Drug Discovery

8 The Rate of Contemporary Drug Discovery BARRY M . B L O O M M e d i c a l Research Laboratories, Pfizer Pharmaceuticals, Groton, C o n n . 06340

Downloaded by CORNELL UNIV on September 27, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch008

While

the rate at which

received

regulatory

new single

approval

and

United

States during

until the early 1960's, it has declined by drug category,

ately

preceding

Law

Amendments,

that appear while certain

One

important vascular

vexing

and

approval, medical

vitally problems

and pulmonary

newly introduced

cancer

drug

the con-

since.

periods

immedi-

1962

Drug

for the

decline

U.S.

observation

central

drugs

in

sharply

to the evolving

particularly

products

increased

of the

some reasons

types of drugs, notably

antibiotics,

regulatory

passage

to be attributable

tory climate. agents,

identifies

1941-1970

comparing

and following

drug

introduced

tinually

An analysis

the period

entity

were

regulais that

nervous

continue

system to

gain

needed types of agents for

other

of our time,

such

diseases, are notably

as

cardio-

absent

among

products.

T n t r y i n g to u n d e r s t a n d the m e c h a n i s m of a process, chemists often A

find

i t e n l i g h t e n i n g to a n a l y z e the rates i n v o l v e d . I n l i k e f a s h i o n , n e w

insights i n t o the nature of c o n t e m p o r a r y d r u g d i s c o v e r y m i g h t b e o b t a i n e d if w e c o u l d l e a r n about the rate at w h i c h that process has o c c u r r e d i n recent years.

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

i n the rate at w h i c h n e w d r u g s are b e i n g d i s c o v e r e d a n d m a d e a v a i l a b l e for m e d i c a l use. T h i s p a p e r assesses the rate of n e w d r u g p r o d u c t i n t r o d u c t i o n over the last 30 years, a p e r i o d w h i c h corresponds essentially to the entire m o d e r n era of d r u g research. T h e a p p r o a c h is to a n a l y z e a list of the basic n e w agents i n t r o d u c e d to m e d i c a l p r a c t i c e i n the U . S . since 1941, u s i n g t h e D e H a e n " N e w P r o d u c t S u r v e y " a n d " N o n - P r o p r i e t a r y N a m e I n d e x " as p r i m a r y source materials ( J ) .

T h e D e H a e n lists, w h i c h c o n t a i n m a n y k i n d s of n e w d r u g

p r o d u c t s , h a v e b e e n c u l l e d a c c o r d i n g to a set of e x c l u s i o n rules w e h a v e d e v i s e d to m a k e t h e m a m o r e m e a n i n g f u l i n d e x o f t h e rate of bona drug discovery. 176

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

fide

8.

BLOOM

Contemporary

Drug

177

Discovery

A c c o r d i n g to these rules, a d r u g p r o d u c t w a s i n c l u d e d i n o u r e d i t e d list o n l y i f i t was, at the t i m e of m a r k e t i n t r o d u c t i o n , a n e w , single c h e m i c a l e n t i t y i n t e n d e d f o r h u m a n t h e r a p e u t i c use, that d i d n o t f a l l into a n y of the f o l l o w i n g , e x c l u d e d categories: b i o l o g i c a l s s u c h as vaccines; d i a g nostic aids; h o s p i t a l solutions; n o n - a b s o r b e d h i g h m o l e c u l a r w e i g h t c o m p o u n d s ; i m p u r e extracts of n a t u r a l o r i g i n ; n e w uses a n d / o r f o r m u l a t i o n s of p r e v i o u s l y m a r k e t e d d r u g s ; n e w single components i n c l u d e d i n p r e v i o u s l y m a r k e t e d mixtures; a n d n e w salts of p r e v i o u s l y m a r k e t e d d r u g s . A l t h o u g h n e w salts have b e e n e x c l u d e d , o u r e d i t e d list does i n c l u d e n e w esters a n d other c o v a l e n t l y b o n d e d derivatives of p r e v i o u s l y m a r k e t e d drugs. Downloaded by CORNELL UNIV on September 27, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch008

T h e i n h e r e n t l i m i t a t i o n s of this a p p r o a c h are r e a d i l y apparent. B e cause i t is the o n l y f o r m i n w h i c h c o m p r e h e n s i v e data are a v a i l a b l e to us, w e h a v e h a d to use dates of U . S . n e w p r o d u c t i n t r o d u c t i o n s as a n i n d e x of the rate at w h i c h n e w d r u g s are b e i n g d i s c o v e r e d t h r o u g h o u t the w o r l d . T h e justification f o r a s s u m i n g that there is a c o r r e l a t i o n b e t w e e n the t i m e w h e n a d r u g is first d i s c o v e r e d a n d the date w h e n i t is i n t r o d u c e d i n the U . S . m a r k e t derives f r o m the c o n s i d e r a t i o n that, i n a l l l i k e l i h o o d , the sponsors of a n y significant n e w d r u g t o d a y w i l l b e s t r o n g l y m o t i v a t e d to m a k e i t a v a i l a b l e c o m m e r c i a l l y i n the U n i t e d States as soon as possible. R e c o g n i z i n g that the t i m e p e r i o d f r o m d i s c o v e r y to U . S . m a r k e t introd u c t i o n is l i k e l y to differ s i g n i f i c a n t l y f r o m case to case, w e have sought to m i n i m i z e this p o t e n t i a l source of error b y r e s t r i c t i n g the analyses to comparisons i n v o l v i n g p e r i o d s of n o less t h a n five years. A n y effort to d e t e r m i n e w h i c h d r u g p r o d u c t s deserve to b e o n a list restricted to n e w , single c h e m i c a l entities is b o u n d to l e a d to a f e w quest i o n a b l e j u d g m e n t s , a n d the s i m p l e exclusion rules w e u s e d are n o exception. H o w e v e r , the n u m b e r of d e b a t a b l e cases i n this study is too s m a l l to cause a n y serious c o n c e r n . W e have n o t a t t e m p t e d to d i s t i n g u i s h the d i f f e r i n g degrees of i n n o v a t i o n that i n d i v i d u a l discoveries represent.

W e treat a n u n i m p o s i n g

m o l e c u l a r m o d i f i c a t i o n of a w e l l - e s t a b l i s h e d t h e r a p e u t i c p r i n c i p l e as i f i t w e r e e n t i r e l y e q u i v a l e n t to the d i s c o v e r y of p e n i c i l l i n G or cortisone. A t t e m p t s to assess c o m p a r a t i v e degrees of i n n o v a t i o n a n d m e d i c a l significance objectively are so d i f f i c u l t that despite the p o t e n t i a l v a l u e of s u c h j u d g m e n t s i n a s t u d y l i k e this one, efforts to d o so m u s t r e m a i n outside the scope of this p a p e r .

Analyses of Data W e have a n a l y z e d o u r e d i t e d list to see i f i t supports t h e w i d e l y h e l d c o n c l u s i o n that the rate of n e w p r o d u c t i n t r o d u c t i o n has s l o w e d signific a n t l y of late.

T a b l e I gives clear e v i d e n c e that this is true.

W e have

c a r r i e d o u r analysis t h r o u g h A u g u s t 1970 a n d b r o k e n t h e 30-year p e r i o d u n d e r s t u d y into

five-year

segments.


178

DRUG


Table I.

DISCOVERY

Rate of N e w Product Introductions By Category Five-Year Period

A v e r a g e N u m b e r of Basic New Agents Introduced Per Year

1941-45 1946-50 1951-55 1956-60 1961-65 1966-70 ( t h r o u g h A u g u s t )

10 18 31 39 20 12

T h e rate that p r e v a i l e d d u r i n g t h e w a r years (1941-45)

increased

steadily to a m a x i m u m d u r i n g t h e last h a l f of t h e 1950's, w h e n n e w entities w e r e b e i n g i n t r o d u c e d at a n average rate o f almost 40 p e r year. T h e r e w a s a sharp d e c l i n e i n 1962, c o i n c i d i n g w i t h t h e passage o f t h e K e f a u v e r - H a r r i s A m e n d m e n t s to t h e F o o d a n d D r u g s A c t late that year. T h e n e t effect w a s a decrease b y h a l f of the rate o f n e w p r o d u c t i n t r o ductions

d u r i n g the p e r i o d 1961-65 i n c o m p a r i s o n w i t h t h e p r e v i o u s

p e r i o d . T h e rate d e c l i n e d f u r t h e r , b y almost h a l f a g a i n , i n t h e present five-year

p e r i o d , r e a c h i n g a l o w i n 1969, w h e n o n l y seven

a p p e a r o n t h e list. U.S.

compounds

( O n t h e other h a n d , 11 b a s i c n e w agents g a i n e d

r e g u l a t o r y a p p r o v a l d u r i n g the first eight m o n t h s of 1 9 7 0 ) . N e x t , w e c o m p a r e d the p r o d u c t i v i t y o f each five-year p e r i o d t o deter-

m i n e w h e t h e r a n y factors that m i g h t b e responsible f o r i n d u c i n g i m p o r tant changes i n t h e rate o f e m e r g e n c e of n e w p r o d u c t s w e r e d i s c e r n i b l e . A l t h o u g h t h e conclusions w i l l h a r d l y p r o v e s u r p r i s i n g , they d o offer a means o f e n h a n c i n g o u r p e r s p e c t i v e o n t h e e v o l u t i o n o f the m o d e r n d r u g d i s c o v e r y effort. G o i n g b a c k to t h e first five-year p e r i o d — 1 9 4 1 - 4 5 — t h e o v e r - a l l l e v e l of research a c t i v i t y w a s s i g n i f i c a n t l y l o w e r t h a n that of today.

