CENTER FoR DRuG EvALUATION AND RESEARCH
`
`Guidance for Industry
`
`The FDA published Good Guidance Practices in February 1997.
`This guidance was developed and issued prior to that date.
`
`Additional copies are available from:
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`5600 Fishers Lane
`Rockville, MD 20857
`
`(l'el) 301-827-4573
`(Internet) http://www.fda.gov/cder/guidance/index.htm
`
`u.s. DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOOD AND DRUG ADMINISTRATION
`
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`. }:
`
`\
`
`1
`
`POINTS TO CONSIDER
`
`DIVISION OF ANTI-INFECTIVE DRUG PRODUCTS
`
`CLINICAL DEVELOPMENT AND LABELING
`OF ANTI-INFECTIVE DRUG PRODUCTS
`
`NUMBER TWO
`
`PREAMBLE
`
`Changing or unclear interpretations of clinical trial data needed
`to demonstrate the effectiveness and safety of antimicrobial drug
`products have at times led to confusion and frustration on the part
`of both applicants and Division of Anti-Infective Drug Products
`reviewers. The Federal Food, Drug, and Cosmetic Act (FD&C Act) and
`the implementing regulations clearly state that adequate and well(cid:173)
`controlled investigation~ (emphasis added) are necessary
`to
`demonstrate the safety and effectiveness of a given drug product.
`The
`intent of
`these
`regulations
`is
`to
`require safety and
`effectiveness
`data
`from
`well-performed,
`interpretable,
`independently corroborated studies as the basis for marketing a
`drug product in the United States. How to interpret this statutory
`requirement with respect to antimicrobial drug therapies, where
`there
`is no clear consensus on
`the boundaries of possible
`''indications", has, over time, resulted in confusion. The terms -
`"adequate",
`"well-controlled",
`and "indication"
`have been
`interpreted variously by the Division over time. Manufacturers of
`new drug applications approved in the United States, also, have
`interpreted
`these
`terms variously and have
`taken,
`in
`some
`instances, wide liberties in the promotion of their antimicrobial
`drug products based on the semantics of approved labeling rather
`than the strength of the submitted scientific data.
`
`This document is not intended to undergird a "cookbook" approach to
`antimicrobial drug development.
`Rather, it is a "Points
`to
`Consider" document
`for applicants and reviewers alike, which
`suggests minimal
`information appropriate
`for
`the clinical
`development of routine antimicrobial drug products and identifies
`issues common to many antimicrobial new drug applications that
`should be addressed. This document should not replace the exercise
`of good scientific judgment by applicants or reviewers at any point
`in the development or review process.
`Likewise it should not
`supplant appropriate scientific and technical advice available to
`the Division from Advisory Committees and other appropriate outside
`consultants.
`It should be cons ide red complementary
`to other
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`( ·
`
`2
`
`guidance documents that suggest specifics of clinical trial design
`and administration.
`
`All circumstances and contingencies surrounding the development of
`antimicrobial drug products,
`including all the possible desired
`infection claims and all the extenuating c1rcumstances for certain
`diseases and compounds, cannot reasonably be addressed in a general
`"Points to Consider" document. Many antimicrobial drug product
`development programs should be discussed with
`the Agency so
`agreements can be reached on effectiveness criteria that could be
`used in the evaluation of a specific antimicrobial drug product in
`order to facilitate desired final product labeling. For example,
`applicants wishing to develop unique antimicrobial drug products
`(e.g., one with dosing regimens
`that de-part
`from established
`practices, one with unusual pharmacokinetic or pharmacodynamic
`properties, or one with evidence of sub-inhibitory antimicrobial
`drug concentrations at sites of infection) should discuss clinical
`development plans with the Division prior to the initiation of a
`capital-intensive development program, which
`is based on
`the
`assumption
`the
`information
`identified
`in
`this document
`is
`applicable
`in all situations.
`If an applicant is in doubt,
`discussion with the Division is highly encouraged.
`In every case,
`however, the appraisal of a desired labeling statement will take
`into account the entire NDA data package and will not be decided by
`viewing specific data in isolation.
