Drug Discovery - ACS Publications

9 Drugs—The American System W. C L A R K E W E S C O E , M . D .

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Sterling D r u g Inc., 90 Park A v e . , N e w York, Ν. Y . , 10016 The American opment

and

man's past.

system

of medicines—their

use—stems Although

national

counterparts,

unique

in many ways.

in the extent to which consumer

scrutiny

of regulations the system—yet, ductive, very

and

from

rooted

devel

deeply

it shares this history

with

the American

is distinct

system

Not the least of these is it has become political

and controls it remains

thoroughly

discovery,

a history

viable.

its

has become It continues

renewed

A

plethora

the everyday

highly creative,

and

embodied

the object of

maneuvering.

in

inter

enormously to serve its

lot of pro public

well.

Τ η this e m o t i o n a l e r a of d i s c o r d , d i s c u s s i o n , dissent, a n d d e m a g o g u e r y , i n this p e r i o d of q u e r y about a l l things m a d e a n d u s e d a n d ingested, i n this age o f quest f o r a better l i f e i n a better e n v i r o n m e n t , a c o n c e r n w i t h drugs u s e d f o r spectacular

therapeutic

achievement

a n d abused

w i t h d e v a s t a t i n g results has b e c o m e a n A m e r i c a n p r e o c c u p a t i o n .

The

d i s c o v e r y of n e w c h e m i c a l c o m p o u n d s w i t h i m p o r t a n t m e d i c i n a l p r o p erties, once h e r a l d e d w i t h a d m i r a t i o n a n d a c c l a m a t i o n , is n o w , it seems, m o r e often l o o k e d u p o n as a threat to the i n t e g r i t y of the h u m a n b o d y , if n o t to the structure of society.

T h e w o r d d r u g itself has c o m e to b e

u s e d n e a r l y a l w a y s i n a pejorative sense; f o r that reason I retitle this presentation, to p u t i n t o p r o p e r p e r s p e c t i v e the discussions to f o l l o w : "Medicines, T h e A m e r i c a n System." T h e r e is n e e d f o r a d i s c u s s i o n s u c h as this because of the p u b l i c p r e o c c u p a t i o n w i t h the d i s c o v e r y , d e v e l o p m e n t , a n d u l t i m a t e d e l i v e r y of medicines.

T h e great d i s a p p o i n t m e n t m a y b e that v e r y f e w other t h a n

ourselves w i l l ever b e a w a r e that this s y m p o s i u m w a s h e l d . W e m a y b e e n g a g e d i n another exercise w h e r e i n t h e w e l l i n f o r m e d a n d the most k n o w l e d g e a b l e w i l l b e t a l k i n g o n l y to each other. Nonetheless, I p r o c e e d w i t h t h e g l i m m e r of h o p e that together w e m i g h t p r o d u c e a l i t t l e l i g h t w h e r e presently there appears to b e o n l y h e i g h t e n i n g heat a n d g a t h e r i n g darkness. 195

Bloom and Ullyot; Drug Discovery Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

196

DRUG DISCOVERY

The Evolution of Medicines M a n i n h i s search f o r m e d i c i n e s to ease his p a i n , hasten h i s h e a l i n g , a n d c u r e h i s disease has c r e a t e d a n e n t h r a l l i n g story.

H i s early

quest

f o r m e d i c i n e s settled l o g i c a l l y o n the l i v i n g plants w h i c h s u r r o u n d e d h i m : bushes a n d trees, their roots, t h e i r leaves, t h e i r b a r k . B y t r i a l , error, a n d experience h e a c c u m u l a t e d a s u b s t a n t i a l k n o w l e d g e s u c h that b y t h e t i m e a w r i t t e n l a n g u a g e a p p e a r e d a list of u s e f u l p r o d u c t s c o u l d b e re-


c i t e d . S u c h a list of p l a n t materials is f o u n d i n the T h e b e s p a p y r u s d a t i n g f r o m the p e r i o d of 1600 B . C . E v e n w i t h o u t c h e m i c a l techniques a c e r t a i n s o p h i s t i c a t i o n w a s established a b o u t p l a n t materials, f o r as early as the f o u r t h c e n t u r y B . C . T h e o p h r a s t u s w a s able to w r i t e a b o u t differences i n p o t e n c y d e p e n d e n t u p o n the parts of the p l a n t u s e d , the age of t h e p l a n t , the area of its o r i g i n , a n d its m a n n e r of p r e s e r v a t i o n . B y the first c e n t u r y A . D . the alchemists of A l e x a n d r i a w e r e able p a r t l y to p u r i f y substances b y d i s t i l l a t i o n a n d filtration, a n d D i o s c o r i d e s d e v e l o p e d some c r u d e sensory a n d p h y s i c a l m e t h o d s f o r testing botanicals. P e r h a p s the earliest o r i g i n s of t h e p h a r m a c e u t i c a l i n d u s t r y are to b e f o u n d i n t h e trade i n v o l v i n g the root gatherers a n d t h e m i d d l e m e n : the druggists a n d the alchemists, w e l l established b y G a l e n ' s d a y . F r o m h i m c a m e a classification of p l a n t materials a n d , a d d i t i o n a l l y , a l o n g series of complicated plant-based prescriptions for various therapeutic indications. T h e specificity a n d p u r i t y of p r o d u c t s w e r e as i m p o r t a n t t h e n as t h e y are n o w . T o assure u n i f o r m i t y , the M i d d l e E a s t e r n c i v i l i z a t i o n s r e q u i r e d that m e d i c i n a l materials b e p r o d u c e d b y druggists u n d e r the s u p e r v i s i o n of a g o v e r n m e n t a l f u n c t i o n a r y . T h e c o n c e r n of t h e r e p u t a b l e druggists, p h a r m a c i s t s , a n d apothecaries

of the W e s t e r n w o r l d w a s ex-

pressed b y t h e p u b l i c a t i o n o f a f o r m u l a r y i n F l o r e n c e i n 1498. T h u s , b y the b e g i n n i n g of the 16th c e n t u r y b o t h the f r a m e w o r k a n d t h e p r i n c i p l e s of o u r present system h a d b e e n i n t r o d u c e d : c o m m e r c e , p u r i t y of p r o d u c t , self-regulation, integrity, a n d governmental supervision. W i t h Paracelsus i n the 1 6 t h c e n t u r y c a m e the i n p u t of i n n o v a t i o n , creativity a n d investigation.

T h r o u g h h i m c a m e the i n t r o d u c t i o n i n t o

m e d i c i n e o f o p i u m a n d t h e metals m e r c u r y , s u l f u r , a n t i m o n y , a n d i r o n . T h e first m e d i c i n e s f r o m t h e N e w W o r l d , c i n c h o n a a n d i p e c a c , i n t r o d u c e d i n t o E u r o p e i n t h e early 17th c e n t u r y .

were

I n the 18th c e n t u r y

c a m e the i n t r o d u c t i o n of d i g i t a l i s t h e r a p y b y W i t h e r i n g a n d the r e m a r k a b l e d i s c o v e r y of t h e v a l u e of v a c c i n a t i o n b y Jenner. T h e 19th c e n t u r y p r o d u c e d the a p p l i c a t i o n of true scientific p r i n ciples to man's search f o r d r u g s . A n a l y t i c a l m e t h o d s w e r e d e v e l o p e d to d e t e r m i n e t h e c h e m i c a l a n d p h y s i c a l p u r i t y of c o m p o u n d s , a n d the p r i n ciples of b i o l o g i c a l assay w e r e i n t r o d u c e d . W i t h t h e c o n t r i b u t i o n s o f Pasteur a n d E h r l i c h , the foundations were laid for chemotherapy. Sem-


9.

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Drugs—The

American

197

System

melweis, Holmes, and Lister began controlled clinical experimentation a n d i n t r o d u c e d the p r i n c i p l e s of antisepsis.