M u c h of

the t e c h n o l o g y r e q u i r e d to s u p p o r t operations o f the efficiency a n d sophist i c a t i o n that are n o w c o m m o n p l a c e w a s n o t y e t a v a i l a b l e . T h e N e w D r u g A p p l i c a t i o n h a d a l r e a d y c o m e into existence a f e w years earlier, i n 1938, f o l l o w i n g t h e e l i x i r of s u l f a n i l a m i d e tragedy, a n d certification h a d b e g u n —first, w i t h i n s u l i n i n 1941 a n d s u b s e q u e n t l y w i t h p e n i c i l l i n i n 1945. I n a d d i t i o n , there w e r e t h e m a n y c o m p l i c a t i o n s t h a t t h e w a r itself i n t r o duced.

D e s p i t e a l l of this, t h e research effort o f t h e p e r i o d p r o v e d r e -

markably productive.

These were

t h e e x c i t i n g years w h e n A m e r i c a n

m e d i c i n e first g a i n e d t h e use o f antibiotics l i k e p e n i c i l l i n a n d streptom y c i n , a n d the first of the i m p r o v e d s u l f a d r u g s . R e s e a r c h at this t i m e w a s h i g h l y eclectic. an

unprecedented

Research

Chemists were applying

effort to p r o b i n g , e m u l a t i n g , a n d e x p l o i t i n g nature.

o n v i t a m i n s , a m i n o acids, a n d other n u t r i t i o n a l factors w a s

highly productive.

Efforts to i m p r o v e u p o n s u c h hormones as e p i n e p h -


8.

BLOOM

Contemporary

Drug

179

Discovery

rine, e s t r a d i o l , a n d testosterone w e r e b e g i n n i n g to b e a r f r u i t . M o l e c u l a r m o d i f i c a t i o n , w h i c h some c o n s i d e r a r e l a t i v e l y n e w f o r m of

research

endeavor, was a l r e a d y a w e l l - p r a c t i c e d art, a n d the p r e v a i l i n g s t a n d a r d of t h e r a p y that scientists sought to supersede w a s often p r e t t y l o w . E v e n at this e a r l y t i m e , i m p r o v e d analogs of m o r e t h a n a d o z e n different m a j o r classes of drugs w e r e b e g i n n i n g to b e d e v e l o p e d a n d m a r k e t e d , i n c l u d i n g the b a r b i t u r a t e h y p n o t i c s , analgesics, a n t i p y r e t i c s , l o c a l anesthetics, m u s cle relaxants, pressor amines, m e r c u r i a l d i u r e t i c s , xanthines, p a r a s y m pathomimetic

drugs,

sex

hormones,

sulfonamide

antibacterials,

and


antimalarials. T h i s k i n d of p r o d u c t i v i t y b r o u g h t a b o u t g r o w t h i n d r u g

research

o r g a n i z a t i o n s , a n d the i n c r e a s e d l e v e l of research a c t i v i t y w a s c e r t a i n l y a c o n t r i b u t i n g factor when

major

breakthroughs

d u r i n g the e n s u i n g p e r i o d

occurred in

an

almost

(1946-50),

almost constant

stream.

W i d e s p r e a d screening of f e r m e n t a t i o n broths, p r o m p t e d b y the d r a m a t i c success of p e n i c i l l i n G , p r o d u c e d , i n r a p i d succession, the

first

three

b r o a d - s p e c t r u m a n t i b i o t i c s ( c h l o r t e t r a c y c l i n e , c h l o r a m p h e n i c o l , a n d oxyt e t r a c y c l i n e ). H o r m o n e research, e x p l o i t i n g a g r o w i n g base of k n o w l e d g e a b o u t s t e r o i d c h e m i s t r y , s u d d e n l y y i e l d e d r i c h d i v i d e n d s w i t h the d e m o n stration of the m e d i c a l i m p o r t a n c e of cortisone.

There were

notable

successes i n b o t h the search f o r i m p r o v e d analogs of e s t a b l i s h e d m e d i c i nals a n d the d i s c o v e r y of e n t i r e l y n e w d r u g classes a n d p r o t o t y p e s . first

antihistamines a p p e a r e d , as d i d the first s y n t h e t i c

The

anticholinergic

d r u g s . I s o p r o t e r e n o l was m a d e a v a i l a b l e to m e d i c a l p r a c t i c e , as w e r e the forebears of n i t r o f u r a n antibacterials, n i t r o g e n m u s t a r d s , a d r e n e r g i c , a n d g a n g l i o n i c b l o c k i n g agents, a m o n g others. E a c h n e w research t r i u m p h f o l l o w e d close u p o n the heels of the last. T h e n u m b e r of i m p o r t a n t goals for d i s c o v e r y research r e c o g n i z a b l e to m e d i c i n a l chemists a n d p h a r m a c o l o g i s t s v i r t u a l l y d o u b l e d w i t h i n a f e w short years, a n d it is h a r d l y d i f f i c u l t to a p p r e c i a t e , i n retrospect,

how

these e x h i l a r a t i n g achievements set the stage f o r the p e a k rate of p r o d u c t i n t r o d u c t i o n that o c c u r r e d a b o u t a d e c a d e later. T h e next

five-year

period (1951-55) saw a continuing parade

of

i m p o r t a n t n e w a n t i b i o t i c s p r o d u c e d d i r e c t l y b y f e r m e n t a t i o n , s u c h as p e n i c i l l i n V , n e o m y c i n , p o l y m y x i n , a n d the m e d i u m - s p e c t r u m m a c r o l i d e s . T h e massive c h e m i c a l effort m o u n t e d i n the c o r t i c o s t e r o i d field, f o l l o w i n g r e c o g n i t i o n of the m e d i c a l i m p o r t a n c e of cortisone, q u i c k l y l e d to g r e a t l y i m p r o v e d c o m p o u n d s , as first h y d r o c o r t i s o n e a n d t h e n p r e d n i s o l o n e , a t r i u m p h of a n a l o g research, b e c a m e a v a i l a b l e i n c o m m e r c i a l quantities, h e l p e d b y a major i n f u s i o n of n e w t e c h n o l o g y , the d e v e l o p m e n t of p r a c t i c a l m i c r o b i o l o g i c a l methods for effecting 11-oxygenation of the s t e r o i d nucleus.

C o m p e l l i n g e v i d e n c e that one c o u l d create v a l u a b l e synthetic

m o d i f i c a t i o n s i n the a n t i b i o t i c field also a p p e a r e d w i t h the synthesis of


180

DRUG

tetracycline

b y h y d r o g e n o l y s i s of c h l o r t e t r a c y c l i n e .

n o w , to take some of these achievements

DISCOVERY

Perhaps

we

tend,

for g r a n t e d , b u t the p a t h to

successful d i s c o v e r y i n these fields was a n y t h i n g b u t clear at the t i m e . H o w m a n y scientists w o u l d h a v e a c c u r a t e l y p r e d i c t e d i n the e a r l y 1950's that k n o w l e d g e of the r e l a t i v e l y s i m p l e structure of the a n t i b i o t i c , Chlorom y c e t i n , w o u l d not l e a d to the d i s c o v e r y of a single significant a n a l o g , w h i l e d e c i p h e r i n g the n a t u r e of o x y t e t r a c y c l i n e w o u l d u l t i m a t e l y a l l o w c h e m i c a l m o d i f i c a t i o n of that c o m p l e x , m u l t i f u n c t i o n a l m o l e c u l e to afford a n u m b e r of m e d i c a l l y u s e f u l n e w d r u g s ?


M e a n w h i l e , the era of t r a n q u i l i z e r t h e r a p y w a s d a w n i n g as successf u l i s o l a t i o n of c r y s t a l l i n e reserpine f a c i l i t a t e d the d i s c o v e r y of its u n i q u e effects o n m e n t a l f u n c t i o n , w h i l e m o r e or less c o n c u r r e n t l y , astute c l i n i c a l research

revealed

the

then

unique

psychotherapeutic

properties

of

chlorpromazine. S t i l l other i m p o r t a n t a n d i n n o v a t i v e n e w drugs w e r e i n t r o d u c e d d u r i n g the

same p e r i o d , i n c l u d i n g the

antihypertensive

hydralazine,

a n t i - i n f l a m m a t o r y d r u g p h e n y l b u t a z o n e , the c a r b o n i c a n h y d r a s e

the

inhibi-

t o r / d i u r e t i c a c e t a z o l a m i d e , a n d i s o n i a z i d for the treatment of tuberculosis. H o w e v e r , the p e r i o d of p e a k p r o d u c t i v i t y ( 1 9 5 5 - 6 0 ) s t i l l l a y a h e a d . I n retrospect,

it is a p p a r e n t that b r e a k t h r o u g h discoveries, c a p a b l e

of

c r e a t i n g entirely n e w fields of research, w e r e no l o n g e r o c c u r r i n g freq u e n t l y , a l t h o u g h i n t r o d u c t i o n of the first o r a l c o n t r a c e p t i v e was yet to come (1957).

Instead, a m o n g the 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 this

p r o l i f i c p e r i o d a n u n u s u a l l y h i g h p e r c e n t a g e of d r u g s r e p r e s e n t e d

major

i m p r o v e m e n t s over the t h e n e x i s t i n g standards of t h e r a p y . V a l u a b l e n e w antibiotics, both direct fermentation products, and important

synthetic

m o d i f i c a t i o n s l i k e the m a c r o l i d e esters a n d the first penicillinase-resistant penicillins appeared.

I n a d d i t i o n to "the p i l l , " s t e r o i d research p r o v i d e d

a specific antagonist to the h o r m o n e , aldosterone, a n d s u p e r i o r n e w t o p i c a l corticosteroids.

