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Follow-On

Biologics:Economic,

Innovation

and

PolicyReflectionsThe

Fuqua

School

of

BusinessDuke

UniversityNovember

6-7,

2008av72电影Charles

DiLibertiV.P.

Global

Pharmacokineticsand

Bioequivalence,Barr

Laboratories,

Inc.“Commercial

Opportunities

andChallenges

for

Follow-onBiologics”Presentation

OverviewGeneric

BiologicsCommercial

Opportunities

&

SavingsScience

&

Technology

ChallengesRegulatory

&

Intellectual

PropertyIssuesSummaryCommercial

Opportunities

&SavingsBenefitsofGeneric

CompetitionSignificant

Cost

Saving

OpportunitiesSavings

for

consumers

and

taxpayers

Generic

CompetitionInnovationBrand

companies

will

have

the

incentiveneeded

to

vigorously

pursue

newbiologicsIncreasing

Significance

of

BiologicProducts

US

Biologic

Revenues–

1997:

$17.4

Billion–

2007:

$

65.2

Billion*

400

Biologics

&

Vaccines

Currently

inClinical

Trials

Targeting

>200

Diseases**

Between

2003

and

2006,

biologicsrepresented

24%

of

all

new

chemical

entitiesapproved

by

the

US***

Sales

of

biotech

products

in

the

US

showedan

annual

growth

rate

of

20%

between

2001and

2006

compared

with

6%

to

8%

in

thepharmaceutical

market****

Ernst

&

Young**

Biotechnology

Industry

Organization***

Journal

of

American

Medical

Association,

October

22,

2008High

Cost

of

Brand

BiologicsEnbrel

(Arthritis)

$20,000*Cerezyme

(Gaucher

Disease)

$200,000**Remicade

(Arthritis)

$35,000-$66,000***ion

Wiese

C*Baltimore

Sun

January

28,

2007**Bloomberg

January

11,

2007***Philadelphia

Inquirer

September

19,

2006Significant

Cost

SavingsOpportunityGeneric

Biologics

Represent

Significant

Cost

SavingsOpportunities

and

Stimulate

InnovationEpogenMarket

Before

Generic

Launch:

$2.5Billion*Brand/Year

Today:$9,000**GenericSavings/Yearassuming

50%

savings:$4,500EnbrelMarket

Before

Generic

Launch:

$2.7Billion*Brand/Year

Today:$20,000***GenericSavings/Yearassuming

50%

savings:$10,000*ABN

AMRO

February

2008**National

Journal

February

10,

2007***Baltimore

Sun

January

28,

2007Generic

CompetitionPrice

Drops

as

Number

of

Manufacturers

IncreasesMarket

Size

for

Select

BiologicProductsProduct2006

Sales($

Millions)Patent

ExpirationAranesp

(Darbapotein

alfa)$2,7902016Enbrel

(Etanercept)$2,7362012Epogen

(Epotein

alfa)$2,5112004Remicade

(Infliximab)$2,3552013Rituxan

(Rituximab)$2,0712013Eprex

(Ortho

Biotech)$2,0642004Avastin

(Bevacizumab)$1,7462019Rebetron

(Ribavirin

&

Interferonalfa-2B)$1,3612001Lantus

(Insulin

glargine)$1,2602015Source:

ABN

AMRO

February

2008Market

Size

for

Select

BiologicProductsProduct2006

Sales($

Millions)PatentExpirationHumira

(Adalimumab)$1,1762013Avonex

(Interferon

beta-1a)$1,0222003Cerezyme

(Imiglucerase)$1,0072010Neupogen

(Filgrastim)$8302013Humalog

(Insulin

lispro)$8112013Ceredase

(alglucerase)$5372001Rebif

(Interferon

beta-1a)$4932005Neulasta

(Pegfilgrastim)$4932015Source:

