Drug Discovery - ACS Publications

13 Government Regulations and Drug Development: FDA J O H N JENNINGS, M . D .

Downloaded by CORNELL UNIV on August 10, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch013

Associate Commissioner for M e d i c a l Affairs, F o o d and D r u g Administration, Public H e a l t h Service, Parklawn Building, 5600 Fishers Lane, Rockville, Md. 20852

The Food and Drug Administration moting

regulations

which

stifle

(FDA), research

accused and

drugs off the market, replies that the regulations tices that have evolved represent

in the pharmaceutical

FDA efforts to improve

the processing

of submissions

of pro-

keep

good

reflect

prac-

sciences,

the quality

and

and the introduction

and

expedite of

really

new drugs. Studies cited suggest that the cause of decline the introduction ment

of new drugs is that research

by the drug

provement covery

industry

of products

devoted

to imitative

entities.

imaginative

rather

Industry's

in that scientific rather

appeal is made to examine vigorous,

been primarily

or processes

of new chemical

be counter-productive

have

than

than innovative

in

developthe

im-

the

dis-

approach

expertise

this proposition

programs

to return to the innovative

and

may

has

been

research.

An

and to

of drug research

promote

in an effort

stage.

^^phe F o o d a n d D r u g A d m i n i s t r a t i o n is k e e p i n g g o o d d r u g s off t h e market. T h e i r regulations are stifling research.

T h e dearth of n e w drugs

is a d i r e c t result of the 1962 efficacy a m e n d m e n t s . T h e s e charges ( r e f e r r i n g to A m e n d m e n t s to t h e F o o d , D r u g a n d C o s m e t i c A c t ) are a l l too f a m i l i a r to those c o n c e r n e d w i t h t h e d i s c o v e r y a n d d e v e l o p m e n t of n e w d r u g s . T h i s c h a p t e r examines t h e basis o f s u c h charges a n d offers a suggestion r e g a r d i n g research a n d d e v e l o p m e n t .

History of the Food and Drug Administration Since

1906, t h e year t h e F o o d a n d D r u g s A c t w a s passed, t h e

p r i m a r y c o n c e r n o f t h e F D A has b e e n c o n s u m e r p r o t e c t i o n . I n t h e area 247

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

248

DRUG DISCOVERY

of d r u g s , i t has m e a n t that p r o p r i e t a r y or patent m e d i c i n e s w i t h dangerous h a b i t - f o r m i n g i n g r e d i e n t s a n d a d u l t e r a t e d m e d i c i n e s , a great threat at the t u r n of the c e n t u r y , w e r e t a k e n off the m a r k e t . I n the e a r l y days, the F D A was r e s t r i c t e d to a c t i o n after i n j u r y h a d o c c u r r e d a n d the a g e n c y h a d to p r o v e not o n l y cause a n d effect b u t also intent.

T h e n , just as better l a w s are o f t e n b o r n o u t of t r a g e d y , i n

1938

the C o n g r e s s s a w the n e e d f o r the n e w F o o d , D r u g a n d C o s m e t i c A c t after m o r e t h a n 100 persons h a d d i e d of t a k i n g a n u n t e s t e d e l i x i r of s u l f a n i l a m i d e m a d e w i t h a toxic solvent.

T h e n e w l a w r e q u i r e d f o r the

first t i m e that d r u g s be p r o v e d safe b e f o r e b e i n g a l l o w e d o n the m a r k e t . Downloaded by CORNELL UNIV on August 10, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch013

F o r m a l e v i d e n c e of efficacy was not r e q u i r e d , a l t h o u g h , as w e a l l k n o w , the t w o factors of safety a n d efficacy cannot r e a l l y b e separated. I n 1962 the A c t was f u r t h e r a m e n d e d to r e q u i r e s u b s t a n t i a l p r o o f of efficacy b e f o r e a d r u g c o u l d b e m a r k e t e d .

T h e hearings l e a d i n g to the

1962 a m e n d m e n t s w e r e first f r a m e d i n the context of e c o n o m i c c o n s i d e r a tions. H o w e v e r , the t h a l i d o m i d e t r a g e d y r e l a t i n g to the safety of d r u g s c h a n g e d the c o m p l e x i o n of the d e l i b e r a t i o n s a n d l e d almost i r o n i c a l l y to the a m e n d m e n t s w h i c h r e q u i r e d a p r o o f of efficacy.

O f course, at the

same t i m e , f u r t h e r regulations c o n c e r n e d w i t h safety,

i n c l u d i n g those

g o v e r n i n g the i n v e s t i g a t i o n a l use of n e w d r u g s a n d those w h i c h p r o v i d e d f o r c o n t i n u e d s u r v e i l l a n c e of m a r k e t e d d r u g s , w e r e p r o m u l g a t e d . H e n c e , w e are k e e p i n g some d r u g s off the m a r k e t , b u t at the same t i m e , w e are h e l p i n g to s p e e d safe a n d effective d r u g s to the

market.

