, namely: (3) meeting a bioequivalence range of 90- 111.11% for the 90% CI for both AUC and Cmax and require that the data "cross the one" (i.e., cross the 100% point); and (4) meeting a drug substance potency range of 95.0-105.0%. 85 FDA's current bioequivalence recommendations for other NTI drugs are summarized below.

Product and · Recommended Studies Why Drug is NTI Guidance Date86 Carbamaze72.ine extended- 2 studies: fasting and fed single-dose, 2- (1) Range between effective and toxic release tablets; oral treatment, 2-sequence, 4-period, fully- concentrations narrow replicated crossover studies in vivo (2) Sub-optimal doses or concentrations Recommended February cause therapeutic failure or severe toxicity 2008; Revised March 2015 RSABE for both studies (3) Subject to therapeutic monitoring based on PK measures (4) Low to moderate within-subject variability Carbamaze~12.ine extended- 3 studies: fasting, fed, and fasting (capsule Same as above release capsules; oral sprinkled on applesauce) single-dose, 2- treatment, 2-sequence, 4-period fully- Recommended March replicated crossover studies in vivo 2004; Revised November 2007 and March 2015 RSABE for all studies Carbamaze12ine 2 studies: fasting and fed single-dose, 2- Same as above suspension; oral treatment, 2-sequence, 4-period, fully- replicated crossovers studies in vivo Recommended May 2008;

85 The current USP Digoxin Tablets monograph states that the tablets "contain not less than 90.0 percent and not more than 105.0 percent of the labeled amount" of digoxin. USP 38/NF 33, through First Supplement (official August 1, 2015). 86 All product-specific bioequivalence guidance documents are found on FDA's "Product-Specific Recommendations for Generic Drug Development" webpage, available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/ucm075207.htrn. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 16

Product.and Recommended Studies· .Why Drug is NTI. 86 . Guidance Date ·. .. '..· revised March 2015 RSABE for both studies Levothrroxine sodium 1 study: fasting single dose, 4-way, fully- (1) Range between effective and toxic tablet; oral replicated crossover study in vivo concentrations naiTow (2) Some toxicities are serious and/or Recommended December May consider using RSABE approach ilTeversible 2014 (3) Sub-therapeutic levels lead to poor clinical outcomes (4) Requires dose titration (5) Therapeutic drug monitoring routine (6) Small to medium within-subject variability Phen}!_toin sodium extended 4 studies: fasting and fed single-dose, 2- (1) Range between effective and toxic release capsule; oral treatment, 2-sequence, 4-period, fully- concentrations narrow replicated crossover in vivo studies (dose = (2) Sub-optimal doses or concentrations Recommended May 2007; 3x100 mg); same fasting and fed study cause therapeutic failure or severe toxicity Revised December 2014 designs with dose= 10x30 mg (3) Subject to therapeutic monitoring based on PK measures RSABE for all studies (4) Low to moderate within-subject variability (5) Doses adjusted in small increments ( < 20%) in clinical practice Phen}!_toin sodium extended 2 studies: fasting and fed single-dose, 2- Same as above release capsule; oral treatment, 2-sequence, 4-period, fully- replicated crossover studies in vivo Recommended May 2007; Revised December 2014 RSABE for both studies War{grin sodium tablet; 2 studies: fasting and fed 4-way fully- (1) NaiTow range between therapeutic and oral replicated crossover studies in vivo toxic doses or associated blood or plasma concentrations (i.e., exposures) Recommended December May consider using RSABE approach (2) Toxicities are serious and not 2012 symptomatic or reversible (3) Subtherapeutic concentrations may lead to serious and life-threatening concentrations ( 4) Subject to therapeutic monitoring based on PD markers (5) Low within-subject variability

Each of these guidance documents was recommended, finalized, or revised after the 2010 and 2011 AC meetings. As a result, each incorporates several of the NTI drug bioequivalence recommendations. The digoxin guidance, on the other hand, was finalized before these AC meetings. It has never been amended to include any of the AC's recommendations for bioequivalence studies, even though there is no dispute that digoxin is an NTI drug.

At a minimum, FDA should revise the digoxin bioequivalence guidance to reflect the same recommendations made in these other documents. However, the Agency should also Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 17 implement the AC's recommendations with respect to a narrowed bioequivalence range of 90- 111.11% and a narrowed potency range of 95.0-105.0%. These additional recommendations are particularly salient here because of the ongoing product specification, tablet splitting, and cGMP issues for digoxin products as discussed in Section V.B., C., and D., below.

C. Updated NTI Drug Bioequivalence Requirements Will More Closely Align the U.S. with Other Countries

In October 2013, FDA published an article87 on the similarities and differences between bioequivalence requirements on systemically available, orally administered generic drugs, including NTI drugs, across various regions of the world. As demonstrated by the table below, 88 FDA's treatment ofNTI drugs does not generally align with these other regions. Amending the digoxin bioequivalence guidance document to more closely adhere to. the AC's recommendations would make the U.S. approach more similar to the approaches in these other countries and regions, and would help alleviate the difficulties of adhering to multiple bioequivalence standards.

Australia Generic NTI drugs must reference a drug product marketed in Australia FollowsEMA Canada Provides list of "critical dose" drugs 90% CI for AUC = 90.0-112.0 (inclusive) 90% CI Cmax = 80.0-125.0 (inclusive) China If the drug has an especially narrow therapeutic range, bioequivalence limits may need to be Singapore tightened if clinically justified WHO EMA Does not define a set of criteria for NTI drugs; based on case-by-case determination AUC = 90.00-111.11% If Cmax is particularly important for safety, efficacy, or drug level, then Cmax = 90.00- 111.11% Japan Provides list ofNTI chugs AUC, Cmax=90.00-111.11% u.s. AUC, Cmax = 80-125% (as of date of Per 2011 AC meeting: (1) develop defmition ofNTI drug and post for notice and comment; article (2) require potency specifications of95-105%; (3) when within-patient variability <20%, publication) use RSABE; ( 4) if within-patient variability 2': 20%, then use 80-125%; ( 5) develop statistical methods to assure that within-subject variability of generic product does not exceed RLD; (6) post recommendations for NTI drugs in product-specific bioequivalence _g_uidance documents

Many other countries already hold NTI drugs to a different bioequivalence standard than non­ NTI drugs. When FDA published its article in late 2013, it acknowledged that it was further

87 Davit B. et al. International Guidelines for Bioequivalence of Systemically Available Orally Administered Generic Drug Products: A Survey of Similarities and Differences. THE AAPS JoURNAL 15(4):974-990, at 985 (October 2013). 88 Note that not all countries listed in the original published article are included here. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 18

developing its NTI drug bioequivalence standards, but that it would be following the AC's earlier recommendations regarding narrowed acceptance criteria, narrowed potency specifications, and the use of the RSABE approach. 89 As discussed, FDA has already in practice adopted these AC recommendations and incorporated some of them into its product-specific guidance documents. Likewise, these criteria also need to be added to the digoxin guidance to ensure continued approval and use of safe generic digoxin products. v. SECOND ARGUMENT: GENERIC DIGOXIN DRUG PRODUCTS ARE NOT THERAPEUTICALLY EQUIVALENT TO LANOXIN AND SHOULD BE RATED BX

A. Therapeutic Equivalence Depends Upon Bioequivalence

FDA's Orange Book lists therapeutic equivalence evaluations for multisource prescription drug products approved under FFDCA § 505.9° FDA bases these determinations on several factors. For example, the Agency will conclude that two products are not therapeutically equivalent if they are not ~ioequivalent. Likewise, if a generic drug is not manufactured according to cGMPs, then it cannot be therapeutically equivalent to the RLD. In light of bioequivalence and cGMP concerns for digoxin, FDA should change the rating for these generic drugs from AB to BX. This is not a novel concept. As addressed below, problems with the generic versions of Concerta® illustrate the need to amend therapeutic equivalence ratings for approved AND As by assigning a BX rating when warranted. This is the case with digoxin.

