`
`
`
`
`
`
`
`
`
`Anna Laakmann
`Tel 202.533.2364
`Fax 202.261.0159
`laakmanna@gtlaw.com
`
`SUBMITTED ELECTRONICALLY
`
`November 28, 2017
`
`Division of Dockets Management
`Food and Drug Administration
`Department of Health and Human Services
`5630 Fishers Lane
`Room 1061, HFA-305
`Rockville, MD 20852
`
`
`
`
`CITIZEN PETITION
`
`The undersigned, on behalf of Bracco Diagnostics Inc., submits this Citizen Petition
`
`electronically with respect to section 505(j) of the Federal Food, Drug, and Cosmetic Act
`(“FDCA”) and in accordance with 21 C.F.R. § 10.30 to request that the Commissioner of Food
`and Drugs take the actions described below.
`
`I.
`
`Action Requested
`
`We respectfully request that the Food and Drug Administration (“FDA”) make a
`
`determination that the two-ingredient formulation of KINEVAC for injection was discontinued
`for safety and efficacy reasons. The two-ingredient formulation proved to be unstable,
`increasing the risk that when used as an intended diagnostic it could result in false positives
`leading to unnecessary surgery. The discontinued formulation, as originally approved by the
`agency, contained 5 µg sincalide with 45 mg sodium chloride to provide tonicity using sodium
`hydroxide or hydrochloric acid to adjust pH to 5.5 to 6.5.
`
`The petitioner specifically requests that FDA make a determination (i) that the two-
`
`ingredient formulation was discontinued for safety and efficacy reasons, and (ii) that any
`proposed generic product referring to the discontinued two-ingredient formulation would result
`in a product that is less safe and effective than the KINEVAC formulation currently marketed by
`Bracco Diagnostics Inc. (“Bracco”) under NDA 17-697/S-013 approved on November 27, 2002.
`The petitioner further requests that FDA determine that the discontinued formulation is not a
`suitable reference drug for an Abbreviated New Drug Application (“ANDA”), and that FDA
`shall not accept for review or approve any ANDA that refers to the discontinued two-ingredient
`formulation of KINEVAC for injection.
`
`II.
`
`Statement of Grounds
`
`Regulatory Background
`
`A.
`
`
`
`WDC 373592361v1
`
`GREENBERG TRAURIG, LLP  ATTORNEYS AT LAW  WWW.GTLAW.COM
`2101 L Street NW, Suite 1000, Washington, DC 20037  Tel: 202.331.3100  Fax 202.331.3101
`
`Bracco Ex. 2002
`Maia v. Bracco
`IPR2019-00345
`
`1
`
`

`

`
`November 28, 2017
`Page 2
`
`The ANDA process under which generic drugs are approved and marketed in the United
`States is codified in Section 505(j) of the FDCA. Section 505(j)(4) provides:
`
`
`[T]he Secretary shall approve an application for a drug unless the Secretary finds—
`
`(A) the methods used in, or the facilities and controls used for, the manufacture,
`
`processing, and packing of the drug are inadequate to assure and preserve its identity,
`strength, quality, and purity;…
`
`(H) information submitted in the application or any other information available to
`
`the Secretary shows that (i) inactive ingredients of the drug are unsafe for use under the
`conditions prescribed, recommended, or suggested in the labeling proposed for the drug,
`or (ii) the composition of the drug is unsafe under such conditions because of the type or
`quantity of inactive ingredients included or the manner in which the inactive ingredients
`are included…1
`
`
`
`Under this statutory framework, an ANDA applicant may obtain FDA approval of a drug
`
`that is the “same” as a previously approved drug without conducting the full battery of clinical
`and non-clinical studies that are required for a New Drug Application (“NDA”).2 An ANDA
`applicant is allowed to rely upon a prior FDA finding of safety and efficacy for the approved
`drug that is referenced by the ANDA applicant, provided that the proposed generic drug is the
`same as the approved drug with regard to active ingredients, dosage form, route of
`administration, strength, and labeling.3 The proposed generic drug also must be demonstrated to
`be bioequivalent to the referenced drug.4
`
`Additionally, ANDA applicants must reference a suitable “listed drug,” which FDA
`
`regulations define as “a new drug product…which has not been withdrawn from sale for what
`FDA has determined are reasons of safety or effectiveness…”5 The particular “listed drug
`identified by FDA as the drug product upon which an [ANDA] applicant relies” is further
`defined as the “reference listed drug” (“RLD”).6 FDA will not accept for review or approve
`ANDAs that refer to a drug product that the agency determines has been withdrawn from sale for
`
`
`1 FDCA § 505(j)(4)(A), (H).
`
` 2
`
` 3
`
` 4
`
` 5
`
` 6
`
`
`
`
`
`
`
` See generally FDCA § 505(j).
`
` FDCA § 505(j)(2)(A)(i), (ii), (iii), and (v).
`
` FDCA § 505(j)(2)(A)(iv); 21 C.F.R. § 314.127(a)(6)(i).
`
` 21 C.F.R. § 314.3(b).
`
` Id.
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`2
`
`