F u r t h e r m o r e , w e h a v e r e c e n t l y r e o r g a n i z e d o u r a g e n c y so that o u r s c i entists c a n p e r f o r m the most efficient service p o s s i b l e f o r the A m e r i c a n people. T o d a y , the p r o f e s s i o n a l p e r s o n n e l of the F D A i n c l u d e s a p p r o x i m a t e l y 200 p h y s i c i a n s , 80 p h a r m a c o l o g i s t s , 100 p h a r m a c i s t s , 900 chemists, a n d 100 m i c r o b i o l o g i s t s . T h e staff also i n c l u d e s 650 inspectors a n d s u p p o r t i n g a d m i n i s t r a t i v e a n d c l e r i c a l p e r s o n n e l . T h e most recent r e o r g a n i z a t i o n of the a g e n c y p r o v i d e s f o r three separate bureaus a n d the Office of

the

C o m m i s s i o n e r , c o n s t i t u t i n g the W a s h i n g t o n h e a d q u a r t e r s , a n d 17 d i s t r i c t offices. E a c h of the bureaus, the B u r e a u of D r u g s , the B u r e a u of F o o d s , Pesticides, a n d P r o d u c t Safety, a n d the B u r e a u of V e t e r i n a r y M e d i c i n e , is sufficient i n scientific a n d r e g u l a t o r y c a p a b i l i t i e s .

I n the f u t u r e ,

as

m o r e f u n d s a n d p e r s o n n e l are a v a i l a b l e , c e r t a i n subunits of these bureaus m a y b e e l e v a t e d i n stature to c a r r y out m o r e efficiently the i n t e n t of the l a w a n d to p r o v i d e better c o n s u m e r p r o t e c t i o n . T o take the B u r e a u of D r u g s as a n e x a m p l e , there is a n Office of Scientific E v a l u a t i o n w i t h d i v i s i o n s f o r m e d a l o n g p h a r m a c o l o g i c

lines

s u c h as the D i v i s i o n of N e u r o p h a r m a c o l o g i c a l D r u g s , t h e D i v i s i o n

of

C a r d i o p u l m o n a r y - R e n a l D r u g s , a n d the D i v i s i o n of M e t a b o l i c a n d E n d o c r i n e D r u g s ; a n Office of C o m p l i a n c e ; a n Office of P h a r m a c e u t i c a l R e -


13.

JENNINGS

search

Government

249

Regulations

a n d T e s t i n g , w i t h d i v i s i o n s s u c h as D r u g

Biology and

Drug

C h e m i s t r y , a n d a n Office of Scientific C o o r d i n a t i o n w i t h d i v i s i o n s of B i o m e t r y a n d E p i d e m i o l o g y , E x t r a m u r a l a n d C l i n i c a l R e s e a r c h , a n d the C e n t e r for D r u g I n f o r m a t i o n . T h e r e o r g a n i z a t i o n of the F D A into bureaus o n p r o d u c t lines i n creases its efficiency b y d e l i n e a t i n g c l e a r l y the responsibilities of the v a r i ous units a n d b y c o o r d i n a t i n g the scientific a n d r e g u l a t o r y

activities

r e l a t i n g to the m a j o r p r o d u c t categories. D i s c u s s i o n of F D A responsibilities l e a d to the q u e s t i o n : w h a t p a r t Downloaded by CORNELL UNIV on August 10, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch013

does the F o o d a n d D r u g A d m i n i s t r a t i o n p l a y i n the d i s c o v e r y a n d d e v e l o p m e n t of d r u g s ?

T h e F D A is b a s i c a l l y a r e g u l a t o r y agency

p r i m a r y c o n s i d e r a t i o n is c o n s u m e r p r o t e c t i o n . specific acts of C o n g r e s s — t h e

one

of interest

D r u g a n d C o s m e t i c A c t , as a m e n d e d . t i v e l y s i m p l e a n d m i g h t w e l l serve regarding all products.

It administrates here b e i n g the

Its b a s i c r e q u i r e m e n t s

whose several Food,

are r e l a -

as a m o d e l f o r f u t u r e l e g i s l a t i o n

B e f o r e a d r u g is i n t r o d u c e d i n t o the m a r k e t , i t

m u s t be s h o w n to b e safe a n d p r o v e d to be effective.

T h e l a n g u a g e of

the A c t states that the p r o o f of efficacy of a d r u g m u s t consist of s u b stantial e v i d e n c e d e r i v e d f r o m adequate,

w e l l - c o n t r o l l e d investigations,

i n c l u d i n g c l i n i c a l investigations, c o n d u c t e d b y q u a l i f i e d experts. r e q u i r e m e n t , w h i c h seems so o b v i o u s a n d s i m p l e , after eight years

This has

not yet b e e n c o m p l e t e l y a c c e p t e d b y a l l c o n c e r n e d a n d is the f o c a l p o i n t of

the

criticisms

of

the

F D A as

a barrier

to

d r u g discovery

and

development. T h e decisions r e q u i r e d of F D A scientists f a l l i n t o t w o b r o a d categories. O n e of these concerns is the safety a n d efficacy of the d r u g substance as a t h e r a p e u t i c entity. A l t h o u g h the d e c i s i o n that a d r u g is safe a n d efficacious is a d i f f i c u l t one a n d f r a u g h t w i t h danger, o n the

one

h a n d , of p r e m a t u r e l y r e l e a s i n g a d r u g w h i c h later proves to b e h a r m f u l , or o n the other h a n d , of u n d u l y d e l a y i n g because of excessive c a u t i o n a n agent w h i c h w o u l d be of benefit i n a serious c o n d i t i o n , it is nevertheless a d e c i s i o n w h i c h is u s u a l l y m a d e w i t h i n a reasonable l e n g t h of t i m e .

