BIO Comments on India Biosim Guidelines

The Biotechnology IndustryOrganization (BIO) is grateful for the opportunityto respond to theIndian Guidelines on Similar Biologics:Regulatory Requirements for Marketing Authorization, hereafterreferred to as"Guidelines".

About BIO andthe Biotechnology Industry

BIO is atradeassociation representingmorethan1,100 companies, academiccentersand research institutions involved in the researchanddevelopment of innovative biotechnologyproducts and services.  Our members areprimarilysmall-and medium- sized enterprises working to develop and commercializecutting-edgeproducts in the areas of healthcare, agriculture, energy,and the environment.  Sinceits inception roughly 30years ago, thebiotechnologyindustryhas spurred the creationofmorethan one milliondirect jobs, and millions of related jobsin countries throughout theworld.

Thebiotechnologyindustryhas developed hundreds of innovativeproductsthat are helpingto heal, feed,andfuel theworld.  In the healthcaresectoralone, this industryhas developed andcommercialized morethan 300 biotechnologytherapies, cures, vaccines, and diagnostics that arehelpingmorethan 325 million peopleworldwide who are sufferingfrom cancer,HIV/AIDS, and numerous otherserious diseases andconditions.

Another 400biotechnologymedicines arein thepipeline.  In theagricultural field,biotechnologyinnovations areincreasingfood supplies, conservingnatural resources of land waterand nutrients,increasingfarm income,and growingtheeconomyworldwide. Within thefield ofindustrial biotechnology,biotech companies areleading the wayin creatingboth conventional and next generationadvanced biofuels,which can be produced from forest residues, algae, municipal solid waste, orother renewable sources of biomass,withoutcompromisingthe environment.  Renewable chemicalsand biobased product platforms arealso providingreal opportunities to creategreen jobs, reduce dependenceon foreign oil, increaseenergysecurity,andreducegreenhousegas emissions.

India's biotechnologysector is a burgeoningone,with morethan 325 companiesand some with revenues in thebillions of dollars.  Accordingto theBioSpectrum-ABLE (Association ofBiotechnologyLed Enterprises)BiotechIndustrySurveyof2011, the industryhasgrown by21.5% in 2006-2011, surgingto $4 billion.  Foradditional information aboutIndia'sbiotechnologysector, pleaseseethe full9thBioSpectrum publication.1

BIO'sOverallViews onIndia's Guidelines onSimilarBiologics

At the outset, BIOwantstocommend the government ofIndia's MinistryofHealth in its endeavor to provideguidancefor companies engaged in developingsimilar biologics. BIO urges that in approvingSBPs, regulatoryauthorities ensurethat publicsafetyis the top priority, andalso that incentives to innovate new products arenot undermined.   As indicated bythe Guidelines,"biologics"arecomplexmedicines that aremanufactured usinglivingorganisms.  Thesedrugs aredifferent and far morecomplexthan most small molecule chemical drugs, and includemanyof thelatest breakthrough medical therapies forserious and life-threateningillnesses, suchas cancer, multiplesclerosis, diabetes, and HIV/AIDS, as wellas manyserious rarediseases.  Dueto their sizeand complexity, biologicsgenerallycannot be scientificallycharacterized to thesamedegreeas small molecule chemical drugs.

As theWorld Health Organization has recognizedin its guideline fortheevaluation of similar biotherapeuticproducts, similar biologic products, orSBPs, arenot– and cannot betreatedas--genericdrugs.  Agenericdrugis aproduct that is shown to be thesameas an innovative drug, and is generallydesignated astherapeuticallyinterchangeable with the innovator drug.  Unlikegenericdrugs, an SBPis a product that is similar to, but not the same as, the innovator drug.  Therecognitionofthe scientificdifferences between drugsand biologics is critical in assessingthe types anddegrees of teststhat maybe necessaryto demonstratean SBP’s quality, safetyand efficacyprofiles.  Because of the complexscienceinvolvedwith manufacturingbiosimilar medicines, manyadvanced regulatoryagencies2haveindicated that thegenericdrugapproval pathwayis not appropriateforcomplexbiologics.  TheWorld Health Organization'sguidelines referenced above, mayserveas a startingpointforanyscientificallybased regulatory approval pathwayforbiologics.