T h e general

ether a n d c h l o r o f o r m — w e r e a d o p t e d i n t o s u r g i c a l p r a c t i c e .

anesthetics— F i n a l l y , the

c o n t r i b u t i o n s of E h r l i c h t h o r o u g h l y established synthetic o r g a n i c c h e m istry as a r i c h source of n e w m e d i c i n e s . T h r e e other aspects of the system as w e k n o w it t o d a y w e r e also i n t r o d u c e d i n the 19th c e n t u r y .

Regulatory legislation was adopted b y

the B r i t i s h P a r l i a m e n t i n 1875. A d v e r t i s i n g , c o m p l e t e w i t h p r o d u c t c l a i m s , Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

a p p e a r e d — d i r e c t e d b o t h to the p h y s i c i a n a n d the p u b l i c , b u t p r i m a r i l y to the latter.

T h e r e also arose d e t e r m i n e d c o m p l a i n t s a b o u t the cost of

m e d i c i n e s , centered o n the d i s c o v e r y a n d m a r k e t i n g of S a l v a r s a n . T h e d e v e l o p m e n t s of the 2 0 t h c e n t u r y d e f y d e t a i l i n g here.

Suffice

it to say that i n this c e n t u r y c a m e the discoveries of b a r b i t u r a t e s , of h o r mones ( a n d t h e i r c h e m i c a l s y n t h e s i s ) , of antibacterials a n d a n t i b i o t i c s , of o r a l d i u r e t i c s , of better analgesics, a n d of a host of other c o m p o u n d s . F i n a l l y , the p h y s i c i a n was p r o v i d e d w i t h m e d i c a t i o n s not o n l y f o r the treatment of s y m p t o m s b u t often for the u n d e r l y i n g cause of disease itself. It m i g h t seem that man's search for drugs has t r a n s c e n d e d a l l his other quests.

C e r t a i n l y , it has a l w a y s b e e n one of his intense p r e o c c u -

pations. P e r h a p s it is a l l best s u m m a r i z e d b y the w o r d s of S i r W i l l i a m O s i e r w h o s a i d , i n m a n y speeches to diverse audiences, that the single characteristic s e p a r a t i n g m a n f r o m the l o w e r a n i m a l s is his intense desire to take m e d i c i n e s . T o w h i c h t h o u g h t I m i g h t a d d , i n the l i g h t of h i s t o r y , m a n s d e t e r m i n a t i o n to d i s c o v e r n e w m e d i c i n e s .

The Origin of Pharmaceuticals I n the r e c i t a t i o n of h i s t o r y there is a l w a y s the risk that the s u r v i v i n g relatives of a n i n d i v i d u a l b e c o m e i n c e n s e d b y the o m i s s i o n of his n a m e . T h e same r i s k is r u n w h e n one attempts r e t r o s p e c t i v e l y to c o m p a r e the c o n t r i b u t i o n s of v a r i o u s countries to m o d e r n t h e r a p y .

A s is the case

w i t h i n d i v i d u a l c r e d i t , w h e r e the significant c o n t r i b u t i o n of one m a n is almost a l w a y s the c u l m i n a t i o n of the w o r k s of m a n y , there is no n a t i o n a l science w h i c h c l e a r l y stands out a b o v e others. A l l science is i n t e r n a t i o n a l ; a l l science d e p e n d s u p o n the c o l l e c t i v e c o n t r i b u t i o n s of m a n y . D i s c o v e r y is most often the result of s u p e r b t i m i n g a n d surpassing g o o d f o r t u n e . A t the risk, therefore, of p r e c i p i t a t i n g a m i l d i n t e r n a t i o n a l crisis, let m e a t t e m p t to assign n a t i o n a l c o n t r i b u t i o n s to p h a r m a c e u t i c a l progress i n the 10 categories into w h i c h p h a r m a c e u t i c a l research effort is most u s u a l l y classified. I n the field of c e n t r a l nervous system p h a r m a c o l o g y the c o n t r i b u tions g e n e r a l l y h a v e b e e n E u r o p e a n . T h e m i l d analgesic agents, a s p i r i n a n d p h e n a c e t i n , w e r e s y n t h e s i z e d i n G e r m a n y , as was the first l o c a l a n -


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esthetic agent ( p r o c a i n e ) , a n d the o r i g i n a l d e r i v a t i v e s of b a r b i t u r i c a c i d as w e l l as the a c i d itself.

Meperidine likewise came from G e r m a n y al-

t h o u g h its usefulness as a n analgesic was d e v e l o p e d i n the U n i t e d States. Insofar as the n e w e r t r a n q u i l l i z e r s , depressants, a n d antidepressants

are

c o n c e r n e d the c o n t r i b u t i o n is s h a r e d a m o n g m a n y : S w i t z e r l a n d , G e r m a n y , the U n i t e d States, E n g l a n d , a n d F r a n c e . A n t i - i n f e c t i v e s a n d a n t i b i o t i c s h a v e b e e n c o n t r i b u t e d i n l a r g e measure b y G e r m a n y , E n g l a n d , a n d the U n i t e d States. T h e l a n d m a r k c o n t r i b u t i o n Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

of m e d i c i n e s affecting neoplasms a n d the e n d o c r i n e systems c a n b e att r i b u t e d p r i m a r i l y to the U n i t e d States a n d C a n a d a . M e d i c i n e s affecting the d i g e s t i v e a n d g e n i t o u r i n a r y systems w e r e d e r i v e d f r o m the U n i t e d States a n d G e r m a n y .

R e s p i r a t o r y agents, i n c l u d i n g a n t i h i s t a m i n e s , c a n

be a t t r i b u t e d to F r a n c e , the U n i t e d States, G e r m a n y , a n d E n g l a n d . V i t a m i n t h e r a p y has b e e n e n h a n c e d b y w o r k e r s f r o m the N e t h e r l a n d s , E n g l a n d , a n d the U n i t e d States.

C a r d i o v a s c u l a r m e d i c i n e s , of w h i c h there

are m a n y , c a n be a t t r i b u t e d to E n g l a n d , the U n i t e d States, S w i t z e r l a n d , and

Germany.

D e r m a t o l o g i c a l s a n d b i o l o g i c a l s are d i f f i c u l t to classify

because of t h e i r large n u m b e r s .

D i a g n o s t i c agents, p a r t i c u l a r l y r a d i o -

p a q u e substances, have b e e n c o n t r i b u t e d b y the U n i t e d States, G e r m a n y , a n d the S c a n d i n a v i a n countries. W h a t a resume of the last 75 years indicates is that most c o n t r i b u tions are l i k e l y to b e d e r i v e d f r o m h i g h l y d e v e l o p e d , t e c h n o l o g i c a l societies, possessed of s u p e r b universities. T h e y result, m o r e often t h a n not, f r o m a c o m p l e x i n t e r p l a y b e t w e e n e d u c a t i o n , i n d u s t r y , a n d institutes for research.

H i s t o r y indicates

e v e n m o r e c l e a r l y that major

discoveries

e m a n a t e f r o m those countries i n w h i c h the p h a r m a c e u t i c a l i n d u s t r y is h i g h l y d e v e l o p e d a n d e x c e p t i o n a l l y research o r i e n t e d . O n e is l e d to the i n e v i t a b l e c o n c l u s i o n that m a n y , if not most, significant c o n t r i b u t i o n s w i l l c o n t i n u e to c o m e f r o m the research efforts of w e l l - f u n d e d , c o m p e t e n t l y staffed i n d u s t r i a l l a b o r a t o r i e s — t h a t

w i t h o u t s u c h laboratories,

progress

w i l l be s l o w a n d advances f e w e r . The

American

System

O u r d o m e s t i c system is s t i l l e v o l v i n g . It b e g a n w i t h f r o n t i e r m e d i cine, w i t h practitioners of w i d e l y v a r y i n g e d u c a t i o n a l b a c k g r o u n d s a n d p r o f e s s i o n a l skills.