ABN

AMRO

February

2008Perspective:Historical

Growth

in

SubstitutionLL

stimatesGeneric

BiologicsOpportunityGeneric

Pharmaceuticals

-

A

Vital

Part

in

HealthCare

System

Approximately

67%

of

the

Prescriptions

Dispensed

in

theUS

Are

Generics*BiologicsWorldwide

Market

Estimated

around

$75

Billion*Per

Patient

Cost

for

Biologic

Products

Can

Exceed$100,000

Per

YearGeneric

Biologics

US

Consumers

Could

Save

$43

Billion

Between

2011

and2020**

Estimated

Value

of

Biologics

that

have

already

lost

PatentProtection:

$10

Billion***

Estimated

Value

of

Biologics

to

lose

Patent

Protection

inthe

Next

Ten

Years:

$20

Billion****

IMS

Health**Citizens

Against

Government

Waste

(CAGW)

Release,

May

2,

2007***ABN

AMRO

February

2008Science

&

Technology

ChallengesScientific

Challenges

forGeneric

BiologicsCharacterizationSafety

AssessmentTherapeutic

EquivalenceManufacturing

ControlsGeneric

BiologicsGeneric

biologics,

sometimes

called

follow-on

biologics(FOBs),

are

protein

products

that

are

pharmaceuticallyand

therapeutically

equivalentGeneric

biologics

do

not

utilize

the

reference

product’sproprietary

process,

specifications

or

clinical

dataFor

established

products,

therapeutic

equivalence

can

bedemonstrated

usingIn

vitro

studies

and/orPharmacokinetics

and/orSurrogate

markers

and/orClinical

outcomesdepending

on

the

characteristics

of

the

proteinInter2804MonoclonalAntibody21112

atomsrDNA

Technology

Drugs:BiologicsSize

Does

Matter...124

atomsChemical

Drug:Misinformation

CampaignAbout

Generic

BiologicsMyth:

Raw

materials

of

biologic

origin

are

hardto

source

and

only

brand

biotechs

knowwhere

to

find

them.Reality:

Raw

materials

are

available

today

formany

generic

biologics

including

insulin,G-CSF,

erythropoietin,

interferons,

etc.Misinformation

CampaignAbout

Generic

BiologicsMyth:Biologics

are

too

complicated

to

becharacterized.Reality:Numerous

highly

sophisticated

analyticalmethods

have

been

developed,

permittingcomplete

characterization.

More

advances

willbe

achieved

each

year.Misinformation

CampaignAbout

Generic

BiologicsMyth:Generic

companies

lack

the

medical,

scientific,and

technical

ability

to

produce

safe

andeffective

biotech

products.Reality:Generic

companies

can

and

do

make

safe

andeffective

biologics.

Many

safe

and

effectivebiologics

currently

are

made

in

controlledenvironments

and

marketed

by

genericcompanies

outside

the

U.S.Generic

Biologics

(Biosimilars)in

the

EUThe

ability

to

make

generic

biologics

is

far

froma

theoretical

possibility.In

2004

EU

issued

EMEA

Draft

Guidelines

forfour

classes

of

generic

biologics,

referred

to

asbiosimiliars

in

the

EU.Since

2004,

the

EU

has

approved

severalbiosimilar

products.EU

Biosimilar

ApprovalsDRUGSandoz’s

Omnitrope®(somatropin)

EU

MARKET

AUTHORIZATION

DATEApril

12,

2006BioPartners’

Valtropin®(somatropin)April

24,

2006Sandoz’s

Binocrit®Medice’s

Abseamed®Hexal

Biotech’s

Epoetin

alfa

Hexal®(recombinant

human

erythropoietin

alfa)August

28,

2007Stada

Arzneimittel’s

Silapo®Hospira’s

Retacrit®(epoetin

zeta)December

18,

2007Teva’s

Tevagrastim®Ratiopharm’s

Ratiograstim®Ratiopharm’s

Filgrastim

ratiopharm®CT

Arzneimittel’s

Biograstim®(human

G-CSF)September

15,

2008current

through

September

25,

2008FDA

Approves

Sandoz’sOmnitrope

There

has

been

some

movement

in

the

USto

approve

generic

biologics.FDA

approved

Omnitrope

in

May

2006.

