Drug Discovery - ACS Publications

10 Research and Development in the

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Pharmaceutical Industry C. W . P E T T I N G A

1

Eli Lilly & C o . , Indianapolis, Ind. 46206

In recent years, research

and development

industry

rapidly

and

have increased

pharmacological

equipment search

is on mechanisms

cology,

problems

problems ing

plexity

of

increased

have

training.

the

validity

of

safety

of new drug applications

and evaluation

drugs and must rely on statistical

research absolutes

impossible

and safety.

The industry,

striving

nology

thoroughness

to provide

and

agents, must have the cooperation and patients

to achieve

and Work

and

public

faces increased

demands

scientifically

toxi

testing,

regulation

industry

with

of

in

of the medical

public

effectiveness

all available best

com existing

when the

the

in re

and

and control procedures.

government

the pharmaceutical

expensive

emphasis

animal

drug

chemical

required

Today,

of drug action,

in pharmaceutical

under

scrutiny,

techniques

and specialized

costs in the

as sophisticated

tech

therapeutic profession

this g o a l .

T n h i s excellent r e v i e w ( J ) , W . C . W e s c o e has r e c o u n t e d some of t h e h i s t o r y of drugs a n d 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 i n t h e U n i t e d States. H i s k e y points a r e : ( 1 ) T h e d e v e l o p m e n t of t h e d r u g i n d u s t r y as w e k n o w it t o d a y has s u b s t a n t i a l l y o c c u r r e d o n l y i n t h e last 50 years. ( 2 ) T h e most r a p i d d e v e l o p m e n t , a c c o m p a n i e d b y t h e greatest n u m b e r of c h a n g i n g circumstances, has t a k e n p l a c e i n the last f e w years. E l i L i l l y & C o . , f o r e x a m p l e , is 94 years o l d ; yet, i n terms of g r o w t h , i t t o o k 75 years to r e a c h t h e first $100 m i l l i o n sales l e v e l , 14 years to r e a c h $200 m i l l i o n , 4 years to a t t a i n $300 m i l l i o n , o n l y 2 years f o r $400 m i l l i o n , a n d a little m o r e t h a n 1 year f o r $500 m i l l i o n . Stated i n another w a y , the n u m b e r of years r e q u i r e d to a d v a n c e $100 m i l l i o n i n sales d e c l i n e d r a p i d l y f r o m 75 to 14 to 4 to 2 to a little m o r e t h a n 1. 1

Present address: Elizabeth Arden, Inc., 3 East 54th St., New York, Ν. Y. 10022. 211

In Drug Discovery; Bloom, Barry, et al.; Advances in Chemistry; American Chemical Society: Washington, DC, 1971.

DRUG DISCOVERY

212

O t h e r business parameters c h a n g e d s w i f t l y i n a s i m i l a r f a s h i o n . D u r i n g the last 10 years, w h i l e sales g r e w 2 0 0 % ,

the n u m b e r of employees

n e a r l y d o u b l e d ; earnings p e r share i n c r e a s e d m o r e t h a n 3 0 0 % ;

R & D

expenditures are m o r e t h a n 2V2 times w h a t t h e y w e r e . T h e d r u g i n d u s t r y as a w h o l e is g r o w i n g r a p i d l y a n d c h a n g i n g r a p i d l y . i n c r e a s e d sales h a v e p r o v i d e d the


search a n d d e v e l o p m e n t ( R & D )

financial

I n recent

years

base f o r e v e r - i n c r e a s i n g re-

expenditures.

A r e these expenditures

g e n e r a t i n g the n e w t e c h n o l o g y a n d p r o d u c t s that c a n p r o v i d e a b r o a d e r base for p r o j e c t i n g i n c r e a s i n g sales d o l l a r s d u r i n g t h e next

decade?

T h e q u e s t i o n is not a n s w e r e d easily. H o w e v e r , at this t i m e , there is little or no e v i d e n c e that the d r u g i n d u s t r y plans to c u r t a i l research a n d d e v e l o p m e n t s p e n d i n g i n the 1970's. I n fact, the present l e v e l of r e c r u i t i n g supports the general b e l i e f that 1971 R & D expenditures a g a i n w i l l increase f o r the t o t a l p h a r m a c e u t i c a l i n d u s t r y . It is a w e l l r e c o g n i z e d fact that the so-called research p r o d u c t i v i t y w i t h i n the d r u g i n d u s t r y is c h a n g i n g .