T h e horse-and-buggy doctor p r o v i d e d more pastoral

t h e r a p y t h a n he d i d m e a n i n g f u l m e d i c a t i o n . A r m e d w i t h f e w specifics, he l a i d o n his h a n d s , he c o m f o r t e d , a n d he c a r e d as best he c o u l d for s u r g i c a l emergencies. A c o n s i d e r a b l e part of the d e v e l o p m e n t of the A m e r i c a n system c a n b e r e l a t e d to h o m e o p a t h y , a t y p e of p r a c t i c e w h i c h c o u n t r y w e l l i n t o the 20th c e n t u r y .

flourished

i n this

It was h o m e o p a t h y that established


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the concepts of close o b s e r v a t i o n of s y m p t o m a t o l o g y , of m e d i c i n a l thera p y f o r a l l ailments, a n d of specific responses to m e d i c a t i o n .

It

was

h o m e o p a t h y as w e l l that c o n t r i b u t e d i n large measure to p o l y p h a r m a c y , a n d i t w a s p o l y p h a r m a c y that gave b i r t h to the A m e r i c a n p h a r m a c e u t i c a l industry.

T h e i n d u s t r y has its roots i n the p r o d u c t i o n a n d d i s t r i b u t i o n

of p r o p r i e t a r y m e d i c i n e s a n d nostrums b y p h y s i c i a n s a n d possessed of business a c u m e n .

pharmacists

T h o s e early f o u n d e r s of the i n d u s t r y are

i m m o r t a l i z e d i n the names of m a n y of the l e a d i n g c o m p a n i e s t o d a y . Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

T h e early days of the A m e r i c a n system w e r e c h a r a c t e r i z e d b y overstatement of t h e r a p e u t i c v a l u e , most o f t e n expressed i n u n c o n s c i o n a b l e a d v e r t i s i n g to the g e n e r a l p u b l i c . T h o s e days m i g h t best be d e s c r i b e d as the era of g u l l i b i l i t y c h a r a c t e r i z e d b y o u t l a n d i s h c l a i m s , a n overtrust i n t h e m o n the part of the p u b l i c , a n d a l a c k of c o n c e r n for q u a l i t y of p r o d u c t . As

a

result

of

these

excesses,

Congress

passed

the

Food

and

D r u g s A c t of 1906, the first major A m e r i c a n d r u g l e g i s l a t i o n . T h a t

act

dealt p r i m a r i l y w i t h the i m p o r t a n t matters of a d u l t e r a t i o n a n d m i s b r a n d ing.

T h e extent of g o v e r n m e n t a l a u t h o r i t y e n c o m p a s s e d

b y it w a s ex-

c e e d i n g l y l i m i t e d , b u t it presaged a c o n t i n u i n g g o v e r n m e n t a l

concern

w i t h medicines. It is of m o r e t h a n p a s s i n g note that the l a w w a s w r i t t e n s i m u l t a n e ously w i t h the expression of great c o n c e r n over the q u a l i t y of A m e r i c a n medical education.

L i t e r a l l y , the d e v e l o p m e n t of the system

proceeded

h a n d i n h a n d w i t h the establishment of m e d i c a l e d u c a t i o n as a u n i v e r s i t y d i s c i p l i n e , a n d the d e v e l o p m e n t of m e d i c a l p r a c t i c e as a science as w e l l as a n art. T h e b l a t a n c y o f p h a r m a c e u t i c a l a d v e r t i s i n g a n d the l a c k of effective p r o d u c t s l e d to a n o v e r r e a c t i o n to d r u g t h e r a p y : t h e r a p e u t i c g a i n e d a n ascendancy.

nihilism

I n the early days of this c e n t u r y p r i m a r y interest

was c e n t e r e d i n the classification of disease.

C l i n i c a l pathology achieved

a n e w status, a n d m e d i c i n e s w e r e l a r g e l y i g n o r e d save f o r the less t h a n a d o z e n c o n s i d e r e d u s e f u l i n treatment b y the s o p h i s t i c a t e d p h y s i c i a n . A l e a p f o r w a r d w a s a c c o m p l i s h e d b y the system w h e n the i n d u s t r y t u r n e d to a research

o r i e n t a t i o n a n d d e v e l o p e d research

laboratories.

O r i g i n a l l y , the i n d u s t r i a l research laboratories w e r e staffed w i t h d i f f i c u l t y i n respect to those t r a i n e d i n the basic m e d i c a l sciences.

There was a

t i m e w h e n m e m b e r s h i p i n the A m e r i c a n Society f o r P h a r m a c o l o g y a n d E x p e r i m e n t a l T h e r a p e u t i c s w a s d e n i e d to those e m p l o y e d b y i n d u s t r y a n d r e m o v e d f r o m those w h o left universities to j o i n i n d u s t r i a l l a b o r a tories.

T h i s a r t i f i c i a l split a m o n g scientists w a s h e a l e d , b u t its echoes

are s t i l l h e a r d o c c a s i o n a l l y . T h e A m e r i c a n system, i n its finest sense, operates w i t h i n d u s t r i a l a n d a c a d e m i c laboratories a c t i n g i n close c o o p e r a t i o n .

Individuals based i n

universities f r e q u e n t l y serve as p a i d consultants to i n d u s t r y a n d p e r f o r m


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research u n d e r w r i t t e n b y grants f r o m i n d i v i d u a l c o m p a n i e s . T h e s e grants sometimes s u p p o r t specific projects b u t o f t e n p r o v i d e u n r e s t r i c t e d f u n d s f o r basic research.

I n this w a r m , s y m b i o t i c r e l a t i o n s h i p rests the greatest

strength of the A m e r i c a n system.

'Pharmaceutical Research D r u g d i s c o v e r y begins i n the c h e m i c a l l a b o r a t o r y w i t h the synthesis Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

of n e w c o m p o u n d s . T h e s e are screened i n b i o l o g i c a l m o d e l systems f o r specific p h a r m a c o l o g i c a c t i v i t y ; f r o m the results of this p r e l i m i n a r y screeni n g , a c t i v e candidates are selected

f o r m o r e t h o r o u g h testing.

When

e s p e c i a l l y attractive c a n d i d a t e s are i d e n t i f i e d , investigations are e n l a r g e d to i n c l u d e m e t a b o l i c studies, the d e v e l o p m e n t of a n a l y t i c a l m e t h o d s , t o x i c o l o g y i n several species, a n d finally, c a r e f u l l y c o n t r o l l e d c l i n i c a l studies. W h e n the o c c a s i o n a l w i n n e r is p r o d u c e d , as ascertained f r o m c a r e f u l c l i n i c a l i n v e s t i g a t i o n , a l l of the d a t a are b r o u g h t together for s u b m i s s i o n to the F o o d a n d D r u g A d m i n i s t r a t i o n i n s u p p o r t of a request f o r a N e w D r u g Application ( N D A ) .

F i n a l l y , agreement is r e a c h e d w i t h the F o o d

a n d D r u g A d m i n i s t r a t i o n w i t h respect p r e c a u t i o n s , adverse reactions

to l a b e l i n g , t h e r a p e u t i c

claims,

that m i g h t be a n t i c i p a t e d , dosage,

and

administration. T h e actors

i n v o l v e d i n this c o m p l e x d r a m a are n u m e r o u s .

They

range f r o m chemists, biologists, technicians, pathologists, a n d c l i n i c a l p h a r m a c o l o g i s t s i n i n d u s t r i a l laboratories to biologists, chemists, a n d p h y sicians i n a c a d e m i c laboratories a n d c l i n i c s , to a d m i n i s t r a t i v e biologists a n d p h y s i c i a n s i n the F e d e r a l agency a n d g o v e r n m e n t research institutes, to c l i n i c a l p h a r m a c o l o g i s t s i n n o n - u n i v e r s i t y hospitals, to c l i n i c i a n s i n the p r i v a t e p r a c t i c e of m e d i c i n e . If the actors are n u m e r o u s , the o u t p o u r i n g s of d a t a are e v e n m o r e so. T h e final s u m m a r i z a t i o n of d a t a f o r a n N D A is e n c y c l o p e d i c i n content a n d v o l u m e . It is r e m a r k a b l e that a system so h i g h l y d i v e r s i f i e d f u n c t i o n s so w e l l . A l t h o u g h there are creaks here a n d r u m b l i n g s there, sometimes o m i n o u s signs of f r i c t i o n a m o n g the m o v i n g parts, the system is m a n a g e a b l e , a l t h o u g h the processes are s l o w . T h a t i t does f u n c t i o n so w e l l is a t r i b u t e to the d e d i c a t i o n a n d i n t e l l i g e n c e of those w h o p l a y the major r o l e s — t h e scientists i n i n d u s t r y a n d universities a n d g o v e r n m e n t w h o strive together to resolve differences a n d obliterate difficulties. It takes l i t t l e i m a g i n a t i o n to r e a l i z e that a system so d i v e r s i f i e d , w h o s e p r o d u c t i o n is so c o m p l i c a t e d b y necessarily r i g i d standards, m u s t b e of enormous d i m e n s i o n . B e c a u s e of its d i m e n s i o n , it is d i f f i c u l t t o ascertain w i t h accuracy

the a c t u a l d o l l a r investment.

