ARNOLD & PORTER LLr
`
`March 6, 2015
`
`Division of Dockets Management
`Food and Drug Administration
`5630 Fishers Lane
`Room 1061, HFA-305
`Rockville, MD 20852
`
`Daniel A. Kracov
`DanieLKracov@aporter.com
`
`+1 202.942.5120
`+1 202.942.5999 Fax
`
`555 Twelfth Street, NW
`Washington, DC 20004-1206
`
`:.
`
`Re:
`
`Celgene Corporation and Abraxis BioScience LLC Citizen Petition
`
`To Whom it May Concern:
`
`On behalf of Celgene Corporation and Abraxis BioScience LLC ("Celgene"), I hereby
`submit the attached Citizen Petition to request that the Food and Drug Administration
`("FDA") establish appropriately stringent standards, as set forth in the Petition, with
`respect to: (I) approval of oncologic drug products incorporating nanotechnology, (2) the
`review and approval of any abbreviated new dmg application ("AND A'') relying on the
`approval of ABRAXANE"' (paclitaxel protein-bound particles for injectable suspension)
`(albumin-bound) as a reference listed drug, and (3) any 505(b)(2) new drug application
`("NDA'') for any similar product referencing ABRAXANE or paclitaxel.
`
`This Petition is being submitted under Section 505 of the Federal Food, Drug, and
`Cosmetic Act, and in accordance with the requirements set forth in21 C.F.R. §§ 10.20
`and I 0.30. Should you have any questions regarding this Petition, please do not hesitate
`to contact me.
`
`Enclosures
`
`Respectfully submitted,
`
`Daniel A. Kracov
`
`Counsel to Celgene Corporation and
`Abraxis BioScience LLC
`
`01
`
`i
`
`~:
`
`

`

`CITIZEN PETITION
`
`Requesting that the Food and Drug Administration establish stringent standards
`with respect to any abbreviated new drug application relying on the approval of
`ABRAXANE® (paclitaxel protein-bound particles for injectable suspension)
`(albumin-bound) as a reference listed drug, and any 505(b)(2) new drug
`application for any similar product referencing ABRAXANE or paclitaxel
`
`Celgene Corporation
`and
`Abraxis BioScience, LLC, a wholly owned subsidiary of Celgene Corporation
`
`March 6, 2015
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`ACTIONS REQUESTED ................................................................................................... 7
`
`A.
`
`B.
`
`C.
`
`Approval of Oncologic Drug Products Incorporating
`Nanotechnology ...................................................................................................... 7
`
`AND As ................................................................................................................... 8
`
`505(b )(2) NDAs ...................................................................................................... 9
`
`II.
`
`III.
`
`STATEMENT OF GROUNDS .......................................................................................... 9
`
`SUMMARY OF FDA'S AUTHORITY TO TAKE THE REQUESTED
`ACT! ONS ......................................................................................................................... II
`
`A.
`
`FDA Has the Legal Authority to Impose Standards Beyond
`Current Bioequivalence Requirements for Products With Unique
`Properties .............................................................................................................. II
`
`I.
`
`2.
`
`Statutory and Regulatory Standards .......................................................... II
`a.
`FDA Is Developing Tailored Guidance Regarding
`the Emerging Field ofNanoparticle Drugs ................................... II
`FDA Has
`the Authority
`to Require ANDA
`Applicants to Show that Their Products Actually
`Contain
`the Same Active
`Ingredient and are
`Bioequivalent to ABRAXANE ..................................................... 14
`
`b.
`
`FDA Has the Authority to Require 505(b)(2) Applicants to
`Provide Adequate and Well-Controlled Studies
`Demonstrating Their Products' Safety and Efficacy
`Profiles ...................................................................................................... 16
`
`IV.
`
`FACTUAL BASIS FOR THE REQUESTED ACTION .................................................. 17
`
`A.
`
`B.
`
`C.
`
`Overview ............................................................................................................... I 7
`
`Unique Structure of ABRAXANE ........................................................................ 17
`
`I.
`
`Critical Role of Albumin in Mechanism of ABRAXANE
`Transport ................................................................................................... 19
`
`The Physicochemical Prope1iies of ABRAXANE Necessitate
`Stringent Bioequivalence Standards ..................................................................... 22
`
`I.
`
`FDA Proposes Certain In Vitro Characterization Tests To
`Demonstrate Sameness ............................................................................. 22
`Particle Morphology ..................................................................... 23
`a.
`b.
`Particle Size .................................................................................. 24
`c.
`Surface Potential ........................................................................... 27
`d.
`Paclitaxel Crystallinity .................................................................. 28
`
`- 2 -
`
`