E a c h y e a r the

Pharmaceutical

M a n u f a c t u r e r s ' A s s o c i a t i o n p u b l i s h e s the total d o l l a r expenditures R & D

s u b m i t t e d b y its m e m b e r firms ( 2 ) .

for

If this t o t a l figure is d i v i d e d

b y the n u m b e r of n e w p r o d u c t s i n t r o d u c e d d u r i n g that year, one c a n a r r i v e at the average cost f o r R & D p e r p r o d u c t . D u r i n g the last 10 years this cost has r i s e n a b o u t 20- or 3 0 - f o l d ( a v a l u e w h i c h m a y v a r y w i t h i n that range since there are different w a y s of d e f i n i n g a n e w p r o d u c t ).

The

average cost of r e s e a r c h i n g a n d d e v e l o p i n g a significant n e w p r o d u c t is now

r a p i d l y a p p r o a c h i n g $50 m i l l i o n d o l l a r s . T h e s e escalating expenditures are a factor of p r i m e significance not

o n l y f o r R & D m a n a g e m e n t b u t also for t o t a l c o m p a n y m a n a g e m e n t .

It

is a m a t t e r that s h o u l d c o n c e r n the p u b l i c at large a n d especially those w h o h a v e research experience a n d t e c h n i c a l t r a i n i n g . It w i l l h e l p us to u n d e r s t a n d the reasons f o r the r a p i d increase i n R & D

costs p e r p r o d u c t entity if w e go b a c k to D r . Wescoe's h i s t o r i c a l

viewpoint.

S o p h i s t i c a t e d broad-scale research is r e l a t i v e l y n e w , b u t its

b e g i n n i n g s are r o o t e d i n a n u m b e r of d i s c i p l i n e s : b o t a n i c a l science, p h a r m a c o g n o s y , a n a l y t i c a l c h e m i s t r y , a n d other basic p h a r m a c e u t i c a l sciences. O r g a n i c c h e m i s t r y , b i o c h e m i s t r y , a n d p h a r m a c o l o g y w e r e not i n t r o d u c e d to the i n d u s t r y u n t i l the 1920's a n d 1930's. E v e n at that t i m e c h e m i s t r y w a s rather u n s o p h i s t i c a t e d , a n d p h a r m a c o l o g i c a l t e c h n i q u e s w e r e r u d i mentary.

N o t u n t i l the 1940's a n d 1950's d i d w e see the i n t r o d u c t i o n of

m o d e r n p h a r m a c o l o g y w i t h its c o m p l e x i n t r u m e n t a t i o n a n d

electronic

sensing. O n l y i n the last 10 or 20 years has o r g a n i c c h e m i s t r y b r o a d l y a p p l i e d s u c h devices as i n f r a - r e d spectrometry, n u c l e a r m a g n e t i c nance, mass spectrometry, a n d x-ray d i f f r a c t i o n a p p a r a t u s .

reso-

Previously,

the i d e n t i f i c a t i o n of the structure of a n a n t i b i o t i c o f t e n r e q u i r e d 10 to 20 man-years of w o r k . C o m p a r e this c o m m i t m e n t of t i m e a n d effort w i t h


10.

PETTINGA

The

Pharmaceutical

213

Industry

the achievements of the late 1960's, w h e n it w a s p o s s i b l e to e l u c i d a t e f u l l y the structure of a n a n t i b i o t i c b y x-ray d i f f r a c t i o n sometimes i n as short a p e r i o d as 30 d a y s — l / 1 2 t h of a m a n year. H o w e v e r , modern equipment a n d modern technology, although they speed progress, are extremely expensive. T h e i n v e s t m e n t of a q u a r t e r of a m i l l i o n dollars i n e q u i p m e n t alone f o r one p h y s i c a l c h e m i s t r y l a b is not at a l l u n u s u a l . Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 28, 2015 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch010

T h e i n s t a l l a t i o n , use, a n d m a i n t e n a n c e of s u c h e q u i p m e n t r e q u i r e scientists w i t h a n u n u s u a l degree of s p e c i a l i z e d t r a i n i n g . M o d e r n d r u g m e t a b o l i s m p r o c e d u r e s enable us to select f o r p h a r m a c o l o g y a n d t o x i c o l o g y studies those species of a n i m a l s w h o s e m e t a b o l i c patterns

most

n e a r l y resemble those of h u m a n beings. A f t e r a l l , o u r k n o w l e d g e of the safety a n d efficacy of a d r u g substance is of p a r a m o u n t i m p o r t a n c e f o r man.

