8/10/2019 Journal of General Internal Medicine Volume 21 Issue 9 2006 [Doi 10.1007%2Fbf02743153] Raymond de Vries; Ca

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J IM

E D I T O R I L S

W hy D isclosure

I n M a r c h 2 0 0 6 , 6 p r e v io u s l y h e a l t h y r e s e a r c h s u b j e c t s

i n L o n d o n w e r e n e a r l y k i l le d i n a P h a s e 1 t r i a l o f a n i n v e s t i -

g a t i o n a l m o n o c l o n a l a n t i b o d y c a l le d T G N 1 4 1 2 . S h o r t ly a f t e r

b e i n g g i v e n t h e i n v e s t i g a ti o n a l d ru g , t h e s u b j e c t s d e v e l o p e d

m u l t i s y s t e m o r g a n f a il u r e a n d w e r e r u s h e d t o a n i n t e n -

s i ve c a r e u n i t a t a n e a r b y h o s p i t a l. 1 T h e s u b j e c t s h a d

b e e n p r o m i s e d 2 0 0 0 ( $ 3 5 00 ) a p i e c e u p o n c o m p l e t i o n o f t h e

t ri a l, w h i c h w a s c o n d u c t e d b y a C o n t r a c t R e s e a r c h O r g a n i z a -

t i o n c a l l e d P a r e x e l. a A c c o r d i n g t o i t s w e b s i t e . P a r e x e l p a r t -

n e r s w i t h c l i e n t s t o a c c e l e r a t e t i m e - t o - m a r k e t , c o n t r o l

d e v e l o p m e n t co s t s , re d u c e r i s k , a n d m a x i m i z e r e t u r n o n

i n v e s t m e n t . - 3

I t i s p h r a s e s l ik e m a x i m i z e r e t u r n o n i n v e s t m e n t t h a t

s h o u l d b e t r o u b l i n g to p o t e n t i a l r e s e a r c h s u b j e c t s . T h e

T G N 1 4 1 2 s t u d y i s o n l y o n e a m o n g a n u m b e r o f r e c e n t i n d u s -

t r y - f u n d e d c l i n ic a l t r i a l s w h e r e f i n a n c i a l i n t e r e s t s h a v e

a r g u a b l y p l a c e d r e s e a r c h s u b j e c t s a t r i s k .

I n D e c e m b e r 2 0 0 5 , n e w s r e p o r t s re v e a l e d t h a t 9 h e a l t h y

s u b j e c t s h a d t e s t e d p o s i ti v e fo r t u b e r c u l o s i s a f t e r t a k i n g

p a r t i n a n i n d u s t r y - s p o n s o r e d t ri a l o f a n i m m u n o s u p p r e s s -

a n t d r u g a t t h e A n a p h a r m r e s e a r c h f a ci li ty in M o n t r e a l . A

l a t e r i n v e s t i g a t i o n r e p o r t e d t h a t 1 1 e m p l o y e e s a t t h e t r i a l

s i t e w e r e a l s o i n f e c t e d . 4

I n N o v e m b e r 2 0 0 5 . i t w a s r e p o r t e d t h a t S FB C , A n a p h a r m ' s

p a r e n t c o m p a n y , h a d p a id u n d o c u m e n t e d L a t i n o

i m m i g r a n t s t o t a k e u n t e s t e d d r u g s i n a c o n v e r t e d M i a m i

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

d i r e c to r w h o s e d e g r e e c a m e f r o m a n o f fs h o r e m e d i c a l s c h o o l

i n t h e C a r i b b e a n . T h e f o r - p r o f it IR B t h a t a p p r o v e d

m a n y S F B C t r ia l s w a s o w n e d b y t h e w i fe o f a n S F B C

v i c e - p r e s i d e n t , s

I n A p r i 1 2 0 0 2 , a c c o r d i n g t o n e w s r e p o r t s , t h e F a b r e R e s e a r c h

C l in i c i n H o u s t o n r e c r u i t e d a h o m e l e s s V i e t n a m v e t e r a n

n a m e d G a r r y P o l s g r o v e f o r a t r i a l o f c l o z a p i n e . T h e t r i a l

w a s f u n d e d b y I v ax C o r p o r a ti o n , t h e n a t i o n ' s l a r g e s t

m a n u f a c t u r e r o f g e n e r i c d r u g s . T w e n t y - tw o d a y s a f t e r

