Recombinant allergens: what needs to come next?. Where we are with natural allergens n All natural,...

Recombinant allergens: Recombinant allergens: what needs to come next?what needs to come next?

Where we are with natural Where we are with natural allergensallergens

All natural, mixes based largely on an All natural, mixes based largely on an unselective extraction of source materialunselective extraction of source material• Different diluents Different diluents • Varying potency and stabilityVarying potency and stability

Documented efficacy in the Documented efficacy in the immunotherapy of allergic disease due immunotherapy of allergic disease due to hymenoptera, ragweed, grass, cat, to hymenoptera, ragweed, grass, cat, and dust mite allergen exposureand dust mite allergen exposure


Unitage for non-standardized products Unitage for non-standardized products uninformativeuninformative

Standardized products are controlled for Standardized products are controlled for potency and stabilitypotency and stability

Standardization is based on identity to US Standardization is based on identity to US standardstandard

Standardized products constitute a small Standardized products constitute a small minority of product number, but a greater minority of product number, but a greater percentage of product volumepercentage of product volume


Allergenicity = immunogenicity = Allergenicity = immunogenicity = potencypotency

Products may be used for diagnosis and Products may be used for diagnosis and immunotherapy (not all approved for immunotherapy (not all approved for both)both)

Production issues associated with Production issues associated with certain products (e.g. precipitates)certain products (e.g. precipitates)

Where we are with natural Where we are with natural allergens - summaryallergens - summary

A diverse group of products, many of A diverse group of products, many of which are of uncertain potency, but which are of uncertain potency, but several of which are standardized and several of which are standardized and are of documented efficacy both for the are of documented efficacy both for the diagnosis and treatment of allergic diagnosis and treatment of allergic disease.disease.

How can we improve the use of How can we improve the use of natural allergens?natural allergens?

Increase the number of standardized Increase the number of standardized productsproducts• Improve the standardization of some Improve the standardization of some

current products by improving the definition current products by improving the definition of the measured allergensof the measured allergens

Increase purity standards Increase purity standards • selective extraction techniques, purificationselective extraction techniques, purification

Improve characterization methodsImprove characterization methods

How can we improve the use of How can we improve the use of natural allergens?natural allergens?

Improve stability (glycerol, lyophilization, Improve stability (glycerol, lyophilization, other)other)

Improve delivery systemsImprove delivery systems Better definition of indicationsBetter definition of indications More consistent and rational More consistent and rational

applicationsapplications

Where we are with recombinant Where we are with recombinant allergensallergens

Current: Potent research toolsCurrent: Potent research tools• dissect immune responsesdissect immune responses• modify immune responsesmodify immune responses• study allergen structurestudy allergen structure• determine structure-function relationshipsdetermine structure-function relationships• generate novel productsgenerate novel products

Where we can be with recombinant Where we can be with recombinant allergensallergens

Clinical opportunities (positive):Clinical opportunities (positive):• Possible standardization toolsPossible standardization tools• Allergenicity Allergenicity immunogenicity immunogenicity• Greater purity and consistency of productGreater purity and consistency of product• Greater product stability (both due to purity Greater product stability (both due to purity

and engineering)and engineering)• Improve delivery systems (in ways not Improve delivery systems (in ways not

possible using native proteins)possible using native proteins)

Where we can be with recombinant Where we can be with recombinant allergensallergens

Clinical opportunities (negative):Clinical opportunities (negative):• Challenges to standardization (unique Challenges to standardization (unique

products with different biological features)products with different biological features)• Challenges to standardization (allergenicity Challenges to standardization (allergenicity

immunogenicity immunogenicity potency)) potency))• Indications will be very specificIndications will be very specific

– IT products may be ineffective for diagnosisIT products may be ineffective for diagnosis– Diagnostic products may be ineffective for ITDiagnostic products may be ineffective for IT– Usage may be population-specificUsage may be population-specific

Where are we in the process?Where are we in the process?

Lab-based scienceLab-based science Clinical/financial interestClinical/financial interest Preclinical safety and efficacy studiesPreclinical safety and efficacy studies Human studiesHuman studies• Phase 1Phase 1• Phase 2Phase 2• Phase 3Phase 3

LicensingLicensing Post-licensingPost-licensing

How does the FDA decide? How does the FDA decide?