T h e a p p r o p r i a t e selection of a species for p h a r m a c o l o g y testing

a n d f o r safety e v a l u a t i o n c a n b e d o n e c r i t i c a l l y o n l y i f w e h a v e a m o d e l system w h i c h is v a l i d . W e m u s t be able to extrapolate k n o w l e d g e g a i n e d i n a n i m a l s to the area of c l i n i c a l p h a r m a c o l o g y a n d c l i n i c a l m e d i c i n e i f our l e n g t h y a n i m a l experiments are to h a v e a n y r e a l m e a n i n g . It is often s a i d that d r u g research is m o r e d i f f i c u l t t o d a y t h a n it w a s 25 years ago because of the greater c o m p l e x i t y of the m e d i c a l p r o b l e m s b e i n g s t u d i e d . I n p a r t this is true; i n p a r t it is false. F o r e x a m p l e , i n the e a r l y 1920s the usefulness of i n s u l i n i n t r e a t i n g diabetes was d i s c o v e r e d b y B a n t i n g a n d Best.

F o r n e a r l y 50 years diabetics h a v e b e e n a b l e to

l e a d active a n d u s e f u l lives of r e l a t i v e l y n o r m a l d u r a t i o n as a result of this d i s c o v e r y . If one c r i t i c a l l y r e v i e w s the literature of diabetes t o d a y , l o o k i n g f o r a n e x p l a n a t i o n of the m e c h a n i s m of a c t i o n of i n s u l i n , one c a n n o t h e l p b u t b e astonished that after 50 years w e h a v e r e a l l y a c h i e v e d v e r y l i t t l e i n a true u n d e r s t a n d i n g of the disease itself, b u t w e d o k n o w a great d e a l m o r e a b o u t insulin's role i n c a r b o h y d r a t e a n d l i p i d m e t a b o l i s m . W e d o not k n o w w h y c e r t a i n i n h e r i t e d characteristics c a n l e a d to a p r e d i s p o s i t i o n to the disease.

W e cannot e x p l a i n w h y some

a p p e a r to have a d e q u a t e stores of i n s u l i n i n t h e i r pancreas.

diabetics

T h e interre-

lationships of i n s u l i n , g l u c a g o n , other h o r m o n e s , a n d the c e n t r a l n e r v o u s system are p o o r l y u n d e r s t o o d .

N o one has e x p l a i n e d satisfactorily

the

r e g u l a t i o n of i n s u l i n synthesis w i t h i n the islet cells or its release i n t o the b l o o d stream w h e n f o o d is ingested.

A l t h o u g h u s e f u l c l i n i c a l entities

f o r the treatment of diabetes h a v e b e e n f o u n d , the w a y s i n w h i c h these d r u g substances act are s t i l l l a r g e l y u n e x p l a i n e d . M u c h the same c a n b e s a i d f o r a n t i b i o t i c s . A l t h o u g h some 30 different a n t i b i o t i c substances are a v a i l a b l e for the treatment a n d p r o p h y l a x i s of i n f e c t i o u s b a c t e r i a l disease, the r o l e of n a t u r a l factors a n d t h e i r interr e l a t i o n s h i p w i t h the a n t i b a c t e r i a l a c t i o n of a n t i b i o t i c s are not c o m p l e t e l y understood.

O n l y s m a l l b e g i n n i n g s have b e e n m a d e i n the t r u e u n d e r -


214

DRUG DISCOVERY

s t a n d i n g of the relationships b e t w e e n

infectious agents a n d h o w this

r e l a t i o n s h i p c a n b e m o d i f i e d f a v o r a b l y b y the use o f antibiotics.

I n no

w a y d o I w i s h to m i n i m i z e the i m p o r t a n c e of present d r u g s i n m a i n t a i n i n g h e a l t h i n treating disease, a n d i n a l l e v i a t i n g p a i n .

Today's modern phy-

s i c i a n has m a n y p o w e r f u l p h y s i o l o g i c a l substances w i t h o u t w h i c h p r a c t i c e w o u l d b e severely h a m p e r e d .

W e can predict w i t h

his

certainty


that 10 to 20 years f r o m n o w m a n y other u s e f u l agents w i l l b e a d d e d to the p h y s i c i a n ' s a r m a m e n t a r i u m against disease a n d suffering. T h e p h y s i o l o g i c a l systems i n w h i c h these d r u g s operate a n d the w a y i n w h i c h t h e y exert their influence w i l l i n a l l l i k e l i h o o d r e m a i n the subject of considerable s t u d y f o r decades to come.

T o d a y , m o r e t h a n at any t i m e d u r i n g

the last 50 years scientists are e n g a g e d i n c a r b o h y d r a t e a n d l i p i d research. F r o m this research s h o u l d c o m e n e w k n o w l e d g e l e a d i n g to better t h e r a p y a n d , h o p e f u l l y , p r e v e n t i o n of

diabetes.