Drug products must meet a number of criteria to be considered therapeutically equivalent. These criteria include the following: 91

(1) The generic drug is approved as safe and effective; and (2) The generic drug and RLD are "pharmaceutical equivalents" (a) They contain identical amounts of the same API, in the same dosage form and route of administration; and (b) They meet compendia! or other standards of strength, quality, purity, and identity; and (3) The generic drug and RLD are bioequivalent (a) They do not present a bioequivalence problem (known or potential); or (b) If they do pose a known or potential problem, they meet an appropriate bioequivalence standard; and (4) The generic drug is adequately labeled; and (5) The generic drug is manufactured in accordance with cGMPs. - As the Orange Book notes, "FDA believes that products classified as therapeutically equivalent can be substituted with the full expectation that the substituted product will produce the same

89 Davit 2013, at 984. 90 Orange Book, at iv. 91 Orange Book, at vii. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 19

clinical effect and safety profile as the prescribed product" (emphasis added).92 The Agency has rated digoxin tablets as "AB," indicating that the drugs have "actual or potential bioequivalence problems" that have been addressed with adequate evidence (in vivo or in vitro) that supports a finding of bioequivalence. According to FDA, these products are therapeutically interchangeable. On the other hand, drugs rated "BX" are those drugs for which there is insufficient data to determine therapeutic equivalence "under the policies stated in this document [the Orange Book]."93 Demonstrating a lack of safety or effectiveness is not required.

There are several reasons why generic digoxin tablets should be rated BX. First, the design of the bioequivalence studies for at least tln·ee of the five approved ANDAs does not meet the AC's contemporary recommendations for NTI drug bioequivalence study design or acceptance criteria. Second, digoxin has a history of bioavailability, dissolution, content uniformity, and potency issues that exacerbate bioequivalence testing and which are compounded by concerns over tablet splitting, particularly in the elderly. Third, recent generic digoxin recalls establish that some of these products are not meeting cGMP requirements - another critical aspect of therapeutic equivalence. Finally, several States have already recognized that NTI drugs should not routinely be substituted. Each of these reasons supporting a BX rating for digoxin is discussed herein

B. Several Approved Generic Digoxin Drugs Do Not Meet the AC NTI Drug Bioequivalence Recommendations

A review of bioequivalence data for three of the approved digoxin AND As reveals that those generic drugs do not meet the AC's contemporary NTI drug bioequivalence recommendations. 94 Using more current and scientifically appropriate NTI drug bioequivalence standards, these drugs would not be bioequivalent to Lanoxin.

1. Mylan ANDA 40-282

Mylan conducted two bioequivalence studies in suppmi of its ANDA approval. One of these studies was a 3-way crossover randomized study (test/fasted; test/fed; reference/fed) that enrolled 21 normal healthy males (19 completed the study). The individuals received 2 x 0.25 mg tablets. The ratio of geometric means for test/reference ratio was 0.84 (AUCt), 0.86 (AUCi), and 0.98 (Cmax). According to FDA, "[r]atios of means for AUCt, AUCi, and Cmax between test non-fasting and reference non-fasting are within the acceptable limits of 80-125%."95 However, under the more current NTI drug acceptance criteria of 90-111.11%, the AUCt and AUC would fall outside ofthe lower end of this window (0.84 and 0.86, respectively).

92 Orange Book, at viii. 93 Orange Book, at xxi. 94 Information for the Mylan and Jerome Stevens AND As was available on FDA's Drugs@FDA webpage; the information for the Impax Labs ANDA was obtained through a Freedom of Information Act ("FOIA") request. 95 ANDA 40-282, Bioequivalence Review(s), Review of an Amendment: Bioequivalent Study and Dissolution Testing, at 2-7. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 20

The second bioequivalence study was an open-label, randomized, 2-way crossover study under fasting conditions. The study enrolled 26 normal healthy males (23 completed the study). Individuals were dosed with 2 x 0.25 mg tablets. The 90% CI for AUCh AUCt. and Cmax (as well as the log-transformed values of each) were reported as follows:

Lower90% CI Upper 90% CI AUCi 8920: 106.35 AUCt 90.87 107.67 Cmax 100.77 11.5.79, Log-transformed AUCi 89;5'1 107.20 Log_-transformed AUCt 91.54 108.73 Log-transformed Cmax 99.79 115.65

According to FDA, "[t]he 90% confidence intervals for the log-transformed AUCt, AUCi and Cmax were all within 80-125% range."96 However, under a more current NTI acceptance standard of 90-111.11%, AUCi and log-transformed AUCi fall below the lower limit of the 90% CI (89.20 and 89.57, respectively). Moreover, Cmax and log-transformed Cmax fall above the upper limit of 111.11% (115.79 and 115.65, respectively). Therefore, applying the AC's recommended NTI drug bioequivalence parameters, this generic drug would not be bioequivalent to Lanoxin.

Furthermore, FDA granted the firm's request for an in vivo bioequivalence waiver for the 0.125 mg dosage strength because the "formulation for the 0.125 mg strength is proportionally similar to the 0.25 mg strength that underwent bioequivalency testing.'m However, because the data indicate that the 0.25 mg dosage strength would not be found bioequivalent under the contemporary NTI drug standard, allowing a waiver for the 0.125 mg strength only raises additional questions about dose titration, therapeutic monitoring, and patient safety.

2. Jerome Stevens ANDA 76-268

Jerome Stevens similarly conducted two bioequivalence studies in support of ANDA approval. One study was designed as a randomized, 2-period, 2-treatment crossover study in fasting patients. The study population consisted of normal healthy male volunteers (28 enrolled, 27 completed, 24 subject sera analyzed). Individuals received 2 x 0.25 mg tablets. The data for the 90% CI included the following:

I Log-transformed AUCo-t 188;6-117------··'. .1%

96 ANDA 40-282, Bioequivalence Review(s), Review of an In Vivo Bioequivalence Study, Dissolution Data and Waiver Requests, at 2-9. 97 ANDA 40-282, Review of an Amendment: Bioequivalent Study and Dissolution Testing, at 1, 11. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 21

Log-transformed AUCo-t

Log-transformed AUCo-inf 89.1HIJ2;Q%

Log-transformed Cmax 85.~-106.2%

According to FDA, "[t]he reviewer substituted the original analytical values into the data set, statistically reanalyzed the data and found that the log-transformed 90% confidence intervals for LAUCt, LAUCh and Cmax changed only slightly and remained within the range of 80-125%. 98 However, using a 90-111.11% acceptance interval, all three data values fall outside the lower end of the range, and LAUCo-t and LAUCo-inf fall outside the higher end of the range (117.1 and 112.0, respectively).

