Creativity  &  Constraint

Creativity

 & Constraint

© Copyright Merry Lampi and Pratt Institute. No part of this work may be copied, reproduced, or translated in any form or medium without the prior written consent of both Merry Lampi and Pratt Institute.

In Creativity and Constraint, the question of how creativity is affected by constraint is asked. FDA regulation is used as a starting point in this discussion, which is by no means over yet. The conclusion to this thesis has served as a springboard for several issues facing designers within the field of pharmaceutical advertising. Hopefully readers unfamiliar with the field will take away an appreciation for the issues and effort that make up medical advertising. For those who work in the field, my greatest hope is to have gotten my facts straight for you and that my love of this industry shines through.

—Merry Lampi

Creativity & Constraint

Table of Contents

Hypothesis 1

Introduction 3

1. Creativity and constraint

1.1 Overview of creativity and constraint 5

1.2 What is the ‘Creativity Problem?’ 7

1.3 How can you solve the creativity problem? 9

1.4 What is the difference between constraint and predetermined mediocrity? 11

1.5 How does constraint impact creativity? 15

1.6 How can identifying different constraint types aid creativity? 17

1.7 Interview: Wilson Capellán 19

1.8 Professor survey 21

2. Overview of DTC advertising

2.1 What are the differences between DTC and OTC advertising? 23

2.2 What are the differenced between DTC and general advertising? 27

2.3 What are the different kinds of DTC ads consumers see? 29

2.4 What can professional advertising be? Interview: Lena Shabus 31

3. Jumping to conclusions

3.1 An analysis of the evidence gathered in 35 the pursuit of the truth about constraint

3.2 Designers help test the hypothesis 37

Interviews 47

Thanks 49

Appendix 41

References 43

Glossary 45

It is possible that creativity is enhanced by constraint. This thesis examines whether constraints imposed on designers within direct to consumer advertising help or hinder the creative process. By studying constraint in the form of FDA regulation, this thesis will illustrate how these rules impact print advertising of prescription medication.

Hypothesis

1

What if creativity and constraint were inseparable?

What if there were no rules?

What if the sky were the limit?

What if everything was always beautiful?

What if we only ever saw the truth?

What if?

2

Introduction“Constraints shape and focus problems, and provide clear challenges to overcome as well as inspiration.

Creativity, in fact, thrives best when constrained… . Yet constraints must be balanced with a healthy disregard for the impossible… . The creativity realized in this balance between constraint and disregard for the impossible are fueled by passion and result in revolutionary change.”1 —Marissa Mayer

Pharmaceutical advertising is also called DTC (direct-to-consumer) advertising. DTC is different from OTC (over-the-counter) advertising in several ways. First, a doctor must prescribe a DTC medication, and this doctor is the ultimate authority on whether or not the consumer receives a particular medication. Second, sometimes a patient might not have any choice in the kind of treatment they can receive, as is the case with cancer or HIV. A kind of marketing referred to as ‘Professional’ will be used to describe advertising directed towards physicians.

The largest difference between DTC and general advertising appears in the impact a product has on the consumer. What design teams accomplish in this field reaches far beyond selling a product; they communicate complicated science to the disparate audiences of consumers and health care practitioners. Another difference can be seen in the potential impact of DTC advertising on the health of the consumer. DTC advertising has helped improve patient compliance with medical regimens,3 helped to increase treatment of under-diagnosed diseases4 and provided consumers with knowledge to help them make the best treatment decisions.5 This range of impact is very different than in the selling of, say, jeans.

From this point on, ‘DTC’ will be used to describe the type of advertising this study addresses. DTC in the form of printed materials in magazines, television advertisement and promotion, takes center stage in this study, but Web-based marketing efforts are also considered.

Many sources have considered how creativity is affected by constraint,2 yet there is little research regarding how this applies to DTC advertising. Understanding how constraint influences creativity within this niche of advertising can offer several benefits for designers. Creatives within this field regularly convert obstacles into outstanding concepts—often with great success. Interviews with designers who have worked on both general and DTC have established that the actual process of creation is roughly the same, once all of the elements and boundaries have been established.

Even with constraint, creativity is possible. It might even be said that creativity is enhanced by limitation. This thesis will study how FDA regulation (a form of constraint) may increase creative opportunities within DTC advertising. Health care advertising can describe any form of marketing relating to health, fitness or well-being, while DTC advertising is the marketing of prescription medication to consumers.

DTC has as many supporters6 as it has detractors. Like most cultural phenomena, the impact of DTC advertising may not be fully understandable until a period of time elapses. In the years to come, court battles involving the legitimacy of this form of advertising will be won or lost. World drug markets, which largely prohibit DTC advertising, will possibly continue on a trend of slowly allowing more types of drug advertising towards consumers. Currently, most counties allow no branded promotion to consumers.

The European Union allows drug makers to promote drugs to consumers for a handful of diseases, such as AIDS, asthma and diabetes. New Zeland is the only country to have adopted drug marketing regulation similar to the United States. At the closing of 2006, the global industry for drug manufacturing cost around $643 billion. Total global pharmaceutical sales include audited and estimated unaudited information.7 2007 marked the 10-year anniversary of the birth of pharmaceutical advertising as we know it today.8 While DTC was never specifically forbidden or banned, examples of DTC had appeared only sporadically before 1997. The majority of marketing was, and still remains, focused on physicians. Consumers have responded to the emerging industry with emotions that range from joy to outrage.

An informal survey,9 designed to capture attitudes about DTC advertising found that TV and magazine ads were the focus of the most heated opinions. Since many of the responders were in some way familiar with DTC (via having acquaintances in the fields or being in the industry themselves), it was surprising to see so many negative responses to DTC advertising.

Responses came in a range of less-than-positive adjectives such as: confusing, dreadful, misleading and surreal. Lost in the debate is any consideration as to why DTC ads look the way they do. This thesis hopes to fill this gap in the documentation of an industry that will continue to grow, and will perhaps become more important as our population becomes more focused on health issues and longevity.

3

The first section of this study will look at the relationship between creativity and constraint. The second section examines how constraint acts on DTC, professional and consumer advertising. Having established the effects of constraint on creativity, a brief history of medical advertising will be presented alongside the evolution of FDA regulation. This section highlights how the constraint of FDA regulation has influenced the look of DTC advertising. Exceptional historic ads will be showcased to prove it is possible to break the mold—without leaving the box. After examining the juicy history of DTC advertising, we land on the very solid, dry ground of FDA regulation.

An overview of what the FDA’s role is within DTC advertising is presented. The final section offers a look at all of the elements within a DTC campaign that are constraints, and how designers work within and around them. The appendix is a look at some of the misconceptions people have about pharmaceutical advertising.

The products of the teams I work with have an impact on the health and well-being of society. I’ve found that the criticism this industry receives, when not balanced by all of the positive aspects, creates the potential for missed opportunities. I want to be in a position to help people clearly understand treatment choices available and the truly marvelous scientific advances that are constantly emerging.

ROZE

REM

TM

(ram

elte

on) T

able

ts

DESC

RIPT

ION

ROZE

REM

™ (r

amelt

eon)

is an

ora

lly ac

tive h

ypno

tic ch

emica

lly d

esign

ated

as

(S

)-N

-[2-(1

,6,7

,8-te

trahy

dro-

2H

-inde

no-[5

,4-b

]fura

n-8-

yl)eth

yl]pr

opion

amide

and

cont

aining

one

chira

l cen

ter. T

he co

mpo

und

is pr

oduc

ed as

the (

S)-e

nan-

tiom

er, w

ith an

empir

ical f

orm

ulaof

C 16H 21

NO2,

mole

cular

weigh

t of 2

59.3

4,

and

the f

ollow

ing ch

emica

l stru

cture

:

Ram

elteo

n is

freely

solub

le in

orga

nic so

lvent

s, su

ch as

meth

anol,

etha

nol,

and

dimeth

yl su

lfoxid

e; so

luble

in 1-

octan

ol an

d ac

etonit

rile;

and

very

sligh

tly

solub

le in

water

and

in aq

ueou

s buf

fers f

rom

pH

3 to

pH

11.

Each

ROZ

EREM

table

t inc

ludes

the f

ollow

ing in

activ

e ing

redie

nts:

lacto

se

mon

ohyd

rate,

star

ch, h

ydro

xypr

opyl

cellu

lose,

mag

nesiu

m st

eara

te,

hypr

omell

ose,

copo

vidon

e, tita

nium

diox

ide, y

ellow

ferri

c oxid

e, po

lyeth

ylene

glyco

l 800

0, an

d ink

cont

aining

shell

ac an

d sy

nthe

tic ir

on o

xide b

lack.

CLIN

ICAL

PHA

RMAC

OLOG

Y

Phar

mac

odyn

amics

and

Mec

hani

sm o

f Acti

on

ROZE

REM

(ram

elteo

n) is

a m

elato

nin re

cept

or ag

onist

with

bot

h hig

h aff

inity

for m

elato

nin M

T 1an

d M

T 2re

cept

ors a

nd se

lectiv

ity o

ver t

he M

T 3re

cept

or.

Ram

elteo

n de

mon

strate

s full

agon

ist ac

tivity

in vi

tro

in ce

lls ex

pres

sing

hum

an M

T 1or

MT 2

rece

ptor

s, an

d hig

h se

lectiv

ity fo

r hum

an M

T 1an

d M

T 2

rece

ptor

s com

pare

d to

the M

T 3re

cept

or.

The a

ctivit

y of r

amelt

eon

at th

e MT 1

and

MT 2

rece

ptor

s is b

eliev

ed to

cont

ribut

e

to its

slee

p-pr

omot

ing p

rope

rties

, as t

hese

rece

ptor

s, ac

ted u

pon

by en

doge

nous

mela

tonin

, are

thou

ght t

o be

invo

lved

in th

e main

tenan

ce o

f the

circa

dian

rhyth

m

unde

rlying

the n

orm

al sle

ep-w

ake c

ycle.

Ram

elteo

n ha

s no

appr

eciab

le aff

inity

for t

he G

ABA

rece

ptor

com

plex o

r for

rece

ptor

s tha

t bind

neu

rope

ptide

s, cy

tokin

es, s

erot

onin,

dop

amine

, nor

adre

n-

aline

, ace

tylch

oline

, and

opia

tes. R

amelt

eon

also

does

not

inter

fere w

ith th

e

activ

ity o

f a n

umbe

r of s

electe

d en

zym

es in

a sta

ndar

d pa

nel.

The m

ajor m

etabo

lite o

f ram

elteo

n, M

-II, i

s acti

ve an

d ha

s app

roxim

ately

one

tenth

and

one f

ifth

the b

inding

affin

ity o

f the

par

ent m

olecu

le fo

r the

hum

an

MT 1

and

MT 2

rece

ptor

s, re

spec

tively

, and

is 1

7 – 2

5-fo

ld les

s pot

ent t

han

ram

elteo

n in

in vit

ro

func

tiona

l ass

ays.

Alth

ough

the p

oten

cy o

f M-II

at M

T 1

and

MT 2

rece

ptor

s is l

ower

than

the p

aren

t dru

g, M

-II ci

rcula

tes at

high

er

conc

entra

tions

than

the p

aren

t pro

ducin

g 20

– 100-

fold

grea

ter m

ean

syste

mic

expo

sure

whe

n co

mpa

red

to ra

melt

eon.

M-II

has

wea

k affi

nity f

or th

e ser

oton

in

5-HT

2Bre

cept

or, b

ut n

o ap

prec

iable

affini

ty fo

r oth

er re

cept

ors o

r enz

ymes

.

Sim

ilar t

o ra

melt

eon,

M-II

doe

s not

inter

fere w

ith th

e acti

vity o

f a n

umbe

r of

endo

geno

us en

zym

es.

All o

ther

know

n m

etabo

lites o

f ram

elteo

n ar

e ina

ctive

.

Phar

mac

okin

etics

The p

harm

acok

inetic

pro

file o

f ROZ

EREM

has

bee

n ev

aluate

d in

healt

hy su

bjects

as w

ell as

in su

bjects

with

hep

atic o

r ren

al im

pairm

ent.

Whe

n ad

mini

stere

d or

ally

to h

uman

s in

dose

s ran

ging

from

4 to

64m

g, ra

melt

eon

unde

rgoe

s rap

id, h

igh

first-

pass

meta

bolis

m, a

nd ex

hibits

linea

r pha

rmac

okine

tics.

Max

imal

seru

m

conc

entra

tion

(C max

) and

area

und

er th

e con

cent

ratio

n-tim

e cur

ve (A

UC) d

ata

show

subs

tantia

l inter

subje

ct va

riabil

ity, c

onsis

tent w

ith th

e high

first-

pass

effec

t;

the c

oeffic

ient o

f var

iation

for t

hese

value

s is a

ppro

ximate

ly 10

0%. S

ever

al

meta

bolite

s hav

e bee

n ide

ntifie

d in

hum

an se

rum

and

urine

.

Abso

rptio

n

Ram

elteo

n is

abso

rbed

rapid

ly, w

ith m

edian

pea

k con

cent

ratio

ns o

ccur

ring

at

appr

oxim

ately

0.75

hou

r (ra

nge,

0.5

to 1

.5 h

ours

) afte

r fas

ted o

ral a

dmini

s-

tratio

n. A

lthou

gh th

e tot

al ab

sorp

tion

of ra

melt

eon

is at

least

84%

, the

abso

lute

oral

bioav

ailab

ility i

s only

1.8%

due

to ex

tensiv

e firs

t-pas

s meta

bolis

m.

Distr

ibutio

n

In vi

tro

prot

ein b

inding

of r

amelt

eon

is ap

prox

imate

ly 82

% in

hum

an se

rum

,

indep

ende

nt o

f con

cent

ratio

n. B

inding

to al

bum

in ac

coun

ts fo

r mos

t of t

hat

bindin

g, si

nce 7

0% o

f the

dru

g is

boun

d in

hum

an se

rum

albu

min.

Ram

elteo

n

is no

t dist

ribut

ed se

lectiv

ely to

red

blood

cells

.

Ram

elteo

n ha

s a m

ean

volum

e of d

istrib

ution

after

intra

veno

us ad

mini

strati

on

of 7

3.6

L, su

gges

ting

subs

tantia

l tiss

ue d

istrib

ution

.

Meta

bolism

Meta

bolis

m of

ram

elteo

n con

sists

prim

arily

of ox

idatio

n to h

ydro

xyl a

nd ca

rbon

yl

deriv

ative

s, wi

th se

cond

ary m

etabo

lism

pro

ducin

g glu

curo

nide c

onjug

ates.

CYP1

A2 is

the m

ajor i

sozy

me i

nvolv

ed in

the h

epati

c meta

bolis

m o

f ram

elteo

n;

the C

YP2C

subf

amily

and

CYP3

A4 is

ozym

es ar

e also

invo

lved

to a

mino

r deg

ree.

The r

ank o

rder

of t

he p

rincip

al m

etabo

lites b

y pre

valen

ce in

hum

an se

rum

is

M-II

, M-IV

, M-I,

and

M-II

I. Th

ese m

etabo

lites a

re fo

rmed

rapid

ly an

d ex

hibit

a

mon

opha

sic d

eclin

e and

rapid

elim

inatio

n. Th

e ove

rall m

ean

syste

mic

expo

sure

of M

-II is

appr

oxim

ately

20- t

o 10

0-fo

ld hig

her t

han

pare

nt d

rug.

Elimina

tion

Follo

wing

oral

adm

inistr

ation

of ra

diolab

eled r

amelt

eon,

84%

of to

tal ra

dioac

tivity

was e

xcre

ted in

urin

e and

appr

oxim

ately

4% in

fece

s, re

sultin

g in

a mea

n re

cov-

ery o

f 88%

. Les

s tha

n 0.1

% o

f the

dos

e was

excr

eted

in ur

ine an

d fec

es as

the

pare

nt co

mpo

und.

Elim

inatio

n wa

s ess

entia

lly co

mple

te by

96

hour

s pos

t-dos

e.

Repe

ated

once

dail

y dos

ing w

ith R

OZER

EM d

oes n

ot re

sult

in sig

nifica

nt

accu

mula

tion

owing

to th

e sho

rt eli

mina

tion

half-

life o

f ram

elteo

n (o

n av

erag

e,

appr

oxim

ately

1-2.

6 ho

urs)

.

The h

alf-li

fe of

M-II

is 2

to 5

hou

rs an

d ind

epen

dent

of d

ose.

Seru

m co

ncen

-

tratio

ns o

f the

par

ent d

rug

and

its m

etabo

lites i

n hu

man

s are

at o

r belo

w th

e

lower

limits

of q

uant

itatio

n wi

thin

24 h

ours

.

Effec

t of F

ood

Whe

n ad

mini

stere

d wi

th a

high-

fat m

eal, t

he A

UC0-

inffo

r a si

ngle

16m

g do

se o

f

ROZE

REM

was

31%

high

er an

d the

C max

was 2

2% lo

wer t

han w

hen g

iven i

n a

fasted

state

. Med

ian T m

axwa

s dela

yed

by ap

prox

imate

ly 45

minu

tes w

hen

ROZE

REM

was

adm

iniste

red w

ith fo

od. E

ffects

of fo

od on

the A

UC va

lues f

or M

-II

were

simila

r. It is

there

fore r

ecom

men

ded t

hat R

OZER

EM no

t be t

aken

with

or

imm

ediat

ely af

ter a

high-

fat m

eal (

see D

OSAG

E AND

ADM

INIS

TRAT

ION)

.

Special Pop

ulatio

ns

Age:

In a

grou

p of

24

elder

ly su

bjects

aged

63

to 7

9 ye

ars a

dmini

stere

d a s

ingle

ROZE

REM

16m

g do

se, t

he m

ean

C max

and

AUC 0-

infva

lues w

ere 1

1.6ng

/mL

(SD,

13.8)

and

18.7

ng·hr

/mL

(SD,

19.4

), re

spec

tively

. The

elim

inatio

n ha

lf-life

was

2.6 h

ours

(SD,

1.1)

. Com

pare

d wi

th yo

unge

r adu

lts, t

he to

tal ex

posu

re (A

UC0-

inf)

and

C max

of ra

melt

eon

were

97%

and

86%

high

er, re

spec

tively

, in

elder

ly

subje

cts. T

he A

UC0-

infan

d C m

axof

M-II

wer

e inc

reas

ed b

y 30%

and

13%

,

resp

ectiv

ely, i

n eld

erly

subje

cts.

Gend

er: T

here

are n

o cli

nicall

y mea

ningf

ul ge

nder-

relat

ed d

iffer

ence

s in

the

phar

mac

okine

tics o

f ROZ

EREM

or i

ts m

etabo

lites.

Hepa

tic Im

pairm

ent:

Expo

sure

to R

OZER

EM w

as in

crea

sed

almos

t 4-fo

ld in

subje

cts w

ith m

ild h

epati

c im

pairm

ent a

fter 7

day

s of d

osing

with

16 m

g/da

y;

expo

sure

was

furth

er in

crea

sed

(mor

e tha

n 10

-fold)

in su

bjects

with

mod

erate

hepa

tic im

pairm

ent.

Expo

sure

to M

-II w

as o

nly m

argin

ally i

ncre

ased

in m

ildly

and

mod

erate

ly im

paire

d su

bjects

relat

ive to

hea

lthy m

atche

d co

ntro

ls. T

he

phar

mac

okine

tics o

f ROZ

EREM

hav

e not

bee

n ev

aluate

d in

subje

cts w

ith

seve

re h

epati

c im

pairm

ent (

Child

-Pug

h Cl

ass C

). RO

ZERE

M sh

ould

be u

sed

with

caut

ion in

pati

ents

with

mod

erate

hep

atic i

mpa

irmen

t (se

e WAR

NING

S).

Rena

l Impa

irmen

t: The

pha

rmac

okine

tic ch

arac

terist

ics o

f ROZ

EREM

wer

e stu

d-

ied af

ter ad

mini

sterin

g a 1

6 mg

dose

to su

bjects

with

mild

, mod

erate

, or s

ever

e

rena

l impa

irmen

t bas

ed o

n pr

e-do

se cr

eatin

ine cl

eara

nce (

53 to

95,

35 to

49,

or

15 to

30m

L/m

in/1.7

3 m

2 , res

pecti

vely)

, and

in su

bjects

who

requ

ired

chro

nic

hem

odial

ysis.

