14
and t hat i s what I di d my Ph. D. on:
t he anat omy and t he
phar macol ogy of t he post er i or pi t ui t ar y gl and of t he ni ne- banded ar madi l l o. The ar madi l l o i s not one of your common l abor at or y ani mal s, I can assur e you.
I coul d say t hat nobody bef or e or si nce has
wor ked on i t , but t hat i s not qui t e t r ue.
I t was of some
i nt er est , because f or some r eason or anot her t hey al ways had genet i cal l y i dent i cal quadr upl et s, so t he genet i ci st s wer e i nt er est ed.
Then, l o and behol d, about 1972 i t was di scover ed
t hat t he ar madi l l o i s t he onl y ani mal t hat can be ext ensi vel y i nf ect ed wi t h l epr osy.
Her e was an ani mal t hat coul d be used i n
st udyi ng l epr osy, t he l esi ons and al l , and t he dr ugs t hat mi ght be ef f ect i ve.
So l i ke t he post er i or pi t ui t ar y, t he ar madi l l o
came i nt o i t s own. f r om about 1960.
I mi ght add anot her ver y st r ange coi nci dence, A doct or i n I sr ael who was t r eat i ng l epr osy
pat i ent s f or sl eepl essness f ound qui t e acci dent al l y t hat t hal i domi de r el i eved t hei r pai n and caused r egr essi on of t he l esi ons.
Today t hal i domi de i s one of t he mai n dr ugs used i n
t r eat i ng l epr osy, whi ch i l l ust r at es t hat even t he wor st of dr ugs may be used under cer t ai n ci r cumst ances wher e t he r i sks ar e j ust i f i ed. I di d my Ph. D. on t he adul t ar madi l l o, r ecei vi ng my degr ee i n 1938, and t hen a year ' s post - gr aduat e st udy on why t hese t wo l obes wer e separ at e.
That meant st udyi ng t he embr yos.
Ar madi l l os have a ver y wei r d cycl e and t her e i s no way t hey can
15
be br ed i n t he l abor at or y. at t hat t i me.
We had t o get our suppl i es f r om Texas
Possi bl y t hat i s st i l l done.
Ther e was an
ar madi l l o f ar m i n Texas, ver y cl ose t o t he Lyndon Bai nes J ohnson r anch.
They used t o shi p t he ar madi l l os up t o us.
On one
occasi on when I want ed t o st udy embr yo ar madi l l os, I had t o go down t o t he ar madi l l o f ar m i n Texas t o hunt and cat ch a f ew t o get my embr yoni c ar madi l l os. Bef or e I l eave t hi s per i od of gr aduat e wor k, I woul d l i ke t o descr i be t wo pi eces of wor k whi ch act ual l y I di d out on t he West Coast .
One was wor k wi t h whal es, and t he ot her was i nvol ved t he
l i ng cod, r at her di f f er ent ani mal s.
As I ment i oned, Dr . Gei l i ng,
my maj or pr of ess or at Chi cago, had f ound t hat t he whal e pi t ui t ar y had onl y t hese t wo l obes and even bef or e he came t o Chi cago, he had l ocat ed t he whal i ng st at i ons i n t he Queen Char l ot t e I sl ands, one i n t he nor t her n i sl and at Naden Har bor and one at t he sout h at Rose Har bor .
Each summer , he woul d t ake st udent s or guest s,
pr of essors or t echni ci ans, out t o t he whal i ng st at i ons and col l ect pi t ui t ar i es, pl us ot her or gans.
Once peopl e knew we wer e
doi ng wor k on whal es, t hey sai d "Oh, pl ease, br i ng me back an adr enal or pl ease br i ng me back a hear t . "
Hear t s, whi ch wei ghed
200- 300 l bs. , coul d not be br ought back, but st i l l we al ways t r i ed t o obl i ge. Dur i ng t wo summer s I got t o go t o t he whal i ng st at i on at Rose Har bor .
Once was wi t h a medi cal st udent who t ook good
phot ogr aphs.
The second t i me, I was by mysel f .
The vi si t or s
16
woul d st ay at t he manager ' s house, eat i n t he bunkhouse wi t h t he manager i al st af f , and t hen we wer e f r ee t o wander ar ound t he whal i ng pl ant s and get mat er i al as we want ed. The whal es wer e caught by 90- f oot boat s.
I t hi nk t hey had a
cr ew of about 11 or 13, and t he har poon gun was at t he bow.
Now
t he gr eat advent ur e each year , f or t he sci ent i st s goi ng out t her e, was t o be abl e t o go out i n t he whal e boat .
The f i r st
year I was t her e, I hear d ever y excuse under t he sun, " I t was a bad day, t hi s, t hat , and t he ot her , " and I coul d not go i n t he boat .
The second year I was abl e t o go and I t hi nk, i n par t , i t
was because t he son of t he manager was spendi ng hi s summer s wor ki ng on t hat boat , and he was t o keep an eye on me.
I t was a
l ovel y day, ear l y i n t he mor ni ng, and he ver y ki ndl y t ook me up i n t he bar r el wi t h hi m and we spot t ed a sper m whal e.
The
di f f er ent ki nds of whal es can be di st i ngui shed by t he spout .
I
cannot r emember t he di f f er ences now, but I know t hat i s how you t el l .
We di r ect ed t he hel msmen, t he har pooner , and ever yt hi ng,
and we got t he whal e.
Now, I di d not r eal i ze how l ucky I was,
because I l ear ned t he r eason I had not been abl e t o go bef or e was t hat whal er s ar e ver y super st i t i ous, and one of t he super st i t i ons was t hat havi ng a woman on boar d a whal i ng vess el br i ngs bad l uck.
Thi s was i mpor t ant t o t he cr ew because a cer t ai n amount of
t hei r pay was based on t he number and t ype of whal e t hat was caught .
At l east I t hi nk I br oke t hat j i nx.
I di d scor e anot her
mar k f or women i n t hat I was t he onl y sci ent i st t aken out on
17
t hese whal i ng expedi t i ons who was not vi ol ent l y seasi ck. The second vent ur e on t he West Coast , i nvol vi ng t he l i ng cod, was of a somewhat di f f er ent nat ur e.
I t had t o do wi t h t he
f act t hat i t was known t hat t he pancr eas had a r at her unusual l y hi gh l evel of zi nc i n i t compar ed t o ot her par t s of i t s body.
It
was not a dr amat i cal l y hi gh amount , and i t was qui t e di f f i cul t t o measur e because i t was so sl i ght .
But i t was di st i nct l y hi gher
t han i n cer t ai n ot her par t s of t he body. pi t ui t ar y, r eal l y i s a t wo- par t or gan.
The pancr eas, l i ke t he Ther e i s t he mai n body,
t he mai n pancr eas, t hat secr et es t he di gest i on enzymes and pour s t hem i nt o t he i nt est i ne, and t hen scat t er ed amongst t hese ar e l i t t l e i sl et s of t i ssue t hat wer e l ong t hought t o be wher e i nsul i n came f r om.
But t hi s was pr et t y har d t o pr ove because,
when t he pancr eas was gr ound up, t he enzymes at e up t he i nsul i n so t her e was not hi ng t o be measur ed.
That was a pr obl em.
The quest i on of wher e t he i nsul i n came f r om was sol ved ver y neat l y by Dr . Macl eod, who was at t he Uni ver si t y of Tor ont o, and l at er , of cour se, got t he Nobel Pr i ze f or hi s wor k on i nsul i n. He was awar e t hat i n cer t ai n f i sh t he i sl et t i ssue was an ent i r el y separ at e or gan ( a l i t t l e sor t of pea- l i ke body) qui t e apar t f r om t he r est of t he pancr eas.