For

one t h i n g , the d r u g that is t r u l y effective u s u a l l y attracts supporters a n d becomes k n o w n to investigators a n d practitioners t h r o u g h scientific journals, a n d the agency's d e c i s i o n - m a k i n g process is u s u a l l y c a r r i e d o n i n the l i g h t of these p u b l i c discussions.

F o r another, as scientists a n d c o n -

sumers, w e i n the agency are eager to speed to p h y s i c i a n s a n d patients drugs that are t r u l y safe a n d effective.

T h e p r i m a r y cause of the m u c h

t o u t e d d e l a y i n F D A d e c i s i o n - m a k i n g is b e y o n d a l l q u e s t i o n the p o o r q u a l i t y of the d a t a , p a r t i c u l a r l y those of the c l i n i c a l investigations, s u b m i t t e d to us. A l t h o u g h the q u a l i t y of the d a t a has i m p r o v e d over recent years, some sponsors still d o not r e c o g n i z e that a f e w c a r e f u l l y c o n d u c t e d


250

DRUG DISCOVERY

studies are m u c h m o r e persuasive t h a n a mass of p o o r l y d o c u m e n t e d case studies or e v e n c a r e f u l l y d o c u m e n t e d r a n d o m c l i n i c a l reports. T h e s e c o n d t y p e of d e c i s i o n that the F o o d a n d D r u g A d m i n i s t r a t i o n m u s t m a k e is one that is at least as i m p o r t a n t a n d — u n l i k e the decisions r e g a r d i n g safety a n d e f f i c a c y — m u s t b e m a d e r e p e a t e d l y .

T h i s is the

s u r v e i l l a n c e of the q u a l i t y of d r u g p r o d u c t s o n the m a r k e t .

I n its a p -

p r o v a l of a n e w d r u g a p p l i c a t i o n the F D A approves not a d r u g substance b u t a finished dosage f o r m . I n d e e d , the c l i n i c a l trials w h i c h demonstrate safety a n d efficacy of the d r u g m u s t b e c a r r i e d out w i t h the m a r k e t e d dosage f o r m or w i t h a dosage f o r m that c a n be established as t h e r a Downloaded by CORNELL UNIV on August 10, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch013

p e u t i c a l l y e q u i v a l e n t . T h u s , q u a l i t y c o n t r o l enters e a r l y i n t o the a p p r o v a l of a d r u g f o r m a r k e t i n g a n d continues to b e of c o n s i d e r a b l e i m p o r t a n c e u n t i l the d r u g is r e m o v e d or r e p l a c e d b y n e w e r p r o d u c t s . A r r a n g e m e n t s w e r e m a d e w i t h the N a t i o n a l A c a d e m y of Science (NAS)

t h r o u g h its N a t i o n a l R e s e a r c h

Council

( N R C ) to

r e s p o n s i b i l i t y for e v a l u a t i n g d r u g s m a r k e t e d b e t w e e n

1938

undertake and

1962,

years i n w h i c h i m p o r t a n t A m e n d m e n t s to the F o o d , D r u g a n d C o s m e t i c A c t w e r e enacted.

P a r t of the i m p l e m e n t a t i o n of the A c a d e m y ' s

findings

is the a p p r o v a l of a b b r e v i a t e d N D A ' s ( n e w d r u g a p p l i c a t i o n s ) o n the basis of l a b e l i n g w h i c h c o n f o r m s to p u b l i s h e d r e q u i r e m e n t s ,

adherence

to g o o d m a n u f a c t u r i n g practices, a n d d e m o n s t r a t i o n of b i o a v a i l a b i l i t y , or another adequate d e m o n s t r a t i o n of d r u g a c t i v i t y . T h i s is the first step t o w a r d assuring the p h y s i c i a n a n d the c o n s u m e r that c h e m i c a l l y i d e n t i c a l d r u g s w i t h i d e n t i c a l l a b e l i n g are t h e r a p e u t i c e q u i v a l e n t s . F r o m t i m e to t i m e the a g e n c y has f o u n d it necessary to p r o p o s e changes i n , a n d a d d i t i o n s to, the regulations. F o r the most p a r t t h e y are a i m e d at c l a r i f y i n g the r e q u i r e m e n t s of the A c t as w e i n t e r p r e t i t , p r o viding

consumer

protection, dealing w i t h

e x p e d i t i n g the p r o c e s s i n g of submissions.

c l i n i c a l investigations,

and

A t the agency, w e have not

c o n c e i v e d of these f u n c t i o n s as c o n s t i t u t i n g any n e w r e s t r i c t i o n o n the d i s c o v e r y , d e v e l o p m e n t , or i n v e s t i g a t i o n of drugs. F o r e x a m p l e , o u r n e w r e q u i r e m e n t of a 30-day d e l a y before b e g i n n i n g c l i n i c a l trials, after the r e c e i p t of a n a p p l i c a t i o n f o r t r i a l of a n e w d r u g ( i n the f o r m of a n I N D or notice of c l a i m e d e x e m p t i o n f r o m the r e s t r i c t i o n o n interstate s h i p m e n t ), p r o v i d e s the a g e n c y a c h a n c e to evaluate the p r o p o s e d use of the d r u g i n the h u m a n subject a n d to d e t e r m i n e w h e t h e r there are safety d a t a f r o m experiments i n a n i m a l s to w a r r a n t the of h u m a n studies.

adequate

commencement

U n d e r p r e v i o u s regulations, the investigator c o u l d

b e g i n c l i n i c a l trials i n h u m a n s as soon as he h a d m a i l e d his n o t i c e .