`

`e.
`
`f.
`g.
`h.
`
`1.
`
`Fraction of Albumin to Paclitaxel Associated with
`the Particles ...................... -. ........................................................... 30
`Nature of the Bond between Paclitaxel and Albumin ................... 32
`In Vitro Release Kinetics .............................................................. 3 3
`Oligomeric Status of
`the Starting Albumin
`Ingredient and the Albumin in the Final Drug
`Product .......................................................................................... 35
`Oligomeric Status of Albumin Coating Associated
`with the Particles ........................................................................... 3 7
`Recovery of Paclitaxel Following Filtration ................................. 39
`J.
`Summary of Physicochemical Attributes ...................................... 40
`k.
`Functional Attributes Also Distinguish ABRAXANE from
`Purported Copies ....................................................................................... 42
`a.
`Solubility
`is a Functional Attribute
`that
`is
`Influenced by Various Physicochemical Properties ..................... 43
`Release Kinetics of the Reconstituted Suspension
`after Accelerated Storage Demonstrate that Details
`of the Manufacturing Process Alter the Final
`Product .......................................................................................... 44
`Stability of Reconstituted Suspension During
`Accelerated Storage Reveals Differences
`in
`Purported Copies as Compared to ABRAXANE ......................... 45
`
`2.
`
`b.
`
`c.
`
`3.
`
`Sameness of the Listed Physicochemical Attributes is
`Necessary but Not Sufficient to Ensure Product
`Functionality ............................................................................................. 48
`
`D.
`
`E.
`
`Additional Clinical Immunological Assays Should Be Required of
`Any Applicant Referencing ABRAXANE ........................................................... 49
`
`Paclitaxel Formulations with Different Delivery Vehicles Are
`Distinct Products with Distinct Pharmacology. Traditional
`Phannacokinetic Studies are not Adequate to Demonstrate
`Bioequivalence ...................................................................................................... 52
`
`I.
`
`2.
`
`3.
`
`Pharmacokinetic Modeling and Simulations for
`ABRAXANE versus Taxol Suggest that Plasma Drug
`Levels Cannot Be Used as a Surrogate for Tissue
`Penetration for Different Formulations ofPaclitaxel... ............................. 53
`
`Paclitaxel-Based Products with Different Formulations
`Delivered to a Tumor Site Demonstrate Differential Spatial
`Distribution and Differential Mitotic Arrest in the Tumor,
`Suggesting that Equivalent Gross Tumor Drug Levels May
`Not Translate into Equivalent Therapeutic Effect .................................... 60
`
`Glucocorticoid Premedication Used to Prevent
`Hypersensitivity of Certain Paclitaxel-based Products Can
`Affect Tumor Cell Kill In- Vitro Suggesting that the use of
`
`0
`
`- .) -
`
`