The second bioequivalence study similarly was a randomized, 2-period, 2-treatment crossover study, but under fed conditions. Normal healthy male volunteers were included in the study (28 emolled, 27 completed, 24 subject sera analyzed). Individuals received 2 x 0.25 mg tablets. Although the arithmetic mean of AUCJAUC and arithmetic mean of T/R ratios were reported, no 90% CI values were included in the publicly available summary. According to FDA, "[t]he point estimates for AUCt, AUCb Cmax are within the acceptable limits of 80-125%." Furthermore, "[t]he firm reported that 90% confidence intervals for log transformed AUCo-t, AUCo-inf, and Cmax are within acceptable limits of 80-125%, but they are not currently required by DBE [Division ofBioequivalence] for food studies."99

Similar to the Mylan ANDA, FDA reviewers of this application waived the in vivo bioequivalence testing of the 0.125 mg strength because it is "proportionally identical" to the 0.25 mg strength. 100 This conclusion raises the same dose titration, therapeutic monitoring, and patient safety issues as expressed above.

3. Impax Labs ANDA 78-556

Like the sponsors of these other two AND As, Impax Labs similarly conducted a fasting and fed bioequivalence study on the 0.25 mg dosage strength. In these two studies, subjects only received 1 x 0.25 mg tablet rather than the 2 x 0.25 mg tablets used by Mylan and Jerome Stevens.

98 ANDA 76-268, Bioequivalency Review(s), Review of Two Bioequivalence Studies, Dissolution Data, A Waiver Request and New Correspondence (Long Term Stability Data on Digoxin in Frozen Serum), at 2-6. 99 ANDA 76-268, Bioequivalency Review(s), Review of Two Bioequivalence Studies, Dissolution Data, A Waiver Request and New Conespondence (Long Term Stability Data on Digoxin in Frozen Serum), at 6-9. 100 ANDA 76-268, Review of an Amendment (Long Term Stability Data on Digoxin in Frozen Serum), at 2. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 22

The first study was a fasting, single-dose, 2-treatment, 2-period crossover study in vivo in 34 healthy male and female adult subjects. Of these subjects, 31 were used in the statistical analysis. Although the sponsor presented the initial PK measurements, the sponsor re-integrated the data with both the original and current integration parameters in res~onse to an FDA deficiency letter. This re-integrated data for the fed study is presented below: 1 1

Fasting Study 90% CI- 90% CI- Original Current Integration Integration

AU Co-t 96.44-107.11 95.76-106.77

AUCinf 96.81-107.00 94.99-105.72

92.72-114:31 90.63-109.53 Cmax --- -·-··

Likewise, the second study was a fed, single-dose, 2-treatment, 2-period crossover study in vivo in 30 healthy male and female adult subjects. Of the 30 enrolled subjects, 29 completed the study and were used for statistical analyses. The sponsor similarly re-integrated the data for this study for the same reasons cited in the FDA deficiency letter. The re-integrated for the fasting study is presented below: 102

Fed Study 90% CI- 90% CI- Original Current Integration Integration

AU Co-t 96.46-113 .3 4 95.89-'112.88.

AUCinr 96.27-111.61·------··· 95.77-110.64

Cmax :88.88-120.~7 ~8.86,-140._35]

Upon reviewing this re-integrated data for both studies, FDA commented that "[t]he reviewer conducted statistical analysis using the data re-integrated using the original and current integration parameters. No significant difference was observed by using the current integration parameters for LAUCt, LAUCh and LCmax for digoxin." The Agency concluded, for both studies, that "[t]he 90% confidence intervals for digoxin of In-transformed AUCt, AUCb and

101 ANDA 78-556, Division ofBioequivalence Review, Review of an Amendment, Executive Summary, at 2. 102 ANDA 78-556, Division ofBioequivalence Review, Review of an Amendment, Executive Summary, at 3. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 23

Cmax ratios are within the acceptable limits of 80-125%."103 FDA also waived the bioequivalence studies for the 0.125 mg dosage strength, as it had with the other two generic digoxin products. 104

It is clear that many of the values for AUCo-t, AUCinf, and Cmax for the fed study fall outside of an NTI-appropriate 90% confidence interval of 90-111.11%. Although the fasting study data more closely align to this narrowed range, the Cmax value for the original integration (114.37) lies outside the upper limit of 111.11%. As is the case for the other two digoxin ANDAs, this data would not meet the NTI standard for demonstrating generic drug bioequivalence.

4. Summary

None of the studies discussed above for any of the ANDAs utilized a 4-way, fully­ replicated crossover design, and none of them used a RSABE approach. Based upon more contemporary NTI drug bioequivalence recommendations, these products would not meet the 90% CI acceptance criteria of 90-111.11% for both AUC and Cmax· In addition, the sponsors of these ANDAs were granted waivers of in vivo bioequivalence studies of the 0.125 mg dosage strength. In light of the NTI drug bioequivalence issues identified, waiving studies for the lower dosage strength only compounds the substitutability and safety concerns identified in this Petition.

The Administrative Procedure Act ("APA") and FDA's regulations require that the basis for Agency decisions be made publicly available for review. The decisions must be reasonable and reflect all of the facts. Moreover, the fact that not all digoxin ANDA BE reviews are publicly available violates the AP A and FDA regulations. 105 Until all the information is made publicly available, no AB rating in this factual situation is legally appropriate.

C. Continued Bioavailability, Dissolution, Content Uniformity, and Potency Concerns- Which are Exacerbated by Tablet Splitting, Particularly in the Elderly -Further Support a BX Rating

1. Digoxin Bioavailability, Dissolution, Content Uniformity, and Potency

Dissolution and content uniformity are critical to NTI drugs such as digoxin, as well as drugs with high excipient to API ratios such as Lanoxin tablets. Dissolution and content uniformity form part of the required chemistry, manufacturing, and control ("CMC") data in an application, 106 which in turn form part of the required cGMP data necessary for FDA to approve

103 ANDA 78-556, Division ofBioequivalence Review, Review of an Amendment, at 12, 14. 104 ANDA 78-556, Division ofBioequivalence Review, Review of an Amendment, Executive Summary, at 3. 105 21 C.F.R. § 20.20; 21 C.F.R. § 314.430(e). 106 The CMC section of an application must include tests, analytical procedures, and acceptance criteria for dissolution rate for a drug product. 21 C.F.R. § 314.50(d)(1)(ii)(a) [NDA requirements]; 21 C.F.R. § 314.94(a)(9)(i) Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 24

an application. These characteristics are therefore critical to the approval of safe and effective generic digoxin drugs.

As discussed, digoxin has historically had bioavailability and related specification problems. FDA addressed these issues by first implementing a voluntary certification program for FDA to test existing marketed products to assess compliance with USP potency and content uniformity requirements. Studies revealing differences in bioavailability between products (and lots of a single product) later led to mandatory certification of digoxin drugs. Because of a conelation between dissolution and bioavailability, this mandatory certification included performing USP digoxin monograph dissolution testing.

