Drugs and the Real World of Medical Practice - ACS Publications

15 Drugs and the Real World of Medical Practice G E O R G E E . B U R K E T , JR., M . D .

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M e d i c a l Arts Center, 349 North M a i n St., K i n g m a n , K a n . 67069

Two worlds

revolve

in the field of medicine—the

drugs and the world of medical the same direction munication physician search,

and with amazing

between

and although

practice.

synchronization.

them takes many paths to many

it is quite complex,

is indebted in public

world

it is improving

to the drug industry

and private

institutions,

drugs. pects disease

For the future more and

pharmaceutical

miracle cancer

and timesaving the clinical drugs.

daily.

the

The

for providing

so offer

way to prescribe

physician

Arteriosclerotic

represent

Com areas,

as well as to re

many new drugs for so many valid uses. Tradenames an easy, convenient,

of

They both move in

foremost

confidently

new ex

cardiovascular challenges

to

researchers.

Τ η discussing d r u g s a n d t h e r e a l w o r l d of m e d i c a l p r a c t i c e , w e must first c o n t e m p l a t e the significance of the title. T h e p r a c t i c e of m e d i c i n e has a l w a y s b e e n associated w i t h the use of drugs w h e t h e r t h e y b e t e r m e d drugs, concoctions, or potions. H i s t o r y records p h y s i c i a n s ' c o m p o u n d i n g p r e s c r i p t i o n s i n a n E g y p t i a n society 15 centuries b e f o r e C h r i s t , a n d t h e annals of m e d i c i n e t h r o u g h m o r e t h a n 2000 years are filled w i t h n e w remedies f o r o l d a n d n e w diseases a n d ailments.

W h y , t h e n , does t h e

title of this p a p e r suggest a d i s t i n c t separation b e t w e e n d r u g s a n d m e d i c a l practice?

O n e m u s t trace the p a t h w a y of t i m e f o r the answer.

Through

the ages drugs h a v e not b e e n the exclusive p r o p e r t y of p h y s i c i a n s .

His

tory records the use of drugs i n religious ceremonies, a n d c h e m i c a l w a r fare c a n b e t r a c e d to t h e fifth c e n t u r y B . C . " T r u t h s e r u m s " h a v e b e e n a d v o c a t e d i n s o l v i n g crimes, a n d thousands of p r o p r i e t a r y d r u g s are u s e d w i t h o u t the a d v i c e of a p h y s i c i a n . L o o k i n g elsewhere, one also finds that p h y s i c i a n s h a v e n o exclusive c l a i m to the d e v e l o p m e n t of d r u g s or to the c o m p o u n d i n g of m e d i c a t i o n . 267

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

268

DRUG

DISCOVERY

A s f a r b a c k as H i p p o c r a t e s , 2500 years ago, apothecaries p r e p a r e d p r e s c r i b e d concoctions.

U n t i l the d a w n of o u r present scientific era, i t w a s

c o m m o n p l a c e f o r f r i e n d s or relatives to p r e p a r e " a p p r o p r i a t e m e d i c a t i o n " ( u s u a l l y b a s e d o n f o l k l o r e ) . T h o s e i n f a m i l y m e d i c i n e are a w a r e that a c e r t a i n a m o u n t of f o l k l o r e m e d i c i n e still remains—e.g., h o n e y a n d v i n e g a r f o r arthritis, potato p o u l t i c e s for c e l l u l i t i s , a n d s p i d e r w e b s to stop b l e e d i n g i n a l a c e r a t i o n . W e n o w k n o w that m a n y of the c r u d e d r u g s w h i c h w e r e f o u n d e m p i r i c a l l y to be effective l o n g before the m o d e r n scientific era a c t u a l l y c o n t a i n e d d r u g s w h i c h h a v e b e e n i d e n t i f i e d a n d are u s e d


today—e.g., q u i n i n e f r o m c i n c h o n a b a r k , d i g i t a l i s f r o m f o x g l o v e , a n d o p i u m f r o m the p o p p y . I n fact, p h a r m a c e u t i c a l c o m p a n i e s are e x p l o r i n g b o t a n i c a l species a r o u n d the w o r l d i n search of basic n e w d r u g s w h i c h c a n b e s y n t h e s i z e d or a l t e r e d f o r m e d i c i n a l purposes ( 1 ). Since the c i v i l i z a t i o n s b e f o r e C h r i s t there has b e e n a d i v i s i o n bet w e e n the p h y s i c i a n s w h o d i a g n o s e d a n d p r e s c r i b e d d r u g s a n d those w h o d i s c o v e r e d a n d c o m p o u n d e d t h e m , w i t h the grey area i n b e t w e e e n i n w h i c h certain physicians performed equally w e l l . W e have then what c o u l d be t e r m e d t w o w o r l d s of m e d i c i n e , w o r l d s w h i c h f o r t u n a t e l y r e v o l v e i n the same d i r e c t i o n a n d w i t h a m a z i n g s y n c h r o n i z a t i o n . S i n c e the b e g i n n i n g of scientific m e d i c i n e , d a t i n g f r o m a n i n d e f i n i t e p o i n t i n the 18th century, these t w o areas have b e c o m e

increasingly

d i s t i n c t , a n d w i t h the scientific e x p l o s i o n of the past 30 years, i d e n t i f i c a t i o n seems c o m p l e t e .

M e d i c a l p r a c t i c e is n o w i n v o l v e d w i t h n e w m e t h -

ods of diagnosis, t h e r a p e u t i c techniques, a n d h e a l t h care d e l i v e r y w h i l e the d r u g i n d u s t r y is i n v o l v e d i n the d e v e l o p m e n t of n e w c h e m i c a l s a n d b i o l o g i c a l s a n d t h e i r m a n u f a c t u r e — e a c h w o r l d s t i m u l a t i n g the other a n d w o r k i n g r e m a r k a b l y w e l l together.

O u r subject t h e n deals w i t h h o w some

of the p r o d u c t s of one w o r l d are u t i l i z e d w i t h i n the o t h e r — t h e r e a l w o r l d of m e d i c a l p r a c t i c e . I n m e d i c a l p r a c t i c e the use of drugs a n d their f u n c t i o n h a v e a sign i f i c a n c e v e r y different f r o m that i n the w o r l d of strict scientific research and manufacturing.

T h e c l i n i c a l p h y s i c i a n m u s t consider not o n l y the

p h y s i o l o g i c aspects of t h e r a p y b u t the p s y c h o l o g i c a l a n d s o c i a l aspects as w e l l ( 1 ). T h e p h a r m a c e u t i c a l i n d u s t r y seems to b e a w a r e of this fact as e v i d e n c e d b y a d v e r t i s i n g i n m e d i c a l journals.

F o r e x a m p l e one i l l u s -

t r a t i o n depicts a m i d d l e a g e d m a n w h o was able to r e s u m e

marital

relations after t a k i n g a c o r o n a r y d i l a t o r . A n o t h e r a d d e p i c t e d the c u r v a ceous d o l l w h o w a s able to w e a r her b i k i n i after h e r e c z e m a w a s c l e a r e d b y a c e r t a i n u n g u e n t u m . S t i l l another asked, " H o w l o n g c a n she w a i t ? " w h e n r e f e r r i n g to a p r e p a r a t i o n for c u r i n g m o n i l i a l v a g i n i t i s . O t h e r i l l u s trations m i g h t i n c l u d e , "If h e kisses y o u once, w i l l he kiss y o u a g a i n , " a n d , " E v e n y o u r best f r i e n d w o n ' t t e l l y o u . "


15.

BURKET, JR.

Drugs and

Medical

269

Practice

T h e c l i n i c a l p h y s i c i a n m u s t relate to situations l i k e this e v e r y d a y . S u c h situations m a y seem i d i o t i c to the science w r i t e r or to those w h o seek a n y reason to c r i t i c i z e the p h a r m a c e u t i c a l a n d m e d i c a l professions, b u t t h e y are v e r y r e a l concerns to the p h y s i c i a n a n d his patients. If critics or skeptics t h i n k that the illustrations i n a n y w a y affect the j u d g m e n t of the c l i n i c i a n s , regardless of the p h y s i o l o g y i n v o l v e d , the t h e r a p e u t i c re sults, or possible adverse effects, they are s a d l y m i s t a k e n .


Development and Use of Drugs T h e i m p o r t a n c e i n m e d i c a l p r a c t i c e of f u n c t i o n r e l a t i n g to drugs is best o u t l i n e d b y B a r b e r ( 1 ) i n " D r u g s a n d S o c i e t y . " " Ά d r u g , ' say G o o d m a n and G i l m a n (2)

i n their s t a n d a r d textbook o n t h e r a p e u t i c p h a r m a

c o l o g y , m a y b e b r o a d l y d e f i n e d as a n y c h e m i c a l agent w h i c h affects l i v i n g p r o t o p l a s m , a n d f e w substances w o u l d escape i n c l u s i o n b y this d e f i n i t i o n / So b r o a d a d e f i n i t i o n indicates that the p r o b l e m of d e f i n i t i o n is s t i l l w i t h us. I n d e e d it is, a n d a l l the m o r e so since a n y t h i n g c o n s i d e r e d to b e a d r u g takes o n a n i m p o r t a n t p a r t of its significance f r o m s o c i a l a n d p s y c h o l o g i c a l meanings a t t a c h e d to it b y i n d i v i d u a l s a n d b y s o c i a l systems," B a r b e r illustrates w i t h a f e w examples. the

Food and D r u g

" A recent d i s p u t e b e t w e e n

Administration and a pharmaceutical

manufac

turer o r i g i n a t e d i n the assertion b y the F D A that the p r o d u c t Q u e l l w h i c h was b e i n g s o l d as a d i e t a r y f o o d w a s i n fact a m i s b r a n d e d d r u g . ' " A g a i n , the F D A has h e l d that the i n k stain used for diagnosis i n f u n g a l i n f e c t i o n is a d r u g .