Fre-

q u e n t l y e n o u g h to cause r e a l c o n c e r n , w e h a v e f o u n d that data f r o m studies i n a n i m a l s w e r e not a d e q u a t e to s u p p o r t the t y p e of studies that h a d b e e n u n d e r t a k e n i n h u m a n beings.

W e b e l i e v e that this

30-day

d e l a y , w i t h its w a i v e r p r o v i s i o n for e x t r a o r d i n a r y circumstances, c o n s t i -


13.

JENNINGS

Government

251

Regulations

tutes a m i n o r r e s t r i c t i o n — i f a n y — c o m p a r e d w i t h the p o t e n t i a l benefits i n the p r o t e c t i o n of subjects. A n o t h e r r e g u l a t i o n that has s t i r r e d c o n s i d e r a b l e controversy is t h a t w h i c h sets f o r t h o u r c r i t e r i a f o r a n adequate, w e l l - c o n t r o l l e d c l i n i c a l t r i a l . W e are c o n v i n c e d that this r e g u l a t i o n m e r e l y reflects the practices have become w i d e l y accepted clinical pharmacology.

that

d u r i n g the e v o l u t i o n of the science of

W e see i n this r e g u l a t i o n no r e s t r i c t i o n b e y o n d

that i m p o s e d b y Congress i n its 1962 A m e n d m e n t s to the A c t , a n d b y setting f o r t h c l e a r l y w h a t is e x p e c t e d , w e h o p e that the d a t a s u b m i t t e d


w i l l b e i m p r o v e d thus s p e e d i n g the p r o c e s s i n g

of a p p l i c a t i o n s .

Our

recent a p p r o v a l s of c e r t a i n n e w d r u g s w i t h a s m a l l e r v o l u m e of

data

t h a n has often b e e n the case, I b e l i e v e , s h o w that w e are p r e p a r e d to a p p l y these scientific p r i n c i p l e s i n a reasonable

fashion.

Role of the National Research Council S h o u l d the N a t i o n a l R e s e a r c h C o u n c i l be r e q u e s t e d to r e v i e w p e n d i n g n e w d r u g a p p l i c a t i o n s ? T h e f a c t that the l a w fixes the r e s p o n s i b i l i t y for r e v i e w a n d a p p r o v a l of n e w d r u g a p p l i c a t i o n s o n the F o o d a n d D r u g A d m i n i s t r a t i o n ( t h r o u g h d e l e g a t i o n f r o m the Secretary of

Department

of H e a l t h , E d u c a t i o n , a n d W e l f a r e ) is s o m e t h i n g that n e e d not b e c o n s i d e r e d as i n s u r m o u n t a b l e since l a w s c a n b e a m e n d e d .

H o w e v e r , unless

the l a w w e r e a m e n d e d r a d i c a l l y to change the s u b s t a n t i a l e v i d e n c e req u i r e m e n t , it is d i f f i c u l t to u n d e r s t a n d h o w experts of the A c a d e m y c o u l d , i n satisfaction of the A c t , r e q u i r e less r i g o r o u s p r o o f t h a n that n o w dem a n d e d b y the F D A . W e h a v e u s e d consultants f r o m t i m e to t i m e , i n c l u d i n g panels of the N a t i o n a l A c a d e m y of S c i e n c e - N a t i o n a l

Research

C o u n c i l ( N A S - N R C ) w h e n c o n f r o n t e d b y e s p e c i a l l y k n o t t y p r o b l e m s of safety a n d efficacy, b u t w h e n these experts w e r e f u l l y a w a r e of the req u i r e m e n t s of the F o o d , D r u g a n d C o s m e t i c A c t , i n every case they a p p l i e d standards a n d c r i t e r i a that w e r e every b i t as strict as those of the F D A ' s o w n r e v i e w i n g officers. If the proposals f o r r e v i e w of n e w d r u g a p p l i c a t i o n s b 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 , the N a t i o n a l Institutes of H e a l t h , or other scientific b o d i e s are a d v a n c e d w i t h the i d e a of p r o v i d i n g m o r e expertise t h a n resides i n the F D A , o u r use of outside experts makes this a p p r o a c h unnecessary—regardless

of the r e q u i r e m e n t s f o r a

change i n the l a w . If these proposals are a d v a n c e d to separate the a p p r o v i n g f u n c t i o n f r o m the r e g u l a t o r y f u n c t i o n , the t w o are inseparable f r o m a p r a c t i c a l p o i n t of v i e w . O u r r e g u l a t o r y actions m u s t be b a s e d o n scientific d e c i sions, a n d o u r scientists must b e f u l l y a w a r e of o u r r e g u l a t o r y responsibilities.