In 1974, FDA recognized the complexity of ensuring bioequivalence and potency from proper blend uniformity and dissolution methods when the Agency first addressed the problems of oral digoxin product uniformity, stating that "the commissioner has determined that immediate actions must be taken to assure better uniformity of all digoxin products for oral use."107 In the ensuing decades, digoxin production and testing methods evolved, and the Agency reassessed its labeling and other testing requirements. 108

These critical features of digoxin are also evident in FDA's regulation for "bioproblem" drugs. 109 When the API level in a drug product is extremely low, bioavailability, bioequivalence, potency, dissolution, and content uniformity are especially critical drug features. By regulation, the Agency has identified both NTI drugs110 and drugs with a greater than 5:1 excipient to API ratio 111 as those products for which FDA should recognize potential bioequivalence problems. In the case of digoxin, the excipient to API ratio in the 0.0625 mg (800:1) and 0.1875 mg (490:1) 112 Lanoxin tablets , for example, is two orders of magnitude greater than this 5:1 ratio the Agency has set as a benchmark for signaling possible bioequivalence concerns. Likewise, USP General Chapter <905> (uniformity of dosage units) states that tablets with a drug dose of less than 25 mg or a ratio of drug substance less than 25% should follow the content uniformity test to ensure um'£ orm1ty . ofd osage umts.. 113

[ANDA regulations cross-referencing CMC requirements for NDAs at 21 C.F.R. § 314.50(d)(1)]. Similarly, the CMC section must include in-process controls, which includes in-process testing requirements to ensure the adequacy of mixing for uniformity and homogeneity. 21 C.F.R. § 314.50(d)(l)(ii)(a) [NDA requirements]; 21 C.F.R. § 314.94(a)(9)(i) [ANDA regulations cross-referencing CMC requirements for NDAs at 21 C.F.R. § 314.50(d)(l)]; 21 C.F.R. § 211.110(a)(3) [setting forth requirement for adequacy of mixing]. 107 39 Fed. Reg. 2471, 2472 (January 22, 1974). 108 41 Fed. Reg. 17755, 17756 (April28, 1976). 109 21 C.F.R. § 320.33. 110 21 C.F.R. § 320.33(c). 111 21 C.F.R. § 320.33(e)(5). 112 The excipient to API ratios for the 0.125 mg (800:1) and 0.250 mg (490:1) are likewise two orders of magnitude greater than the 5:1 ratio identified by the Agency as being an indicator of potential bioequivalence problems. 113 General Chapter <905> Uniformity of Dosage Units, USP 38/NF 33, through First Supplement (official August I, 2015); Digoxin Tablets monograph, USP 38/NF 33, through First Supplement (official August 1, 2015) (requiring digoxin tablets to comply with <905>). Division ofDockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 25

This issue is particularly critical in drugs prescribed to elderly patients, as the pharmacokinetics of drug products is generally different in the elderly. 114 Physiological features associated with aging, including decreased lean body mass, gastrointestinal changes, reduced metabolism, and reduced renal function can have an impact on the absorption, distribution, metabolism, and excretion of drug products in elderly patients. 115 In the case of an NTI drug such as digoxin, such changes become even more significant and have a greater impact. 116 Even among otherwise healthy, younger patients, digoxin use requires careful dose titration and monitoring to assess digoxin levels and maintain a safe and effective blood level. Digoxin use in the elderly requires even more care. Not only do the physiological changes of aging, impact their ability to absorb, distribute, metabolize and excrete the drug, but memory loss and confusion common in elderly patients may create compliance issues that result in accidental overdosing and toxicity. 117 It is therefore critical that digoxin dosing in the elderly should start with a low dose, with slow upwards titration as necessary. 118

As addressed in Covis' Bioequivalence Petition, 119 FDA required that Covis include information on content uniformity and dissolution before the Agency would approve two new dosage strengths (0.0625 mg and 0.1875 mg). Covis had sought a waiver of testing requirements for these strengths, which the Agency implicitly rejected by responding that those strengths had never been manufactured and the labeling had never been reviewed. Covis therefore filed a PAS. During the prior approval inspection of the manufacturing facility, the inspector expressed concern about the thorough blending of ingredients, and directed the sponsor to be in full compliance with all blend uniformity testing requirements. Following this inspection, FDA issued a Complete Response letter requesting dissolution data for these two new strengths. This requirement for contemporary content uniformity and dissolution testing signifies the Agency's ongoing concerns about digoxin bioa~ailability. These difficulties ensuring bioavailability support the request to change the AB rating to BX.

2. Tablet Splitting by the Elderly Exacerbates these Digoxin Issues

Tablet splitting is becoming increasingly common as a way to save on drug costs, whether authorized by a physician or not. Tablet splitting is also used to accomplish dose titration and to assist with swallowing large drug products. 120 The concerns regarding tablet

114 Expert Statement, at ~10. 115 Expert Statement, at ~11 116 Id. 117 Expert Statement, at ~12. 118 Expert Statement, at ~14. 119 Bioequivalence Petition, at 4. 120 Shah R. et al. Tablet Splitting of a Narrow Therapeutic Index Drug: A Case with Levothyroxine Sodium. AAPS PHARMSCITECH 11(3);1359-1367 (September 2010); FDA, "Guidance for Industry- Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation" (March 20 13), available at Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 26

splitting have been well documented, including fragmentation, loss of mass, failed content of uniformity, friability, stability, and dissolution. 121 In one study, nearly 40% of Lanoxin tablet pmis showed 2: 15% deviation from the normal weight of a half-tablet. 122

Both the American Pharmacists Association ("APhA") and the American Medical Association ("AMA") have formally taken positions against mandatory tablet splitting. 123 FDA and USP have also been aware of these issues for some time. 124 FDA has, in fact, publicly acknowledged the risks associated with tablet splitting, and has issued consumer updates warning that the practice of tablet splitting is not only difficult, but that equal distribution of medicine in split tablets is questionable. 125 Additionally, requiring patients to split tablets rather than prescribing lower doses can have the effect of confusion regarding correct dose, which in turn may result in accidental over-dosing. 126 The problems associated with this practice are particularly heightened among the elderly patient population. Due to their greater physical limitations, issues with memory loss and comprehension, and polypharmacy (i.e., pill) burdens, elderly patients not only have greater difficulty with the physical act of tablet splitting, which exacerbates the uniformity and distribution issues associated with split tablets, but are also at greater risk of over-dosing. 127

In an attempt to mitigate these problems, FDA has issued guidelines for consumers that outline tablet splitting "best practices". 128 In particular, the Agency recommends that tableting splitting "should be done only under the supervision of a healthcare professional."129 However, in a real world setting, tablet splitting in the presence of a healthcare professional is rare and impractical, and so dosing and cutting errors and associated adverse events continue to occur.

Although these problems can arise when splitting any dmg product, they are particularly acute for NTI drugs such as digoxin. 130 In a case study involving another NTI drug (levothyroxine sodium), the authors concluded that tablets split by hand or with the aid of a http://www.fda.gov/Dmgs/GuidanceComplianceRegulatorylnformation!Guidances/UCM269921 (hereinafter "Tablet Scoring Guidance"). 121 Expert Statement, at ~31. 122 Green G.A. et al. "Accuracy and Ease of Splitting Scored Coumadin, Lanoxin and Toprol XL Tablets." Poster presented at the American Association of Pharmaceutical Scientists, Los Angeles, CA (November 2009). See Accu­ Break Pha1maceuticals, Inc. website, available at http://www.accubreakpharmaceuticals.cmn/. 123 Expert Statement, at ~32. 124 Tablet Scoring Guidance, at 2; Green G. et al. Pharmacopeia! Standards for the Subdivision Characteristics of Scored Tablets. PHARMACOPEIAL FORUM 35(6) (November-December 2009). 125 Expert Statement, at~ 33; FDA Consumer Update, "Tablet Splitting: A Risky Practice", available at http://www.fda.gov/F orConsumers/ConsumerUpdates/ucm171492.htm. 1z6 Id 127 Expmt Statement, at ~35. 128 Expert Statement, at ~34; FDA Consumer Information, "Best Practices for Tablet Splitting", available at http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseoWedicine /ucm184666.htm. 129 Id. 130 Expert Statement, at ~34. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 27

tablet splitter produced more assay failures than the whole tablet. The use of a tablet splitter produced more fragmentation, leading to content uniformity and friability failures. The use of a granulation step during manufacturing, as well as the type of binder in the formulation, also plays a role in tablet splitting outcomes. 131