E x c l u d i n g governmental

f u n d s , the closest a p p r o x i m a t i o n to a c t u a l expenditures c a n b e d e r i v e d f r o m the d a t a c o m p i l e d b y the P h a r m a c e u t i c a l M a n u f a c t u r e r s A s s o c i a t i o n


9.

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Drugs—The

American

201

System

( I ) , b a s e d u p o n figures s u p p l i e d b y 71 m e m b e r firms w h o s e a n n u a l exp e n d i t u r e s range f r o m less t h a n $1 to m o r e t h a n $20 m i l l i o n . I n 1969, the latest year a v a i l a b l e , these d a t a r e v e a l a n i n d u s t r y o p e r a t i n g e x p e n d i t u r e o n research a n d d e v e l o p m e n t of $549 m i l l i o n .

F o r 1970, b u d g e t e d ex-

p e n d i t u r e s for research w e r e at the l e v e l of $624 m i l l i o n , a n increase of nearly 1 4 % 98.8%

over the p r e v i o u s year.

of those expenditures w e r e

O f specific interest is the fact that

financed

b y the i n d u s t r y itself.

O f the t o t a l o p e r a t i n g expenditures i n 1969, 8 8 . 6 % Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

the i n d u s t r y , 9 . 7 %

was spent w i t h i n

was spent outside the i n d u s t r y ( f o r consultants, re-

search institutions, m e d i c a l schools, h o s p i t a l s ) , a n d 1 . 7 %

was spent o n

g o v e r n m e n t contracts. T h e research installations of the i n d u s t r y i n 1969 e m p l o y e d 20,230 p e r s o n n e l of w h o m 10,345 w e r e scientific a n d professional staff a n d 9,885 w e r e technicians a n d s u p p o r t i n g staff. O f the total, 3,775 h e l d d o c t o r a l degrees. W i t h respect to other industries, the p h a r m a c e u t i c a l i n d u s t r y stands h i g h i n the a m o u n t of d o l l a r s e x p e n d e d for research; w i t h respect to its o w n d o l l a r s e x p e n d e d a n d l a c k of s u p p o r t f r o m g o v e r n m e n t a l contracts it stands highest.

B e y o n d that, the industry's a l l o c a t i o n of 1 8 %

of its

o w n f u n d s to i n n o v a t i v e , f u n d a m e n t a l research is the highest ratio rep o r t e d for a n y i n d u s t r y i n the U n i t e d States, a c c o r d i n g to the N a t i o n a l Science F o u n d a t i o n . O n e strength of the A m e r i c a n system, b e y o n d the c o l l a b o r a t i o n bet w e e n i n d u s t r y a n d a c a d e m i c institutions of h i g h q u a l i t y , rests i n the c o m p e t i t i o n b e t w e e n laboratories, a h a l l m a r k of the free enterprise syst e m . A l t h o u g h it is d i f f i c u l t to assign u l t i m a t e c r e d i t f o r discoveries, it is safe to say that the i n d u s t r i a l laboratories m a k e a significant c o n t r i b u t i o n to science.

T h e y stand n o w as the p r i m e developers of n e w m e d i c i n a l s ,

a fact p o i n t e d out b y S i r D e r r i c k D u n l o p ( 2 ) i n a statement m a d e i n 1967: O f the seventy most v a l u a b l e d r u g s i n t r o d u c e d to m e d i c i n e i n this cent u r y since the d i s c o v e r y of a s p i r i n i n 1899,

sixty w e r e d i s c o v e r e d a n d

d e v e l o p e d b y scientists i n the laboratories of i n d u s t r y . " A l l systems h a v e their u n u s u a l characteristics, exception.

a n d d e v e l o p m e n t to sales. 11.1%

a n d this one is no

O n e of these is the h i g h ratio of expenditures o n research I n 1969 the i n d u s t r y e x p e n d e d o n research

of the d o l l a r s generated b y sales ( I ) ,

a p p r o x i m a t e l y five times

the average percentage of a l l other i n d u s t r y . T h e research

o r i e n t a t i o n of the p h a r m a c e u t i c a l i n d u s t r y , d e m o n -

strated b y its h e a v y investment, is d i c t a t e d not o n l y b y the s t r i v i n g to b r i n g n e w a n d i m p r o v e d p r o d u c t s to the m a r k e t for the benefit of m a n , b u t also b y the fact that m e d i c i n a l p r o d u c t s t e n d to r a p i d

obsolescence.

C o n c e i v a b l y , this t e n d e n c y m a y lessen i n the f u t u r e . T h a t it has b e e n a factor i n the past c a n n o t be d e n i e d .


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W h a t w a s true i n the past a b o u t d i s c o v e r y , h o w e v e r , w i l l u n d o u b t e d l y c o n t i n u e i n t o the f u t u r e .

T h a t t r u t h is, a great m a n y c o m p o u n d s

m u s t b e s y n t h e s i z e d to find one that is safe, efficacious, a n d u s e f u l . I n 1967, f o r instance, almost 176,000 c o m p o u n d s w e r e tested b y p h a r m a c e u t i c a l laboratories.

O f those, o n l y 1,375 w e r e active e n o u g h a n d suffi-

c i e n t l y safe to w a r r a n t testing i n h u m a n s . F o r each c o m p o u n d r e a c h i n g the m a r k e t , 7,000 w e r e screened a n d u n d e r w e n t p r e l i m i n a r y testing ( 3 ) . T o p u t this another w a y , a n d i n a m o r e g l o b a l context, i n t h e d e c a d e Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

1958-1968 there w e r e 300 n e w basic d r u g entities i n t r o d u c e d to p h y s i cians. I n that same d e c a d e expenditures m a d e f o r research a n d d e v e l o p m e n t exceeded $3 b i l l i o n (4).

O n t h e average, t h e n , a n e x p e n d i t u r e of

$10 m i l l i o n w a s r e q u i r e d p e r entity before $1 w a s generated i n sales. A l t h o u g h i t is n o t statistically f a i r to m a k e s u c h a c o m p a r i s o n , note that $549 m i l l i o n w e r e e x p e n d e d o n research a n d d e v e l o p m e n t i n 1969, a n d o n l y n i n e n e w c h e m i c a l entities w e r e released to the m a r k e t ( 5 ) . T h i s p e c u l i a r i t y of r i s i n g research expenditures a n d d e c l i n i n g i n t r o d u c t i o n s of m e d i c i n e s serves to p o i n t o u t that d e v e l o p m e n t a l research w i l l c o n t i n u e to b e i n c r e a s i n g l y m o r e costly. I n v o l v e d i n these costs are the r e l a t i v e l y n e w r e q u i r e d investigations r e l a t i n g to b i o - a v a i l a b i l i t y , m e t a b o l i s m , d r u g interactions, a n d a n a l y t i c a l p r o c e d u r e s .

A l l of this i n d i -

cates that the l i k e l i h o o d of t h e p r i c e of p r e s c r i p t i o n d r u g s f a l l i n g signific a n t l y is remote at best i f the p h a r m a c e u t i c a l i n d u s t r y is to s u r v i v e as an e c o n o m i c a l l y v i a b l e enterprise.