`
`this document will not be viewed as an onerous,
`Hopefully,
`obstreperous intrusion into antimicrobial drug product research,
`but rather as effort to help define good scientific methodology and
`good scientific discipline in these research efforts. It is hoped
`this document will be a vital communication vehicle between the
`Division,
`the pharmaceutical
`industry,
`the infectious disease
`academic community, and the public. As our collective knowledge of
`this class of drug products expands and as our collective
`perspective of the clinical trial process {GCP)
`involving these
`drug products further matures, the Division anticipates that this
`document will change to reflect that new knowledge and perspective.
`This document will hopefully afford all parties interested in the
`development of new antimicrobia 1 drug products a mechanism by which
`both to apprise others and to become apprised themselves of this
`new knowledge and these new perspectives.
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`INTRODUCTION TO ISSUES
`
`ADEQUATE CLINICAL TRIALS:
`
`3
`
`introduce a more objective approach for
`In an effort to
`interpreting "equivalence" or "superiority" of antimicrobial
`drug products, more rigorous statistical analyses and better
`database review procedures have been employed recently by the
`Division.
`These changes, along with
`the
`tightening of
`evaluability criteria and more definitive delineation of
`infections under investigation, have resulted in 'the need to
`enroll more patients in clinical trials of antimicrobial drug
`products. They have also placed a premium on monitoring these
`studies more effectively to maximize the number of evaluable
`patients in a given trial. This has incurred the ire of some
`applicants, who contend the Division is requiring more data
`today
`to
`establish
`the
`effectiveness
`of
`their
`new
`antimicrobial drug products than was required for "similar"
`products in the past.
`
`Any discussion of the "adequacy" of a clinical study requires
`discussion of issues of clinical trial design and management,
`primary effectiveness variables and endpoints, evaluability
`criteria, and statistical analysis. Several of these issues
`are addressed
`in
`this document.
`Other
`issues, more
`appropriately,
`are
`addressed
`in
`greater detail
`in
`complementary documents
`on clinical
`trial design
`and
`management published by the FDA and others.
`
`Recently most clinical trials of antimicrobial drug products
`have been
`randomized; yet,
`the masking
`( 1'blinding") of
`patients, clinicians, evaluators, and applicants has been
`varied at best.
`In addition, several open trial designs have
`also been accepted previously by
`the Division when pre(cid:173)
`determined effectiveness standards have been achieved (i.e.,
`trials establishing effectiveness
`in
`treating gonococcal
`urethritis/cervicitis).
`Such
`trial designs have
`their
`limitations and their own inherent problems with potential
`bias introduction that must be recognized and addressed.
`
`WELL-CONTROLLED CLINICAL TRIALS:
`
`A "well-controlled clinical trial" has been more clearly and
`consistently defined, as the implementing regulations describe
`five categories of clinical trials that can be classified as
`"well-controlled".
`In clinical trials of antimicrobial drug
`products, we only occasionally have the luxury of placebo(cid:173)
`controlled trials, because it is often felt to be ethically
`unacceptable not to treat infected patients when effective
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`,.
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`4
`
`therapy is available. Therefore, we have most often relied
`upon active-controlled studies to establish effectiveness of
`a new antimicrobial drug product, usually using comparator
`agents already approved for similar indications in the United
`States.
`(See comments on "Issues with Comparator Agents".)
`With
`the
`increasing effectiveness' of antimicrobial drug
`products in many infections, high cure rates make it nearly
`impossible or impractical for a new antimicrobial drug product
`to demonstrate statistical or clinically-relevant superiority
`to an approved comparator agent.
`However, when patient
`numbers for studies can reasonably be obtained, effectiveness
`end points are fairly well established, and studies can be
`completed in a reasonable time frame, the Agency~has granted
`"unrestricted 11 (i.e., no caveats or limitations regarding the
`breadth of the specific claim) effectiveness claims for new
`antimicrobial drug products when
`those new products,
`in
`clinical
`trials, demonstrate statistical
`and clinical
`equivalence to a product already approved for treatment of the
`same infection. ·Most recently, the Division has used a "two(cid:173)
`tailed 95% confidence
`interval around
`the difference
`in
`outcomes" approach to determine such statistical equivalence
`between two products.
`
`Presently, the Division also has great interest in exploring
`the possibility of using alternate clinical trial designs to
`characterize the dose-response of a new antimicrobial drug
`product in treating a given infection and also using these
`data as pivotal data for evaluating the approvability of a new
`drug application. This issue is discussed further in the
`"1992 Addendum" at the conclusion of this document.