Useful new

tranquilizers, including chlordiazepoxide,

a p p e a r e d , a l o n g w i t h a p r o f u s i o n of d r u g s f o r t r e a t i n g m e n t a l d e p r e s s i o n : i m i p r a m i n e a n d v a r i o u s m o n o a m i n e oxidase i n h i b i t o r s . R e s e a r c h t o w a r d n o v e l s u l f o n a m i d e d e r i v a t i v e s , a process that h a d b e g u n 20 years earlier, r e a c h e d its c u l m i n a t i o n w i t h the i n t r o d u c t i o n of two i m p o r t a n t n e w p r o t o t y p e d r u g s : the d i u r e t i c c h l o r t h i a z i d e a n d the h y p o g l y c e m i c d r u g t o l b u t a m i d e ; a host of other i n n o v a t i v e p r o d u c t s also a p p e a r e d at this t i m e , i n c l u d i n g the a n t i h y p e r t e n s i v e d r u g g u a n e t h i d i n e a n d the

antidiabetic

agent p h e n f o r m i n . Then

the

t r e n d s h i f t e d rather

abruptly.

During

the

succeeding

p e r i o d ( 1 9 6 1 - 6 5 ) the average y e a r l y rate of n e w p r o d u c t i n t r o d u c t i o n s d r o p p e d b y half.

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

d e n t e d p r o d u c t i v i t y to b r i n g about s u c h a sharp d e c l i n e ?

The

decline

set i n at just a b o u t the t i m e of the t h a l i d o m i d e t r a g e d y a n d the passage


8.

BLOOM

Contemporary

Drug

181

Discovery

of l e g i s l a t i o n r e q u i r i n g that p r o d u c t efficacy, as w e l l as safety, b e d e m o n strated t o t h e satisfaction of F D A . But what actually happened?

W e set a b o u t to t r y to a n s w e r this

q u e s t i o n b y c o m p a r i n g t h e rate of n e w p r o d u c t i n t r o d u c t i o n s b y d r u g category, f o r the five-year p e r i o d s i m m e d i a t e l y p r e c e d i n g ( 1 9 5 S - 6 2 ) a n d f o l l o w i n g (1963-67) establishment

of the n e w F D A regulations.

It is

r e a d i l y d e m o n s t r a b l e , as s h o w n b y T a b l e I I , that i n v a r i o u s w e l l - e s t a b l i s h e d d r u g categories,

where a number of adequately

u s e f u l agents

a l r e a d y existed, t h e d e v e l o p m e n t of n e w p r o d u c t s to t h e p o i n t o f o b t a i n i n g


FDA

m a r k e t i n g a p p r o v a l either ceased altogether

or declined sharply

f o l l o w i n g i n t r o d u c t i o n of the n e w regulations. Table II.

Pre- and Post-1962 D r u g L a w Amendments

Product Category

Period

1957-62

1963-67

9 4 7 8 10 5 4 14 3

0 0 2 0 2 0 1 3 1

64

9

Antihistamines Antitussives Antispasmodics M u s c l e relaxants/antiparkinson drugs Thiazide-type diuretics Sulfonamide antibacterials Antiobesity drugs V o r t i c o s t e r o i d s (systemic a n d topical) Antinauseants Totals

Since the same p h e n o m e n o n o c c u r r e d i n a n u m b e r of other, m i n o r classifications that w e h a v e n o t a t t e m p t e d to tabulate, a p p r e c i a b l y m o r e t h a n h a l f of the d e c l i n e i n the rate of n e w p r o d u c t i n t r o d u c t i o n s that o c c u r r e d after passage of t h e 1962 a m e n d m e n t s ,

c a m e about

i n this

manner. T h e t r e n d i n three other, major d r u g categories w a s s o m e w h a t d i f ferent, h o w e v e r ( T a b l e I I I ) . I n t h e v a r i e g a t e d category, t h e n r e l a t i v e l y Table III.

Pre- and Post-1962 D r u g L a w Amendments

Product Category

Period

1957-62 Psychotherapeutic drugs tranquilizers psychostimulants Antibiotics (antibacterial, antifungal) Cancer chemotherapy Totals

16 9

25

1963-67 7 4

11

13 5

10 5

43

26


182

DRUG

n e w , c o m p r i s i n g the different types of p s y c h o t h e r a p e u t i c

DISCOVERY

d r u g s , there

was a f a l l off i n n e w p r o d u c t i n t r o d u c t i o n s , b u t not n e a r l y to the extent o b s e r v e d w i t h the m o r e exhaustively researched classes of d r u g s t a b u l a t e d above. T h e r e was v i r t u a l l y no d e c l i n e i n the i n t r o d u c t i o n of n e w antibiotics. T h i s was p a r t l y caused b y the e m e r g e n c e of a n u m b e r of i m p o r t a n t n e w semisynthetic

β-lactam a n d t e t r a c y c l i n e

compounds.

Research

in

the

p e n i c i l l i n a n d c e p h a l o s p o r i n fields h a d b e e n p r o f o u n d l y s t i m u l a t e d b y the d e v e l o p m e n t a f e w years earlier of the first p r a c t i c a l m e t h o d for


p r e p a r i n g large quantities of 6 - a m i n o p e n i c i l l a n i c a c i d , a n d this techno l o g i c a l b r e a k t h r o u g h , a l o n g w i t h some b r i l l i a n t n e w c e p h a l o s p o r i n c h e m istry, affected the 1962-66 p e r i o d to a degree that h e l p e d offset any c o n s t r a i n i n g influence the n e w regulations m i g h t h a v e h a d . I n fact, the i n t r o d u c t i o n of i m p o r t a n t semisynthetic β-lactam p r o d u c t s l i k e a m p i c i l l i n a n d c e p h a l o t h i n i n 1963-64 has u n d o u b t e d l y s t i m u l a t e d a h i g h l e v e l of research a c t i v i t y i n those fields t h r o u g h o u t the d e c a d e a n d o n i n t o the 1970's. W i t h the c a n c e r c h e m o t h e r a p e u t i c

agents, w e are p r o b a b l y seeing

the c u m u l a t i v e effect of a joint effort o n the p a r t of government, u n i v e r s i ties, a n d the p h a r m a c e u t i c a l i n d u s t r y to c u r b this d r e a d disease.

Because

d r u g s of this t y p e t e n d , u n f o r t u n a t e l y , to have a rather n a r r o w r a n g e of usefulness, a large n u m b e r of t h e m are d e v e l o p e d . T h e t r e n d t o w a r d i n t r o d u c i n g m o r e n e w p r o d u c t s i n this category has c o n t i n u e d to present,

a n d d u r i n g 1969

the

no less t h a n three of the seven n e w drugs

m a r k e t e d i n the U . S . w e r e f o r t r e a t i n g various f o r m s of

cancer.

A s i d e f r o m a f e w situations l i k e these, the rate of n e w p r o d u c t i n t r o d u c t i o n i n this c o u n t r y has d e c l i n e d s u b s t a n t i a l l y d u r i n g the 1960's. A n analysis of the list of n e w d r u g s i n t r o d u c e d i n the U . S . b e t w e e n 1966 a n d the present c e r t a i n l y underscores this c o n c l u s i o n . agents m a d e a v a i l a b l e d u r i n g this most recent

O f the 58 b a s i c n e w

five-year

p e r i o d , no less

t h a n 41 ( 7 1 % ) w e r e for t r e a t i n g c e n t r a l nervous system i n d i c a t i o n s infectious diseases (12)

or c a n c e r ( 9 ) .

(20),

M o r e striking still, a n d certainly

m o r e v e x i n g , is the fact that d u r i n g this most recent h a l f - d e c a d e a t o t a l of o n l y seven n e w drugs w e r e i n t r o d u c e d for t r e a t i n g the host of other i m p o r t a n t c h r o n i c diseases that p l a g u e m o d e r n m a n , diseases l i k e h y p e r tension,

angina

pectoris,

r h e u m a t o i d arthritis. two

noteworthy

atherosclerosis,

diabetes,

emphysema,

and

A l t h o u g h the p e r i o d d i d see the i n t r o d u c t i o n of

l i p i d - r e g u l a t i n g drugs, t w o

valuable

diuretics,

a

β-

a d r e n e r g i c b l o c k i n g agent a p p r o v e d for t r e a t i n g c a r d i a c a r r h y t h m i a s , a n d a n o v e l agent for the treatment of gout, not one n e w d r u g for t r e a t i n g h i g h b l o o d pressure o b t a i n e d U . S . r e g u l a t o r y clearance. t h a n some d i u r e t i c s ) since 1963.

N o r has one

N o t one n e w single e n t i t y

d i l a t o r p r o d u c t has c o m e onto the U . S . m a r k e t since 1961.

(other

broncho-

( A mucolytic


8.

BLOOM

Contemporary

Drug

183

Discovery

agent i n t r o d u c e d i n 1963 is the o n l y recent single entity p u l m o n a r y d r u g . ) N o t one n e w n o n - s t e r o i d a l agent for the treatment of r h e u m a t o i d arthritis has b e e n m a d e a v a i l a b l e since

1965.