`

`
`November 28, 2017
`Page 3
`reasons of safety and effectiveness.7 FDA regulations describe safety and effectiveness data to
`“include all studies and tests of a drug on animals and humans and all studies and tests of the
`drug for identity, stability, purity, potency, and bioavailability.”8 “A determination whether a
`listed drug that has been voluntarily withdrawn from sale was withdrawn for safety or
`effectiveness reasons may be made by the agency at any time after the drug has been voluntarily
`withdrawn from sale, but must be made [p]rior to approving an [ANDA] that refers to the listed
`drug…”9
`
`
`
`B.
`
`Factual Background
`
`KINEVAC is a cholecystopancreatic-gastrointestinal hormone peptide for parental
`
`administration. The active pharmaceutical ingredient (“API”), sincalide, is a synthetically-
`prepared C-terminal octapeptide of cholecystokinin (“CCK”), with the following amino acid
`sequence: Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2. Sincalide is the biologically active
`moiety of the natural CCK molecule, and binds to receptors that stimulate contraction of the
`smooth muscle in the walls of the gallbladder and small bowel. The main clinical use of
`KINEVAC is to induce emptying of the gallbladder as part of a diagnostic test called functional
`cholescintigraphy. The purpose of this test is to determine whether the gallbladder should be
`surgically removed due to functional gallbladder disorder (“FGBD”) in patients who have an
`ultrasonographically normal appearing gallbladder.
`
`The discontinued formulation of KINEVAC was approved by FDA in 1976 under an
`
`NDA first filed by E.R. Squibb & Sons, Inc. and later held by Bristol-Myers Squibb. From the
`time of its introduction, FDA raised concerns about manufacturing and analytical issues
`regarding the now discontinued two-ingredient formulation. FDA expressed particular concerns
`about the stability and potency of the two-ingredient formulation. In a letter to E.R. Squibb &
`Sons, Inc. FDA stated: “We request that you investigate the reasons for this stability problem
`and…propose a solution.”10 Indeed, for several years, product accommodations which were not
`disclosed in the label were made at the request of FDA to temporarily address the stability
`problem. FDA permitted the NDA holders to manufacture the now discontinued KINEVAC
`product with certain overages that were not included in the label pending permanent resolution of
`the stability problem with the two-ingredient formulation.
`
`
`7 FDA Draft Guidance for Industry, “Referencing Approved Drug Products in ANDA Submissions (January 2017),
`at 4-5 (explaining that a discontinued drug “may be eligible to be an RLD, unless FDA makes a determination that
`the listed drug was withdrawn from sale for reasons of safety or effectiveness. If FDA makes such a determination,
`the listed drug will be removed from the Orange Book and is no longer eligible to be an RLD.”).
`
` 8
`
` 9
`
` 21 C.F.R. § 314.430(a).
`
` 21 C.F.R. § 314.161(a)(1).
`
`
`10 See Letter from Stewart J. Ehrreich, Deputy Director, Division of Cardio-Renal Drug Products, Office of Drug
`Research and Review, Center for Drugs and Biologics, Food and Drug Administration, to Charles L. Kroll, Director,
`Regulatory Operations, E.R. Squibb & Sons, Inc., September 18, 1984.
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`3
`
`