Moreover,while it is important to ensurethat safe and effectiveSBPs reachthe hands of patients who need them,itis important also not tolose sight of the need fornew and innovative products as well.  Accordingly, in developing guidelines fortheapproval and marketingof SBPs, thegovernment ofIndia should ensurethat incentives to research, develop and manufacturenew and innovative therapies and cures, as wellas new indications forsuchproducts, arepreserved.  In particular, itis important that there be substantial non-patent data exclusivitygranted to the original innovatorduringwhich time SBPmanufacturerscould notrelyonanyhealth authority’s priorapproval of the innovator’s ReferenceBiologic Product (RBP).

Indian approval processas soon as fouryears post approval of theRBPin a countrywith awellestablishedregulatoryframework, if the RBPis not marketed inIndia(which suggeststhat, contrarytoU.S. and EUregulations,India mightpermit approval, even in the absenceof anIndianapproved RBP).  TheGuidelines do not specify when such SBPs mayactuallybeapproved. But it is important to note that, whileasimilar four-year period exists under U.S. lawforthe submission ofaSBPapplication, U.S. law also prohibits theactual approval of a SBPuntil theexpiration ofa12-year period post- approval of theRBPin theUnited States.  Moreover, the Guidelines do not specifythe amountof protectionthatwould bereceived for innovatorbiologics thatareapproved for marketinginIndia prior to the submission ofan application for SBPapproval.

Ineither case, substantialnon-patent dataexclusivityis necessarytoprevent unfair competition in the marketand to promoteinnovation.  Thetest data required by governments forapproval of innovator biologic productsis proprietaryandrequires massive investment, and thereforedeservingof adequate protection.  Further, the fledglingnatureof thebiologics industry, its heavydependenceon access to significant amounts of high-cost publicand privateinvestment capital, thehighrisks and costs involved in thedevelopment of new biologic medicines, and the less certaintyprovided bytraditional forms ofintellectual property allwarrant a substantial period of data exclusivityforinnovatorbiologics.  In this regard,itis important to emphasizethat, under this new pathway,theSBPsare approved based on “similarity”not “identity”with the RBP.  Accordingly, patents that protect a biological product areless likelythan patents coveringtraditional smallmolecule medicinesto prevent competitors from bringinga“similar”product to marketdueto thegreater abilityto design around such patents.  Therefore, downstream protection for biologicsshouldincludesufficient data exclusivity.  This dataexclusivity,which in theUnited Statesis 12years, is necessary to enable recoupment ofthesignificant investment and the lengthyR&D process required to develop a biotechnologyproductand to fostercontinued innovation forpatients. We respectfullyurgethe Government ofIndia toconsider establishing asimilarperiod of protection.

Finally, itis important that SBPs be identified byaunique nomenclature(includingthe assignment ofa non-proprietaryname orINN), readilydistinguishablefromthe RBPand anyother SBP.  This nomenclaturewouldpermitaccurate traceabilityofadverseevents that maybeattributableto the sourceproduct.

BIO's Specific Areas ofInterest

Manufacturing Process and Qualityof Similar Biologics

With respect to the manufacturingprocess and qualityof SBPs, wenote that on page8 of the Guidelines thereis arecognition ofthe need to perform comparabilitystudies.  It should berecognized that such an assessment is different than the requirement to evaluate manufacturing changes.  In this regard, whilethemethods used byReferenceBiologic Product (RBP) manufacturer to demonstratecontinued safetyand effectiveness aftera manufacturingprocess changecan inform theanalyticcomparabilityassessment, by themselves thesemethods areinsufficient to demonstrate safetyand effectiveness of an SBPmadebyadifferentmanufacturer usingadifferent process. TheSBPmanufacturer willnot haveaccess to protocols used bythe RBPsponsor to show that the product remains comparable pre-and post-implementation of amanufacturingchange.