FDA

stated,

however,

that

this

approvaldoes

not

create

a

pathway

for

all

genericbiologics.

Omnitrope

referenced

a

brandproduct

(Genotropin)

approved

under

theFDCA.Misinformation

CampaignAbout

Generic

BiologicsMyth:“The

Product

is

the

Process.”Reality:“Old

models

and

mantras

are

inhibitingprogress

–

the

product

is

no

longer

theprocess.”

(Statement

of

Mathias

Hukkelhoven,Ph.D.,

Senior

V.P.,

Global

Head,

DrugRegulatory

Affairs,

Novartis,

Sept.

14-15,

2004).Misinformation

CampaignAbout

Generic

BiologicsReality

(continued):Biotech

products

can

be

fully

characterized

andcompared

analytically.Biotech

Firms

routinely

justify

their

own

processchanges

via

FDA

approved

comparabilityprotocols.Development

ofGeneric

BiologicsStrictly

Controlled

Process

(Validated)Extensive

Analytical

Comparability(Characterization)Comparable

Biological

Activity(In

Vitro/In

Vivo)Non-Clinical

Comparability

(Safety,Immunogenicity...)Comparable

pharmacokinetics

(bloodconcentration

profile)Comparable

Clinical

Efficacy

and

SafetyDevelopment

ConsiderationsProduct

ComplexityFrom

Development

To

ClinicalCharacterizationBiosynthesis,

In-Process

and

Finished

ProductNomenclatureLack

of

Strict

Definition,

INN

IssueHigh

Cost

of

DevelopmentMarketing

Requirements

and

CostPost-Marketing

Safety

SurveillanceIP

StrengthRegulatory

&

Intellectual

ProperIssuesChallenges

for

GenericBiologicsRegulatoryCongress

needs

to

create

an

abbreviatedapproval

pathwayIntellectual

PropertyBrand

exclusivityGeneric

exclusivityResolution

of

patent

litigation

prior

to

generilaunchRegulatory

Issues

Regulatory

Framework

Complicated

ByExistence

of

Two

Laws

For

BiologicsFDCA

for

NDA

ProductsPHSA

for

BLA

ProductsNDA

ProductsGeneric

Pathway

Exits,

But

FDA

ImplementationIs

UnclearBLA

ProductsThree

Issues

Need

To

Be

ResolvedMechanics

of

Approval

Pathway

Need

To

Be

DefinedBrand/Generic

ExclusivityAn

Efficient

Patent

Dispute

Resolution

MechanismAbbreviatedGeneric

PathwayUnder

PHSAA

Generic

Pathway

Should:Give

FDA

Authority

To

Decide

ApprovalRequirements

For

Generic

ProductsAdopt

Exclusivity

Provisions

No

GreaterThan

Those

Found

In

Hatch-WaxmanPermit

Pre-Launch

Adjudication

of

CertainPatent

DisputesAbbreviatedGeneric

PathwayUnder

PHSA

FDA

should

be

permitted

to

decide

whattests/data

are

necessary

for

approval

as

acomparable

or

interchangeable

generic.

Congress

should

not

impose

unnecessarybarriers

to

generic

approvals,

e.g.,mandatory

guidance

or

rule-makingrequirements;

mandatory

clinical

trials;requirement

that

generics

seek

approval

forall

approved

brand

uses.AbbreviatedGeneric

PathwayUnder

PHSA

Congress

should

carefully

consider

anynew,

additional

exclusivities

awardedto

brand

biologics.

