20092009--20112011
UpdateUpdate toto thethe EUEU GuidelineGuideline onon AntibacterialAntibacterial AgentsAgents CurrentCurrent guidanceguidance
NoteNote forfor GuidanceGuidance onon evaluationevaluation ofof medicinalmedicinal productsproducts indicatedindicated forfor treatmenttreatment ofof bacterialbacterial infectionsinfections CPMP/EWP/558/95CPMP/EWP/558/95 revrev 1;1; 20042004
ReplacedReplaced 19971997 versionversion andand aa separateseparate sectionsection 5.15.1 guidanceguidance documentdocument
IncludesIncludes microbiology,microbiology, PK/PD,PK/PD, clinicalclinical developmentdevelopment andand sectionssections ofof thethe SPCSPC RevisionRevision startedstarted 20092009
55 yearsyears experienceexperience indicatedindicated needneed to:to:
ClarifyClarify positionposition onon somesome issuesissues
EstablishEstablish aa positionposition onon somesome issuesissues
ModifyModify positionposition onon somesome issuesissues AntibacterialAntibacterial agentsagents 19971997--20102010 ** sincesince 20042004
Daptomycin * Oritavancin * Telithromycin Dalbavancin * Tigecycline * Telavancin * Ertapenem Ceftobiprole * Doripenem * Iclaprim * MRP Gemifloxacin * Levofloxacin Garenoxacin * Cefditoren Trovafloxacin Linezolid MRP Moxifloxacin Cefdinir Synercid Grepafloxacin Gatifloxacin RevisionRevision PlanPlan
ConceptConcept paperpaper adoptedadopted FebFeb 20092009
ReleaseRelease forfor consultationconsultation FebFeb 20102010
ConsultationConsultation extendedextended fromfrom AugustAugust toto NovemberNovember 20102010 duedue toto plannedplanned WSWS
FinalisationFinalisation duringduring 20112011 (2Q)(2Q) ContentContent ofof PresentationsPresentations
WhatWhat doesdoes thethe currentcurrent draftdraft saysay onon thethe topictopic ??
RationaleRationale forfor currentcurrent draftdraft ??
CommentsComments receivedreceived ??
UpdatedUpdated proposalproposal (if(if appropriate)appropriate) NonNon--inferiorityinferiority studiesstudies
AcceptedAccepted forfor allall indicationsindications forfor whichwhich superioritysuperiority studiesstudies notnot feasiblefeasible oror notnot consideredconsidered necessarynecessary
PatientPatient selectionselection criteriacriteria andand choicechoice ofof comparatorcomparator criticallycritically importantimportant
PrimaryPrimary endpointendpoint == clinicalclinical and/orand/or microbiologicalmicrobiological outcomeoutcome atat TOCTOC NonNon--inferiorityinferiority studiesstudies
It is preferred that each clinical indication for use is supported by at least two randomised and controlled studies
The provision of a single pivotal study may be acceptable if this has been conducted in accordance with applicable CHMP guidance
The choice of non-inferiority margin requires particular attention in accordance with the available CHMP guidance HAP/VAPHAP/VAP –– exampleexample
DORI-09 HAP/early VAP Expected cure rate ~ 65% according to piptazobactam NP studies
DORI-10 VAP Expected cure rate ~ 60% based on previous imipenem studies
Both studies pre-defined a NI margin -20%
ACTUAL lower bound 95% CI in both studies and both co-primary populations were all within -10%
APPROVED FOR: • Nosocomial pneumonia, including ventilator-associated pneumonia cSSTIcSSTI –– exampleexample
9801 Daptomycin vs. vancomycin or SSP
9901 Daptomycin vs. vancomycin or SSP
The primary efficacy endpoint was clinical outcome at TOC in CE and MITT populations
The pre-defined NI margin was 10% for both studies
ACTUAL lower bound 95% CI in both studies and both co-primary populations were all within -9% CommentsComments receivedreceived
Request to specify the acceptable NI margins (e.g. cSSTI, CAP, HAP/VAP, cUTI, IAI)
Request to provide more detailed guidance on patient selection criteria
Request to re-consider pre-approval requirements (study size; single study)
How to meet different regulatory expectations using same studies? NINI studiesstudies -- futurefuture
State that same studies can be used to satisfy more than one regulatory body
Specify single primary endpoint for protocol that would lead to the largest sample size
Develop separate SAPs for each agency
Will further discuss developing an addendum with indication-specific guidance SuperioritySuperiority studiesstudies -- issuesissues
NINI studiesstudies unreliableunreliable ifif activeactive treatmenttreatment notnot consistentlyconsistently superiorsuperior toto placeboplacebo inin aa defineddefined patientpatient population/subsetpopulation/subset