Prospects for the Future O n e c o u l d r e a c h the r a t h e r q u e s t i o n a b l e c o n c l u s i o n that the process of d i s c o v e r y of significant n e w agents i n these classes has g r o u n d to a halt, b u t a p e r u s a l of the c u r r e n t w o r l d m e d i c a l literature reveals

that


potentially important n e w drugs have been discovered recently i n each of these classes, a n d several of these n e w d r u g s are a l r e a d y a v a i l a b l e to p h y s i c i a n s elsewhere i n the w o r l d . strong inference

that

current

T h i s makes a l l b u t u n a v o i d a b l e the

U . S . r e g u l a t o r y attitudes

governing

the

d e m o n s t r a t i o n of c l i n i c a l efficacy a n d safety r e q u i r e d f o r N D A a p p r o v a l h a v e p r o v e d so i n o r d i n a t e l y d e m a n d i n g a n d b u r d e n s o m e as to seriously i m p e d e d r u g d e v e l o p m e n t a n d stifle p r o d u c t i v i t y . C a r l D j e r a s s i , w h o h e l p e d p i o n e e r o r a l c o n t r a c e p t i v e d r u g s , has rep e a t e d l y stated i n the most c o n v i n c i n g terms that this is p r e c i s e l y w h a t has a l r e a d y h a p p e n e d i n the field of f e r t i l i t y c o n t r o l research

(2).

T h e present analysis offers other e v i d e n c e that r e g u l a t o r y factors are c o n t r i b u t i n g i m p o r t a n t l y to the s l o w d o w n . C a n it be e n t i r e l y fortuitous that n e w a n t i b i o t i c s , t r a n q u i l i z e r s , a n d c a n c e r d r u g s c o n t i n u e to g a i n F D A a p p r o v a l w i t h some r e g u l a r i t y , w h i l e n e w p r o d u c t s f o r the treatment of i m p o r t a n t , c h r o n i c m e t a b o l i c diseases are c o n s p i c u o u s o n l y b y t h e i r absence? T h o s e f a m i l i a r w i t h c l i n i c a l p h a r m a c o l o g y are w e l l a w a r e that the d i f f i c u l t y of e s t a b l i s h i n g efficacy a n d safety of a n e w

antibacterial

d r u g is i n n o w a y c o m p a r a b l e w i t h the c o r r e s p o n d i n g task i n v o l v i n g a n agent f o r the treatment of a disease l i k e a n g i n a pectoris, f o r e x a m p l e . P r o p r a n o l o l , the o n l y n e w single e n t i t y c a r d i o v a s c u l a r d r u g to r e a c h the U . S . m a r k e t d u r i n g the last three years, has yet to b e a p p r o v e d f o r use i n the treatment of a n g i n a , its m a i n a p p l i c a t i o n f o r s e v e r a l years n o w i n other m e d i c a l l y s o p h i s t i c a t e d countries l i k e the U n i t e d K i n g d o m .

Perhaps

w h a t recent events suggest is that b u r d e n s o m e regulations m a y be r e l a t i v e l y tolerable i n the t e c h n i c a l l y easier fields, b u t p r o v e to b e the " s t r a w that breaks the camel's b a c k " i n the m o r e d e m a n d i n g

fields.

W e c l e a r l y h a v e m u c h to w o r r y a b o u t w i t h r e g a r d to the effect of the present r e g u l a t o r y c l i m a t e o n the process of t r a n s l a t i n g n e w d r u g discoveries into p r o d u c t s that c a n be m a d e a v a i l a b l e to o u r h e a l t h c a r e system. H o w e v e r , it is a p p r o p r i a t e to ask also a b o u t the l i k e l y i m p a c t of the c u r r e n t regulations u p o n the process of d i s c o v e r y itself.

T h i s is a n

issue that defies rigorous analysis, b u t one c a n r e a s o n a b l y speculate

that

i n a s e l f - s t i m u l a t i n g process of the sort this s t u d y c l e a r l y suggests d r u g d i s c o v e r y research to be, any factor, s u c h as restrictive r e g u l a t i o n s , w h i c h


184

DRUG DISCOVERY

decreases t h e rate at w h i c h v i t a l n e w i n f o r m a t i o n flows f r o m t h e c l i n i c b a c k to the l a b o r a t o r y w i l l h a v e a p r o f o u n d depressant effect o n t h e rate of d i s c o v e r y . Since w e d o n o t k n o w h o w l o n g i t s h o u l d take f o r a n i m p o r tant n e g a t i v e influence o f this sort to exert its f u l l effect o n s l o w i n g d o w n the rate o f d i s c o v e r y o f i n n o v a t i v e n e w d r u g s , o n e c a n o n l y h o p e ( a n d p r a y ) that w e h a v e a l r e a d y seen the w o r s t of i t . James S h a n n o n , f o r m e r h e a d of N I H , has r e m i n d e d us r e c e n t l y that the great a n d s u b s t a n t i a l d r u g i n n o v a t i o n s of the 1940s a n d 1950s w e r e m a d e u n d e r a m o r e "laissez f a i r e " attitude of r e g u l a t o r y l a w ( 3 ) . A n


analysis of t h e sort u n d e r t a k e n i n this p a p e r helps o n e a p p r e c i a t e h o w r a p i d l y benefits o f d r a m a t i c m a g n i t u d e a c c r u e d to society f r o m d r u g research d u r i n g that p e r i o d . A t t h e same t i m e , i t generates a c e r t a i n p e s s i m i s m about t h e f u t u r e , b y m a k i n g so c l e a r l y e v i d e n t t h e p r o f o u n d n e g a t i v e i m p a c t o n research p r o d u c t i v i t y that r e s t r i c t i v e r e g u l a t o r y atti tudes h a v e a l r e a d y h a d i n this c o u n t r y d u r i n g the b r i e f p e r i o d since 1962. J o s e p h C o o p e r o f A m e r i c a n U n i v e r s i t y , w r i t i n g o n " T h e S o c i o l o g y of I n n o v a t i o n i n M e d i c i n e , " points out that " a l l progress tends to b e i n h i b i t e d b y spontaneously a r i s i n g n e g a t i v e forces w h i c h . . . e v e n t u a l l y offset o r k i l l t h e progress w i t h w h i c h t h e y are a s s o c i a t e d " ( 4 ) . O n e c a n o n l y h o p e that society w i l l r e a l i z e q u i c k l y that i t is to its o w n great d e t r i m e n t to f a i l to p l a c e i n t o p r o p e r p e r s p e c t i v e t h e p r o b l e m s o f benefit a n d r i s k i n e v i t a b l y associated w i t h t h e d e v e l o p m e n t a n d use o f n e w d r u g s . A s this s t u d y so c l e a r l y reveals, recent progress i n m a k i n g n e w d r u g s a v a i l able f o r t r e a t i n g t h e i m p o r t a n t c h r o n i c diseases o f m a n k i n d h a s b e e n p i t i f u l l y s l o w . Society c a n i l l afford to legislate a w a y o n e o f t h e most i m p o r t a n t sources o f its o w n w e l l b e i n g .

Literature Cited (1) Paul deHaen, Inc., 11 W. 42nd Street, New York, Ν. Y. 10036. (2) Djerassi, C., Science (1969) 166, 468; (1970) 169, 941. (3) Shannon, J. Α., M.D., "The Economics of Drug Innovation," p. 83, The American University Center for the Study of Private Enterprise, Wash ington, D. C. (4) Cooper J. D., Proc. Roy. Soc. Med. (1969) 62, 48. RECEIVED

November 5, 1970.


Discussion Leland Chinn (to S. Morris K u p c h a n ) : T h e d e v e l o p m e n t of c h e m o t h e r a p e u t i c agents f r o m p l a n t sources i n the past was b a s e d m a i n l y o n f o l k l o r e a n d g e n e r a l screening p r o g r a m s .

C o u l d this a p p r o a c h b e m a d e

m o r e efficient a n d i n t e l l e c t u a l l y m o r e a p p e a l i n g b y d e v o t i n g a greater Downloaded by CORNELL UNIV on September 27, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch008

effort to u n d e r s t a n d i n g the f u n c t i o n w h i c h these agents serve plants themselves?

in

the

F o r e x a m p l e , w h a t role does reserpine p l a y in the

p l a n t that w o u l d correlate w i t h its a n t i h y p e r t e n s i v e effect i n a n i m a l s ? W h a t is the f u n c t i o n of d i g i t a l i s i n the p l a n t that w o u l d justify its use as a c a r d i o t o n i c agent? D r . Kupchan: I t h i n k it would be f a s c i n a t i n g , just as a s t u d y in basic science, to k n o w w h a t reserpine does i n r a u w o l f i a a n d d i g i t a l i s does i n foxglove, b u t I ' m not sure just h o w m u c h this w o u l d c a r r y over to the r o l e these agents p l a y i n a n i m a l tissues.

W e have h a d some

experience

i n this r e g a r d , in c o l l a b o r a t i v e efforts w i t h p l a n t physiologists a n d p l a n t pathologists to answer the q u e s t i o n as to w h a t some c o m p l e x n a t u r a l p r o d u c t s m a y be d o i n g i n the p l a n t .

I n general, it appears that p l a n t

biologists are s o m e w h a t less a d v a n c e d t h a n a n i m a l biologists i n e x p e r i m e n t a l approaches to m e c h a n i s m of action. So, in response to y o u r quest i o n , it w o u l d be most interesting to l e a r n m o r e a b o u t the f u n c t i o n of c o m p l e x p l a n t - d e r i v e d c o m p o u n d s , b u t I d o u b t that this a p p r o a c h w o u l d constitute a m o r e effective p a t h w a y to d i s c o v e r y of n e w n a t u r a l p r o d u c t s w i t h n o t e w o r t h y b i o l o g i c a l a c t i v i t y i n animals. Glenn Ullyot (to D r . K u p c h a n ) : T h e logistics of s u p p l y of a d e q u a t e quantities of p l a n t m a t e r i a l is a major factor i n seeking d r u g s f r o m p l a n t sources.