`
`"INDICATION"
`
`The definition of "indication" as applied to antimicrobial
`drug products has evolved over time.
`In the past it assumed
`a broader interpretation, such as "lower respiratory tract
`infections" or "upper respiratory tract infections". More
`recently,
`a more
`def ini ti ve
`interpretation,
`such
`as
`"community-acquired
`pneumonia"
`or
`"acute
`bacterial
`exacerbation of chronic bronchitis", has been applied. This
`recent change recognizes the different pathophysiologies of
`certain infectious diseases and the inability to extrapolate
`effectiveness
`in one disease to effectiveness
`in another
`disease when pathophysiology or microbiology are different.
`This change in perspective has been undertaken in an effort to
`fulfill the mission of the Agency to inform physicians, as
`accurately as possible, about the established effectiveness of
`a product and to limit manufacturer promotion of products only
`to those indications for which adequate effectiveness and
`safety have been established.
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`5
`
`PERSPECTIVE ON ANTIMICROBIAL DRUG PRODUCT UNIQUENESS
`
`Antimicrobial drug products do not usually exert their intended
`therapeutic effect directly on humans as do most other human drug
`products. Rather the human therapeutic effect is a by-product of
`the drug's ability to kill or inhibit the growth of microorganisms.
`Pharmacologic effects on humans are, usually, unintended adverse
`events. Antimicrobial drug products often also have standardized
`in vitro techniques that afford reproducible data on the amount of
`drug
`required
`to kill or
`inhibit
`the growth of certain
`microorganisms in an in vitro setting. Better techniques for
`assessing the pharmacokinetic properties of certain antimicrobial
`drug products in humans often afford reproducible knowledge of the
`rate and extent of drug present in various body tissues and fluids.
`
`These in vitro data do not reproduce the exact conditions of
`drug/microbe interface in the human host. The human host normally
`does not present a constant level of antimicrobial exposure to the
`microorganism, and the in vitro methodology does not replicate the
`intrinsic defense mechanisms of the human host. Nonetheless, one
`can deduce useful knowledge from these types of in vitro and human
`pharmacokinetic data applied in concert. The amount and depth of
`human clinical data required to corroborate and confirm the in
`vitro/pharmacokinetic assumptions should be a primary question in
`establishing clinical effectiveness of antimicrobial drug products.
`
`Other questions arise from these observations.
`
`Does each body site of infection caused by each species
`of microorganism (or even each strain of microorganism in
`the event of heterogenous resistance patterns) qualify as
`a separate "indication" requiring at least two adequate
`and well-controlled studies?
`If so, does it become
`essentially unrealistic to expect truly adequate studies
`or fully-studied products?
`
`If they are not separate indications, how do we maintain
`a
`scientifically
`sound approach
`to
`labeling
`that
`furnishes clinicians with valid information yet restrains
`misleading or disinformative marketing campaigns?
`
`Do the in vitro data for certain microorganisms, along
`with other pharmacokinetic, pharmacodynamic data, and
`relevant clinical data from comparable body sites provide
`adequate scientific corroboration of certain clinical
`data and allow corroboration of effectiveness claims?
`
`for
`in vitro data
`listing
`the value of
`is
`What
`microorganism(s) when the microorganism(s) do not cause
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`6
`
`infections in the body sites for which the effectiveness
`of
`a
`given antimicrobial drug product has
`been
`established?
`
`the in vitro
`in
`the listing of microorganisms
`Does
`Microbiology subsection of the ·labeling furnish
`the
`clinician with clinically relevant data, or has it simply
`become a de
`facto 1 icense for the antimicrobial drug
`product to be promoted by the manufacturer for implied
`clinical
`indications
`that have not been adequately
`studied?
`
`Does the present Divisional practice of placing asterisks
`beside certain microorganisms in the
`INDICATIONS AND
`USAGE section of the product labeling actually satisfy
`any relevant clinical need, or has this become simply
`another area for clinically irrelevant "one-ups-man-ship"
`in
`the commercial exploitation of Product A versus
`Product B?
`
`These are issues with which the Division of Anti-Infective Drug
`Products has to contend.