W e h a v e a l r e a d y a l l u d e d to the increased d e m a n d for the k n o w l e d g e of safety a n d t o x i c i t y factors a n d of the m e c h a n i s m s of d r u g actions.

As

n e w technology becomes a v a i l a b l e to pharmacologists, biochemists, a n d biologists, their n a t u r a l c u r i o s i t y , p l u s the d e m a n d s of the

physicians

to k n o w h o w d r u g s operate a n d exert their influence, h a v e l e d to f u r t h e r studies of the m e c h a n i s m s of d r u g actions.

I n a d d i t i o n , m a n y studies are

a i m e d at d e m o n s t r a t i n g the safety of b o t h n e w a n d o l d m e d i c i n a l substances. T h e d i s c o v e r y that t h a l i d o m i d e , a n extremely u s e f u l d r u g , was dangerous because it c a u s e d a b n o r m a l d e v e l o p m e n t of the fetus w h e n t a k e n i n the early p a r t of p r e g n a n c y d i d m o r e t h a n a n y other

single

factor to stimulate r e n e w e d interest i n a n i m a l t o x i c o l o g y studies.

I am

c o n v i n c e d that the d e m o n s t r a t i o n b y L e n z i n G e r m a n y ( 3 )

a n d others

that t h a l i d o m i d e caused p h o c o m e l i a , was the p r i m e m o v e r i n g e t t i n g C o n g r e s s to pass the 1962 A m e n d m e n t s to the F o o d a n d D r u g s A c t . Inserts i n the packages of m a n y w i d e l y u s e d d r u g s c a r r y statements s u c h as: " N o t r e c o m m e n d e d i n p r e g n a n c y , " " I n w o m e n of c h i l d - b e a r i n g age w e i g h p o t e n t i a l benefits

against

possible f e t a l h a z a r d s , " or,

"The

safety of ' X ' for use i n p r e g n a n c y has not b e e n established; therefore, this d r u g s h o u l d be u s e d i n p r e g n a n t patients o n l y w h e n , i n the

judgment

of the p h y s i c i a n , its use is d e e m e d essential to the w e l f a r e of the p a t i e n t . " T o d a y a l l n e w d r u g s are subjected to teratology studies to i n d i c a t e their safety i n pregnant females.

H o w e v e r , w h e n o u r studies o n a n e w

d r u g are c o m p l e t e , w e c a n be reasonably certain o n l y that the i n c i d e n c e of a b n o r m a l m i c e , rats, r a b b i t s , or other a n i m a l species is not i n c r e a s e d a b o v e the n o r m a l i n c i d e n c e , e v e n t h o u g h the d r u g is a d m i n i s t e r e d i n h i g h doses to the a n i m a l m o t h e r before, as w e l l as after, c o n c e p t i o n , a n d d u r i n g the f u l l - t e r m of p r e g n a n c y .

W e c a n l i k e w i s e be q u i t e

certain

a b o u t the l a c k of effects o n the n e w b o r n w h e n the d r u g is a d m i n i s t e r e d


10.

PETTINGA

The

Pharmaceutical

215

Industry

to the l a c t a t i n g f e m a l e , b u t , w e cannot say w i t h c e r t a i n t y that t h e d r u g w i l l b e safe i n h u m a n beings w h e n a d m i n i s t e r e d d u r i n g p r e g n a n c y . It is i m p e r a t i v e that scientists, p h y s i c i a n s , a n d the l a y p u b l i c , as w e l l as o u r legislative bodies, be m a d e a w a r e that no a m o u n t of testing i n a n i m a l s c a n guarantee the safety of a m e d i c i n e i n a l l h u m a n beings. c o m p l e t e l a c k of side effects i n a n i m a l s does not prove

A

safety i n m a n .


S i m i l a r l y , the a p p e a r a n c e of a b n o r m a l o f f s p r i n g i n the litters of a n i m a l s g i v e n drugs d u r i n g p r e g n a n c y

does not necessarily

m e a n that

these

substances w i l l b e unsafe w h e n t a k e n b y p r e g n a n t w o m e n . H o w e v e r , n o one c a n ever r e c o m m e n d that p r e g n a n t w o m e n m a k e the h e r o i c e x p e r i m e n t of testing substances that p r o d u c e p h o c o m e l i a i n a n i m a l s . I n a d d i t i o n to the g r o w t h i n scope a n d c o m p l e x i t y of the p h y s i c a l , c h e m i c a l , a n d b i o l o g i c a l sciences i n i n d u s t r i a l p h a r m a c e u t i c a l w e h a v e seen a r e n e w e d interest i n p h a r m a c e u t i c a l research,

research including

p r o d u c t f o r m u l a t i o n , efficacy standards, n e w regulations g o v e r n i n g g o o d m a n u f a c t u r i n g practices, a n d better c o n t r o l p r o c e d u r e s to ensure

the

q u a l i t y of drugs f o r d o m e s t i c a n d f o r e i g n markets. It is i n a p p r o p r i a t e to d w e l l at l e n g t h o n the n e w standards

for

d e t e c t i n g b a c t e r i a i n p a r e n t e r a l p r o d u c t s a n d p r o d u c t s d e s i g n e d for o r a l or t o p i c a l m e d i c a t i o n .