Wide

inter

subje

ct va

riabil

ity w

as se

en in

ROZ

EREM

expo

sure

para

mete

rs. H

owev

er, n

o eff

ects

on C m

axor

AUC

0-t

of p

aren

t dru

g or

M-II

wer

e

seen

in an

y of t

he tr

eatm

ent g

roup

s; th

e inc

idenc

e of a

dver

se ev

ents

was s

imila

r

acro

ss g

roup

s. Th

ese r

esult

s are

cons

isten

t with

the n

eglig

ible r

enal

clear

ance

of ra

melt

eon,

whic

h is

princ

ipally

elim

inated

via h

epati

c meta

bolis

m. N

o

adjus

tmen

t of R

OZER

EM d

osag

e is r

equir

ed in

pati

ents

with

rena

l impa

irmen

t,

includ

ing p

atien

ts wi

th se

vere

rena

l impa

irmen

t (cr

eatin

ine cl

eara

nce o

f

≤30

mL/

min/

1.73

m2 ) a

nd p

atien

ts wh

o re

quire

chro

nic h

emod

ialys

is.

Chronic

Obstru

ctive Pulm

onary

Dise

ase:

The e

ffects

of R

OZER

EM w

ere ev

aluate

d

after

adm

iniste

ring

a 16m

g do

se o

r plac

ebo

in a c

ross

over

des

ign to

subje

cts

with

mild

to m

oder

ate ch

ronic

obs

tructi

ve p

ulmon

ary d

iseas

e. Tr

eatm

ent w

ith

ROZE

REM

16 m

g fo

r one

nigh

t sho

wed

no d

iffer

ence

com

pare

d wi

th p

laceb

o

on m

ean

arter

ial o

xyge

n sa

tura

tion

durin

g sle

ep fo

r the

entir

e nigh

t, fo

r eac

h

stage

of s

leep,

or f

or ea

ch h

our o

f slee

p, an

d no

sign

ifican

t diff

eren

ce in

the

Apne

a/Hyp

opne

a Ind

ex. W

hile R

OZER

EM d

id no

t sho

w a r

espir

atory

dep

ress

ant

effec

t in

this

study

of p

atien

ts wi

th ch

ronic

obs

tructi

ve p

ulmon

ary d

iseas

e,

the e

ffect

of R

OZER

EM in

pati

ents

with

seve

re C

OPD

(e.g.

, tho

se w

ith el

evate

d

pCO 2

levels

or t

hose

nee

ding

noctu

rnal

oxyg

en th

erap

y) h

as n

ot b

een

studie

d.

Sleep

Apn

ea: T

he ef

fects

of R

OZER

EM w

ere e

valua

ted af

ter ad

mini

sterin

g a

16m

g do

se o

r plac

ebo

in a c

ross

over

des

ign to

subje

cts w

ith m

ild to

mod

erate

obstr

uctiv

e slee

p ap

nea.

Treatm

ent w

ith R

OZER

EM 1

6mg

for o

ne n

ight s

howe

d

no d

iffere

nce c

ompa

red

with

plac

ebo

on th

e Apn

ea/H

ypop

nea I

ndex

(the

prim

ary

outco

me v

ariab

le), a

pnea

inde

x, hy

popn

ea in

dex,

cent

ral a

pnea

inde

x, m

ixed

apne

a ind

ex, a

nd o

bstru

ctive

apne

a ind

ex. M

ean

SaO 2

durin

g th

e REM

stag

e of

sleep

was

stati

stica

lly si

gnific

antly

high

er fo

r ROZ

EREM

than

for p

laceb

o. No

dif-

feren

ces f

rom

plac

ebo

were

dete

cted

in all

oth

er se

cond

ary o

utco

me v

ariab

les.

Thes

e res

ults i

ndica

te th

at RO

ZERE

M d

oes n

ot ex

acer

bate

mild

to m

oder

ate

obstr

uctiv

e slee

p ap

nea.

ROZE

REM

has

not

bee

n stu

died

in su

bjects

with

seve

re

obstr

uctiv

e slee

p ap

nea;

use o

f ROZ

EREM

is n

ot re

com

men

ded

in su

ch p

atien

ts.

Resu

lts o

f dru

g-dr

ug in

terac

tion

trials

are d

iscus

sed

unde

r PRE

CAUT

IONS

.

CLIN

ICAL

TRI

ALS

Cont

rolle

d Tr

ials

Supp

ortin

g Ef

ficac

y

Chronic

Inso

mnia

ROZE

REM

was

stud

ied in

two

rand

omize

d, d

ouble

-blin

d tri

als in

subje

cts w

ith

chro

nic in

som

nia em

ployin

g po

lysom

nogr

aphy

(PSG

).

One s

tudy

enro

lled

youn

ger a

dults

(age

d 18

to 6

4 ye

ars,

inclus

ive) w

ith ch

ronic

insom

nia an

d em

ploye

d a p

arall

el de

sign

in wh

ich th

e sub

jects

rece

ived

a sing

le,

night

ly do

se o

f ROZ

EREM

8m

g or

16m

g or

matc

hing

place

bo fo

r 35

days

. PSG

was p

erfo

rmed

on

the f

irst t

wo n

ights

in ea

ch o

f Wee

ks 1

, 3, a

nd 5

of t

reatm

ent.

Both

dos

es o

f ROZ

EREM

redu

ced

the a

vera

ge la

tency

to p

ersis

tent s

leep

at ea

ch

of th

e tim

e poin

ts wh

en co

mpa

red

to p

laceb

o.

The s

econ

d stu

dy em

ployin

g PS

G wa

s a th

ree-

perio

d cr

osso

ver t

rial p

erfo

rmed

in su

bjects

aged

65

year

s and

olde

r with

a his

tory

of c

hron

ic ins

omnia

. Sub

jects

rece

ived

ROZE

REM

4m

g or

8m

g or

plac

ebo

and

unde

rwen

t PSG

asse

ssm

ent in

a slee

p lab

orato

ry fo

r two

cons

ecut

ive n

ights

in ea

ch o

f the

thre

e stu

dy p

eriod

s.

Both

dose

s of R

OZER

EM re

duce

d late

ncy t

o pers

isten

t slee

p com

pared

to pl

aceb

o.

A ra

ndom

ized,

doub

le-bli

nd, p

arall

el gr

oup

study

was

cond

ucted

in o

utpa

tient

s

aged

65

year

s and

olde

r with

chro

nic in

som

nia an

d em

ploye

d su

bjecti

ve

mea

sure

s of e

ffica

cy (s

leep

diarie

s). S

ubjec

ts re

ceive

d RO

ZERE

M 4

mg

or 8

mg

or p

laceb

o fo

r 35

night

s. Bo

th d

oses

of R

OZER

EM re

duce

d pa

tient

-repo

rted

sleep

laten

cy co

mpa

red

to p

laceb

o. A

sim

ilarly

des

igned

stud

y per

form

ed in

youn

ger a

dults

(age

d 18

-64

year

s) u

sing

8 mg

and

16m

g of

ram

elteo

n did

not r

eplic

ate th

is fin

ding

of re

duce

d pa

tient

-repo

rted

sleep

laten

cy co

mpa

red

to p

laceb

o.

Tran

sient In

somnia

In a

rand

omize

d, d

ouble

-blin

d, p

arall

el-gr

oup

trial

using

a fir

st-nig

ht-e

ffect

mod

el, h

ealth

y adu

lts re

ceive

d pla

cebo

or R

OZER

EM 8

mg

or 1

6 mg

befo

re

spen

ding

one n

ight i

n a s

leep

labor

atory

and

being

evalu

ated

with

PSG

. The

8mg

dose

dem

onstr

ated

a dec

reas

e in

mea

n lat

ency

to p

ersis

tent s

leep

as

com

pare

d to

plac

ebo.

Stud

ies P

ertin

ent t

o Sa

fety

Conc

erns

for S

leep

-Pro

mot

ing

Agen

ts

Resu

lts from

Hum

an Lab

orato

ry Abu

se Liab

ility S

tudie

s

A hu

man

labo

rato

ry ab

use p

oten

tial s

tudy

was

per

form

ed in

14

subje

cts w

ith a

histo

ry o

f sed

ative

/hyp

notic

or a

nxiol

ytic d

rug

abus

e. Su

bjects

rece

ived

single

oral

dose

s of R

OZER

EM (1

6, 8

0, o

r 160

mg)

, tria

zolam

(0.2

5, 0

.50,

or 0

.75

mg)

or p

laceb

o. A

ll sub

jects

rece

ived

each

of t

he 7

trea

tmen

ts se

para

ted b

y a

wash

-out

per

iod an

d un

derw

ent m

ultipl

e stan

dard

tests

of a

buse

pot

entia

l. No

differ

ence

s in

subje

ctive

resp

onse

s ind

icativ

e of a

buse

pot

entia

l wer

e fou

nd

betw

een

ROZE

REM

and

place

bo at

dos

es u

p to

20

times

the r

ecom

men

ded

ther

apeu

tic d

ose.

The p

ositiv

e con

trol d

rug,

triaz

olam

, con

sisten

tly sh

owed

a

dose

-resp

onse

effec

t on

thes

e sub

jectiv

e mea

sure

s, as

dem

onstr

ated

by th

e

differ

ence

s fro

m p

laceb

o in

peak

effec

t and

ove

rall 2

4-ho

ur ef

fect.

Resid

ual P

harm

acolo

gical

Effec

ts in

Inso

mnia

Trials

In o

rder

to ev

aluate

pot

entia

l nex

t-day

resid

ual e

ffects

, the

follo

wing

scale

s

were

use

d: a

Mem

ory R

ecall

Test,

a W

ord

List M

emor

y Tes

t, a V

isual

Analo

g

Moo

d an

d Fe

eling

Sca

le, th

e Digi

t-Sym

bol S

ubsti

tutio

n Te

st, an

d a p

ost-s

leep

ques

tionn

aire t

o as

sess

aler

tnes

s and

abilit

y to

conc

entra

te. T

here

was

no

evi-

denc

e of n

ext-d

ay re

sidua

l effe

ct se

en af

ter 2

nigh

ts of

ram

elteo

n us

e dur

ing

the c

ross

over

stud

ies.

In a

35-n

ight,

doub

le-bli

nd, p

laceb

o-co

ntro

lled,

par

allel-

grou

p stu

dy in

adult

s

with

chro

nic in

som

nia, m

easu

res o

f res

idual

effec

ts we

re p

erfo

rmed

at th

ree

time p

oints.

Ove

rall,

the m

agnit

udes

of a

ny o

bser

ved

differ

ence

s wer

e sm

all.

At W

eek 1

, pati

ents

who

rece

ived

8 mg

of R

OZER

EM h

ad a

mea

n VA

S sc

ore

(46 m

m o

n a 1

00m

m sc

ale) i

ndica

ting

mor

e fati

gue i

n co

mpa

rison

to p

atien

ts

who

rece

ived

place

bo (4

2 mm

). At

Wee

k 3, p

atien

ts wh

o re

ceive

d 8 m

g of

ROZE

REM

had

a low

er m

ean

scor

e for

imm

ediat

e rec

all (7

.5 o

ut o

f 16

word

s)

com

pare

d to

pati

ents

who

rece

ived

place

bo (8

.2 w

ords

); an

d th

e pati

ents

treate

d wi

th R

OZER

EM h

ad a

mea

n VA

S sc

ore i

ndica

ting

mor

e slug

gishn

ess

(27 m

m o

n a 1

00m

m V

AS) i

n co

mpa

rison

to th

e plac

ebo-

treate

d pa

tient

s

(22 m

m).

Neith

er R

OZER

EM d

ose h

ad n

ext-m

ornin

g re

sidua

l effe

cts th

at we

re

differ

ent f

rom

plac

ebo

at W

eek 5

.

Rebo

und Inso

mnia

/With

draw

al

Poten

tial r

ebou

nd in

som

nia an

d wi

thdr

awal

effec

ts we

re as

sess

ed in

thre

e lon

g-

term

inso

mnia

stud

ies in

whic

h su

bjects

rece

ived

ROZE

REM

for 3

5 da

ys. T

hese

studie

s inc

luded

a to

tal o

f 208

2 su

bjects

, of w

hom

829

wer

e elde

rly.

Tyrer B

enzodia

zepin

e With

draw

al Sy

mptom

Que

stion

naire

(BWSQ

):

The

BWSQ

is a

self-

repo

rt qu

estio

nnair

e tha

t soli

cits s

pecif

ic inf

orm

ation

on

20

sym

ptom

s com

mon

ly ex

perie

nced

dur

ing w

ithdr

awal

from

ben

zodia

zepin

e

rece

ptor

agon

ists.

In tw

o of

the t

hree

35-

day i

nsom

nia st

udies

, the

que

stion

naire

was a

dmini

stere

d on

e wee

k afte

r com

pletio

n of

trea

tmen

t; in

the t

hird

study

,

the q

uesti

onna

ire w

as ad

mini

stere

d on

Day

s 1 an

d 2

after

com

pletio

n.

In al

l thr

ee st

udies

, sub

jects

rece

iving

ROZ

EREM

4m

g, 8

mg,

or 1

6mg

daily

repo

rted

BWSQ

scor

es si

mila

r to

thos

e of s

ubjec

ts re

ceivi

ng p

laceb

o.

Rebo

und I

nsom

nia: R

ebou

nd in

som

nia w

as as

sess

ed in

thre

e of t

he lo

ng-te

rm

studie

s by c

ontin

uing

to m

easu

re sl

eep

laten

cy af

ter ab

rupt

trea

tmen

t disc

ontin

-

uatio

n. On

e of t

hese

stud

ies em

ploye

d PS

G in

youn

ger a

dult s

ubjec

ts re

ceivi

ng

ROZE

REM

8m

g or

16m

g; th

e oth

er tw

o stu

dies e

mplo

yed

subje

ctive

mea

sure

s

of sl

eep-

onse

t inso

mnia

in el

derly

subje

cts re

ceivi

ng R

OZER

EM 4

mg

or 8

mg,

and

in yo

unge

r adu

lt sub

jects

rece

iving

ROZ

EREM

8m

g or

16m

g. In

each

of

thes

e stu

dies,

ther

e was

no

evide

nce t

hat R

OZER

EM ca

used

rebo

und

insom

nia

at an

y tim

e dur

ing th

e pos

t-tre

atmen

t per

iod at

any o

f the

thre

e dos

es.

Spec

ial S

tudi

es to

Eva

luat

e Ef

fects

on

Endo

crin

e Fu

nctio

n

Two c

ontro

lled s

tudies

evalu

ated t

he ef

fects

of RO

ZERE

M on

endo

crine

func

tion.

Inth

e first

trial,

ROZE

REM

16m

g once

daily

orpla

cebo

was a

dmini

stere

d to99

healt

hyvo

luntee

r sub

jects

for 4

week

s.Th

isstu

dy ev

aluate

d th

e thy

roid

axis,

adre

nal a

xis an

d re

prod

uctiv

e axis

. No

clinic

ally s

ignific

ant e

ndoc

rinop

athies

were

dem

onstr

ated

in th

is stu

dy. H

owev

er, th

e stu

dy w

as lim

ited

in its

abilit

y

to d

etect

such

abno

rmali

ties d

ue to

its l

imite

d du

ratio

n.

In th

e sec

ond

trial,

ROZ

EREM

16 m

g on

ce d

aily o

r plac

ebo

was a

dmini

stere

d

to 1

22 su

bjects

with

chro

nic in

som

nia fo

r 6 m

onth

s. Th

is stu

dy ev

aluate

d th

e

thyr

oid ax

is, ad

rena

l axis

and

repr

oduc

tive a

xis. T

here

wer

e no

signif

icant

abno

rmali

ties s

een

in eit

her t

he th

yroid

or t

he ad

rena

l axe

s. Ab

norm

alitie

s

were

, how

ever,

not

ed w

ithin

the r

epro

ducti

ve ax

is. O

vera

ll, th

e mea

n se

rum

prola

ctin

level

chan

ge fr

om b

aseli

ne w

as 4

.9 µ

g/L

(34%

incr

ease

) for

wom

en

in th

e ROZ

EREM

gro

up co

mpa

red

with

-0.6

µg/

L (4

% d

ecre

ase)

for w

omen

in

the p

laceb

o gr

oup

(p=0

.003

). No

diff

eren

ces b

etwee

n ac

tive-

and

place

bo-

treate

d gr

oups

occ

urre

d am

ong

men

. Thir

ty-tw

o pe

rcen

t of a

ll pati

ents

who

were

trea

ted w

ith ra

melt

eon

in th

is stu

dy (w

omen

and

men

) had

pro

lactin

leve

ls

that

incre

ased

from

nor

mal

base

line l

evels

com

pare

d to

19%

of p

atien

ts wh

o

were

trea

ted w

ith p

laceb

o. S

ubjec

t-rep

orted

men

strua

l patt

erns

wer

e sim

ilar

betw

een

the t

wo tr

eatm

ent g

roup

s.

In a

12-m

onth

, ope

n-lab

el stu

dy in

adult

and

elder

ly pa

tient

s, th

ere w

ere t

wo

patie

nts w

ho w

ere n

oted

to h

ave a

bnor

mal

mor

ning

corti

sol le

vels,

and

subs

e-

quen

t abn

orm

al AC

TH st

imula

tion

tests.

A 2

9-ye

ar-old

fem

ale p

atien

t was

also

diagn

osed

with

a pr

olacti

nom

a. Th

e rela

tions

hip o

f the

se ev

ents

to R

OZER

EM

ther

apy i

s not

clea

r.

INDI

CATI

ONS

AND

USAG

E

ROZE

REM

is in

dicate

d fo

r the

trea

tmen

t of i

nsom

nia ch

arac

terize

d by

diff

iculty

with

slee

p on

set.

CONT

RAIN

DICA

TION

S

ROZE

REM

is co

ntra

indica

ted in

pati

ents

with

a hy

pers

ensit

ivity

to ra

melt

eon

or an

y com

pone

nts o

f the

ROZ

EREM

form

ulatio

n.

WAR

NING

SSi

nce s

leep

distu

rban

ces m

ay b

e the

pre

sent

ing m

anife

statio

n of

a ph

ysica

l

and/

or p

sych

iatric

diso

rder,

sym

ptom

atic t

reatm

ent o

f ins

omnia

shou

ld be

initia

tedon

ly aft

er a

care

ful e

valua

tion

of th

e pati

ent.

The f

ailur

e of i

nsom

nia

to re

mit

after

a re

ason

able

perio

d of

trea

tmen

t may

indic

ate th

e pre

senc

e of a

prim

ary p

sych

iatric

and/

or m

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4

Two sources help support the idea that creativity may be enhanced by constraint. In Creativity From Constraints: the Psychology of Breakthrough, Patricia Stokes presents constraint as a theoretical group of boundaries that are consciously used by all designers. Stokes proposes that all f ields share common constraints: “Domain, Cognitive, Variability and Talent.”10 Stokes analyzes how masters of art history, literature, f ine art, architecture, fashion, etc., use constraint sets to solve design problems. This thesis borrows Stokes’ constraint structure in order to clarify the types of constraint facing the different departments within a DTC advertising agency.

György Doczi’s The Power of Limits; Proportional Harmonies in Nature, Art & Architecture provides concrete evidence that nature conspires to instill order. Doczi analyzes everything, including music, bones, plants, architecture, literature, and religion. His intention is to prove that “…[natural] proportions are shared limitations that create harmonious relationships out of differences. Thus they teach us that limitations are not just restrictive, they are also creative.”11 Doczi builds his research on the work of history’s greatest mathematical, literary and social-science giants. This thesis incorporates Doczi’s theory that any object or

concept can be measured, and will most likely contain one of several recurrent patterns that are innate in all that exists. Fibonacci sequences, the Golden Section (1:1.618) and the “rule of thirds” will all make appearances throughout. These boundaries or rules can be applied as templates to aid in making compositions work better. They can also be used to measure work that seems ‘off ’, or is somehow unpleasant to look at. Usually the problem lies in the composition violating one or all of these systems. In Figures 1.1–1.2 combinations of grid systems have been applied to demonstrate the use of grids (intentional or not). In the best examples of the DTC design, the compositions f it almost exactly in one grid system or another.

Creativity and Constraint

“The power of the Golden Section to create harmony arises from its unique capacity to unite the different parts of a whole so that each preserves its own identity, and yet blends into the greater pattern of a single whole. The golden section’s ratio is an irrational, infinite number which can only be approximated, yet such approximations are possible even within the limits of small whole numbers.”

—György Doczi

5

Figure 1.2 Lybrel ad paired with Fibonacci spiral, rule of thirds grid

Figure 1.1 Fibonacci Spiral and golden section

6

Rules create an even playing field for drug companies, a boundary that all must acknowledge. The rules are, above all, fair and reasonable. The rules are also a life-saver thrown to designers awash in choices. The regulations of DTC stem from a portion of the United States constitution that protects commercial speech.

On the most basic level, an ad promoting a medication must be truthful, the product should cause no harm and there must be ‘fair balance’ prominently displayed on the ad. Fair balance is the risk information that describes the kinds of side effects and possible adverse effects that can come from taking the drug. Some drugs are required to have a ‘black box warning’ if there are serious side effects. These requirements will be explained later in this thesis.