ResultsResults cannotcannot establishestablish thatthat testtest agentagent wouldwould bebe superiorsuperior toto placeboplacebo ifif comparedcompared
ConstancyConstancy isis alsoalso anan issueissue i.e.i.e. historicalhistorical datadata vs.vs. nono treatment/placebotreatment/placebo mightmight notnot givegive thethe samesame resultsresults ifif repeatedrepeated inin 20092009 SuperioritySuperiority studiesstudies -- 20042004
Superiority vs placebo expected in infections with high spontaneous cure rates
Justify absence of superiority study
Third (active treatment) arm preferred
No mention of superiority vs an active control
CHMP objected to AECB and ABS based on NI only SuperioritySuperiority studiesstudies -- 20102010
InIn suchsuch casescases superioritysuperiority studystudy expectedexpected e.g.e.g. AMS,AMS, AECB,AECB, OM,OM, somesome topicaltopical usesuses
IfIf vs.vs. placeboplacebo inclusioninclusion ofof aa thirdthird (active(active comparator)comparator) armarm isis preferredpreferred [Not[Not necessarynecessary toto showshow NINI vs.vs. comparator]comparator]
IfIf vs.vs. activeactive comparatorcomparator thenthen superioritysuperiority vs.vs. activeactive basedbased onon aa clinicalclinical endpointendpoint demonstratingdemonstrating benefitbenefit sufficientsufficient CommentsComments receivedreceived
SuperioritySuperiority vs.vs. activeactive comparatorcomparator ratherrather thanthan placeboplacebo isis welcomedwelcomed asas anan optionoption
RequestRequest forfor specificspecific examplesexamples
PossiblePossible situationssituations inin whichwhich superioritysuperiority cannotcannot bebe demonstrateddemonstrated forfor anyany variablevariable
SubSub--populationspopulations existexist inin whichwhich NINI couldcould andand shouldshould bebe acceptableacceptable SuperioritySuperiority studiesstudies -- futurefuture
RecognitionRecognition thatthat placeboplacebo controlcontrol designdesign notnot acceptableacceptable inin somesome subsub--populationspopulations
StillStill paucitypaucity ofof consistentconsistent datadata toto indicateindicate andand definedefine thesethese subsub--populationspopulations
LeaveLeave openopen possibilitypossibility thatthat sponsorsponsor maymay provideprovide adequateadequate evidenceevidence toto supportsupport selectionselection ofof aa NINI marginmargin applicableapplicable toto aa wellwell--defineddefined populationpopulation RareRare infections/pathogensinfections/pathogens –– 20042004
Possible licensure based on “limited data” for agents shown to be clinically active against:
- ProblematicProblematic resistantresistant organismsorganisms -- DifficultDifficult toto treattreat and/orand/or rarerare infectionsinfections -- InfectionsInfections withwith fewfew treatmenttreatment optionsoptions
Advice from EU Regulators should be sought RareRare infections/pathogensinfections/pathogens -- 20102010
NoNo clinicalclinical datadata possiblepossible OROR
VeryVery limitedlimited clinicalclinical datadata possiblepossible
DataData maymay bebe collectedcollected duringduring aa (large)(large) indicationindication--specificspecific studystudy and/orand/or aa (smaller)(smaller) targetedtargeted studystudy RareRare infections/pathogensinfections/pathogens --20102010
Adequately powered RCT not possible
Randomisation step always preferred
The justification for a randomised study planned with lower than standard levels of statistical power must include comment on the prevalence of the infection and on the statistical performance characteristics of the trial (e.g. Type I and Type II errors to investigate an effect size of interest) RareRare infections/pathogensinfections/pathogens -- 20102010
Aim for 10-20 cases per treatment groupgroup
< 10 per group may be acceptable if very rare
Pool data across studies in single indication if same or very similar design and population
ForFor veryvery rarerare pathogenspathogens itit maymay bebe appropriateappropriate toto conductconduct studiesstudies inin whichwhich patientspatients withwith clinicallyclinically confirmedconfirmed infectionsinfections duedue toto thesethese organismsorganisms areare enrolledenrolled regardlessregardless ofof thethe sitesite ofof thethe infectioninfection RareRare infections/pathogensinfections/pathogens CommentsComments
Pool data across indications if same body site (e.g. CAP/HAP; IAI/Pelvic) or across all sites?
Unqualified pathogen-specific indications?
Supplement indication-specific NI study with study of rare pathogens vs. OBT (low power) including wide range of infection types?