`

`PK Bioequivalence as a Surrogate for Therapeutic
`Equivalence Between a Glucocorticoid Requiring Regimen
`and a Non-Glucocorticoid Requiring Regimen May Not Be
`Valid .......................................................................................................... 62
`
`4.
`
`Bioequivalence Based on Plasma Concentration of
`Paclitaxel Alone Cannot Be Used as a Surrogate for
`Therapeutic Equivalence for Paclitaxel-Based
`Formulations with Different Delivery Vehicles ....................................... 63
`
`The in vitro and in vivo Behavior of ABRAXANE Suggests that
`Bioequivalence of Paclitaxel Cannot Be Demonstrated with
`Pharmacokinetic Assessment of Free and Protein Bound Paclitaxel
`Alone. Additional Measurements of Particle Distribution in vivo
`are Needed to Ensure Follow-on Albumin Preparations
`Demonstrate Bioequivalence ................................................................................ 64
`
`There are Clinical Implications of Varying Delivery Vehicles on
`Safety and Efficacy for Paclitaxel-Based Formulations ....................................... 66
`
`Any 505(b)(2) Applicant Referencing ABRAXANE Should Be
`Required to Perform Adequate and Well Controlled Clinical
`Studies to Appropriately Assess the Dosing, Safety, and Efficacy
`for Each Indication in Order to Meet Statutory Requirements for
`Approval. .............................................................................................................. 66
`
`F.
`
`G.
`
`H.
`
`I.
`
`2.
`
`b.
`
`Overview of Clinical Differentiation of Various Paclitaxel
`Formulations ............................................................................................. 66
`a.
`Different Paclitaxel Formulations Have Clearly
`Demonstrated Differences in Efficacy and Safety in
`Metastatic Breast Cancer in Phase 3 Randomized
`Clinical Studies ............................................................................. 67
`Different Paclitaxel Formulations Have Clearly
`Demonstrated Differences in Efficacy and Safety in
`NSCLC in Phase 3 Randomized Clinical Studies ......................... 70
`Different Paclitaxel Formulations Have Clearly
`Demonstrated Differences in Efficacy and Safety in
`Pancreatic Cancer -- Other Than ABRAXANE,
`They Have Failed to Meet Their Clinical Endpoints
`When Compared to Taxol, Despite Encouraging
`Phase 2 Results ............................................................................. 72
`
`c.
`
`Due to the Complexity ofPaclitaxel-Based Products, Each
`505(b )(2) NDA Paclitaxel Product Requires a Full
`Characterization of its Unique Risk/Benefit Profile for
`Each Indication ......................................................................................... 76
`a.
`Safety of ABRAXANE - Each Indication Requires
`its own Characterization ............................................................... 76
`
`I.
`
`Since ABRAXANE Is a Complex Nanoparticle Product and
`
`- 4-
`
`

`

`Because Paclitaxel-Based Products are Highly Dependent on Their
`Formulation, Adequate and Well-Controlled Clinical Studies are
`Necessary to Ensure the Safety and Efficacy of 505(b)(2) NDAs
`Referencing the Product ........................................................................................ 78
`
`CONCLUSIONS ........................................................................................................................... 79
`
`Given the above, Celgene requests that FDA refrain from receiving for
`substantive review or approving any ANDA referencing ABRAXANE or
`any 505(b)(2) NDA for a similar product referencing ABRAXANE or
`paclitaxel unless and until the data requirements for such applications as
`specified herein are satisfied ............................................................................................. 80
`
`ENVIRONMENTAL IMPACT .................................................................................................... 80
`
`ECONOMIC IMPACT ................................................................................................................. 80
`
`CERTIFICATION ........................................................................................................................ 80
`
`Attachment A: Suggested Guidance (redlined and clean versions)
`Attachment B: ABRAXANE Prescribing Information
`
`References enclosed
`
`- 5 -
`
`

`

`CITIZEN PETITION
`
`Celgene Corporation and Abraxis BioScience LLC, a wholly owned subsidiary of
`Celgene Corporation, ("Celgene") submit this Citizen Petition ("Petition") under section 505 of
`the Federal Food, Drug, and Cosmetic Act (the "FDCA" or "Act") and 21 C.F.R. § 10.30 to
`request that the Food and Drug Administration ("FDA") establish appropriately stringent
`standards, as set forth in this Petition, with respect to: (I) approval of oncologic drug products
`incorporating nanotechnology, (2) the review and approval of any abbreviated new drug
`application ("ANDA'') relying on the approval of ABRAXANE"' (paclitaxel protein-bound
`particles for injectable suspension) (albumin-bound) as a reference listed drug, and (3) any
`505(b)(2) new drug application ("NDA'') for any similar product referencing ABRAXANE or
`paclitaxel.
`
`Drug products incorporating nanotechnology possess unique and complex characteristics,
`and FDA has stated that technical assessments of such products should be product-specific and
`take into account the effects of nanomaterials in the particular biological and mechanical context
`of the product and its intended use. 1 ABRAXANE is a novel nanotechnology agent that was
`developed to address the significant limitations of conventional paclitaxel formulations, and it is
`the only protein-based nanotechnology agent approved for the treatment of metastatic breast
`cancer, non-small cell lung cancer, and pancreatic cancer in the United States and in markets
`around the world? As described in this Citizen Petition, beyond ABRAXANE, no other non(cid:173)
`Cremophor-EL ® (polyethoxylated castor oil)-based formulations of paclitaxel have been
`approved by FDA to date. As detailed in this Petition, the pharmacology of paclitaxel is strongly
`dependent on its delivery vehicle, and formulations that appear to have similar physicochemical
`and/or pharmacokinetic attributes have been proven to have very different clinical outcomes. For
`example, ABRAXANE demonstrated a clinical benefit in both taxane refractory patient
`populations and in pancreatic cancer, a disease in which taxanes have failed to show clinical
`benefit.
`
`The data on ABRAXANE demonstrate that the unique distribution of components of
`ABRAXANE is essential to the delivery of the drug at the site of action-the tumor
`microenvironment. The distribution of ABRAXANE to tumor and non-target tissues is complex,
`and cannot be assessed by simply measuring analytes in the blood. This Citizen Petition seeks to
`ensure that other formulations purporting to be the same or similar to ABRAXANE address these
`unique characteristics and meet the relevant statutory standards; namely, "sameness" for ANDA
`applicants and "safe and effective" for 505(b )(2) NDA applicants.
`
`The principal requests of this petition can be summarized as follows:
`
`• Nanotechnology Products: Celgene requests that FDA consider the characteristics of
`
`1 National Cancer Institute Alliance for Nanotechnology in Cancer, webpage entitled "Nanotechnology: Where It
`Stands Now" available at http://nano.cancer.gov/learn/now/.
`2 ABRAXANE Prescribing Information (Revised December 12, 20!4) (Attachment B).
`
`- 6 -
`
`