He ext r act ed t hese l i t t l e
i sl et s and sur e enough he was abl e t o get t he bl ood sugar l ower i ng ef f ect of i nsul i n.
That cl i nched t he quest i on of
whet her t he i nsul i n came f r om t hese t i ssues. Dr . Gei l i ng and Dr . E. W. Schoef f el , a mi cr ochemi st at t he
18
Amer i can Medi cal Ass oci at i on wer e cur i ous as t o whet her t hi s was act ual l y i n t he par t of t he pancr eas excr et i ng t he enzymes or i n t he par t t hat made t he i nsul i n.
They t hought one way t o f i nd out
woul d be t o go back t o t he f i sh t hat had t hese separ at e or gans, and anal yze t hem.
Ther e was a publ i c Canadi an publ i cat i on t hat
descr i bed t hi s, and t he l i ng cod was one speci es t hat had t he separ at e pancr eas. I had j i gged ( not ver y successf ul l y) f or l i ng cod of f Mi l l Bay.
So I r at her r ashl y vol unt eer ed t o col l ect i sl et t i ssue
dur i ng my summer vacat i on.
I set of f wi t h t hese bot t l es,
pr eser vat i ves, and so on.
They had t o be expl ai ned t o t he
cust oms, whi ch was a l i t t l e di f f i cul t , but I di d, and I knew wi t h my l uck i n f i shi ng I coul d not possi bl y get enough by j i ggi ng.
I
went t o see wher e t he commer ci al l i ng cod f i shi ng was done, i n Myst er i a.
Thi s was i n 1937 or 1938, I am not qui t e sur e.
t ol d i t was al l done by J apanese f i sher man. f r i end, Commander Guy Wi ndeyer .
I was
Then I t hought of my
I knew he spoke J apanese
f l uent l y and I knew he was f r i ends wi t h many of t he pr omi nent , wel l known J apanese i n t he ar ea.
Sur e enough, i n next t o no
t i me, he had f i xed wi t h t hi s ver y f i ne f i sher man, t o pi ck us up at Cr of t on or Chemai nus at dawn.
Guy Wi ndeyer , mysel f , and my
young br ot her went , and Guy Wi ndeyer ’ s ni ece was al so, I r emember , anot her one on t hi s expedi t i on. London.
She was a vi si t or f r om
The f i sher men woul d sl aught er f or t he weekl y mar ket ,
t ens or hundr eds, I do not know how many, of t hese cod and t he
19
ent r ai l s woul d be spr ead out al l over t he deck.
Ther e we wer e
down l i ke soot hsayer s por i ng over t he ent r ai l s l ooki ng f or t hese t i ny l i t t l e nubbi ns of t i ssue.
We di d get enough of t hem, sent
t hem back, and sur e enough t he zi nc was i n t he i sl et t i ssue and not i n t he aci nar t i ssue. Now l et me descr i be my f i r st i nt r oduct i on t o pr obl ems wi t h new dr ugs.
That occur r ed not l ong af t er I had come t o t he
Uni ver si t y of Chi cago.
I n f act i t was i n Sept ember of 1937.
Thi s i s known as t he " El i xi r of Sul f ani l ami de Tr agedy" and t hi s was t he equi val ent of t he t hal i domi de t r agedy but at an ear l i er dat e.
I shoul d expl ai n t hat t he U. S. f ood and dr ug l aws came i n
1906, but t hey wer e pr i mar i l y di r ect ed t owar ds f oods.
Foods wer e
t hen usual l y pr epar ed i n t he homes, but t hey wer e begi nni ng t o be mass pr oduced.
Ref r i ger at i on was poor , t he f oods wer e f i l l ed
wi t h pr eser vat i ves, and so on.
They wer e ver y unheal t hy and
unpl easant , so t he l aws wer e t o make t hi ngs bet t er i n t hat l i ne. Wi t h r egar d t o dr ugs, t her e wer e not many dr ugs avai l abl e, because Amer i ca had been busy wi t h t he Ci vi l War , medi ci ne was at a pr et t y l ow ebb, and most of t he dr ugs wer e nost r ums, pat ent medi ci nes, and so on.
Ther e was one ser i ous pr obl em, many of t he
dr ugs cont ai ned ( al t hough i t was not i n t he l abel i ng or anyt hi ng) such addi ct i ng subst ances as mor phi ne, her oi n, mar i j uana, and so on.
I have r ead st at i st i cs t hat t he r at e of addi ct i on i n t hose
days was as hi gh as i t i s now, but , of cour se, peopl e wer e not awar e t hen t hat t hey wer e i nadver t ent l y t aki ng t hese addi ct i ng
20
dr ugs.
So one of t he r equi r ement s of t he 1906 Act was t hat t he
pr esence of al l 13 of t hese subst ances had t o be not ed i n t he l abel i ng and t he second was t hat t he dr ugs s houl d be l abel ed honest l y.
Resear ch i n dr ugs pi cked up dur i ng Wor l d War I and
af t er war ds.
Ther e wer e a l ot of new and act i ve dr ugs and some
qui t e t oxi c ones, but t he ol d l aw st i l l hel d ( al t hough many peopl e t r i ed t o change i t , qui t e unsuccessf ul l y) , and t hen came t hi s epi sode. Sul f ani l ami de had been i nt r oduced about 1933 i n Ger many.
It
was t he wonder dr ug; i t compl et el y changed t he f ace of medi ci ne. Her e was somet hi ng t hat woul d act ual l y at t ack some i nf ect i ous ger ms and save many l i ves.
Peopl e, who pr evi ousl y woul d have
di ed of pneumoni a, or st r ept ococcus or st aphyl ococcus i nf ect i ons and so on, wer e saved by t hi s new dr ug.
I t caught f i r e, and i t s
use spr ead ver y r api dl y al l over t he wor l d, so f ast t hat no basi c sci ent i f i c wor k had r eal l y been done on t hi s dr ug.
But i t had
dr awbacks, t he pat i ent had t o t ake a l ar ge dose, t he pi l l s wer e pr et t y unpal at abl e and di sagr eeabl e t o t ake, i t caused gast r oi nt est i nal upset s, and so on. One manuf act ur er had a gr eat i dea.
I t was deci ded t o put up
a l i qui d sol ut i on, whi ch woul d be easi er t o t ake and woul d be par t i cul ar l y agr eeabl e t o chi l dr en.
Now t he dr ug i s not sol ubl e
i n ei t her al cohol or wat er , whi ch most dr ug sol ut i ons ar e made up i n, so t he company of f i ci al s had t hei r chemi st s go al ong t he shel f and f i nd a sol vent t hat woul d di ssol ve t he sul f ani l ami de.
21
I guess t he f i r st t hi ng t he manuf act ur er f ound t hat was successf ul was di et hyl ene gl ycol , whi ch i s ant i f r eeze.
Thi s was
never t est ed i n ani mal s and t he l i qui d f or m of t he dr ug was j ust put r i ght on t he mar ket .
A l i t t l e pi nk col or i ng and a l i t t l e
cher r y f l avor i ng was put i n i t , and i t sol d l i ke wi l df i r e. I t was a gr eat boon especi al l y i n t he Sout h wher e t hey l i ke l i qui d medi ci nes and f i nd t hem easi er t o t ake, and of cour se i t i s easi er f or chi l dr en t oo.
Then, t he r epor t s came i n of f at al i t i es.
One
doct or i n a smal l t own had f i ve pat i ent s di e i n a shor t space of t i me.
They had al l t aken t hi s dr ug.
Peopl e knew so l i t t l e about
sul f ani l ami de t hat t hey wer e not sur e whet her i t was t he sul f ani l ami de or t he sol vent t hat was causi ng t he deat hs. The Food and Dr ug Admi ni st r at i on i mmedi at el y went ar ound and sei zed al l t he st ocks i n bot t l es t hat i t coul d get .