Therefore, itis important that theSBPsponsor independentlydevelop a robust suiteof state-of-the-art techniques to demonstrate that a SBPand RBPhavesimilar quality, safety, andefficacyprofiles.  Furthermore, in themeasurement ofqualityattributes a validated assayshould always be used when itis available, oralternatively,a scientificallyjustifiablereason should bepresented fornot doingso.  With respect to structural and physiochemical properties, whiletheGuidelines direct manufacturers to investigate, identifyandquantifypost-translationallymodified forms ofbiologics, it does not requireanassessment of theimpact of thesechanges.  It has been ourexperiencethat oftentimes thesechangeshaveasignificant impact on thequalityof biologics, particularlyin thecontext of immunogenicitybut also in the context of function.

Toxicological Studies

On page13 oftheGuidelines, thereis referenceto theuse of certain types of animal models in the event that therelevant animal models arenot available.Animal toxicity assessments should beconducted to comparethe referenceproduct and thebiosimilar product, unless otherwisescientificallyjustifiedbythe sponsor.  Theyshould be consistent withInternational Conferenceon Harmonization guidelines andconducted in an appropriate, pharmacologicallyrelevant animalspecies.


Confirmatory Safety and EfficacyStudy

TheGuidelines, on page16, allow forwaivingconfirmatoryclinical and safetystudies if certain structural and comparabilityconditions and acceptablepharmacokinetic (PK)/pharmacodynamic(PD)and non-clinical requirements aremet.  Specifically, these requirements can bewaived when aPK/PD studyhas demonstrated comparabilityhas preferentiallybeen donein an in-patient settingwith safety(includingimmunogenicity) and efficacymeasurements.  However,given thatimmunogenicitymayaffect PK/PD of the SBPaffectingtheinterpretation ofthe resultson the test system, an immunogenicity determination should also be apart of thepre-clinical/animal comparabilitytests.

Moreover,itis important onceagain to emphasizethe significanceof ensuringpatient safety.  Patients should nothaveto acceptgreaterrisks or uncertainties in usingan SBP ratherthanan innovator'sproduct.  BIO believes that both preclinical andclinical trial evidenceand dataare fundamental forevaluatingand demonstratingthe quality, safety and effectiveness of an SBP, and acomplete non-clinical and clinical program must be performedand conductedon aproduct-by-productbasis.In particular, immunogenicity testingis necessaryto avoid putting patients at risk of adverseeffects fromimmune reactions.  Such adetermination cannot be effectivelymadewithoutin-patient testing.

Extrapolation ofEfficacyand SafetyData to other Indications

Theguidelines, on page18, allow forextrapolation of safetyand efficacydata ofa particular indication to anotherclinical indicationif certainconditions aremet.  Caution is necessaryregardinganyextrapolation across patient populations.  Safetyrisk profiles maydiffer between indications because of variables such as concurrent conditions or

concomitant medications.  Therefore,extrapolation of safetydatato other indications will often beinappropriate, and PK studies mayneed to be conducted in different patient populations.



Wecommend the Government ofIndia fortaking steps to develop guidelines for SBP regulatoryrequirements.  Weurgethat theguidelines includeprocesses and requirements that ensurepatient safety.  This is particularlyimportant, given thecomplexities associated with the production and manufactureofbiological products wheresmall changes in production and manufacturecan affectthe immunogenicity, toxicityand

overallefficacyof theproduct.  Wefurtherurgethat theGuidelines also takeinto account the need to preserveincentives to research, develop and manufacturenew and innovative biological products.  Given the significant expense associatedwith theresearch, development and manufactureof new biological products, it is unlikelythat theshortand uncertain time frame ofexclusivityprovided in thedraft Guidelines willenable recoupment ofthis investment.  As such, webelievethat, in order to preserve the incentives forinnovationof biological products, the Government ofIndia should implement sufficientnon-patent dataexclusivitypriorto approval ofan SBP.

In summary, we believe that it is possibleto implement a regulatorypathwayfor SBPs that willresultin access to safe and effective medicines, whileat thesametime preservingthe incentives for innovation.  We urge continued consultation with relevant stakeholders in order to arrive at thebest possible pathway for the approval and marketingof SBPs.

We appreciate the opportunity to express our views.  Foradditional information regarding the positions of TheBiotechnologyIndustryOrganization pleasesee