`

`drug products incorporating nanotechnology when developing approval standards and
`requirements for oncologic nanomedicines, including in finalizing the September 12,
`2012 Draft Bioequivalence Guidance on Paclitaxel3 ("Draft Guidance") and
`in
`developing the "Drug Products Containing Nanomateria1s" guidance document listed in
`CDER's 2015 guidance agenda.
`
`o Paclitaxel Draft Guidance: Celgene requests that FDA revise the Paclitaxel Draft
`Guidance to be consistent with Celgene's suggested revision to the guidance ("Suggested
`Guidance"), which is included as Attachment A of this Petition. Specifically, Celgene
`requests that products referencing ABRAXANE be required to demonstrate sameness
`with respect to the functional attributes and additional physicochemical properties set
`fm1h in Celgene's Suggested Guidance 4
`
`o ANDA Applicants: Because, as detailed herein, we believe that a demonstration of
`physicochemical and pharmacokinetic sameness, while necessary, may not be sufficient
`to ensure the equivalence of a generic product to ABRAXANE, Celgene requests that
`FDA consider requiring manufacturers of any purported copy of ABRAXANE to
`demonstrate therapeutic equivalence through clinical studies.
`
`• SOS(b )(2) Applicants: Similarly, with respect to any 505(b )(2) NDA referencing
`ABRAXANE or any other paclitaxel-based formulation, Celgene requests that any such
`applicant's product including nanopm1icle formulations clinically demonstrate safety and
`effectiveness as described herein.
`
`Celgene requests that FDA refrain from receiving for substantive review or approving
`any ANDA referencing ABRAXANE or any 505(b)(2) NDA for a similar product referencing
`ABRAXANE or paclitaxel unless and until the data requirements for such applications as
`specified herein are satisfied.
`
`I.
`
`ACTIONS REQUESTED
`
`A.
`
`Approval of Oncologic Drug Products Incorporating Nanotechnology
`
`As noted above, Celgene requests that FDA expressly consider the unique characteristics
`of drug products incorporating nanotechnology when developing approval standards and
`requirements for nanomedicines for oncologic indications, including in the recommendations
`provided
`in the Paclitaxel Draft Guidance. With respect to paclitaxel nanomedicines
`specifically, Celgene requests that FDA revise its Draft Guidance to be consistent with the
`revised Suggested Guidance included as Attachment A to this Citizen Petition. Additionally,
`
`3 FDA, Draft Guidance on Paclitaxel (September 2012), available at
`http://www. fda.gov I down loads/ drugs/ guidancecom pl ianceregulatoryin formation/ gui dances/ucm3 200 15. pdf
`4 See CDER, "Guidance Agenda: New & Revised Guidances COER is Planning to Publish During Calendar Year
`20 15" (January 6, 20 15).
`
`- 7 -
`
`