T h i s stain, m a n u f a c t u r e d b y a c o m p a n y p r o d u c i n g i n k for

f o u n t a i n pens, is essentially no different f r o m the f o u n t a i n p e n i n k .

Dial

soap, because of its a n t i b a c t e r i a l claims is also classified as a d r u g . d e e d , a n y i t e m l i s t e d i n the U n i t e d States P h a r m a c o p o e i a

In

(U.S.P.)

is

l e g a l l y d e f i n e d b y the F o o d , D r u g , a n d C o s m e t i c A c t as a d r u g . I n c l u d e d , therefore, as drugs are c e r t a i n g a u z e bandages l i s t e d i n the U . S. P .

The

social a n d p s y c h o l o g i c a l definitions of materials of a l l k i n d s are h i g h l y relevant to their b e i n g n a m e d " d r u g s . " W e m i g h t even say that n o t h i n g is a d r u g , b u t n a m i n g makes it so. D r . B a r b e r c o n c l u d e s , " A n adequate d e f i n i t i o n of a d r u g w i l l start w i t h the a s s u m p t i o n that a n y t h i n g i n v o l v e d i n h u m a n b e h a v i o r needs to b e c o n s i d e r e d at the p h y s i o l o g i c a l l e v e l , the p s y c h o l o g i c a l l e v e l , a n d the s o c i a l l e v e l , a n d p a r t i c u l a r l y needs to consider these three levels i n i n t e r a c t i o n w i t h one another . . ." T h e s e statements illustrate the considerations the p h y s i c i a n m u s t give to drugs i n m e d i c a l p r a c t i c e .

T h e y also i n d i c a t e h o w l e n g t h y this p a p e r

m i g h t be i f this subject w e r e discussed t h o r o u g h l y a n d i n d e t a i l .

Instead,

let us d w e l l m o r e s p e c i f i c a l l y o n the c l i n i c a l p h y s i c i a n ' s attitudes c e r n i n g subjects of m o r e i m m e d i a t e a n d m u t u a l interest.


con

270 The

DRUG DISCOVERY

Pharmaceutical

Industry

T h e p h a r m a c e u t i c a l i n d u s t r y h o l d s the highest p o s i t i o n of a d m i r a t i o n a n d respect i n the o p i n i o n of most p h y s i c i a n s . T h e p h y s i c i a n v i e w s its a c c o m p l i s h m e n t s i n the past 30 years as s o m e t h i n g a k i n to m i r a c u l o u s . T h o s e w h o have b e e n i n c l i n i c a l m e d i c i n e for over 30 years

remember

too w e l l the d e p r e s s i n g deaths f r o m p n e u m o n i a , p u e r p e r a l s e p t i c e m i a , m e n i n g i t i s , i n f l u e n z a , t y p h o i d fever, b a c t e r i a l e n d o c a r d i t i s , tuberculosis, tetanus, a n d c o m p l i c a t i o n s of s y p h i l i s , a n d w e easily recollect the c r i p -


p l i n g of p o l i o m y e l i t i s , osteomyelitis, a n d r h e u m a t i c fever. T o d a y a l l of these a n d h u n d r e d s of other diseases a n d ailments are c o n t r o l l e d or c u r e d b y m o d e r n d r u g s . I n 1910 q u i n i n e , ether, m o r p h i n e , alcohol, mercury, iodine, digitalis, diphtheria antitoxin, and arsphenamine w e r e a v a i l a b l e . T o d a y w e h a v e antiinfectious agents, t r a n q u i l i z i n g agents, c a r d i o v a s c u l a r a n d d i u r e t i c agents, steroids, a n t i d i a b e t i c agents, analgesics a n d anesthetics,

antihistamines, antianemics,

biological products

hormones, v i t a m i n s , a n d

(3).

W h i l e w e m a y be c r i t i c a l at times of the s e e m i n g l y h i g h cost of drugs to o u r patients, w e are q u i c k to r e c a l l that the cost of m e d i c i n e consists of o n l y 2 0 % of the total cost of h e a l t h care i n the U n i t e d States a n d has risen little, c o m p a r a t i v e l y s p e a k i n g , i n the past 10 years. W e also r e c o g n i z e that the d r u g i n d u s t r y invests a p p r o x i m a t e l y one m i l l i o n d o l l a r s a d a y i n the search for n e w a n d better drugs ( 7 ) . H o w the p h a r m a c e u t i c a l i n d u s t r y operates i n the eyes of the c l i n i c a l p h y s i c i a n is best d e s c r i b e d b y C h e s t e r K e e f e r ( 3 )

in "The Medicated

Society." They work in chemistry—on physical, organic a n d medicinal chemistry, a n d t o d a y p u r s u e the m i c r o m o l e c u l a r fields of D N A - R N A , p o l y p e p t i d e s a n d enzymes. T h e y seek to relate the changes i n the c o n f i g u r a t i o n of a c h e m i c a l c o m p o u n d w i t h its i m p a c t o n the h u m a n o r g a n i s m , i n the t r a d i t i o n o f — b u t f o r t u n a t e l y m u c h m o r e k n o w l e d g e t h a n — E r l i c h seventy years ago as he sought the " m a g i c b u l l e t " f o r target sites or target diseases. T h e y w o r k w i t h m i c r o o r g a n i s m s — b a c t e r i a , viruses, f u n g i , a n d the c y c l i c existence of parasites; a n d t h e y seek vaccines, as f o r p o l i o , i n f l u e n z a , measles, m u m p s , a n d r u b e l l a . T h e y w o r k w i t h a n i m a l s — m i c e , rats, m o n k e y s , dogs, cats, p i g s , c h i c k ens, h o r s e s — a n estimated n i n e m i l l i o n of t h e m a year. E a c h p l a y s a role i n finding out first w h e t h e r the d r u g does a n y t h i n g to the l i v i n g o r g a n i s m a n d s e c o n d l y w h e t h e r it has toxic effects i n the r a n g e of a m o u n t s necessary to a c h i e v e u s e f u l effects. T h e y w o r k w i t h tissues—the sections of organs a n d samples of b l o o d that, w h e n e x a m i n e d , s h o w m i c r o s c o p i c a l l y w h e t h e r d a m a g e has b e e n d o n e a n d h o w m u c h of the d r u g m a y be h a r m f u l , a n d w h a t to l o o k for if h u m a n s take too m u c h .



15.

BURKET, JR.

Drugs and

Medical

271

Practice

T h e y w o r k i n the skills of the a p o t h e c a r y , c a r r i e d i n t o t h e m o d e r n science of p h a r m a c y , to p r e p a r e the c h e m i c a l i n a f o r m the b o d y c a n a n d w i l l take, absorb, m e t a b o l i z e , a n d excrete—the capsule, the tablet, the s o l u t i o n or suspension or ointment. T h e i r l a b o r a t o r y w o r k d o n e , they t u r n to the c l i n i c s , m e d i c a l centers, a n d p h y s i c i a n ' s offices f o r the s t u d y of drugs i n h u m a n s . A n d w h e n a l l the studies h a v e b e e n c o m p l e t e d , t h e y w i l l ask a p p r o v a l of the F e d e r a l 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 to m a r k e t the p r o d u c t f o r the uses that h a v e b e e n p r o v e d out b y research. F r o m the basic c h e m i c a l i n d u s t r y c o m e r a w materials to use i n largescale f o r m u l a t i o n of the n e w p r o d u c t . F r o m the vast f e r m e n t a t i o n vats c o m e a n t i b i o t i c s . I n l a b o r a t o r y - l i k e f o r m u l a t i o n facilities, the m i x i n g , b a k i n g , c o m p r e s s i n g , c o a t i n g , a n d other p h a r m a c e u t i c a l processes take p l a c e , u n d e r the w a t c h f u l eye of q u a l i t y c o n t r o l inspectors. I n the spaceage-clean rooms of b i o l o g i c a l p r o d u c t i o n , v i r u s vaccines are g r o w n , harvested, p u r i f i e d , a n d endlessly tested. F r o m start to finish, statistical, n u m e r i c a l , p r o c e d u r a l , p h y s i c a l , c h e m i c a l , a n d a n a l y t i c a l c o n t r o l systems a t t e m p t to r e d u c e to near-zero the p o t e n t i a l error, m i x u p , d i s t o r t i o n , or hazard. C o n c u r r e n t l y , a large g r o u p of w e l l - i n f o r m e d m e n p r o m o t e u s e f u l k n o w l e d g e a b o u t the n e w l y d i s c o v e r e d d r u g s a n d p r o v i d e i n f o r m a t i o n to doctors, p h a r m a c i s t s , a n d hospitals. Communication W h a t a s u p e r b job D r . K e e f e r has d o n e i n d e s c r i b i n g the p h a r m a c e u t i c a l i n d u s t r y as the p h y s i c i a n k n o w s it t o d a y .