But t hey di d
not have t he sci ent i f i c st af f or exper t i se at t hat t i me t o use i n r unni ng t he cul pr i t t o ear t h nor di d t hey have t he l abor at or y f aci l i t i es.
Dr . Gei l i ng had wor ked wi t h t he Food and Dr ug
Admi ni st r at i on pr evi ousl y, when he had been i n Bal t i mor e, hel pi ng t hem i n ot her cases, some of whi ch he used t o descr i be i n hi s t oxi col ogy cl asses. out ! "
So t he FDA cal l ed hi m up and sai d " Hel p us
He sai d he cer t ai nl y woul d, and i n t hi s i nst ance, he
wor ked ver y cl osel y wi t h t he Amer i can Medi cal Ass oci at i on, whi ch i n t hose days had ver y good l abor at or i es and ver y good peopl e eval uat i ng new dr ugs. Dr . Gei l i ng i mmedi at el y set up ani mal st udi es f or acut e and
22
chr oni c t oxi ci t y- - dogs, r abbi t s, r at s, and, I t hi nk, some monkeys.
He coul d see t he i mpor t ance of t hose cases.
None of
t he r est of us r eal l y coul d, I suppose bei ng f ai r l y new i n t he ar ea.
And he was wel l awar e of t he i nadequacy of t he 1906 l aw.
So he r equi r ed t hat al l t he gr aduat e st udent s pi t ch i n and pl ay some r ol e, smal l t hough i t mi ght be, i n t hese ani mal exper i ment s. My par t i cul ar t ask was t o wat ch t he r at s.
Dr . Gei l i ng set
up cages of r at s and t hey wer e si t t i ng- - I can see t hem yet - - on bi g gl ass f unnel s t hat l ed i nt o gl ass beaker s, gr aduat ed cyl i nder s, t hat measur ed t he vol ume of ur i ne. var i ousl y t r eat ed.
The r at s wer e
One l ot , f or exampl e, got t he sul f ani l ami de
al one; one t he di et hyl ene gl ycol al one; one got t he ext r act of what was sol d on t he mar ket ; one got t he f l avor i ng and mat er i al s; and one got a l i qui d wi t h not hi ng wr ong wi t h i t at al l .
Fi nal l y
t he l ast l ot got t he mi xt ur e we made up i n t he l abor at or y, di et hyl ene gl ycol and sul f ani l ami de.
I n no t i me at al l , i t was
per f ect l y appar ent t hat i t was t he di et hyl ene gl ycol t hat was at f aul t .
For al l t he r at s get t i ng mi xt ur es wi t h di et hyl ene gl ycol
i n t hem, one coul d see t he ur i ne gr adual l y t ur n r ed, and t hen decr ease i n vol ume, and t hen f i nal l y st op, because t he pr obl em was wi t h t he ki dneys.
The r at s soon di ed, j ust as t he ki ds di d.
Thi s pr eci pi t at ed pass age of t he 1938 Food and Dr ug l aw, whi ch was s t i l l i n ef f ect i n 1960 when I went t o wor k wi t h t he Food and Dr ug Admi ni st r at i on.
The 1938 l aw r equi r ed t hat bef or e
a new dr ug was put on t he mar ket , t he sponsor , or t he
23
manuf act ur er , must gi ve evi dence of why he t hought t hat t he dr ug was saf e f or i t s pr oposed use or uses.
The t ype of evi dence t hat
he was r equi r ed t o pr esent was f i r st t he chemi st r y; what was t hi s dr ug, how was i t br oken down, how was i t st or ed, t hi ngs l i ke t hat .
The second was t he ani mal t est s t hat he had done, and t he
t hi r d was t he cl i ni cal st udi es.
I f t he agency f el t t hat t hose
wer e sat i sf act or y t hen t he dr ug coul d be mar ket ed. Bef or e l eavi ng sul f ani l ami de, I woul d l i ke t o not e one i nt er est i ng mat t er , and t hat i s t hat at about t he t i me t he Amer i can company was consi der i ng put t i ng t hi s dr ug on t he mar ket , a Canadi an f i r m pet i t i oned t he Canadi an Food and Dr ug di r ect or at e f or per mi ssi on t o change t he sol vent i n t hei r vani l l a ext r act f r om al cohol t o di et hyl ene gl ycol .
The f i r m f el t t hat t he l at t er
was a good subst ance f or a sol vent , but al so t hat i t woul d avoi d exci se t ax.
Ast ut e phar macol ogi st s i n t he Canadi an gover nment
l abor at or i es sai d " We don' t know anyt hi ng about t he t oxi ci t y of t hi s di et hyl ene gl ycol , l et us get a l i t t l e mor e backgr ound. " Then, of cour se, t he wor d on t he el i xi r came out and t he Canadi an manuf act ur er qui ckl y wi t hdr ew hi s pet i t i on.
I t hi nk i t
i l l ust r at es t hat by car ef ul wor k wi t h ani mal s, somet hi ng l i ke t he el i xi r sul f ani l ami de t r agedy can be avoi ded.
I n t hat i nst ance,
pr obl ems woul d have shown up i n j ust a f ew r at s. Af t er get t i ng my Ph. D. i n 1938 and a year or t wo of post gr aduat e wor k, t he j ob si t uat i on di d not l ook much bet t er . The Depr ess i on was st i l l on.
I di d have one or t wo
24
oppor t uni t i es.
One was t hat I t hought I mi ght be abl e t o go back
t o Canada, but i t di d not pan out .
The pr of essor coul d not get
t he necess ar y money f or my sal ar y ( $1, 800) , and i t began t o l ook a l i t t l e bad. t han woman.
I r eal l y wonder ed i f men had mor e oppor t uni t i es Then Wor l d War I I came.
That changed t he whol e
si t uat i on not onl y f or sci ent i st s, but f or ever yone.
No l onger
coul d a per son hope t o get by or get an i nt er est i ng j ob wi t hout a good educat i onal backgr ound. Qui t e suddenl y a gr oup wor ki ng under Dr . Gei l i ng at t he Uni ver si t y of Chi cago got i nvol ved i n a bi g pr oj ect t o f i nd new ant i - mal ar i al dr ugs.
I woul d l i ke t o descri be t hi s, because I
t hi nk i t i l l ust r at es ver y wel l t he way new dr ugs can be br ought ont o t he mar ket .
The way t hi s happened was t hat obvi ousl y
mal ar i a was a ser i ous pr obl em i n war t i me, and of cour se Wor l d War I I had br oken out by t hat t i me.
But t hen wi t h t he f al l of
t he Dut ch East I ndi es, 90 per cent of t he wor l d' s suppl y of qui ni ne, at l east f or t he Al l i es, di sappear ed.
Ther e was one
ot her dr ug avai l abl e, a Ger man dr ug cal l ed At abr i ne, but i t was consi der ed pr et t y t oxi c and peopl e di d not l i ke t o t ake i t .
So,
t her e had t o be a cr ash pr ogr am t o get some ot her t r eat ment f or mal ar i a.
An of f i ce was set up i n Washi ngt on, D. C. , t he Of f i ce of
Sci ent i f i c Resear ch and Devel opment , and var i ous uni ver si t i es and ot her l abor at or i es ar ound t he count r y conduct ed t he st udi es, whi ch wer e di r ect ed f r om Washi ngt on. mor e or l ess i n sequence.
Var i ous t hi ngs happened
Fi r st , of cour se, t he gover nment l ai d
25
i t s hands on al l exi st i ng suppl i es of qui ni ne.
Ther e was st i l l a
l i t t l e mal ar i a i n t he Uni t ed St at es, and qui ni ne was used f or t r eat i ng t hat .
I t was used a bi t i n obst et r i cs.