`

`Celgene proposes that FDA initiate a more general stakeholder dialogue regarding concerns with
`respect to the approval requirements for these complex "follow on" nanomedicines in order to
`ensure that FDA requirements are consistent with the applicable statutory framework. We also
`request that FDA take our Suggested Guidance recommendations into consideration when
`developing the "Drug Products Containing Nanomaterials" guidance document listed in CDER's
`2015 guidance agenda 5
`
`B.
`
`ANDAs
`
`With respect to the review of any ANDA application, Celgene specifically requests that
`FDA adopt suitably stringent requirements for any paclitaxel protein (albumin)-bound
`nanoparticle product referencing ABRAXANE, as described in detail in this Citizen Petition. In
`light of the current state of the science, we believe that a demonstration of physicochemical and
`pharmacokinetic sameness, while necessary, may not be sufficient to ensure the equivalence of a
`generic product to ABRAXANE. Consequently, we request that FDA consider requiring
`manufacturers of any purpm1ed copy of ABRAXANE to demonstrate therapeutic equivalence
`through clinical studies. Specifically, Celgene requests that FDA require that any marketing
`application for a product referencing ABRAXANE have, as detailed herein:
`
`(a)
`
`(b)
`
`(c)
`
`chemical composition that is qualitatively and quantitatively the same as
`ABRAXANE, except as allowed under 21 C.F.R. § 314.94(a)(9)(iii), and
`physicochemical properties, as set fm1h in the Suggested Guidance and further
`explained in Section IV.C of this Petition, that are equivalent to those of
`ABRAXANE;
`
`bioequivalence of the pharmacokinetic properties, particularly the rate of
`paclitaxel tissue distribution and extent of paclitaxel exposure in tissues set forth
`in Section IV.E in the Citizen Petition and in the Suggested Guidance in
`Attachment A; and
`
`including, where
`to ABRAXANE,
`therapeutic equivalence
`demonstrated
`necessary, via adequate and well-controlled comparative clinical studies with
`appropriate endpoints for each indication.
`
`In the case of paclitaxel protein-bound products, the statutory "sameness" requirement for
`generic approval will be challenging for any ANDA applicant to meet because drug sameness
`may not be fully assured based on available data and analytical methods. As described in this
`Petition, ABRAXANE is a complex nanoparticle product6 composed of a small molecule drug,
`paclitaxel, and a biological component, albumin, which contributes to the performance of
`ABRAXANE, and thus standard chemical, physicochemical and pharmacokinetic assays may
`
`5 !d
`
`6 ABRAXANE Prescribing Information (Revised December 12, 2014) (Attachment B).
`
`- 8 -
`
`

`

`not be sufficient to characterize the contribution of the delivery vehicles aiding the tissue
`distribution of paclitaxel and
`to ensure
`that a purported generic product referencing
`ABRAXANE is in fact the same as the reference drug. Comparative clinical data may be
`necessary in order to determine how even slight differences in chemical composition, structure,
`function, and nonclinical pharmacology may impact clinical outcomes. Such a requirement
`would appear to be particularly important given the potential safety and effectiveness concerns
`associated with patients who could be switched between various formulations, including multiple
`generics. Celgene thus requests that FDA refrain from receiving for substantive review or
`approving any ANDA referencing ABRAXANE unless and until the data requirements for such
`applications as specified herein are satisfied.
`
`C.
`
`505(b)(2) NDAs
`
`With respect to any 505(b )(2) NDA referencing ABRAXANE or any other paclitaxel(cid:173)
`based formulation, Celgene requests that any such applicant's product including nanoparticle
`formulations (regardless of whether albumin-bound) 7
`, clinically demonstrate safety and
`effectiveness as described herein. Celgene performed extensive clinical studies to fully
`characterize the safety and efficacy of ABRAXANE. Any 505(b )(2) NDA applicant referencing
`ABRAXANE or any other paclitaxel-based formulation should be required to do the same in
`order to meet the statutory substantial evidence standard with respect to each indication. Celgene
`thus requests that FDA refrain from receiving for substantive review or approving any 505(b )(2)
`NDA for a similar product referencing ABRAXANE or paclitaxel unless and until the data
`requirements for such applications as specified herein are satisfied.
`
`II.
`
`STATEMENT OF GROUNDS
`
`ABRAXANE is a prescription drug approved to treat life-threatening cancers that affect
`hundreds of thousands of patients in the United States. Specifically, ABRAXANE is indicated
`for the treatment of:
`
`• Metastatic Breast Cancer ("MBC"), after failure of combination chemotherapy for
`metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy
`should have included an anthracycline unless clinically contraindicated.
`
`• Locally advanced or metastatic non-small cell lung cancer ("NSCLC"), as first-line
`treatment in combination with carboplatin, in patients who are not candidates for curative
`surgery or radiation therapy.
`
`• Metastatic adenocarcinoma of the pancreas as first-line treatment, in combination with
`
`7 An albumin-bound paclitaxel nanopm1icle product may be required to file a 505(b)(2) NDA if it contains a
`different ratio of albumin or different excipient in the formulation.
`
`- 9 -
`
`