H o w e v e r , the story

w o u l d not be c o m p l e t e w i t h o u t d i s c u s s i n g the methods of c o m m u n i c a t i o n b e t w e e n the i n d u s t r y a n d the p h y s i c i a n for here is the m e c h a n i s m w h i c h benefits of the d e s c r i b e d system r e a c h the p a t i e n t — t h e

by

i l l and

the d i s a b l e d . T h i s e d u c a t i o n a n d c o m m u n i c a t i o n m e c h a n i s m is c o m p l e x a n d ext r e m e l y i n v o l v e d . It takes m a n y paths i n a n attempt to r e a c h a l l areas w i t h c o n s i d e r a b l e d u p l i c a t i o n a n d o v e r l a p p i n g . I n c l u d e d are the d e t a i l m e n , advertisements i n m e d i c a l journals, d i r e c t m a i l a d v e r t i s i n g , exhibits at m e d i c a l meetings, scientific articles i n m e d i c a l journals, scientific p r o grams at m e d i c a l meetings, t h e r a p e u t i c h a n d b o o k s , U . S. P h a r m a c o p e i a , the P . D . R . , p u b l i c a t i o n s s u c h as the Medical

Letter,

and an obvious

source, the m e d i c a l s c h o o l w i t h its u n d e r g r a d u a t e i n s t r u c t i o n a n d increasi n g l y active postgraduate schools for p r a c t i c i n g p h y s i c i a n s .

T h e degree

of i n v o l v e m e n t of the p h a r m a c e u t i c a l i n d u s t r y i n these e d u c a t i o n a l a n d communication mechanisms

varies c o n s i d e r a b l y i n different areas, b u t

c e r t a i n l y its c o n t r i b u t i o n is a major factor. I n a l l of these endeavors perhaps the best representatives the i n d u s try has are the d e t a i l m e n , most of w h o m the p r a c t i c i n g p h y s i c i a n has come to respect a n d enjoy. T h e y b r i n g i n f o r m a t i o n c o n c e r n i n g n e w drugs


272

DRUG DISCOVERY

d i r e c t l y to the p h y s i c i a n i n his office, c l i n i c , a n d h o s p i t a l . T h e s e m e n are t r u l y the p u b l i c relations p e o p l e f o r p h a r m a c e u t i c a l c o m p a n i e s . T h e w i s e d e t a i l m a n regards the p h y s i c i a n as the i n t e l l i g e n t a n d e d u c a t e d i n d i v i d u a l that he is a n d discusses o n l y one or t w o d r u g s at e a c h visit.

He

c a r e f u l l y relates adverse or side effects of the d r u g as w e l l as its therap e u t i c effect a n d advantages. T h e r e l a t i v e l y n e w a n d i n e x p e r i e n c e d m a n w i l l stress the t h e r a p e u t i c advantages a n d t e n d to i g n o r e the effects.

T h e e x p e r i e n c e d m a n w i l l present b o t h sides.

adverse

The physician

tolerates the first a n d w e l c o m e s the latter.


A n i n c r e a s i n g p r o b l e m to the b u s y p h y s i c i a n is finding the t i m e for p o s t g r a d u a t e e d u c a t i o n . T h e d e t a i l m a n is n o e x c e p t i o n . T h e n u m b e r of p h a r a m a c e u t i c a l c o m p a n i e s seems to be i n c r e a s i n g , a n d m o r e t h a n 30 representatives n o w visit m y office as w e l l as m e n f r o m x-ray laboratories, c l i n i c a l laboratories, s u p p l y c o m p a n i e s , s u r g i c a l s u p p l y houses, etc.

Time

s i m p l y does not a l l o w f o r a session w i t h e a c h representative at e v e r y visit, a n d I a m sure that most p h y s i c i a n s h o p e that these m e n r e a l i z e this. E q u a l l y h e l p f u l is the presence of the d e t a i l m e n w i t h t h e i r t e c h n i c a l exhibits at m e d i c a l meetings.

H e r e the p h y s i c i a n , a w a y f r o m his office,

m a y seek the d r u g i n f o r m a t i o n he needs at his leisure. H e is at the meeti n g intent o n p o s t g r a d u a t e e d u c a t i o n a n d is " t u n e d i n " to the l e a r n i n g process. M o s t p h y s i c i a n s seek p o s t g r a d u a t e e d u c a t i o n at every o p p o r t u n i t y to k e e p abreast of n e w k n o w l e d g e a n d techniques.

T h e nearer these

e d u c a t i o n a l p r o g r a m s are to the b u s y p h y s i c i a n s , the better t h e i r a t t e n d a n c e since t h e y c a n c o n t i n u e to serve their patients. T h u s , the p o p u l a r i t y of p o s t g r a d u a t e e d u c a t i o n has i n c r e a s e d i n c o m m u n i t y hospitals.

The

p h a r m a c e u t i c a l i n d u s t r y has p e r f o r m e d a great service i n c o n t r i b u t i n g so generously to these l o c a l seminars. M e n t i o n w a s m a d e p r e v i o u s l y to advertisements i n m e d i c a l journals as a means of c o m m u n i c a t i o n b e t w e e n the d r u g i n d u s t r y a n d the c l i n i c a l p h y s i c i a n . T h i s m e c h a n i s m m u s t rate h i g h o n the v a l u e scale of effectiveness i n p o s t g r a d u a t e e d u c a t i o n , a n d the observant d o c t o r recognizes a d o u b l e c o n t r i b u t i o n i n this source. F i r s t , h e has the o p p o r t u n i t y to scan q u i c k l y f o r names he does not r e c o g n i z e a n d w h i c h he m a y w i s h to p u r s u e f u r t h e r ; s e c o n d l y , he has a v a i l a b l e the benefits of the scientific articles i n a j o u r n a l m a d e e c o n o m i c a l l y possible b y the a d v e r t i s i n g . P e r h a p s the least effective means of c o m m u n i c a t i o n s is one w e l i v e w i t h d a i l y , one w h i c h fills o u r wastebaskets

a n d increases the l o a d o n

our j a n i t o r i a l services—the d i r e c t m a i l i n g s . A c c o r d i n g to D e n o a n d his colleagues i n 1959 ( 4 ) " A n eastern m e d i c a l j o u r n a l r e c e n t l y c o m p l e t e d a s u r v e y w h i c h i n d i c a t e d that the p r a c t i c i n g p h y s i c i a n receives a n n u a l l y b y d i r e c t m a i l m o r e t h a n 4,000 pieces of p h a r m a c e u t i c a l l i t e r a t u r e . "

I

h a v e no accurate statistics to offer f o r I c o u l d find n o n e I felt w e r e v a l i d .


15.

BURKET, JR.

Drugs and

Medical

M o s t pharmaceutical companies probably have b u t I w o n d e r a b o u t their a c c u r a c y .

273

Practice figures

o n this subject,

M y acquaintanceship w i t h physicians

s p a n this l a n d , a n d f r o m p e r s o n a l conversations of the d i r e c t m a i l i n g is never r e a d .

I c o n c l u d e that

most

Occasional worthwhile information

m a y b e missed, b u t there are just too m a n y e m p t y oyster shells to

find

the p e a r l .

New Drugs I suppose the p h y s i c i a n is a b o r n skeptic or perhaps becomes one


i n m e d i c a l s c h o o l for a l t h o u g h he appreciates the benefits of n e w d r u g s , he does not t u r n to t h e m as r a p i d l y a n d as eagerly as his critics w o u l d l i k e to h a v e others believe. H e is a w a r e of possible t o x i c i t y a n d adverse side effects of d r u g s . H e k n o w s that most drugs i n p r o p e r dosage h e l p his patients i f his diagnosis is correct a n d that overdosage p r o d u c e s adverse effects a n d c a n be f a t a l . H e is c o m f o r t a b l e w i t h the drugs he k n o w s w e l l a n d c a n p r e s c r i b e w i t h confidence to p r o d u c e the t h e r a p e u t i c a n d p h y s i o l o g i c effect he desires. T h e m a j o r i t y of c l i n i c a l p h y s i c i a n s m o v e s l o w l y i n u s i n g n e w d r u g s . T h e y m u s t k n o w , specifically, w h a t advantages

a new medication

has

over a c u r r e n t one a n d h o w it w i l l fit into their a r m a m e n t of therapy. T h e y insist o n h a v i n g the i m p o r t a n t facts r e l a t i n g to p h y s i o l o g i c a l a c t i o n , dosage range, adverse effects, a n d possible short a n d l o n g range t o x i c i t y . O n l y t h e n w i l l most change to a n e w d r u g or a d d it to their list for t r i a l . O f t e n the p h y s i c i a n must d e c i d e w h e t h e r the benefits of a c e r t a i n d r u g o u t w e i g h its possible adverse effects. H o w e v e r , he has b e e n m a k i n g s u c h decisions since the days of H i p p o c r a t e s , a n d there is no i n d i c a t i o n that he intends to desert this r e s p o n s i b i l i t y n o w . A r i s t o t l e expressed it well (5).

"It is an easy matter to k n o w the effects of h o n e y , w i n e ,

helebone, c a u t e r y a n d c u t t i n g . B u t to k n o w h o w , for w h o m , a n d w h e n w e s h o u l d a p p l y t h e m — i s no less a n u n d e r t a k i n g t h a n b e i n g a p h y s i c i a n . " T h e difference t o d a y is that there are so m a n y m o r e scientifically v a l i d uses f o r drugs a n d so m a n y n e w drugs to consider.