M o r e p e o p l e t h a n ever before

are at w o r k i n

A m e r i c a n industries, g o v e r n m e n t laboratories, a n d a c a d e m i c circles rev i e w i n g d r u g standards. U n d e r s t u d y are s u c h subjects as b i o - a v a i l a b i l i t y of drugs a n d m e t h o d s for d e t e c t i n g not o n l y the a m o u n t of active i n gredients present i n p h a r m a c e u t i c a l p r e p a r a t i o n s b u t also the

presence

of trace i m p u r i t i e s . T h e latter m a y either negate the d e s i r e d d r u g a c t i o n or m a y cause u n w a n t e d side effects.

Government Regulation P e r h a p s the greatest single change

that has o c c u r r e d w i t h i n o u r

i n d u s t r y has b e e n i n the area of g o v e r n m e n t r e g u l a t i o n a n d p u b l i c s c r u t i n y of o u r t o t a l operations.

F o r years the p h a r m a c e u t i c a l i n d u s t r y felt

that its o b l i g a t i o n consisted solely of r e l a t i n g to the p r o f e s s i o n a l m e m b e r s of the h e a l t h professions: p h y s i c i a n s , dentists, p h a r m a c i s t s , a n d nurses. L i t t l e or no a t t e m p t w a s m a d e to m a k e o u r i n d u s t r y u n d e r s t o o d b y the man

i n the street, b y the legislator i n the state c a p i t o l , or b y the C o n -

gressman i n W a s h i n g t o n . B y a n d large, w e felt w e h a d o n l y one p u b l i c — the p h y s i c i a n s a n d m e d i c a l p e r s o n n e l w h o u s e d o u r p r o d u c t s to treat patients. A l t h o u g h a f e w articles a p p e a r e d i n the p o p u l a r press i n a v e i n s i m i l a r to P a u l D e K r u i f s " M i c r o b e H u n t e r s " (4),

there w a s l i t t l e u n d e r -

s t a n d i n g of the d r u g i n d u s t r y . P e o p l e d i d not k n o w h o w d r u g research was c a r r i e d out; t h e y h a d l i t t l e i d e a h o w d r u g s w e r e d i s t r i b u t e d or h o w they w e r e m a d e a v a i l a b l e t h r o u g h the c h a i n of d i s t r i b u t i o n , i n c l u d i n g wholesalers, d r u g stores, a n d h o s p i t a l pharmacists.


216

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T h e K e f a u v e r hearings i n 1960 d i d m u c h to change this t o t a l situation.

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 a n d the safety a n d efficacy of d r u g s

h a v e been, a n d w i l l c o n t i n u e to be, the subject of c o n v e r s a t i o n over b r i d g e tables, b y n e w s commentators, a n d i n the d a i l y press.

Senators a n d c o n -

gressmen w i l l c o n t i n u e to h o l d hearings because the p u b l i c is interested i n h e a l t h a n d p e o p l e are c o n c e r n e d w i t h the safety a n d efficacy of the d r u g substances p r e s c r i b e d b y t h e i r p h y s i c i a n s . T h e F o o d a n d D r u g A d m i n Downloaded by UNIV OF CALIFORNIA SAN DIEGO on December 28, 2015 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch010

i s t r a t i o n has f o r m u l a t e d its r e q u i r e m e n t s for the safety a n d effectiveness of n e w d r u g substances ( 5 ) , w h i c h have greatly i n c r e a s e d t h e c o m p l e x i t y a n d scope of the investigations n o w r e q u i r e d f o r a n e w d r u g a p p l i c a t i o n . F o r e x a m p l e , i n the mid-1950's

less t h a n 100 patients w e r e n e e d e d for

c l i n i c a l testing to secure F D A a p p r o v a l of a n e w a n t i b i o t i c . T o d a y , h o w ever, no d r u g m a n u f a c t u r e r w o u l d s u b m i t a n e w d r u g a p p l i c a t i o n to the FDA

unless several h u n d r e d s or e v e n thousands of cases w e r e s t u d i e d

i n d e t a i l , a n d a l l the results w e r e c a r e f u l l y c o r r e l a t e d .