252

DRUG DISCOVERY

P r e s u m a b l y , a n y s u c h a r r a n g e m e n t w o u l d leave w i t h i n t h e t r u n c a t e d F D A t h e r e s p o n s i b i l i t y f o r t h e d e c i s i o n r e l a t i n g to t h e c o n t i n u e d q u a l i t y of t h e m a r k e t e d p r o d u c t . T i m e after t i m e changes i n t h e status o f t h e m a r k e t e d p r o d u c t h a v e r e q u i r e d t h e f o c u s i n g o f expertise f r o m a l l o f the d i s c i p l i n e s c u r r e n t l y r e p r e s e n t e d i n t h e F D A . T o r e m o v e f r o m t h e A g e n c y t h e b a s i c m e d i c a l expertise ( a n d s u c h a n a r r a n g e m e n t w o u l d r e sult i n n e a r l y t o t a l r e m o v a l ) w o u l d s e r i o u s l y i m p a i r c o n s u m e r p r o t e c t i o n . F i n a l l y , I firmly b e l i e v e that r a t h e r t h a n d i s m e m b e r i n g t h e agency w e s h o u l d c o n t i n u e o u r efforts, i d e a l l y w i t h t h e s u p p o r t o f e v e r y o n e c o n c e r n e d , to b r o a d e n a n d d e e p e n t h e expertise r e s i d e n t i n t h e a g e n c y , a n d Downloaded by CORNELL UNIV on August 10, 2016 | http://pubs.acs.org Publication Date: June 1, 1971 | doi: 10.1021/ba-1971-0108.ch013

to m a k e

e v e n m o r e effective

o u r e m p l o y m e n t o f scientific

expertise

w h e r e v e r i t m a y reside.

Appearance of New Drugs " W h y d o w e see so f e w t r u l y n e w d r u g s ? " O n e a n s w e r offered freq u e n t l y b y i n d u s t r y is r e p r e s e n t e d i n t h e t e s t i m o n y i n 1969 b y t h e P r e s i d e n t of the P h a r m a c e u t i c a l M a n u f a c t u r e r s A s s o c i a t i o n , C . J o s e p h

Stetler.

H e told the Subcommittee o n P u b l i c H e a l t h , E d u c a t i o n , a n d W e l f a r e of t h e H o u s e Interstate a n d F o r e i g n C o m m e r c e C o m m i t t e e : " W i t h o u t att e m p t i n g to i d e n t i f y t h e cause, i t is a f a c t that t h e n u m b e r o f n e w d r u g s , p a r t i c u l a r l y n e w single c h e m i c a l entities m a r k e t e d e a c h year, has d r a s t i c a l l y decreased since t h e passage of t h e 1962 a m e n d m e n t s .

T h e impact

of that l e g i s l a t i o n has b e e n f e l t t h r o u g h o u t t h e i n d u s t r y , p a r t i c u l a r l y i n research a n d d e v e l o p m e n t areas." M r . Stetler w e n t o n t o cite figures f o r 1959 a n d 1968 s h o w i n g t h e d e c l i n e of 7 2 % i n n e w p r e s c r i p t i o n d r u g s m a r k e t e d a n d a d e c l i n e of 8 3 % f o r n e w single c h e m i c a l entities.

While

d i s c l a i m i n g a n y a t t e m p t to " i d e n t i f y t h e cause," M r . Stetler i m p l i e d that i t arises f r o m " a d m i n i s t r a t i v e e n c u m b r a n c e s " a n d " i m p o r t a n t differences i n the p r o c e d u r e that m u s t b e f o l l o w e d i n d e v e l o p i n g present n e w d r u g a p p l i c a t i o n s . " H e s a i d , " A n o t h e r cause of d e l a y is t h e g e n e r a l l a c k of q u a l i f i e d experts w i t h i n F D A . " T h e d e a r t h o f n e w d r u g s is o f t e n a t t r i b u t e d to the 1962 a m e n d m e n t s a n d the F o o d a n d D r u g A d m i n i s t r a t i o n , b u t i t is a f a c t that t h e postW o r l d W a r I I p e a k f o r a p p r o v e d n e w d r u g s c a m e l o n g before the 1962 amendments. proved.

I n 1955 357 n e w d r u g a p p l i c a t i o n s

(NDA's)

were ap-

E x c e p t f o r 1959, there has b e e n a steady d e c l i n e since 1 9 5 5 —

w i t h o n l y 70 N D A ' s a p p r o v e d i n 1963 w h e n t h e K e f a u v e r - H a r r i s A m e n d ments b e c a m e effective.

T h u s , there w a s a sharp d e c l i n e of a p p r o v e d

n e w d r u g s b e f o r e 1963. F o l l o w i n g i m p l e m e n t a t i o n of t h e 1962 a m e n d m e n t s , t h e o n l y m a r k e d c h a n g e i n t h e d o w n w a r d c u r v e o f the slope w a s i n 1967 w h e n the n u m b e r of a p p r o v e d N D A ' s rose to 74, after w h i c h i t d r o p p e d to 56 i n 1968, a n d


13.

JENNINGS

Government

f e l l off to 48 i n 1969.