S t i l l the w i s e

p h y s i c i a n does not m a k e decisions w i t h o u t facts. " E v e r y y e a r , " says p h a r m a c o l o g i s t L o u i s L a s a g n a ( β ) , "300 to 400 n e w f o r m u l a t i o n s h i t the m a r ket, e a c h w i t h a n average l i f e s p a n of w e l l u n d e r five years. these are m e r e l y c o m b i n a t i o n s of o l d r e m e d i e s — t h e r e

M a n y of

are 300 a n t i b i o t i c

preparations o n the market, b u t o n l y a d o z e n or so u s e f u l single a n t i b i o t i c s — b u t i n a n y case the d o c t o r is f a c e d w i t h the o v e r w h e l m i n g task of e v a l u a t i n g these n e w remedies, their c l a i m e d effects a n d side effects, and

i n t e g r a t i n g t h e m into his p r a c t i c e . "

The

young physician today

c e r t a i n l y faces a l i f e t i m e of l e a r n i n g . L e t us look n o w at the d i s p u t e c o n c e r n i n g tradenames a n d generic names f o r d r u g s . T h e average p h y s i c i a n has v i e w e d this t u g - o f - w a r w i t h


274

DRUG DISCOVERY

a m u s e m e n t a n d at times w i t h anger a n d a l a r m . M o s t w h o a d v o c a t e the change to generic p r e s c r i b i n g a n d the d i s c a r d i n g of tradenames are not i n c l i n i c a l m e d i c i n e a n d the " f r o n t - l i n e " of p a t i e n t care.

They simply

do not u n d e r s t a n d nor h a v e they e x p e r i e n c e d d a i l y office p r a c t i c e .

They

h a v e not f a c e d l o n g office schedules a n d evenings filled w i t h emergencies. A n y factor w h i c h w o u l d unnecessarily consume m o r e t i m e w o u l d p l a c e an

o v e r w h e l m i n g b u r d e n o n those w h o c a r r y a major p o r t i o n of

m e d i c a l care l o a d — t h e p r i m a r y p h y s i c i a n .

T h i s i n c l u d e s the

the

general

p r a c t i t i o n e r , the general internist, the g e n e r a l p e d i a t r i c i a n , a n d the gen-


e r a l surgeon. I have no a r g u m e n t w i t h the t h o u g h t that the p h y s i c i a n s h o u l d k n o w the generic n a m e as w e l l as the t r a d e n a m e of the d r u g he prescribes. F u r t h e r m o r e , he s h o u l d k n o w the " f a m i l y " of drugs to w h i c h e a c h belongs. H o w e v e r , to r e q u i r e h i m to w r i t e the u s u a l l y l o n g generic n a m e rather t h a n the u s u a l l y shorter trade n a m e is to me unreasonable a n d a b s u r d . U n d o u b t e d l y , the use of generic p r e s c r i b i n g , i g n o r i n g the q u a l i t y of the d r u g i n v o l v e d , w o u l d result i n some l o w e r i n g of cost to the consumer. H o w e v e r , the m a n - h o u r s lost w o u l d most c e r t a i n l y result i n a n increase i n t o t a l h e a l t h care costs.

T o the economist this m a y seem i l l o g i c a l , b u t

to a b u s y p r i m a r y p h y s i c i a n it makes a great d e a l of sense. I a m f a m i l i a r w i t h a l l of the pros a n d cons i n this controversy, h a v i n g f o l l o w e d it w i t h interest the past f e w years, b u t the s i m p l e s a v i n g of t i m e w i t h o u t d e c r e a s i n g q u a l i t y i n the d e l i v e r y of h e a l t h care d u r i n g this era of h e a l t h m a n p o w e r shortage is the most salient of a l l .

Summary T h e w o r l d of drugs a n d the w o r l d of m e d i c a l care are r e v o l v i n g i n the same d i r e c t i o n w i t h a m a z i n g s y n c h r o n i z a t i o n . I n the w o r l d of m e d i c a l care the c l i n i c a l p h y s i c i a n has a great d e a l of respect a n d g r a t i t u d e for the i n d u s t r y that has p l a c e d at his d i s p o s a l m o r e drugs f o r p r e v e n t i n g a n d t r e a t i n g h u m a n ills t h a n at a n y t i m e i n history. T h e system w h i c h has b e e n d e v e l o p e d to p e r f o r m this task is c o m p l e x b u t f o l l o w s a definite p a t t e r n . It has d e v e l o p e d t h r o u g h c o o p e r a t i o n b e t w e e n the d r u g i n d u s t r y , p r i v a t e a n d p u b l i c m e d i c a l institutions, a n d government. better system i n the w o r l d .

T h e r e is no

It w i l l change as t i m e dictates, b u t the p h y -

s i c i a n has every confidence that it w i l l a l w a y s serve the best interests of the A m e r i c a n p e o p l e . T h e m e t h o d s of c o m m u n i c a t i n g d r u g i n f o r m a t i o n to p h y s i c i a n s f o l l o w m a n y paths to m a n y areas a n d are i m p r o v i n g d a i l y .

A chief c o n c e r n is

the shortage of h e a l t h m a n p o w e r necessary to d e l i v e r the benefits of n e w t h e r a p y to those i n n e e d , b u t this is a p r o b l e m of the w o r l d of m e d i c a l care a n d not the w o r l d of d r u g s .


15.

BURKET, JR.

Drugs and Medical

Practice

275

A t times t h e p h y s i c i a n is a n n o y e d b y too m a n y tradenames f o r t h e same o r a s i m i l a r d r u g , b u t he is g r a t e f u l f o r t h e t r a d e n a m e f o r its ease i n d e t e r m i n i n g q u a l i t y a n d i n p r e s c r i b i n g . H e dislikes i n f o r m a t i o n w h i c h stresses benefits of t h e r a p y w i t h o u t stating c l e a r l y adverse effects, b u t this is c h a n g i n g r a p i d l y . W h a t does t h e c l i n i c i a n expect of the d r u g i n d u s t r y i n t h e f u t u r e ? He

c o n f i d e n t l y expects m o r e m i r a c l e s f o r t o m o r r o w . S u c h ailments as

arteriosclerotic c a r d i o v a s c u l a r disease a n d cancer w h i c h together

with

h i g h w a y accidents a r e today's c h i e f k i l l e r s offer major challenges. T h e


p h y s i c i a n is c e r t a i n that research scientists i n i n d u s t r y a n d p r i v a t e a n d p u b l i c m e d i c a l institutions w i l l c o n t i n u e to find n e w m e t h o d s t o diagnose a n d c u r e disease a n d that the system of d r u g m a n u f a c t u r i n g a n d d i s t r i b u t i o n w i l l b e c o m e e v e n m o r e efficient i n m a k i n g benefits a v a i l a b l e t o a l l .

Literature Cited (1) Barber, B., Ed., "Drugs and Society," The Russell Sage Foundation. (2) Goodman, L., Gilman, Α., "The Pharmacologic Basis of Therapeutics," 2nd ed., Macmillan, New York. (3) Keefer, Chester, "The Contributions of the Pharmaceutical," in "The Medicated Society," S. Proger, Ed., Macmillan, New York. (4) Deno, R. et al., in "Drugs and Society," B. Barber, Ed., The Russell Sage Foundation. (5) Lasagna, Louis, "Drugs through the Ages," in "The Medicated Society," S. Proger, Ed., Macmillan, New York. (6) Lasagna, Louis, "The Doctors Dilemma," in "The Medicated Society." (7) Garland, J., "Dissemination of Information on Drugs to the Physician," in "Drugs in Our Society," P. Talalay, Ed., The Johns Hopkins Press, 1964. RECEIVED November 5, 1970.


Discussion Warren J. Close: T o o p e n this d i s c u s s i o n , I s h a l l b r i n g u p a subject w h i c h has i m p o r t a n t i m p l i c a t i o n s in m a n y of the papers p r e s e n t e d t o d a y —i.e., the cost of research.

I n d e a l i n g with this matter I f e e l that w e are

too often c o n f u s i n g " r e s e a r c h " w i t h "research


q u e n t l y I see

and development."

p u b l i s h e d d a t a l a b e l i n g c e r t a i n costs " r e s e a r c h "

Frewhen,

i n d e e d , the research a n d d e v e l o p m e n t process w a s b e i n g a l l u d e d to.

We

see this in financial analyses, too, a n d w e hear c o r p o r a t i o n heads u s i n g the t e r m " r e s e a r c h " w h e n i n d e e d they m e a n "research a n d d e v e l o p m e n t . " E v e n t o d a y , I n o t e d that some of o u r d i s t i n g u i s h e d panelists r e f e r r e d to " r e s e a r c h " w h e n they m e a n t "research a n d d e v e l o p m e n t . " T h e p o i n t I a m m a k i n g is t h i s : the d e v e l o p m e n t a c t i v i t y has different d i m e n s i o n s f r o m the research a c t i v i t y . If one w e r e to go to a research m a n a n d say, " D i s c o v e r a n e w synthesis

of P e n t o t h a l , " that

scientist

w o u l d not be able to p r e d i c t w i t h a n y degree of a c c u r a c y h o w l o n g i t w o u l d take him to d o this or h o w m u c h it w o u l d cost. H o w e v e r , i f he w e r e to succeed i n d i s c o v e r i n g a n e w process a n d w e r e to b r i n g i t to a d e v e l o p m e n t c h e m i s t a n d say, "I h a v e a n e w w a y of m a k i n g P e n t o t h a l ; h o w l o n g is i t g o i n g to take a n d h o w m u c h is it g o i n g to cost t o i n s t a l l this n e w process," t h e d e v e l o p m e n t c h e m i s t c a n m a k e p r e d i c t i o n s w i t h a n almost u n c a n n y degree of a c c u r a c y .