T i m e delays, expense of c o l l e c t i n g , a n d p r o b l e m s of i d e n t i f i c a -

t i o n m u s t be f a c e d . W h a t has b e e n y o u r experience w i t h these p r a c t i c a l considerations? D r . Kupchan: A c t u a l l y , w e ' v e b e e n v e r y fortunate. W e have enjoyed the close c o l l a b o r a t i o n w i t h the g r o u p u n d e r R o b e r t E . P e r d u e , Jr.,

at

the U n i t e d States D e p a r t m e n t of A g r i c u l t u r e . W h i l e there c e r t a i n l y h a v e b e e n delays a n d the logistics p r o b l e m s h a v e b e e n c o n s i d e r a b l e , not b e e n o v e r w h e l m i n g , b y a n y means. a r e l a t i v e l y accessible source

they've

I n d e e d , the p l a n t k i n g d o m offers

of c o m p o u n d s .

Certainly, plant-derived

c o m p o u n d s are less accessible t h a n synthetic p r o d u c t s , b u t they are v a s t l y m o r e accessible t h a n , for instance, p r o d u c t s f r o m m a r i n e sources. 185


186

DRUG

DISCOVERY

H . C . Caldwell (to Lloyd Conover): Please discuss p e n i c i l l i n a l l e r g i c t y p e reactions i n the c e p h a l o s p o r i n s .

Is there a crossover, a n d w h a t is

the prognosis for allergy-free c e p h a l o s p o r i n s ? D r . Conover: I'd l i k e to i n t r o d u c e m y comments w i t h the i n t r o d u c t o r y phrase, "It is m y i m p r e s s i o n that . . . ," rather t h a n c l a i m to speak f r o m the fullness of precise k n o w l e d g e . T h e r e m a y be someone here w h o can a m p l i f y w h a t I say or p o s s i b l y correct m e .

It's m y i m p r e s s i o n that the

a l l e r g i c effects w h i c h f o l l o w a d m i n i s t r a t i o n of ^ - l a c t a m a n t i b i o t i c s

are

caused b y the f o r m a t i o n of a c o v a l e n t b o n d b e t w e e n the a n t i b i o t i c or Downloaded by CORNELL UNIV on September 27, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch008

its d e g r a d a t i o n p r o d u c t a n d s e r u m p r o t e i n or tissue p r o t e i n . T h i s p e n i c i l l o y l or c e p h a l o s p o r o y l p r o t e i n is r e c o g n i z e d b y the b o d y as f o r e i g n (i.e., a n t i g e n i c ) , a n d antibodies are f o r m e d . T h e r e are r e a l l y t w o factors to be c o n s i d e r e d .

F i r s t , the c a p a b i l i t y

of a p a r t i c u l a r d r u g to cause the event w h i c h I just d e s c r i b e d , a n d sec o n d l y the c a p a b i l i t y of a d r u g a d m i n i s t e r e d to a p e r s o n i n w h i c h this process has t a k e n p l a c e to be i m m e d i a t e l y r e c o g n i z e d as a n t i g e n i c a n d to e l i c i t an a n a p h y l a c t i c r e a c t i o n . A n u m b e r of different c h e m i c a l reac tions have b e e n associated w i t h this p h e n o m e n o n . O n e of t h e m is s i m p l e a c y l a t i o n of p r o t e i n b y the ^ - l a c t a m .

I n a s m u c h as the m e c h a n i s m

of

a c t i o n of b o t h the p e n i c i l l i n s a n d c e p h a l o s p o r i n s is also t h o u g h t to i n v o l v e a c y l a t i o n b y the ^ - l a c t a m , I t h i n k that it is v e r y u n l i k e l y that there w i l l ever be a β-lactam a n t i b i o t i c w h i c h is active a n d w h i c h w i l l not i n some patients

f o r m a n t i g e n i c m a t e r i a l b y this same m e c h a n i s m .

It

is m y

i m p r e s s i o n that c e p h a l o s p o r i n s have a lesser t e n d e n c y to sensitize t h a n some p e n i c i l l i n s a n d that not a l l p e n i c i l l i n - s e n s i t i v e p e o p l e react to a g i v e n c e p h a l o s p o r i n . T h e differences are p r o b a b l y q u a n t i t a t i v e a n d w i l l never be q u a l i t a t i v e . Barry M . Bloom: I s h o u l d l i k e to address a q u e s t i o n to D r . B i e l . J o h n , as the s p o k e s m a n f o r o r g a n i c synthesis o n o u r p a n e l , y o u gave several examples of rationales that h a v e g u i d e d synthesis efforts to successful d r u g discovery, but I recall relatively little comment about total unabashedly e m p i r i c a l a p p r o a c h e s to e x p l o i t i n g the f r u i t s of the o r g a n i c chemist's l a b o r . T h i s q u e s t i o n is r e a l l y a request to t e l l it l i k e it is. W h a t percentage of successful d r u g discoveries a m o n g synthetic c o m p o u n d s d o y o u suppose is a t t r i b u t a b l e to p e o p l e w h e are just s y n t h e s i z i n g i n t e r e s t i n g structures a n d m a k i n g them available for biological evaluation i n various screening pro grams w i t h o u t a n y p a r t i c u l a r l y significant u n d e r l y i n g rationale? John Biel: A v e r y g o o d statistical analysis was d o n e d u r i n g the days of the A r m y p r o g r a m o n i n c a p a c i t a t i n g d r u g s , a n d those p r o g r a m s that w e r e b a s e d o n b l i n d screening of c h e m i c a l s y i e l d e d about three active c o m p o u n d s i n 10,000 w h i l e m i s s i o n - o r i e n t e d t y p e d r u g research d u c e d p r o b a b l y 10 active c o m p o u n d s p e r 3000.


pro

187

DISCUSSION

D r . Bloom: T h i s is r e a l l y an interesting q u e s t i o n to a lot of us, I t h i n k . M o r r i s , w o u l d y o u l i k e to c o m m e n t o n it? D r . Kupchan: I w o u l d suggest m o d i f i c a t i o n of J o h n B i d ' s o t h e r w i s e v e r y b e a u t i f u l slide c o n c e r n i n g " r a t i o n a l d r u g d e s i g n " i n the d i s c o v e r y of n e w drugs. S p e c i f i c a l l y , a clear d i s t i n c t i o n s h o u l d b e d r a w n b e t w e e n the l i m i t e d past c o n t r i b u t i o n s of r a t i o n a l d r u g d e s i g n to the d i s c o v e r y of n e w s t r u c t u r a l prototypes, a n d , i n contrast, the extensive c o n t r i b u t i o n s to the m o l e c u l a r m o d i f i c a t i o n of p r o t o t y p e d r u g s . A c r i t i c a l r e v i e w of the literature reveals that the vast m a j o r i t y of p r o t o t y p e d r u g s i n v a r i o u s


areas have c o m e f r o m systematic screening a n d / o r fortuitous a n d serend i p i t o u s d i s c o v e r y rather t h a n f r o m r a t i o n a l d e s i g n f r o m first p r i n c i p l e s . W o u l d n ' t y o u agree, J o h n , that, i n fact, r a t i o n a l d r u g d e s i g n has p l a y e d a f a r greater role i n the m o l e c u l a r m o d i f i c a t i o n of p r o t o t y p e s t h a n i n the d i s c o v e r y of n e w prototypes? D r . Biel: I t h i n k that s e r e n d i p i t y has to be p l a n n e d . U n l e s s y o u h a v e a research person w h o is p r i m e d to m a k e a d i s c o v e r y , he w i l l not m a k e a d i s c o v e r y . T h e r e are other factors that p l a y into the h a n d s of s e r e n d i p i t y ; that's one i t e m I h a d to leave out because of the pressure of time, b u t a d r u g d i s c o v e r y is r e a l l y s o m e t h i n g relative.

T h e t e r m d i s c o v e r y is r e l a -

tive i n the sense that other d i s c i p l i n e s h a v e to b e r e a d y to r e c o g n i z e the discovery. I t h i n k L i b r i u m a n d V a l i u m are prefect examples of that thesis; h a d they b e e n d i s c o v e r e d 20 to 30 years earlier, neither the m e d i c a l , c u l t u r a l , nor s o c i o l o g i c a l c l i m a t e w o u l d h a v e b e e n r e a d y to s t a m p this

finding

as

a major d i s c o v e r y . T h e c o n c e p t of t r e a t i n g anxiety b e c a m e r e a l l y f a s h i o n a b l e after the w o r l d w a r . It was the a c c e p t a n c e b y the m e d i c a l p r o f e s s i o n a n d the a d m i s s i o n b y the p a t i e n t that he is anxious that c o n t r i b u t e d to the d i s c o v e r y of anti-anxiety drugs. So i n answer to D r . K u p c h a n ' s question, I t h i n k there are factors

many

that n e e d to be i n t e g r a t e d for a p e r s o n to b e c o m e i n t u i t i v e .

Y o u ' r e not just i n t u i t i v e because you're b o r n that w a y , b u t i t does r e q u i r e a k n o w l e d g e of a c e r t a i n n u m b e r of facts that n e e d to b e

integrated

into m a k i n g a d i s c o v e r y . D r . Bloom: C h e t , d o y o u h a v e a c o m m e n t o n this question? Chester Cavallito: A s w i t h m a n y differences of o p i n i o n , the differences are m o r e s e m a n t i c a l l y b a s e d t h a n issue based. b y rational?