253

Regufotions

F i f t y - o n e , h o w e v e r , w e r e a p p r o v e d b y the F D A

t h e fiscal y e a r 1969-70 ( close to one a w e e k ) . O f the 51 n e w d r u g s a p p r o v e d i n fiscal y e a r 1970, a b o u t 20 c o u l d b e c o n s i d e r e d " n e w entities"—i.e., n e w c h e m i c a l s n o t p r e v i o u s l y m a r k e t e d i n the U n i t e d States. H o w e v e r , m a n y of these, a l t h o u g h t e c h n i c a l l y n e w entities, r e p r e s e n t e d m e r e l y v a r i a t i o n s o n f a m i l i a r themes a n d i n some cases n o t h i n g m o r e t h a n m o l e c u l a r m a n i p u l a t i o n . T h e n u m b e r of n e w d r u g s a p p r o v e d i n that p e r i o d that c o u l d b e c o n s i d e r e d as s i g n i f i c a n t c o n t r i b u t i o n s to the p h a r m a c o p o e i a is s m a l l i n d e e d . T h e n u m b e r of N D A ' s u n d e r r e v i e w i n the F D A at a n y one t i m e is


u s u a l l y b e t w e e n 100 a n d 150. least, w i l l represent

A l t h o u g h w e h o p e that some of t h e m , at

significant c o n t r i b u t i o n s to t h e r a p e u t i c s ,

e x a m i n a t i o n leads to the c o n c l u s i o n that the p e r c e n t a g e

a

casual

w i l l be

about

the same as i n the recent past. A l o o k at the d r u g s i n the e a r l i e r phases of i n v e s t i g a t i o n , the I N D stage, does not p r o v i d e any reason to expect i m p r o v e m e n t w i t h i n near f u t u r e .

the

A b o u t 1000 I N D ' s w e r e s u b m i t t e d i n 1963 i n response

the 1962 a m e n d m e n t s .

to

B y 1967 I N D submissions h a d d e c l i n e d to less

t h a n 700 b u t rose a g a i n to n e a r l y 1000 i n 1969.

H o w e v e r , a b o u t one-half

r e p r e s e n t e d m u l t i p l e submissions f o r a f e w s p e c i a l d r u g s , n o t a b l y l i t h i u m carbonate a n d L - d o p a . W e are c u r r e n t l y r e s p o n s i b l e f o r a t o t a l of 3430 I N D ' s , c e r t a i n l y a large e n o u g h n u m b e r to c o n t a i n a respectable q u a n t i t y of significant d r u g s . A l t h o u g h p r o g n o s t i c a t i o n is e v e n m o r e

dangerous

at this e a r l y stage of d e v e l o p m e n t there are n o t m a n y r e a l b r e a k t h r o u g h d r u g s i n that large v o l u m e . T h e r e is no q u e s t i o n of the constant d o w n - t r e n d i n the i n n o v a t i v e significance of the d r u g s b e i n g d e v e l o p e d t o d a y . T h e q u e s t i o n i s : " w h y s h o u l d this be, w h e n m i l l i o n s of d o l l a r s are p o u r e d i n t o research

and

d e v e l o p m e n t ( R & D ) each year b y o u r d r u g i n d u s t r y ? " O u r m a j o r

firms

s p e n d vast amounts of m a n p o w e r a n d t i m e b u d g e t e d f o r research

and

d e v e l o p m e n t . W h y is it u n r e w a r d i n g i n terms of a c t u a l m e d i c a l progress — w h y is it u n r e w a r d i n g f o r the consumer, f o r the p a t i e n t ? A s scientists w e m u s t a c c e p t the results of scientific studies w h e n t h e y upset c h e r i s h e d beliefs. R & D

effectiveness of the large laboratories i n major i n d u s t r i e s points to

the f a c t that f o r several reasons the largest c o m p a n i e s w i l l not b e largest

even

V i r t u a l l y e v e r y t y p e of s t u d y o n the

contributors

i n terms

of

o r i g i n a l research

and

the

development.

W h e t h e r w e l o o k at a b r o a d , h o r i z o n t a l s t u d y of i n d u s t r y i n g e n e r a l over a c o n s i d e r a b l e p e r i o d of t i m e , or a n a r r o w v e r t i c a l s t u d y of a n y one c o m p a n y , the results are the same. I n a b r o a d s t u d y b a s e d o n extensive research, D . H a m b e r g ( 1 ), of the U n i v e r s i t y of B u f f a l o , has f o u n d that " w i t h f e w exceptions, t h e l a r g e i n d u s t r i a l laboratories are l i k e l y to be m i n o r sources of major i n v e n t i o n s . "


254

DRUG DISCOVERY

H e p o i n t s o u t that the larger firms are p r i m a r i l y i n v o l v e d w i t h i m p r o v e m e n t i n v e n t i o n s — d e v o t i n g m u c h research t o w a r d b e t t e r i n g the p r o d u c t s t h e y a l r e a d y t u r n out or t o w a r d i m p r o v i n g the processes of p r o d u c t i o n . T h i s is not to gainsay s u c h i m p r o v e m e n t s or to q u e s t i o n the n e e d f o r s u c h research.