`"Correct" answers are not easy to
`formulate. Any policy dealing with these areas must be flexible
`enough to encompass innovation and medical progress while informing
`practicing physicians forthrightly and completely. Yet the policy
`must also be rigid enough to maintain - as level as possible -
`the
`regulatory "playing field" on which these products must compete.
`
`Wishing to help clarify for applicants and reviewers the present
`perspective of the Division of Anti-Infective Drug Products on some
`of
`these
`issues and recognizing that no document can be all
`inclusive,
`the following divisional "Points to Consider" are
`presented.
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`SPECIFIC POINTS TO CONSIDER:
`
`7
`
`POINTS REGARDING ANTIMICROBIAL DRUG PRODUeT LABELING:
`
`(I)
`
`ISSUES WITH THE DEFINITION OF "INDICATION" AND THE FORMAT FOR
`THE
`INDICATIONS and USAGE SECTION OF ANTIMICROBIAL DRUG
`PRODUCT LABELING:
`
`Background:
`
`21 CFR 201.57(c) (2) states: All indications shall be supported
`by substantial evidence of effectiveness based on adequate and
`well-controlled studies as defined in 314.126 (b) of this
`chapter unless the requirement is waived under 201.58 or
`314.126(b) of this chapter.
`
`to
`respect
`with
`this paragraph
`the purpose of
`For
`antimicrobial drug products -the Division of Anti-Infective
`Drug Products recognizes the term "indication" to mean "the
`treatment (andjor prevention) of infection(s) at a specified
`to
`body
`site(s)
`due
`a
`specified,
`susceptible
`microorganism(s)".
`
`two potential
`Antimicrobial drug products basically have
`indications: the treatment or the prophylaxis of infection.
`At
`least
`two statistically adequate and well-controlled
`clinical trials will be necessary to establish that a given
`antimicrobial drug product
`indeed
`treats or prevents
`infection. Antimicrobial drug products will not usually be
`approved for marketing on the basis of only one adequate and
`well-controlled trial.
`
`pharmacokinetic,
`in microbiologic,
`to diversity
`Due
`toxicologic parameters,
`individual
`pharmacodynamic,
`and
`antimicrobial drug products often have varied spectra
`regarding the types of infections usually amenable to therapy
`with the compound. Antimicrobial drug products that have been
`found effective at other body sites of infection and have
`appropriate antimicrobial activity in vitro, nonetheless, at
`times fail when
`tested
`for new uses.
`Therefore,
`the
`INDICATIONS AND USAGE section of the product labeling should
`include only those types of specific infections,
`including
`specific pathogens,
`for which evidence of
`safety
`and
`effectiveness have been established by corroborated data from
`well-conducted, well-documented, well-controlled trials as
`outlined
`subsequently
`in
`this document.
`Two
`active(cid:173)
`comparator, statistically adequate. well-controlled trials for
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`8
`
`each specific type of infection may not always be necessary to
`establish such effectiveness. When an antimicrobial drug
`product has been subjected to a
`large, standard clinical
`development program
`such as
`is most
`common
`today,
`it
`frequently may be possible to extrapolate information from a
`statistically adequate, well-controlled trial at one body site
`to corroborate efficacy at another body site under appropriate
`conditions.
`However, much depends on the extent of
`the
`innovation of
`the use of
`the drug product (i.e., a new
`category of antimicrobial drug product, a new indication for
`a class of antimicrobial drug products, or a new modality of
`drug administration may require approaches to establishing
`effectiveness and safety different from the general suggestion
`outlined subsequently in this document.)
`
`Suggested Product Labeling {INDICATIONS AND USAGE section):
`
`The Division suggests that the INDICATIONS AND USAGE section
`of product
`labeling for prescription antimicrobial drug
`products ordinarily read as follows:
`
`Treatment:
`
`indicated for
`is
`(Trade name of compound}
`treatment of infection as follows:
`
`the
`
`(Site or name of infection} due to susceptible
`strains of (name of pathogen(s)].
`
`(List however many infections for which
`effectiveness and safety are established.
`The Division suggests using nomenclature
`specified
`in
`section XIII of
`this
`document and does not suggest grouping
`specific infections in body systems, as
`such an approach has continued to lead to
`promotional
`abuses.