Considerable

incentives

already

existfor

brand

biotech

companies.Existing

Incentives

for

BrandBiotech

CompaniesINCENTIVEPatent

Term

RestorationDrug

manufacturers

get

back

up

to

5

years

of

time

lostto

product

testing

and

approval

delays.PTO

Patent

RestorationIf

the

patent

approval

is

delayed

by

PTO’s

fault,patentee

gets

back

each

day

in

excess

of

3

years.Orphan

Drug

Exclusivity7

years

of

exclusivity

for

drugs

treating

rare

diseases.General

Business

R&DTax

CreditAllows

manufacturers

to

claim

20%

of

qualifiedspending

in

the

U.S.

above

the

base

amount.Puerto

Rico

Tax

CreditAllows

U.S.

corporations

to

exempt

40%

of

incomefrom

business

operations

owned

in

P.R.,

U.S.V.I.,

etc.Foreign

Tax

CreditAllows

U.S.

corporations

to

claim

limited

tax

credit

fortaxes

paid

to

foreign

governments.URAAPatent

Term

RestorationThe

Uruguay

Rounds

Agreement

Act

(“URAA”)gives

drug

companies

a

20

year

patent

from

the

date

itwas

filed

(rather

than

17

years

from

issue).AbbreviatedGeneric

PathwayUnder

PHSA

If

Congress

decides

to

give

additionalexclusivities

to

brand

companies,Hatch-Waxman

establishes

themaximum

length

and

number

ofexclusivities

that

can

be

justified:5

years

for

truly

new,

innovative

products3

years

for

certain

improvements

to

already-approved

brand

productsAbbreviatedGeneric

PathwayUnder

PHSA

Unlike

the

incentives

that

already

existo

develop

new

brand

biologics,

noincentives

exist

to

develop

genericbiologics.

Generic

biologics

legislation

shouldinclude

an

incentive,

just

as

Hatch-Waxman

does

for

small

moleculedrugs,

for

the

development

of

genericbiologics.AbbreviatedGeneric

PathwayUnder

PHSA

Effective

generic

biologics

legislatiowill

include

a

mechanism

forexpeditious

resolution

of

patentdisputes.

Hatch-Waxman

has

shown

that

patentmechanisms

can

be

abused

to

delaygeneric

market

entry.AbbreviatedGeneric

PathwayUnder

PHSA

Only

those

patent

disputes

that

wouldcause

the

generic

company

to

delaylaunch

should

be

litigatedsimultaneously

with

the

FDA

approvalprocess.

Disputes

over

any

other

patent

that

thebrand

owns

should

wait

until

thegeneric

company

actually

launches.AbbreviatedGeneric

PathwayUnder

PHSA

Such

a

process

ensures

that

brandcompanies

cannot

use

weak

orsuspect

patents

to

delay

genericmarket

entry.

At

the

same

time,

the

process

protectsall

legitimate

patent

rights

–

it

allowlitigation

over

all

patents,

but

controlwhen

that

litigation

can

start

so

thatgeneric

marketing

isn’t

undulydelayed.Negotiations

Are

OngoingMuch

Momentum

Gained

in

DebateOptimistic

for

Ultimate

ResolutionRegulatory

IssuesU.S.

Proposed

LegislationSummaryGeneric

Biologics

in

USSignificant

Momentum

in

US

Congress

Failed

to

Pass

in

2007-08

Session;Likely

to

Be

On

Legislative

Agenda

in2009

Strong

Consensus

for

Generic

BiologicsAmong

Payers,

Consumer

GroupsDebate

Centers

On

Three

IssuesMechanics

of

PathwayHow

to

Resolve

IP

IssuesExclusivity

IssueBroad,

Bipartisan

Support

for

aWorkable

Pathway

for

Generic

BiologicsGroups

in

SupportConsumer

GroupsAARPAFL-CIOAFSCMECalifornia

Public

Employees’