T h e d i s c o v e r y of p e n i c i l l i n w o u l d h a v e benefited h u m a n i t y b u t

l i t t l e i f r a p i d i m p r o v e m e n t s i n t e c h n o l o g y h a d not m a d e i t a v a i l a b l e o n a massive scale, b u t i f w e are l o o k i n g f o r o r i g i n a l c o n t r i b u t i o n s — i n other w o r d s , n e w d r u g s a n d n u m b e r s of n e w d r u g s , s u c h as p r o d u c e d the " G o l d e n A g e of the W o n d e r D r u g " f o l l o w i n g W o r l d W a r I I — a p p a r e n t l y


w e m u s t l o o k to other t h a n the R & D p r o g r a m s of the large d r u g firms. Studies f r o m the t u r n of the c e n t u r y s h o w the m a j o r

laboratories

c o n t r i b u t e a v e r y s m a l l p e r c e n t a g e of o u r n e w i m p o r t a n t i n v e n t i o n s . instance, W . M . G r o s v e n o r (2)

For

i n 1929 f o u n d that of 72 major i n v e n t i o n s

— s u c h as the s u b m a r i n e , the d i a l telephone, the d i e s e l engine, a n d c a l cium carbide—produced between

1889

a n d 1929,

o n l y 12

(or

17%)

o r i g i n a t e d i n c o r p o r a t e laboratories. A s t u d y h e a d e d b y J e w k e s ( 3 ) a n d p u b l i s h e d i n 1958, f o u n d that of 61 m a j o r i n v e n t i o n s after 1930 o n l y 2 0 % e m a n a t e d f r o m the laboratories of large

corporations.

S u c h inventions as

air-conditioning,

automatic

transmissions, a n d the jet engine w e r e the w o r k of i n d e p e n d e n t inventors. I n 1962 W . F . M u e l l e r ( 4 ) at D u P o n t , f o u n d that b e t w e e n 1920 a n d 1950 only 2 8 %

of their 18 n e w p r o d u c t s o r i g i n a t e d f r o m their o w n research.

T w o of the c o m p a n y ' s three most c o m m e r c i a l l y i m p o r t a n t p r o d u c t s w e r e c o m p l e t e d b y t h e i r research laboratories b y the e a r l y 1930s, w h e n their research b u d g e t a v e r a g e d $5 m i l l i o n a y e a r — f a r less t h a n it is t o d a y . A s t u d y i n 1965 b y W i l l i a m S. C o m a n o r ( 5 ) , deals w i t h research a n d t e c h n i c a l c h a n g e solely w i t h i n the p h a r m a c e u t i c a l i n d u s t r y .

Comanor's

analysis p r o v i d e s "some e v i d e n c e that i n the p h a r m a c e u t i c a l i n d u s t r y there are s u b s t a n t i a l diseconomies of scale i n R & D w h i c h are associated w i t h large firm size; a n d that these disadvantages are e n c o u n t e r e d e v e n by moderately sized

firms."

S t u d y after s t u d y points out w h a t has a n d has not c o m e out of massive research efforts, b u t there is one i n t e r e s t i n g p a p e r p r e p a r e d i n 1958 b y M c G r a w - H i l l ( 6 ) t h e i r research.

that shows w h a t the c o m p a n i e s expect f r o m

I n the s u r v e y almost e v e r y large c o m p a n y i n U . S . i n d u s t r y

a n d c o m m e r c e was a s k e d : " h o w soon d o y o u expect y o u r expenditures o n R & D to p a y off?"

N i n e t y - o n e percent s a i d w i t h i n five years, b u t the

h i s t o r y of major inventions shows that most h a v e t a k e n m u c h m o r e t i m e b e f o r e they w e r e even r e a d y for m a r k e t i n g . So it w o u l d seem that major laboratories—although heavily f u n d e d and stocked w i t h

expertise—are

not so m u c h l o o k i n g to o r i g i n a l p r o d u c t s as they are to i m p r o v e d p r o d u c t s a l r e a d y i n the l i n e , w h i c h w o u l d r e q u i r e a shorter p e r i o d of d e v e l o p m e n t .


13.

JENNINGS

Government

255

Regulations

T o d a y w e h a v e f e w e r s m a l l firms t h a n w e h a d 10 years ago; some o f t h e m h a v e passed o u t of existence, b u t others h a v e b e e n a b s o r b e d i n t o t h e l a r g e r l a b o r a t o r i e s ; hence, w e h a v e m o r e talent c o m i n g u n d e r t h e u m b r e l l a of the l a r g e

firms—subject

to t h e i r goals a n d d i r e c t i o n .

W h a t has c o r p o r a t e talent p r o d u c e d ? If w e r e t u r n to r e v i e w some r e c e n t l y a p p r o v e d d r u g s a n d confine o u r a t t e n t i o n to a p a r t i c u l a r categ o r y , n e u r o p h a r m a c o l o g y , there are three d r u g s of some c l i n i c a l i m p o r tance. T w o of these, l i t h i u m c a r b o n a t e a n d L - d o p a , w e r e not the p r o d u c t s of

the

t y p e of research

that

characterizes

the

drug industry today.