P o l s g r o v e c h e c k e d i n t o t h e c l i n ic , h e d i e d o f m y o c a r d i t i s

i n t h e c a r e o f a n u n l i c e n s e d c l in i c a s s i s t a n t . T h e F D A

a l l o w e d t h e c l i n ic t o o p e r a t e f o r 3 m o r e y e a r s b e f o r e c l o s i n g

i t d o w n . 6

I n F e b r u a r y 2 0 0 4 , T r a c i J o h n s o n , a 1 9 - y e a r - ol d h e a l t h y

v o l u n t e e r , c o m m i t t e d s u i c i d e i n E l i L il ly ' s t e s t i n g f a c i l it y i n

I n d i a n a p o li s , w h i le t a k i n g t h e a n t i d e p r e s s a n t d u l o x e t i n e

( C y m b al ta ) . J o h n s o n h a d n o p r e v i o u s h i s t o r y o f m e n t a l

i ll n es s . S h e w a s b e i n g p a i d $ 1 5 0 / d a y . 7

A d d r e s s c o r r e s p o n d e n c e a n d r e q u e s t s f o r r e p r i n t s t o D r E l li ot t: C e n t e r

f o r B i o e t h ic s , U n i v e r s i t y o f M i n n e s o t a , N 5 0 4 B o y n t o n , 4 1 0 C h u r c h S t .

S E , M i n n e a p o l is , M N 5 5 4 5 5 - 0 3 4 6 e - m a il : e U i o O 2 3 @ t c .u m n . e d u ).

I n M a y 2 0 0 6 , t h e W a s h i n g t o n P o s t u p d a t e d t h e o n - g o in g

s t o r y o f P fi z e r' s 1 9 9 6 t r ia l o f t h e a n t i b i o t i c T r o v a n i n K a n o ,

N i g e ri a . A t le a s t 1 1 c h i l d r e n d i e d i n a c l i n i c a l t r i a l o f T r o v a n ,

w h i c h w a s c o n d u c t e d i n t h e m i d s t o f a m e n i n g i t i s e p i de m i c .

S i x c h i l d r e n d i e d a f t e r b e i n g g i v e n T r o v a n , w h i l e 5 d i e d a f t e r

b e i n g g iv e n a n i n a d e q u a t e d o s e o f t h e c o m p a r i s o n d r u g . A c-

c o r d i n g t o t h e

P o s t ,

a N i g e ri a n g o v e r n m e n t r e p o r t c o n d e m n -

i n g t h e P f iz e r s t u d y m y s t e r i o u s l y d i s a p p e a r e d f or 5 y e a r s

b e f o r e a c o p y w a s f i n a l l y f o u n d a n d l e a k e d t o t h e p r e s s . T h e

l e a k e d r e p o r t s a i d t h a t P f i z er h a d n o t t o l d t h e c h i l d r e n o r

t h e i r p a r e n t s t h a t t h e y w e r e p a r t o f a n e x p e r i m e n t , a n d t h a t

a l e t t e r o f a p p r o v a l f r o m a N i g e r i a n e t h i c s c o m m i t t e e , w h i c h

P f i ze r u s e d t o j u s t i f y i ts a c t i o n s , h a d b e e n c o n c o c t e d a n d

b a c k d a t e d b y t h e c o m p a n y ' s l e a d r e s e a r c h e r i n K a n o . T h e

r e p o r t a l s o s a i d t h a t t h e o r a l f o r m o f T r o v a n w i t h w h i c h t h e

c h i l d r e n i n t h e t r i al w e r e t r e a t e d h a d n e v e r b e e n g i v e n to

c h i l d r e n w i t h m e n i n g i t i s b e f o r e . 8

M e d i c a l r e s e a r c h , o n c e l a r g e ly t h e p r o v i n c e o f a c a d e m i c

r e s e a r c h e r s w o r k i n g i n u n i v e r s it i e s , h a s b e c o m e a m u l t i n a -

t i o n a l c o r p o r a t e e n t e r p r i s e . O n l y a b o u t a q u a r t e r o f c l i n i ca l

t r ia l s n o w t a k e p l a c e i n a c a d e m i c s e t t in g s ; a c a d e m i c r e s e a r c h -

e r s t h e m s e l v e s h a v e c o n s i d e r a b l e f i n a n c i a l t i e s t o i n d u s t r y ;