T h i s does

not

necessarily m e a n that i n a l l cases the F D A receives better i n f o r m a t i o n t o d a y t h a n i t d i d 15 years ago. T w e n t y - f i v e w e l l d o c u m e n t e d , t h o r o u g h l y s t u d i e d cases m a y g i v e almost as f u l l a n u n d e r s t a n d i n g of t h e c l i n i c a l effectiveness a n d safety of a n a n t i b i o t i c as several h u n d r e d cases that a p p e a r to b e less w e l l s t u d i e d a n d r e p i t i t i o u s . H o w e v e r , the facts of the m a t t e r are s u c h that v o l u m e s of i n f o r m a t i o n must b e c o l l e c t e d , c o r r e l a t e d , and

indexed. S e v e r a l h u n d r e d s of p o u n d s of d o c u m e n t s c o v e r i n g the c h e m i c a l a n d

p h y s i c a l properties of a n e x p e r i m e n t a l substance a n d its b e h a v i o r i n a n i mals m u s t b e p r e p a r e d f o r s u b m i s s i o n to W a s h i n g t o n . C l i n i c a l p h a r m a c o l o g y a n d c l i n i c a l experience o b t a i n e d w i t h a n e w d r u g substance i n m a n y centers of research m u s t b e correlated, r e v i e w e d , a n d s u m m a r i z e d . T h i s i n f o r m a t i o n is r e v i e w e d not o n l y b y the s p o n s o r i n g c o m p a n y ' s scientists b u t also b y outside investigators. It is finally r e v i e w e d e x h a u s t i v e l y b y the F D A . F o l l o w i n g a p p r o v a l , the c o m p a n i e s m u s t c o n t i n u e at r e g u l a r intervals to s u b m i t a d d i t i o n a l reports to the F D A o n a l l experiments i n a n i m a l s a n d i n h u m a n beings to s u p p o r t the c o n t i n u a t i o n of F D A app r o v a l to d i s t r i b u t e a p r o d u c t i n interstate c o m m e r c e .

The industry and

I b e l i e v e that m o d e r n t e c h n o l o g y a n d o u r m o d e r n society d e m a n d that as m u c h i n f o r m a t i o n as possible to m a d e a v a i l a b l e not o n l y to the F D A b u t to m e d i c a l investigators a n d to p h y s i c i a n s r e g a r d i n g the safety a n d efficacy of t h e r a p e u t i c agents s o l d i n the U n i t e d States t o d a y . W e s u p p o r t c o m p l e t e l y the general p u r p o s e a n d objectives of the F D A . H o w e v e r , w e m u s t r e m e m b e r that i n the b i o l o g i c a l sciences a n d i n the m e d i c a l sciences, e s p e c i a l l y w i t h i n the g e n e r a l area of b i o l o g i c a l sciences, there are v e r y f e w absolutes.

B i o l o g i s t s a l l t e l l us that v a r i a t i o n

is the u s u a l event rather t h a n the u n u s u a l event.

T h i s is w h y statistical

research a n d the use of statistics is so i m p o r t a n t i n a l l b i o l o g i c a l science.


10.

PETTiNGA

The

Pharmaceutical

217

Industry

F o r this reason the m i c r o b i o l o g i s t s use m i l l i o n s of organisms i n a m i c r o b i o l o g i c a l assay. It is the reason w h y precise measurements of the g r o w t h response of a n e w n u t r i t i o n a l agent m u s t b e m e a s u r e d i n m o r e t h a n one h o g or i n m o r e t h a n one beef a n i m a l . T h e presence of c e r t a i n u n u s u a l genetic characteristics w i t h i n

the

h u m a n race, the c o n c o m m i t a n t use of other drugs, a n d a l l of the factors


w h i c h m a k e each p a t i e n t a n i n d i v i d u a l r e q u i r e that m e d i c i n e be p r a c t i c e d by m e n w i t h professional judgment.

I k n o w of no drugs that are abso-

l u t e l y safe or a b s o l u t e l y effective. F o r e x a m p l e , c o m b i n a t i o n s of estrogens a n d progestins, as f o u n d i n m o d e r n b i r t h c o n t r o l p r o d u c t s , are v i r t u a l l y 1 0 0 % effective. H o w e v e r , i f these agents are g i v e n to 100 n o r m a l m a r r i e d w o m e n w h o are fertile, a b o u t one p r e g n a n c y w i l l o c c u r each year that these 100 w o m e n are o n t h e r a p y .