`

`
`November 28, 2017
`Page 4
`In 1994, the KINEVAC NDA was transferred to Bracco. Bracco subsequently submitted
`
`a supplemental NDA for KINEVAC that incorporated product changes to resolve these
`outstanding FDA issues. Such product changes included a new formulation of the drug product
`with the addition of excipients to maintain the stability of the peptide in both bulk solution and
`final lyophilized product. In addition to addressing stability issues, the reformulated product
`eliminated the requisite overages that had been incorporated into the discontinued two-ingredient
`formulation as a stopgap measure to address FDA’s concerns about the instability of the two-
`ingredient formulation.
`
`The shelf life of both the discontinued KINEVAC formulation and the currently marketed
`
`KINEVAC formulation is listed as 18 months. Within this period of time, the discontinued
`unstable formulation degraded significantly. By contrast, the currently marketed formulation of
`KINEVAC has been shown to be relatively stable.
`
`The assay in the NDA for the discontinued formulation is the USP potency method for
`
`sincalide for injection. It is a bioassay which measures the gallbladder contractile responses in
`guinea pigs following intravenous administration of product. Using this assay, three batches of
`the discontinued formulation have been tested and shown to degrade at an average rate of more
`than 20% over the 18-month shelf life. The sincalide assay stability (25°C) profiles for three
`commercial lots of the discontinued formulation demonstrated that the period of time in which
`the amount of sincalide fell from 5 µg to the NDA standard limit of 4.25 µg ranged from 9.7
`months to 16.7 months. Specifically, samples with initial amounts of 5.85 µg, 5.2 µg, and 4.9 µg
`sincalide degraded at rates of 27.8%, 17.3%, and 16.1 %, respectively. Based on these
`degradation rates, samples containing 5 µg sincalide fell below 4.25 µg in 9.7, 15.6, and 16.7
`months, respectively, all of which are shorter than the FDA-approved shelf life of 18 months.
`
`The assay for the currently marketed KINEVAC formulation is an HPLC method suitable
`
`as a stability-indicating method to monitor the degradation profile of sincalide. Using this assay,
`batches of the currently marketed formulation have been tested and shown to be consistently and
`significantly more stable than the discontinued formulation. The sincalide assay stability (25°C)
`profiles for three commercial lots of the currently marketed formulation remained within the 4.5
`µg/vial limits through 24 months. This is a substantial improvement over the stability profiles
`shown for the discontinued formulation. Moreover, the currently marketed formulation – unlike
`the discontinued formulation - does not contain an overage that would render the product
`labeling inaccurate.
`
`
`
`
`
`
`
`C.
`
`Argument
`
`
`
`
`
`
`
`
`
`1.
`
`
`
`
`
`Bracco discontinued the two-ingredient KINEVAC
`formulation for safety and effectiveness reasons after it developed a
`more stable formulation
`
`
`
`
`Bracco discontinued the two-ingredient KINEVAC formulation after it developed the
`
`more stable currently marketed formulation, because the instability of the old formulation limited
`
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`4
`
`

`

`
`November 28, 2017
`Page 5
`its clinical effectiveness as a diagnostic tool for patients contemplating gallbladder surgery.
`Cholecystokinin-stimulated cholescintigraphy (“CCK-CS”) with measurement of gallbladder
`ejection fraction (“GBEF”) is the standard in clinical practice for diagnosing FGBD.11 During
`this diagnostic procedure, a technetium (Tc-99m)-labeled radiopharmaceutical is taken up by the
`liver and excreted into the biliary system where it accumulates in the gallbladder. A GBEF is
`then calculated after stimulating gallbladder emptying with CCK. An abnormally low GBEF is
`indicative of FGBD, therefore CCK-CS aids in the decision whether to proceed with
`cholecystectomy in patients presenting with suspected biliary pain and anatomically normal
`appearing gallbladder.12
`
`Clinicians have recognized that the safety and efficacy of KINEVAC significantly
`
`depend on its stability and potency. Degradation of an unstable sincalide formulation “may
`result in less than the expected amount of sincalide available for injection, which could result in
`falsely low gallbladder emptying that might be misinterpreted as chronic colecystitis.”13 By the
`same token, super-potent sincalide can increase the frequency and severity of side effects, while
`sub-potent sincalide can result in falsely low GBEF measures and misdiagnoses of gallbladder
`dysfunction.14
`
`Because of the stability problem with the two-ingredient formulation, vials of KINEVAC
`
`containing the two-ingredient formulation contained drug product of variable potency depending
`on the length of time that a particular vial had been on the hospital shelf prior to its listed 18-
`month expiration date. This variability in potency made it more difficult to develop a diagnostic
`test that could accurately detect the presence of FGBD based on measures of GBEF in
`individuals whose gallbladders had been stimulated by KINEVAC. After Bracco developed the
`currently marketed KINEVAC formulation, it discontinued the two-ingredient formulation in
`order to ensure that only the stable and effective formulation was used for CCK-CS diagnostic
`procedures. Clinical use of the new formulation provided a safe and effective diagnostic,
`because vials of the more stable formulation contained less variability in potency than vials of
`the old unstable formulation.
`
`Bracco discontinued the two-ingredient KINEVAC formulation for the additional reason
`
`that it produced higher levels of impurities than the currently marketed KINEVAC formulation.
`Sincalide degradation results in a desulfated sincalide impurity in which the sulfate group on the
`tyrosine side chain of sincalide is hydrolyzed. In addition to this desulfated sincalide, several
`
`
`11 See DiBaise JK, et al. Cholecystokinin-Cholescintigraphy in Adults: Consensus Recommendations of an
`Interdisciplinary Panel. Clin. Gastroenterol. Hepatol. 2011 May; 9 (5): 376-384.
`
`12 Id.
`
`13 Norenberg, JP, et al. Prescriber Beware: It Is Ill Advised to Administer Compounded Sincalide. J. Nucl. Med.
`2013 Nov.; 54(1): 23N-24N.
`
`14 Id.at 23N.
`
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`5
`
`