No licensed OBT patients default to test agent in a parallel non-comparative arm? RareRare infections/pathogensinfections/pathogens –– 20042004
Clinical efficacy against MDR organisms:
If activity of new agent is unaffected: nono needneed toto searchsearch forfor organismsorganisms ofof thethe speciesspecies withwith this/thesethis/these typestypes ofof resistanceresistance inin
If activity affected butclinicalclinical efficacy trialstrials still expected: atat leastleast limitedlimited clinicalclinical datadata shouldshould bebe soughtsought RareRare infections/pathogensinfections/pathogens –– 20102010
In-vitro activity unaffected by R-mechanism(s) to other agent(s) or affected but efficacy still expected (e.g. animal models, PK/PD): ..patients..patients harbouringharbouring multidrugmultidrug pathogenspathogens areare moremore likelylikely toto havehave alreadyalready receivedreceived otherother agentsagents andand toto havehave underlyingunderlying conditionsconditions thatthat complicatecomplicate thethe clinicalclinical coursecourse soso thatthat clinicalclinical andand microbiologicalmicrobiological--resistantresistant successsuccess
At least limitedratesrates maymayclinical bebe lowerlowerdata should andand moremore be sought variablevariable ““ProblematicProblematic”” indicationsindications
IndicationsIndications discusseddiscussed 20102010 include:include:
––BacteraemiaBacteraemia ––FebrileFebrile neutropenianeutropenia ––CatheterCatheter--relatedrelated infectionsinfections ––EradicationEradication ofof carriagecarriage BacteraemiaBacteraemia
Defined as the isolation from blood culture(s) of one or more species likelylikely toto bebe responsible for or contributing to the clinical signs and symptoms of infection
A qualified indication for: treatmenttreatment ofof bacteraemiabacteraemia whenwhen occurringoccurring inin associationassociation withwith[type of infection ± restriction to specific pathogens] might be considered on provision of a sufficient number of cases BacteraemiaBacteraemia
. UnqualifiedUnqualified impliesimplies cancan treattreat anyany underlyingunderlying infectioninfection focusfocus andand associatedassociated withwith anyany pathogenpathogen
. QualificationQualification byby pathogenpathogen stillstill impliesimplies treatmenttreatment ofof anyany underlyingunderlying infectioninfection focusfocus RecentRecent ExampleExample –– ArtArt 3030
The current draft guidance suggests that an indication for use in bacteraemia ± qualification by species might be possible once an agent has been approved for a wide range of indications
This statement was re-considered w.r.t. CHMP decision on 3 parallel Art 30 applications completed in late 2010 RecentRecent ExampleExample –– ArtArt 3030
Adults and adolescents
- Severe pneumonia including hospital-acquired and ventilator-associated pneumonia - Complicated urinary tract infections (including pyelonephritis) - Complicated intra-abdominal infections - Complicated skin and soft tissue infections (including diabetic foot infections)
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above.
Tazocin may be used in the management of neutropenic patients with fever suspected to be due to a bacterial infection. BacteraemiaBacteraemia -- commentscomments
. FewFew basedbased onon currentcurrent wordingwording
. MoreMore concernconcern regardingregarding guidanceguidance rere cathetercatheter--relatedrelated infectioninfection andand eradicationeradication ofof carriagecarriage EradicationEradication ofof carriagecarriage
Indications that relate to the reduction or eradication of a pathogen from a specified body site are not acceptable unless the microbiological findings were shown to result in a measurable clinical outcome
Require a placebo-controlled study (unless usage has become widely accepted as SOC)
Use of published data to substantiate link between eradication and clinical benefit not acceptable (with one exception) EradicationEradication ofof carriagecarriage
Fully validated microbiological techniques must be used to detect and quantify pathogens (may need pilot study)
Need to define reduction in or eradication of carriage (cfu/mL and duration) as well as failure to eradicate and relapse/re-infection
May be appropriate to use very sensitive detection methods (such as PCR) in addition to culture and to type organisms EradicationEradication ofof carriagecarriage -- commentcomment
Comments seem to have come from only 2 sources directly involved in developing agents intended for elimination of carriage
Request that elimination of carriage is perper sese viewed as a clinical benefit meriting an indication for use
Propose taking into account reduction in cross-infection but no proposal to provide data to support such claims SectionSection 5.15.1 –– removeremove tabletable
Current table with classification of target pathogens according to expected susceptibility has caused many problems
One SmPC for 30 countries AR is frequently pocketed; data unreliable Classification in terms of likely R Rates is meaningless to the individual prescriber and his local working environment
Continue to highlight possible R problems in descriptive paragraphs regularly updated DemonstrationDemonstration ofof clinicalclinical efficacyefficacy byby pathogenpathogen
Removing the table removes the asterisk system
• New section specific to clinical efficacy against specific pathogens, listed by indication
• Optional section to describe other very relevant species S inin vitrovitro but insufficient clinical data
• Optional section to describe inherently resistant species (e.g. unexpected gaps in spectrum)
• No description of studies (details in EPAR) UNLESS there is a problem that needs to be highlighted PlansPlans forfor finalisationfinalisation
IDWPIDWP willwill discussdiscuss commentscomments receivedreceived inin writingwriting andand heardheard duringduring thisthis WSWS
AimAim toto finalisefinalise mainmain guidanceguidance byby endend 2Q2Q 20112011 forfor adoptionadoption byby CHMPCHMP
WillWill discussdiscuss possiblepossible needneed forfor anan indicationindication-- specificspecific addendumaddendum andand itsits contentcontent WillWill draftdraft aa ConceptConcept PaperPaper ifif thisthis isis agreedagreed toto bebe thethe nextnext stepstep (with(with BSBS WPWP input)input)