FDA has published guidance documents that address tablet scoring issues. 132 Those products that meet the criteria outlined in these documents can be labeled as having "functional scoring." In the case of an immediate release solid oral dosage form, this means that the tablet meets USP General Chapter <905> (uniformity of dosage units), tablet splitting has been tested, and dissolution of the split tablets meets the finished product release specifications.133 A product labeled as having "functional scoring" must include this designation in several specific sections of the labeling. ~ 34

Lanoxin oral tablets, 0.125 mg and 0.250 mg strengths, are in fact scored tablets. As a result, the generic tablets are scored as well. 135 However, Lanoxin was never developed with "functional scoring" in mind because there are several different Lanoxin dosages available that already allow for dose titration for specific patient needs. Furthermore, digoxin is a pre-193 8 drug product and these splitting concerns were less evident when the NDA was approved in 1997. Therefore, because of the inherent difficulties associated with tablet splitting, and to avoid any confusion that Lanoxin is functionally scored and can therefore be split, Concordia intends to revise its labeling to specifically state that tablet splitting is not recommended. This labeling change will enhance patient safety and encourage patients to use the approved dosage strengths to achieve the optimal dose without resorting to tablet splitting.

Concordia asserts that these tablet splitting problems exacerbate the bioavailability, content uniformity, dissolution, and potency issues already noted - particularly if the drug product is not bioequivalent to the RLD in the first place. Furthermore, as discussed, at least three of the approved generic digoxin tablet products received waivers for the lower strength (0.125 mg). Therefore, splitting a tablet that has not been tested fiuther compounds the bioavailability and safety concerns for this drug. As discussed below, these concerns are particularly magnified given that most generic digoxin tablets have not, and likely cannot be

131 Shah, at 1366. 132 Tablet Scoring Guidance; FDA, "Draft Guidance for Industry- Safety Considerations for Product Design to Minimize Medication Enors" (December 20 12), available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/UCM33181 0. 133 Tablet Scoring Guidance, at 3-4. 134 Tablet Scoring Guidance, at 5. USP 38/NF 33, through First Supplement (official August 1, 2015) also includes General Chapter <705>, "Quality Attributes of Tablets Labeled as Having a Functional Score"; however, this chapter is not referenced in the FDA Tablet Scoring Guidance. 135 FDA, Manual of Policies and Procedures ("MAPP") 5223.2, "Scoring Configuration of Generic Drug Products" (recettified September 5, 20 12), available at http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofP oliciesProcedures/UCM079779 .pdf. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 28

manufactured in compliance with cGMPs. These issues lend further credence to the argument that generic digoxin oral tablets should be rated BX.

D. Drugs Not Manufactured Using cGMPs are Not Therapeutically Equivalent

For a generic drug to be considered therapeutically equivalent to the RLD, the generic product must comply with cGMPs. Compliance with cGMPs has been a critical component of therapeutic equivalence ratings since the cGMP regulations were enacted over thirty-five years ago- even though the Agency often ignores this cGMP criterion once an ANDA is approved, in contravention of law and policy. Several high profile generic digoxin tablet recalls call into question the ability of manufacturers to meet appropriate cGMP specifications, leading to an additional basis for a BX rating. For an NTI drug such as digoxin, this manufacturing issue is critical and must be considered essential both to the safe use of the drug and to the therapeutic equivalence rating.

1. Digitek® Recall- 2008

The first such high-profile digoxin recall occurred in April 2008. Actavis Totowa, LLC ("Actavis"), which acquired Amide Pharmaceutical, Inc. ("Amide") in 2005 136 (including ANDA 137 8 40-282 for digoxin ), initially received an FDA warning letter on February 1, 2007Y The warning letter arose out of a mid-2006 inspection of Actavis' Little Falls, New Jersey manufacturing plant in which cGMP deviations were identified. Among other noted deficiencies for products manufactured at that facility, "the failure to meet in-process specifications during tablet compression operations was not always documented in production records and there is no indication that the process deviations were promptly corrected during compression operations to avoid releasing tablets that did not have their appropriate quality."139

In April 2008, Actavis initiated a patient-level (Class I) recall of Digitek brand digoxin tablets (0.125 mg and 0.250 mg) on a nationwide basis. 140 At that time, Actavis was manufacturing Digitek for both Mylan Pharmaceuticals Inc. ("Mylan") under the "Bertek" label and for UDL Laboratories, Inc. ("UDL") under the "UDL" label. These products were recalled "due to the possibility that tablets with double the appropriate thickness may have been

136 BioSpace, "Actavis Completed Acquisition ofNJ-Based US Generics Company Amide Pharmaceutical, Inc." (October 19, 2005), available at http://www.biospace.com/News/actavis-completes-acquisition-of-nj-based­ us/20762220. 137 FDA approval letter for ANDA 40-282 (December 23, 1999). 138 Warning Letter from FDA to Actavis Totowa, LLC (February 1, 2007). 139 Id. 14°FDA, "Actavis Totowa (Formerly Known as Amide Pharmaceutical, Inc.) Recalls All Lots ofBertek and UDL Laboratories Digitek (digoxin tablets, USP) as Precaution" (April25, 2008), available at http://www.fda.gov/Safety/Recalls/ArchiveRecalls/2008/ucm112435.htm; FDA, "Digitek (digoxin tablets, USP)" (April 28, 2008), available at http://www.fda.gov/Safety/MedWatch/Safetyinformation/SafetyAlertsforHumanMedicalProducts/ucm084304.htm; FDA, Enforcement Report 08-32 (August 13, 2008). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 29

commercially released" and "may contain twice the approved level of active ingredient than it [sic] appropriate." UDL also initiated its own Class I recall. 141 The digoxin recall resulted in thousands of plaintiffs and hundreds of court cases which were consolidated in federal court in West Virginia. This multidistrict litigation was settled in 2010,142 and the docket closed in 2012. 143

In 2014, FDA approved Mylan's supplement to the Digitek ANDA, which (1) permits Mylan LLC in Puerto Rico to be an "alternate manufacturing, packaging and analytical testing site for Digitek Tablets," and (2) permits Mylan Pharmaceuticals Inc. in West Virginia to be "an alternate analytical testing site for the components of the finished drug product."144 As a result, the Digitek product- the subject of recalls and extensive product liability litigation- remains on the market.