Sometimes a project begins with what Stokes calls “constraints for conformity” which specify the use of templates or the use of a proven idea; or, to put it less kindly, regurgitation. When this unfortunate reality rears its head, there is very little a design team can do but comply.

When real change and creativity is needed, Stokes has identified a “Creativity Problem.”12 The creativity problem is constraint, broken down into two separate parts: strategic and structural.

The strategic effort is the choosing of “paired constraints” or the juxtaposition of opposites. Constraints become the skeleton on which a problem builds; they are also responsible for the tension that provides visual interest. Stokes identifies “Constraints for Creativity” as specific substitutions. It is not just enough to swap out old for new. The concept, when applied to a DTC design problem, could potentially help leap the hurdle between what is allowed and what is possible.

Figures 1.5–1.7 represent classic design/copy solutions. Figure 1.5 shows Anacin, a parity product. A parity product is one that has many competitors with similar features. Stokes identifies the ad as a classic Rosser Reeves solution. He often created ads presenting graphics and copy concepts in sets of threes. This solution speaks to what Stokes terms a “cognitive constraint”, or consumers inability . Stokes offers a theory that most consumers can only recall from 3 and 7 items about an ad. Figure 1.6 depicts an ad considered radical at the time for promoting an activity associated with loose morals.

Dying one’s hair at the time the ad was created was an activity that was viewed so negatively that coloring one’s hair was kept secret. Stokes identifies Shirley Polykoff’s challenge with promoting hair coloring as a “product constraint”. Polykoff was a copywriter whose contributions to the field of advertising came in the form of outstanding copy for beauty products. Polykoff’s goal was to change people’s perceptions about a product that had negative social connotations. By linking an image of motherhood with the product and introducing the notion that “good girls” could color their hair, Polykoff normalized what was then a subversive activity. In Figure 1.7, we see one of the most successful re-brands of all time. Marlboro cigarettes went from being a ladies brand to a global symbol for masculinity by giving the product a distinct personality.

These examples set the stage for exploration of the challenges faced by today’s DTC designers. DTC designers often face the problem of having to differentiate a product that swims in a sea of other similar products. The wide range of erectile dysfunction medication would be an example of today’s parity products carrying a certain taboo. DTC marketing has been continuously challenged by groups that believe the products should not be marketed to consumers.

1.2 What is the ‘Creativity Problem’?

7

Figure 1.5 1960’s Rosser Reeves Anacin ad

Figure 1.6 1950’s Shirley Polykoff ad, “Does she... or doesn’t she?” Figure 1.7 1960’s Leo Burnett ad, “Marlboro Man”

8

1.3 How can you solve the creativity problem?

According to Stokes, it is the conscious choice of one set of values over another that will lead the way to a great idea. For example, in DTC advertising, there are many products that offer similar benefits and efficacy. Why would a doctor prescribe one antihypertensive over another when there is little to differentiate the actual products? How do you differentiate erectile dysfunction (ED) medications if they essentially all work the same way?

Stokes refers back in time to Rosser Reeves’ “Unique Selling Proposition”14 as a way to differentiate parity products. Stokes’ advice to someone faced with the challenge of promoting a parity product would be to identify the ‘emotional links’ and to create a ‘graphic promise’15 that differentiates the product from its competition. The paired constraint for a parity product would be identifying a key aspect of the product that separates it from other similar products, and matching that with a unique graphic. What makes this process interesting for DTC teams is that the list of what one can and can’t reveal or claim about a product is predetermined by law. So even if you have a fantastic way to represent your ‘big idea’ or ‘USP’, it might not be legal.

The following images are of three products that are essentially the same medication. Viagra has differentiated its brand by focusing attention on the actual pill. “The little blue pill” has become synonymous with Viagra. The current ‘Viva Viagra’ ads promote the product as less a medication and more a party drug. Cialis has one advantage over its competitors, one pill provides coverage for 24 to 36 hours. This has earned the product the nickname: “le weekender”. The only way Cialis can differentiate itself from other erectile dysfunction (ED) products is by stating that fact. Cialis ads focus on spontaneity and the emotional aspects that may be involved in promoting intimacy between a husband and wife. The paired constraint in Cialis ads is the message of ‘freedom from a timetable’ linked with images of mature married couples at leisure. Cialis’ approach would seem the most appealing and positive of the three. The weakest brand would be the Levitra series, which has not made nearly as much of a cultural or sales impact compared with the other two leading ED brands. Both Viagra’s and Levitra’s marketing fail to address the one aspect crucial to the achievement of product goals: the patients partners.

9

®

10

1.4 What is the difference between a constraint and predetermined mediocrity?

When starting any design project there is usually one document that will provide structure for the entire project. In architecture, the physical creation of a building begins with blueprints. In plastic surgery, lines are drawn on areas to be treated. In DTC design, guidance often comes in the form of the creative brief. The brief assumes agreement among creative professionals: you have to start somewhere.

If a brief is not specific enough, time is squandered chasing the wrong goal. If the parameters are too rigid or adhere to the constraints promoting conformity referred to previously, the project might be a technical success, but visually uninspiring. Maritess Gonzales, an Account Supervisor with Saatchi and Saatchi describes the brief as follows:

Agency and client partner in the creation of the brief and follow the contents for scope (duration and campaign elements). The brief is a form of constraint that when designed properly, allows creativity to build from it. But when followed rigidly without openness to the possibility of unforeseen associations, disaster and mediocrity strike.

The two images on the next page and on the following pages are designed for physicians encountering a range of illnesses in patients of all ages.

These ads are called ‘professional’ to differentiate them from ads directed towards consumers. The difference between DTC, professional and general advertising will be explained in later sections. Marketers tailor the ads to a ‘learned intermediary’, a person assumed to have an understanding of how and why these medicines should be prescribed. Less space is devoted to education compared to DTC ads.

In 1.2.2a, the use of an older female demonstrating fine motor skills is the easiest choice for many images in marketing Parkinson’s disease treatments. The image illustrates that the drug may reduce a symptom of Parkinson’s: shaking. The patch graphic on her left shoulder indicates the product in use. Not very interesting, but viewers get the point immediately, and forget it just as quickly.

Figure 1.2.2b represents metaphoric overkill. The origami bird emits musical notes, the musical bars morph into branches. Out of curiosity, a visit to the product website gave little clue to the link between the details of the illustration and the product. The texture in the patches exists in the Amitiza mechanism of action (MOA) video only as decoration. The origami bird speaks to the opposite of pattern, as birds’ flight is random, playful even. The ad is eye-catching, but there is no correlation between the image, copy and product.

“[The creative brief ] is the most important document in the whole process.... [It] spells out the assignment and sets expectations up that the creatives should follow. Before a piece is shown to the client, a good team would go through the brief and ask themselves, did we answer every single question or challenge proposed in the piece? And if we did not, then we should have a reason why. It is the foundation of all creative work, and if the TV spot, magazine ad, or web design did not meet the fundamental question posed on the brief, then it’s a failure.”18

11

Figure 1.2.2b Amitiza for constipationFigure 1.2.2a Neuropro for early-stage Parkinson’s

12

1.4 Constraint and predetermined mediocrity, continued

One common complaint heard from DTC advertising designers is that clients might ask for blockbuster fireworks, but can only accept the risk of a sparkler. Clients want to avoid being sanctioned for overstating efficacy or promoting a drug for uses other than its FDA-approved indication. Risk aversion is one of the many reasons some pharmaceutical clients cleave to the tried and true. But what seems to be a more common occurrence is that clients cling to imagery that has already proven to be profitable. However, by not being open to the change, opportunities for more effective messages can be overlooked. When a client is unwilling to make any changes to a brand that is meeting its sales goals, sometimes there is very little designers can do to change this course. Sometimes it is just a simple fact that a campaign was conceived with the intention of being plain and simple.

Stokes recognizes that sometimes constraints are specifically put in place to recreate past success: “Free to do anything, most of us do what’s worked best…. [This is] a behavior that increases in frequency because it has been successful. Successful solutions are reliable, not surprising; predictable, not novel; already accepted, not creative….Being completely free hinders [the] creativity problem.”20

The Chantix ad in Figure 1.2.3a is direct: the broken cigarette addresses the problem ‘see and say’ style. So, while the image is powerful, using the object of addiction skips over what might be the underlying cause of addiction, perhaps ignoring an opportunity for more subtle, engaging messages.

Of the four ads, the Vesicare ad, Figure 1.2.3b may be the most successful in matching the message to the image. The dry pants jumping for joy communicates the elation felt by patients free from symptoms of incontinence.

The bottom lineIf you ask 100 designers in the field of DTC why these ads were successful or unsuccessful, you’d get as many answers. A constant chorus gleaned from interviews has been that if the designers could recreate ads they had done in the past (without fear of fines, tight deadlines or medical/legal reviews), they would focus more energy on making typography lovely instead of merely communicative. It might be safe to say that sometimes the look and feel of DTC ads are driven by many factors other than FDA regulation.

“ Free to do anything, most of us do what’s worked best.... Successful solutions are reliable, not surprising; predictable, not novel; already accepted, not creative.” —Patricia Stokes

13

Figure 1.2.3a Chantix for smoking cessation Figure 1.2.3b Vesicare for incontinence

14

1.5 How does constraint impact creativity?

Fine artists impose limits on their projects more often than not. Serial projects, for example, often, contain a beginning, middle and an end. In most famous series throughout art history, none would have been completed without at least several constant elements being chosen before the project began. In the case of Hokusai’s “36 views of Mount Fuji”20 (Figures 1.3.1–1.3.4) the artist chose an edition number (36), a medium (wood block printing), a subject that would pool out into 36 unique iterations, and a constant size and color scheme.

Medium, type of paper, canvas size, pigment, subject matter, color and edition number function in the same way a creative brief does. By imposing order on process before the production of the work begins, a framework for judgment emerges and the artist is able to gauge wether she is meeting those goals.

Monet’s “Wheatstacks”21 series, Figures 1.3.5–1.3.8, published between 1890 and 1891 are an extreme example of paring down choice. Monet reduced his options, going even further than Hokusai and reaching a level bordering on abstract. This trend towards a conscious reduction of choices continued on through time, briefly hiccupping with the introduction of post-modernism and reaching extreme levels of limitation in modern artists. For the artists who did create serial works based on a list of conditions, the medium constraints themselves became a part of the artwork.

Figure 1.3.1 Print number 3, Dog Eye Pass In Kai Province Figure 1.3.2 Print number 6, Back View of Mount Fuji from Dream Mountain in Kai Province

Figure 1.3.4 Print number 31, Below Ryogoku Bridge in the Eastern Capital

Figure 1.3.3 Print number 21, Aoyama in the Eastern Capital

15

The bottom lineDesigners don’t often have a chance to define their boundaries in the way that fine artists do. It must also be acknowledged that the rules for promoting prescription drugs are in a different solar system than the self-imposed rules artists place on themselves, but there is a connection between the sets of choices that are made in any creative process. Even though in DTC advertising constraints are mandated by law and core campaign images are chosen via focus group, the most successful campaigns will tap into the same emotional current that fine artists will.

It is almost counter intuitive to imagine that a designer would long for boundaries. In DTC design, it can be said that visuals are driven by copy. The core message is usually developed in advance with the visuals evolving after, or in tandem. It is the limiting of possibilities that allows a project to begin. According to John Furness, a Product Manager with Bayer Healthcare Pharmaceuticals, “…it all starts with the PI (Prescribing Information).”22 Most designers would not want the task of winnowing through a drug’s prescribing information to find the kernel that would sprout into a campaign. Luckily, copywriters distill the message for the team. Within the narrow scope of the core message, there are an infinite number of possibilities to choose from, and finding just the right visual for the unique selling proposition can truly be like finding a needle in a haystack.

Figure 1.3.7 Stacks of Wheat (Sunset, Snow Effect)

Figure 1.3.5 Stack of Wheat (Snow Effect, Overcast Day) Figure 1.3.6 Stack of Wheat (Thaw, Sunset)

Figure 1.3.8 Stacks of Wheat (End of Day, Autumn)

16

1.6 How can identifying different constraint types aid creativity?

Pharmaceutical advertising can be defined as the communication of complicated science to doctors and the average consumer. Identifying different types of constraint will aid anyone involved in a creative project where there are many different variables and sources of incoming information.

A designer cannot pick up a pencil and begin to plot without stubbing her toe on gestalt theory. Like it or not, there is a natural order of things that every student of design must face at one point or another. One fantastic source for all things relating to ‘constraint’ is Rudolph Arnheim’s tome on the subject of design.

Arnheim lays out all of the elements that one will find in an advertisement: Balance, Shape, Form, Growth, Space, Light, Color, Movement, Dynamics, and Expression. Within these deceptively simple chapter headings lie the reasons why we prefer reading left to right, how compositions evolve from simple to complex and why we ‘just know’ when something is good.

In his essay, Entropy and Art; an Essay on Disorder and Order, Arnheim clarifies his thoughts on constraint: “Order is a necessary condition for anything the human mind is to understand. Arrangements such as the layout of a city or building, a set of tools, a display of merchandise, or a painting or piece of music are called orderly when an observer or listener can grasp their overall structure and the ramification of the structure in some detail.”24

Knowing how these concepts function in the field of design can rescue the designer from a tight spot when interpreting concepts into visuals. Sometimes a piece is ‘off ’ somehow and one just can’t put a finger on it. Understanding the reason behind the unnerving feeling can only be a positive thing. In Entropy, Arnheim combined a number of different theories about art and design in his attempt to reign in disorder.

Entropy is dedicated to reconciling a point in science stating that all things head towards disintegration and man’s need for order.

On the same theme of reconciling science and art, Arthur Miller in Insights of Genius, makes the case that creativity is ruled by boundaries, noting that, “…either consciously or unconsciously, many artists compose work along guidelines of gestalt psychology.”25 He references the works of Picasso: how the artist set up rules, exploited them, then discarded them in fits of passion. On the opposite end of the emotional scale, Klee and Mondrian—who chose more formal graphic shapes and linear composition to focus on—studied gestalt psychology, and those principles drove the constraints they chose in their work.26

Figure 1.5.2, Picasso’s Guernica, has a golden section grid applied. The golden section can be described as “A ratio …between the two dimensions of a plane figure or the two divisions of a line such that the smaller is to the larger as the larger is to the sum of the two, a ratio of roughly three to five.”27 In this composition, the canvas is divided in half, and several triangles live in the bisected planes.

“Paintings are but research and experiment. I never do a painting as a work of art. All of them are researches. I search constantly and there is a logical sequence in all this research. That is why I number them. It’s an experiment in time. I number and date them. Perhaps one day someone will be grateful.”—Pablo Picasso

17

Figure 1.5.2 Guernica, 1937. Pablo Picasso

18

1.7 Wilson Capellán

Finding the thread, or the holy grail of ideas, can happen in many ways. In some companies, Creative is driven by an ‘if/then’ style, conjuring up expected results from past successes or failures. Some groups will ‘brainstorm’ to work through the most obvious choices. Stokes’ methods of observing constraints tend to shy away from using creative energy in such an arbitrary way. Her prescription for creative health is daunting: “There are no six or seven easy steps…. There are only two and they’re both difficult. The first step is mastering the constraints that define the domain (its first choruses); the second is devising novel constraints that expand it.”16

What Stokes proposes tends to suggest that pre-knowledge of FDA regulation is requisite for the best creative solutions. Just as she feels an artist must understand the formal techniques of that artist’s chosen medium, so too must DTC designers know the rules first. Her advice to any artist would be to learn the fundamental lessons of your craft well. Once you know how to accomplish all that is physically possible, it’s time to do what has never been done before. Interviews and personal experience have tended to support the idea that knowledge of FDA regulation was a plus, with one notable dissenter, Wilson Capellán. Wilson is an art supervisor with DRAFTFCB. He has over 10 years of experience in healthcare advertising. His thoughts are contrary to the majority of people who weighed in on this issue.17

Interview excerpt; Wilson Capellán

The following exchange stemmed from the discussion of whether knowledge of FDA regulation enhanced creativity or hindered the creative process.

Merry Davis: You wouldn’t have been hired in the first place if you didn’t have extensive knowledge of pharmaceutical advertising. You’re familiar with all of the minutia, the details, what the FDA is looking for, what you’re going to get pulled over for in DDMAC (see glossary for definition) submission…you’re expected to know all the boundaries, and you’re expected to know what the parameters of the work are.

Wilson Capellán: The thing with health care is that for freelancers or for anybody who’s actually trying to get into health care, you actually think you have an advantage because you have experience. I think that’s part of the problem with creativity in health care. We have a tendency to hire people who have experience who self-limit because they think the FDA may not approve an idea, but it’s been proven that when you actually get a few loose guns out there, or guys that have no health care experience, what you’re doing is you’re broadening the creativity. Yes, there may be a lot of stuff that actually may not be FDA approved, but there also may be stuff that you would never thought of that might be approved by the FDA and would improve the creativity of the industry.

Merry Davis: Wilson, do you have any opinion on how creativity enhances or is enhanced or constrained by the dreaded FDA regulations?

Wilson Capellán: I think that problems are the only things that will lead us to solutions and if we actually didn’t have those, we would have absolutely nothing to overcome. The fact that the FDA establishes an even playing field for everybody—it’s a good thing, but I think that the more constraints they give us, the bigger the opportunity they give us to be more creative. You brought up jeans as an example earlier on.

A size 32/32, isn’t going to fit the same if you buy them from Gap or if you buy them from Abercrombie and Fitch or whomever. They are going to be different sizes because of their style. And in a way you have to thank the FDA for making the rules the same for everybody. At the end of the day, you don’t want to go buy a drug thinking it’s like jeans. Otherwise I’d buy a 32 and depending on where I buy them, they would be super big compared to actually where I should buy. So I thank the FDA, I curse them every day, but I do think that if we didn’t have a problem, we wouldn’t [look so hard] for a solution.

[Laughter]

“ So I thank the FDA, I curse them every day, but I do think that if we didn’t have a problem, we wouldn’t look so hard for a solution.”

19

20

1.8 Professor survey

In a survey conducted to determine attitudes of design professors at Pratt Institute towards DTC advertising and the impact of constraint on creativity, an overwhelming sentiment emerged. That sentiment tasted a lot like a cup of vitriol. Most professors would like to see the field of DTC advertising disappear at best, and at worst, be incarcerated. From some of the side notes written in addition to the survey responses, it also appeared that responders thought that the actual designers were party to some type of crime. The images of fictitious designers in a perp walk seemed to be the most appropriate illustration to sum up the feelings expressed in the survey responses.

2. Have you created a logo, an advertising campaign or designed a package for an over-the-counter or prescription medication?

57.1% have no experience with DTC design

14.2% have some kind of experience with DTC design

7.1% designed OTC promotional material

7.1% created logos and packaging

7.1% have created a Web site for a health care product

7.1% have been involved with professional/direct to physician campaigns

7.1% did not answer question

Madge ‘the Violator’ Valentine, 11 years, Graphic Designer

1. In your opinion, how is pharmaceutical or direct to consumer design different from other fields of advertising?

35.7% cited FDA/legal issues

28.5% had negative comments on appearance of DTC ads

28.5% described DTC as manipulative/dangerous

14.2% thought DTC advertising was not different from general advertising

14.2% thought the purpose of DTC was to educate consumers

7.1% thought DTC ads played to people’s emotions/about health concerns and promoted irrational fears

7.1% described the difference between general advertising and DTC advertising

7.1% did not answer question

Carmine ‘Drop-Shadow’ DiCarlo, 15 years to life, Art Director

21

Jesse ‘DDMAC’ McDonald, 12 years, Interactive Designer

4. If you could change the look of pharmaceutical ads, what would that change be?

28.5% wanted ads presented with more clarity and information, fewer gimmicky images

28.5% would ban DTC advertising

21.4% suggested avoiding small type

14.2% had a negative comment

14.2% thought more realistic patient types would be beneficial

7.1% were bored with the same old ads and wanted more variety

21.4% did not answer question

Kaya ‘P value’ Petrovski, 8 years, Creative Director

3. How do you think the FDA regulations affect creativity within DTC advertising?

28.5% thought regulation increases creativity

21.4% believed FDA regulations have no effect on creativity

14.2% agreed that FDA regulations have some effect on creativity

7.1% did not know what FDA regulations are

7.1% call for more regulation

7.1% had a negative comment

7.1% described regulations in terms of the look of a product

14.2% did not answer question

A 40% response rate (14 professors responded out of the 35 who were sent surveys) encouraged me to look at the responses as a skewed pulse-check of designers who are not familiar with DTC advertising. In follow-up conversations with both responders and non-responders, it became clear that there was plenty of confusion about what DTC advertising is, and what role designers play in the collaborative process. The fact that almost 30% of responders would ban DTC advertising caused me to ask the question: Why hasn’t DTC advertising been banned yet?

