Center for Biologics Center for Biologics Evaluation and ResearchEvaluation and Research

Current Activities Current Activities Future DirectionsFuture Directions

Carolyn A. Wilson, Ph.D.Carolyn A. Wilson, Ph.D.Associate Director of ResearchAssociate Director of Research

CBER/FDACBER/FDAJanuary 12, 2009January 12, 2009

CBER CBER The MissionThe Mission

To ensure the safety, purity, potency, To ensure the safety, purity, potency, and effectiveness of biological and effectiveness of biological

products, including vaccines, blood and products, including vaccines, blood and blood products, and cells, tissues and blood products, and cells, tissues and

gene therapies for the prevention, gene therapies for the prevention, diagnosis, and treatment of human diagnosis, and treatment of human

diseases, conditions or injury.diseases, conditions or injury.

CBERCBERThe VisionThe Vision

Protect and improve public and individual Protect and improve public and individual health in the US and, where feasible, globally health in the US and, where feasible, globally

Facilitate development, approval and access to Facilitate development, approval and access to safe and effective products and promising new safe and effective products and promising new technologies technologies

Strengthen CBER as a preeminentStrengthen CBER as a preeminentregulatory organization for biologicsregulatory organization for biologics

INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH

Critical Products for Public Critical Products for Public Health, National Preparedness Health, National Preparedness

& 21st Century Medicine& 21st Century MedicineVaccinesVaccines

Allergenics Allergenics

Somatic Cell & Somatic Cell & Gene TherapyGene Therapy

DevicesDevices

XenotransplantationXenotransplantationTissuesTissues

DevicesDevices

Whole BloodWhole Blood

Blood ComponentsBlood Components

Blood DerivativesBlood Derivatives30 million 235 million

1 million

CBER Science CBER Science The The CuttingCutting EdgeEdge of Biologicsof Biologics

The Challenge: The Challenge: Regulate Regulate complex biologicscomplex biologics

The Opportunity: The Opportunity: Integrate Integrate new knowledgenew knowledge into into facilitating development of safe and effective facilitating development of safe and effective productsproducts

Challenges and Opportunity Challenges and Opportunity ThemesThemes

Assuring Product SterilityAssuring Product SterilityEnabling Product CharacterizationEnabling Product CharacterizationImproving Predictive Value of Nonclinical Improving Predictive Value of Nonclinical TestsTestsMoving towards Personalized Medicine and Moving towards Personalized Medicine and Improving postImproving post--marketing marketing surveillance/safetysurveillance/safetyAddressing GlobalizationAddressing Globalization

SterilitySterilityAA Challenge Facing BiologicsChallenge Facing Biologics

Most biologicsMost biologics cannot becannot be terminally terminally sterilizedsterilized

Many biologicsMany biologics cannot be subject to cannot be subject to processing that inactivates or removes processing that inactivates or removes infectious agentsinfectious agents

Some productsSome products cannot be stored while cannot be stored while waiting for sterility or mycoplasma testingwaiting for sterility or mycoplasma testing

New GuidanceNew GuidanceAn Opportunity for BiologicsAn Opportunity for Biologics

Draft Guidance for IndustryDraft Guidance for Industry: Validation of : Validation of growthgrowth--based rapid microbiological methods for based rapid microbiological methods for sterility testing of cellular and gene therapy sterility testing of cellular and gene therapy productsproducts

Recognition that certain cellRecognition that certain cell--based products based products cannot be cryopreserved or terminally cannot be cryopreserved or terminally sterilized, but that sterilized, but that parenteral administrationparenteral administrationrequires assurance of sterilityrequires assurance of sterility

Addresses need to develop, validate, and Addresses need to develop, validate, and implement sterility methods that are more implement sterility methods that are more rapid than those described in 21 CFR 610.12rapid than those described in 21 CFR 610.12

Mycoplasma testingMycoplasma testing21 CFR 610.30 and Points to Consider 21 CFR 610.30 and Points to Consider Advantages

Limit of Detection (1 cfu/ml or less) Detection of viable mycoplasmacontamination

DisadvantagesRequires 2 agar/broth culture and and indicator cell culture methods (for both cultivable & non-cultivable mycoplasmas, respectively)Use of different media and environmental incubation conditions Time-consuming (minimum 28 days)

Sensitive and rapid mycoplasma detection Sensitive and rapid mycoplasma detection and identification by enrichment on and identification by enrichment on