a n d e v e n t h e e t h i c s r e v i e w o f c l i n ic a l t r i a l s h a s b e c o m e a m a j o r

c o m m e r c i a l e n te r p r i s e . C l ea r ly t h e e n o r m o u s a m o u n t o f m o n -

e y a t s t a k e i n m e d i c a l r e s e a r c h t o d a y p r e s e n t s p o t e n t i al s u b -

j e c t s w i t h a p r o b le m . H o w c a n a r e s e a r c h s u b j e c t b e s u r e t h a t

t h e e m p h a s i s o n r e t u r n o n i n v e s t m e n t w i ll n o t t r a n s l a t e in t o

a d a n g e r o u s t r ia l ? A r e s u b j e c t s e v e n a w a r e t h a t t h e i n v e s ti g a -

t o r s c o n d u c t i n g t h e t r i al s m a y h a v e a c o n s i d e r a b l e f i n a n c i a l

s t a k e i n t h e r e s e a r c h ?

A s r e p o r t e d i n t h i s i s s u e o f th e J o u r n a l , W e i n f u r t e t a l . 9

d e c i d e d t o p u t t h e s e q u e s t i o n s d i r e c t ly t o r e s e a r c h s u b j e c t s

t h e m s e l v e s . I n a s e r i e s o f f o c u s g r o u p s , W e i n f u r t a n d h i s c o l -

l e a g ue s a s k e d s u b j e c t s w h a t t h e y w o u ld w a n t t o k n o w a b o u t

c l i n ic a l r e s e a r c h e r s ' f i n a n c i a l i n t e r e s t s . W h a t d i d t h e y f i n d ?

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

n o i d e a w h a t t o t h i n k . S o m e s u b j e c t s a p p a r e n t l y d o n o t w a n t t o

k n o w a b o u t c o n f l ic t s o f i n t e re s t ; o t h e r s s a y t h e y d o w a n t t o

k n o w a b o u t c o n f l ic t s of i n t e r e s t, o n t h e g r o u n d s t h a t t h i s

k n o w l e d g e w i ll h e lp t h e m m a k e b e t t e r d e c i s io n s ; a n d s t il l

o t h e r s d o n o t u n d e r s t a n d e n o u g h t o k n o w w h a t t h e y w a n t .

A c k n o w l e d g i n g t h i s c o n f u s i n g r e s u l t, t h e a u t h o r s c o n c l u d e

o n a r a t h e r e q u i v o c a l n o t e : ' T h i s d o e s n o t n e c e s s a r i l y m e a n . . . -

t h a t d i s c l o s u r e s s h o u l d n o t b e m a d e .

W h a t a r e w e t o m a k e o f th e s u b j e c t s w h o s i m p l y d o n o t

w a n t t o k n o w a b o u t a r e s e a r c h e r ' s c o n f l ic t s o f i n t e r e s t ? W e i n -

f u r t a n d h i s c o l l e a g u e s w r it e t h a t t h e s e s u b j e c t s a p p a r e n t l y

a s s u m e t h a t i g n o r a n c e i s b l i s s. P e r h a p s , b u t it i s n o t ir r a-

t i o n a l o f t h e m t o d i s t r u s t d i s c l o s u r e a s a r e m e d y f o r c o n f li c t o f

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interest. In fact, the most interes t ing research yet publ ished on

conflict of interest, fro m a group at Car negie Mellon, sug ges ts

tha t t hese sub jec t s who do no t hea r d i sc losures may make

bet ter decisions than those who h ear them. lo Not only has this

re sea rch cas t doubt on the a ssumpt ion tha t d i sc losure i s a

good remedy for confl ict of interest; i t sugge sts that disc losure

may m ak e the effects of the conflicts even worse.

In the Carnegie Mel lon study, res earche rs devised an ex-

periment where one group of people was inst ru cted to look

from a dis tanc e at large jar s fi l led with coins. These people,

cal led est imators, were asked to est imate how much mon ey

the jars had in them. The c loser an est imator came to the r ight

amou nt , the more money that part icular est imator would get.

Thus the est imators had a st rong f inancia l incent ive to get

thei r est im ates r ight .

Anot her group, the so-called advisors, had a different

job. Their job was to get closer to the jars , look at the coins

more carefully, and th en give written advice to the es timat ors.

But the advisors had a different set of financial incentives.