22

DTC overviewInterview excerpt: Fard Johnmar, M.A., Founder of Envision Solutions

Mr. Johnmar is a leader in the frontier of social media and its applications within pharmaceutical advertising. Here he discusses OTC and DTC advertising.

DTC (direct to consumer) and OTC (over the counter) ads are overseen by separate governmental bodies. OTC medication ads (along with ads for foods, medical devices, supplements and make-up) are regulated by the Federal Trade Commission (FTC). DTC ads are regulated by the Food and Drug Administration (FDA). The FDA also regulates the labeling on all medication, food and prescription medical devices. While there are very definite and different rules to guide each segment, both governing bodies adhere to ‘truth in advertising’ regulations that apply to all products. The following two interview excerpts expand on the different marketing segments. Please see the Glossary for descriptions of the agencies mentioned above.

Fard Johnmar: The OTC marketing regulations are much less stringent than the FDA regulations, and the major reason is that the FTC has control over that OTC advertising, but they still must adhere to truth in advertising regulations.... Because the internet has been around for over 10 years, the FDA has not put a lot of guidance out there for pharmaceutical companies looking to utilize this media, so what companies have done is that they have taken the regulations as they relate to print and television advertising and applied them to the Internet. If you have a web-site that is developed for Viagra, the FDA says that if you put information out there, that you must have the prescribing information or the [fair balance] available one click away or easily accessible. If you look at a Viagra ad in, say Time magazine, the opposite side has the label so that, clearly meeting the FDA’s requirement that consumers are informed of the side effects and the safety and efficacy profile of the medication. The way that companies have adopted that to the Internet is that they’ve put a prominently displayed link at the bottom of each page of the website so that people can click to the same information online, so you see how companies have applied the spirit of the FDA regulation to the Internet.

Fard Johnmar: So when you’re talking about marketing an over the counter product versus marketing a drug prescription product, the regulatory issues are completely different when you start talking about an over the counter product....The major differences in terms of creative is that you don’t have to get into all the nasty side effects that a drug has. All you have to show is the drug facts.... That’s what the folks at Alli have done. What you’re seeing is that you have the ability to much lighter—I shouldn’t say loosey goosey, but you have a lot more flexibility in terms of what you can talk about. If a drug is over the counter [you have to focus on its packaging]. That’s a big issue in terms of people to actually notice the drug, to get into what the promises are versus other over the counter drugs benefits that you see on the shelf. So in terms of the differences, the major difference is that it’s a much more flexible environment. You’re thinking about the packaging a lot more than you think about it for an Rx drug, because that doesn’t matter as much. You think about pharmacy strategies in terms of where the placement’s going to be... you don’t talk a lot about side effects because it’s assumed that the drug has manageable side effects or they’re very well known. So it’s just a very different context that you’re working in.

23

24

Interview excerpt continued: Fard Johnmar, M.A., Founder of Envision Solutions

In this segment of the interview Mr. Johnmar explains how some DTC advertising manages to get away with really interesting creative concepts and not get fined.

Merry Davis: Have you seen a campaign that struck you as being fantastically creative or effective, specifically a prescription medication?

Fard Johnmar: Unfortunately most of the ads I see for drugs pretty much blend into each other, because there’s not a lot of differentiation, I think. The one campaign that I can discuss a little bit because it is interesting and innovative—but I’m not sure it really met the marketing goals for this drug to driving prescriptions—and that’s the Rozerem ‘your dreams miss you’ campaign. A lot of people think that campaign has gotten a lot of awards because it’s been very creative in terms of its interpretation, and yet it has taken the brand personality of the drug and spoke to the outer layer of the brand personality versus the core. Because the major difference for Rozerem from a medical perspective is that it…

Merry Davis: Not addictive?

Fard Johnmar: Right. So it’s not addictive...you might have seen people talking about that. But instead, the marketers decided it should have weird, surreal images, signifying that the drug gives you the ability to dream.

Merry Davis: Very surreal images. The buzz surrounding these ads was huge. I just can’t get over how different these ads are from just about everything else though.

Fard Johnmar: Well, they targeted the functional attributes of the drug, but in terms of driving prescriptions, people will remember that campaign because it’s different, but they clearly haven’t asked their doctor to prescribe it. So I would say that campaign is certainly memorable and interesting, but at the same time, there are a lot of questions about its overall effectiveness.

Merry Davis: Right. They spent more money on the campaign, as of now, than they’re actually making.

Fard Johnmar: Yes and that’s not good.

Merry Davis: No, it really isn’t, but one of the things that I’ve read about that particular campaign is they said that they meant to do that and that’s an interesting stance for the company to take. One of the reasons they may not have gained as much market share as other sleep aids, I guess, could be that they willingly withheld their marketing for a year. I’m not 100% sure what they were waiting for, but…

Fard Johnmar: Well, YOU should know why! Pharma has voluntary regulations* designed to stave off congressional regulation and some companies—not all of them—agreed to postpone their marketing of the drugs, I think it’s six months after launching, that’s the reason why they decided to delay.

Merry Davis: Right. I’m glad you picked Rozerem’s campaign as an example, because it speaks directly to what I’m looking at in pharmaceutical advertising—a lot of the ads do look generic. They look a little bit the same. Why is it that Rozerem and the creative team that worked on the clinical and the DTC ads, why did they get away with this creativity? How come they were able to do this? Why don’t other companies make the same types of choices?

Fard Johnmar: The reason why they were able—but I shouldn’t say get away with it, because from a regulatory perspective, there is nothing about the commercial that is either (1) off label promotion, (2) does not have adequate fair balance for television commercial, or (3) doesn’t talk about the safety/efficacy profile of the drug. So from a regulatory perspective, they were able to hit all three things required for the campaign to exist. It’s not a reminder ad, because Pharma voluntary guidelines, say you can’t run it about a reminder ad anymore. A lot of companies are going to have to adhere to that. So when you’re talking about creative in the pharmaceutical company space, what happens with a lot of companies is because of the regulatory issues and the conservatism of companies, that’s why a lot of the ads seem to look the same; whereas the Rozerem folks, they decided to do something that’s a little bit different and provide something that wasn’t quite linked to the product.

DTC overview, continued

25

Rozerem Consumer website

26

2.2 What are the differences between DTC and general marketing?

‘General’ is a term used to describe all advertisement that is not for any health-related product. The similarity between general advertising and DTC advertising is that there are multiple choices of drugs and jeans that can be considered parity products or have very little to differentiate them by way of effectiveness. The drugs used to treat these kinds of ailments are sometimes referred to as ‘lifestyle’ drugs, which may take away the impact these conditions have on people that suffer from them. Going forward when the term lifestyle is used, it is only to differentiate drugs used to treat conditions that are not life threatening. Have you ever wondered how drugs for cancer, HIV and diabetes are promoted? Chances are, unless you subscribe to publications devoted to patient education about these conditions, you would never see them.

An obvious difference between general and DTC advertising can be seen in items such as fair balance, brief summaries, prescribing information, and black box warnings. The examples on the next page show what must accompany a DTC print ad. Since DTC advertising is in its infancy compared with other kinds of advertising, the rules are constantly expanding—to include new technology, new attitudes and expectations about medicine and above all, because people demand to be informed and knowledgeable about their health.

Brief summaryThis document appears only in DTC print ads. It is a pared down version of the PI (described below). The brief summary describes side effects, warnings, precautions, and contraindications.28

Prescribing information (PI)All newly approved drugs must design their prescribing information in a specific format. New or relaunching drugs must include a highlights and contents section. Prescribing information is also known as labeling, package insert, professional labeling, direction circular, or package circular. The revised content and format requirements apply only to the prescribing information of FDA-approved prescription drug and biological products. The requirements also do not change the content or format of FDA-approved patient information, including medication guides.29 Drugs that have been previously approved are exempt from this change.

Fair balanceFair balance is information that must be on any drug ad making a claim of efficacy. Risks and benefits must be presented with equal scope, depth, and detail, and that information relating to the product’s effectiveness must be fairly balanced by risk information.30 This information is usually derived from the PI.

Black box warningThis type of warning, with large type and an actual thick black rule around the information, must be present on all ads, prescribing information and brief summaries for drugs that have serious risks, or have proven to be responsible for causing serious adverse events in patients. Since 1979, over 400 drugs have received the dreaded black box warning and in 2001 the rules were redefined specifying what must be present in the warning and the look of the box,31 thus shaping the black box warning seen on the figures on the next page.

Image of jeans from Lucky Brand website

27

ADDERALL XR® CAPSULES

CII Rx O

nly

DESCRIPTION

ADDERALL XR® is

a once daily

extended-re

lease,

single-e

ntity am

phetamine

product. ADDERALL XR

® combines the n

eutral su

lfate s

alts of dext

roampheta

mine

and ampheta

mine, with th

e dext

ro isomer

of ampheta

mine sacc

harate

and d,l-

ampheta

mine asparta

te monohydrate

. The A

DDERALL XR® cap

sule contain

s two

types

of drug-contain

ing beads desi

gned to give a double-p

ulsed deliv

ery of

ampheta

mines, which

prolongs the r

elease

of ampheta

mine from ADDERALL XR

®

compared to the c

onventional A

DDERALL® (im

mediate-re

lease)

tablet

formulati

on.

EACH CAPSULE CONTAINS:5 mg 10 mg

15 mg20 mg 25 mg 30 mg

Dextroam

phetamine

1.25 mg 2.5 mg 3.75 mg5.0 mg 6.25 mg 7.5 mg

Sacchara

te

Amphetamine A

spartate

1.25 mg 2.5 mg 3.75 mg5.0 mg 6.25 mg 7.5 mg

Monohydrate

Dextroam

phetamine

1.25 mg 2.5 mg 3.75 mg5.0 mg 6.25 mg 7.5 mg

Sulfate U

SP

Amphetamine

1.25 mg 2.5 mg 3.75 mg5.0 mg 6.25 mg 7.5 mg

Sulfate U

SP

Total am

phetamine b

ase

equivalen

ce

3.1 mg 6.3 mg9.4 mg 12.5 mg 15.6 mg 18.8 mg

Inactive

Ingredien

ts and Colors:

The inactive

ingredien

ts in ADDERALL XR

®

capsules

include: g

elatin ca

psules, hydroxyp

ropyl meth

ylcellu

lose, meth

acrylic

acid

copolymer,

opadry beig

e, sugar

spheres, t

alc, an

d trieth

yl citra

te. Gela

tin capsules

contain ed

ible inks,

kosher g

elatin, an

d titanium dioxid

e. The 5

mg, 10 mg, and 15

mg capsules

also co

ntain FD

&C Blue #2. The 2

0 mg, 25 m

g, and 30 m

g capsules

also co

ntain red

iron oxid

e and ye

llow iron oxid

e.

CLINICAL PHARMACOLOGY

Pharmacodynamics

Amphetamines

are non-ca

techolam

ine sym

pathomimetic

amines

with CNS

stimulan

t activi

ty. The m

ode of th

erapeutic

action in Atten

tion Deficit H

yperactiv

ity

Disorder

(ADHD) is not kn

own. Ampheta

mines are

thought to

block the r

euptake

of norep

inephrine a

nd dopamine i

nto the p

resynaptic

neuron and in

crease

the

release

of these

monoam

ines into th

e extr

aneuronal space

.

Pharmacokin

etics

Pharmaco

kinetic

studies

of ADDERALL XR

® have been

conducte

d in healthy a

dult

and pediatric (

6-12 yrs) su

bjects,

and adoles

cent (1

3-17 yrs) an

d pediatric p

atients

with ADHD. Both ADDERALL®(im

mediate-re

lease)

tablets

and ADDERALL XR

® cap-

sules co

ntain d-am

phetamine a

nd l-ampheta

mine salts

in the ratio of 3:1. Fo

llowing

administratio

n of ADDERALL®(im

mediate-re

lease)

, the p

eak plas

ma concen

trations

occurre

d in about 3 hours f

or both d-am

phetamine a

nd l-ampheta

mine.

The time to

reach

maxi

mum plasma c

oncentra

tion (T max) fo

r ADDERALL XR

® is

about 7 hours, which

is about 4 hours l

onger compare

d to ADDERALL®(im

medi-

ate-re

lease)

. This is c

onsisten

t with th

e exte

nded-relea

se natu

re of th

e product.

Figure 1 Mean d-amphetamine and l-amphetamine plasm

a concentratio

ns

following administr

ation of

ADDERALL XR® 20 m

g (8 am) a

nd ADDERALL®

(immediate-re

lease) 10 m

g bid (8 am and 12 noon) in

the fe

d state.

A single d

ose of A

DDERALL XR® 20 m

g capsules

provided co

mparable p

lasma

concentra

tion profiles o

f both d-ampheta

mine and l-a

mphetamine to

ADDERALL®

(immediate

-relea

se) 10 m

g bid administe

red 4 hours

apart.

The mean

eliminatio

n half-life

for d-am

phetamine is

10 hours in ad

ults; 11 hours

in adoles

cents a

ged 13-17 years

and weig

hing less th

an or equal t

o 75 kg/165 lbs;

and 9 hours in ch

ildren ag

ed 6 to 12 ye

ars. F

or the l-

ampheta

mine, the m

ean

eliminatio

n half-life

in ad

ults is

13 hours; 13 to

14 hours in ad

olescen

ts; and

11 hours in ch

ildren ag

ed 6 to 12 ye

ars. O

n a mg/kg

body weig

ht basi

s children

have a h

igher cle

arance

than adoles

cents o

r adults

(See Speci

al Populati

ons).

ADDERALL XR® dem

onstrates

linear

pharmaco

kinetic

s over

the dose

range o

f 20 to

60 mg in adults

and adoles

cents w

eighing grea

ter than 75 kg

/165 lbs, over

the dose

range o

f 10 to 40 mg in adoles

cents w

eighing les

s than or eq

ual to 75 kg

/165 lbs,

and 5 to 30 mg in children aged 6 to 12 yea

rs. There

is no unexp

ected

accumulati

on at ste

ady state

in children

.

Food does not af

fect th

e exte

nt of absorption of d-am

phetamine a

nd l-ampheta

mine,

but prolongs T max

by 2.5 hours

(from 5.2 hrs

at fas

ted st

ate to

7.7 hrs afte

r a

high-fat meal

) for d

-ampheta

mine and 2.1 hours (

from 5.6 hrs a

t faste

d state t

o 7.7

hrs after

a high fat

meal) fo

r l-am

phetamine a

fter ad

ministratio

n of ADDERALL XR

®

30 mg. Opening th

e capsule a

nd sprinklin

g the c

ontents o

n apples

auce res

ults in

comparable a

bsorption to the intac

t capsule t

aken in the fa

sted sta

te. Equal d

oses of

ADDERALL XR® stre

ngths are b

ioequivalen

t.

Metabolism

and Excr

etion

Amphetamine is

reported

to be oxid

ized at

the 4 positi

on of the b

enzene ri

ng to form

4-hydroxyampheta

mine, or on the s

ide chain

α or ß carbons to

form alp

ha-hydroxy-

ampheta

mine or n

orephedrine, r

espect

ively.

Norephedrine a

nd 4-hydroxy-am

phet-

amine are

both active

and each is

subsequently

oxidized

to form 4-hydroxy-

norephedrin

e. Alpha-h

ydroxy-am

phetamine

undergoes

deaminatio

n to form

phenylacet

one, which

ultimate

ly form

s benzoic a

cid an

d its glucuronide a

nd the

glycine c

onjugate hippuric

acid. A

lthough the e

nzymes

involved in

ampheta

mine

metabolism

have not b

een cle

arly defin

ed, CYP2D6 is

known to be in

volved with

formatio

n of 4-hydroxy-

ampheta

mine. Since

CYP2D6 is genetic

ally polym

orphic,

population va

riations in

ampheta

mine meta

bolism are

a possi

bility.

Amphetamine is

known to inhibit monoamine oxid

ase, where

as the ability

of

ampheta

mine and its

meta

bolites t

o inhibit v

arious P

450 isozym

es and other

enzymes

has not b

een ad

equately

elucid

ated. In

vitro

experim

ents with human

microsomes

indicate

minor inhibitio

n of CYP2D6 by a

mphetamine a

nd minor

inhibition of C

YP1A2, 2D6, and 3A4 by o

ne or m

ore meta

bolites. H

owever, d

ue to

the probability

of auto-inhibitio

n and th

e lack

of inform

ation on th

e concen

tration

of these

meta

bolites r

elative

to in viv

o concentrat

ions, no pred

ications r

egarding

the poten

tial for am

phetamine o

r its m

etabolite

s to inhibit th

e meta

bolism of other

drugs by C

YP isozym

es in viv

o can be m

ade.

With normal u

rine p

Hs approxim

ately h

alf of an

administe

red dose

of ampheta

-

mine is re

coverable i

n urine a

s deriv

atives

of alpha-h

ydroxy-am

phetamine a

nd

approximate

ly another

30%-40% of the dose

is rec

overable

in urine

as

ampheta

mine itse

lf. Since

ampheta

mine has

a pKa o

f 9.9, u

rinary

recover

y of

ampheta

mine is highly d

ependent on pH an

d urine fl

ow rates

. Alka

line urin

e pHs

result i

n less io

nization an

d reduced

renal e

liminatio

n, and ac

idic pHs a

nd high

flow rates

result in incre

ased ren

al elim

ination with cle

arances

greater

than

glomerular

filtratio

n rates

, indica

ting the in

volvement o

f active

secre

tion. Urin

ary

recover

y of am

phetamine

has been

reporte

d to range

from 1% to 75%,

depending on urinary

pH, with th

e rem

aining fra

ction of th

e dose

hepatically

metabolize

d. Conseq

uently, both hepatic

and ren

al dysf

unction have

the poten

tial

to inhibit the e

liminatio

n of ampheta

mine and re

sult in prolonged ex

posures. In

addition, drugs that

effect

urinary

pH are known to alte

r the eliminatio

n of

ampheta

mine, and an

y decr

ease in

ampheta

mine’s m

etabolism

that m

ight occu

r

due to drug inter

actions o

r genetic

polymorphism

s is m

ore like

ly to be c

linically

signific

ant when re

nal elim

ination is

decreas

ed, (See

PRECAUTIONS).

Special P

opulations

Comparison of the

pharmaco

kinetic

s of d- and l-am

phetamine

after oral

administratio

n of ADDERALL XR

® in pediatric (

6-12 years

) and ad

olescen

t (13-17

years)

ADHD patients a

nd healthy a

dult voluntee

rs indica

tes that b

ody weig

ht is the

primary

determ

inant of a

pparent d

ifferen

ces in

the p

harmaco

kinetic

s of d

- and

l-ampheta

mine acro

ss the a

ge range. S

ystem

ic exposure

measured

by area

under

the curve

to infinity (AUC ∞

) and maxi

mum plasma c

oncentrat

ion (C max) d

ecreas

ed

with increase

s in body w

eight, w

hile oral

volume of distr

ibution (V z/F),

oral cle

arance

(CL/F), an

d eliminatio

n half-life

(t 1/2) in

crease

d with increase

s in body w

eight.

Pediatric P

atients

On a mg/kg

weig

ht basi

s, children

eliminate

d ampheta

mine fast

er than ad

ults.

The elim

ination half-

life (t 1/2

) is ap

proximate

ly 1 hour sh

orter fo

r d-am

phetamine

and 2 hours shorte

r for l-ampheta

mine in children than in adults.

However,

children had higher

system

ic exp

osure to am

phetamine (

C maxand AUC) th

an

adults for a

given dose

of ADDERALL XR

® , which

was attr

ibuted to

the h

igher

dose administe

red to ch

ildren on a m

g/kg body w

eight basi

s compare

d to adults.

Upon dose norm

alizatio

n on a mg/kg

basis, c

hildren sh

owed 30% less s

ystem

ic

exposure

compared to

adults.

Gender

System

ic exposure

to ampheta

mine was

20-30% higher in women (N

=20) than

in men (N

=20) due to

the h

igher dose

administered

to women on a m

g/kg body

weight b

asis. W

hen the e

xposure para

meters

(C maxand AUC) w

ere norm

alized

by dose

(mg/kg

), these

differen

ces diminish

ed. Age a

nd gender had no direc

t

effect o

n the p

harmaco

kinetic

s of d

- and l-a

mphetamine.

Race

Formal

pharmaco

kinetic

studies

for r

ace have

not been

conducte

d. Howeve

r,

ampheta

mine pharm

acokin

etics a

ppeared to

be compara

ble among Caucas

ians

(N=33), Blac

ks (N=8) a

nd Hispanics

(N=10).

Clinica

l Trials

Children

A double-blind, ran

domized, plac

ebo-contro

lled, para

llel-group stu

dy was

conducted in

children

aged 6-12 (N

=584) who m

et DSM-IV

® criteria

for A

DHD

(either

the combined type or the hypera

ctive-im

pulsive typ

e). Patie

nts were

randomize

d to fix

ed dose tre

atment g

roups rece

iving fin

al doses

of 10, 20, or 3

0

mg of ADDERALL XR

® or plac

ebo once daily

in th

e morning fo

r three

week

s.