RetirementSystem

(CalPERS)Consumer

Federationof

AmericaConsumers

UnionFamilies

USANational

Consumers

LeagueNational

Multiple

Sclerosis

Society(MS)National

Research

Centerfor

Women&

FamiliesNational

Organizationfor

Rare

Disorders(NORD)National

Women"s

Health

NetworkPharmaceutical

Care

ManagementPublic

CitizenService

Employees

International

Union(SEIU)Spastic

Paraplegia

FoundationUSPublic

Interest

Research

GroupUnited

Auto

Workers(UAW)Groups

in

OppositionBIOPhRMABusiness

GroupsCaterpillar,

Inc.DaimlerChrysler

CorporationEastman

Kodak

CompanyFord

Motor

CompanyGeneral

Motors

CorporationHealth

PlansAetna

Inc.America’s

Health

Insurance

PlansBlue

Cross

Blue

Shield

AssociationHumanaKaiser

PermanenteUnited

Health

GroupWellpointPharmaceutical

StakeholdersApotexBen

VenueBarr

LaboratoriesCaremarkExpress

ScriptsGeneric

Pharmaceutical

Association(GPHA)HospiraMedcoS•tMaomteentGaovernorsNational

Associationof

Chain

Drug

StoresNational

Associationof

Health

UnderwritersPharmaceutical

Care

Management

Association(PCMA)Ranbaxy

PharmaceuticalsSandozTeva

Pharmaceuticals

USAWatson

PharmaceuticalsWalgreens

CompanyStateGovernorsVermontWisconsinMinnesotaKansasMontanaVirginiaWest

VirginiaMississippiWashington如何在媒介购买中完美的实现媒介计划？没有愚蠢的问题！愚蠢的是有问题而不问！Lorem

ipsum

dolor

sit

amet如何在媒介购买中完美的实现媒介计划？(一)什么是媒介购买(二)怎样定义“完美的媒介计划”、媒介计划是什么、怎样评估它的目标？(三)怎样完美地实现媒介计划？(

一

) 什么是媒介购买？与媒介就价格、服务及其他合作事宜进行谈判与媒介沟通、联系购买及执行一切有关行政工作(如订单、付钱等)与媒介计划、客户部及客户沟通，反馈讯息及提供媒介机会制作媒介排期媒介购买的演变及发展与媒介谈判与媒介沟通、联系购买以前媒介购买的演变及发展向客户沟通提供讯息及机会制作排期与媒介谈判与媒介沟通、联系购买现在以前媒介购买的演变及发展独立媒介公司：-与客户直接联系-提供专业咨询及顾客服务-独立的营运体系自负盈亏现在/将来向客户沟通提供讯息及机会制作排期与媒介谈判与媒介沟通、联系购买现在以前被动只与媒介及内部沟通主动、直接

多方面接触、竞争从被动变成主动媒介购买负责制作排期的好处？对客户媒介购买获得最多，最直接及最快的市场讯息可作出最灵活的应变对广告公司减少沟通时间及内部流程加强客户与媒介购买的联系，提高效益及竞争能力(

二

) 实现媒介计划的目标目标必须是：客观的

(

Objective)可量度的

(Measurable), 可比较的

(Comparable)媒介计划的目标-

(1)-

(2)-

(3)效果(Effectiveness)成本效益(Efficiency)准确(Accuracy)(

1

) 效果

(

Effectiveness

)一个媒介计划是否有效果可以用以下客观的量度标准去评估：有效到达率及频率(Effective

Reach

&

Frequency)品牌知名度(

BrandAwareness)媒体比重占有率(

Share

ofVoice

)市场占有率(

Shareof

Market)普及率其他调研方法(

Penetration

)(

Other

research

measures

)(

2

) 具成本效益

(

Efficiency

)一个媒介计划是否具成本效益，可以用以下客观的量度标准去评估：千人成本(CPM)总接触人次(GrossImpression)覆盖率(Coverage)(

3

) 准确

(

Accuracy

)在执行时，是否准确达到原本要求，可透过以下方法去评估：监察报告

(

Monitoring

)l

漏刊、播l

错刊、播事后评估

(

Post

Analysis

)以实际广告效果与计划比较：收视率、收听率有效到达率及频率发行量平均暴露频次从事后评估

(

Post

Analysis

) 累积经验及教训例子

(

一

)

：还珠格格第一辑收视率在各地相当高，但当中的广告段的收视率则很低：对于购买第二辑的策略：尽量避免片中广告购买电视剧前广告，如预算许可，考虑节目前较好的位置从事后评估