I t was al so
used i n t hi ngs l i ke br omoqui ni ne, t oni c wat er , and so on.
So t he
st andi ng suppl i es wer e saved f or r eal emer genci es and al so t o be used as a dr ug agai nst whi ch t o compar e ot her possi bl e ant i mal ar i al s . Chemi st s wer e put t o wor k synt hesi zi ng At abr i ne.
Thi s was
soon accompl i shed, but i t t ook about a year t o ass ur e t he aut hor i t i es t hat t he Amer i can At abr i ne was at l east no mor e t oxi c t han t he Ger man At abr i ne.
Ot her s t r i ed t o synt hesi ze qui ni ne.
Thi s was accompl i shed, but i t i s such a t edi ous pr ocess wi t h a l ow yi el d, t hat i t has never , as f ar as I know, become economi cal l y f easi bl e.
Then ever yone was asked t o comb t hei r
shel ves f or chemi cal s t hat mi ght possi bl y ser ve as ant i mal ar i al s or have ant i mal ar i al act i vi t y.
These wer e al l t o be sent t o
Washi ngt on wher e t hey wer e gi ven a sur vey number and t hen t hey wer e sent out t o t he var i ous cooper at i ng i nst i t ut i ons f or ass ayi ng.
Ot her or gani c chemi st s wer e put t o wor k synt hesi zi ng
compounds t hat mi ght be l i ke exi st i ng compounds t hat wer e known t o have at l east some ant i mal ar i al act i vi t y. At t he Uni ver si t y of Chi cago, we had a t oxi col ogi cal set up wher eby t he mor e pr omi si ng dr ugs wer e f ed t o ani mal s- - r at s and dogs, f or exampl e, and occasi onal l y monkeys.
I n addi t i on, t her e
was a scr eeni ng pr ocedur e usi ng chi ckens and ducks.
Li t t l e baby
26
chi cks and duckl i ngs wer e gi ven t ypes of mal ar i a.
The mal ar i a
was not exact l y t he same as t he human f or m, but a t ype t hat r esponded t o t he dr ugs i n t he same way.
I bel i eve t hat dur i ng
Wor l d War I I somet hi ng l i ke 5 or 10 per cent of al l t he duck eggs and duckl i ngs i n t he Uni t ed St at es wer e used i n t hese scr eeni ng oper at i ons.
We wor ked most l y wi t h chi cks, and we woul d i nf ect
t he chi ckens wi t h t he mal ar i a par asi t e and t hen mi x t he dr ugs we wer e t est i ng i nt o t he f ood, usual l y at sever al di f f er ent doses. Then, as t i me went by, we woul d t ake bl ood sampl es f r om t he chi ckens and l ook t o see whet her mal ar i a par asi t es wer e pr esent or absent . t he chi cks.
Al so, we woul d obser ve t he heal t h and wel l - bei ng of Some of t he bi r ds wer e gi ven qui ni ne as a cont r ol .
Dur i ng t he cour se of t he war , over 14, 000 dr ugs wer e scr eened as possi bl e ant i mal ar i al s.
I n addi t i on t o t he peopl e
synt hesi zi ng dr ugs f or t hi s pur pose, ot her s wer e asked t o send i n r emedi es.
Dr ug f i r ms, chemi st s, and phar maci st s wer e ur ged t o
sear ch t hei r shel ves f or anyt hi ng pr omi si ng, and we di d get some ver y f unny r emedi es t hat peopl e woul d wr i t e i n about .
I r emember
one, a dr i ed f i sh t hat was supposed t o be soaked i n mi l k. sol emnl y di d t hat and f ed t he chi cks wi t h i t . a vet er i nar i an i n Texas.
We
Anot her came f r om
I t l ooked l i ke i nk and was shi pped i n
what l ooked l i ke an i nk bot t l e.
He sai d he was hopi ng t o use i t
t o t r eat a pl asmodi um- l i ke par asi t e i n cat t l e.
He al so sai d t hat
he had j ust t r i ed i t on hi s secret ar y wi t hout i l l ef f ect s, and he pl anned next t o t r y i t on cat t l e.
When we r ead t hi s, we sai d i t
28
ver y acti ve i n t hi s.
Dr . Wi l l i am Tal i af er r o was one of t he f i r st
t o descr i be what i s known as t he exoer yt hr ocyt i c st age of t he mal ar i a par asi t es.
The par asi t es ar e not i n t he r ed bl ood cel l s,
but i n t he spl een and l i ver , and t hey ar e t he ones r esponsi bl e f or t he r epeat ed at t acks. Our uni t wor ked on some of t he dr ugs t hat pr oved usef ul among t he hundr eds of ot her s t hat had t o be di scar ded.
We wor ked
on chl or oqui ne, whi ch i s now avai l abl e.
But , over al l , t he
pr oj ect di d not r eal l y f i nd t he answer .
The subst i t ut e dr ugs
have t hei r unpl easant si de ef f ect s.
Al so, st r ai ns of mal ar i a
have devel oped t hat ar e r esi st ant t o dr ugs t hat pr evi ousl y wer e us ef ul . The pr oj ect st ar t ed about 1941 and went on t o about 1945. We wer e abl e t o do a l i t t l e r esear ch on t he si de, par t i cul ar l y i n st udyi ng t he met abol i sm of t he dr ugs- - how t hey wer e handl ed i n t he body.
One of t he st udi es we di d was r at her i nt er est i ng i n
t hat connect i on.
Rabbi t s ar e ver y good at br eaki ng down qui ni ne.
They have an enzyme i n t he l i ver t hat br eaks i t down ver y r api dl y.
Thi s i s not somet hi ng we di scover ed.
I n f act , af t er we
t hought t hat we had done so, we f ound t hat i t had been di sc over ed af t er t he Fi r st Wor l d War . mor e dept h.
But we di d l ook i nt o i t i n somewhat
We t hought i t woul d be i nt er est i ng t o f i nd out how
t hi s enzyme, or how t hi s abi l i t y t o br eak down qui ni ne, mi ght act : ( a) i n pr egnant r abbi t s; and ( b) i n embr yo r abbi t s.
We
f ound t hat dur i ng pr egnancy t her e was l ess abi l i t y i n t he mot her
29
t o br eak down t he qui ni ne and t hat t he embr yo r abbi t s had no abi l i t y at al l t o do so unt i l af t er bi r t h.
Thi s was one of t he
ear l y i l l ust r at i ons- - not t he f i r st - - t hat t he embr yo or t he young may handl e a dr ug di f f er ent l y f r om t he mot her , because t hei r enzyme syst ems devel op sl owl y and ar e not al l pr esent at t he t i me of bi r t h.
Thei r ki dney f unct i on i s not per f ect at t hat t i me so
t hey do not excr et e dr ugs as r api dl y as t hey do l at er . I coaut hor ed an ar t i cl e on t hi s wor k on qui ni ne i n r abbi t s wi t h a col l eague, F. E. Kel sey.
He became my husband.
F. El l i s Kel sey was an i nst r uct or at t he Uni ver si t y of Chi cago.
He ar r i ved j ust about t he t i me t he ant i mal ar i al wor k
st ar t ed, or per haps a year bef or e, and we wor ked t oget her on t hat .
He had a Ph. D. i n bi ochemi st r y f r om t he Uni ver si t y of
Rochest er .
We mar r i ed i n 1943, dur i ng t he war .
When t he war was
over , a pr obl em ar ose, because t wo member s of t he same f ami l y i n t hose days- - I do not know i f i t i s st i l l t r ue now- - coul d not be empl oyed i n t he same depar t ment by t he Uni ver si t y.
They f el t
t hat was nepot i sm or despot i sm or somet hi ng l i ke t hat .
So, we
t hought t he onl y way out woul d be f or one of us t o go t o medi cal school .