I n d e e d , a n y other i n d u s t r y w o u l d b e

c o n s i d e r i n g s u b s t a n t i a l p r i c e increases i n s i m i l a r circumstances. Yet, despite these facts, t h e " h i g h cost" of m e d i c i n e s , o f t e n c o n f u s e d w i t h other h e a l t h care costs, continues to b e a matter of great c o n c e r n to the p u b l i c . W h a t t h e p u b l i c does n o t c o m p r e h e n d is t h e r e m a r k a b l e s t a b i l i t y of m e d i c i n a l prices i n a h i g h l y i n f l a t i o n a r y e c o n o m y . T h e B u r e a u of L a b o r Statistics' d a t a h a v e b e e n l a r g e l y i g n o r e d : t h e y s h o w o n a base of 1957-1959 as 100, a rise i n the cost of l i v i n g i n d e x b y 1969 to n e a r l y 128 a n d a c o n c o m i t a n t d e c l i n e i n the r e t a i l cost of p r e s c r i p t i o n d r u g s to an i n d e x o f o n l y 89 (6).

N o prices are c o m p l a i n e d a b o u t as m u c h as are

those f o r m e d i c i n e s , y e t n o greater benefit is d e r i v e d f r o m a n y other products. For

perspective, i n 1969 t h e average charge f o r a p r e s c r i p t i o n w a s

$3.68 ( 7 ), c o n s i d e r a b l y less t h a n the p r i c e of a c a r t o n of cigarettes, or a n e v e n i n g m e a l i n a n average restaurant.

Generics, Patents, and Advertising P e r t i n e n t to this d i s c u s s i o n are t h e matters of generic p r e s c r i b i n g a n d t h e c o m p u l s o r y l i c e n s i n g of patents, w h e r e b y t h e results o f o n e c o m pany's costly research c o u l d b e s h a r e d b y others w h o h a d m a d e n o invest-


9.

WESCOE

ment.

Drugs—The

American

203

System

I t appears n o w that t h e i n e q u i t y of this s i t u a t i o n is b e c o m i n g

well appreciated.

F u r t h e r , scientific e v a l u a t i o n has i n d i c a t e d t h e p i t f a l l s

i n h e r e n t i n the use of generic d r u g s . P r i c e cannot b e t h e o n l y c o n s i d e r a t i o n . T h e w o r d s of J o h n R u s k i n p u t t h e matter of p r i c e i n p r o p e r context: "It's u n w i s e to p a y t o o m u c h , b u t it's w o r s e to p a y too l i t t l e . W h e n y o u p a y too m u c h , y o u lose a l i t t l e m o n e y .

W h e n y o u p a y too little, y o u

sometimes lose e v e r y t h i n g , because t h e t h i n g y o u b o u g h t w a s i n c a p a b l e of d o i n g t h e t h i n g i t w a s b o u g h t to d o . T h e c o m m o n l a w of business


b a l a n c e p r o h i b i t s p a y i n g a little a n d g e t t i n g a l o t — i t can't b e d o n e . " F i n a l l y , as a characteristic of t h e system, w e d e a l w i t h a n u n i q u e situation i n w h i c h the sales effort is d i r e c t e d n o t t o w a r d t h e c o n s u m e r b u t t o w a r d a professional w h o makes a c h o i c e f o r h i m . A great d e a l of controversy has c e n t e r e d a b o u t t h e p r o m o t i o n of e t h i c a l m e d i c i n e s .

There

are those w h o b e l i e v e that l i t t l e a d v e r t i s i n g of e t h i c a l m e d i c i n e s s h o u l d b e d o n e ; there are those w h o b e l i e v e that there s h o u l d b e none.

Some

p h y s i c i a n s request a n d a p p r e c i a t e d i r e c t m a i l materials w h i l e others ask to b e r e m o v e d f r o m m a i l i n g lists. E t h i c a l m e d i c a l a d v e r t i s i n g s h o u l d b e l o o k e d u p o n as e d u c a t i o n a l m a t e r i a l , as i n d e e d I l o o k u p o n i t . It is f o o l h a r d y to b e l i e v e that b u s y p h y s i c i a n s w i l l r e a d e n o u g h of t h e scientific literature o r attend sufficient p o s t g r a d u a t e courses to k e e p alert to a d vances i n therapeutics.

E t h i c a l a d v e r t i s i n g is r e s t r a i n e d to t h e p o i n t of

dullness; i t is p r i m a r i l y i n f o r m a t i o n a l . W i t h o u t i t , t h e benefits of some m e d i c a t i o n m i g h t b e d e n i e d to some patients.

It is true that " f u l l m a n y

a rose is b o r n to b l u s h unseen"; there is n o reason f o r a significant m e d i c i n a l d i s c o v e r y to b e k e p t secret o r m e r e l y to h o p e that a p h y s i c i a n w i l l s t u m b l e u p o n i t as h e reads t h e literature.

T o d o that w o u l d b e

f o o l h a r d y o n the p a r t of the i n d u s t r y a n d i n i m i c a l to t h e best interests of m e d i c i n e a n d patients a l i k e .

The Impact of a Changing Society R e m a r k a b l e changes i n society i n t h e past 10 years h a v e h a d great i m p a c t u p o n t h e system; p e r h a p s the greatest has b e e n w r o u g h t b y a t r e m e n d o u s i m p r o v e m e n t i n t h e m e c h a n i s m s of c o m m u n i c a t i o n s .

From

a society r e l a t i v e l y u n i n v o l v e d i n w o r l d affairs because i t felt r e m o t e f r o m t h e m , w e h a v e t u r n e d i n t o a society d e e p l y i n v o l v e d because w e are c a t a p u l t e d into t h e m i d s t o f events b y t h e m i r a c l e of instant c o m m u n i c a tions w i t h pictures.

W e see a w a r b e i n g f o u g h t h a l f - w a y r o u n d t h e

w o r l d as w e sit i n o u r l o u n g e chairs; w e observe riots i n distant cities of o u r o w n a n d other lands w h i l e t h e y are s t i l l i n progress. Instant c o m m u n i c a t i o n leads to instant i n v o l v e m e n t a n d instant c o n cern. It also leads to l a c k of c o n t e m p l a t i o n a n d l a c k of t h o u g h t ; rather, i t leads t o e m o t i o n a l responses a n d a desire f o r instant r e a c t i o n .


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m o v i n g w o r l d it is l o g i c a l to t h i n k that a l l processes s h o u l d b e

speeded

u p a n d a l l things s h o u l d b e i m p r o v e d i n a matter of hours. It looks a n d seems so s i m p l e that the l o g i c a l t e n d e n c y is to forget that c o m p l e x i t i e s exist. I n a n e x c e e d i n g l y c o m p l e x w o r l d w e see a y e a r n i n g for a r e t u r n to the s i m p l e life, a w i t h d r a w a l o n the p a r t of some of o u r y o u n g f r o m the realities of l i f e . F o r m a n y of the y o u n g , a s i m p l e , u n c o m p l i c a t e d , u n r e g u l a t e d existence seems the i d e a l . A t the same t i m e , w e h a v e entered Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

i n t o a d e c a d e of c o n c e r n that p r o m p t s n e w complexities, m o r e r e g u l a t i o n , and more governmental supervision. A l l of this leads to a society c h a r a c t e r i z e d b y contentiousness.

There

is t o d a y , i n m a n y instances, no t h o u g h t for reasoned d i s c u s s i o n ; there is, instead, the p r e s e n t a t i o n of n o n - n e g o t i a b l e c o n v e n i e n t catchphrases.

d e m a n d s , the m o u t h i n g of

T h i s is a t i m e w h e n m a n y p l e a d f o r the f e d e r a l

g o v e r n m e n t to step i n w i t h c e n t r a l i z e d r e g u l a t o r y a u t h o r i t y over b r o a d n e w areas—the e n v i r o n m e n t , c o n s u m e r

products, health—and

a

time

w h e n there is a d e t e r m i n e d thrust f o r the d e c e n t r a l i z a t i o n of m u c h other a u t h o r i t y . T h e r e are those w h o b e l i e v e that p a r t i c i p a t o r y d e m o c r a c y c a n w o r k f o r large social structures as it once w o r k e d i n the s m a l l t o w n meeti n g . T h i s is the d a y of " p o w e r to the p e o p l e " e v e n i f the p e o p l e d o not f u l l y u n d e r s t a n d the ramifications of p r o b l e m s .