MDCK cellsMDCK cellsALTERNATIVE STRATEGYALTERNATIVE STRATEGY

Sensitivity of new method: Sensitivity of new method: ≤≤ 1 CFU/ml1 CFU/mlTurnaround time: Turnaround time: less than one weekless than one week

(instead of 28 days)(instead of 28 days) V. Chizikhov, OVRR/CBER

Public Workshop: Public Workshop: Rapid Methods for Detecting Rapid Methods for Detecting Mycoplasma Contamination in the Manufacture Mycoplasma Contamination in the Manufacture

of Vaccines, Including Pandemic Influenza of Vaccines, Including Pandemic Influenza Vaccines, and Other Biological Products, Sept 08Vaccines, and Other Biological Products, Sept 08

Product CharacterizationProduct CharacterizationA Challenge Facing BiologicsA Challenge Facing Biologics

Complexity of genetic, cellular, and tissueComplexity of genetic, cellular, and tissue--based based products will require identification of products will require identification of predictive predictive markersmarkers

fates & oncogenicity of productsfates & oncogenicity of productscell differentiation, function, and regulation cell differentiation, function, and regulation cell responses to host environmentcell responses to host environment

Product characterization may require reference Product characterization may require reference reagents, standardization of methods, etc.reagents, standardization of methods, etc.

www.gene.com

OpportunityOpportunityNew Guidance Documents for Industry New Guidance Documents for Industry

on Product Characterizationon Product Characterization

Process Validation: General Process Validation: General Principles and Practices, Principles and Practices, November 2008November 2008 (draft)(draft)

Potency Tests for Cellular and Potency Tests for Cellular and Gene Therapy Products, October Gene Therapy Products, October 20082008 (draft)(draft)

New New ScienceScienceNew New OpportunitiesOpportunities

Breakthrough of the Year:Induced Pluripotent Stem Cells

OpportunityOpportunityNew Ways to Characterize New Ways to Characterize

Complex ProductsComplex ProductsComprehensive mass-spectrometry-based proteome quantification ofhaploid versus diploid yeast; De Godoy, et al, Nature 455:1251

Retrovirus reference materialCBER; available from ATCC

Adenovirus reference materialConsortium; available from ATCC

External RNA spike-in controls

Quantitative flow cytometryCBER, NIST; available from NIST

Fluorescent standard solutionFluorescent micro-bead standard

OpportunityOpportunityReference Materials for Improved Reference Materials for Improved

Product Characterization of Cell and Gene Product Characterization of Cell and Gene Therapy ProductsTherapy Products

OpportunityOpportunityImproved Reagents for Product Improved Reagents for Product

CharacterizationCharacterization

Potency assay for anthrax vaccine and Potency assay for anthrax vaccine and therapeutic antibody developmenttherapeutic antibody development

CellCell--based assay to detect based assay to detect Anthrax toxin functionAnthrax toxin function

ProblemProblem:: Different lots Different lots lethal factorlethal factor ((LF) resulted in LF) resulted in differences in potency measurementsdifferences in potency measurements

Why?Why?

D. Burns, OVRR, CBER

Cytotoxic activity of LF Cytotoxic activity of LF preparationspreparations

The The NN--terminal amino acidterminal amino acid of LFof LF significantly affects its significantly affects its activity in cellactivity in cell--based assaysbased assaysRecombinant forms of LFRecombinant forms of LF should be designed with this should be designed with this characteristic in mindcharacteristic in mindCare should be takenCare should be taken to ensure that proteolytic nicking to ensure that proteolytic nicking of the Nof the N--terminal residue does not occur during terminal residue does not occur during purificationpurification

Challenge Challenge Developing PredictiveDeveloping Predictive

Nonclinical TestsNonclinical Tests

Identification of Identification of in vitroin vitro or or in vivoin vivocorrelates of bioactivity, safety, toxicitycorrelates of bioactivity, safety, toxicity

LackLack of appropriate nonclinical modelsof appropriate nonclinical models

UndefinedUndefined biomarkers in some clinical biomarkers in some clinical indicationsindications

““Animal RuleAnimal Rule”” for biofor bio--defensedefense--related productsrelated products

Opportunity Opportunity CBER Concept PaperCBER Concept Paper

Animal Models Animal Models –– Essential Elements to Essential Elements to Address Efficacy Under the Animal Rule Address Efficacy Under the Animal Rule

(Sept. 2008)(Sept. 2008)

Additional data elements to considerAdditional data elements to consider•• CharacteristicsCharacteristics of agentof agent•• HostHost susceptibility and response to etiologic agentsusceptibility and response to etiologic agent•• PathophysiologicPathophysiologic comparabilitycomparability•• TriggerTrigger and characterization of interventionand characterization of intervention•• Design Design considerations for efficacy studiesconsiderations for efficacy studies•• SafetySafety informationinformation

OpportunityOpportunityDevelop Develop in vitroin vitro Assay for Assay for

Adjuvant Safety AssessmentAdjuvant Safety AssessmentIssue:Issue: Improving prediction of adverse events Improving prediction of adverse events from novel adjuvants. from novel adjuvants.