W h a t do w e mean

I don't b e l i e v e y o u r q u e s t i o n has b e e n a n s w e r e d

satisfac-

t o r i l y because w e ' r e not a l l u s i n g the t e r m r a t i o n a l i n the same sense. D r . Bloom: O n the a s s u m p t i o n that some of y o u i n the a u d i e n c e m a y feel q u i t e strongly o n the subject, is there anyone else w h o w o u l d l i k e to make a brief comment? Saul Neidleman: I t h i n k i n one sense the t w o d i s t i n g u i s h e d panelists h a v e b e e n c o m p a r i n g peaches a n d apples.

It is one t h i n g to talk a b o u t


188

DRUG DISCOVERY

10,000 p u r e c o m p o u n d s a n d q u i t e another t h i n g to t a l k a b o u t 300

fer-

m e n t a t i o n broths or 300 p l a n t extracts w h e r e y o u r e a l l y don't k n o w h o w m a n y c o m p o u n d s are i n v o l v e d . I w o u l d suggest that y o u c o u l d , b y m a k i n g a p p r o p r i a t e mixtures of 10,000 c o m p o u n d s , b e a b l e to w o r k

the

statistics to y o u r a d v a n t a g e to m a k e it l o o k as t h o u g h r a n d o m s c r e e n i n g is better t h a n r a t i o n a l screening. I w o u l d agree that it is m o r e a s e m a n t i c d i f f i c u l t y t h a n a n y t h i n g else.

Y o u h a v e to define p r e c i s e l y w h a t i t is

y o u ' r e t e s t i n g — p r e c i s e l y w h a t i t is y o u ' r e l o o k i n g a t — o r else the questions a n d answers h a v e r e l a t i v e l y little m e a n i n g .


James McFarland (to William P u r c e l l ) : T h e r e is a n a i r of m y s t i c i s m i n the use of m o l e c u l a r o r b i t a l parameters. parameters

D o y o u f e e l that

these

relate to b i o l o g i c a l processes that w e are a l r e a d y f a m i l i a r

w i t h or d o t h e y p e r h a p s relate to s o m e t h i n g w e d o n ' t yet u n d e r s t a n d a b o u t h o w d r u g s act? If it is the f o r m e r , w o u l d y o u elaborate o n h o w w e m i g h t i n t e r p r e t successful correlations w i t h s u c h terms as

"highest

occupied molecular orbital," "lowest unoccupied molecular orbital," and "frontier orbital"? D r . Purcell: A c t u a l l y , there is a b l a c k box a r o u n d the m o l e c u l a r orbital calculations.

T h i s is w h y I p u r p o s e l y t h r e w the w h o l e t h i n g

together this a f t e r n o o n to t r y to m a k e it clear that there s h o u l d n ' t b e this distinction, i n m y m i n d anyway, between a calculated parameter

and

one w h i c h is m e a s u r e d . W i t h r e g a r d to the correlations a n d t h e i r m e a n i n g , i f one suspects that e l e c t r o n - d o n a t i n g properties are i m p o r t a n t , one m i g h t l o o k f o r correlations w i t h the energies of the highest o c c u p i e d m o l e c u l a r orbitals. y o u measure

A n d I d o n ' t t h i n k it makes a n y difference w h e t h e r

this p o l a r o g r a p h i c a l l y or w h e t h e r y o u c a l c u l a t e

molecular orbital calculations.

it f r o m

If the p a r a m e t e r is there a n d it is sig-

nificant a n d it is a factor i n the b i o l o g i c a l process, I t h i n k it is q u i t e l e g i t i m a t e to correlate it.

Y o u h a v e to r e l y o n statistics to

determine

w h e t h e r there is a c o r r e l a t i o n or not. I h a d a q u e s t i o n the other d a y , " Y o u k n o w w h a t I ' d l i k e to d o , I'd l i k e to see a H a n s c h analysis o n a series of c o m p o u n d s a n d t h e n I ' d l i k e to see some m o l e c u l a r o r b i t a l calculations o n the same series." T h e p o i n t is that y o u don't c o m p a r e this t y p e of c o r r e l a t i o n w i t h that t y p e of correl a t i o n i n this sense.

R a t h e r I t h i n k it is m o r e i m p o r t a n t to l o o k at a

p a r t i c u l a r m o d e l a n d t h e n use w h a t e v e r t e c h n i q u e s y o u n e e d to get the parameters

that go into that m o d e l , w h e t h e r y o u measure

the d i p o l e

m o m e n t or w h e t h e r y o u c a l c u l a t e it f r o m w a v e f u n c t i o n s or w h e t h e r y o u take the c h a r g e densities f r o m pK measurements or w h e t h e r y o u c a l c u l a t e the c h a r g e density.

It is not the H a n s c h m o d e l vs. m o l e c u l a r orbitals.

T h a t makes no sense to me. R a t h e r it is u s i n g m o l e c u l a r o r b i t a l c a l c u l a tions to get at f u n d a m e n t a l properties of the m o l e c u l e s — t h e same w a y that y o u w o u l d get at t h e m if y o u m e a s u r e d the i n f r a r e d a b s o r p t i o n of


189

DISCUSSION

the c a r b o n y l to get at the stretch f r e q u e n c y a n d t h e n use that d a t u m i f it has a n y m e a n i n g i n the m o d e l f o r the c o r r e l a t i o n . D r . Bloom: I n v i e w of the w a y that w e h a v e s o l i c i t e d questions f o r the p a n e l , i t is o b v i o u s that the a u d i e n c e hasn't h a d m u c h of a c h a n c e to s u b m i t a n y t h i n g w i t h r e g a r d to the last f e w papers, b u t let m e i n v i t e c o m m e n t s or questions f r o m the floor w i t h r e g a r d to D r . Burns's p a p e r . A r e there a n y questions for J o h n ? D r . Ullyot: J o h n , y o u t a l k e d a b o u t setting u p the institute i n w h i c h you're g o i n g into the i n v e s t i g a t i o n of b a s i c b i o l o g y . D o y o u t h i n k that i n Downloaded by CORNELL UNIV on September 27, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch008

itself w i l l l a y the basis f o r r a t i o n a l d e s i g n of d r u g s , or is it a source of k n o w l e d g e of b i o l o g i c a l systems w h i c h w e c a n c o n t r o l a n d influence a n d use i n s e e k i n g n e w d r u g s ? John J. Burns: T h e first t h i n g I s h o u l d say is that the d r u g d e v e l o p ment procedure should have proper balance.

W e hear a lot a b o u t b a s i c

vs. a p p l i e d research, a n d it is v e r y h a r d f o r m e to define w h a t is b a s i c a n d w h a t is a p p l i e d . W h a t is b a s i c t o d a y m a y be a p p l i e d t o m o r r o w , or vice-versa.

It w o u l d be a serious m i s t a k e to go o v e r b o a r d o n a n y one

specific t y p e of a p p r o a c h . T h e r e are c e r t a i n things w h i c h w e find most e x c i t i n g , a n d the fact that w e find t h e m most e x c i t i n g p e r h a p s

means

that they s h o u l d b e most p r o d u c t i v e . M y o w n f e e l i n g o n the subject is that i f one is g o i n g to h a v e a b r o a d l y b a s e d d r u g d e v e l o p m e n t p r o g r a m , one must have a g o o d b a l a n c e b e t w e e n b a s i c a n d a p p l i e d research. T h e q u e s t i o n of r a n d o m s c r e e n i n g came u p earlier.

When I

first

w e n t i n t o i n d u s t r y I was v e r y s k e p t i c a l a b o u t r a n d o m screening.

I

t h o u g h t it a waste of t i m e a n d effort to m a k e thousands of c o m p o u n d s a n d t h e n to screen t h e m b y thousands a n d thousands of tests.

There

must be a better w a y , or to use a better t e r m , a m o r e r a t i o n a l w a y of finding

a n e w d r u g . B u t I t h i n k it w o u l d be a m i s t a k e o n the p a r t of a n y

d r u g d e v e l o p m e n t o r g a n i z a t i o n to d o a w a y w i t h r a n d o m screening.

One

doesn't h a v e to justify r a n d o m s c r e e n i n g because it has c e r t a i n l y g i v e n us leads, b u t to m a k e it p a y , y o u h a v e to h a v e g o o d biologists, a n d t h e y n e e d a p r o p e r scientific e n v i r o n m e n t to c a r r y out t h e i r w o r k . I n the o l d days at the N I H t h e y w o u l d say " n o w w h y don't w e set u p d r u g testing facilities for m e d i c i n a l chemists w h o h a p p e n to be s y n t h e s i z i n g c o m p o u n d s u n d e r N I H grants so that w e c a n get together

a

lot of b i o l o g i c a l d a t a so w e ' l l k n o w w h a t these c o m p o u n d s are d o i n g . " I a l w a y s t h o u g h t this w o u l d be a waste of t i m e because to m a k e r a n d o m s c r e e n i n g w o r k , y o u must h a v e the necessary p h a r m a c o l o g i c a l b a c k - u p . If a c o m p o u n d shows a n i n t e r e s t i n g p h a r m a c o l o g i c effect i n an a n i m a l , y o u have to h a v e g o o d biologists a r o u n d to s t u d y it. F u r t h e r m o r e , y o u must have g o o d f e e d b a c k to the chemists.

If y o u don't h a v e g o o d f e e d -

back, biologists-to-chemists, a n d chemists-to-biologists, a n d have t h e m i n


190

DRUG DISCOVERY

a p o s i t i o n w h e r e t h e y c a n t a l k to each other, y o u ' r e not g o i n g to h a v e the proper environment. G e t t i n g to y o u r q u e s t i o n a b o u t the d e v e l o p m e n t of a n Institute, there are a lot of things w e don't k n o w , a n d i n o r d e r to k n o w these t h i n g s , we're g o i n g to h a v e to take a r e l a t i v e l y l o n g range a p p r o a c h . I m e n t i o n e d i n m y presentation the q u e s t i o n of l o o k i n g for a n e w d r u g f o r v i r u s disease, b u t i f y o u l o o k at the effort w h i c h has gone i n t o v i r a l r e s e a r c h over the past 20 years a n d the p r o d u c t of this effort, it's r a t h e r d i s c o u r aging.