Significant improvem

ents in patie

nt behavior, base

d upon teacher

ratings of

attention and hypera

ctivity,

were obser

ved for all

ADDERALL XR® doses

compared to patie

nts who rec

eived plac

ebo, for al

l three

weeks, i

ncluding the fi

rst

week of tr

eatment, w

hen all ADDERALL XR

® subjects w

ere rec

eiving a d

ose of 10

mg/day. Patie

nts who rec

eived ADDERALL XR

® showed behavioral

improvements

in both morning an

d aftern

oon asses

sments c

ompared to

patients o

n placebo.

In a cla

ssroom an

alogue s

tudy, patie

nts (N=51) re

ceivin

g fixed doses

of 10 m

g,

20 mg or 3

0 mg ADDERALL XR

® demonstr

ated sta

tistica

lly sig

nificant im

prove-

ments in tea

cher-rat

ed behavior and perf

ormance

measures

, compared to

patients t

reated

with placebo.

Adolescents

A double-blind, ra

ndomized, m

ulti-center,

parallel

-group, placebo-co

ntrolled

study

was conducte

d in adoles

cents a

ged 13-17 (N=327) w

ho met D

SM-IV® crit

eria fo

r

ADHD. The p

rimary

cohort

of patie

nts (n=287, w

eighing ≤

75kg/165lbs) was

randomized

to fixed dose

treatm

ent groups and rec

eived four w

eeks o

f treat

ment.

Patients w

ere ra

ndomized to

recei

ve final d

oses of 1

0 mg, 20 m

g, 30 mg, an

d 40

mg ADDERALL XR® or p

lacebo once

daily in the m

orning; patients r

andomized to

doses grea

ter than 10 m

g were tit

rated to

their

final doses

by 10 m

g each week

.

The seco

ndary co

hort consis

ted of 4

0 subjec

ts weig

hing >75kg/165lbs who were

randomized

to fixed dose

treatm

ent groups recei

ving fin

al doses

of 50 mg and 60

mg ADDERALL XR® or p

lacebo once

daily in the m

orning for 4 week

s. The p

rimary

efficac

y variab

le was

the ADHD-RS-IV total

scores

for the primary

cohort.

Improvem

ents in th

e prim

ary co

hort were

statis

tically

signific

antly grea

ter in all

four prim

ary co

hort activ

e treat

ment groups (

ADDERALL XR® 10 m

g, 20 m

g, 30

mg, and 40 m

g) compare

d with th

e plac

ebo group. There

was

not adequate

evidence

that doses

greater

than 20 mg/day

conferred ad

ditional b

enefit.

Adults

A double-blind, ran

domized, plac

ebo-contro

lled, para

llel-group stu

dy was

conducted in ad

ults (N=255) w

ho met D

SM-IV® crit

eria fo

r ADHD. P

atients w

ere

randomized

to fix

ed dose trea

tment g

roups rece

iving fin

al doses

of 20, 40, or 6

0

mg of ADDERALL XR

® or plac

ebo once daily

in th

e morning fo

r four w

eeks.

Significant improvem

ents, meas

ured with the Atten

tion Deficit

Hyperactiv

ity

Disorder-

Rating Scal

e (ADHD-RS), a

n 18- item sc

ale that m

easures

the core s

ymp-

toms of A

DHD, were

observed

at endpoint fo

r all ADDERALL XR

® doses co

mpared

to patients

who receiv

ed placebo for

all four

weeks.

There was

not

adequate ev

idence that d

oses grea

ter than 20 mg/day

conferred ad

ditional b

enefit.

INDICATIONS

ADDERALL XR® is i

ndicated

for th

e trea

tment o

f Atten

tion Deficit H

yperactiv

ity

Disorder

(ADHD).

The effic

acy of A

DDERALL XR® in th

e treat

ment of A

DHD was est

ablished on th

e

basis o

f two co

ntrolled

trials

in children

aged 6 to 12, one c

ontrolled

trial i

n adoles

-

cents a

ged 13 to 17, and one c

ontrolled

trial in

adults

who met DSM-IV

® criteria

for

ADHD (see C

LINICAL PHARMACOLOGY), along with ex

trapolati

on from the k

nown

efficac

y of A

DDERALL® , the im

mediate-re

lease

formulati

on of this s

ubstance.

A diagnosis

of Attention Defic

it Hypera

ctivity

Disorder (

ADHD; DSM-IV

® ) implies

the

presence

of hyperactiv

e-impulsiv

e or in

attentive

symptoms th

at caused

impairm

ent

and were pres

ent before

age 7 years.

The symptoms must

cause

clinica

lly

signific

ant impairm

ent, e.g., in

socia

l, acad

emic,

or occu

pational f

unctioning, an

d

be pres

ent in tw

o or more

settings,

e.g., s

chool (or w

ork) an

d at home.

The

symptoms m

ust not b

e bette

r acco

unted fo

r by a

nother mental

disorder.

For the

Inattentive

Type, a

t least

six of th

e following sy

mptoms must h

ave pers

isted for at

least

6 months:

lack o

f atten

tion to deta

ils/car

eless

mistakes

; lack

of susta

ined

attention; poor lis

tener;

failure t

o follow through on tasks;

poor organization; av

oids

tasks

requirin

g susta

ined mental effo

rt; loses

things; easi

ly distr

acted; fo

rgetful. F

or

the Hypera

ctive-Im

pulsive T

ype, at le

ast six

of the fo

llowing symptoms m

ust have

persiste

d for a

t least

6 months:

fidgeting/sq

uirming; le

aving se

at; inappropriat

e

running/climbing; diffic

ulty with quiet

activit

ies; "on the go"; exc

essive

talking;

blurting an

swers

; can't w

ait turn; in

trusiv

e. The C

ombined Type r

equires both

inattentive

and hypera

ctive-im

pulsive c

riteria

to be met.

Special Diagnostic

Consideratio

ns:Speci

fic etio

logy of this

syndrome

is

unknown, and th

ere is

no single d

iagnostic

test. A

dequate diag

nosis re

quires th

e

use not o

nly of m

edical b

ut of s

pecial

psychologica

l, educat

ional, and so

cial

resource

s. Lear

ning may

or may

not be im

paired. T

he diag

nosis m

ust be b

ased

upon a complete histo

ry and eva

luation of the child and not solely

on the

presence

of the r

equired number

of DSM-IV

® characte

ristics

.

Need for Comprehensiv

e Treatm

ent Program: ADDERALL XR

® is indica

ted as

an

integral

part of a total

treatm

ent program for ADHD that

may inclu

de other

measures

(psyc

hological, e

ducational,

social) f

or patie

nts with th

is syn

drome.

Drug treatm

ent may not be indica

ted for all

children with this

syndrome.

Stimulan

ts are

not intended for use

in the child who exhibits

symptoms

secondary

to en

vironmental

factors

and/or other

primary

psychiatr

ic diso

rders,

including psyc

hosis. Appropria

te educat

ional plac

ement is

essential

and

psychosocia

l inter

vention is

often help

ful. When re

medial meas

ures al

one are

insufficien

t, the d

ecisio

n to pres

cribe s

timulan

t medica

tion will depend upon th

e

physicia

n's asse

ssment o

f the c

hronicity a

nd sever

ity of th

e child's s

ymptoms.

Long-Term

Use: The effec

tiveness

of ADDERALL XR

® for long-te

rm use,

i.e., fo

r

more than 3 week

s in ch

ildren an

d 4 weeks in

adoles

cents

and adults,

has not

been sy

stematic

ally ev

aluate

d in co

ntrolled

trials

. There

fore, the p

hysicia

n who

elects

to use

ADDERALL XR® for e

xtended perio

ds should perio

dically

re-eva

lu-

ate th

e long-te

rm usef

ulness of th

e drug fo

r the in

dividual p

atient.

CONTRAINDICATIONS

Advanced

arterio

sclero

sis, sym

ptomatic car

diovascular

disease

, moderate

to

severe

hypertensio

n, hyperthyro

idism, kn

own hypersensiti

vity or id

iosyncra

sy to

the sym

pathomimetic

amines,

glaucoma.

Agitated sta

tes.

Patients w

ith a histo

ry of d

rug abuse.

During or within 14 days following the administr

ation of monoam

ine oxidase

inhibitors (hyperte

nsive c

rises m

ay res

ult).

WARNINGS

Serious C

ardiovascular E

vents

Sudden Death an

d Pre-exi

sting Stru

ctural

Cardiac

Abnormalit

ies or O

ther Serio

us

Heart P

roblems

Children an

d Adolescen

ts

Sudden death has

been re

ported in

associa

tion with CNS stimulan

t treat

ment at

usual doses

in ch

ildren an

d adoles

cents

with structu

ral car

diac ab

normalit

ies or

other ser

ious hear

t problem

s. Although so

me serio

us hear

t problem

s alone c

arry

an increase

d risk o

f sudden deat

h, stimulan

t products genera

lly should not be u

sed

in children

or adoles

cents

with known se

rious stru

ctural

cardiac

abnorm

alities

,

cardiomyopath

y, ser

ious heart rhyth

m abnormalit

ies, or other

serious car

diac

problems th

at may

place th

em at

increase

d vulnera

bility to

the s

ympath

omimetic

effects

of a stim

ulant drug (se

e CONTRAINDICATIONS).

Adults

Sudden deaths,

stroke,

and m

yocardial

infarction have

been re

ported in

adults

taking sti

mulant d

rugs at u

sual doses

for A

DHD. Although th

e role o

f stimulan

ts

in these adult cas

es is

also unknown, adults

have a grea

ter like

lihood than

children of havi

ng serious str

uctural

cardiac

abnormalit

ies, car

diomyopathy,

serious h

eart rh

ythm ab

normalit

ies, c

oronary ar

tery d

isease

, or o

ther ser

ious

cardiac

problems.

Adults with su

ch abnorm

alities

should als

o generally

not be

treate

d with stimulan

t drugs (

see CONTRAINDICATIONS).

Hypertensio

n and other

Cardiovas

cular Conditio

ns

Stimulan

t medica

tions cause

a modest

incre

ase in

avera

ge blood pres

sure (ab

out

2-4 mmHg) a

nd avera

ge hear

t rate (

about 3-6 bpm) [s

ee ADVERSE EVENTS], a

nd

individuals

may have

larger i

ncrease

s. While

the mean

changes

alone w

ould not be

expect

ed to have

short-t

erm co

nsequences

, all p

atients

should be monitored

for

larger

changes in hear

t rate

and blood pressure.

Caution is indica

ted in

treatin

g

patients w

hose underly

ing medical co

nditions m

ight be compromise

d by incre

ases in

blood pressure o

r hear

t rate,

e.g., th

ose with pre-

existin

g hypertensio

n, heart fa

ilure,

recent m

yocardial

infarction, or ve

ntricular

arrhyth

mia (see

CONTRAINDICATIONS).

Assessi

ng Cardiovas

cular Statu

s in Patie

nts bein

g Treate

d with Stimulan

t

Medications

Children, a

dolescen

ts, or a

dults who ar

e bein

g consid

ered fo

r treat

ment with

stimulan

t medica

tions should have

a care

ful history

(inclu

ding asses

sment fo

r a

family

history

of sudden deat

h or ventric

ular arr

hythmia)

and physical

exam

to

assess

for th

e pres

ence of c

ardiac

disease

, and sh

ould recei

ve furth

er car

diac

evaluatio

n if findings

suggest such dise

ase (e.

g. electr

ocardiogram

and

echocar

diogram). P

atients w

ho develop sy

mptoms such as

exert

ional chest

pain,

unexplain

ed syncope,

or other

symptoms s

uggestive

of card

iac dise

ase durin

g

stimulan

t treat

ment should underg

o a prompt ca

rdiac ev

aluatio

n.

Psychiatric

Adverse Events

Pre-Exis

ting Psychosis

Administratio

n of stimulan

ts may

exacer

bate sy

mptoms of b

ehavior d

isturbance

and thought d

isorder

in patients w

ith pre-exi

sting psyc

hotic diso

rder.

Bipolar Illn

ess

Particular

care s

hould be take

n in usin

g stimulan

ts to tre

at ADHD patie

nts with

comorbid bipolar diso

rder beca

use of concer

n for possible

induction of

mixed/m

anic episo

de in such patients.

Prior to initiating trea

tment with a

stimulan

t, patie

nts with co

morbid depressiv

e sym

ptoms should be a

dequately

screen

ed to dete

rmine i

f they

are at

risk f

or bipolar

disorder;

such scree

ning

should include a

detailed

psychiatr

ic histo

ry, inclu

ding a fam

ily histo

ry of su

icide,

bipolar diso

rder, and depres

sion.

Emergence

of New

Psychotic

or Manic S

ymptoms

Treatm

ent emerg

ent psychotic

or manic s

ymptoms, e

.g., hallu

cinatio

ns, delu

sional

thinking, o

r mania i

n children

and ad

olescen

ts without p

rior histo

ry of p

sychotic

illness

or mania c

an be caused

by stim

ulants a

t usual d

oses. I

f such sy

mptoms

occur, c

onsidera

tion should be g

iven to a p

ossible c

ausal ro

le of th

e stim

ulant, a

nd

discontinuatio

n of treat

ment may

be appropriat

e. In a p

ooled an

alysis

of multip

le

short-term

, placebo-co

ntrolled

studies

, such sy

mptoms occu

rred in ab

out 0.1% (4

patients w

ith events o

ut of 3

482 exposed

to m

ethylp

henidate or a

mphetamine fo

r

severa

l weeks at

usual doses

) of stimulan

t-treat

ed patients

compared to 0 in

placebo-tre

ated patie

nts.

Aggressio

n

Aggressiv

e behavi

or or h

ostility

is often

observed

in children

and ad

olescen

ts with

ADHD, and has

been rep

orted in cli

nical tr

ials an

d the postm

arketin

g experie

nce of

some medica

tions indica

ted fo

r the t

reatm

ent of A

DHD. Although th

ere is

no

system

atic evi

dence that

stimulan

ts cau

se aggres

sive

behavior or hostil

ity,

patients b

eginning treatm

ent for A

DHD should be m

onitored for th

e appear

ance of

or worse

ning of aggres

sive b

ehavior o

r hostil

ity.

Long-Term

Suppression of G

rowth

Careful fo

llow-up of weig

ht and heig

ht in ch

ildren ag

es 7 to

10 years

who were

randomized

to eit

her meth

ylphenidate

or non-m

edication tre

atment g

roups over

14 months, a

s well

as in natu

ralistic

subgroups o

f new

ly meth

ylphenidate

-treate

d

and non-medica

tion treate

d children

over 36 m

onths (to th

e ages

of 10 to

13

years)

, suggest

s that c

onsisten

tly medica

ted ch

ildren (i.e

., treat

ment for 7 days

per

week th

roughout the y

ear) h

ave a t

emporar

y slowing in growth ra

te (on av

erage,

a total

of about 2

cm les

s growth in heig

ht and 2.7 kg

less g

rowth in weight o

ver

3 years

), without ev

idence of g

rowth rebound during th

is perio

d of deve

lopment.

In a contro

lled tri

al of A

DDERALL XR® in ad

olescen

ts, mean

weight ch

ange from

baseline within the initia

l 4 weeks of thera

py was –1.1 lbs.

and –2.8 lbs.,

respect

ively,

for patie

nts rec

eiving 10 m

g and 20 m

g ADDERALL XR® . H

igher

doses were

associa

ted with grea

ter weig

ht loss within the initia

l 4 weeks of

treatm

ent. Publish

ed data ar

e inadequate

to dete

rmine w

hether

chronic use

of

ampheta

mines may

cause

a similar

suppressio

n of growth, however,

it is

anticipate

d that t

hey will l

ikely h

ave th

is effec

t as well.

There

fore, growth sh

ould

be monitored

during treatm

ent with sti

mulants,

and patients w

ho are not growing

or gain

ing weight as

expect

ed may

need to have

their trea

tment in

terrupted

.

Seizures

There is

some clinica

l evidence

that stim

ulants

may lower

the convulsive

threshold in

patients

with prior h

istory

of seiz

ure, in patie

nts with prio

r EEG

abnormalit

ies in absen

ce of sei

zures, and ver

y rarely

, in patients

without a

history

of seiz

ures an

d no prior E

EG evidence

of seiz

ures. I

n the p

resence

of

seizures

, the d

rug should be d

iscontinued.

Visual D

isturbance

Difficultie

s with ac

commodation an

d blurring of v

ision have

been re

ported with

stimulan

t treat

ment.

PRECAUTIONS

General: The least

amount o

f ampheta

mine feas

ible should be p

rescrib

ed or dis-

pensed at

one time in

order to m

inimize the p

ossibility

of over

dosage. A

DDERALL

XR® should be u

sed with ca

ution in patients w

ho use other s

ympath

omimetic drugs.

Tics: Ampheta

mines have

been rep

orted to ex

acerbate

motor and phonic t

ics an

d

Tourette’s

syndrome.

Therefore,

clinica

l eval

uation fo

r tics

and Touret

te’s sy

n-

drome in ch

ildren an

d their fam

ilies s

hould precede u

se of st

imulant m

edications.

Information fo

r Patients:

Amphetamines

may impair

the ability

of the p

atient to

engage in poten

tially h

azardous a

ctivitie

s such as

operating mach

inery or ve

hicles;

the patie

nt should there

fore be c

autioned accordingly.

Prescrib

ers or o

ther heal

th professio

nals sh

ould inform

patients,

their fam

ilies,

and their

caregive

rs about th

e benefit

s and ris

ks ass

ociated

with treatm

ent with

ampheta

mine and should counsel

them in its

appropriate

use. A patie

nt

Medication Guide is

availab

le for ADDERALL XR

® . The prescrib

er or heal

th

professio

nal should instr

uct patie

nts, their

familie

s, and th

eir car

egivers

to read

the Medication Guide and should ass

ist them

in understan

ding its conten

ts.

Patients

should be give

n the opportu

nity to disc

uss the

contents

of the

Medication Guide a

nd to obtain

answ

ers to

any q

uestions t

hey may

have. T

he

complete tex

t of th

e Medica

tion Guide is re

printed

at the e

nd of this d

ocument.

Drug Interactions:

Acidifyi

ng agents—Gast

rointestin

al aci

difying agents

(guanethidine, r

eserpine, g

lutamic a

cid HCI, a

scorbic a

cid, et

c.) lower a

bsorption

of ampheta

mines.

Urinary aci

difying agents—

These agents

(ammonium chlorid

e, sodium aci

d

phosphate, et

c.) incre

ase the c

oncentra

tion of the io

nized sp

ecies

of the a

mphet-

amine m

olecule,

thereby i

ncreasi

ng urinary

excre

tion. Both groups o

f agents

lower blood lev

els an

d effica

cy of am

phetamines.

Adrenerg

ic blocke

rs—Adren

ergic b

lockers

are inhibited

by ampheta

mines.

Alkalinizin

g agents—Gast

rointestinal

alkalin

izing agents

(sodium bica

rbonate,

etc.) i

ncrease

absorption of am

phetamines.

Co-administr

ation of A

DDERALL XR®

and gastrointes

tinal alk

alinizin

g agents,

such as an

tacids,

should be avoided.

Urinary

alkalin

izing agents

(aceta

zolamide,

some thiaz

ides) incre

ase the

concentra

tion of the n

on-ionize

d speci

es of th

e ampheta

mine molec

ule, there

by

decreas

ing urinary

excre

tion. Both groups o

f agents

increase

blood level

s and

therefore

potentiat

e the a

ctions o

f ampheta

mines.

Antidepressan

ts, tric

yclic—

Amphetamines

may enhance

the activ

ity of tr

icyclic

antidepressan

ts or s

ympath

omimetic ag

ents; d-am

phetamine w

ith desipram

ine

or protriptyli

ne and possi

bly other

tricycl

ics cau

se str

iking and susta

ined

increase

s in th

e concen

tration of d

-ampheta

mine in th

e brain

; card

iovascular

effects

can be p

otentiat

ed.

MAO inhibitors—MAOI an

tidepressan

ts, as

well as

a meta

bolite of fu

razolidone,

slow am

phetamine

metabolism

. This slo

wing potentiat

es am

phetamines,

increasi

ng their

effect

on the r

elease

of norep

inephrine a

nd other monoam

ines

from ad

renerg

ic nerv

e endings;

this can

cause

headach

es and other

signs o

f

hypertensiv

e cris

is. A var

iety of toxic

neurological effe

cts and malig

nant

hyperpyre

xia ca

n occur, s

ometimes

with fatal r

esults.

Antihistamines—

Amphetamines

may countera

ct the s

edative e

ffect of an

tihistamines.

Antihypertensiv

es—Ampheta

mines may

antagonize

the h

ypotensiv

e effec

ts of

antihypertensiv

es.