`

`
`November 28, 2017
`Page 6
`other impurities may be produced by the oxidation of amino acid residues of sincalide. In its
`supplemental NDA for the currently marketed KINEVAC formulation, Bracco used HPLC
`analysis to demonstrate that the total percentage of impurities relative to sincalide remained low
`even under severely stressed storage conditions. These data indicated a substantially superior
`impurity profile for the new formulation as compared to the old unstable formulation. Since the
`administration of sincalide containing impurities may result in adverse reactions,15 Bracco
`discontinued the old KINEVAC formulation in favor of the new formulation for safety and
`efficacy reasons. Bracco’s decision-making in this regard mirrored FDA’s calculus of risk. The
`agency will permit a suboptimal drug to remain on the market if it is the only drug to treat or
`diagnose a given ailment because “completely removing a unique product from the market could
`be very dangerous to people who depend on the drug.”
`https://www.fda.gov/AboutFDA/Transparency/Basics/ucm194984.htm. However, once a safer
`or more effective alternative is approved by the agency, the suboptimal drug ceases being the
`“only game in town” and is no longer a “safe and effective” product.
`
`
`
`2.
`
`The unstable two-ingredient KINEVAC formulation has no
`established practice guideline leading to an increased risk of false-
`positive FGBD diagnoses and unnecessary gallbladder surgery
`
`
`In 2010, the Society of Nuclear Medicine (“SNM”) issued a Practice Guideline on
`hepatobiliary scintigraphy stating that the optimal method for determining GBEF after sincalide
`stimulation is an infusion of 0.02 µg/kg over 60 minutes. The reference GBEF with this
`methodology should be ≥38%, i.e., a GBEF < 38% is indicative of gallbladder dysfunction under
`this approach.16 The SNM guideline was based on published results of a multi-center clinical
`dosing trial that studied 60 healthy volunteers enrolled from July 2008 to June 2009. The
`researchers found that a 60-minute infusion duration with GBEF calculated after 60 minutes is
`the optimal regimen for the CCK-CS procedure because it has the best-defined normal values.17
`
`Since its codification in the SNM Practice Guideline, this regimen for performing CCK-
`
`CS diagnostic tests has become a professional standard for assessing gallbladder dysfunction.
`The reference GBEF level of ≥ 38%, established on normal healthy volunteers, has therefore
`become a “cut-off” value for determining whether a patient has normal gallbladder function
`(GBEF ≥ 38%), or possibly abnormal gallbladder function (<38%) that would be consistent with
`chronic cholecystitis. Patients with normal gallbladder function are generally not considered to
`be candidates for gallbladder removal surgery, but patients with chronic cholecystitis are. The
`
`15 Id. at 24N.
`
`16 Tulchinsky M, et al. SNM Practice Guideline for Hepatobiliary Scintigraphy 4.0. J. Nuc. Med. Technol. 2010 Dec;
`38 (4): 210-218.
`
`17 Ziessman HA, et al. Sincalide-Stimulated Cholescintigraphy: A Multicenter Investigation to Determine Optimal
`Infusion Methodology and Gallbladder Ejection Fraction Normal Values. J. Nucl. Med. 2010; 51: 277-281.
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`6
`
`