2. Digoxin Recall- 2009

Less than one year after the Digitek recall, Caraco Pharmaceutical Laboratories, Ltd. ("Caraco") recalled its own digoxin product.145 Most notably, this recall for digoxin tablets that "may differ in size and therefore could have more or less of the active ingredient" occurred in the middle of an FDA inspection of Caraco's Detroit, Michigan manufacturing facility. 146

This inspection detailed numerous cGMP problems with the company's digoxin products related to tablets of incorrect size, including (1) failure to establish control procedures to monitor output and validate performance of manufacturing processes, resulting in "thick and soft" and "thick and thin" digoxin tablets; (2) failure to include weights and measures of drug components in batch production and control records; (3) failure to have quality control ("QC") responsibilities and procedures in writing and followed, as demonstrated by a quality assurance ("QA") specialist handling tablets to inspect for "size variation and soft/low weight tablets"; (4) failure to completely evaluate complaints of incorrect size digoxin tablets; and (5) failure to use appropriately designed equipment to facilitate the intended use, including using an alternate tablet press without process verification that resulted in "soft and thick" digoxin tablets. On June 24, 2009, FDA seized drug products at several Caraco Michigan facilities, including the Detroit facility, for "continued failure" to adhere to cGMP requirements. 147

141 FDA, Enforcement Report 08-34 (August 27, 2008). 142 In re: Digitek Products Liability Litigation (MDL No. 1968), Pretrial Order #64 (Re: Settlement Agreement and Deadlines). 143 In re: Digitek Products Liability Litigation (MDL No. 1968), Pretrial Order #90 (Order Closing MDL). 144 Letter from FDA to Mylan Pharmaceuticals Inc. (September 3, 2014). 145 FDA, "Caraco Pharmaceutical Laboratories, Ltd. Announces a Nationwide Voluntary Recall of All Lots of Digoxin Tablets Due to Size Variability" (March 21, 2009), available at http://www .fda.gov/Safety/Recalls/ ArchiveRecalls/2009 /ucm 128443 .htm. 146 Form FDA 483, Caraco Pharmaceutical Laboratories, Ltd., Detroit, MI (issued May 12, 2009). 147 FDA, "Transcript for FDA's Media Briefmg on Seizure of Drug Products Manufactured by Caraco Pharmaceutical Laboratories Limited" (June 24, 2009), available at http://www .fda.gov/downloads/NewsEvents/Newsroom!MediaTranscripts/UCM186312.pdf. Division of Dockets Management U.S. Food and Drug Administration Depmiment of Health and Human Services December 1, 2015 Page 30

Today, Sun Pharmaceutical Industries Ltd. ("Sun") manufactures this generic digoxin product, as it acquired Caraco in 2010. 148 Similar to Digitek, this generic digoxin product remains on the market despite its history of cGMP failures.

3. Recall Conclusions

Following these recalls, there was a significant spike in digoxin-reported adverse events in 2008, as well as an elevated number in 2009. 149 The continued market presence of historically problematic drug products suggests that there could be a repeat of the previous spike in adverse events. As the NDA holder, Concordia will therefore continue to have a responsibility to monitor adverse events, and will continue to carry a large burden of marketplace liability for digoxin tablets not manufactured to appropriate cGMP standards, as addressed in Section V.G., below.

Digoxin tablet manufacturing issues continue to present tangible patient health risks. These recalls confirm the initial digoxin concerns raised in the 1970s that were thought to have been resolved by requiring NDAs and ANDAs for digoxin drugs. Nonetheless, despite the requirement for approved applications- and adherence to cGMPs- these problems persist. As FDA repmied in 2011, sub- and super-potency, lack of stability data, stability data that does not support the expiration date, and failed USP dissolution testing accounted for those situations where recall rates were higher for NTI drugs than for other drug products. 150 If generic digoxin drug products cannot be cGMP-compliant- an essential element of therapeutic equivalence­ then they cannot be rated AB. The only legal option is to rate them BX.

E. States' Concerns with NTI Drug Product Substitutability

The Orange Book was initially developed as a resource for States to make therapeutic substitution decisions. In the case ofNTI drugs, however, some States are choosing to limit their substitution regardless of the Agency's therapeutic equivalence rating. These State approaches confirm that there are serious questions about substitution ofNTI drugs.

North Carolina has perhaps the most stringent NTI drug non-substitution policy. According to State statute, unless a pharmacist first notifies a prescriber and the prescriber and patient both give documented consent, "[a] prescription for a narrow therapeutic index drug shall be refilled using only the same drug product by the same manufacturer that the pharmacist last dispensed under the prescription."151 North Carolina defines a "nanow therapeutic index" drug as one with a narrow risk/benefit range and that has "less than a twofold difference in the

148 Sun Pharmaceutical Industries Ltd. website, available at http://www.sunpharma.com/about-us/acquisitions-and­ joint-ventures. 149 See adverseevents.com, last visited June 11, 2015. 150 2011 GPhA Yu Slides. 151 N.C.G.S.A. § 90-85.28(b1) (text effective October 1, 2015). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 31 minimum toxic concentration and minimum effective concentration in the blood or those drug product formulations that exhibit limited or · erratic absorption, formulation-dependent bioavailabili~, and wide intrapatient pharmacokinetic variability that requires blood-level monitoring." 52

Several other States also limit NTI drug substitutability to varying degrees. In Massachusetts, State statute provides that if a patient is covered by MassHealth and is prescribed an NTI immunosuppressant drug for an organ or tissue transplant, then the pharmacist must notify the prescriber if a substitution is made. 153 In Mississippi, the State Administrative code requires prior authorization to receive the brand name of a multiple source drug that has a generic equivalent, except for NTI drugs as defined by the State Division of Medicaid. 154 Finally, the Oregon Administrative Rules similarly require prior authorization to receive a brand name drug if there are two or more generic equivalents available, and the drug is not an NTI drug (as determined by the State DUR/P&T Committee). 155 The Oregon Statute contains similar provisions. 156

These State actions to restrict substitution of NTI drugs demonstrate awareness that such substitutions can be harmful to patients. FDA should similarly recognize that NTI drugs are not interchangeable to the same degree as non-NTI products. In light of the various bioequivalence­ and therapeutic-equivalence issues raised in this Petition, FDA should change the digoxin AB rating to BX.

F. FDA Has Authority to Make Individual Drug or Drug Category Therapeutic Equivalence Rating Changes

The Orange Book provides that FDA can make changes to a therapeutic equivalence code for either a single drug product or an entire category of drugs. For example, FDA will change a code if there is a change in the RLD after approval that may impact generic drug substitutability, unless the generic manufacturer provides evidence that its product remains equivalent even with the RLD changes. 157 Furthermore, FDA can change the code for an entire category of drug products "when the Agency becomes aware of new scientific information affecting the therapeutic equivalence of an entire category of drug products in the List [Orange Book]."158

152 N.C.G.S.A. § 90-85.27(4a) (text effective October 1, 2015). 153 A "narrow therapeutic index immunosuppressant drug" is "an immunosuppressant drug for the treatment of an organ or tissue transplant that has a narrow range in blood concentrations between efficacy and toxicity and requires therapeutic drug concentration or pharmacodynamic monitoring." M.G.L.A. 112 § 12D. 154 Miss. Admin. Code 23-214:1.8(C). 155 OAR 410-121-0040(6). An NTI drug is "[a] drug that has a narrow range in blood concentrations between efficacy and toxicity and requires therapeutic drug concentration or pharmacodynamic monitoring." OAR 410-121- 0000(3)(v). 156 O.R.S. § 414.325(8)(a)-(b). 157 Orange Book, at xv. 158 Orange Book, at xxiii. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 32

The Agency has the authority to reconsider and make changes to a therapeutic equivalence code when justified, and Concordia argues that a code change is warranted for digoxin.