K e t a m i n e , the o n l y other d r u g i n this category of m o r e t h a n p a s s i n g


interest, a p p a r e n t l y w a s the result of a m a s s i v e s c r e e n i n g p r o g r a m w h i c h c o u l d p r o b a b l y b e c a r r i e d o u t o n l y i n a l a b o r a t o r y of the t y p e w e h a v e b e e n d i s c u s s i n g . C o m m e r c i a l considerations aside, the efficiency of this a p p r o a c h m u s t b e q u e s t i o n e d i n the l i g h t of the f a i l u r e of this t e c h n i q u e to p r o d u c e a n y t h i n g of r e a l significance i n cancer t h e r a p y . T h e a p p r o a c h to research i n i n d u s t r y t o d a y — t h e massive f r o n t a l assault o n research p r o b l e m s — s i m p l y is n o t p r o v i n g , a n d m a y

never

p r o v e , to b e as effective as the f o r a y of the i n d e p e n d e n t researcher. T h e a p p r o a c h t a k e n to research i n i n d u s t r y t o d a y is a c t u a l l y counterp r o d u c t i v e to the goals. V a s t r e s o u r c e s — i n t i m e , i n m o n e y , i n e x p e r t i s e — are b e i n g t i e d u p o n projects of q u e s t i o n a b l e or l i t t l e s i g n i f i c a n c e to a c t u a l m e d i c a l progress. E v e n today a study b y M u e l l e r and Tilton (7)

does n o t c h a n g e the

i m p r e s s i o n that m u c h of o u r scientific expertise i n the field of d r u g s is b e i n g u s e d s o l e l y f o r e c o n o m i c g o a l s — w i t h the o c c a s i o n a l h a p p y c o i n c i d e n c e of m e d i c a l progress. A c c o r d i n g to these a u t h o r s : T h e b u l k of the e m p i r i c a l e v i d e n c e o n the o r i g i n of m a j o r i n v e n t i o n s suggest that the R & D laboratories of l a r g e c o r p o r a t i o n s h a v e n o t b e e n a n i m p o r t a n t source of major i n v e n t i o n s . . . . T h e same c o m m u n i c a t i o n g a p w h i c h m a y k e e p large firms f r o m financing R & D a c t i v i t y d i r e c t e d t o w a r d major i n v e n t i o n s m a y i n h i b i t t h e m f r o m f u n d i n g the d e v e l o p m e n t n e e d e d to c o n v e r t a major i n v e n t i o n i n t o a c o m m e r c i a l l y successful p r o d u c t o r process i n n o v a t i o n . T h i s is p a r t i c u l a r l y l i k e l y w h e n the i n v e n t i o n is m a d e b y s m a l l firms or i n d i v i d u a l s o u t s i d e the c o m p a n y . W e are c o n f r o n t e d w i t h a p r o b l e m of t r e m e n d o u s i m p o r t a n c e to us as scientists a n d as citizens : the steady d e c l i n e i n the d i s c o v e r y a n d d e v e l o p m e n t of significant n e w d r u g s . A n y t h i n g that m i g h t h e l p to resolve that p r o b l e m deserves serious attention. T h e p r o p o s i t i o n set f o r t h here, o b v i o u s l y not a n o r i g i n a l one, s h o u l d b e e x a m i n e d . s h o u l d be either a c c e p t e d or p r o v e d i n v a l i d . it t i m e to c o n s i d e r n e w a p p r o a c h e s

T h e studies c i t e d

If they are v a l i d , t h e n isn't

to p r o d u c t i v e , creative

Isn't i t t i m e to c o n s i d e r t u r n i n g to some of the m o r e

research?

research-oriented

schools a n d u n i v e r s i t i e s a n d f u n d i n g some of t h e i r operations i n d e p e n d -


256

DRUG DISCOVERY

e n t l y o r setting u p s m a l l satellite laboratories to c o n d u c t b a s i c r e s e a r c h autonomous f r o m b u t f u n d e d b y the large parent company?

Isn't i t

t i m e to r e t u r n to t h e i n n o v a t i v e r a t h e r t h a n t h e i m i t a t i v e stage o f r e s e a r c h a n d d e v e l o p m e n t i n the d r u g

field?

O b v i o u s l y n o o n e k n o w s f u l l y w h y w e see so f e w n e w a n d significant drugs.

Scientists m u s t e x a m i n e t h e p r o b l e m s c i e n t i f i c a l l y a n d n o t settle

f o r easy answers that m a y p u t t h e m i n d at rest b u t b r i n g us n o closer t o a true s o l u t i o n .


Literature Cited (1) Hamberg, D., "Invention in the Industrial Research Laboratory,"J.Political Econ. (1963) 71, 95-115. (2) Grosvenor, W. M., "The Seeds of Progress," in "Chemical Markets," pp. 23, 24, 26 (1929). (3) Jewkes, J. Sawers, D., Stillerman, R., "The Sources of Invention," pp. 72-88, Part II, London, 1958. (4) Mueller, W. F., "The Origins of the Basic Inventions Underlying Du Pont's Major Product and Process Innovations, 1920-1950," in "Universities -National Bureau Conference, The Rate and Direction of Inventive Ac tivity: Economic and Social Factors," pp. 323-346, Princeton, N . J., 1962. (5) Comanor, W. S., "Research and Technical Change in the Pharmaceutical Industry," Rev. Econ. Statistics (1965) 47, pp. 182-190. (6) "The Annual McGraw-Hill Research and Development Survey," in "Meth odology of Statistics on Research and Development," National Science Foundation, Washington, D. C., 1959. (7) Mueller, D. C., Tilton, J. E., "Research and Development Costs as a Barrier to Entry," Can. J. Econ./Rev. Can. Econ. (1969) 2, 570-579. RECEIVED November 5, 1970.


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