I t h i n k w e get into a bind w h e n

w e t r y to l u m p these t w o k i n d s of activities together.

I w o u l d l i k e to

refer this c o m m e n t to M r . B l e e ; I w o n d e r if he accepts this thesis

or

disagrees with it. Frank J. Blee: D r . C l o s e raises a v e r y interesting q u e s t i o n . W h e n I say research, I guess I u s u a l l y m e a n research a n d d e v e l o p m e n t , a n d w h a t I m e a n is the a m o u n t of m o n e y that is spent o n the p e o p l e i n the o r g a n i z a t i o n a l chart f r o m d i r e c t o r of research a n d d e v e l o p m e n t o n d o w n to the lab technician.

I n other w o r d s , I refer to the process w h i c h is d e v o t e d

to d i s c o v e r i n g a n d d e v e l o p i n g a new

d r u g p r o d u c t . T h i s is the creative

process of c o m i n g u p w i t h that u n i q u e n e w c h e m i c a l entity. I f e e l that this is the major reason for existence of the R e s e a r c h a n d D e v e l o p m e n t Division—development

meaning

getting

that

product

ready

for

the

market. T h e other s i t u a t i o n D r . C l o s e m e n t i o n s relates to p r o d u c t X w h i c h , let's say, y o u r c o m p a n y has b e e n m a k i n g for five years a n d thinks that i t c a n be m a d e cheaper. or not it c a n be m a d e c h e a p e r

someone

T h e attempt to d e t e r m i n e w h e t h e r

I w o u l d c a l l process

improvement.

276


I

277

DISCUSSION

w o u l d n ' t r e a l l y c a l l this research at a l l because y o u are not i n search of a n e w c o m p o u n d ; y o u are a t t e m p t i n g to l o w e r costs.

A l s o , I m i g h t say

q u a l i t y c o n t r o l — i n other w o r d s , the process that takes p l a c e i n t h e P r o d u c t i o n D i v i s i o n to insure that the p r o d u c t is u p to q u a l i t y — i s n o t research a n d d e v e l o p m e n t . W h a t the i n d u s t r y fails to r e a l i z e is that the figure w e talk a b o u t w h e n w e say 1 0 - 1 1 % of sales are spent o n R & D is a f a i r l y p u r e n u m b e r i n the sense that i t is d e v o t e d to d i s c o v e r i n g a n d d e v e l o p i n g n e w p r o d ucts. N o w the a v e r a g e — a n d this is w h y I k e p t h a m m e r i n g a w a y o n the


f a c t that the p h a r m a c e u t i c a l i n d u s t r y is u n i q u e — t h e average f o r a l l U . S . i n d u s t r y is less t h a n 2 % , w h i c h means that this i n d u s t r y is s p e n d i n g at least 5 or m o r e times the average a m o u n t as a percentage of sales. A n other t h i n g is that a g o o d d e a l of that 2 %

of other industries is c a l l e d

research b u t is often n o t h i n g m o r e t h a n process i m p r o v e m e n t or cost r e d u c t i o n . If i n a c h e m i c a l c o m p a n y that is m a k i n g n y l o n s , for e x a m p l e , someone says, " L e t ' s l o w e r the cost," that's process i m p r o v e m e n t ; it's not research, b u t it m a y s h o w u p i n the R & D b u d g e t . A n o t h e r p o i n t to r e m e m b e r , as D r . C l o s e s a i d , i f y o u are f a c e d w i t h essentially a p r o d u c t i o n cost a c c o u n t i n g p r o b l e m , w h i c h is w h a t process i m p r o v e m e n t or cost r e d u c t i o n r e a l l y is, this is m u c h m o r e p r e d i c t a b l e t h a n the cost of d i s c o v e r i n g a n d d e v e l o p i n g a n e w c o m p o u n d .

Indeed,

if the q u e s t i o n is asked t o d a y , " W h a t is the cost of d e v e l o p i n g a d r u g f o r P a r k i n s o n ' s disease," it w o u l d b e v i r t u a l l y i m p o s s i b l e t o a n s w e r because the l e n g t h of t i m e a n d m a n p o w e r r e q u i r e d are u n p r e d i c t a b l e . H a r r y Yale (to Brian Hoffman): I w o u l d q u e s t i o n y o u r

statement

r e g a r d i n g f a i l u r e to find another d r u g as u s e f u l as q u i n i d i n e . T h e r e is g o o d c l i n i c a l e v i d e n c e that p r o c a i n e a m i d e is a u s e f u l a n d effective m e d i cine.

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

development

based

on

observations

concerning

procaine

in

human

arrhythmias. D r . Hoffman: I don't disagree at a l l w i t h these statements.

I would

stick to w h a t I s a i d i n m y p a p e r , t h o u g h , that the a d v e n t of p r o c a i n e a m i d e , later d i p h e n y l h y d a n t o i n a n d l i d o c a i n e a n d most r e c e n t l y p r o p r a n o l o l , as a n t i a r r h y t h m i c agents was not the result of a n y d i r e c t or d e l i b e r a t e a t t e m p t b y i n d u s t r y to d e v e l o p u s e f u l a n t i a r r h y t h m i c agents. Some chance observations b y c a r d i a c surgeons suggested that p r o c a i n e m i g h t be a u s e f u l a n t i a r r h y t h m i c agent.

T h e subsequent d e v e l o p m e n t of

p r o c a i n e a m i d e is w h a t I w o u l d c a l l a g o o d e x a m p l e of g o a l - o r i e n t e d research i n i n d u s t r y . P r o c a i n e was u s e f u l b u t was f o u n d to have c e r t a i n disadvantages, p r i m a r i l y its short b i o l o g i c a l h a l f - l i f e a n d the ease w i t h which

it p e n e t r a t e d

the c e n t r a l nervous system.

To

overcome

these

obstacles was not too m u c h of a p r o b l e m for a g o o d chemist, a n d so a m o d i f i c a t i o n of p r o c a i n e — p r o c a i n e a m i d e — w a s m a d e .

It wasn't suscep-


278

DRUG DISCOVERY

t i b l e to r a p i d h y d r o l y s i s b y p l a s m a esterases a n d d i d n ' t penetrate r e a d i l y into the C N S a n d thus b e c a m e a g o o d a n t i a r r h y t h m i c

as

drug.

H o w e v e r , this is s i m p l y an i m p r o v e m e n t of a m o l e c u l e w h i c h d i d exist a n d w h e r e the necessary m a n i p u l a t i o n of the m o l e c u l e w a s rather m i n o r . W h a t I was t a l k i n g about this m o r n i n g was c o m p a n y - s p o n s o r e d p r o g r a m s w h i c h h a d as a g o a l the i n t r o d u c t i o n of n e w a n t i a r r h y t h m i c d r u g s .

I

t h i n k that u s e f u l a n t i a r r h y t h m i c d r u g s h a v e not c o m e a b o u t b y s e a r c h i n g for t h e m i n the l a b o r a t o r y .

D i l a n t i n was s h o w n b y M e r r i t t a n d P u t n a m

i n 1938 to be u s e f u l for e p i l e p s y , a n d almost b y c h a n c e it w a s b r o u g h t


into the treatment of c a r d i a c a r r h y t h m i a s . L i d o c a i n e was b r o u g h t i n as a l o c a l anesthetic.

A g a i n almost b y c h a n c e it was f o u n d to b e a u s e f u l

a n t i a r r h y t h m i c , a n d n o w it's u s e d v e r y w i d e l y . So the a d d i t i o n s h a v e b e e n the k i n d of t h i n g that h a p p e n s w h e n s o m e b o d y w h o k n o w s a l i t t l e b i t about p h a r m a c o l o g y a n d m e d i c i n e is u s i n g drugs a n d makes observations that c l u e h i m i n o n other diseases or a b n o r m a l i t i e s w h e r e m i g h t be effective.

they

H o w e v e r , d e v e l o p m e n t of a n t i a r r h y t h m i c s , starting

f r o m scratch, I t h i n k has not s u c c e e d e d yet. I t h i n k one c o u l d say the same t h i n g for m a n y other classes of d r u g s . A s i m i l a r sort of h i s t o r y describes the search for better a n t i a n g i n a l agents than nitroglycerine. over the years.

M a n y c o r o n a r y vasodilators h a v e b e e n

developed

I t h i n k p e o p l e don't r e a l l y f e e l t h e y h a v e m a d e r e a l l y

significant a d d i t i o n s to the treatment

of a n g i n a w i t h t h e m except f o r

changes i n d u r a t i o n of a c t i o n perhaps, a n d this p r o b a b l y is because the benefit that comes f r o m n i t r o g l y c e r i n e is not solely the result of its a b i l i t y to d i l a t e the c o r o n a r y arteries.

W e l l this i n f o r m a t i o n d i d n ' t a c c u m u l a t e

u n t i l about 10 years ago, so for years a n d years p e o p l e t r i e d to d e v e l o p other c o r o n a r y dilators because they assumed that this was the

only

m a n n e r b y w h i c h n i t r o g l y c e r i n e was u s e f u l . N o w I t h i n k m o r e c o m p a n i e s are b e g i n n i n g to l o o k for a n t i a n g i n a l agents that r e d u c e the w o r k of the heart a n d d o other things so it m a y be successful.