T h e r e has b e e n m u c h p u b l i c i t y a n d

m u c h attention p a i d to the c o n c e p t i o n rate i n w o m e n w h o are o n the p i l l . N o t e d m e d i c a l research m e n h a v e a r g u e d w i t h the p r e g n a n c y 0.6/100 w o m a n years; 1.0; or 1.3. of little consequence

rate—

T h e s e s m a l l differences t u r n o u t to be

to the biologists w h o p r e f e r to v i e w the n u m b e r s

as 98.7; 99.0; or 9 9 . 4 %

effective.

O f course, it is l i t t l e c o m f o r t to the w o m a n w h o w a n t e d to a v o i d p r e g n a n c y w h e n h e r d o c t o r tells her she is the 1 i n 100 w h o has c o n c e i v e d . T h e p u b l i c has b e e n l e d to b e l i e v e that m o d e r n m e d i c a l science a n d effective d r u g r e g u l a t i o n , c o u p l e d w i t h the g o o d p r a c t i c e of m e d i c i n e , w i l l guarantee absolute effectiveness

a n d absolute safety.

This

cannot

be true. R e c e n t l y , 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 reports ( 6 ) o n the effectiveness a n d safety of c e r t a i n d r u g have been

demanding considerable

attention—and

substances

work—within

the

F D A , w i t h i n the i n d u s t r y , a n d w i t h i n m e d i c a l circles. C e r t a i n p r o d u c t s h a v e b e e n f o u n d to be of q u e s t i o n a b l e v a l u e , even t h o u g h they h a v e l o n g had a time-honored place i n A m e r i c a n medicine. A s an i n d i v i d u a l , and as a scientist I c a n g e n e r a l l y agree w i t h most if not a l l of the conclusions c o n t a i n e d i n the presently p u b l i s h e d reports r e n d e r e d b y those scientists a n d m e d i c a l p e o p l e w h o m a d e u p the ad hoc the N A S - N R C .

committees a p p o i n t e d b y

M a n y of the a n t i b i o t i c c o m b i n a t i o n s w h i c h the F D A

has n o w f o u n d to be of lesser i m p o r t a n c e i n the p h y s i c i a n s ' a r m a m e n t a r i u m are i n d e e d p r o d u c t s w h o s e f u n c t i o n c a n b e p e r f o r m e d p e r h a p s e v e n better b y n e w e r , safer, m o r e effective p r o d u c t s . H o w e v e r , the c o m b i n a t i o n of p e n i c i l l i n a n d p r o c a i n e p e n i c i l l i n , w h i c h does p r o v i d e a l o n g a c t i n g dosage f o r m of this t i m e - h o n o r e d d r u g , a n d is still v e r y effective a n d v e r y safe, i n m y o p i n i o n o u g h t not to h a v e b e e n q u e s t i o n e d b y the F D A . I a p p l a u d , h o w e v e r , the F D A ' s recent d e c i s i o n to ask i n d u s t r y to s u p p l y n e w a d d i t i o n a l e v i d e n c e i n one year.


218

DRUG

DISCOVERY

Q u i t e f r a n k l y , I d o fear the t e n d e n c y w i t h i n A m e r i c a n s is to l o o k for a q u i c k , ready, p a t answer to a l l of o u r p r o b l e m s . A s scientists, w e k n o w that o u r biggest job is c r i t i c a l l y to define the p r o b l e m before w e b e g i n to seek answers.

O n e must be c e r t a i n of his facts b e f o r e j u d g m e n t is

r e n d e r e d , a n d e v e n then one must be p r e p a r e d to alter his d e c i s i o n if n e w facts emerge.

F o r e x a m p l e , a f e w years ago it was d e c i d e d that the

i n s t a l l a t i o n a n d subsequent use of seat belts i n a u t o m o b i l e s w o u l d sigDownloaded by UNIV OF CALIFORNIA SAN DIEGO on December 28, 2015 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch010

n i f i c a n t l y r e d u c e deaths a n d p e r s o n a l injuries i n accidents.

L a t e r , it was

d e c i d e d that s h o u l d e r harnesses w o u l d f u r t h e r r e d u c e the t o l l .

Hence,

these safety devices are n o w m a n d a t o r y i n a u t o m o b i l e s s o l d i n the U n i t e d States.

A l t h o u g h m y s a m p l e is s m a l l , I h a v e statistics

o n the d r i v e r s

w h o w e a r a n d those w h o d o not w e a r s h o u l d e r harnesses i n a l l cars that are e q u i p p e d w i t h h e a d rests ( w h i c h b e c a m e m a n d a t o r y about a year after s h o u l d e r harnesses w e r e r e q u i r e d ) .