The lawThe law• Food Drug and Cosmetics Act of 1938 (FD&C Act)Food Drug and Cosmetics Act of 1938 (FD&C Act)

– FDA Modernization Act of 1997FDA Modernization Act of 1997

• Public Health Service Act of 1944 (PHS Act)Public Health Service Act of 1944 (PHS Act) The regulationsThe regulations

• Code of Federal Regulations (CFR)Code of Federal Regulations (CFR) The International Conference on Harmonisation of The International Conference on Harmonisation of

Technical Requirements for Registration of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)Pharmaceuticals for Human Use (ICH)

Guidance DocumentsGuidance Documents

Guidance documents that apply to Guidance documents that apply to allergenic productsallergenic products

Guidance for Industry On the Content and Format Guidance for Industry On the Content and Format of Chemistry, Manufacturing and Controls of Chemistry, Manufacturing and Controls Information and Establishment Description Information and Establishment Description Information for an Allergenic Extract or Allergen Information for an Allergenic Extract or Allergen Patch Test (1999)Patch Test (1999)

Guidance for Industry: Testing Limits in Stability Guidance for Industry: Testing Limits in Stability Protocols for Standardized Grass Pollen Extracts Protocols for Standardized Grass Pollen Extracts (2000) (2000)

Guidance for Reviewers: Potency Limits for Guidance for Reviewers: Potency Limits for Standardized Dust Mite and Grass Allergen Vaccines: Standardized Dust Mite and Grass Allergen Vaccines: A Revised Protocol (2000)A Revised Protocol (2000)

Guidance documents that apply Guidance documents that apply specifically to recombinant productsspecifically to recombinant products

(ICH) Quality of Biotechnology Products: Analysis of the Expression (ICH) Quality of Biotechnology Products: Analysis of the Expression Construct in Cells Used for Production of R-DNA Derived Protein Construct in Cells Used for Production of R-DNA Derived Protein Products (1995)Products (1995)

(FDA) Guidance for Industry: Submission of Chemistry, Manufacturing, (FDA) Guidance for Industry: Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for Product or a Monoclonal Antibody Product for In-VivoIn-Vivo Use (1996) Use (1996)

(ICH) Viral Safety Evaluation of Biotechnology Products Derived from Cell (ICH) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (1997)Lines of Human or Animal Origin (1997)

(FDA) Guidance for Industry: Content and Format of Chemistry, (FDA) Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description Manufacturing and Controls Information and Establishment Description Information for a Vaccine or Related Product (1999)Information for a Vaccine or Related Product (1999)

How to get there from hereHow to get there from here

Make a product that Make a product that • is safe and effectiveis safe and effective• can be manufactured consistentlycan be manufactured consistently

Follow current Good Manufacturing Follow current Good Manufacturing PracticesPractices

Do the necessary studiesDo the necessary studies


Preclinical studiesPreclinical studies• Product specific – efficacy, mechanism; Product specific – efficacy, mechanism;

choice of modelchoice of model• ToxicologyToxicology


IND submissionIND submission• To show that the product is To show that the product is safesafe and and

effectiveeffective• To support the labeled indications and To support the labeled indications and

dosingdosing

IND processIND process

Investigational New DrugInvestigational New Drug Section 262 of the PHS ActSection 262 of the PHS Act Section 505 of the FD&C ActSection 505 of the FD&C Act http://www.fda.gov/cber/ind/ind.htmhttp://www.fda.gov/cber/ind/ind.htm

FDA’s objectives in reviewing an IND:FDA’s objectives in reviewing an IND:• to assure the safety and rights of subjectsto assure the safety and rights of subjects• in Phase 2 and 3 , to help assure that the in Phase 2 and 3 , to help assure that the

quality of the scientific evaluation of drugs quality of the scientific evaluation of drugs is adequate to permit an evaluation of the is adequate to permit an evaluation of the drug’s effectiveness and safety (21 CFR drug’s effectiveness and safety (21 CFR 312.22(a))312.22(a))

IND - Phase 1IND - Phase 1

initial introduction into humansinitial introduction into humans dose rangingdose ranging closely monitoredclosely monitored safetysafety activityactivity