Not t hat ei t her of us i nt ended t o pr act i ce, but i t
seemed l i ke a ver y good ext r a asset t o have an M. D. i n addi t i on t o a Ph. D.
I do not know whet her I won or I l ost out .
I t hi nk I
act ual l y won, but I was t he mor e l ogi cal choi ce t o get an M. D. si nce, i n f act , I had had al most t he f i r st t wo year s of medi ci ne whi l e get t i ng my Ph. D. , and, of cour se, as a woman, I needed t he
30
ext r a credent i al s.
Let us f ace i t , I needed al l t he hel p I coul d
get t o obt ai n a j ob. I ent er ed medi cal school at t he Uni ver si t y of Chi cago i n t he cl ass of 1946, and my husband cont i nued hi s t eachi ng and r esear ch i n t he Depar t ment of Phar macol ogy at t he uni ver si t y.
Medi cal
school was not bad, because t hi s was t he f i r st year af t er t he war .
St udent s wer e much ol der .
On t he aver age, t hey wer e aged
27, i nst ead of 21 or 20.
They wer e much mor e mat ur e, and l ess
l i kel y t o r ag t he women.
Then, because of t he scar ci t y of men,
t her e was a hi gher per cent age of women i n t he cl ass.
Ther e wer e
seven of us f or 70 pl aces ( 10 per cent ) , and ear l i er onl y one or t wo per year woul d get i n.
Now 35 t o 50 per cent of i ncomi ng
medi cal sc hool cl asses ar e women and t hey do ver y wel l and get r esi dency t r ai ni ng i n a way t hat we never di d.
So, medi cal
school was not bad as f ar as I was concer ned, par t i cul ar l y, as we had some ver y f i ne women pr of essor s on t he st af f , who had t he r espect of t hei r mal e count er par t s.
Fur t her mor e, t he uni ver si t y
medi cal school at Chi cago was or i ent ed mor e f or t eachi ng and r esear ch t han f or pr i vat e pr act i ce.
Agai n, t he at mospher e was
not as compet i t i ve. I had al r eady done, as I not ed, a good deal of t he wor k needed f or t he f i r st t wo year s of medi cal school .
I t hi nk t hat
st udent s pr obabl y f i nd t hose t he har dest , i n a way, because t hey f eel t hey ar e not get t i ng t o car e f or peopl e.
I nst ead t hey ar e
l ear ni ng a l ot of sci ence t hat t hey f eel may not be appl i cabl e
29
t o br eak down t he qui ni ne and t hat t he embr yo r abbi t s had no abi l i t y at al l t o do so unt i l af t er bi r t h.
Thi s was one of t he
ear l y i l l ust r at i ons- - not t he f i r st - - t hat t he embr yo or t he young may handl e a dr ug di f f er ent l y f r om t he mot her , because t hei r enzyme syst ems devel op sl owl y and ar e not al l pr esent at t he t i me of bi r t h.
Thei r ki dney f unct i on i s not per f ect at t hat t i me so
t hey do not excr et e dr ugs as r api dl y as t hey do l at er . I coaut hor ed an ar t i cl e on t hi s wor k on qui ni ne i n r abbi t s wi t h a col l eague, F. E. Kel sey.
He became my husband.
F. El l i s Kel sey was an i nst r uct or at t he Uni ver si t y of Chi cago.
He ar r i ved j ust about t he t i me t he ant i mal ar i al wor k
st ar t ed, or per haps a year bef or e, and we wor ked t oget her on t hat .
He had a Ph. D. i n bi ochemi st r y f r om t he Uni ver si t y of
Rochest er .
We mar r i ed i n 1943, dur i ng t he war .
When t he war was
over , a pr obl em ar ose, because t wo member s of t he same f ami l y i n t hose days- - I do not know i f i t i s st i l l t r ue now- - coul d not be empl oyed i n t he same depar t ment by t he Uni ver si t y.
They f el t
t hat was nepot i sm or despot i sm or somet hi ng l i ke t hat .
So, we
t hought t he onl y way out woul d be f or one of us t o go t o medi cal school .
Not t hat ei t her of us i nt ended t o pr act i ce, but i t
seemed l i ke a ver y good ext r a asset t o have an M. D. i n addi t i on t o a Ph. D.
I do not know whet her I won or I l ost out .
I t hi nk I
act ual l y won, but I was t he mor e l ogi cal choi ce t o get an M. D. si nce, i n f act , I had had al most t he f i r st t wo year s of medi ci ne whi l e get t i ng my Ph. D. , and, of cour se, as a woman, I needed t he
32
mar ket , t her e shoul d be mor e ar t i cl es i n J AMA about t hem, but he al so f el t t he cal i ber of wr i t i ng i n many of t he ar t i cl es submi t t ed was not ver y good.
He want ed me t o pi ck out good
paper s and hel p t he of f i ce pol i sh t hem up a bi t .
Wel l , not al l
t he sci ence was ver y good ei t her and I do not know i f I was ver y success f ul i n t hat l i ne, but my mai n j ob was t o t r y and pi ck good paper s, and I hope we di d t hat . When I went t o t he AMA ( Amer i can Medi cal Ass oci at i on) , t her e wer e t wo ot her medi cal r evi ewer s besi des mysel f who had r ecent l y come aboar d.
Ther e was al so t he associ at e edi t or , ot her edi t or s
and so on, but we wer e t he l ower echel on so t o speak.
We shar ed
one l ar ge bul l pen, a r oom t hat had hal f - gl ass par t i t i ons so we l ooked out over t hi s sea of manuscr i pt edi t or s, who, of cour se, knew al l t he nuances of gr ammar and t hi ngs l i ke t hat wi t h whi ch we coul d not al t oget her cope. We al l agr eed t hat many of t he submi ssi ons wer e poor , and we al so obser ved t hat no mat t er whet her we t ur ned t hem down or not t hey i nevi t abl y got publ i shed i n some ot her j our nal , because t he j our nal s ci r cul at ed amongst us.
We woul d see t hese ar t i cl es and
r eal i ze t hat we had r evi ewed t hem and r ecommended t hey not be accept ed.
Cer t ai n names woul d keep r ecur r i ng bot h i n ar t i cl es
and t hi ngs l i ke l et t er s and so f or t h. l i st .
We kept a sor t of i nf or mal
We woul d j ot down, "Oh, i t ' s Dr . So- and- so agai n, or So-
and- so and So- and- so. "
Then ei ght year s l at er , when I came t o
t he FDA, I saw many f ami l i ar names as cont r i but or s of cl i ni cal
33
st udi es t o t he NDAs ( New Dr ug Appl i cat i ons) .
I have t o be honest
and admi t t hat t her e wer e some ar t i cl es I t ur ned down t hen t hat now I woul d have accept ed, but I t hi nk t hat i s t r ue of al l edi t or s.
I am gl ad t o say t hat t hose ar t i cl es t oo got publ i shed.
My l i st - keepi ng t hen dat ed f r om an ear l y per i od. Medical Teaching, Research, and Practice in South Dakota
I was at t he AMA f or t wo year s unt i l 1952, and t hen my husband got an of f er t o be head of t he Phar macol ogy Depar t ment at t he Uni ver si t y of Sout h Dakot a Medi cal School i n Ver mi l l i on, Sout h Dakot a. t r agedy t her e.
That was a st or y, t oo.
Ther e had been a gr eat
The t r agedy was t hat t wo vol unt eer subj ect s di ed
i n what we woul d now cal l a Phase 1 dr ug st udy.
At t hat t i me,
t he medi cal school at t he Uni ver si t y of Sout h Dakot a was a t woyear medi cal school si t uat ed i n a smal l t own of about 5, 000, whi ch had a smal l hospi t al , but i t was mor e f or emer genci es and mi nor t hi ngs.