`

`
`November 28, 2017
`Page 7
`test result (i.e., the determination of the GBEF) therefore guides an important decision in patient
`management.
`
`
`Notably, the SNM Practice Guideline, which is used to perform reliable CCK-CS to help
`guide clinical treatment decisions, is based on data from a clinical trial using the currently
`marketed KINEVAC formulation, as manufactured by Bracco during the 2006-2008 time period.
`The validity of the Practice Guideline that is based on the results of that clinical trial therefore
`depends on the use of a KINEVAC formulation with the same qualities as the KINEVAC that
`was administered to the trial subjects. It is particularly critical that the KINEVAC used in
`clinical practice possess the same potency as the KINEVAC that was used to establish the 38%
`GBEF cut-off in the SNM Practice Guideline. Only the new version meets this requisite. There
`is no Practice Guideline for the old two-ingredient formulation making it ill-suited for use as a
`diagnostic drug.
`
`Gallbladder stimulation with KINEVAC was performed under a wide variety of dosing
`
`schemes prior to the publication of the SNM clinical guideline in 2010. Those schemes
`produced mixed results, and attendant debate over the diagnostic value of CCK-CS. The
`problems stemmed from the fact that biological CCK receptors are very specific in how they
`respond to the presence of CCK in the bloodstream; they respond best to a rise in CCK levels
`that matches the normal physiological release of CCK that is stimulated by eating. Providing a
`super-potent KINEVAC dose will cause gallbladder tetany and a low GBEF, while providing a
`sub-potent KINEVAC dose produces insufficient gallbladder stimulation and will also result in a
`low GBEF.
`
`Therefore, clinical use of the discontinued KINEVAC formulation to perform the CCK-
`
`CS diagnostic procedure according to established SNM Practice Guideline would increase the
`risk of a false-positive FGBD diagnosis and attendant unnecessary gallbladder surgery.
`KINEVAC dosing that deviates from the dosing used to establish the 38% GBEF cut-off will
`result in a calculated GBEF that is lower than the GBEF that would be expected under the
`clinical guideline. If a generic sincalide formulation enters the marketplace that claims to be
`equivalent in safety and efficacy to the KINEVAC formulation marketed by Bracco, but is
`instead measurably less potent per µg than currently marketed KINEVAC, then clinicians who
`use it for CCK-CS will obtain lower GBEFs in their patients than with Bracco’s KINEVAC.
`When these clinicians refer to the SNM Practice Guideline (which was developed with the
`currently marketed KINEVAC formulation), they will unwittingly obtain more false-positive test
`results, leading to an increase in the number of inappropriate recommendations for, and
`performance of, gallbladder removal surgery. This in turn will lead to an increase in overall risk
`for patients being evaluated for potential FGBD (and greater financial costs for individual
`patients and for the healthcare system), without an increase in clinical benefit. This clearly
`undesirable outcome would reduce the safety and efficacy of diagnostic testing using KINEVAC
`by injection.
`
`
`
`
`
`
`
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`7
`
`

`

`
`November 28, 2017
`Page 8
`
`
`D.
`
`Conclusion
`
`
`On behalf of Bracco, we respectfully request FDA determine that the old two-ingredient
`formulation was withdrawn for reasons of safety and efficacy, that the old formulation is less
`safe and effective than the currently marketed formulation and that FDA will not accept for
`review or approve ANDAs that refer to the discontinued two-ingredient formulation of
`KINEVAC for injection. Such a determination would comport with the statutory and regulatory
`mandates of the ANDA approval process and the agency’s public health goals of promoting
`patient health and safety.
`
`III.
`
`Environmental Impact
`
`This petition is categorically exempt from the requirement for an environmental
`
`assessment or an environmental impact statement pursuant to 21 CFR §§ 25.30 and 25.31.
`
`IV.
`
`Economic Impact
`
`
`
`Information on the economic impact of the petition will be provided upon request.
`
`Certification
`
`The undersigned certifies that, to the best knowledge and belief of the undersigned, this
`
`petition includes all information and views on which the petition relies, and that it includes
`representative data and information known to the petitioner that are unfavorable to the petition.
`
`
`
`Respectfully submitted,
`
`
`
`Anna Laakmann
`
`
`
`
`
`
`
`
`GREENBERG TRAURIG, LLP  Attorneys at Law  www.gtlaw.com
`
`8
`
`