`Ordering
`of
`infections in this list should be either
`alphabetically or
`by
`importance of
`product use in the community.}
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`9
`
`Prevention/prophylaxis:
`
`(Trade name
`prevention
`situations:
`
`of
`of
`
`compound)
`infection
`
`the
`indicated for
`is
`in
`the
`following
`
`(List situations - medical andjor surgical for
`which
`effectiveness
`and
`safety
`are
`established.)
`
`(See DOSAGE AND ADMINISTRATION section.)
`(See Pediatric Use andjor Geriatric Use subsections.) -
`as applicable.
`
`Products that: (1) are combinations of active drug substances
`or that otherwise result in two or more active moieties at the
`site of infection, (2) are less safe or less effective than
`comparator agents, or
`(3)
`have not established
`their
`effectiveness against all major pathogens in an infection that
`is
`routinely
`treated
`empirically
`should usually
`be
`"restricted" to claiming effectiveness in the treatment of
`infections due to specific organisms (where appropriate) where
`there is a clear rationale for use of the combination or a
`clear expectation of effectiveness or safety that results, in
`certain circumstances, in a clinically relevant offsetting
`advantage. These restrictions should usually be highlighted
`in a "NOTE" that is prominently placed in the INDICATIONS AND
`USAGE section of the labeling.
`(See Section II of this
`document. )
`
`Effect on Promotional Activities:
`
`It is the position of the Division of Anti-Infective Drug
`Products that any attempt by an applicant to promote (either
`directly or by misleading or disinformative promotional
`practices)
`an antimicrobial drug product
`for specific
`infections other than those listed in the INDICATIONS AND
`USAGE section of
`the product
`labeling would not be
`in
`compliance with Section 502 of the FD&C Act and implementing
`regulations.
`Further,
`any advertisement or promotional
`labeling for products will be considered false and misleading
`under the Act if it does not include the entire INDICATIONS
`AND USAGE section of the
`labeling when referring to the
`infections for which these products are approved. The "NOTES"
`and other added statements
`in
`the
`INDICATIONS AND USAGE
`section are considered
`integral parts of
`the approved
`indication and
`should not be deleted or edited.
`In
`advertising or promotional labeling,
`the "NOTES" and other
`added statements should not be spatially separated from the
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`
`in the initial part of the
`wording
`INDICATIONS AND USAGE
`section so as to minimize· their impact.
`Such information
`should be presented in advertising or promotional pieces in at
`least the same print size and with at least the same impact as
`any other information from this section of the labeling. The
`Division of Anti-Infective Drug Products will work closely
`with
`the Division of Drug Marketing, Advertising,
`and
`Communications to enhance enforcement of this position.
`
`10
`
`(II) ISSUES WITH RESTRICTED/UNRESTRICTED LABELING:
`
`The minimal scientific information for individual infections
`discussed subsequently in this document should usually be
`an "unrestricted"
`adequate
`to
`support
`listing
`1.n
`the
`INDICATIONS AND USAGE section of the final product labeling.
`some situations, however, warrant a "restricted" label (e.g.,
`a product possesses a significantly improved safety profile or
`offers some significant advantage to the patient of physician
`but does not meet the statistical or clinical equivalence
`requirements for an unrestricted listing), a "restricted"
`listing should be placed in the INDICATIONS AND USAGE section
`of the product label. Such restriction(s) (e.g., limitations
`to the treatment of only certain levels of severity of
`infections, specifications of comparative cure/ eradication
`rates,
`recommendations that a product not be first line
`therapy for a given
`infection, restrictions to treating
`certain subclasses of pathogens, etc.) should be prominently
`placed in the label, usually in the form of a "NOTE" placed in
`the INDICATIONS AND USAGE section. As discussed previously in
`Section I, the Division of Anti-Infective Drug Products will
`work closely with the Division of Drug Marketing, Advertising,
`and Communications to assure that the spirit of the label and
`the strength of the submitted scientific data are accurately
`portrayed in any promotional efforts of a sponsor regarding
`such "restricted" labeling.