Ten mi l es away t her e was a ver y excel l ent hospi t al
st af f ed wi t h speci al i st s and so f or t h.
The bui l di ng t hat t he
medi cal sc hool was housed i n t hen was known as t he ol d chemi st r y bui l di ng, because t hat , i n essence, i s what i t was.
When t hey
got a new chemi st r y bui l di ng, t he pr e- cl i ni cal sci ences moved i n t o t he ol d chemi st r y bui l di ng.
So i t was not a moder n, up- t o-
dat e bui l di ng of any sor t . But t he dean of t he medi cal school , Dr . Donal d Sl aught er , who was al so chai r man of t he phar macol ogy depar t ment , was ver y i nt er est ed i n r esear ch.
He had spent a number of year s at t he
34
Uni ver si t y of Mi chi gan wher e t her e was, and I t hi nk st i l l i s- - i t i s suppor t ed by t he Publ i c Heal t h Ser vi ce- - a uni t devot ed t o st udi es on mor phi ne and r el at ed compounds. I nt er est i ngl y enough, Dr . Ral ph Smi t h, who r ecr ui t ed me t o t he FDA, al so wor ked at Mi chi gan and I t hi nk got hi s Ph. D. t her e.
2
I am not absol ut el y cer t ai n.
He al so was i nvol ved i n
r esear ch on mor phi ne bef or e he came t o t he FDA.
Af t er Dr . Smi t h
r et i r ed f r om t he FDA, he ser ved f or t wo or t hr ee year s at t he Nat i onal Academy of Sci ences as execut i ve secr et ar y or what have you, f or a gr oup i nt er est ed i n or f ocusi ng on dr ugs of addi ct i on. Anyway, mor phi ne was t he ar ea of Dr . Donal d Sl aught er ' s i nt er est .
He was a wel l - known phar macol ogi st and coaut hor of a
t ext book on phar macol ogy. per son.
He was an i nt er est i ng sor t of a
Thi s st udy i nvol ved a compar i son of t wo mor phi ne- l i ke
compounds.
I have an i dea what t hey wer e, but I have no r eal
means of document i ng i t . act i ve t han t he ot her . t he st udy.
But one compound was a good deal mor e I t hi nk t hat was per haps t he essence of
The compounds wer e t o be gi ven t o vol unt eer s, ei t her
bl i nded or al t er nat el y- - I f or get whi ch.
Then t he vol unt eer s wer e
t o be t est ed f or t hei r per cept i on of pai n. not pat i ent s.
The vol unt eer s wer e
They wer e uni ver si t y empl oyees or r el at i ves of
uni ver si t y empl oyees who had vol unt eer ed f or some dr ug t r i al s. 2
Ral ph G. Smi t h r ecei ved hi s M. D. f r om t he Uni ver si t y of Tor ont o i n 1925; hi s Ph. D. i n phar macol ogy f r omt he Uni ver si t y of Chi cago i n 1928; served on t he f acul t i es of t he Uni ver si t y of Mi chi gan ( 1928- 1943) and Tul ane Uni ver si t y ( 1943- 1950) ; and came t o FDA i n 1950 t o head t he new dr ug br anch.
33
st udi es t o t he NDAs ( New Dr ug Appl i cat i ons) .
I have t o be honest
and admi t t hat t her e wer e some ar t i cl es I t ur ned down t hen t hat now I woul d have accept ed, but I t hi nk t hat i s t r ue of al l edi t or s.
I am gl ad t o say t hat t hose ar t i cl es t oo got publ i shed.
My l i st - keepi ng t hen dat ed f r om an ear l y per i od. Medical Teaching, Research, and Practice in South Dakota
I was at t he AMA f or t wo year s unt i l 1952, and t hen my husband got an of f er t o be head of t he Phar macol ogy Depar t ment at t he Uni ver si t y of Sout h Dakot a Medi cal School i n Ver mi l l i on, Sout h Dakot a. t r agedy t her e.
That was a st or y, t oo.
Ther e had been a gr eat
The t r agedy was t hat t wo vol unt eer subj ect s di ed
i n what we woul d now cal l a Phase 1 dr ug st udy.
At t hat t i me,
t he medi cal school at t he Uni ver si t y of Sout h Dakot a was a t woyear medi cal school si t uat ed i n a smal l t own of about 5, 000, whi ch had a smal l hospi t al , but i t was mor e f or emer genci es and mi nor t hi ngs.
Ten mi l es away t her e was a ver y excel l ent hospi t al
st af f ed wi t h speci al i st s and so f or t h.
The bui l di ng t hat t he
medi cal sc hool was housed i n t hen was known as t he ol d chemi st r y bui l di ng, because t hat , i n essence, i s what i t was.
When t hey
got a new chemi st r y bui l di ng, t he pr e- cl i ni cal sci ences moved i n t o t he ol d chemi st r y bui l di ng.
So i t was not a moder n, up- t o-
dat e bui l di ng of any sor t . But t he dean of t he medi cal school , Dr . Donal d Sl aught er , who was al so chai r man of t he phar macol ogy depar t ment , was ver y i nt er est ed i n r esear ch.
He had spent a number of year s at t he
35
I t was a pr et t y st r ai ght f or war d sor t of st udy, except t hat i t i nvol ved i nj ect i on of t he dr ugs ei t her i nt r amuscul ar l y or subcut aneousl y or i nt r avenousl y.
I cannot r emember whi ch.
I t j ust so happened t hat when t he st udy was sc hedul ed t o t ake pl ace Dr . Sl aught er had t o go t o a hospi t al because of sever e gout , I bel i eve, i n a knee. ot her epi sodes.
Thi s was not new; he had had
He had demanded gr eat at t ent i on addi t i onal l y at
t hi s t i me because hi s wi f e, sadl y enough, was dyi ng of one of t he aut oi mmune di seases, and t hi s was i n t he days bef or e t her e wer e st er oi ds or adequat e t r eat ment of any t ype.
He al so had t he
usual st r esses and st r ai ns of bei ng dean of a medi cal school . However , i n hi s absence t he st udy went on under t he gui dance of hi s young assi st ant who had j ust compl et ed hi s i nt er nshi p, and had had some exper i ence as an i nst r uct or i n phar macol ogy.
It is
sai d t hat t he subj ect s wer e t o r ecei ve t he dr ug and t hen t est i ng was t o begi n at a sui t abl e per i od t her eaf t er .
They had not
f i ni shed t he i nj ect i on of al l t he subj ect s- - maybe t hey had done t hr ee or f our or f i ve- - when t he f i r st one l ost consci ousness. Whi l e t hey wer e t r yi ng t o r evi ve t hi s per son, anot her one had a si mi l ar exper i ence, and t hen a t hi r d. st opped mi dway i n t he t hi r d one.
I t hi nk t he i nj ect i on was
At l east , t her e was some
depr essi on of t he needl e or somet hi ng, but i t was r ever si bl e. The t wo subj ect s t hat coul d not be r evi ved wer e t aken of f by ambul ance t o t he hospi t al about t en mi l es away.
Thi s was al so
bef or e t he days when t her e wer e mor phi ne ant agoni st s.
I t hi nk
36
t hey wer e bei ng devel oped, and I bel i eve Par ke- Davi s act ual l y f l ew some out t o t he hospi t al i n Yankt on, but i t di d not pr event t hi s t r agedy.
Some of t hese der i vat i ves Dr . Sl aught er was
t est i ng wer e not mor phi ne, and whet her t hey woul d r eact i n a si mi l ar f ashi on I do not t hi nk was known.
Anyway, t hey cer t ai nl y
di d not have t hem on hand i n t he phar macy, and I under st and t hey had t o get t hem f r om el sewher e. Then, af t er t hi s occur r ed, as I under st and i t , t her e was a hear i ng, and Dr . Sl aught er ass umed compl et e r esponsi bi l i t y even t hough he had not been pr esent . seni or i nvest i gat or .