(

Post

Analysis

) 累积经验及教训例子

(

二

)

：当北京的“个人收视仪” 收视报告

(

People

Meter) 诞生, 中央台的黄金时段收视率并没有象以往“日记” 式收视报告的那样高对于以后的策略：可能考虑增强各地区的投放量减少在中央台黄金时段投放，考虑其他时段(

三

) 怎样完美地实现媒介计划？(1)效果l

具创意的、崭新的媒介点子(Creative)l

对市场、品牌及媒介了解(Informative

andKnowledgeable)具创意的媒介点子-

创新的媒介点子：利用新媒体：如

： 飞艇在空中巡走在网上以一元拍卖汽车在公车

/ 地铁把手作广告利用旧媒体：如： 同一时间在不同电视频道播放相同的广告(

Horizontal

Block

Buy

)具创意的媒介点子震撼的媒介点子通过增加播放量增加冲击力(Impact):在杂志上的连续广告(Consecutive

Buy)垄断媒体作地铁车身广告创意效果•PART•01对市场、品牌及媒介的了解市场、品牌

：-

有效利用市场及品牌数据：

地区销售分布：( 品牌发展指数BDI

)

地区预算是否合理？

地区是否应在具潜力的市场多投预算？

地区是否应在媒介成本较低的市场多投预算？对市场、品牌及媒介的了解媒介

：不同电视台的互相覆盖

：

省台和市台的运用及分配不同报纸对於不同层次或地区互相覆盖

：

例子

： 北京晚报、北京日报与北京青年报

预算

：

50万左右

目标

： 有效频率

/ 到达率

：

3+/

40%

目标受众

： 男性25岁以上各大市场电视

(

30”) 千人成本比较(RMB)1城市 千人成本北京1782海口1653合肥1364西安1005福州916石家庄897沈阳71省台与市台收视点之比较浙江省目标受众群：女性20-45岁收视率来源：央视-索福瑞媒介收视报告(99年4月30日至7月31日)报纸不同配合目标收众：女性18-35岁资料来源：TGI(目标群众指数)日期：98年12月-99年11月(

三

) 怎样完美地实现媒介计划(

2

)

成本效益制作媒介排期的技术及能力谈判能力制作媒介排期的技术及能力同等预算，但由于制作媒介排期的技术不一样，可以有很大的差别例子一： 北京的电视投放目标受众： 女性 20-45

岁比较方式： 比较当频率为3+时的有效到达率购买策略： 选择一： 北京及北京有线的电视剧、综艺节目两个电视的投放量较平均选择二： 北京有线台与选择一类似但投放量略为倚重选择三： 除黄金时段外，还利用北京有线台的白天广告套餐预算： 所有排期均控制在60万以内表现比较---北京收视报告来源：尼尔森北京收视报告(99年5月10日至7月31日)例子二： 天津的电视投放目标受众： 女性 20-45岁比较方式： 女性 20-45岁购买策略： 选择一： 天津一套及二套晚间电视剧，投放策略重天津一套选择二：天津一套及二套晚间电视剧，投放策略重天津二套选择三： 除黄金时段外，利用天津一套中午电视剧预算： 43万左右表现比较---天津收视报告来源：尼尔森北京收视报告(99年5月10日至7月31日)谈判能力及技巧在大学里，漂亮女生替男生在饭堂排队打饭的例子谈判能力总体的媒介表现及效果谈判行为模式彼此关系高中低低高容忍建立友好关系合作有创意的解决问题以使双方都赢后退能拿多少拿多少战胜不惜一切取得胜利妥协缩小差异，折中中关注谈判结果与媒介谈判的特性媒介位置具极强的时间性媒介需要在特定的时间内，尽量把位置卖掉，否则位置会浪费月饼销售的例子与媒介谈判的特性媒介位置具极强的时间性媒介需要在特定的时间内，尽量把位置卖掉，