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`
`(III)ISSUES WITH THE USE OF ASTERISKS IN THE INDICATIONS and USAGE
`SECTION OF
`THE PRODUCT LABELING AND THE LISTING OF
`MICROORGANISMS IN THE
`IN VITRO Microbiology SUBSECTION OF THE
`CLINICAL PHARMACOLOGY
`SECTION OF THE PRODUCT LABELING:
`
`l l
`
`Background:
`
`the names of
`longer be placed by
`Asterisks should no
`microorganisms in the INDICATIONS AND USAGE section of the
`product
`labeling
`as
`a means
`of
`designating
`those
`microorganisms studied in between 5 and 10 total patients.
`Rather, generally, only those microorganisms considered to be
`an etiologic agent (pathogen) in at least 10% of the evaluable
`cases of the specific infection successfully treated with the
`investigative agent should be included in the INDICATIONS AND
`USAGE section of the product labeling. The "at least 10%"
`here - and throughout this document - should be understood to
`mean "at least 10% of
`the evaluable cases meeting both
`clinical and microbiological evaluability criteria or 10 total
`cases (as just defined), whichever is higher."
`Even though
`a given pathogen may represent "at least 10%" of the evaluable
`cases successfully treated,
`the eradication rate of
`the
`pathogen should be clinically acceptable in order for that
`pathogen to be included in this section of the labeling.
`
`the
`to
`adding microorganisms
`support
`situations
`Some
`INDICATIONS AND USAGE section of the product labeling with
`less than 10% of the cases, as defined in the preceding
`paragraph.
`In such situations, explicit labeling to inform
`the physician of the actual extent of data available should be
`included in the product labeling. Usually, these situations
`would include pathogens: (1) generally accepted as pathogens
`at the site of infection under investigations (however in
`numbers less than 10%) and the number of such infections
`studied
`in
`the clinical trials
`is consistent with
`the
`percentage of such infection due to these pathogens in the
`for which in vitro activity is at
`general population,
`(2)
`least similar to that of other pathogens more substantially
`evaluated
`in
`the clinical
`trials,
`( 3)
`for which
`the
`mechanism(s) of resistance is similar to other pathogens more
`substantially evaluated in the clinical trials, and (4) for
`which there are no scientific data suggesting any differences
`in the management of the infection due to these pathogens or
`in the prognosis of patients with the infection due to these
`pathogens.
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`
`12
`
`Suggested Product Labeling (Microbiology subsection) :
`
`the practicing physician with more
`to provide
`In order
`complete data to characterize an antimicrobial drug product,
`the following format should be used in listing microorganisms
`in the Microbiology subsection of the CLINICAL PHARMACOLOGY
`section of the product labeling:
`·
`
`(1) The following statement should generally precede a
`listing of those microorganisms found specifically
`in the INDICATIONS AND USAGE section of the product
`labeling:
`
`(Generic name of drug) has been shown to be
`active against most strains of the following
`microorganisms, both in vitro and in clinical
`infections as described in the INDICATIONS AND
`USAGE section.
`
`Microorganisms should be listed alphabetically in
`the
`following
`four categories:
`aerobic gram(cid:173)
`positive microorganisms,
`aerobic gram-negative
`microorganisms,
`anaerobic microorganisms,
`and
`"other" microorganisms.
`
`(2) The following statements should immediately follow
`the preceding list (#1):
`
`The following in vitro data are available, but
`their clinical significance
`is unknown.
`(balded and underlined)
`
`11
`
`in vitro
`(Generic name of drug) exhibits
`minimal inhibitory concentrations (MIC's) of
`(clinically relevant "susceptible" breakpoint)
`or less against most (~ 90%} strains of the
`following microorganisms; however, the safety
`and effectiveness of (generic name of drug} in
`treating clinical
`infections due
`to
`these
`microorganisms have not been established in
`adequate and well-controlled clinical trials.
`
`To be included in this "in vitro only" 1 ist ( #2) ,
`the more easily obtained and tested microorganisms
`should have a minimum of at least 100 isolates of
`each individual microorganism (genera and species)
`
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`
`

`
`lJ
`
`tested. Wh~n feasible, it is expected that testing
`should be by both
`the diffusion and dilution
`techniques.
`It
`is suggested
`that
`the great
`majority (>75%) of these isolates should be from
`geographically
`representative,
`recent,
`typical
`clinical isolates obtaine~ from patients (but not
`necessarily
`the specific patients
`in
`the NDA
`clinical trials)
`throughout
`the United States.