So he r ecogni zed t hat he was t he
I t hi nk t he vol unt eer s wer e somehow t est ed,
but t hat i s possi bl y a r econst r uct i on and not a r eal memor y. They wer e never supposed t o l ose consc i ousness gi ven t he dose. I t shoul d not have pr oduced t hi s ef f ect .
Ther e was some t hought
t hat t her e mi ght have been a mi x- up i n t he way t he sol ut i ons wer e pr epar ed si nce one dr ug was known t o be so much mor e pot ent t han t he ot her .
As I say, we wer e not t her e at t he t i me, and i t was
obvi ousl y a ver y t r aumat i c event . I t was s ome t i me mont hs af t er t hi s t hat t he pr of ess or was r eadmi t t ed t o anot her hospi t al because of hi s gout , and t hen i t came t o l i ght t hat he had become addi ct ed t o mor phi ne, as many peopl e who wor ked wi t h t hese dr ugs di d. J ohns Hopki ns, di d.
Many addi ct s, especi al l y pr of ess i onal ones,
can cont r ol t hei r addi ct i on. mi sadvent ur e.
Hal st ed, a sur geon at
I t hi nk t he out come was r ul ed a
I do not know i f t hey gave t he sur vi vor payment s
37
or anyt hi ng l i ke t hat , but t he t r agedy poi nt ed out t he need f or cont r ol over i nvest i gat i onal dr ugs.
Ther e was no quest i on of Dr .
Sl aught er bei ng i mpr i soned or anyt hi ng l i ke t hat .
I f ound out
t hese det ai l s f r om a f r i end who happened t o be at t he uni ver si t y at t he t i me who r ef r eshed my memor y.
I do not t hi nk t her e was
any suggest i on t hat Dr . Sl aught er ' s addi ct i on l ed ei t her t o t he gout or t o t hi s epi sode.
But i t i l l ust r at es sever al t hi ngs:
one, t he need f or gr eat caut i on i n Phase I st udi es, whi ch we now have, of cour se, and t wo, t he hazar d of exper i ment i ng wi t h an addi ct i ng dr ug.
Dr . Sl aught er went f or t r eat ment , and t hen
shor t l y af t er t hat he di ed.
That was why t hey wer e l ooki ng f or
anot her phar macol ogi st at t he Uni ver si t y of Sout h Dakot a. He di ed shor t l y bef or e t he phar macol ogy cour se was goi ng t o be gi ven.
The uni ver si t y cal l ed on sur r oundi ng uni ver si t i es t o
hel p t hem out i n pr ovi di ng t eacher s or i nst r uct or s f or t he cour s e.
Dr . Gei l i ng i n I l l i noi s , whi ch was not , af t er al l , t hat
f ar away f r om t he sout heast er n par t of Sout h Dakot a wher e t he medi cal school was, vol unt eer ed t o go out .
A number of t he
f acul t y or i nst r uct or s at t he Uni ver si t y of Chi cago went out , as wel l as some f r om ot her sur r oundi ng uni ver si t i es.
Dr . Gei l i ng
was ver y i mpr essed by t he school , by t he spi r i t , t he ent husi asm, and t he t ype of st udent s t hat wer e t her e.
So when an openi ng
came f or a new chai r man, he r ecommended t o my husband t hat he l ook i nt o t he mat t er , and he r ecommended my husband t o t he uni ver s i t y aut hor i t i es .
38
Dur i ng t hat year , my husband had l ef t t he Uni ver si t y of Chi cago and was wor ki ng f or a f i r m t hat was a pi oneer i n t he devel opment of nucl ear phar maceut i cal s- - i t was cal l ed Chi cago Nucl ear - - and f i ndi ng ot her uses f or i sot opes.
The f ounder s had
wor ked at Oak Ri dge on t he at omi c bomb pr oj ect and st ar t ed up t hi s smal l company.
My husband was wor ki ng t her e, and whi l e i t
was an i nt er est i ng exper i ence, he want ed t o get back i nt o t eachi ng agai n.
So t hat i s how we consi der ed goi ng t o Sout h
Dakot a. My husband r ecei ved t he of f er t o become head of t he Phar macol ogy Depar t ment at t he medi cal school i n Ver mi l l i on.
As
I not ed, t hi s was i n a t own of 3, 000- 5, 000 peopl e on t he Mi ssour i Ri ver , and as may be i magi ned t her e wer e ver y f ew openi ngs f or a f emal e M. D. , Ph. D. i n a t own of t hat si ze.
I cer t ai nl y was not
el i gi bl e t o wor k at t he uni ver si t y i n my husband' s depar t ment , due t o t he same pr obl em as i n Chi cago.
I di d not have a l i cense.
I di d not par t i cul ar l y want t o pr act i ce medi ci ne, or I was not sur e i f I di d.
So t o go t o Sout h Dakot a was a bi g deci si on f or
us, whi ch of t en happens i n many f ami l i es wher e bot h husband and wi f e have car eer s.
I t i s ver y sel dom t hat bot h can be
accommodat ed wi t h a good j ob at t he same t i me. out s.
I had t wo sor t of
One was t o go t o l aw school , and as I l i ked st udyi ng, t hat
was not t oo bad an opt i on, and t he second was t o t ake an i nt er nshi p.
That woul d at l east gi ve me a l i cense and, who
knows, I mi ght f i nd t hat I l i ked t o pr act i ce medi ci ne.
39
We went ent t o Sou Soutt h Dakot a i n t he s ummer of 1952 1952 and and I s t ar t ed my i nt er nshi p i n J anuar y or or Feb Febr uar y of 1953.
The The Sacr ed Hear t
Hospi spi t al , wi t hi n 10 mi l es of Ver mi l l i on, at Yankt on, wher e I i nt er ned, ed, happ appened ened t o be a ver ver y goo good d hospi ospi t al , and and my i nt er nshi p was a ver ver y go good expe xper i ence, ce, becau cause i t was an ent i r el y di di f f er ent t ype ype of of medi edi ci ne t han what I had been een exp exposed osed t o at at t he r at her acad cademi c Un Uni ver ver si t y of of Chi cag cago. When I f i ni shed shed my i nt er nshi p, I appl i ed f or and was awar ded a Led Leder l e t eachi chi ng f el l owshi shi p f or t hr ee year s.
I t was pa pai d f or
by t hi s l ar ge dr ug f i r m, and t hey di di d not i nf l uence me, t he l east bi t , i n my at t i t ude t o dr ugs.
These f el l owshi shi ps wer e st ar t ed
about t he year I appl i ed, or possi bl y a year or t wo ear l i er ; t hey had not been i n oper at i on l ong.
The They wer e t o supp suppor t f acul cul t y
member s at uni ver ver si t i es and and wer e unr est r i ct ed as t o t he t ype ype of r esear sear ch t hat cou coul d be pur sued sued.
The The ai m was t o upgr ade i n
gener al t he t eachi chi ng of basi c sci ences ces i n medi cal cal scho school s.
It
was a ve ver y ge gener ous f el l owshi shi p and i t di d not cau cause a con conf l i ct wi t h t wo peopl e i n t he depa epar t ment bei ng pai d by t he uni ver ver si t y, becau cause I was pa pai d by an out si de f i r m.
So, i t was po possi bl e f or
me t o spen spend t he nex nextt t hr ee year year s doi ng r esear esear ch an and t eachi eachi ng by vi r t ue of my f el l owshi shi p.
Thi s was f r om 1954 t o 1957.
I di d some l ocum cum t enens wo wor k an and t hen got i nt o t he ne new f i el d of r adi oi sot opes an and r adi oi sot ope dr ugs.