O n e of o u r p r o b l e m s is that w e don't k n o w e n o u g h a b o u t

the


q u e s t i o n of v i r a l r e p l i c a t i o n , h o w c h e m i c a l s m a y interfere w i t h p e n e t r a t i o n of v i r u s i n t o cells, etc. balance between approach)

W h a t w e n e e d is a p r o g r a m w h i c h a l l o w s a

b a s i c research

( i n the sense of a m o l e c u l a r b i o l o g y

a n d a p p l i e d research

a l o n g w i t h g o o d chemists

and good

biologists, w h o are i n a p o s i t i o n to d o the necessary e v a l u a t i o n . D r . Cavallito (to D r . B u r n s ) : W e ' v e h e a r d a great d e a l a b o u t m o l e c u l a r b i o l o g y i n the last decade.

W h e n I r e a d the journals, I find i t

h a r d to d i s t i n g u i s h this f r o m n u c l e i c a c i d c h e m i s t r y .

I am wondering,

J o h n , if y o u c o u l d t e l l us w h a t is y o u r c o n c e p t of m o l e c u l a r b i o l o g y , w h i c h p e r h a p s is b r o a d e r t h a n n u c l e i c a c i d c h e m i s t r y , a n d h o w

that

differs f r o m w h a t was t e r m e d b i o c h e m i s t r y 15 or 20 years ago? D r . Burns: T h e t e r m " m o l e c u l a r b i o l o g y " w a s c o i n e d a n u m b e r of years back.

Institutes of m o l e c u l a r b i o l o g y h a v e b e e n set u p i n v a r i o u s

universities a n d n e w d e p a r t m e n t s of m o l e c u l a r b i o l o g y i n m e d i c a l schools. T h e major emphasis i n m o l e c u l a r b i o l o g y is o n n u c l e i c a c i d

research,

a l t h o u g h m o r e b r o a d l y it is the s t u d y of b i o l o g i c a l processes at a m o l e c u lar

level,

and

I

would

certainly

not

try

to

d i s t i n g u i s h that

from

biochemistry. A . A . Larsen: I sometimes r e g a r d the issue of b i o l o g i c a l k n o w l e d g e as a cop-out.

F r o m w h a t J o h n B i e l has s a i d earlier, there are

many

examples of d r u g s w h i c h w e r e d i s c o v e r e d b e f o r e w e w e r e f u l l y a w a r e of the details of t h e i r m e c h a n i s m . T h e r e is p e r h a p s a l i n k b e t w e e n the suggested b i o l o g i c a l g a p a n d the situation B a r r y just m e n t i o n e d r e g a r d i n g the great effort necessary to get a m e d i c a m e n t t h r o u g h the F D A . I h a v e k n o w n biologists, w h o i f g i v e n the chance, w o u l d go a w a y f o r 20 years to investigate one c h e m i c a l i n one p a r t i c u l a r b i o l o g i c a l system. Question from the floor (to Bernard R. Belleau): I n c o n n e c t i o n w i t h t h r e e - d i m e n s i o n a l m o l e c u l e structure, i f one obtains

d a t a u s i n g x-ray

c r y s t a l l o g r a p h y or some other t o o l , c a n y o u a p p l y these data d i r e c t l y to systems w h e r e the d r u g is u s e d i n s o l u t i o n or in vivo? tions, i n t e r a t o m i c

distances,

a n d b o n d angles

under

D o the c o n f o r m a such

conditions

c o r r e s p o n d to the c r y s t a l l i n e state? D r . Belleau: T h e r e are a n u m b e r of examples w h e r e i n the tertiary structure is k n o w n t h r o u g h x-ray c r y s t a l l o g r a p h y , a n d i t appears that i n


191

DISCUSSION

s o l u t i o n the a c t i v e site at least seems to r e t a i n m a n y of the same p r o p e r ties. H o w e v e r , there is also o p p o s i t e e v i d e n c e t h a t i n s o l u t i o n i n t e r a c t i o n s w i t h the solvent w i l l m o d i f y the structure a p p r e c i a b l y .

N o w the b i g

q u e s t i o n a l w a y s arises w h e n w o r k i n g w i t h p u r e e n z y m e s or p u r e p r o teins as m o d e l s : are y o u not f u r t h e r f r o m r e a l i t y the p u r e r y o u r substances are? W h e n w e are u s i n g a n e n z y m e i n s o l u t i o n , w e h a v e e v i d e n c e that its s p e c i f i c i t y w i l l d e p e n d u p o n its state of a g g r e g a t i o n . differ w h e n it is a t t a c h e d say to a m e m b r a n e .

T h i s w i l l also

T h e r e are changes w h i c h

o c c u r that are q u i t e serious, a n d this is a field f o r f u t u r e research.

We


are just b e g i n n i n g to a p p r e c i a t e the m a g n i t u d e of the p r o b l e m . Paul Craig (to D r . P u r c e l l ) : T o c o n t i n u e a l o n g the same l i n e , is not w h a t w e just s a i d e v e n d o u b l y true f o r q u a n t u m m e c h a n i c a l c a l c u l a t i o n s , w h i c h i n essence c a l c u l a t e a m o l e c u l e i n i s o l a t i o n ? D r . Purcell: There's no a r g u m e n t a b o u t that.

I w o n ' t t r y to d e f e n d

the w o r k that K i e r is d o i n g . If he w e r e here, I ' m sure h e ' d h a v e s o m e t h i n g to say a b o u t it. H i s p o i n t is that i n d o i n g these c a l c u l a t i o n s y o u h a v e to start s o m e w h e r e , a n d y o u start w i t h a n i s o l a t e d m o l e c u l e , a n d y o u r e c o g n i z e that that m o l e c u l e is i n q u i t e a different e n v i r o n m e n t i n the b i o l o g i c a l system, b u t that's i n b o l d face t y p e at the b e g i n n i n g — t h e r e ' s n o a t t e m p t to say y o u ' r e d o i n g the c a l c u l a t i o n i n a b i o l o g i c a l e n v i r o n m e n t . D r . Cavallito: I w a n t to ask a q u e s t i o n of o u r c h a i r m a n r e l a t i v e to his

v e r y fine c l o s i n g p r e s e n t a t i o n .

B e t w e e n 1938

a n d 1962

the F D A

officially h a d the statutory basis f o r r e q u i r i n g e v i d e n c e of safety.

How-

ever, those i n d i v i d u a l s w h o dealt w i t h the F D A are q u i t e a c q u a i n t e d w i t h the fact that a b o u t 1960, i n other w o r d s t w o years b e f o r e the

1962

a m e n d m e n t s , there w a s a n i m p l i e d request f o r e v i d e n c e of efficacy o n the basis of the a r g u m e n t that safety i n the absence of efficacy w a s meaningless. N o w let's project that i n t o o u r present state. T h e '62 statute specifically d i d n o t g i v e the F D A a u t h o r i t y to request c o m p a r a t i v e efficacy. H o w e v e r , there are some g r u m b l i n g s that p e r h a p s w e are b e g i n n i n g to see the b e g i n n i n g of this k i n d of r e q u i r e m e n t . D o y o u h a v e a n y c o m ments o n that a n d w h a t that w o u l d d o to the d r u g i n n o v a t i o n process? D r . Bloom: Y o u p u t it e u p h e m i s t i c a l l y , i n m y o p i n i o n . I t h i n k there are a n u m b e r of f a m i l i a r examples that are h a r d to i n t e r p r e t i n other w a y s t h a n that the F D A is b e g i n n i n g to c o n c e r n itself w i t h matters of r e l a t i v e efficacy. Frank Weisenborn: I n D r . Biel's d i s c u s s i o n of the r a t i o n a l a p p r o a c h , I s t i l l don't t h i n k a n y o n e has r e a l l y s a i d h o w it is or p u t it a l l together. I t h i n k it is a m i x t u r e of r a t i o n a l i t y a n d h o p e i n that i n m a n y fields of m e d i c i n a l c h e m i s t r y w e l o o k f o r the s o p h i s t i c a t e d o r g a n i c c h e m i s t b u i l d a n e w h e t e r o c y c l i c m o l e c u l e because

to

w e w a n t to b u i l d a b r o a d

p r o t e c t i o n i n terms of a patentable area, a n d t h e n w e l o o k f o r a n e x p e r i e n c e d m e d i c i n a l c h e m i s t to a t t a c h the a p p r o p r i a t e side chains.


It is a

192

DRUG DISCOVERY

m i x t u r e of r a t i o n a l i t y a n d h o p e , b u t w e d o l o o k m o r e t o w a r d s the econ o m i c side t h a n w a s expressed b y m e m b e r s of the p a n e l . John Fried: It's d i f f i c u l t to a d d a n y t h i n g r e a l l y significant to the v e r y excellent thesis p r e s e n t e d b y D r . B l o o m a b o u t the rate of c o n t e m p o r a r y d r u g d i s c o v e r y , b u t one p o i n t m i g h t be m a d e w h i c h makes his analysis even m o r e w o r r i s o m e . If one considers that the rate of d r u g d i s c o v e r y has decreased b y a factor of 3 a n d expenditures h a v e gone u p b y at least a factor of 2, the average cost of d e v e l o p m e n t of a n e w d r u g has i n c r e a s e d b y a p p r o x i m a t e l y a factor of 6.