`laboratory, using standardized in
`More
`than one
`vitro susceptibility methods, should be used
`in
`this testing process, and the mean MIC90 for the
`100+ isolates should be equal to or less than the
`final clinical "susceptible" breakpoint for
`the
`investigational drug.
`
`For more fastidious microorganisms or those with
`difficult growth/testing methodologies, testing of
`fewer numbers of isolates should suffice (e.g., 15
`to 25). The requisite numbers should be discussed
`with the Division on an individual case basis. As
`the sufficient number of specific isolates in these
`situations
`becomes
`established
`for
`a
`given
`microorganism, this information will be made known
`publicly - most likely in updates of this document.
`
`Ordinarily, only microorganisms should be listed
`that are recognized as significant (not anecdotal)
`pathogens at
`the
`body
`site(s)
`or
`in
`the
`infection(s) for which clinical effectiveness for
`other pathogens has been established in adequate
`and well-controlled trials.
`
`the
`If clinical data exist that cast doubt on
`potential effectiveness of
`the
`investigational
`compound
`to
`treat
`infections due
`to
`a given
`microorganism at a given body site or in a given
`indication at the dosing regimen approved for use
`with the drug product, the microorganism should not
`usually be included in this list (#2), even if the
`in vitro microbiologic data are consistent with the
`suggestions in these paragraphs.
`
`N.B.: Microorganism susceptibility patterns can
`differ significantly in various parts of the world.
`In situations where an applicant chooses to submit
`microbiologic data derived from sources outside the
`United States,
`it is the responsibility of
`the
`applicant
`to demonstrate
`that
`the data are
`microbiologically relevant
`to
`the
`treatment of
`patients in the United States.
`
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`
`

`
`14
`
`(3) Microorganism susceptibility patterns can change
`with time. As part of its on-going, post-approval
`drug
`safety
`monitoring
`and
`reporting
`responsibilities, the sponsor should report to the
`Division available
`information on
`the continued
`susceptibility of the listed microorganisms to the
`drug product,
`especially
`those microorganisms
`listed as having established clinical relevance.
`This documentation
`should be provided, at
`a
`minimum, in the annual report to the approved NDA.
`Any necessary changes in the drug product labeling
`should be submitted to the Division in accordance
`with the supplemental application reguLations.
`
`Susceptibility Tests
`(4) The
`ordinarily
`be written
`as
`antimicrobial drug product:
`
`subsection
`follows
`for
`
`should
`each
`
`Diffusion techniques:
`
`Quantitative methods that require measurement
`of
`zone
`diameters
`provide
`reproducible
`estimates of the susceptibility of bacteria to
`antimicrobial
`compounqs.
`One
`such
`that
`standardized
`procedure
`has
`been
`recommended for use with disks to test the
`susceptibility of microorganisms to (generic
`name of drug) uses the (x)-~g (generic name of
`drug
`in
`the disk) disk.
`Interpretation
`involves correlation of the diameter obtained
`in the disk test with the MIC for (generic
`name of drug) .
`
`Reports from the laboratory providing results
`of
`the standard single-disk susceptibility
`test with a
`( x] -ILg (generic name of drug in
`the disk] disk should be interpreted according
`to the following criteria:
`
`Zone Diameter (mm)
`a
`b
`c
`
`Interpretation
`Susceptible (S)
`Intermediate(!)
`Resistant (R)
`
`A report of "Susceptible" indicates that the
`pathogen is likely to be inhibited by usually
`achievable concentrations of the antimicrobial
`compound in blood. A report of "Intermediate"
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`
`

`
`15
`
`indicates that the result should be considered
`equivocal, and,
`if the microorganism is not
`fully susceptible to alternative, clinically
`feasible drugs, the test should be repeated.
`This
`category
`implies possible clinical
`applicability in body-sites where the drug is
`physiologically concentrated or in situations
`where high dosage of drug can be u~ed. This
`category also provides a buffer zone that
`prevents small uncontrolled technical factors
`from
`causing major
`discrepancies
`in
`interpretation.
`A report of "Resistant"
`indicates
`that
`usually
`achievable
`concentrations of the antimicrobial compound
`in the blood are unlikely ~o