They were paid accordi ng to how high t he i r e s t ima tors

guessed. That i s , they were given f inancia l incent ives based

not on how close to the t ruth thei r est imators got , but on

how high thei r est imators ' gues ses were . Thus, they had an

incentive to give mislea ding advice.

The resu l ts? Predictably, wh en the es t imator s l i stened to

the adv i sors , t hey made h ighe r guesses . Tha t was unsurp r i s -

ing, as the advisors were being paid to advise them to gues s

high. Less predictable, however, was th e effect of disclosu re.

When the advisors disc losed to the est imators that they were

get t ing paid to have them guess high, the disc losure did not

lead the e st imator s to gues s any lower. They st il l guesse d high,

even though they had been told that thei r advisors had a

confl ic t of interest . Disclosure did not m ake t he est imator s

any more skept ical .

Perhaps even more interest ing was the effect of disc losure

on the advisors th emselves. Once the advisors disc losed thei r

conflicts, their advice got even worse. They started giving ad-

vice that was even more biased tha n before. I t was as i f dis-

c losure had given them moral l icense to exaggerate . The

Carnegie Mellon aut hor s of the stud y conclude that coming

clean leads to playing dirtier. ' '11 They argue tha t the soluti on

to the bia s creat ed by of conflict of inte res t is not simp ly to

disclose the confl ict , which ma kes the bias even worse . Rather ,

the solution is to eliminate the financial conflicts.

The im portan t e thical quest i on ra ised by conflic ts of in-

terest i s not . as Weinfurt as his col leagues seem to ass ume,

Should resear chers disc lose? but ra ther Why has disc losure

become s uch a pop ular way of managi ng f inancia l confl ic ts of

interest in medicine? The standar d, boi lerpla te answer to this

quest ion is that researc hers must disc lose in order to show

respect for persons. Respect for pers ons deman ds th at re-

searchers provide a l l re levant informat ion to would-be re-

search subjects so that thei r decisions to part ic ipate {or to

refuse) i s made in ful l and open aware ness of a ll the r isks they

are as sum ing . However, a more cynical explanat ion of the pop-

ular i ty of disc losure sugges ts that i t i s a remedy for f inancia l

conflicts of intere st th at allows those conflicts to st ay in place.

Thus i t does nothing to threat en the exist ing fundi ng arrange-

men ts for c linical research.

In the hand s of many re search e thic ists , respect for per-

sons becomes synon ymou s wi th autonomy, the r ight of a

research subject to choose or refuse to take part in a t r ia l. This

easy t ransla t ion of respect into autonomy al lows researchers

to ignore the problems that are part and parcel of indust ry -

funde d research. The obl igat ion of resear chers to thei r sub-

jects i s reduced to a process of plying subje cts wi th informa-

t ion, including informat ion about funding. Autonomy has

replaced the overweening pater nal is m of medicine wi th a new

kind of distant paterna l ism where researchers , like a distan t

fa ther , rem ain a loof and detached. The h elpl essn ess of re-

searc h sub jects in the face of medical power is t rans forme d

into helples snes s in the face of incompr ehensib le and mislead-

ing informat ion.

What i s being overlooked here is the need to protect the

welfare of potent ia l researc h subjects. The real problem raised

by indus t ry- funde d re sea rch i s t ha t t he pursu i t o f f inancia l

gain might lead researchers to place subjects a t r i sk in dan-

gerous s tudies. Re search ers have yet to f ind a way to disc lose

thei r f inancia l confl ic ts of interest th at shows a t rue respect for

the varied needs of would-be subjects, b ut even i f they --or

some hard-work ing research e thic is ts--dis covered the ideal

way to disclose, subje cts would sti l l need to be protect ed from

dang erou s t r ia ls . The work of Weinfurt mad his col leagues and

the resea rcher s a t Carnegie Mellon sug ges ts that shou ld we

are placing far too much fa i th in disc losure as a mean s of

protection. Dis closur e works like a warn ing flag: it alerts us

of potent ia l problems, bu t i t does no t f ix them. For that , we

need to look e lsewh ere .-- Ray mond De Vries, x Carl E l l i o t t 2

]Bioethics Program University of Michigan School of Medicine

Ann Arbor MI USA; 2Center or Bioethics University of Minne-

sota Minneapolis MN USA.

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2. The consent form for the trial can be found at web address: http://

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2006.

3. AbramsonJ. Guarding the h uma n guinea pigs. Los Angeles Times. April

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