" R i g h t o n " is the thrust

e v e n if " o n to w h e r e " has not b e e n d e f i n e d . W e exist a n d w e persist i n a p l e t h o r a of paradoxes.

F r u s t r a t i o n is the m o d e of the d a y .

F i n a l l y , w e l i v e i n a society w h e r e the p r o d u c e r of a n y m e d i c a l p r o d u c t has b e c o m e subject to enormous l i a b i l i t y .

F e a r s are r a i s e d de-

l i b e r a t e l y i n the m i n d s of m a n y b y sensational, o n e - s i d e d r e p o r t i n g , to the p o i n t w h e r e one hesitates to take a n y m e d i c i n e .

T h e basic tenet of

p h a r m a c o l o g y , that a n y m e d i c i n e is i n h e r e n t l y a t o x i n , is forgotten.

In a

society r a i s e d to the highest p e a k b y science, i n a society w h i c h is the best e d u c a t e d i n a l l of history, the present t e n d e n c y appears to be t o w a r d non-science a n d i r r a t i o n a l i t y . M a n appears to b e d e s c e n d i n g f r o m the c e r e b r a l to the m i d - b r a i n l e v e l , c o n t r o l l e d b y his gut feelings

rather

t h a n b y his intellect. T h e r e is little w o n d e r t h e n that w e h a v e a d r u g - c o n s c i o u s where medicines developed for therapeutic

advances

society

are a b u s e d

and

w h e r e d r u g s f o r w h i c h there is no r a t i o n a l or t h e r a p e u t i c use are t a k e n i n ever i n c r e a s i n g quantities b y the w e a k , the p o o r l y i n f o r m e d , the m e n t a l l y d i s t u r b e d , a n d the c o n s t i t u t i o n a l l y i n a d e q u a t e .

I n e v i t a b l y , the p h a r -

m a c e u t i c a l i n d u s t r y is b l a m e d for these s h o r t c o m i n g s of society because it h a p p e n s to be the most v i s i b l e target i n a n era w h e n m a n y ( p u b l i c a n d p o l i t i c a l ) refuse to d i s c r i m i n a t e b e t w e e n m e d i c a l use a n d d r u g abuse. T h e p h a r m a c e u t i c a l i n d u s t r y has e x p e r i e n c e d this "target" p h e n o m e n o n before.

T h e extent of g o v e r n m e n t a l a u t h o r i t y w a s b r o a d l y increased


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w i t h the enactment of the F o o d , D r u g a n d C o s m e t i c A c t of 1938 w h i c h p r o v i d e d the i m p o r t a n t g o v e r n m e n t a l p o w e r to r u l e u p o n the safety of m e d i c i n e s b e f o r e t h e y w e r e a l l o w e d to r e a c h the m a r k e t .

Tremendous

advances w e r e m a d e i n the 1940's a n d 1950's i n the i n t r o d u c t i o n of n e w , safe a n d effective m e d i c i n e s , a n d the i n d u s t r y e x p e r i e n c e d growth.

remarkable

It m i g h t b e s a i d , h o w e v e r , that the i n d u s t r y b e c a m e c a r r i e d

a w a y b y its o w n g r o w t h a n d successes. W i t h o u t q u e s t i o n it resorted, i n m a n y instances, m o r e to salesmanship t h a n to a c o n c e r n for w h a t was Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

best f o r the patient a n d the p r a c t i c e of m e d i c i n e . entered

(even engendered)

A s a consequence,

it

a n era of distrust, w h i c h , r e t r o s p e c t i v e l y ,

s i g n a l l e d the r e a l b e g i n n i n g of the n e w times of d i s c o r d a n d dissent i n w h i c h w e live. D u r i n g the C o n g r e s s i o n a l hearings o n the F o o d , D r u g , a n d C o s m e t i c A c t , the p h a r m a c e u t i c a l i n d u s t r y w a s u n f o r t u n a t e l y u n e q u a l to the task of p r e s e n t i n g its story of m a g n i f i c e n t achievement.

Rather than a posi-

tive a p p r o a c h , it a d o p t e d a defensive stance. A s a result of the hearings, the act was a m e n d e d s u b s t a n t i a l l y ; the a m e n d m e n t s

extended

govern-

m e n t a l a u t h o r i t y to m a n u f a c t u r i n g practices, a n d m o r e i m p o r t a n t , to the establishment of efficacy b e f o r e a n e w p r o d u c t c o u l d be m a r k e t e d . N o one c o u l d c o m p l a i n a b o u t these purposes. T h e regret to b e v o i c e d is that these d e v e l o p m e n t s r e s u l t e d f r o m o n e - s i d e d , a c r i m o n i o u s hearings f r o m w h i c h the i n d u s t r y has never f u l l y r e c o v e r e d i n the matter of p u b l i c confidence.

G r e a t a c c o m p l i s h m e n t s w e r e d o w n - g r a d e d ; r i d i c u l e was the

order of the d a y . The

Drug

Evaluation

Study

Just n o w w e are b e g i n n i n g to see the u l t i m a t e results of some

of

these changes as the F o o d a n d D r u g A d m i n i s t r a t i o n begins to i m p l e m e n t the

findings

of panels a p p o i n t e d b y the D r u g R e s e a r c h

B o a r d of

the

N a t i o n a l A c a d e m y of S c i e n c e s - N a t i o n a l R e s e a r c h C o u n c i l to pass u p o n the efficacy of m a r k e t e d drugs. A s the

findings

of these panels are re-

v e a l e d , the i m p r e s s i o n is most often g i v e n that a substantial g r o u p of a l l - k n o w i n g m e n , w i t h b r o a d c l i n i c a l experience, h a v e s t u d i e d i n d e p t h a l l the d a t a p e r t a i n i n g to the d r u g s i n q u e s t i o n a n d h a v e r e a c h e d f r o m those studies a r a t i o n a l , scientific d e c i s i o n .

L e t m e dissent f r o m

that

i m p r e s s i o n , at the risk of p r o v o k i n g anger f r o m some, b u t h o p e f u l l y , c o n s i d e r e d t h o u g h t o n the part of others. I h a v e great respect for scientists.

I have lived w i t h them all m y

a d u l t l i f e . I consider m y s e l f to be one of t h e m . M y experience

indicates

that none of t h e m is a l l - k n o w i n g , that each of t h e m is subject to as m a n y biases a n d prejudices as is the l a y m a n . T h e i m p r e s s i o n g i v e n that

the

N a t i o n a l A c a d e m y ( i n c i d e n t a l l y , a v e r y n a r r o w l y d r a w n g r o u p ) has m a d e


206

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decisions is erroneous; rather, s m a l l groups of a p p o i n t e d a c a d e m i c experts h a v e p r e p a r e d reports. themselves.

F e w if a n y of t h e m , w e r e A c a d e m y m e m b e r s

T h e A c a d e m y itself d i d not r e v i e w t h e i r findings, a n d , cer-

t a i n l y , the A c a d e m y released no reports. D o m i n a n t c h a i r m e n c o u l d exert great influence o n the conclusions of these reports. A s one reads the a c t u a l reports, one cannot f a i l to c o n c l u d e that i n m a n y instances the panels w e r e r e c o m m e n d i n g changes i n i n f o r m a t i o n p r o v i d e d to p h y s i c i a n s a n d not c o n s i d e r i n g ( or r e c o m m e n d i n g ) that t h e i r Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

c o m m e n t s w o u l d r e m o v e m e d i c i n e s f r o m the m a r k e t place. Y e t the latter is exactly w h a t has h a p p e n e d .