Most common:Most common: pain, tenderness, erythema, and pain, tenderness, erythema, and granuloma at the injection site granuloma at the injection site Rare:Rare: systemic (e.g., chills, fever, myalgia, headaches)systemic (e.g., chills, fever, myalgia, headaches)

Approach:Approach: Studies in animals have shown that Studies in animals have shown that fever is associated with an increase in the levels of fever is associated with an increase in the levels of propro--inflammatory cytokines. inflammatory cytokines.

Human promonocytic MM6 cell line with known spectrum Human promonocytic MM6 cell line with known spectrum of TLRs was used to determine the levels of proof TLRs was used to determine the levels of pro--inflammatory cytokines released in presence of inflammatory cytokines released in presence of adjuvants.adjuvants.

02000400060008000

0 0.2 0.4 0.6

Endotoxin (EU/ml)

IL-6

(pg/

ml) 5903.5 (pg/ml)

Induction of IL-6 & TNFα in MM6 cells cultured with adjuvants

0100020003000

0 0.5 1 1.5

Endotoxin (EU/ml)

1474.8 (pg/ml)

0

100

200

300

400

500

0 2.5 5 10 20

Adjuvants (μL/mL)

TNFa

(pg/

ml)

QS21MF59AlOH

020406080

100120

0 2.5 5 10 20

Adjuvants (μL/mL)

IL-6

(pg/

ml)

QS21MF59AlOH

TNFα

(pg/

ml)

TNFα

(pg/

ml)

IL-6

(pg/

ml)

IL-6

(pg/

ml)

Endotoxin (EU/ml) Endotoxin (EU/ml)

Adjuvants (μl/ml) Adjuvants (μl/ml)Golding, OVRR/CBER

CBER Research Finding:CBER Research Finding: Good correlation Good correlation between between in vitroin vitro results with results with in vivo in vivo safety safety records for several adjuvants and delivery records for several adjuvants and delivery systems.systems.Implications:Implications: May provide more rapid, May provide more rapid, inexpensive screen of toxicity for novel inexpensive screen of toxicity for novel adjuvants. Other detector cell lines are under adjuvants. Other detector cell lines are under development to evaluate potential neurotoxicity development to evaluate potential neurotoxicity and hepatotoxicity.and hepatotoxicity.Public WorkshopPublic Workshop on Adjuvants, December, on Adjuvants, December, 20082008

Development of Development of in vitroin vitro Assay for Assay for Adjuvant Safety AssessmentAdjuvant Safety Assessment

OpportunityOpportunityImprove Predictive Value of Preclinical Testing of Improve Predictive Value of Preclinical Testing of

HemoglobinHemoglobin--Based Oxygen CarriersBased Oxygen Carriers

Issue:Issue: HbHb--based oxygen carrying solutions based oxygen carrying solutions might save lives of trauma victims where blood might save lives of trauma victims where blood is not available, but to date, products have shownis not available, but to date, products have shownunexplained toxicitiesunexplained toxicities

Approach:Approach:Identify the link between the Identify the link between the ““oxidative chemistryoxidative chemistry”” of a of a given hemoglobin and its toxicitygiven hemoglobin and its toxicityDevelop suitable animal model (rat and guinea pig) Develop suitable animal model (rat and guinea pig) systems to study blood substitute toxicitysystems to study blood substitute toxicity

Pittsburgh Supercomputing Centerhttp://www.psc.edu/

Rat

vs.