`

`gemcitabine. 8
`
`Since the initial approval of ABRAXANE in 2005, over 200,000 patients in the United
`States have received treatment with the product, and ABRAXANE is an important option in the
`treatment of these cancers. It is therefore critical that FDA ensure that any submission
`referencing ABRAXANE provides assurance that the product is fonnulated and manufactured in
`a manner that will ensure safety and effectiveness. A failure to require such data could result in
`thousands of cancer patients experiencing compromised therapeutic results. The establishment of
`precise and comprehensive data requirements and strict manufacturing and analytical controls is
`(I) necessary to ensure safety and effectiveness of products that reference ABRAXANE, (2)
`consistent with FDA's overall regulatory approach for therapeutic nanoteclmologies, and (3)
`within FDA's regulatory authority and discretion.
`
`This Citizen Petition can be summarized as follows:
`
`• Celgene requests that FDA expressly consider the characteristics of drug products
`incorporating nanotechnology when developing approval standards and requirements for
`oncologic nanomedicines (See Section lV.A).
`
`• ABRAXANE is a complex nanoparticle-based product, including a small molecule drug
`substance (active pharmaceutical ingredient) and albumin (a biologic) with unique
`pharmacology sensitive
`to
`its manufacturing processes. Small changes
`in
`the
`manufacturing process of complex nanomedicines, such as ABRAXANE, are likely to
`affect product safety and effectiveness 9 In this area, there are not necessarily direct or
`well-characterized links between process parameters and the functional performance of
`the end product. Thus, FDA should consider exercising special care to ensure that
`products purporting to be the same as, or otherwise seeking to rely on FDA's findings
`with respect to ABRAXANE, have a rigorously controlled manufacturing process m
`order to generate a safe and effective product. (See Section IV.B).
`
`•
`
`Independent of identity of chemical compositions, there are many physicochemical
`factors that can affect drug release and delivery of nanoparticle-containing paclitaxel
`products.
`In addition to the elements listed in the Draft Guidance, with respect to
`products referencing ABRAXANE, FDA should require any applicant to demonstrate the
`additional functional characteristics set forth in the Suggested Guidance and in Section
`IV.C of this Petition (i.e., sameness as to particle solubility, release kinetics, crystallinity,
`stability in suspension, and 0.2-!lm filtration). (See Section IV.C).
`
`• With respect to any 505(b)(2) NDA, clinical immunogenicity data and clinical safety and
`
`8 ABRAXANE Prescribing Information (Attachment B).
`
`9 See Letter from J. Woodcock, M.D., Director, CDER to S. Rattray Vice President, Regulatory Affairs Ortho
`Biotech, L.P. Regarding Docket No. 2009-P-02 I 6, at I 4 (Feb 4, 20 I 3) explaining how the manufacturing of Doxilw
`involves certain steps that increase the stability of the doxorubicin and the efflux rate of encapsulated material.
`
`- I 0-
`
`