F u r t h e r , one gains the i m p r e s s i o n that

often t h e i r o p i n i o n , rather t h a n fact, r u l e d the d a y — a n o p i n i o n that was substituted, w i t h o u t debate,

for the c u m u l a t i v e , years-long o p i n i o n of

m a n y c l i n i c i a n s . N o one w o u l d desire the d i s c o n t i n u a t i o n of ineffective m e d i c i n e s m o r e t h a n I w o u l d , b u t I q u e s t i o n a r b i t r a r y d i s d a i n for l e n g t h y c l i n i c a l experience, a n d I fear w h a t appears to be the present t h r u s t : the establishment of a single p r o d u c t f o r a single t h e r a p e u t i c i n d i c a t i o n . I b e l i e v e c h o i c e s h o u l d a n d m u s t be a l l o w e d the c l i n i c i a n i n selecting m e d i c i n e s for his patient. T h e w i t h h o l d i n g of a m e d i c a t i o n that has a c h i e v e d c l i n i c a l acceptance o n the basis of c l i n i c a l observations over m a n y years is as i m p o r t a n t a n a c t i o n as the i n t r o d u c t i o n of a n e w c o m p o u n d . I n the c u r r e n t actions f o l l o w i n g u p o n the d r u g e v a l u a t i o n reports, m i l l i o n s of c l i n i c a l observations have b e e n rejected or i g n o r e d . T h i s is i n r e m a r k a b l e contrast to the situation as it relates to adverse reactions, w h e r e a single report, often u n s u b s t a n t i a t e d , is a c c e p t e d w i t h

finality.

T h e r e has b e e n i n the last d e c a d e a great p r e o c c u p a t i o n w i t h u n t o w a r d reactions, a n i n e v i t a b l e resultant of the use of m e d i c i n e s .

Package

inserts r e a d l i k e h o r r o r studies, for every possible r e a c t i o n m u s t be i n c l u d e d , no matter h o w remote the o c c u r r e n c e m i g h t have b e e n , or h o w little c o n n e c t i o n it m i g h t h a v e h a d w i t h the m e d i c i n e i n q u e s t i o n . If there is a n y great n e e d t o d a y it is for a scientific e v a l u a t i o n of adverse reactions. T h e costly scientific s u b s t a n t i a t i o n of safety a n d efficacy so reasona b l y requested stands i n stark contrast to the unscientific e v a l u a t i o n of adverse effect r e p o r t i n g

(8).

W e have h a d a recent p e r s o n a l experience i n respect to p e n t a z o c i n e . A f t e r r e c e i v i n g reports c o n c e r n i n g i n d i s c r i m i n a t e use of the c o m p o u n d , w e m a d e d e t e r m i n e d efforts to o b t a i n b o d y

fluid

samples f o r analysis

f r o m those suspected of s u c h use. I n m o r e t h a n h a l f the instances w h e r e p e n t a z o c i n e h a d b e e n i m p l i c a t e d , analyses r e v e a l e d neither the c o m p o u n d nor its metabolites.

R a t h e r , analyses r e v e a l e d the

parent

presence

of other c o m p o u n d s k n o w n to be a b u s e d . W e are c e r t a i n that if s i m i l a r efforts w e r e m a d e the same w o u l d be f o u n d i n respect to other d r u g s .


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Medicines and the Political Arena O u r past d e c a d e has seen t h e emergence of a d d i t i o n a l p o l i t i c a l figures w i t h a n intense interest i n m e d i c i n a l affairs, m a n y m o r e t h a n w a s once t h e case.

I n e v i t a b l y , t h e n , p o l i t i c s i n t r u d e s into t h e r e g u l a t i o n o f

A m e r i c a n m e d i c i n a l s i n a w a y n o t c o m p a r a b l e elsewhere i n t h e w o r l d . F e d e r a l a d m i n i s t r a t o r s are subjected to t h e s u r v e i l l a n c e of committees sometimes to t h e extent that i t w o u l d a p p e a r d i f f i c u l t f o r t h e m to c a r r y


out t h e i r responsibilities. A c o n s i d e r a b l e a m o u n t of t h e i r t i m e is spent i n hearings, t i m e that c o u l d b e spent m o r e p r o f i t a b l y i n t h e a d m i n i s t r a t i o n of their agencies. C o n g r e s s i o n a l hearings o n i m p o r t a n t subjects are often h e l d o n short notice.

T h e witnesses to b e h e a r d are selected b y c o m m i t t e e

members

a n d , often, u n d e r t h e guise o f lack of t i m e , m a n y w i t h substantive presentations are n o t h e a r d at a l l . H e a r i n g s t e n d to b e c o n t r i v e d a n d ones i d e d ; w h a t p u r p o r t to b e d e m o c r a t i c processes at times resemble t h e w o r s t of t o t a l i t a r i a n exercises. A f e w m e m b e r s of Congress strive f o r the a p p e a r a n c e

of h a v i n g

v i r t u e entirely o n t h e i r side. T h e y h a v e n o c o m p u n c t i o n a b o u t i n v e s t i g a t i n g a n y subject—save that of t h e i r o w n operations. c o m m e n t was q u o t e d i n the New York Times Magazine

A n interesting

of J u l y 19th, 1970

i n that r e g a r d , f r o m a m e m b e r of Congress w h o w a s e x p l a i n i n g w h y n o p u b l i c hearings w e r e h e l d b y t h e E t h i c s C o m m i t t e e : " I t h i n k t h e c o m mittee has p l e n t y of p o w e r . I don't t h i n k w e s h o u l d h a v e a setup w h e r e every c r a c k p o t i n the area c a n f o r p o l i t i c a l reasons or o t h e r w i s e c o m e i n a n d t r y to get some h e a d l i n e s at t h e expense of a C o n g r e s s m a n . w o u l d d o i t . Y o u m u s t k n o w that."

They

A p p a r e n t l y , there is r e c o g n i z e d a

difference i n " c r a c k p o t s " a n d a difference i n g a i n i n g h e a d l i n e s at someone else's expense o r h a v i n g t h e m result f r o m one's o w n p u r p o r t e d actions. S u r p r i s i n g l y a n d d e t r i m e n t a l l y , i n a t i m e w h e n m e d i c i n e s of greater specificity as w e l l as p o t e n c y b e c a m e a v a i l a b l e , there w a s a thrust i n m e d i c a l schools to shorten t h e c u r r i c u l u m i n p h a r m a c o l o g y or to s p r e a d its t e a c h i n g a m o n g m a n y p e o p l e n o t t r a i n e d i n the d i s c i p l i n e . P h a r m a cologists object, b u t there is a m u c h l o u d e r v o i c e f r o m f a m i l y p r a c t i c e , f r o m sociologists a n d f r o m m e d i c a l students w h o seem r e a d y to enter the profession w i t h o u t a r e a l l y basic k n o w l e d g e of w h a t a q u a l i t y p r a c t i c e of m e d i c i n e is a l l about. T h e s e m e d i c a l students c o m e f r o m the student groups that

have

r a i l e d against " t h e e s t a b l i s h m e n t " u n t i l they h a v e c o n v i n c e d themselves that s u c h a g r o u p exists. T h e y s h o u l d l e a r n w h a t the s o - c a l l e d "establishm e n t " does to those t h e students c o n s i d e r m e m b e r s of it. T h e y are u n a w a r e , f o r instance, that g o v e r n m e n t a l agencies d o to c o r p o r a t i o n s w h a t t h e y w o u l d n o t d a r e d o to i n d i v i d u a l s . T h e y are u n a w a r e that t o a c h i e v e


DRUG DISCOVERY

208

a h e a r i n g , a c o r p o r a t i o n first has to present e v i d e n c e that it c a n w i n the h e a r i n g . T h e y are u n a w a r e that i n m a n y of o u r i n d u s t r y - g o v e r n m e n t relations the i n d i c a t i o n is clear that the E n g l i s h p r i n c i p l e of i n n o c e n t u n t i l p r o v e n g u i l t y has b e e n a b a n d o n e d .