Guinea pig

Ascorbate (vitamin C) limits HBOC oxidative reactionsImproved Predictive Animal Models

Ascorbate-producing Non-producer of ascorbate(similar to humans)

Kidney HO-1

NT

HbG

Ren

al H

O A

ctiv

ity(n

mol

bili

rubi

n/hr

/mg

prot

ein)

Time (h)01234567

0 12 24 36 48 60 72

RatGuinea Pig

Heme Oxygenase

Buehler PW et al, JPET (2007) D’Agnillo, OBRR/CBER

Identification of Improved Identification of Improved Nonclinical ModelNonclinical Model

OutcomesOutcomes

Nonclinical testing is becoming more Nonclinical testing is becoming more predictive of clinicalpredictive of clinical performanceperformance

Facilitate design of safer HbFacilitate design of safer Hb--based blood based blood substitutessubstitutes

CBER is able to develop guidance on CBER is able to develop guidance on product development and nonclinical testingproduct development and nonclinical testing

ChallengeChallengePersonalized MedicinePersonalized Medicine

Biomarker DiscoveryBiomarker Discovery•• Improve outcomeImprove outcome•• Reduce riskReduce risk

Improve PostImprove Post--Marketing Marketing SurveillanceSurveillance•• safety surveillancesafety surveillance

OpportunitiesOpportunitiesVoluntary Genomics Data SubmissionVoluntary Genomics Data Submission

http://www.fda.gov/cder/genomics/VGDS.htmhttp://www.fda.gov/cder/genomics/VGDS.htmSharing technology, data, and insights with Sharing technology, data, and insights with industryindustryJoint learning ventureJoint learning venture

Guidance for Industry: Guidance for Industry: PostPost--marketing marketing adverse event reporting for medical products and adverse event reporting for medical products and dietary supplements during an influenza dietary supplements during an influenza pandemicpandemic

Preparing for an outbreakPreparing for an outbreak

Clinical biomarker discovery Clinical biomarker discovery –– predictive predictive of cancer development (CBER/OCTGT of cancer development (CBER/OCTGT ––Marti)Marti)

OpportunityOpportunityCollaborations Increase Vaccine Collaborations Increase Vaccine

Safety MonitoringSafety Monitoring

CDC and Vaccine Safety Datalink CDC and Vaccine Safety Datalink PAHO/CDC/FDA postPAHO/CDC/FDA post--marketing marketing surveillance of rotavirus vaccines surveillance of rotavirus vaccines in Latin Americain Latin AmericaPilot project with CMS to evaluate Pilot project with CMS to evaluate safety of influenza and safety of influenza and pneumococcal vaccines as part ofpneumococcal vaccines as part ofpandemic preparednesspandemic preparednessMOU with Veterans Health Administration to share information on MOU with Veterans Health Administration to share information on FDAFDA--regulated products, including vaccinesregulated products, including vaccinesCollaboration with Department of Defense Medical Surveillance Collaboration with Department of Defense Medical Surveillance System and Vaccine Health CentersSystem and Vaccine Health Centers

Improving PostImproving Post--marketing marketing SurveillanceSurveillance

Issue:Issue: Need to improve ability to detect Need to improve ability to detect low frequencylow frequency adverse eventsadverse events in populations in populations receiving approved biologics.receiving approved biologics.

CBER Research Finding:CBER Research Finding: Analysis of CMS Analysis of CMS database, 40 million >65 yo, allowed rapid database, 40 million >65 yo, allowed rapid analysis of GBS and seasonal flu vaccine (2006). analysis of GBS and seasonal flu vaccine (2006).

Implications:Implications: Pilot study demonstrates power Pilot study demonstrates power of approach; could be applied to other areas.of approach; could be applied to other areas.

0

2000000

4000000

6000000

8000000

10000000

12000000

14000000

8/25

/200

6

9/1/

2006

9/8/

2006

9/15

/200

6

9/22

/200

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9/29

/200

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/200

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10/1

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/200

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/200

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/200

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0

0.5

1

1.5

2

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3

3.5

CMS – RAPID ANALYSIS OF GBS AND SEASONAL FLU VACCINE (2006)

DOSES

GBS rates

GlobalizationGlobalizationCConfronting a World of Emerging onfronting a World of Emerging

ChallengesChallenges

HTTP://Biodefense.niaid.nih.govHTTP://Biodefense.niaid.nih.gov

OpportunityOpportunityCBER & PATHCBER & PATH

Partners in the Partners in the Fight Against MalariaFight Against Malaria

PATH: Program for Appropriate Technology in PATH: Program for Appropriate Technology in HealthHealth

Created in 1999 with funding from Gates FoundationCreated in 1999 with funding from Gates Foundation

CBER/PATH collaboration (Sanjai Kumar, OBRR)CBER/PATH collaboration (Sanjai Kumar, OBRR)Develop laboratory tests to predict the level of safety Develop laboratory tests to predict the level of safety and activity of experimental malaria vaccines before and activity of experimental malaria vaccines before they are used in human clinical trials. they are used in human clinical trials.