Chlorpromazine—

Chlorpromazine

blocks dopam

ine and norep

inephrine

receptors,

thus inhibitin

g the c

entral st

imulant ef

fects o

f ampheta

mines, an

d can

be used

to tre

at ampheta

mine poiso

ning.

Ethosuximide—

Amphetamines

may dela

y intes

tinal absorption of et

hosuximide.

Haloperid

ol—Halo

peridol b

locks dopam

ine rece

ptors, thus in

hibiting th

e central

stimulan

t effec

ts of am

phetamines.

Lithium carbonate

—The anorec

tic and sti

mulatory

effects

of ampheta

mines may

be inhibited

by lithium ca

rbonate.

Meperidine—

Amphetamines

potentiat

e the a

nalgesi

c effec

t of m

eperidine.

Methenam

ine therapy—

Urinary

excret

ion of ampheta

mines is

increase

d, and

efficac

y is re

duced, by a

cidifyi

ng agents u

sed in m

ethenam

ine thera

py.

Norepinephrine—

Amphetamines

enhance the a

drenerg

ic effec

t of norepinephrine.

Phenobarbital

—Amphetamines

may dela

y intes

tinal absorption of p

henobarbital

;

co-administr

ation of phenobarb

ital may

produce a s

ynergisti

c antico

nvulsant ac

tion.

Phenytoin—Ampheta

mines may

delay

intestinal

absorption of phenytoin;

co-administr

ation of p

henytoin m

ay produce

a synerg

istic a

nticonvulsa

nt action.

Propoxyphene—

In cases

of propoxyphene

overdosag

e, am

phetamine

CNS

stimulati

on is poten

tiated an

d fatal c

onvulsions c

an occur.

Veratru

m alkal

oids—Ampheta

mines inhibit t

he hypoten

sive e

ffect o

f vera

trum

alkalo

ids.

Drug/Laboratory Test

Interactions:

Amphetamines

can cau

se a

signific

ant

elevat

ion in plasma c

orticoste

roid levels

. This incre

ase is

greates

t in the e

vening.

Amphetamines

may inter

fere w

ith urinary

steroid dete

rminatio

ns.

Carcinogenesis

/Mutagenesis

and Impairm

ent of Fertility:

No evidence

of

carcin

ogenicity w

as found in stu

dies in which

d,l-ampheta

mine (enantiomer r

atio

of 1:1) was

administered

to mice an

d rats in

the diet

for 2 ye

ars at

doses of up to

30 mg/kg

/day in m

ale m

ice, 1

9 mg/kg

/day in fe

male m

ice, an

d 5 mg/kg

/day in

male an

d female

rats.

These doses

are a

pproximate

ly 2.4, 1

.5, and 0.8 tim

es,

respect

ively,

the maxi

mum recommended human dose

of 30 m

g/day [c

hild] on

a mg/m

2 body surfa

ce are

a basi

s.

Amphetamine,

in the enantiomer

ratio pres

ent in ADDERALL®(im

mediate-

release

)(d- to

l- rati

o of 3:1), w

as not c

lastogenic

in the m

ouse bone m

arrow

micronucle

us test i

n vivo and was

negative w

hen tested

in the E. co

li component of

the Ames

test in

vitro. d,l-A

mphetamine (1

:1 enantiomer r

atio) has

been rep

orted to

produce a p

ositive

response

in the m

ouse bone m

arrow m

icronucle

us test

, an

equivocal

response

in the A

mes tes

t, and negativ

e resp

onses in th

e in vit

rosis

ter

chromatid ex

change and ch

romosomal aberr

ation as

says.

Amphetamine, i

n the e

nantiomer rati

o present in

ADDERALL®(im

mediate-re

lease)

(d- to l- r

atio of 3:1), d

id not adver

sely a

ffect fe

rtility o

r early

embryo

nic deve

lopment

in the r

at at

doses of u

p to 20 m

g/kg/day

(approxim

ately 5

times

the maxi

mum

recommended human dose

of 30 mg/day on a m

g/m2 body s

urface a

rea basi

s).

Pregnancy:Preg

nancy Cate

gory C. A

mphetamine, i

n the enantiomer r

atio pres

ent

in ADDERALL®(d- to

l- rati

o of 3:1), h

ad no appare

nt effec

ts on em

bryofeta

l

morphological deve

lopment or surviv

al when orall

y administe

red to preg

nant rats

and rabbits

throughout the p

eriod of o

rganogenesis a

t doses

of up to

6 and 16

mg/kg/day,

respect

ively.

These doses

are approxim

ately

1.5 and 8 times,

respect

ively,

the maxi

mum recommended human dose

of 30 m

g/day [ch

ild] on a

mg/m2 body surfa

ce are

a basis.

Fetal

malform

ations and deat

h have been

reported

in m

ice fo

llowing parentera

l administr

ation of d

-ampheta

mine doses

of

50 mg/kg

/day (ap

proximate

ly 6 tim

es that o

f a human dose

of 30 m

g/day [ch

ild]

on a mg/m

2 basis)

or grea

ter to preg

nant animals

. Administr

ation of th

ese doses

was als

o associa

ted with se

vere m

aternal t

oxicity.

A number of st

udies in ro

dents indica

te that p

renata

l or early

postnata

l exposure

to ampheta

mine (d- o

r d,l-)

, at doses

similar

to those used

clinica

lly, ca

n result in

long-term neurochem

ical an

d behavioral

alterati

ons. Reported

behavioral

effects

include le

arning an

d mem

ory defic

its, alt

ered locomotor a

ctivity,

and ch

anges in

sexual f

unction.

There are

no adequate

and well-

controlled

studies

in pregnant w

omen. There has

been one r

eport of se

vere c

ongenital bony d

eform

ity, tra

cheo-esophageal

fistula,

and anal atr

esia (va

ter ass

ociation) in a baby born to a woman who took

AMPHETAMINES HAVE A HIGH POTENTIAL FOR ABUSE. A

DMINISTRATION

OF AMPHETAMINES FOR PROLONGED PERIODS OF TIM

E MAY LEAD TO

DRUG DEPENDENCE. PARTICULAR ATTENTION SHOULD BE PAID TO THE

POSSIBILITY OF SUBJECTS OBTAINING AMPHETAMINES FO

R NON-

THERAPEUTIC USE OR DISTRIBUTION TO OTHERS AND THE DRUGS

SHOULD BE PRESCRIBED OR DISPENSED SPARINGLY.

MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS

CARDIOVASCULAR ADVERSE EVENTS.

0 0

4

8

12

16

24

20

5

10

15

20

25

30

TIME (H

OURS)

MEA

N PLA

SMA

CONCEN

TRAT

IONS

OF

DEXTR

O A

ND LEV

OAMPH

ETAM

INE

(ng/

mL)

DEXTROAMPHETAMINE

LEVOAMPHETA

MINEADDERALL XR® 20 m

g qd

ADDERALL® 10

mg bid

ADDERALL® 10

mg bid

ADDERALL XR® 20 m

g qd

1

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

STRATTERA safely and effectively. See full prescribing information for

STRATTERA. STRATTERA® (atomoxetine hydrochloride) CAPSULES for Oral Use

Initial U.S. Approval: 2002

WARNING: SUICIDAL IDEATION IN CHILDREN AND

ADOLESCENTS

See full prescribing information for complete boxed warning.

• Increased risk of suicidal ideation in children or adolescents (5.1)

• No suicides occurred in clinical trials (5.1)

• Patients started on therapy should be monitored closely (5.1)

---------------------------- INDICATIONS AND USAGE ---------------------------

Selective Norepinephrine reuptake inhibitor indicated for treatment of:

• Attention-Deficit/Hyperactivity Disorder (ADHD). (1.1)

----------------------- DOSAGE AND ADMINISTRATION ----------------------

Initial, Target and Maximum Daily Dose (2.1)

Body Weight

Initial Daily Dose Target Total

Daily Dose Maximum Total Daily Dose

Children and adolescents up to

70 kg 0.5 mg/kg 1.2 mg/kg

1.4 mg/kg

Children and adolescents over 70 kg and adults

40 mg

80 mg

100 mg

Dosing adjustment — Hepatic Impairment and Strong CYP2D6 Inhibitor.

(2.3, 12.3)----------------------DOSAGE FORMS AND STRENGTHS ---------------------

Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or

100 mg of atomoxetine. (3, 11, 16)

-------------------------------CONTRAINDICATIONS------------------------------

• Hypersensitivity to atomoxetine or other constituents of product. (4.1)

• STRATTERA use within 2 weeks after discontinuing MAOI or other

drugs that affect brain monoamine concentrations. (4.2, 7.1)

• Narrow Angle Glaucoma. (4.3)

------------------------WARNINGS AND PRECAUTIONS -----------------------

• Suicidal Ideation - Monitor for suicidality, clinical worsening, and unusual

changes in behavior. (5.1)

• Severe Liver Injury. (5.2)

• Serious Cardiovascular Events - Sudden death, stroke and myocardial

infarction have been reported in association with atomoxetine treatment.

Patients should have a careful history and physical exam to assess for

presence of cardiovascular disease. STRATTERA generally should not be

used in children or adolescents with known serious structural cardiac

abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or

other serious cardiac problems that may place them at increased

vulnerability to its noradrenergic effects. Consideration should be given to

not using STRATTERA in adults with clinically significant cardiac

abnormalities. (5.3)

• Emergent Cardiovascular Symptoms - Patients should undergo prompt

cardiac evaluation. (5.3)

• Effects on Blood Pressure and Heart Rate - Can increase blood pressure

and heart rate; orthostasis, syncope and Raynaud’s phenomenon may

occur. Use with caution in patients with hypertension, tachycardia, or

cardiovascular or cerebrovascular disease. (5.4).

• Emergent Psychotic or Manic Symptoms - Consider discontinuing

treatment if such new symptoms occur. (5.5)

• Bipolar Disorder - Screen patients to avoid possible induction of a

mixed/manic episode. (5.6)

• Aggressive behavior or hostility should be monitored. (5.7)

• Possible allergic reactions, including angioneurotic edema, urticaria, and

rash. (5.8) • Effects on Urine Outflow - Urinary hesitancy and retention may occur.

(5.9) • Priapism - Prompt medical attention is required in the event of suspected

priapism. (5.10, 17.5)

• Growth - Height and weight should be monitored in pediatric patients.

(5.11) • Concomitant Use of Potent CYP2D6 Inhibitors - Dose adjustment of

STRATTERA may be necessary. (5.13)

-------------------------------ADVERSE REACTIONS------------------------------

Most common adverse reactions (≥5% and at least twice the incidence of

placebo patients) • Child and Adolescent Clinical Trials - Nausea, vomiting, fatigue,

decreased appetite, abdominal pain and somnolence. (6.1)

• Adult Clinical Trials - Constipation, dry mouth, nausea, fatigue, decreased

appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary

retention and/or dysuria, dysmenorrhea, and hot flush. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and

Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

------------------------------- DRUG INTERACTIONS ------------------------------

• Monoamine Oxidase Inhibitors. (4.2, 7.1)

• CYP2D6 Inhibitors - Concomitant use may increase atomoxetine

steady-state plasma concentrations in EMs. (7.2)

• Pressor Agents - Possible effects on blood pressure. (7.3)

• Albuterol (or other beta2 agonists) - Action of albuterol on cardiovascular

system can be potentiated. (7.4)

------------------------USE IN SPECIFIC POPULATIONS-----------------------

• Pregnancy/Lactation - Pregnant or nursing women should not use unless

potential benefit justifies potential risk to fetus or infant. (8.1, 8.3)

• Hepatic Insufficiency - Increased exposure (AUC) to atomoxetine than

with normal subjects in EM subjects with moderate (Child-Pugh Class B)

(2-fold increase) and severe (Child-Pugh Class C) (4-fold increase). (8.6)

• Renal Insufficiency - Higher systemic exposure to atomoxetine than

healthy subjects for EM subjects with end stage renal disease - no

difference when exposure corrected for mg/kg dose. (8.7)

• Patients with Concomitant Illness - Does not worsen tics in patients with

ADHD and comorbid Tourette’s Disorder. (8.10)

See 17 for PATIENT COUNSELING INFORMATION and the

FDA-approved Medication Guide)

Revised: 03/2008

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL IDEATION IN CHILDREN AND

ADOLESCENTS 1 INDICATIONS AND USAGE

1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)

1.2 Diagnostic Considerations

1.3 Need for Comprehensive Treatment Program

1.4 Long-Term Use

2 DOSAGE AND ADMINISTRATION

2.1 Initial Treatment

2.2 Maintenance/Extended Treatment

2.3 General Dosing Information

2.4 Dosing in Specific Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Monoamine Oxidase Inhibitors (MAOI)

4.3 Narrow Angle Glaucoma

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Ideation

5.2 Severe Liver Injury

The bottom lineIn the course of gathering information about this topic, many people expressed concern that the package inserts or prescribing information were extremely difficult to see and almost impossible to interpret. The images on this page (top to bottom) depict information for two DTC products used to treat ADD. The image on the left is an older example of Prescribing Information and on the right an example of a product’s ‘Highlights of Prescribing Information’ that includes changes to style, font size and layout required by recent changes to FDA regulation. This documentation must accompany any ad which makes a claim about efficacy.

The trend in FDA regulation has been acknowledgement of how savvy and demanding consumers have become. People not only want to be able to see the information in a reasonable 8 point. type, but also want to understand the risks and benefits of the product. While the internet is surpassing just about all forms of delivery of information to consumers, print advertising still continues to be a major resource for those looking for this type of information.

In addition to all of the constraints and obligations that general advertising has, DTC must also pay heed to several additional layers of information before approaching the creative product. Shouldering all of this responsibility might seem like an enormous task, but even in the midst of such a tightly controlled environment, surprising examples of creativity often occur, as will be illustrated in the next section.

1

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

STRATTERA safely and effectively. See full prescribing information for

STRATTERA.

STRATTERA® (atomoxetine hydrochloride) CAPSULES for Oral Use

Initial U.S. Approval: 2002

WARNING: SUICIDAL IDEATION IN CHILDREN AND

ADOLESCENTS

See full prescribing information for complete boxed warning.

• Increased risk of suicidal ideation in children or adolescents (5.1)

• No suicides occurred in clinical trials (5.1)

• Patients started on therapy should be monitored closely (5.1)

----------------------

------ INDICATIONS AND USAGE ----------------------

-----

Selective Norepinephrine reuptake inhibitor indicated for treatment of:

• Attention-Deficit/Hyperactivity Disorder (ADHD). (1.1)

----------------------

- DOSAGE AND ADMINISTRATION ----------------------

Initial, Target and Maximum Daily Dose (2.1)

Body Weight Initial Daily

Dose

Target Total

Daily Dose

Maximum Total

Daily Dose

Children and

adolescents up to

70 kg

0.5 mg/kg 1.2 mg/kg

1.4 mg/kg

Children and

adolescents over

70 kg and adults

40 mg 80 mg

100 mg

Dosing adjustment — Hepatic Impairment and Strong CYP2D6 Inhibitor.

(2.3, 12.3)

----------------------

DOSAGE FORMS AND STRENGTHS ---------------------

Each capsule contains atomoxetine HCl equivalent to 10, 18, 25, 40, 60, 80, or

100 mg of atomoxetine. (3, 11, 16)

----------------------

---------CONTRAINDICATIONS-----------

-------------------

• Hypersensitivity to atomoxetine or other constituents of product. (4.1)

• STRATTERA use within 2 weeks after discontinuing MAOI or other

drugs that affect brain monoamine concentrations. (4.2, 7.1)

• Narrow Angle Glaucoma. (4.3)

----------------------

--WARNINGS AND PRECAUTIONS ----------------------

-

• Suicidal Ideation - Monitor for suicidality, clinical worsening, and unusual

changes in behavior. (5.1)

• Severe Liver Injury. (5.2)

• Serious Cardiovascular Events - Sudden death, stroke and myocardial

infarction have been reported in association with atomoxetine treatment.

Patients should have a careful history and physical exam to assess for

presence of cardiovascular disease. STRATTERA generally should not be

used in children or adolescents with known serious structural cardiac

abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or

other serious cardiac problems that may place them at increased

vulnerability to its noradrenergic effects. Consideration should be given to

not using STRATTERA in adults with clinically significant cardiac

abnormalities. (5.3)

• Emergent Cardiovascular Symptoms - Patients should undergo prompt

cardiac evaluation. (5.3)

• Effects on Blood Pressure and Heart Rate - Can increase blood pressure

and heart rate; orthostasis, syncope and Raynaud’s phenomenon may

occur. Use with caution in patients with hypertension, tachycardia, or

cardiovascular or cerebrovascular disease. (5.4).

• Emergent Psychotic or Manic Symptoms - Consider discontinuing

treatment if such new symptoms occur. (5.5)

• Bipolar Disorder - Screen patients to avoid possible induction of a

mixed/manic episode. (5.6)

• Aggressive behavior or hostility should be monitored. (5.7)

• Possible allergic reactions, including angioneurotic edema, urticaria, and

rash. (5.8)

• Effects on Urine Outflow - Urinary hesitancy and retention may occur.

(5.9)

• Priapism - Prompt medical attention is required in the event of suspected

priapism. (5.10, 17.5)

• Growth - Height and weight should be monitored in pediatric patients.

(5.11)

• Concomitant Use of Potent CYP2D6 Inhibitors - Dose adjustment of

STRATTERA may be necessary. (5.13)

----------------------

---------ADVERSE REACTIONS ----------------------

--------

Most common adverse reactions (≥5% and at least twice the incidence of

placebo patients)

• Child and Adolescent Clinical Trials - Nausea, vomiting, fatigue,

decreased appetite, abdominal pain and somnolence. (6.1)

• Adult Clinical Trials - Constipation, dry mouth, nausea, fatigue, decreased

appetite, insomnia, erectile dysfunction, urinary hesitation and/or urinary

retention and/or dysuria, dysmenorrhea, and hot flush. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and

Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch.

----------------------

--------- DRUG INTERACTIONS ----------------------

--------

• Monoamine Oxidase Inhibitors. (4.2, 7.1)

• CYP2D6 Inhibitors - Concomitant use may increase atomoxetine

steady-state plasma concentrations in EMs. (7.2)

• Pressor Agents - Possible effects on blood pressure. (7.3)

• Albuterol (or other beta2 agonists) - Action of albuterol on cardiovascular

system can be potentiated. (7.4)

----------------------

--USE IN SPECIFIC POPULATIONS----------------------

-

• Pregnancy/Lactation - Pregnant or nursing women should not use unless

potential benefit justifies potential risk to fetus or infant. (8.1, 8.3)

• Hepatic Insufficiency - Increased exposure (AUC) to atomoxetine than

with normal subjects in EM subjects with moderate (Child-Pugh Class B)

(2-fold increase) and severe (Child-Pugh Class C) (4-fold increase). (8.6)

• Renal Insufficiency - Higher systemic exposure to atomoxetine than

healthy subjects for EM subjects with end stage renal disease - no

difference when exposure corrected for mg/kg dose. (8.7)

• Patients with Concomitant Illness - Does not worsen tics in patients with

ADHD and comorbid Tourette’s Disorder. (8.10)

See 17 for PATIENT COUNSELING INFORMATION and the

FDA-approved Medication Guide) Revised: 03/2008

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL IDEATION IN CHILDREN AND

ADOLESCENTS

1 INDICATIONS AND USAGE

1.1 Attention-Deficit/Hyperactivity Disorder (ADHD)

1.2 Diagnostic Considerations

1.3 Need for Comprehensive Treatment Program

1.4 Long-Term Use

2 DOSAGE AND ADMINISTRATION

2.1 Initial Treatment

2.2 Maintenance/Extended Treatment

2.3 General Dosing Information

2.4 Dosing in Specific Populations

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Monoamine Oxidase Inhibitors (MAOI)

4.3 Narrow Angle Glaucoma

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Ideation

5.2 Severe Liver Injury 28

2.3 What are the different kinds of ads a consumer will see?

There are three t ypes of DTC adver t isements: product-claim ads, reminder ads and help-seeking ads. One fact that becomes clear in observing DTC ads is that the communication of risk often takes up an enormous amount of space on a typical ad. The product-claim ad on the adjacent page is an award winning example of DTC design. The image has been annotated to show what kind of information must be on an ad that makes any claim whatsoever. The colored circles on the image correspond to the colors next to the explanation of their presence.

FDA regulation is both necessary and desirable; but there is currently debate on how much information consumers actually retain while viewing print ads. An argument for reexamining regulations is being posed by the Coalition for Health Care Communication. “There is substantial evidence that DTC advertising is successfully meeting its most basic goal—to convince consumers to talk to their doctor about a specific medical condition,” said Jack Angel, Executive Director of the Coalition. Our report concludes that the effectiveness of all DTC advertising, both broadcast and print, can be severely undermined by requiring too much detailed information in the ads.”