O n a recent t r i p I a s k e d m y

c h i l d r e n to c o n d u c t this survey because m y p e r s o n a l observations c a t e d less t h a n 1 0 %

indi-

of the d r i v e r s I o b s e r v e d w e r e w e a r i n g s h o u l d e r

harnesses. T h i s survey was also c a r r i e d out o n a t r i p f r o m I n d i a n a p o l i s to C h i c a g o . W e f o u n d that a b o u t 7 % of the drivers w e r e a c t u a l l y w e a r i n g s h o u l d e r harnesses; no s h o u l d e r harnesses w e r e w o r n i n the r e m a i n i n g 9 3 % of the cars. I a m neither c r i t i c a l of the l a w nor of s h o u l d e r harnesses. T h e p o i n t is that w h i l e regulations c a n force the i n s t a l l a t i o n of s h o u l d e r harnesses, they cannot ensure their a c c e p t a n c e b y d r i v e r s . So, too, w i t h drugs. W e c a n do extensive research; w e c a n exhaust i v e l y s t u d y the b e h a v i o r of p h y s i o l o g i c a l l y active c o m p o u n d s u n d e r a v a r i e t y of circumstances, i n a n u m b e r of different a n i m a l species.

W e can

extensively s t u d y the c l i n i c a l b e h a v i o r of these substances i n research hospitals a n d i n a c a d e m i c institutions w h e r e m e d i c i n a l skills are v e r y h i g h , a n d w h e r e intensive l a b o r a t o r y n u r s i n g a n d other aids are a v a i l a b l e . If, h o w e v e r , the p h y s i c i a n does not c a r e f u l l y use the i n f o r m a t i o n p r e sented to h i m , if he misuses the p r o d u c t , or if the p a t i e n t fails to f o l l o w directions, w e c a n expect i n o r d i n a t e increases i n p r o d u c t failures a n d i n side effects. It is v e r y i m p o r t a n t that w e , as scientists, as m e m b e r s of the i n d u s t r y , as p h y s i c i a n s e n g a g e d i n m e d i c a l research a n d m e d i c a l p r a c t i c e , a n d as responsible r e g u l a t o r y officials, look c a r e f u l l y at the t o t a l p r o b l e m , that w e attempt to use o u r best c a p a b i l i t i e s to w e i g h f u l l y the

balance

of risk vs. benefit, a n d that w e d o not i n d u l g e i n either c a p r i c i o u s r e g u l a t i o n or i r r e s p o n s i b l e

marketing and merchandising

practices.

I

will

q u i c k l y grant that there m a y h a v e b e e n examples w h e r e d r u g c o m p a n i e s h a v e b e h a v e d i n a f a s h i o n of w h i c h none of us c a n be p r o u d . T h e m a i n objectives of the p h a r m a c e u t i c a l i n d u s t r y w i t h i n the U n i t e d States are i d e n t i c a l to those of the m e d i c a l profession a n d of the p u b l i c servants w h o d e a l w i t h r e g u l a t o r y p r o b l e m s at the F D A . W e are a l l anxious to


10.

P E T T I N GA

The Pharmaceutical

219

Industry

p r o v i d e t h e best p o s s i b l e t h e r a p e u t i c agents w h e r e v e r t h e y are n e e d e d b y p h y s i c i a n s a n d patients a l i k e . If w e exercise g o o d j u d g m e n t , i f w e m a k e use o f a l l t h e t e c h n o l o g y that is a v a i l a b l e , w e c a n a c h i e v e o u r joint objectives.

Although many

p r o b l e m s l i e a h e a d of us, these p r o b l e m s are n o t obstacles to progress b u t


offer us greater o p p o r t u n i t i e s to serve.

Literature Cited (1) Wesco, W. Clark, ADVAN. CHEM. SER. (1971) 108, 195.

(2) "Pharmaceutical Manufacturers Association Yearbook, 1969-1970," Washington, D.C.,1970. (3) Lenz, W., Deut. Med. Wochenschr. (1961) 86, 2555-2556; Lancet (1962) 1, 45. (4) DeKruif, Paul, "Microbe Hunters," Pocket Books, Inc., New York, 1966. (5) "Requirements of the U.S. Food, Drug and Cosmetic Act," Food and Drug Administration, U.S. Department of Health, Education, and Welfare, Publ. No. 2, U.S. Government Printing Office, Washington, D.C.,1970. (6) "Drug Efficacy Study, Final Report of the Commissioner of Foods and Drugs, Food and Drug Administration," U.S. Government Printing Office, Washington, D.C.,1969. RECEIVED February 8, 1971.


Drug Discovery - ACS Publications

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