`

`effectiveness data should be required in support of each indication, as FDA required for
`ABRAXANE. Such data may be necessary for purported generics as well. (See Section
`IV.D).
`
`• Bioequivalence, based on plasma measurement of paclitaxel concentrations (total and
`free), is insufficient to ensure sameness and clinical interchangeability. Traditional
`bioequivalence approaches are not applicable to paclitaxel formulations with different
`excipients because (I) small molecule paclitaxel is not released to the site of action at the
`tumor from its delivery vehicles until the delivery vehicles have distributed to the tissue,
`and (2) the distribution of these drug delivery vehicles to the tissue is critically dependent
`on and sensitive to the specific attributes of the nanoparticle formulation. (See Sections
`IV.E and IV.F).
`
`ABRAXANE is a complex nanoparticle product that presents unique scientific and
`clinical reproducibility challenges. The rapid distribution of ABRAXANE to tumor and healthy
`tissue is critically dependent on the nab-particle interaction with tumor and healthy tissue.
`Therefore, the total plasma concentration of paclitaxel is not an appropriate measurement of
`bioequivalence; rather the paclitaxel concentrations at tumor and healthy tissue may better reflect
`both bioequivalence for an ANDA and safety and effectiveness for a 505(b)(2) NDA application
`for a product similar to ABRAXANE. The current guidelines, in both the ANDA and 505(b)(2)
`contexts, will not provide adequate assurance of clinical outcomes for any approved indication
`for ABRAXANE.
`
`In the absence of clinical studies as outlined herein, FDA cannot reach a conclusion that
`applicable statutory standards have been met with respect to any 505(b)(2) NDA when critical
`unanswered questions remain around the strength or meaning of physicochemical and plasma
`pharmacokinetic comparisons in terms of safety and efficacy. Thus, as set fm1h in Section IV.H,
`FDA should require clinical studies in support of each indication, as it did for each approved
`ABRAXANE indication. Such data may also ultimately be necessary for any purported generic,
`particularly given the potential for switching of patients among multiple approved fom1s of the
`product.
`
`HI.
`
`SUMMARY OF FDA'S AUTHORITY TO TAKE THE REQUESTED ACTIONS
`
`A.
`
`FDA Has the Legal Authority to Impose Standards Beyond Current
`Bioequivalence Requirements for Products With Unique Properties
`
`1.
`
`Statutory and Regulatory Standards
`
`a.
`
`FDA Is Developing Tailored Guidance Regarding the Emerging
`Field of Nanoparticle Drugs
`
`As FDA has recognized, the FDCA, applicable regulations, and case law provide FDA
`
`- 11 -
`
`

`

`with some flexibility in detem1ining the appropriate methods for establishing that a drug is
`bioequivalent to its reference listed drug, 10 and thus, as appropriate for the nature of the drug
`product, FDA has the legal authority to impose stricter standards beyond typical requirements
`even where the exercise of that authority may preclude a pathway to approval for a given
`product. For instance, although 21 C.F.R. §320.24 enumerates certain methods for establishing
`bioequivalence (e.g., in vivo PK and PD studies, comparative clinical trials, in vitro studies), the
`regulation, consistent with section 505(j)(8)(c) of the FDCA, also provides that FDA has the
`flexibility to use "[a]ny other approach deemed adequate by FDA to ... establish bioequivalence."
`In addition, as FDA acknowledged in its response to a Citizen Petition submitted by Ortho
`Biotech, L.P., when it enacted the Hatch-Waxman Amendments "Congress intended to grant
`FDA wide discretion to establish bioequivalence standards on a drug-by-drug basis." 11
`
`FDA has demonstrated
`this authority and discretion by
`imposing stringent
`physicochemical and pharmacokinetic bioequivalence standards for cetiain classes of drug
`products with complex structures, including doxorubicin HCL liposomal injection products and
`iron sucrose injection products. However, as detailed herein, the structure, characteristics, and
`functionality, and safety considerations of ABRAXANE are more complex than those of these
`other products. While stringent pharmacokinetic and physicochemical sameness standards for
`any purported ABRAXANE generic m·e necessary
`to provide
`insight
`into potential
`bioequivalence (and we urge FDA to adopt such standards), they may not be sufficient for
`actually establishing bioequivalence. Consequently, we urge FDA to act within its legal
`authority to not only establish the stringent pharmacokinetic m1d physicochemical sameness
`standards that we describe herein for any ABRAXANE generic, but also to require that the
`equivalence of any such purported generic of ABRAXANE be demonstrated through clinical
`studies, where necessary.
`
`As seen in the Agency's FY15 Generic Drug User Fee Amendments Regulatory Research
`Priorities list, FDA has already targeted a need to develop risk-based equivalence standards for
`narrow therapeutic index drugs, as well as guidance and policy that clarifies the ANDA pathway
`for complex drug particles with unique characteristics such as nanomaterials. 12 Additionally,
`under the Biologics Price Competition and Innovation Act of 2009, FDA is currently formulating
`its approach to the determination of biosimilarity and interchangeability of a biologic product
`vis-a-vis a reference product. 13 In developing its guidance with respect to each of the foregoing,
`FDA has actively engaged scientists, industry members and relevant societies. Nanomedicines
`
`10 Woodcock, Janet.