N o w i f one extends this analysis, the


t i m e m a y not be too f a r a w a y before p h a r m a c e u t i c a l c o m p a n i e s

decide

that t h e i r r e t u r n o n i n v e s t m e n t for f u n d s spent i n research are s u c h that those f u n d s m i g h t v e r y w e l l be spent elsewhere.

T h i s is o b v i o u s l y a most

u n f o r t u n a t e c o n c l u s i o n , b u t it is s o m t h i n g that needs to be b o r n e i n m i n d w h e n w e talk a b o u t d r u g d i s c o v e r y . D r . Bloom: T h i s is c e r t a i n l y a n i m p o r t a n t c o m m e n t , a n d I ' m sure, J o h n , y o u w o u l d d i r e c t people's attention i n this r e g a r d to the a r t i c l e b y C a r l D j e r a s s i i n Science

recent

w h i c h offers some s t a r t l i n g t i m e a n d

cost projections f o r the d e v e l o p m e n t of n e w o r a l c o n t r a c e p t i v e John Topliss: I ' d l i k e to c o m m e n t o n y o u r excellent

agents.

presentation.

W h i l e I c e r t a i n l y agree w i t h the thrust of y o u r conclusions, I w o n d e r i f y o u p e r h a p s s i d e - s t e p p e d one p a r t of the analysis w h i c h a d m i t t e d l y is very difficult but w h i c h w o u l d have made your conclusions a little more rigorous.

O n e s h o u l d t r y to estimate the i n d i v i d u a l w o r t h of the d r u g

discoveries w h i c h y o u m e n t i o n e d o n l y i n terms

of n u m b e r s .

In

one

p e r i o d y o u h a d , I t h i n k , 39 n e w entities, b u t w e a l l k n o w i n t h a t p e r i o d m a n y of t h e m w e r e r e l a t i v e l y m i n o r m o d i f i c a t i o n s .

O n e r e a l l y has to

estimate w h a t e a c h d r u g a d d s to the t o t a l v a l u e of t h e r a p y i n t h a t area i n o r d e r to m a k e a f a i r c o m p a r i s o n of the i m p a c t o n m e d i c i n e as a w h o l e . P e r h a p s one m i g h t c o m e u p w i t h the same sort of answers i n this m o r e r i g o r o u s analysis, b u t p e r h a p s the results m i g h t not h a v e l o o k e d so i m pressive i n terms of the changes w h i c h h a v e t a k e n p l a c e . D r . Bloom: A s far as I ' m c o n c e r n e d y o u r c o m m e n t s are f a i r l y t a k e n . I d o t h i n k , h o w e v e r , that m y m a i n thesis w o u l d not b e d i s p r o v e d b y an analysis of that sort.

O u r efforts so f a r stimulate m e to w a n t to t r y to

d o exactly the sort of t h i n g that y o u ' r e t a l k i n g about, b u t I h a v e w a t c h e d others t r y , a n d I've t r i e d a l i t t l e b i t myself. So far, I just don't see a w a y to d o the analysis o b j e c t i v e l y .

It's w o r t h t h i n k i n g about, a n d I

hope

others w i l l a t t e m p t s u c h a n analysis themselves. Robert Cox: Just a c o m m e n t , B a r r y , o n y o u r remarks a n d those of C h e t C a v a l l i t o r e g a r d i n g the present a t t i t u d e of the F D A t o w a r d N e w D r u g A p p l i c a t i o n s . I c e r t a i n l y agree that there is the i m p l i c a t i o n of r e l a t i v e efficacy, not just efficacy p e r se i n some N A S - N R C dations a n d subsequent F D A decisions.

recommen-

I t h i n k t h a t the F D A is o f t e n


193

DISCUSSION

m a k i n g judgments

based

upon comparative

therapeutic

ratios

a n d is

m o v i n g t o w a r d rejection of some N D A submissions i f s u c h cannot justified via

be

a m o r e attractive t h e r a p e u t i c r a t i o t h a n that of p r o d u c t s

a l r e a d y m a r k e t e d for p e r t i n e n t i n d i c a t i o n s . D r . Bloom: D r . U l l y o t , d o y o u w a n t to c o m m e n t o n that? D r . U l l y o t : O n t h e next p a n e l w e l l h a v e a n F D A m a n here, a n d I h o p e some of these questions w i l l b e r a i s e d then.

P e r h a p s i t is a l i t t l e

u n f a i r to go i n t o these questions v e r y extensively w i t h o u t g i v i n g h i m a c h a n c e to hear t h e m .

I ' d r e a l l y l i k e to h a v e h i m c o m m e n t as a repre-


sentative of the F D A . D r . Bloom: D r . C o n o v e r , w h a t d o the results of y o u r q u e s t i o n n a i r e or a n y other i n f o r m a t i o n that y o u m a y have suggest w i t h r e g a r d to the present l e v e l of research a c t i v i t y d i r e c t e d to finding n e w antibiotics a n d f e r m e n t a t i o n broths?

H a s this k i n d of research d e c l i n e d i n the last 10

years a n d w i l l it d e c l i n e i n the f u t u r e ? D r . Conover: O n e of the illustrations that I presented c a r r i e d c u m u lative totals t h r o u g h 1965,

a n d to that p o i n t the t o t a l n u m b e r of n e w

antibiotics r e p o r t e d for a

five-year

Dr.

p e r i o d h a d c o n t i n u e d to

P e r l m a n of W i s c o n s i n has a s u m m a r y w h i c h extends,

1968.

increase.

I t h i n k , to

T h i s makes it a p p e a r that there has b e e n a l e v e l l i n g off, b u t at a

m u c h h i g h e r l e v e l t h a n that of the 1940's a n d 1950's. T h e t o t a l n u m b e r of n e w a n t i b i o t i c entities r e p o r t e d has not d r o p p e d to a l e v e l that is l o w c o m p a r e d w i t h the p e r i o d w h e n i m p o r t a n t discoveries w e r e b e i n g m a d e at a m u c h faster rate.

I w o u l d l i k e to t h i n k that b y b r o a d e n i n g

the target, as I t r i e d to suggest i n m y talk, activities d i r e c t e d t o w a r d finding

d r u g s of m o r e different k i n d s f r o m m i c r o b i o l o g i c a l sources

will

increase. D r . Bloom: W e w i l l close b y a s k i n g D r . B u r n s to r e s p o n d to a question f r o m D r . L a u g h l i n : " M o d e r n drugs a i m to increase the l e v e l of w e l l b e i n g of i n d i v i d u a l organisms, e s p e c i a l l y those w h o c o u l d not o t h e r w i s e f u n c t i o n or s u r v i v e i n their e n v i r o n m e n t .

Is this g o a l t r u l y

w i t h the best interests of f u t u r e m e m b e r s of the

consistent

species?"

D r . Burns: B r i e f l y , I t h i n k w e are f a c e d w i t h c e r t a i n e t h i c a l c o n s i d erations.

If w e are able i n the next 10, 15, or 20 years to extend l i f e f o r

another 10 or 20 years, or p e r h a p s to a l l o w p e o p l e to l i v e w h o n o r m a l l y w o u l d d i e n o w w i t h genetic disease, b u t p e r h a p s to l i v e i n a w a y that w o u l d be i n c o m p a t i b l e w i t h a g o o d life, are w e d o i n g s o m e t h i n g good? I w o u l d say that this is the t y p e of q u e s t i o n I w o u l d rather see p o s e d to a p a n e l of p h i l o s o p h e r s , theologians, a n d m e d i c a l p e o p l e . T h e r e is another q u e s t i o n w h i c h has c o m e u p that relates to

the

F D A , a n d I w o u l d l i k e to c o m m e n t o n it. W e get ourselves i n t o t r o u b l e if w e t e n d to t h i n k that this p r o b l e m is b a s i c a l l y one i n g e t t i n g a n e w d r u g a p p r o v e d . T h e r e is another v e r y i m p o r t a n t issue here.

W h e n we


194

DRUG

DISCOVERY

l o o k at the 1950's there w e r e c e r t a i n things that w e d i d i n the b i o l o g i c a l testing of n e w d r u g s i n terms of t o x i c i t y , etc., b u t n o w w e m u s t d o m u c h more. It is not just that the F D A is t e l l i n g us to d o these things, b u t w e h a v e to d o t h e m because the w h o l e l e v e l of m e d i c a l science has a d v a n c e d . T h e d o c t o r is e x p e c t i n g m o r e i n f o r m a t i o n o n d r u g s . T h e m e d i c a l students are b e i n g t a u g h t a different k i n d of p h a r m a c o l o g y t h a n they w e r e

10

years ago. T h e t y p e of i n f o r m a t i o n w e h a v e to s u p p l y o n drugs is m u c h m o r e costly, a n d it is o b v i o u s l y g o i n g to have a n effect o n the d e v e l o p m e n t process.

It is not just a question of the F D A g i v i n g us p r o b l e m s


i n r e q u i r i n g n e w tests, b u t the tests m u s t be d o n e to satisfy o u r o w n feelings o n w h a t is necessary for a d e q u a t e b i o l o g i c a l i n f o r m a t i o n o n a new drug. Dr.

B l o o m : O n e of the m a i n thrusts, if not the m a i n thrust, of m y

a r g u m e n t is that a n y t h i n g w h i c h serves to i m p e d e the rate at w h i c h n e w k n o w l e d g e is generated i n c l i n i c a l p h a r m a c o l o g y is b o u n d i n the e n d to suppress the w h o l e process.

So r e a l l y w e r e b o t h a r g u i n g f o r the n e e d

for more knowledge.


Drug Discovery

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