Changing a therapeutic equivalence code is not unprecedented. As recently as November 13, 2014, FDA changed the rating for methylphenidate hydrochloride extended release tablets from AB to BX, providing the generic drug sponsors (Mallinckrodt and Kudco Ireland) with an opportunity to confirm their products' bioequivalence within six months using a revised product­ specific bioequivalence guidance document. 159 Mallinckrodt immediately filed a complaint for declaratory and injunctive relief in the U.S. District Court for the District of Maryland, 160 arguing that the coding change would cause pharmacists to not use the company's product to fill prescriptions written for the RLD (Concerta). As Mallinckrodt argued, "FDA classification action effectively takes Mallinckrodt's methylphenidate ER tablets off the market."161

In its memorandum opposing Mallinckrodt' s motion for a temporary restraining order ("TRO"), FDA countered that an increase in adverse event reporting after Mallinckrodt's ANDA approval, 162 coupled with other evidence available after the AND As were approved, led the Agency to re-evaluate the therapeutic equivalence rating. FDA conducted an evaluation of these adverse event reports, reviewed data in the ANDAs, performed laboratory testing (including stability and dissolution testing), and used a "broad interdisciplinary consultation" with numerous Agency experts. 163 Furthermore, FDA argued that the ANDAs were still being marketed; no adverse determination about the safety or efficacy of the generic drugs had been made. As a result, FDA argued that there was no effective withdrawal of the generic sponsors' products, as "[d]iminished marketplace availability does not equate to withdrawal of a drug approval."164 On July 29, 2015, the Court found in favor of FDA, dismissing several counts and finding in favor ofFDA on other counts. 165

This outcome is significant because FDA relied, in part, on new scientific evidence available post-marketing as well as existing evidence in the ANDA to make the coding change. Similarly, a review of at least several of the digoxin ANDAs reveals that they do not conform to the AC's contemporary NTI drug bioequivalence recommendations. In light of the ongoing concerns involving bioavailability, dissolution, content uniformity, potency, tablet splitting, and cGMP/recall issues, a similar review of the therapeutic equivalence rating of the digoxin ANDAs is warranted. As FDA stated in the Mallinckrodt case, "[t]he public benefits most from the

159 FDA Press Release, "FDA Concerns about Therapeutic Equivalence with Two Generic Versions of Concerta Tablets (Methylphenidate Hydrochloride Extended Release)" (November 13, 2014), available at http://www.fda.gov/dmgs/dmgsafety/ucm422568.htm. 160 Mallinckrodt v. FDA, Case 8: 14-cv-03607, Complaint for Declaratory and Injunctive Relief, U.S. Dist. Ct. Md. (filed November 17, 2014) (hereinafter "Mallinckrodt Complaint"). 161 Mallinckrodt Complaint, at~ 30. 162 Case 8:14-cv-03607, Defendant's Memorandum in Opposition to Plaintiff's Motion for Temporary Restraining Order" (filed November 20, 2014), at 6 (hereinafter "FDA Opposition Memorandum"). 163 FDA Opposition Memorandum, at 7. 164 FDA Opposition Memorandum, at 12. 165 See Case 8:14-cv-03607, entry 48, noting that the decision was temporarily filed under seal. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 33

proper resolution of scientific issues and having the agency make correct, well-supported decisions regarding whether drugs are TE to for [sic] one another. "166 This conclusion is particularly salient for digoxin.

G. Concordia Must be Concerned About Non-Therapeutically Equivalent Drugs Because it is the RLD NDA Holder

As the Lanoxin NDA holder, Concordia has ongoing responsibilities to collect, monitor, and report adverse events to FDA. Despite the market fragmentation for the 0.125 mg and 0.250 mg dosage strengths, Concordia remains liable for updating its labeling based upon any new pharmacovigilance data, 167 with such changes applicable to the generic products as well. Therefore, the Company has a vested interest in ensuring that all generic digoxin drugs meet the AC's NTI drug bioequivalence recommendations, comply with contemporary bioavailability, dissolution, content uniformity, and potency specifications, and is manufactured in accordance with cGMPs. Unsuitable bioequivalence standards or specification compliance issues permits too much drug variability, ultimately putting Concordia at marketing risk.

I. Adverse Event Reporting, Pharmacovigilance Requirements, and Labeling Changes

An NDA holder is required to review all adverse drug experience information that it has or obtains from any foreign or domestic source. This information may come from commercial product marketing, postmarketing clinical investigations or epidemiological/surveillance studies, literature reports, and unpublished scientific papers. 168 Although ANDA holders are similarly required to review and report adverse drug experience information, 169 such analysis reflects a different reality for a number of reasons.

First, adverse event reports may only identify a drug by the active ingredient, thus making it impossible to determine if it was the RLD or a generic drug that was involved in the adverse event. Second, even if an NDA holder receives an adverse event that occUlTed with a generic version of its brand drug, it is still obliged to report the event to FDA. Third, because multiple companies are responsible for adverse event reporting, no one company has a complete adverse event profile of the drug product, making meaningful analysis of adverse event trends difficult at best. Finally, no NDA or ANDA holder has control over physician and pharmacist

166 FDA Opposition Memorandum, at 25. 167 Pharmacovigilance constitutes the scientific and data-gathering activities that relate to the detection, assessment, and understanding of adverse events, and includes the identification and evaluation of safety signals. FDA, "Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment" (March 2005), available at http://www .fda.gov/downloads/Drugs/GuidanceComplianceRegulatmylnformation/Guidances/ucm071696. pdf, at 4 (hereinafter "Pharmacovigilance Guidance"). 168 21 C.F.R. § 314.80(b). 169 21 C.F.R. § 314.98(a). Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 34

actions (e.g., filling a prescription written for the RLD with a generic). All of these factors make it difficult for an NDA holder to get a clear picture of the brand drug's adverse event profile once generic drugs are approved.

Both NDA and ANDA holders are required to collect, review, and submit to FDA adverse events of which they become aware, and to engage in pharmacovigilance efforts to identify safety signals warranting labeling changes. In practice the vast majority of these responsibilities lie with the NDA holder, as confirmed in several recent U.S. Supreme Court decisions.

2. NDA Holders Retain Responsibility for Updating Drug Labeling

As Wyeth v. Levine170 confirmed, manufacturers retain responsibility for their product labeling at all times. Wyeth marketed the anti-nausea brand drug Phenergan®, which could be administered intravenously ("IV") or intramuscularly ("IM"). If administered IV, one of two methods can be used (IV -drip or IV -push). Careful administration is imperative, as drug entering the patient's artery causes irreversible gangrene. The drug labeling warned of this gangrene danger, but the plaintiff argued that the labeling failed to tell clinicians to use the IV-drip method instead of the more-risky IV -push method. 171

The Comt noted that manufacturers have the means to make a change to a drug's labeling through the changes being effected ("CBE") process if the manufacturer is adding or strengthening a warning, contraindication, precaution, or adverse reaction. 172 In holding that Federal law did not preempt State failure-to-warn laws, the Court clarified the responsibilities of manufacturers with respect to their product labeling:

Wyeth suggests that the FDA, rather than the manufacturer, bears primary responsibility for drug labeling. Yet through many amendments to the FDCA and to FDA regulations, it has remained a central premise of federal drug regulation that the manufacturer bears responsibility for the content of its label at all times. It is charged both with crafting an adequate label and with ensuring that its warnings remain adequate as long as the drug is on the market (emphasis added). 173

Although Wyeth did not differentiate between the responsibilities of brand and generic drug companies, the Court did so two years later.