So I w o n ' t disagree

w i t h D r . Y a l e , b u t I w i l l stick b y m y guns i n terms of w h a t I s a i d . D r . Yale (to George E . B u r k e t ) : Y o u h a v e stated that "the p h y s i c i a n s do not q u i c k l y p i c k u p n e w d r u g s u n t i l they are c o n v i n c e d of t h e i r m e r i t s . " H o w t h e n d o y o u e x p l a i n the p h e n o m e n a l g r o w t h of some of the recent d r u g entries, some of w h i c h have a h i g h i n c i d e n c e of side effects, f o r e x a m p l e , i n d o m e t h a c i n ? D r . Burket: F i r s t , I t h i n k y o u r e a l i z e that I u s e d the t e r m " m a j o r i t y of p h y s i c i a n s . " W e are a l l a w a r e that some i n d i v i d u a l s i n the m e d i c a l profession use d r u g s q u i c k l y a n d w i t h o u t c a r e f u l c o n s i d e r a t i o n , b u t y o u k n o w w e l i k e to be c o m f o r t a b l e , a n d I t h i n k w i t h o u t k n o w i n g exactly the p h y s i o l o g i c a l effects of a d r u g , its adverse effects, its l o n g t e r m — o r at least its short t e r m — t o x i c effects, w e just don't sleep w e l l at n i g h t w h e n w e give s u c h d r u g s to patients.

A s an e x p l a n a t i o n f o r the specific


279

DISCUSSION

q u e s t i o n I t h i n k the p h y s i c i a n m u s t d e c i d e , as I stated i n m y presentation, w h e t h e r the benefits to a p a r t i c u l a r p a t i e n t — t h e

benefits that h e

will

r e c e i v e — o u t w e i g h p o s s i b l e adverse effects, a n d w e m u s t d o this w i t h a n i n c r e a s i n g n u m b e r of drugs n o w . T h i s is w h y it is so i m p o r t a n t that w e k n o w the adverse effects so that w e c a n m a k e this d e c i s i o n p r o p e r l y . Dr.

Close:

I t h i n k w e ' l l t u r n b a c k to M r . B l e e a g a i n since w e h a v e a

f e w m o r e questions d i r e c t e d to h i m . Is the f a c t that i n d u s t r y p r o m o t i o n a n d d i s t r i b u t i o n costs are t w i c e those of research sufficient e v i d e n c e t h a t they are excessive? W h a t is the s t a n d a r d ? H o w d o other industries c o m -


pare i n cost a n d services?

D o we know? Shouldn't w e k n o w more before

we judge? Mr.

Blee:

F i r s t I d i d n ' t say that they w e r e excessive.

I r a i s e d the

question, a n d I leave it to the i n d u s t r y to p o n d e r this p o i n t .

I d i d say

that o b v i o u s l y the i n d u s t r y m u s t t h i n k they're necessary or t h e y w o u l d not s p e n d the m o n e y .

I w o u l d say that i n general, g i v e n the f a c t that

most other industries s p e n d r e l a t i v e l y l i t t l e o n research, i t is p r o b a b l y v e r y c o m m o n to s p e n d a g o o d d e a l m o r e o n a d v e r t i s i n g a n d p r o m o t i o n t h a n o n research.

E v e n t h o u g h this industry's research b u d g e t is

the

highest i n r e l a t i o n s h i p to sales ( 1 0 - 1 1 % ), its a d v e r t i s i n g is a g o o d d e a l more. I w o u l d say, h o w e v e r , that this is a s p e c i a l k i n d of i n d u s t r y , a n d the i n d u s t r y has to r e a l i z e this.

Y o u ' r e not s e l l i n g a u t o m o b i l e s , y o u ' r e

not s e l l i n g cosmetics, you're not s e l l i n g cigarettes.

There's a s p e c i a l p l a c e

i n the e c o n o m y for this i n d u s t r y ; there are s o c i a l overtones, a n d the econ o m i c s are u n i q u e a n d different.

It is n o t e n o u g h to c o m p a r e i t w i t h

another i n d u s t r y . I w o u l d also say, as I t h i n k w e a l l w e l l k n o w , that there are p l a n s u n d e r w a y w h i c h w o u l d r a d i c a l l y change the d i s t r i b u t i o n system.

For

e x a m p l e , i f drugs are ever i n c l u d e d i n the o u t - p a t i e n t p o r t i o n of M e d i care, i n o r d e r to process the n u m b e r of p r e s c r i p t i o n s that w i l l b e i n v o l v e d ( w h i c h c a n b e 200 or 300 m i l l i o n a y e a r ) , w e are g o i n g to h a v e to c o m e u p w i t h an a u t o m a t e d system to h a n d l e t h e m . T h i s w o u l d p r o b a b l y i n v o l v e slave units i n every r e t a i l p h a r m a c y i n the c o u n t r y f e e d i n g b a c k to c e n t r a l c o m p u t e r s . M y f e e l i n g is t e c h n o l o g i c a l l y this has to c o m e if e v e r y o n e is c o v e r e d i n the n a t i o n , a n d i n d e e d y o u a l l w e l l k n o w t h e y are t a l k i n g about a N a t i o n a l H e a l t h P l a n w h e r e e v e r y b o d y w o u l d

be

c o v e r e d . Just m u l t i p l y that 200 m i l l i o n b y 5, a n d n o w y o u have a h u g e t e c h n o l o g i c a l p r o b l e m w h i c h w i l l o n l y be s o l v e d b y a u t o m a t i o n .

When

that h a p p e n s , y o u c a n h a v e a r a d i c a l change i n the present d i s t r i b u t i o n system. If the i n d u s t r y isn't r e a d y f o r it, this c a n cause s u b s t a n t i a l consequences.

It is i n c u m b e n t u p o n i n d u s t r y to w o r k w i t h the p r o b l e m n o w

because there's no q u e s t i o n that it's a v e r y expensive system.

Again, I'll

not say that it isn't a g o o d system, b u t I w o u l d also say to y o u that the i n d u s t r y has not c o n v i n c e d the g o v e r n m e n t ( a n d I don't m e a n the F D A ,


280

DRUG DISCOVERY

p e r se; I ' m t a l k i n g a b o u t H E W a n d I ' m t a l k i n g a b o u t H E W economists ) that they c a n justify t h e i r a d v e r t i s i n g a n d p r o m o t i o n expenditures.

They

haven't c o n v i n c e d Senator N e l s o n — n o t at a l l . So they've got a lot of w o r k to d o . D r . Close: I w o n d e r i f o u r i n d u s t r y representative, D r . W e s c o e ,

has

a n y c o m m e n t s to m a k e i n r e g a r d to that. D r . Wescoe: N o , I h a v e n o c o m m e n t at this t i m e . D r . Close: I was a l i t t l e s u r p r i s e d that w e r e c e i v e d no d i r e c t e d to D r . Jennings.

questions

A f t e r his presentation, I t o l d D r . Jennings

I


t h o u g h t he gave a v e r y s t r a i g h t f o r w a r d a n d f r a n k p i c t u r e that w a s at v a r i a n c e w i t h the w a y some of us v i e w e d research i n the d r u g i n d u s t r y . I w o u l d l i k e to b e e q u a l l y f r a n k a n d s t r a i g h t f o r w a r d w i t h h i m a n d pose a q u e s t i o n to h i m of m y o w n . D r . Jennings,

y o u h a v e u s e d the phrase, " m o l e c u l a r m a n i p u l a t i o n , "

w h i c h , of course, has s o m e t h i n g of a n u n d e r h a n d e d c o n n o t a t i o n .

Medici-

n a l chemists use the t e r m " m o l e c u l a r m o d i f i c a t i o n " ; w e f e e l that this t e r m is m o r e suitable f o r a process w h i c h w e consider to be a respectable necessary f o r m of research.

and

W e a l l k n o w that v e r y s m a l l m o d i f i c a t i o n s of

molecules c a n result i n q u i t e p r o f o u n d changes i n b i o l o g i c a l a c t i v i t y . T h e steroids are a g o o d e x a m p l e of this; i t doesn't take m u c h o f a change to get f r o m a f e m a l e h o r m o n e to a m a l e h o r m o n e , a n d yet most of us t h i n k the difference is i m p o r t a n t . I w o u l d l i k e to ask D r . Jennings i f h e doesn't r e a l l y b e l i e v e that m o l e c u l a r m o d i f i c a t i o n is a necessary a n d u s e f u l p a r t of the research process? John J. Jennings: O f course i t is. I c e r t a i n l y d i d n ' t m e a n to d o w n g r a d e it at a l l . I t h i n k one of the questions that has b e e n r u n n i n g t h r o u g h the discussions h e r e is research vs. d e v e l o p m e n t .

D r . Hoffman pointed

out that it took m o l e c u l a r m o d i f i c a t i o n or m a n i p u l a t i o n to m a k e p r o c a i n e a useful antiarrhythmic drug.