OpportunityOpportunityCBER & MVPCBER & MVP

Partners to Partners to Fight Epidemic MeningitisFight Epidemic Meningitis

Meningitis Vaccine ProjectMeningitis Vaccine Project2001 Gates Foundation fund PATH & WHO to develop 2001 Gates Foundation fund PATH & WHO to develop vaccines for Africavaccines for Africa

CBER/MVP collaborationCBER/MVP collaborationDeveloped improved polysaccharide conjugate Developed improved polysaccharide conjugate technology to dramatically increase yields and lower the technology to dramatically increase yields and lower the cost per dosecost per dose

CREDIT: MONIQUE BERLIER/MVP-PATH in SCIENCE: 6/27/08

Opportunities Opportunities Global Assistance, Cooperation, Global Assistance, Cooperation,

LeadershipLeadership

PAHO/WHO Collaborating Center for Biological PAHO/WHO Collaborating Center for Biological StandardizationStandardization

Vaccines, blood products & related biologicalsVaccines, blood products & related biologicalsFDA/WHO/Health Canada Pandemic RegulatorsFDA/WHO/Health Canada Pandemic Regulators

Emerging threat preparednessEmerging threat preparednessWHO Global Collaboration for Blood SafetyWHO Global Collaboration for Blood Safety

Safety and availabilitySafety and availabilityEuropean Medicines Agency (EMEA)European Medicines Agency (EMEA)

Regulatory dialogue with peer counterparts (e.g., EMEA)Regulatory dialogue with peer counterparts (e.g., EMEA)International Conference on Harmonisation (ICH)International Conference on Harmonisation (ICH)

Expedite economical approvals in US, Europe, & JapanExpedite economical approvals in US, Europe, & JapanPharmaceutical Inspection Cooperation Scheme Pharmaceutical Inspection Cooperation Scheme (PIC/S)(PIC/S)

International inspection and oversight authorityInternational inspection and oversight authority

OpportunityOpportunityComputational modeling to prepare Computational modeling to prepare

for pandemic influenzafor pandemic influenza

Computer simulationComputer simulationAggregate US blood supply, daily donations, Aggregate US blood supply, daily donations, daily demanddaily demandCenters for Medicare and Medicaid Services Centers for Medicare and Medicaid Services (CMS) database (>65 yo), transfusions(CMS) database (>65 yo), transfusionsImpact of pandemic influenzaImpact of pandemic influenza

50% decrease in blood donations over 3 months50% decrease in blood donations over 3 monthsSimulation shows blood supply is protected with Simulation shows blood supply is protected with controlled usecontrolled use

9090--day donations cut in halfday donations cut in half

Reduced donations start on January 6thBecause of small difference

between inflow and out,after three years, the

system is still not back to normal

Blood use restrictions started 45 days into

outbreak, but continued for six months.

Note reappearance of expired blood

Walderhaug, M., OBE, CBER, et al, Int Soc Blood Transfusion

Controlling Blood Use

Labor day

CBER Collaborates and Cooperates CBER Collaborates and Cooperates with Stakeholderswith Stakeholders

CBER responds to the complexity of biologics by CBER responds to the complexity of biologics by working closely with industry, outside experts, working closely with industry, outside experts,

and other government agencies and other government agencies Industry workshopsIndustry workshops

Advisory committee assistance in defining Advisory committee assistance in defining issues, product development pathways, study issues, product development pathways, study designsdesigns

Collaborative Research, e.g., Collaborative Research, e.g., Critical Path Critical Path National Toxicology ProgramNational Toxicology ProgramIAGs with NIH, CDC, othersIAGs with NIH, CDC, others

Standards Development OrganizationsStandards Development OrganizationsIn 2008, 100 CBER staff participated in 89 standards In 2008, 100 CBER staff participated in 89 standards activities with ~30 organizationsactivities with ~30 organizations

Challenges and OpportunitiesChallenges and Opportunities

Goal:Goal:Improve public health through new regulatory Improve public health through new regulatory pathways that facilitate development of safe and pathways that facilitate development of safe and

effective biologicseffective biologics

Proactive Strategies:Proactive Strategies:

IdentifyIdentify the Challenge!the Challenge!

HarnessHarness new scientific new scientific technology and knowledge!technology and knowledge!

Create Create Partnerships!Partnerships!