In this very in-depth look at the purpose of DTC advertising, a logic problem emerges. If it is true that DTC’s main purpose is to motivate consumers to begin a dialogue with their physicians, then is this goal possible without all of the visual clutter? The ‘white letter’ proposed to the FDA on the effects of less regulation within DTC can be found at cohealthcom.org/content/jan04_fda_comments.htm.

Product-claim adsThe most common DTC ad provides a drug’s name and what condition it’s prescribed to treat. Whenever these pieces of information appear in an ad, the ad must provide fair balance. Often, those who should and shouldn’t take the drug are also mentioned. Recently, the FDA added the requirement that an 800 number be added for patients or physicians to report adverse events associated with taking a particular drug.

Help-seeking adsAlso known as ‘disease-awareness’ or public service announcements (PSAs), these ads are unbranded with no mention of any brand or drug. These kinds of ads are not regulated by the FDA. Educating patients about facts, statistics and possibilities is allowed, as long as the ad is not branded. Again, because no claims are made in these types of ads there is no need for yards of fair balance or the inclusion of prescribing information or brief summaries.

Reminder adsThese ads are rarely seen in print or on television any more due to PhRMA’s guiding principles for DTC ads (PhRMA is a non-profit organization devoted to promoting best practices within DTC marketing). Reminder ads contain minimal information, most often just the name of the drug and sometimes dosage, but never what the drug is prescribed for. Reminder ads make no claims, therefore the FDA does not ask that they contain fair balance or any warnings, theoretically freeing up plenty of space for interesting graphics, but not any relevant information.

29

Key elements of a DTC print ad:

Benefit statementThe core message often centers around what the product hopes to accomplish. There is rarely ever a mention of a cure and language that guarantees the product will work.

Product claimThe product’s main message often states the general symptoms the product is best at helping to alleviate. Often there is language urging consultation with a doctor or health care provider.

Black box warning informationBlack box warnings are common to all antidepressants, required on all print ads promoting this class of medication as of 2004. These warnings must also be present on any drugs that have serious risks, or have been shown to have caused ‘adverse events’.

Please see line Usually located adjacent to or on the back of a print ad, the so-called please see line alerts viewer to required brief summary information.

Patient assistance program informationThis is not required information. Many companies have patient assistance programs designed to help poor or uninsured patients receive medication. More information about this can be found at www.pparx.org.

Logo with genericThe generic must appear at least once on a spread with the trademarked drug name. Usually the generic will appear after the first mention of the drug and will often appear directly under the drug’s logo.

Cymbalta for depression

30

2.4 What can professional advertising be?

With professional advertising, there is no room for guessing what will attract a doctor’s attention...

The images below are from a calendar that was created by designers for the drug Flomax. Flomax is used to treat a prostate condition. The ad was developed at Euro RSCG Life several years ago as a calendar premium for pharma sales reps to give away to doctors. On the following pages Lena Shabus, an art director for the brand at that time, describes the process of creating the illustrations for the project.

31

...and you only have one chance to grab it in today’s crowded playing field.

32

Professional advertising might be considered the lowest rung on the totem pole as far as creativity is concerned. Most designers point to clients demanding ‘clinical ’ pieces. This often translates into 8.5 x 11, black and white, helvetica type with no logo. Hundreds of pieces of material are created with the assumption that doctors want only the facts, presented in the cleanest, simplest way. While that may be the truth most of the time, it is possible that this segment has been a victim of Stokes’ ‘constraints for conformity’. The following is an account of how a professional calendar came to be that was successful, interesting, beautiful even.

Interview excerpt: Lena Shabus

The following exchange stemmed from a discussion on the differences between DTC and professional advertising.

Merry Davis: Was it tough getting the client to buy into [the idea of an illustrated calendar]?

Lena Shabus: We presented the first presentation…It was almost as a joke, and we presented it last. We had the assignment of doing a calendar. They had done a calendar every year. Flomax is about peeing, so one was like great waterfalls and nature scenes…Your prostate gets bigger and disrupts the flow of things; so we presented three that were the kind [the client] expected…We presented this one as a fourth, saying you know, if you really want to catch doctors’ attention…a history of the toilet….

We found these little snippets of stories of major impacts on the toilet and different quirky things, the outhouse, and we presented it last…And the client looked at us and looked around and looked at each other and they’re like okay, do it. We couldn’t believe it. Nobody expected it. And so we got 13 different illustrators, and here is a toilet in the woods…All we did was give them this little snippet [of direction], all they had to do was give us an initial sketch that we approved. So it wasn’t a lot of pharmaceutical information—[so we didn’t have to be so mindful of the FDA regulations] And so they went nuts! They had a blast.

Merry Davis: You’re not making any claims in here...

Lena Shabus: We’re not making any claims. The only thing about the product is the logo and a PI in the back. It was fabulous. People could not get enough of them.

Merry Davis: [The illustrators loved them] because it was probably the most interesting pharma job they’d had?

Lena Shabus: And it was basically restriction-free, which is so unusual. Right now, working on a breast cancer drug, we have so many restrictions, it’s like the exact opposite of the spectrum, which is a story after the story.

Merry Davis: …[the difference between] drugs that you will see on TV and [those] you will see in popular magazines, there is going to be less creative restriction than on drugs that you don’t see advertised; cancer drugs, diabetes drugs, or blood-infection drugs.

Lena Shabus: There are different ranges…I switched from [promoting a] lifestyle drug [that treats enlarged prostates] to a cytotoxic chemotherapy, black box warning drug [that treats cancer]—I mean you can’t advertise a chemotherapy. Patients don’t really get the option. At that point they’re sick; they have to trust the doctors. Flomax, you can go into your doctor and say, “I’ve been getting up in the night, give me a pill.” And kind of the middle ground to that, I would guess would be like heart medicines, depression medicines. You know, my drug now has a warning, you know it will kill you.

Merry Davis: That’s a pretty unique story. Usually you stay in a category if you’re a designer. If you’re into depression drugs, you kind of will be designing [ads for] depression drugs.

Lena Shabus: And once you know a category, then you’re in a niche market. Like now that I have oncology experience; that’s huge. I don’t have to relearn the science. I understand the restrictions. Piece of cake to get a job (don’t record that).

2.3 What can professional advertising be? (continued)

“And so we got 13 different illustrators…All we did was give them this little snippet of direction...So they went nuts! They had a blast. —Lena Shabus

33

34

Is it possible that creativity is enhanced by constraint? This thesis has examined whether constraints imposed on designers within DTC advertising help or hinder the creative process.

The previous sections provided a foundation on which to begin an analysis of how, and in what way, creativity is affected by constraint. In the first section of this study, creativity was examined from a structural vantage point, offering a base from which to dive into the strange pool of DTC design. Grid systems such as the golden section, the rule of thirds and the Fibonacci spiral were proposed as a way to test whether an ad adhered to basic laws of design. These constraints are the first set of constraints a designer encounters, consciously or not.

In a few interviews, some designers described their first days on the job with tales that ranged from mild worry to feelings of horror and fear. The bright side is that once you get the hang of it, the translation of a PI into an entire campaign with global reach turns out to be just like riding a bike. Distilling a conclusion to from this thesis’s hypothesis requires consideration of whether a complete understanding of DTC rules is necessary. This question, although a detour from the main thread of whether constraint impacts creativity, may best sum up the spirit of this inquiry into constraint.

Unfortunately, the question is so subjective a topic as to make the question unanswerable one way or the other; the idea can be argued both ways, endlessly. Wilson Capellán offered a convincing argument that not knowing the

regulations can offer a surprising range of solutions that would have otherwise not been attempted. His idea is that approaching a problem with a clean slate was possibly the best way to achieve the best visuals. His opinion is at odds with just about everyone consulted in this study; However, it was his unique viewpoint that caused me to focus on the possibility that ignorance might truly be bliss.

As Stokes points out in section 1.4, sometimes constraints become vehicles for mediocrity. Some brands have the misfortune of being paired with designers that don’t present the most brilliant solutions. It was interesting to find out that this happens because concepts that pushed the envelope too far were often rejected. If you know you are going to get slapped on the wrist for presenting illustrations when the client clearly prefers photograph, it would follow that you gravitate toward solutions that have been successful in the past.

In instances where an unconventional solution helped redefine the look of DTC of advertising, as in the case of the toilet calender designed by Lena Shabus, we see how the lack of constraint contributes to the creative process. It was in examining the Flomax project that the idea of testing the creative boundaries emerged.

Most of the literature reviewed seemed to be in favor of the idea that creativity was enhanced by boundaries—until two events almost upended the search. The first event was an interview featured previously. Wilson Capellán

vigorously challenged the idea that creativity is enhanced by knowledge of FDA regulation. His description of an exceptional campaign executed by a group of freelancers unaware of the regulations stopped me in my tracks. The second was presented in an interview with Lena Shabus. She described a project where illustrators were given the barest minimum of constraint and produced an engaging promotional piece that was actually requested by doctors.

Over many interviews, a theme emerged. It was the idea that a callus will develop on the heart of anyone put in the position of constantly having to alter good design, after having followed rules and regulations to the letter. Some assignments do not require the pushing of boundaries— efforts to do so are wasted.

Section 1.4 asks the question “What is the difference between constraint and predetermined mediocrity?” It would seem inevitable that pharmaceutical advertising is not easy on the eyes because adherence to rules sometimes must take precedence over stunning visuals. When a drug is branded, that imagery and message are expected to be adapted to fit many different pieces over a period of years, if the drug is successful.

Should designers then just accept as fact that DTC design is just always going to have fewer creative opportunities than selling jeans? The answer is a resounding NO, because there are many brands that manage to accomplish that very thing. In section 2, the campaign for the sleep drug Rozerem is held up as an example of design that managed to transcend selling

Jumping to conclusions

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Jumping to conclusionsa product and capture the attention of anyone watching. The best thing about the campaign was the investment the client made in the creative product—a commendable leap of faith that caused Rozerem to be one of the most widely recognized brands, according to a 2007 survey of broadcast DTC ads.

The marketing of Rozerem captured the hearts of viewers, generating mountains of buzz, praise and awards for the creative teams. Unfortunately the campaign did not capture the minds of physicians and translate into sales. It has been established that not only must the creative aspect be mind blowing, it must also motivate patients to ask their doctors about the product. However tempting it may be to blame the product (or disease category) for poor sales, it has been proven that good design can be squeezed from the proverbial stone. One of the most unsexy conditions of all time, benign prostatic hyperplasia (BPH or enlarged prostate) had one of the most creative design solutions. A drug that helps men urinate—perhaps nothing on earth is less sexy than that.

The rediscovery of the ‘toilet calendar’ was the second event that provided contrast to the prevailing perception of constraint in my research. I came across the Flomax calendar while researching design awards. It was a happy coincidence that this was created by a peer who was willing to share her experiences in an interview. Lena Shabus, a senior art director, structured her project in such a way (abandoning tradition, convention and constraint altogether) that the client was not only extremely pleased with the results, they thanked the team by commissioning a second calendar.

The designers really were taking a chance in presenting this idea, as nothing like it had ever been done before for this client. In this case the effort to stretch the definition of what is possible or allowed was the catalyst for a dramatic departure from what was expected.

When I began the search for possible answers to my hypothesis, I was leaning strongly towards embracing constraints fully as a design ally. Much of the research I found on the topic of boundaries pointed to how positive the effects of constraint can be. However, it became clear that the constraints of FDA regulation were not the sole reason DTC looks the way it does. Because there are many award-winning, visually stunning campaigns, there had to be other boundaries observed in the creation of the less successful DTC ads.

Marissa Mayer is the Vice President of Search Product and User Experience at Google. Her quote from a seminar on creativity provided a springboard for my hypothesis: “Constraints shape and focus problems, and provide clear challenges to overcome as well as inspiration. Creativity, in fact, thrives best when constrained….yet constraints must be balanced with a healthy disregard for the impossible. Disregarding the bounds of what we know or what we accept gives rise to ideas that are non obvious, unconventional, or simply unexplored. The creativity realized in this balance between constraint and disregard for the impossible are fueled by passion and result in revolutionary change.”

In attempting to conclude this thesis’s hypothesis, peers’ opinions and materials collected did not offer a concrete answer either way. To truly test the theory, three illustrators were asked to create images based on as little as two sentences of direction. Dimensions were fixed, but style, color and to some extent content were left at the discretion of the illustrators. The answers tended to suggest that having minimal instruction was not the optimal condition under which to operate. Keeping in mind that the success of the illustration was not the primary goal, but rather to test designers reactions to the lack of constraint.

My final thoughts on the issue of Creativity and Constraint are these: Constraints must be observed for practical reasons within DTC advertising and affect creativity in a positive way; however, they should never be used as a reason not to re-explore solutions that have been put aside out of an assumption they were going to be rejected by DDMAC, or to avoid examining completely new avenues of thought. All of the above are contingent upon the availability of time, budget and a willing team, of course!

Is it possible to test whether constraint has a positive impact on creativity? In order to find out, several designers who loved to illustrate were asked to participate in an attempt to do just that. The parameters were; very limited direction was provided to the illustrators, and the majority of decisions were left to them. The following two illustrators share a little information about themselves and weigh in on the process. The survey consisted of questions based on a 1-10 scale, 1 being the lowest.

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3.2 Testing the hypothesis

Lindsay Levitz, Art director/illustrator

“I’ve been drawing/sketching/painting since I could pick up a crayon. I started taking more concentrated art courses in junior high and all through high school. I majored in Fine Art in College (San Diego State University, graduated 2003) I received my Masters from Pratt in Communication Design in 2007, where I studied Illustration with Scott Menchin. I like to incorporate my illustrations into my graphic design work as much as I can.”

Rationale for illustrations

The image to the far right was the final that Lindsay Levitz provided as a response to the instruction that was given. The image on the near right was not used, because I felt that a more photographic approach was needed. The image on page 40 (the Appendix section following this chapter) was began by Lindsay Levitz and completed by Merry Davis. The direction was provided and then altered to delete a few of the elements: 1940s style pin-up girl type, dressed as a sales rep, with a price tag hanging from her skirt hem bearing the logo of an amalgam of three companies. She wears a sash over her outfit that says “Miss Uber Sales Rep USA, 2008” She’s being held by an American bald eagle flying through clouds (possibly just the hint of a wing and a claw gripping her waist, reminiscent of Fay Ray being held by king kong). The woman holds a rustic horn of plenty, cradled in her arm that has pills flowing out of it, down into the crowd below (you only see their multi-hued arms and hands grasping for the pills). With her free arm, she flings a handful of pills down into the field of hands and arms.

Responses from post-project survey:

How much instruction were you given for the illustrations you chose to work on, compared to other assignments you have had? 8

How did you like working with very little direction. 5

Rate rate the amount of constraints you placed on yourself (number of elements you chose to portray from original instruction, colors, size, etc.) 4

How much conceptualize or preliminary sketches did you do compared with other pieces you have worked on? 5

Does minimal direction help the creative process? 2

Does minimal direction hinder the creative process? 5

How does having almost complete freedom in choosing images compare to other assignments you’ve completed? 8

Do you think that constraints impact creativity in a positive way? 3

If you had to do this all over again would you? Of course!

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Jordan Chow, Studio artist

“[Drawing] all the while going to after-school art classes, eventually attending F. H. Laguardia High School of Performing and Visual Arts which lead to a Bachelor’s of Arts and Fine Arts degree at Alfred Univeristy....

I’ve spent a lot of time drawing. This can mainly be attributed to (1) My father used to do a lot of illustration. (2) My mother was also known to do a few drawings as well. (My parents did meet at Parsons after all.) (3) Early attachment to coloring book, illustrated children’s books, and comic books. Drawing tools and paper were always handy in my household. I started to do my own thing, found some other cool thing, started to copy that, found something else, etc.

Some nights, when in the groove, it’s like playing god. Whatever I’m drawing on becomes a world I’ve created from my mind and body. Creating and destroying. I spend a lot of time drawing.

Rationale for illustrations

The direction was provided and the image essentially is a direct interpretation of the instructions. Baby with a bib that has the letters DTC being thrown out the widow. The baby has a yellow ribbon in it’s hair, a pink cancer ribbon pinned to it’s diaper, ...You see a pair of very feminine women’s hands, red nail polish and a giant diamond ring and wedding band on the appropriate finger dangling from the window, suspended in the act of tossing the baby and the bath water. The hands are still clutching the basin, but the baby and water hang in mid-air. The baby has a WTF? Expression on its face. A blow up of a section of the water shows the words “cure”, “choice”, “knowledge”, “hope”, “understanding”, “personal responsibility”, “control”, “acceptance”, “de-stigmatization”, “compliance”, floating within the water-droplet blow up. The water droplet blowup is framed by a magnifying glass.

Responses from post-project survey:

How much instruction were you given for the illustrations you chose to work on, compared to other assignments you have had? 5

How much concepting or preliminary sketches did you do compared with other pieces you have worked on? 5

How does having almost complete freedom in choosing images compare to other assignments you have completed? ‘Freedom of creativity is almost always preferable...’

Do you think that constraints impact creativity in a positive way? ‘The unexpected results of such constraints can lead to other fascinating paths of exploration. Especially when contradictions to the constraints are offered; contradicting the constraints to seek freedom where it didn’t need to before. On the other hand, when constraints are followed rigorously, it can foster development of techniques and efficiency. An example is preliminary explorations or sketches. In a way, it is constraining ideas. Focusing the

ideas into something more cohesive.

3.2 Testing the hypothesis (continued)

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Interview excerpt: Tara Bruno

In this very candid interview a cardio-metabolic specialist shares her thoughts on some sensitive topics within DTC advertising.

Merry Davis: What is it that you do as a sales representative?

Tara Bruno: I am responsible for going to the doctors that are listed on my target list within my geography, and talking to those doctors about my products.

Merry Davis: Can you describe the kinds of materials you bring along on a visit to a doctor’s office?

Tara Bruno: A lot of what I have is detail leads. I also have reprints of journals; say something that has been published in the New England Journal or American College of Cardiology, Sometimes we are allowed to detail that reprint, and sometimes we’re allowed to just give it to the doctor and we are not supposed to talk about the content.

Merry Davis: Your two ways of contact with doctors are through office visits and through the dine and learns...which one do you think is more effective?

Tara Bruno: Actually it’s another venue altogether...a lot of the times that we get to talk to the doctors and have a meaningful discussion is over lunch in the office. We bring lunch into the doctor’s office and then he’ll sit down with us for 10 minutes and talk to us. You were asking which one is more meaningful?

Merry Davis: Yes, which one do think is more effective or that you see that they respond to more.

Tara Bruno: I think the dinner meetings are more effective however, not all doctors are willing to go out to dinner. For the most part, I probably have maybe, not even 10% of my doctors that will go to dinner after work, because a lot of them have families and lives and go home to their family.

Merry Davis: It’s lunches, dinners, and office visits that are – how long are the office visits?

Tara Bruno: If I don’t have a lunch appointment, five seconds.

Merry Davis: You have five seconds to communicate complicated science and ground breaking discoveries on lifesaving drugs. That’s incredible; you must be really good at what you do then.

Tara Bruno: I would be a lot more effective if I had the time. The doctors...a lot of them are closing their doors, a lot of them only take our samples, and the only time I have with them to talk about anything, is the time that it takes for them to sign my form that they are accepting my samples. They have so many more patients that they are trying to see to make the same amount of money that they made 10 years ago, because managed care is reducing the amount that they pay them per patient.

Merry Davis: So maybe the most lasting impression that you will leave with this doctor is stuff that you leave behind for them and the patients?

Tara Bruno: Yes. So every time I go into a doctors office, I try to leave something, whether it is a journal, a reprinted article, again something that has been approved. I can’t read a good article on the internet, print it off, and bring it to a doctor’s office that is illegal. I can get fired for that.

Merry Davis: Besides samples and journal ads, what are some of the materials that you would leave behind in a doctor’s office?

Tara Bruno: There are little things like pens, note pads, little clipboards, those are the items that the rule says they have to be under $25 in value, and that’s provided by our company, but that’s really all we can leave.

Merry Davis: What would you change if you could be part of the design process?

Tara Bruno: The more simplified the better. For instance I have a spiral bound detail aid that has 10 pages in it. On every page there is a little pocket with a pullout. You can pull it out from the top, you can pull it out from the side. Although [our sales material] has gotten more creative, [the material] needs to be simplified because of time constraints. Because you have 5 seconds-the simplest flashcard, or the simples detail aid is more valuable to you than something with graphics that are arresting or a die cut or a popup or anything like that.

Appendix

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Illustration by Lindsay Levitz, art direction Merry Davis

Appendix

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References 1. Marissa Ann Mayer. Creativity Loves Constraints...but [it] must be Balanced with a Healthy

Disregard for the Impossible. BusinessWeek. Journal on-line. Available from http://www.businessweek.com/magazine/content/06_07/b3971144.htm?chan=search (accessed 1/7/2008).