170 555 u.s. 555 (2009). 171 Wyeth, 555 U.S. at 559-560. 172 Wyeth, 555 U.S. at 568. 173 Wyeth, 555 U.S. at 570-571. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 35

Pliva v. Mensing, 174 which consolidated two cases, held that Federal law pre-empted State law requiring generic companies to change their drugs' labeling because it was impossible to comply simultaneously with both State and Federal laws. Pliva involved lawsuits by two consumers who were prescribed metoclopramide which, when used for long periods of time, can cause a severe neurological disorder (tardive dyskinesia). The plaintiffs were prescribed the brand name drug (Reglan®), but their pharmacists filled the prescriptions with generic versions of the drug. 175 The Court noted that the brand company must ensure the accuracy and adequacy of its labeling, while the generic company must ensure its warning label is the same as the brand's label. 176 Because generic drug labels must be identical to brand drug labels, FDA interprets its CBE regulation as applying to generics only when the generic company changes a label to match the pioneer or FDA tells the generic company to make a labeling change: "[t]he FDA argues that CBE changes unilaterally made to strengthen a generic drug's warning label would violate the statutes and regulations requiring a generic drug's label to match its brand­ name counterpart's."177 Therefore, the generic companies could not use the CBE process to strengthen the generic drugs' labeling absent the pioneer company's efforts to do so. 178

The Supreme Court's most recent decision follows this line of reasoning. In Mutual Pharmaceutical Co., Inc. v. Bartlett,179 a patient received a generic form of the brand name drug Clinoril®, a nonsteroidal anti-inflammatory pain reliever. The patient suffered extremely debilitating adverse effects, the severity of which was not communicated on the drug labeling at the time the patient took the drug. The patient sued the manufacturer of the generic drug in New Hampshire State court on a design-defect claim, 180 and the District Court awarded damages with the Court of Appeals affirming. The Supreme Court, however, reversed the decision. The majority held that New Hampshire's requirement that a product not be "unreasonably dangerous" was preempted by Federal law that expressly prohibits generic drug manufacturers from making unilateral labeling changes. The Court stated that New Hampshire's "unreasonably dangerous" standard can be satisfied by either changing a drug's design or changing the labeling. In this case, Mutual could not change the drug's design, meaning it could only satisfy this State standard by changing the labeling. Such unilateral labeling changes, however, were not legally permitted, particularly under the Pliva decision.

174 131 S.Ct. 2567 (2011). 175 Pliva, 131 S.Ct. at 2572-2573. 176 Pliva, 131 S.Ct. at 2574 (citing 21 U.S.C. § 355(b)(1) and Wyeth, 555 U.S. at 570-571 for the proposition that pioneer companies must ensure the accuracy and adequacy of its labeling; and 21 U.S.C. § 355G)(1)(A)(v), 21 U.S. C. § 355Q)(4)(G), 21 C.F.R. § 314.98(a)(8), and 21 C.F.R. § 314.127(a)(7) for the proposition that a generic drug's labeling must be the same as the brand drug's labeling). 177 Pliva, 131 S.Ct. at 2575 178 The Court acknowledged the plaintiffs' argument that the manufacturers cannot prove impossibility preemption because they did not try to work with FDA to strengthen the labeling. The Court analyzed the Supremacy Clause and determined, however, that pre-emption does not require speculation about how patties could work together to possibly reconcile conflicting state and federal law duties. Pliva, 131 S.Ct. at 2578-2581. 179 133 S.Ct. 2466 (2013). 180 The plaintiff also sued on a failure-to-warn claim, but the District Court dismissed that claim after her physician admitted that he had not read the drug box labeling or package insert. Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 36

Based upon this legal landscape, Concordia must continue to review, assess, and report adverse events after any generic digoxin drug product is approved. Concordia must also continue to engage in its pharmacovigilance efforts, report safety signals to FDA, and make appropriate labeling changes as required. This case law also establishes that any digoxin ANDA sponsor - although required to review, report, and assess adverse events - cannot, under Pliva or Mutual, make unilateral labeling changes to strengthen any warnings. 181 Concordia will therefore continue to bear the responsibility for maintaining adequate and accurate digoxin labeling - even if Lanoxin is no longer the market leader, as is currently the case. This requirement puts Concordia at a heightened risk for product liability cases involving a generic digoxin drug product. 182 As a result, FDA must make appropriate NTI drug changes to the digoxin tablets bioequivalence guidance document and change the generic drug therapeutic equivalence rating from AB to BX.

VI. CoNCLUSIONs

For all of the reasons set forth in this Petition, Concordia respectfully requests that FDA take the following actions:

1. Amend the May 2008 digoxin tablets bioequivalence guidance to reflect digoxin's NTI status and to recommend that generic drug sponsors meet the bioequivalence criteria recommended in other NTI drug guidance documents, including:

a. Conducting a 4-way, fully-replicated crossover design for both in vivo fasting and fed studies; and

b. Using an RSABE approach.

The digoxin guidance should also be amended to reflect the AC's additional NTI drug bioequivalence recommendations, including:

181 The Pliva Court also rejected plaintiffs' argument that the generic companies could have issued "Dear Doctor" letters to provide additional warnings about the drug product. FDA considers "Dear Doctor" letters to constitute labeling; therefore, such a letter containing new information would be inconsistent with the approved labeling, and would imply that the branded and the generic products were not therapeutically equivalent. Pliva, 131 S.Ct. at 2576. 182 See, e.g., Foster v. American Home Products Corp., 29 F.3d 165 (4th Cir. 1994) (holding in a pre-Wyeth and pre­ Pliva case that, under Maryland law, a brand name manufacturer had no duty of care in its own drug representations when patients were given the generic equivalent of the branded drug); but see, e.g., Conte v. Wyeth. Inc., 168 Cal.App.4th 89 (Cal. App. 1 Dist. 2008) (holding in another pre-Wyeth and pre-Pliva case that, in declining to follow Foster, a branded company has a duty to use due care in formulating product warnings and this duty extends to patients who receive generic versions of the drug; the court noted that it departed from the majority of cases that have considered the issue). Division of Dockets Management U.S. Food and Drug Administration Depatiment of Health and Human Services December 1, 2015 Page 37

c. Meeting a bioequivalence range of 90-111.11% for the 90% CI for both AUC and Cmax, and require that the data "cross the one" (i.e., cross the 100% point); and

d. Meeting a drug substance potency range of95.0-105.0%.

2. In the absence of these data as well as based on the other issues set forth herein, determine that approved generic digoxin oral drug products are not therapeutically equivalent to Lanoxin and should therefore be rated BX.

C. Environmental Impact

A categorical exclusion is claimed in accordance with 21 C.P.R. § 25.31(a). Therefore, an environmental impact analysis is not required.

D. Economic Impact

An economic impact statement will be provided upon request.

E. Certification Division of Dockets Management U.S. Food and Drug Administration Department of Health and Human Services December 1, 2015 Page 38

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 on or about the following date: April 21, 2015. 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: Concordia Pharmaceuticals. 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,

Buchanan Ingersoll & Rooney PC 1700 K Street NW Suite 300 Suite 300 Washington, DC 20006 Washington, DC 20006 (202) 452-7985 (202) 452-7906 [email protected] [email protected]

Counsel to Concordia Pharmaceuticals cc (via electronic mail only):

Kathleen Uhl, M.D. Director, Office of Generic Drugs

Lawrence Yu, Ph.D. Director, Office of Pharmaceutical Science

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

Elizabeth Dickson, J.D. Chief Counsel, Office of the Chief Counsel