O f course, I t h i n k this falls

between discovery and development.

somewhere

It is not t r u l y d i s c o v e r y , a n d yet

it is a l i t t l e b i t m o r e t h a n c o s t - l o w e r i n g d e v e l o p m e n t . C e r t a i n l y w e n e e d the m o l e c u l a r m a n i p u l a t i o n s that result i n i m p r o v e d p r o d u c t s i n the sense of the e x a m p l e c i t e d here b y D r . H o f f m a n . D o w e n e e d m o l e c u l a r m a n i p u l a t i o n s that a l l o w us to h a v e m u l t i p l e entries i n t o the same area so that n o w w e g i v e 0.5 m g p e r dose i n s t e a d of 50 m g ? W h a t benefit is there to i n c r e a s i n g the p e r m i l l i g r a m p o t e n c y w h e n side effects are

as i n c r e a s e d

p e r m i l l i g r a m as the

therapeutic

benefits? M y w h o l e a r g u m e n t , a n d I offer it s i m p l y as a p r o p o s a l , is that resources b e so d e p l o y e d that w e m i g h t b e i n a better p o s i t i o n to p i c k u p the leads that h a v e b e e n m e n t i o n e d o v e r a n d o v e r t o d a y . T h e s e leads are t r u l y the origins of i n n o v a t i o n s . I n no w a y d o I d o w n g r a d e the fine techn o l o g i c a l apparatus that exists i n the d r u g i n d u s t r y t o d a y that a l l o w s these


281

DISCUSSION

i n n o v a t i o n s once r e c o g n i z e d to be b r o u g h t to the p o i n t w h e r e they are feasible t h e r a p e u t i c agents. W h a t I ' m t r y i n g to say is that since w e d o accept the studies, the results of scientific studies i n other areas, w h y not i n this area? A n d l e t s just see i f w e are not o v e r l o o k i n g possibilities f o r n e w discoveries. w o u l d h o p e that the l o d e has not b e e n m i n e d out.

I

I w o u l d sincerely

h o p e that there are m a n y n e w discoveries w a i t i n g to be m a d e , a n d m y w h o l e a r g u m e n t is that w e o u g h t to be e x a m i n i n g the apparatus to see w h e t h e r or not there isn't some w a y of i n c r e a s i n g the f r e q u e n c y of these


i n n o v a t i v e discoveries a n d r e c o g n i z i n g t h e m a n d t h e n p u t t i n g t h e m into this m i l l . Dr.

Close: I w o n d e r i f perhaps D r . W e s c o e m i g h t h a v e some c o m -

ments to m a k e o n this same subject. Dr.

Wescoe: I t h i n k p e r h a p s there is another w a y to l o o k at it.

p a r t I agree w i t h D r . Jennings, a n d i n p a r t I disagree.

In

I agree w i t h h i m

i n that the r e d u c t i o n i n s o - c a l l e d n e w c o m p o u n d s is not r e l a t e d p r i m a r i l y to the 1962 a m e n d m e n t s .

I t h i n k w h e n w e b e g i n to date things f r o m that

p o i n t w e r e a l l y m a k e a mistake. T h e fact of the matter is, D r . Jennings, that d i s c o v e r y has b e c o m e m o r e difficult, that p e r h a p s the l o d e has b e e n m i n e d to the p o i n t w h e r e d i s c o v e r y is g o i n g to be less r a p i d t h a n it u s e d to be. T h e p e r i o d i c table of the elements r e a l l y isn't c h a n g i n g , a n d m a n y of the molecules that are possible h a v e a l r e a d y b e e n d i s c o v e r e d , p r e p a r e d , or i n v e s t i g a t e d b y someone. T h i s means we're g o i n g to have to go b a c k over some of the o l d g r o u n d , a n d that is research.

I n fact, O t t o L o e w i w o n the N o b e l p r i z e

o n the basis of an e x p e r i m e n t w i t h the isolated f r o g heart.

This experi-

m e n t h a d b e e n t r i e d a d o z e n times b y others w i t h o u t significant result. T h e o n l y reason it w o r k e d i n his hands is that he u s e d the w i n t e r f r o g a n d not the s u m m e r f r o g . H e w o n the N o b e l p r i z e because he was w i l l i n g to repeat s o m e t h i n g w h i c h someone else h a d a l r e a d y done.

I n just the

same w a y w e w e r e w i l l i n g to repeat the w o r k w h i c h l e d to w h a t y o u c a l l e d a r e j u v e n a t e d s u l f o n a m i d e . F o r that w e m a k e no a p o l o g y b e c a u s e the c o m p o u n d has saved lives. I t h i n k things l i k e that are i m p o r t a n t ; I don't t h i n k that research w o r k that goes b a c k over the o l d fields a n d b r i n g s b a c k s o m e t h i n g that is r e a l l y an i m p r o v e m e n t s h o u l d be d e r i d e d . N o r d o I t h i n k , as y o u i n d i c a t e d just i n passing, that the p e o p l e i n this r o o m , a n d y o u a n d I, represent factions.

W e represent the

entire

system, a system that r e a l l y c a n w o r k together n o w i n m u t u a l trust t h r o u g h a n u n d e r s t a n d i n g of the p r o b l e m s that each of us faces.

We

can't a l w a y s be o n the same side of the l i n e , b u t w e c a n b e together f r o m the s t a n d p o i n t of i n t e g r i t y a n d the t r u t h . T o d a y , d i s c o v e r y is m o r e difficult. R e a d i n g the scientific m a t e r i a l , h a v i n g l i v e d i n a u n i v e r s i t y for 18 years, I a m a w a r e that the great, the


282

DRUG DISCOVERY

m o n u m e n t a l discoveries r e a l l y are not c o m i n g t h r o u g h i n the w a y they d i d i n the past. W e sometimes n e e d a significant b r e a k t h r o u g h i n another area before w e c a n m a k e one i n a field s u c h as ours. B e y o n d that I t h i n k e v e r y o n e s h o u l d k n o w that research institutes 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 do not neglect i n n o v a t i v e research—that

there isn't a n y b o d y

w h o w o u l d rather h a v e a great b r e a k t h r o u g h t h a n w e .

It is that

great

b r e a k t h r o u g h that w e ' r e l o o k i n g f o r w a r d to, b u t it takes a l o n g t i m e to c o m e u p w i t h one. W h e n one does c o m e u p , I c a n assure y o u that there w i l l be some sort of w o r k d o n e b y w a y of m o l e c u l a r r e a r r a n g e m e n t

to


find i n some w a y a better p r o d u c t . F i n a l l y , I w o u l d l i k e to repeat that I b e l i e v e the t h r u s t t o w a r d one m e d i c a t i o n for one i n d i c a t i o n is w r o n g . I t h o u g h t m a y b e D r . B u r k e t w o u l d c o m m e n t u p o n that because I t h i n k the c l i n i c i a n needs the c h o i c e of substances that m i g h t d o n e a r l y the same t h i n g because he m i g h t h a v e a p a t i e n t w h o responds to one better t h a n he does to another.

T h a t is

one of the bases of p h a r m a c o l o g y a n d w h a t someone else m e n t i o n e d this m o r n i n g , the infinite v a r i a t i o n i n b i o l o g i c response. D r . Close: D r . B u r k e t , d o y o u w i s h to c o m m e n t o n this issue? D r . Burket: I hesitate to p u t a p e r s o n a l i n t e r p r e t a t i o n o n D r . Jenn i n g s ' r e m a r k , b u t I have a f e e l i n g that it m a y stem f r o m the f a c t that he was at one t i m e i n c l i n i c a l m e d i c i n e before he a s s u m e d h i s present position.

I n o u r offices i n m e d i c i n e the d e t a i l m e n use this at t i m e s —

this sort of m o l e c u l a r m a n i p u l a t i o n game.

T h e y b r i n g their l i t t l e books

i n w i t h t h e m a n d o p e n t h e m a n d s h o w h o w they have s w i t c h e d the molecules

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

competitor's.

d e a l different f r o m t h e i r

W h e n w e s t u d y it v e r y c a r e f u l l y , sometimes

the

actual

benefits c l i n i c a l l y are not that great, a n d I just w o n d e r i f m a y b e this d i d n ' t affect D r . J e n n i n g s '

attitude

somewhat.

I

d o agree w i t h

Dr.

W e s c o e , h o w e v e r , that w e d o a p p r e c i a t e h a v i n g a c h o i c e of v a l u a b l e d r u g s that w e c a n use w i t h o u r patients because m a n y times w e r u n into sensitivities w i t h one d r u g , a n d w e w o u l d l i k e to h a v e one that does not have these adverse effects b u t s t i l l has the same t h e r a p e u t i c benefit. Question from the floor: I w o u l d l i k e to ask a l e g a l or u n e m o t i o n a l q u e s t i o n of D r . Jennings.

Y o u c i t e d several parts of the m a n d a t e f r o m

C o n g r e s s to the F D A . I ' d l i k e to ask w h e t h e r or not i n c l u d e d i n this m a n d a t e is the j u d g m e n t as to w h e t h e r a n e w m o l e c u l a r m o d i f i c a t i o n is not d e s i r a b l e e v e n t h o u g h it is efficacious a n d safe or r e l a t i v e l y so.

Do

y o u have the m a n d a t e to d e c i d e w h e t h e r the m e d i c a l p r o f e s s i o n has too m a n y diuretics or too m a n y c o m p o u n d s i n a n y other class? D r . Jennings: I ' l l answer the q u e s t i o n d i r e c t l y , t h e n I ' d l i k e to r e t u r n to some of the d i s c u s s i o n that w e n t o n here because I t h i n k that there's some c o n f u s i o n . W e h a v e a f e w questions m i x e d i n together.

F i r s t of a l l ,


283

DISCUSSION

the l a w does not g i v e us a n y a u t h o r i t y to d e t e r m i n e that there are too m a n y of a n y class of d r u g s . I was not s p e a k i n g as a r e g u l a t o r w h e n I a s k e d that w e consider, u n e m o t i o n a l l y a n d scientifically, the q u e s t i o n of w h e t h e r w e are g o i n g a b o u t o u r search f o r n e w d r u g s i n the most efficient way.