2. Sources that have been useful in helping to understand creativity in the context of this study; Eric M. Eisenberg, and H. Lloyd Goodall, Organizational Communication Balancing Creativity and Constraint. [New York: St. Martin’s Press, 1993]., Keith R. Sawyer, Explaining Creativity-the Science of Human Innovation, [Oxford; New York: Oxford University Press, 2006]., Jacob Goldenberg, David Mazursky, and Sorin Solomon, Essays on Science and Society: Creative Sparks, in Science [online journal article], available from http://www.sciencemag.org/cgi/content/full/285/5433/1495 (accessed 1/12/08).

3. Detmer, D.E., Singleton P.D., MacLeod A., Wait, S., Taylor, M., & Ridgwell J. The Informed Patient: Study Report. [Cambridge University Health, 2003]. Available http://www.jbs.cam.ac.uk/research/centres/cuh/tip/index.html. (accessed 1/21/08).

4. Food and Drug Administration, Direct-to-consumer advertising of prescription drugs: physician survey, preliminary results. Available from http://www.FDA.gov/cder/ddmac/globalsummit2003/sld001.htm (accessed 1/21/08).

5. A preliminary look at three national studies conducted over a period of years; Food and Drug Administration, The Impact of Direct-to-Consumer Advertising. Available from http://www.FDA.gov/cder/ddmac/globalsummit2003/sld001.htm (accessed 1/21/08). For the full findings of the study, the meeting notes are available at http://www.FDA.gov/cder/ddmac/dtc2005/default.html.

6. A drug industry executive expresses qualified support of the current state of DTC affairs. Pat Kelly. DTC advertising’s benefits far outweigh its imperfections. Health Affairs (Millwood). 2004;Suppl Web Exclusives:W4-246–248. Available from http://content.healthaffairs.org/cgi/content/full/hlthaff.w4.246v1/DC1 (accessed 1/21/08).

7. Lance Longwell. Global Pharmaceutical Market Grew 7.0 Percent in 2006, to $643 Billion, in IMS Health [database online].Norwalk, CT, Available from http://www.imshealth.com/ims/portal/front/articleC/0,2777,6599_3665_80560241,00.html (accessed 1/12/08).

8. Guidance for Industry. In Center for Drug Evaluation and Research [database online]. Rockville, MD March 08, 2001. Available from http://www.FDA.gov/cder/guidance/1804fnl.htm (accessed 1/17/08).

9. Survey conducted by author, New York, NY, August 31-September 26, 2007.

10. Stokes, Patricia D. Creativity from Constraints The Psychology of Breakthrough, [New York: Springer Pub. Co., 2006], 9-13.

11. György Doczi, The Power of Limits Proportional Harmonies in Nature, Art, and Architecture, [New York: Random House, 2005], 1.

12. Stokes. Creativity from Constraints, xii.

13. Stokes. Creativity from Constraints, xiii.

14. Stokes. Creativity from Constraints, 96.

15. Stokes. Creativity from Constraints, 100.

16. Stokes. Creativity from Constraints, xiv.

17. Appendix, Excerpt from Gang of Four Interview; Wilson Capellán, interview by author, New York, NY, December 20, 2007.

18. Excerpt from questionnaire completed by Maritess Gonzales, New York, NY, November 1, 2007.

19. Stokes. Creativity from Constraints, xii.

20. Ando Hiroshige, 36 Views of Mount Fuji, 1852. Images of prints from http://www.hiroshige.org.uk. The numbers in front of the titles indicate position in the series.

21. Claude Monet, Wheatstacks, 1890-91. Images of paintings from http://www.artic.edu/aic/collections/resource/443

22. Interview with John Furness by author, New York, NY, November 9, 2007.

23. Rudolf Arnheim. Art and Visual Perception A Psychology of the Creative Eye, [Berkeley, Calif: University of California Press, 2004].

24. Rudolph Arnheim. Entropy and Art; an Essay on Disorder and Order. [Berkeley: University of California Press, 1971], 1.

25. Arthur I. Miller. Insights of Genius Imagery and Creativity in Science and Art. [Cambridge, Mass.; London: MIT, 2000], 421.

26. Miller. Insights of Genius Imagery, 421.

27. “Golden section.” The American Heritage Dictionary of the English Language, Fourth Edition. Houghton Mifflin Company, 2004. 09 Feb. 2008. Dictionary.com http://dictionary.reference.com/browse/golden section.

28. Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements: Draft Guidance. Http://www.FDA.gov/cder/guidance/5669dft.pdf. (Accessed 11/12/07).

29. Questions and Answers About the New Content and Format Requirements for Prescribing Information.Http://www.FDA.gov/cder/regulatory/physLabel/physLabel_qa.htm. (Accessed 03/09/08)

30. FDA Consumer magazine. Truth in Advertising: Rx Drug Ads Come of Age. Http://www.FDA.gov/fdac/features/2004/404_ads.html.

31. Draft guidance for industry. Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drug and Biological Products - Content and Format. Http://www.FDA.gov/cber/gdlns/boxwarlb.htm

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Additional Resources

History of medical advertising

The time frame allotted for the completion of this thesis did not allow for the inclusion of a section that would showcase all of the most fascinating books on the topic of medical advertising history. The following materials provided detailed insight into several aspects of

pharmaceutical advertising that receive little attention.

The American Medical Association was one of the earliest organizations to champion regulation and drive efforts to ban deceptive advertising practices. Their web site, http://www.ama-assn.org/ama/pub/category/1915.html, offers an interesting visual time line that also includes significant historical events coinciding with it’s history.

Perhaps one of the few books written about the early history of medical advertising companies is Medicine Ave. The book unfolds chronologically and reveals the histories of several major medical advertising agencies. There are many examples of medical ads from the early 1900s up to the mid 90s: William G., Castagnoli et al. Medicine Ave. : The Story of Medical Advertising in America. Huntington, N.Y.: Medical Advertising Hall of Fame, 1999.

Nancy Tomes ‘The Great American Medicine Show Revisited’ presents a treasure trove of information about FDA regulation and medical advertising. Tomes studies the birth of medical advertising through current times. She seems to follow three avenues through the article; scientific advances in medicine, the evolution of drug marketing and the FDA response to these events. Nancy Tomes. “The Great American Medicine show Revisited.” Bulletin of the History of Medicine 79, no. 4 (2005): 627-663.

Creativity and constraint

I found a nugget of support for a twist in my hypothesis in ‘Explaining Creativity’, Keith Sawyers’ examination of the role of creativity in the sciences. The twist came at the moment of realization that while understanding rules are necessary to structure a problem, they can strangle good ideas in the same way a vicious weed will a delicate flower. On one hand he argues a line of thought similar to Stokes; ‘Creativity is always specific to a domain. No one can be creative until they internalize symbols, conventions, and languages of a creative domain.’ (p. 74) This line of thinking runs throughout this dissection of how creativity works in area’s not usually associated with that word. He also supports is the idea that problem finding is almost even more important than problem solving. He references a quote by Einstein to make his point: ‘The formulation of a problem is often more essential than its solution...To raise new questions, new possibilities, to regard old questions from a new angle, requires creative imagination and marks real advance in science.’, (p. 72). Keith Sawyer. Explaining Creativity the Science of Human Innovation. Oxford; New York: Oxford University Press, 2006.

Prescribing Information

For an amusing look at the evolution of the brief summary, this ppt. slide deck meant to accompany a discussion given on how the brief summary came to be. http://www.fda.gov/cder/ddmac/presentations.htm. A Brief History of the Brief Summary.

If you find yourself hungering for more information on the latest prescribing information guidelines, but have a short attentions span, the FDA has put together an entertaining flash presentation at https://FDA.saic.com/fdaprescriptionlabeling/mainpage_wo_credit.cfm.

The latest FDA guidelines regarding prescribing information are fully explained at http://www.fda.gov/bbs/topics/NEWS/2004/NEW01016.html.

Ever wonder why a drug receives a black box warning? See http://www.fda.gov/CDER/guidance/5538dft.htm.

For An interesting take on black box warnings go to http://druganddevicelaw.blogspot.com/2006/12/preemption-of-black-box-warning-claims.html.

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Glossary

Adverse effectsDuring clinical trials, an unwanted side effect of taking a prescribed medication.

Adverse eventIn clinical trials, all negative changes in the health of participants are recorded as such, during the trial or within a certain time period after the trial has ended. Adverse events are classified as either serious or minor.

AMA styleAmerican Medical Association Manual of Style. A book of rules that is used as a standard for copy content in most pharmaceutical advertising.

ASCOAmerican Society of Clinical Oncology.

Blockbuster drugA drug that consistently generates over 1 billion per year for its creator.

Brief summaryA printed document indicating what the product is to be used for, its side effects and medications it may not be taken with. It must accompany any advertisement that makes a claim.

BTCBehind-the-counter. Drugs that can be purchased after consultation with a pharmacist. Some examples include certain allergy and cold medications with epinephrine, Plan B contraceptives, etc. BTC is sometimes referred to as a third-class or pharmacist-only class of drug.

CMEContinuing medical education. All states require that doctors complete a certain yearly amount of CME credits to maintain their license to practice medicine.

DDMACDivision of Drug Marketing, Advertising and Communications. Division of the FDA responsible for reviewing prescription drug advertising and promotional labeling to ensure that the information contained in these promotional materials is not false or misleading.

Detail aidA printed document used by pharmaceutical sales representatives that contains the most important information regarding dosage efficacy, etc.

DetailingDrug companies use sales reps to inform physicians of the latest information on drugs and promote the prescribing of those drugs during visits to the physicians office.

DTC advertising Direct-to-consumer advertising.

DTPDirect-to-patient advertising. A variation of Direct-to-consumer advertising. They are drug ads that are identified as having a specific condition.

e-detailingA tool that sales reps use when visiting doctors offices. Different forms include promotional educational information via CD, Web, tablet PC’s, phone-in or on-line seminars, CME events or webinars, to name a few.

Fair balanceUsed in DTC advertising to describe the risks versus the benefits of taking a medication.

FDAFood and Drug Administration. The governing body that determines the guidelines, or constraints that regulate the look and message of advertising prescription medicine.

First-in-Class DrugA drug that is the f i rst of its k ind to be ava i lable to market.

Fry readability graphMethod that determines the grade level of writing by analyzing three, 100-word passages from a random sections in a document, taking the average number of syllables and the average number of sentences for each selection and plotting those numbers on a Fry graph.

FTCFederal Trade Commission. Used here to indicate the governing body that controls over-the-counter marketing.

Generic drugA drug which is the same as a brand name drug, but is not branded or under any patent.

HCPHealth Care Professional. Any person related to the healthcare industry (Doctors, nurses, pharmacists, podiatrists etc.).

Help-seeking adAn ad where no claim is made and disease awareness is promoted. Also referred to as an ‘Ask your doctor’ ad.

IndicationWhat conditions a drug has been approved to be used as treatment for.

JAMAJournal of the American Medical Association. Peer reviewed medical journal. The key objective of the publication is “to promote the science and art of medicine and the betterment of the public health.”

The following definitions were compiled over the span of this project. Some of the terms do not appear in the body of the research, but are relevant because they provide support for the topics presented.

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Learned intermediaryA health care provider, usually a doctor or physician, who is properly warned of the dangers of a product by the manufacturer in accordance with the learned intermediary doctrine.

Lifestyle drugA drug that is used to treat a non-fatal disease.

Med Ed or medical educationSee CME.

Med RegMedical Regulatory. The internal process by which a pharmaceutical company internally reviews a promotional piece to ensure the data are correct and that it is in compliance with FDA regulations.

Me-too drugA term used to describe a type of drug that comes to market after another similar drug which little or no difference in efficacy.

MLR or MLRR Medical Legal Regulatory Review. The process by which pharmaceutical companies vet their ads before sending them to DDMAC for approval.

MOAMechanism of action. Description of how a drug acts in the body. May be verbal, graphic or animated.

MoleculeA drug is often described as a molecule during the testing phase, before being marketed.

Most recommendedA term used by drug marketers to indicate that a drug is the most highly prescribed in its class.

Off-label promotionWhen treatment options are presented to doctors for conditions or populations that the drug has not been specifically approved for.

Orphan-class drugA product that treats a disease that affects fewer than 200,000 Americans.

OTC Over-the-Counter drugs. Medications that can be sold legally without a doctor’s prescription.

Personalized medicineTerm usually used to describe the future advent of treating a patient’s illnesses using their genes as tools to help choose medicine and treat a condition, perhaps even prior to its manifestation.

PharmacokineticsThe process by which a drug is absorbed, distributed, metabolized, and eliminated by the body.PIPrescribing Information. A printed document indicating what the product is to be used for, its side effects and medications it may not be taken with. It must accompany any advertisement that makes a claim.

POAPoint of Action or Plan of Action. A periodic marketing strategy for campaigns.

PPIPatient Prescribing Information. A printed document that contains user-friendly information on how to use a drug safely.

Product claim adAn ad that makes a statement about efficacy, indication, safety or MOA.

Professional advertising Advertising directed towards health care providers.

P-valueProbability value. A statistical term that is used in trial drug studies. It is used to describe the probability that a patient’s condition will improve by taking that medication, and that the improvement was not simply due to chance.

Reminder adThese kinds of ads contain minimal information, most often just the name of the drug, its indication and dosage.

Warning lettersLetters issued by the FDA to pharma companies and agencies to alert them to violations.

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In the process of gathering information for this project, the interviews ended up being the richest source of mate-rial. The time people spent considering the questions I sent them in advance and during the interviews and follow-up conversations was greatly appreciated. Below is a listing of the details of each interview and questionnaire, as well as the ‘shining moment quote’ I felt summed up the spirit of the interview. All of the interviews, questionnaires and surveys are included on a disk attached to the back cover of this thesis. Wav. files are also included for the interviews. Some of the material was changed–to correct transcription misunderstandings, but for the most part they are unedited.

Barry BergerBarry David Berger & Associates, PrincipalFDA rules are just another one of the lists of concerns and attributes that you need to understand to effectively respond to a client’s project.

Jonathan BloomCopywriterFDA rules provide guidelines. I’ve always felt that with these restrictions in effect, we actually have to be even MORE creative, than say, someone selling candy bars or toys. With such rules, our creative has to withstand endless scrutiny from internal account team members, to clients, to medical, legal, and regulatory people, all armed with red markers, fearing for their own jobs, and looking to poke holes in everything you come up with.

Tara BrunoNovartis Pharmaceuticals, Cardio-Metabolic SpecialistWhat is most important would be something that is simple and to the point, and that would probably come from a quick flashcard that says, blood pressure with 150 mg of this drug reduces 15 points, and 300 mg reduces by 20 points...

Wilson CapellánDRAFTFCB, Art SupervisorThe fact that the FDA establishes an even playing field for everybody—it’s a good thing, but I think that the more constraints they give us, the bigger the opportunity they give us to be more creative.

Nanette DewesterFreelance Art DirectorI’m glad the FDA presents the hurdles that it does because ...it gives you fuel for the fire to work harder.

Tom DomanicoDRAFTFCB, Chairman, CEO AND Worldwide Creative DirectorRestrictions are a challenge. And we’re always challenged. Every day we’re solving problems...Challenge leads to education, education and understanding lead to good work. You can’t do [DTC design] unless you understand those restrictions.

John FurnessBayer HealthCare Pharmaceuticals, Product ManagerAt the end of the day in creativity, I don’t know if there are boundaries. Ultimately, if there are boundaries, you have to be creative within them.

Bob GlaserMedsn, Chief Marketing & Sales OfficerI don’t think FDA actions have a positive or a negative effect upon the creative aspects of introducing a campaign. I think that good creative can work within the advertising guidelines [regardless of FDA regulation].

Maritess GonzalesSaatchi and Saatchi, Senior Account ExecutiveI think constraint forces advertisers to be more creative. Also, it provides structure or framework to work with.

Tim HawkeyDRAFTFCB, VP Creative Director, Copy[FDA regulation makes] you have to be more creative...It’s very easy to brainstorm ideas about jeans. It’s very difficult to brainstorm ideas about a condition that you’ll never have with a constrained set of words. You know you have there are physically 50 words you can use...you have to be really creative in order to do something that’s unexpected with such a very, very tight path that you can walk on.

Fard Johnmar, M.A.Founder of Envision SolutionsI think that [pharmaceutical advertising is] still one of the best ways to get information out there to physicians and patients about drugs. But if you really want to get into loyalty, you want to get into [patient compliance], if you want to get into lifestyle changes that need to be put in place around the drug, advertising doesn’t really cut it. And that’s why social media provides pharmaceutical companies who embrace it with a much richer way of communicating with the public.

Interviews

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Sarah KatzAgency Rx, Senior Art DirectorNo, I don’t really see [FDA regulation] as constraints or obstacles. It’s part of what you’re being told to do. As a designer, you should know better than that than to have an outside organization dictate how you design. It’s about your brain. The rules, they’re just rules. It’s just an aspect, fair balance. It’s a design element that you have to work around.

Loretta LinserDRAFTFCB, Vice President, Director of Editorial ServicesSo, in that way, yes, [FDA regulation] does cramp one’s style. But on the other hand, by having to think around and within these rules it promotes creativity I think in a way that if anything went, you wouldn’t see the same degree of creativity.

Kaya MulkowskaDRAFTFCB, Senior Art DirectorI think that if you don’t step back to think about it, [FDA rules] could inhibit [creativity], but I think that a challenge makes for better results in the end.

Linda StrykerThe CementWorks, Senior Group Art Director[Constraint in the form of FDA regulation] challenges you to be more creative to get your message across but yet it’s very restrictive in that the med reg and DDMAC submissions can water down a really creative ad....

Karin TaylorJohnson & Johnson, Art SupervisorI think if the regulations are outlined clearly, they can encourage creativity. For designers, especially, who learn them enough to feel that they are second nature the same way a budget or language might be, the regulations just become part of the design library they call upon when starting any project.

Roy TuckCreative Director, Art Director, IllustratorI worked at Ogilvy as Group Creative Director, for a guy named Norman Barry, who was a Brit, Executive Creative Director, at the time, and he used to say, “Give me the freedom of a tightly defined strategy,” and what that means is, basically, very simply, you’ve got all the guidelines, the rest of it should be negotiable. It’s like doing the painting, if you know the size of the canvas, the shape of canvas, it’s going to be square rather than round, it’s going to be canvas rather than wood—once you get that stuff out of the way, you’re free to think.

Caroline WaloskiSirens Song Gallery, Artist in Residence and DirectorOf course rules limit you, but you need to get around them. Pharma advertising is not just a creative process, but one performing a service to dispense information, to either get a doctor to prescribe, or a patient to inquire. The rules need to be there to prevent misuse or misinformation. Good creative is only good if it is truthful and responsible along with being seductive and entertaining.

Ken ZierlerVP, Group Art Supervisor......Definitely the rules effect and drive the creative.

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Thanks

Special Thanks to everyone who participated in the development of this thesis:

Chava Ben-Amos

Dominic Aradio

Quentin Ball

Michael Bierut

Barry Berger

Jonathan Bloom

Tara Bruno

Wilson Capellán

Jordan Chow

Nanette Dewester

Tom Domanico

John Furness

Bob Glaser

Maritess Gonzales

Tim Hawkey

Fard Johnmar

Sarah Katz

Lindsay Levitz

Loretta Linser

Alan Mathios

Kaya Mulkowska

J.R. Meloro

Harriet Perdikaris

Ralph Skorge

Linda Stryker

Karin Taylor

Roy Tuck

Caroline Waloski

Ken Zierler

My warmest and most heartfelt thanks go out to the people that spent time with me discussing my topic and helping give structure to my inquiry. The two people I’d like to single out are Wilson Capellán and Lena Shabus for changing the rhythm and tone of my research. If either of them realized that their comments provided counterpoint to my hypothesis I’ll never know—unless they’ve read this thesis all the way to this particular page. If that should occur, I’m putting it in print that I owe the two of them a really nice dinner.

I’d like to give a special mention to Ginger Wilmot and Susan Pilshaw (transcriptionists), Shavsha Davis (statistics), Judy Hoffman and Tim Simmonds (editorial comments), Rima Mason (who cooked for me in my hour of need). I have a profound respect for Harry Ettling who read several passes of my thesis and provided great commentary and support throughout the process. I owe him a great debt for looking the other way at my abuse of serial commas, ellipses and butchering grammar. Professors who responded to my survey and everyone who answered my questionnaire early on in my research. Chava Ben-Amos deserves a special thank you for her comments on the design of my project and also for being so flexible and understanding with my work schedule. Miguel Unson, Ana Garcia and Ron Wolfson were my pillars of strength during the duration of this project and I owe them a huge thanks for their time and consideration of my work.

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