T h e y are u n a w a r e that pres-

e n t l y there are b e i n g p r o p o s e d w i d e - r a n g i n g statutes that w o u l d m a k e F e d e r a l agencies the l a w m a k e r s , the prosecutors, t h e juries a n d the judges.


International Regulations P e r h a p s o n e of the most d r a m a t i c changes i n the last d e c a d e has b e e n the " i n t e r n a t i o n a l i z a t i o n " of m e d i c i n a l controls. nation operating entirely independently.

N o longer is e a c h

The W o r l d Health Organiza-

t i o n is b e c o m i n g a m o r e p r o m i n e n t o r g a n i z a t i o n ; a great d e a l of d a t a are s h a r e d b e t w e e n governments.

A governmental decision i n one country

t o d a y is v e r y l i k e l y to b e r e p e a t e d p r o m p t l y i n m a n y others.

M u c h of

this is f o r the g o o d ; w h a t has to b e assured is that n a t i o n a l prejudices w i l l not b e s u b s t i t u t e d f o r scientific a c c u r a c y . B e c a u s e there is this t e n d e n c y t o w a r d the r a p i d s h a r i n g of d a t a bet w e e n governments a n d because some c o m p a n i e s f r o m t h e U n i t e d States m a r k e t n e w p r o d u c t s a b r o a d , i t is a p p r o p r i a t e to describe t h e systems as t h e y exist elsewhere. T h e d r u g r e g i s t r a t i o n system i n B r i t a i n is less c o m p l e x a n d m u c h less costly t h a n that of the U n i t e d States a l t h o u g h i t is c e r t a i n l y n o less effective a n d n o less p r o t e c t i v e of the consumer.

T h e B r i t i s h system is

m u c h less f o r m a l , less b u r e a u c r a t i c , a n d operates o n a l e v e l of m u c h m o r e m u t u a l respect t h a n ours. It is r e l a t i v e l y n e w i n p r i n c i p l e of o p e r a t i o n b u t appears to w o r k effectively.

U n d e r that system a request is m a d e

of t h e r e g i s t r a t i o n a u t h o r i t y to c a r r y o u t c l i n i c a l trials after the c a r e f u l l a b o r a t o r y studies have b e e n m a d e . T h e request is a c c o m p a n i e d b y f u l l d a t a o n a n i m a l studies, i n c l u d i n g teratology, a n d o n tolerance

studies

p e r f o r m e d o n h u m a n volunteers. W h e n p e r m i s s i o n is g i v e n , the c l i n i c a l trials are p e r f o r m e d a n d , w h e n c o m p l e t e , are s u b m i t t e d to the C o m m i t t e e o n Safety of D r u g s ( S c o w e n C o m m i t t e e ) w i t h a request f o r p e r m i s s i o n to market.

T h e C o m m i t t e e either a p p r o v e s , requests f u r t h e r studies, o r

disapproves.

I n the event that f o r m u l a changes a n d changes i n dosage

forms are r e q u i r e d after that time, these too are s u b m i t t e d to t h e C o m m i t t e e just as is the case w i t h a n N D A s u p p l e m e n t i n this c o u n t r y . T h e system i n F r a n c e is a v e r y r i g i d one, albeit a less b u r e a u c r a t i c one. A visa expert m u s t b e u s e d , u s u a l l y a n a c a d e m i c i a n w h o is a n ack n o w l e d g e d expert i n t h e field of disease f o r w h i c h the m e d i c i n e is i n t e n d e d . T h e c o m p a n y seeks o u t s u c h a visa expert; there is a p p a r e n t l y little c o n c e r n a b o u t possible conflict of interest i n this system a n d a p p a r e n t l y a trust i n b o t h parties b y the g o v e r n m e n t authorities. W h e n a visa


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expert has a g r e e d to serve, a l l the p r e l i m i n a r y d a t a are s u b m i t t e d to h i m : a n i m a l studies, t o x i c o l o g y , a n d c l i n i c a l studies. O r d i n a r i l y , h e w i l l t h e n p e r f o r m some a n i m a l or c h e m i c a l studies himself.

A p p r o v a l can be

sought f o r o n l y one dosage f o r m at a t i m e , a n d a l l tests m u s t b e perf o r m e d o n t h e same b a t c h of d r u g . If the visa expert a p p r o v e s , h e i n d i cates that fact to t h e g o v e r n m e n t , a n d m a r k e t i n g c a n p r o c e e d . F o r a n e w dosage f o r m , a l l w o r k m u s t b e r e p e a t e d . A t present the S c a n d i n a v i a n countries are i n t h e process of r e c o n c i l Downloaded by STONY BROOK UNIV SUNY on May 20, 2018 | https://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch009

ing now

t h e i r system a m o n g themselves. h a v e systems l i k e that of B r i t a i n .

Denmark, Finland, and Norway In Sweden, however, a protocol

m u s t b e s u b m i t t e d to the H e a l t h M i n i s t r y f o r each c l i n i c a l s t u d y to b e undertaken.

Such a protocol must contain a l l animal work, including

t o x i c o l o g y a n d , specifically, p e r i n a t a l t o x i c o l o g y i n at least one species. The Health Ministry

finally

evaluates the e v i d e n c e after the protocols

h a v e b e e n c o m p l e t e d a n d , i f i t a p p r o v e s , grants p e r m i s s i o n to m a r k e t .

The Future T h e A m e r i c a n system has m a t u r e d t h r o u g h successive eras:

gulli-

b i l i t y , n i h i l i s m , scientific d i s c o v e r y , a n d distrust. T h r o u g h the m a t u r i n g process great changes h a v e o c c u r r e d , a n d changes w i l l c o n t i n u e to b e m a d e . W h a t concerns the A m e r i c a n p u b l i c is that these changes

occur

i n a n atmosphere of trust a n d m u t u a l confidence c r e a t e d b y statesmen (not demagogues)

a n d i n d u s t r i a l leaders ( n o t t y c o o n s ) , w i t h a single-

m i n d e d c o n c e r n f o r the p u b l i c g o o d . T h e r e is n o reason w h y i n d u s t r y a n d g o v e r n m e n t cannot w o r k together t o w a r d this e n d ; i n d e e d , p r e l i m i n a r y moves t o w a r d this e n d are i n progress. W h a t is r e q u i r e d is i n t e g r i t y and

fairness of m i n d i n a l l i n v o l v e d , s u c h that e q u i t a b l e decisions c a n

be r e a c h e d . R e a s o n a b l e c h a n g e f o r t h e p u b l i c g o o d s h o u l d b e sought. U n r e a s o n able suggestions f o r change s h o u l d b e o p p o s e d . S i n g l e standards, e q u i t a b l y a d m i n i s t e r e d , s h o u l d b e t h e r u l e . P e d a n t r y s h o u l d n o t stand i n t h e w a y of efficient d i s c o v e r y ; b u r e a u c r a c y s h o u l d n o t stand i n t h e p a t h of t h e r a p e u t i c progress. O u r h o p e is that w e enter u p o n a n e w e r a — a n e r a of t r u s t — t r u s t e a r n e d a n d d e s e r v e d , a n era w h e r e r a t i o n a l i t y g u i d e d b y intellect serves f o r t h e p u b l i c , n o t t h e p o l i t i c a l , g o o d .

Literature Cited (1) "Annual Survey Report," Pharmaceutical Manufacturers Association, Washington, D. C., Dec. 1970. (2) Address before the American College of Clinical Pharmacology and Chemotherapy, Atlantic City, N. J., April 28, 1967. (3) "Commentaries," p. 5, Pharmaceutical Manufacturers Association, Washington, D. C., Feb. 1969.


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(4) Douglas, James M., Financial Analysts J. (Sept./Oct. 1970) 115. (5) deHaen, Paul, "New Products Parade," January 1971, page 1. (6) "Social Security Bulletin," pp. 44-5, U. S. Department of Health, Education and Welfare, Social Security Administration, March 1970. (7) Amer. Druggist (April 6, 1970). (8) Roth, Catherine H., Trout, Monroe E., Hospital Formulary Management (1970) 5, 13.

November

5,

1970.


RECEIVED


Drug Discovery - ACS Publications

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