N o t o n l y are w e not a l l o w e d to m a k e a d e t e r m i n a t i o n t h a t there

are too m a n y of a p a r t i c u l a r class of d r u g s a n d thus stop a p p r o v a l of f u r t h e r d r u g s i n that class, w e are not even a l l o w e d to m a k e a d e t e r m i n a t i o n that one d r u g is not as effective as other d r u g s i n the same category a n d , therefore, s h o u l d not b e a l l o w e d o n the m a r k e t .


T h e legislative h i s t o r y of the act is q u i t e clear o n this p o i n t , the s o - c a l l e d c o m p a r a t i v e efficacy.

T h i s does not enter i n t o the

argument.

W h a t does enter i n t o it, of course, is the benefit-to-risk r a t i o of a n y d r u g . L e t m e a p o l o g i z e i f I s e e m e d to h a v e s p o k e n s l i g h t i n g l y of m o l e c u l a r m a n i p u l a t i o n . I t h i n k it is not o n l y d e s i r a b l e b u t a b s o l u t e l y necessary i n o r d e r to r e n d e r the d r u g t r u l y u s e f u l . H o w e v e r , s p e a k i n g n o t as one w h o m u s t pass an a p p l i c a t i o n , b u t as one w h o , as D r . W e s c o e p o i n t e d out, is a p a r t of this system a n d is c o n c e r n e d w i t h the u l t i m a t e p r o d u c t i v i t y of the system, I a m c o n c e r n e d w i t h the u t i l i z a t i o n of resources to d e v e l o p another t h i a z i d e that n o w c a n be g i v e n i n s m a l l e r dosages, another p h e n o t h i a z i n e , another c o r t i c o s t e r o i d w i t h no t r e m e n d o u s increase

i n thera-

p e u t i c ratio, n o t r e m e n d o u s increase i n risk-to-benefit r a t i o . M y w h o l e q u e s t i o n to y o u was s i m p l y t h i s — a r e

we overlooking

s o m e t h i n g ? I u s e d a sort of m i l i t a r y a n a l o g y . W e are a t t a c k i n g the p r o b l e m w i t h a massive f r o n t a l a s s a u l t — a h u m a n w a v e sort of t h i n g — w h e n the e n e m y is so elusive that p e r h a p s w h a t w e n e e d is m o r e p a t r o l s o u t there, m o r e scouts, m o r e p r o b i n g e x p e d i t i o n s . M a y b e w e n e e d some w a y to r e c o g n i z e these s e r e n d i p i t o u s

findings.

I t h i n k the starting p o i n t s h o u l d be a v o y a g e of d i s c o v e r y b u t c e r t a i n l y t o w a r d the e n d , or after a c e r t a i n a m o u n t of this t y p e of i n v e s t i g a t i o n , w e m u s t t u r n to the h e a v i l y financed, w e l l e q u i p p e d i n d u s t r i a l l a b o r a t o r y to b r i n g the p r o d u c t to a p o i n t w h e r e it w i l l b e v i a b l e i n today's m e d i c a l a n d e c o n o m i c s i t u a t i o n . T h a t was m y w h o l e p o i n t . I d i d n o t d e c r y the efforts. I a p p l a u d the efforts of i m p r o v i n g p r o d u c t s a n d l o w e r i n g costs, a n d I p o i n t e d out that the t r e m e n d o u s , u n i q u e l y A m e r i c a n t e c h n o l o g y makes i t p o s s i b l e for these discoveries to b e b r o u g h t to a p o i n t w h e r e t h e y c a n b e useful.

B u t o r i g i n a l discoveries have b e e n

d e c l i n i n g since

the

early

1950's, a n d I just suggested that p a r t of the e x p l a n a t i o n m i g h t b e t h a t w e are not p r o v i d i n g the p r o p e r c l i m a t e f o r this t y p e of d i s c o v e r y . A n o t h e r p o i n t was b r o u g h t u p , a n d I m u s t a d m i t that it w a s the first t i m e that I e n c o u n t e r e d it, a l t h o u g h it c a m e u p a g a i n a n d a g a i n : the i d e a of a single entity for a single disease.

I k n o w of no p o l i c y , I k n o w of n o

r e g u l a t i o n , I k n o w of no a u t h o r i t y i n o u r act, I k n o w of n o t e n d e n c y o n the p a r t of the agency, to a d v a n c e that concept.


284

DRUG

DISCOVERY

Glenn Ullyot to D r . Jennings: I t h i n k w e r e a l l g o i n g i n the same d i r e c t i o n , b u t there's a p o i n t that's v e r y m u c h m i s s e d , a l t h o u g h D r . H o f f m a n a n d D r . W e s c o e h a v e a l l u d e d to i t i n some w a y s . W e a l l w o u l d l i k e to get the b r e a k t h r o u g h , b u t w h a t y o u h a v e to s t u d y is h o w some of the r e a l b r e a k t h r o u g h s c a m e about.

W e w o r k w i t h w h a t w e k n o w , a n d it's

l i k e g o i n g i n an e v e r - w i d e n i n g c i r c l e .

L e t ' s just take one r e a l e x a m p l e :

i n studies o n the antihistamines, the p h e n o t h i a z i n e s c a m e a l o n g . It w a s o b s e r v e d that they p r o d u c e d a sedative effect, a n d i t w a s d e c i d e d that this m i g h t b e a n area to p u r s u e . W h e n L a r g a c t i l , the l y t i c c o c k t a i l , c a m e


a l o n g , the c o n c e p t that it w o u l d b e u s e d to treat m e n t a l a n d e m o t i o n a l disease h a d n ' t d e v e l o p e d yet.

It just h a p p e n e d that w h e n w e e v e n t u a l l y

b e c a m e i n v o l v e d ( a n d it w o u l d be a n interesting story t o t e l l y o u h o w that c a m e a b o u t ) L a r g a c t i l (as T h o r a z i n e ) w e n t o n the m a r k e t i n this c o u n t r y f o r t r e a t i n g nausea a n d v o m i t i n g . T h e t r a n q u i l i z i n g effect w a s t h e n d i s c o v e r e d i n the c l i n i c . W e c o u l d not h a v e p r e d i c t e d this. So one w o r k s w i t h the tools that w e h a v e to p r o c e e d f r o m one p o i n t to the next, a n d i n this process w e m a k e these discoveries.

M a n y other examples of

h o w drugs are t r u l y d i s c o v e r e d c o u l d b e g i v e n ; these discoveries are not a l w a y s as r e p o r t e d i n the literature. Question from the floor: W e ' v e h e a r d the t e r m " o r i g i n a l d i s c o v e r i e s " for some t i m e . I w o u l d l i k e D r . Jennings to define " o r i g i n a l d i s c o v e r i e s " because w e a l l k n o w these d o not c o m e as flashes of l i g h t . T h e y are often c o n t r i b u t i o n s of m a n y p e o p l e .

W h a t is y o u r d e f i n i t i o n of an " o r i g i n a l

discovery"? D r . Jennings: I ' m not sure that I c a n give one that w o u l d satisfy e v e r y b o d y , b u t the examples that have b e e n c i t e d here w o u l d suffice.

I

w o u l d say that i t is the p u t t i n g together of a u n i q u e or n e w or n o v e l c h e m i c a l entity for t r e a t i n g a c l i n i c a l disease w h i c h heretofore has not b e e n treated w i t h that p a r t i c u l a r c h e m i c a l entity.

I t h i n k it b o i l s d o w n

to the o r i g i n a l l i n k i n g of a c h e m i c a l entity, since w e ' r e t a l k i n g a b o u t d r u g s , w i t h a c l i n i c a l entity.

The

finding

that i s o n i a z i d e h a d the effect

o n the c e n t r a l nervous system that it d i d is an e x a m p l e of this. q u i n i d i n e a n d a n t i a r r h y t h m i a story is another e x a m p l e .

The

T h e effects of

the corticosteroids o n the i n f l a m m a t o r y process is a f u r t h e r e x a m p l e .

In

contrast to o r i g i n a l d i s c o v e r y of that sort w o u l d b e the f u r t h e r d e v e l o p m e n t a n d refinement of the d r u g . W h e r e this stops b e i n g research starts b e i n g d e v e l o p m e n t I ' l l leave to the economists. p a r t i c u l a r l y care a b o u t that.

and

I ' m not sure that I

M y w h o l e modest p r o p o s i t i o n w a s that w e

m i g h t not b e d o i n g a l l w e c a n to m a k e sure that w e are p r o v i d i n g a c l i m a t e for o r i g i n a l discoveries of this sort a n d t h e n the r e c o g n i t i o n a n d d e v e l o p m e n t of t h e m .


285

DISCUSSION

Dr.

Close:

T h a n k y o u , D r . Jennings.

I b e l i e v e w e h a v e c o v e r e d es-

sentially a l l of the questions w h i c h w e r e s u b m i t t e d to m e . G l e n n , d o y o u h a v e f i n a l c o m m e n t s b e f o r e w e close? Dr.

Ullyot:

I w a n t to t h a n k o u r speakers a n d panelists f o r t a k i n g the

t i m e to c o m e here a n d talk to us t o d a y . W e h a v e r e v i e w e d i n a v e r y t h o r o u g h m a n n e r the system of d r u g d i s c o v e r y a n d d e v e l o p m e n t a n d the


p r o b l e m s associated w i t h it.


Drugs and the Real World of Medical Practice - ACS Publications

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