Reasons for “hold” on Phase 1 Reasons for “hold” on Phase 1 studystudy

unreasonable and significant risk of unreasonable and significant risk of illness or injuryillness or injury

clinical investigator is not qualifiedclinical investigator is not qualified Investigator’s Brochure is misleading, Investigator’s Brochure is misleading,

erroneous or materially incompleteerroneous or materially incomplete insufficient information to assess riskinsufficient information to assess risk


controlled clinical trialscontrolled clinical trials effectiveness (preliminary)effectiveness (preliminary) closely monitoredclosely monitored relatively small numbers (100’s)relatively small numbers (100’s)


evaluate efficacyevaluate efficacy larger studies (100’s - 1000’s)larger studies (100’s - 1000’s) controlledcontrolled pivotalpivotal

Reasons for “hold” on Phase 2/3 Reasons for “hold” on Phase 2/3 studystudy All the Phase 1 reasonsAll the Phase 1 reasons• unreasonable and significant risk of illness or unreasonable and significant risk of illness or

injuryinjury• clinical investigator is not qualifiedclinical investigator is not qualified• Investigator’s Brochure is misleading, erroneous Investigator’s Brochure is misleading, erroneous

or materially incompleteor materially incomplete• insufficient information to assess riskinsufficient information to assess risk

protocol or plan is deficient in design to protocol or plan is deficient in design to meet its stated objectivesmeet its stated objectives

IND processIND process

Protects human subjectsProtects human subjects• safetysafety• civil rightscivil rights

Improves the scienceImproves the science• rigorous study designrigorous study design

Facilitates product approvalFacilitates product approval• design previeweddesign previewed


General hurdles for new allergensGeneral hurdles for new allergens• Biological justificationBiological justification• Manufacturing practicesManufacturing practices– Lot to lot consistencyLot to lot consistency

• Good potency assayGood potency assay– if you can’t measure it, how can you study it?if you can’t measure it, how can you study it?

• Study powerStudy power

Study powerStudy power

The study needs to be of The study needs to be of adequate size to support adequate size to support the stated study objectivesthe stated study objectives

The failure to demonstrate The failure to demonstrate a difference is not a difference is not sufficient to demonstrate sufficient to demonstrate equivalenceequivalence

= 0.05; = 0.05; = 0.2 = 0.2


Specific hurdles for new recombinant Specific hurdles for new recombinant allergensallergens• character and stability of gene constructcharacter and stability of gene construct• if cell line is used, the cell line needs to be if cell line is used, the cell line needs to be

extensively tested for absence of adventitious extensively tested for absence of adventitious agents (such as retroviruses, EBV, SV40)agents (such as retroviruses, EBV, SV40)

• fermentation/growth media/growth conditionsfermentation/growth media/growth conditions• purificationpurification• characterization/proof of structurecharacterization/proof of structure


More specific hurdles for new More specific hurdles for new recombinant allergensrecombinant allergens• study design must target the appropriate study design must target the appropriate

patient population (may be different from patient population (may be different from the natural counterpart)the natural counterpart)

• indications must be carefully considered indications must be carefully considered priorprior to study design (may be different from to study design (may be different from the natural counterpart)the natural counterpart)


Unitage will have to be biological Unitage will have to be biological unlessunless• purity is assuredpurity is assured• correlation of biological activity to mass correlation of biological activity to mass

unitage is constantunitage is constant• stability of biological activity is assured stability of biological activity is assured

under conditions under which the product under conditions under which the product will be shipped, stored and usedwill be shipped, stored and used

But it But it hashas been done before... been done before...

Antihemophilic factorAntihemophilic factor Coagulation Factor VIIa Coagulation Factor VIIa

Coagulation factor IXCoagulation factor IX EtanerceptEtanercept

Epoetin alfaEpoetin alfa

FilgrastimFilgrastim

Hepatitis B vaccineHepatitis B vaccine

InfliximabInfliximab

Interferon alfacon-1Interferon alfacon-1

OprelvekinOprelvekin

PalivizumabPalivizumab

SargramostimSargramostim

TrastuzumabTrastuzumab

PegfilgrastimPegfilgrastim

Peginterferon alfa-2bPeginterferon alfa-2b

AlemtuzumabAlemtuzumab

AnakinraAnakinra

Darbepoetin alfaDarbepoetin alfa

Drotrecogin alfaDrotrecogin alfa

ResourcesResources

http://www.fda.gov/cber/ind/ind.htmhttp://www.fda.gov/cber/ind/ind.htm AAAAI Future Immunomodulation AAAAI Future Immunomodulation

InitiativeInitiative pre-IND meetingpre-IND meeting

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