Ther e was i ncr easi ng
i nt er est i n i sot opes and and nu nucl ear medi ci ne, so I " com commut ed" t o Chi cag cago t o get t r ai ni ng i n t hat .
I t was an an over ni ght t r ai n t r i p
40
t o go t o Chi cago. cago.
I woul oul d go f or t wo or t hr ee days ays t o wat ch and and
ass i st and t hen com come back t o Ver mi l l i on.
To get l i cen censed a
doct or was r equi r ed t o have ave ass i st ed i n t he t r eat ment or di agn agnosi s of a cer cer t ai n nu number of pat i ent ent s and and t o hav have e beco becom me f ami l i ar wi wi t h cal cal cul cul at i ng doses ses an and t hi ngs l i ke t hat .
I was t he
f i r st per son son i n t he st at e of Sout h Dakot kot a t o get l i cen censed sed t o use r adi oi sot opes i n medi ci ne.
I was no not t he l ast , becau cause we
or gani zed cl ass es f or t he doct or s who wer e out i n t he st at e, and t r ai ned t hem al so t o appl y f or l i cen censes. ses. My r esear esear ch at at Sout out h Dakot akot a had had t o do do wi t h t he t hyr oi d gl and and.
Thu Thus I was goi ng back t o end endocr i nol ogy. ogy.
Par Par t of my wor k
was con conduct ed at a l ar ge ment al i nst i t ut i on not f ar f r om Ver mi l l i on.
Ther e had al ways been some sor t of bel i ef t hat
t hyr oi d di sor sor der s we wer e t i ed i n wi t h cer cer t ai n ment al di sor sor der s, and t her e wer e numer ous s t udi es on t he t hyr oi d gl and i n t hi s t ype ype of popul at i on.
Si nce t her e was a new di agnost i c pr oced ocedur e f or
t hyr oi d di sor sor der s, r adi oact i ve i odi ne, som some of t he pat i ent s at at t he ment al i nst i t ut i on woul d be ref er r ed t o us us t o see see i f t hey ha had any t hyr oi d pr obl ems.
I n t he cour cour se of our wor k we di d seem seem t o
f i nd an an ab abnor mal number of pat i ent ent s who had had what we cal l a hi hi gh i odi ne upt ake, ke, al t hough t hey cer cer t ai nl y show showed no si gn of bei ng hyper t hyr oi d.
I t t ur ned out t hat t hi s i nst i t ut i on was si si t uat ed
j ust on t he edge edge of t he goi t er bel bel t and and t hey had had never never used i odi zed zed sal t t her e f or some r eason; son; per haps i t was due due t o a smal l econ conomy, or t hey j ust never ver t hought of i t .
When t hey r epl aced ced
41
t he or or di nar y sal sal t wi t h i odi zed zed sal t , we went back an and f ound t hese sub subj ect s t o be nor mal i n t hei r i odi ne upt ake. ke. I n t hi s i nst ance, ce, i t t ur ned out t o be i odi ne def i ci encycy- - a di et ar y pr obl em.
I f t hat i s seve severr e enough, i t can can i n t ur n cau cause
seve sever e ment al pr obl ems or or l ear ni ng di sabi sabi l i t y.
The Ther e wer e t he
occasi ccasi onal pat i ent s i n t he ment al i nst i t ut i on whom we di d di agnose as havi ng def i ni t e t hyr oi d pr obl ems.
But t he over ver al l
popul at i on was suf suf f er i ng f r om a l ow- gr ade i odi ne de def i ci ency. cy. Whi l e i n Sout h Dakot kot a, t oo, I act ual l y r et ur ned t o my ear l i er st udi es on t he pi t ui t ar y be becau cause we f ound t hat t he be beaver ver was l i ke t he ar madi l l o, whal e, por poi se, and some bi r ds i n t hat i t , t oo, si mpl y had t hese t wo l obes- - t he ant er i or and t he post er i or - - and no i nt er medi at e l obe.
The beaver ver wa was avai vai l abl e.
We had had a f r i end end who was a gr gr eat eat hunt er and and was al ways ays wi l l i ng t o get a beav beaver er .
I r emember we we had a l i ve one one once. once.
We kept kept i t
over ni ght and i t gnawed al l t he l egs of of f t he st ool s. Af t er my Led Leder l e f el l owshi shi p yea year s f r om 1954 t o 19 1957, I was a sor t of vol vol unt eer r esear sear che cher , but I al so di di d what was kno known as " pr act i ce si t t i ng. "
Thi s was som somewhat l i ke babysi t t i ng.
Ther e
wer e many any r ur al ar eas eas wher e on onl y on one doct doct or woul oul d be be ava avaii l abl abl e, so, when t he physi ci an wi shed t o get away t o go t o a medi edi cal meet i ng or t ake a va vacat cat i on, I woul d go an and l ook af af t er hi s pr act i ce f or var var yi ng per i ods, say say t wo or t hr ee days.
I t hi nk t he
l ongest per i od I di d t hi s f or was abo about si x or or ei ght weeks when t he pe peopl opl e i n a t own wer e l ooki ng f or a r epl epl acem cement f or a do doct or
42
i n one of t hese ar eas. I di d t hi s r at her t han openi ng my own pr act i ce, because I somehow f el t t hat woul d t i e me down, and t he gi r l s wer e st i l l f ai r l y young. t oo.
Pl us I enj oyed t he t eachi ng- - I di d some of t hat
I r at her enj oyed t he amount of pr act i ce I di d.
var i et y and i t was not t oo conf i ni ng.
I t of f er ed
Al so, I di d st i l l have t he
cont act s at t he uni ver si t y. Cer t ai nl y doct or s wer e i n shor t suppl y i n t he l at e 1950s i n t he i sol at ed ar eas wher e i t was qui t e har d t o at t r act and hol d physi ci ans.
Many of t hese pl aces had ver y ni ce hospi t al s- - by
vi r t ue of t he Hi l l - Bur t on Act - - and t he pat i ent s got excel l ent car e, I t hought .
I t was possi bl e t o get t o a l ar ger cent er
ei t her by f l yi ng or by ambul ance or dr i vi ng.
But , f or t he day-
t o- day ai l ment s and emer gency si t uat i ons, i t was essent i al t o have t he doct or r easonabl y cl ose. Ever y medi cal encount er was of i nt er est because I was on my own and t her e wer e a var i et y of emer genci es or even j ust or di nar y r un- of - t he- mi l l condi t i ons t hat I woul d have t o cope wi t h or t r eat .
I t was a ver y good exper i ence f or me, because t he medi cal
school I had been t r ai ned i n was ver y r esear ch or i ent ed.
We saw
many pat i ent s wi t h esot er i c di seases at t he Uni ver si t y of Chi cago, but ver y sel dom a br oken l i mb or a case of measl es or appendi ci t i s.
I saw t he mor e common ai l ment s i n Sout h Dakot a.
I
di d whi l e I i nt er ned t oo, because t hat was i n a gener al hospi t al . Coming to FDA and an Introduction to the Drug Approval Process
43
Then af t er my husband and I had been i n Ver mi l l i on f or some t i me i t seemed as t hough we had an i t ch t o get back t o t he bi g ci t y agai n.
Thi s t i me I got t he f i r st j ob of f er , and I wi l l say
t hat I got col d f eet at t he i dea of bei ng t he sol e suppor t of t he f ami l y unt i l my husband got a j ob.
Ver y f or t unat el y, al most at
t he same t i me, he was of f er ed one by t he Nat i onal I nst i t ut es of Heal t h, so i n 1960 we moved t o Washi ngt on, D. C. , bot h wi t h j obs. Mi ne came about because we r an i nt o t he Di r ect or of t he Bur eau of Medi ci ne of t he Food and Dr ug Admi ni st r at i on at t hat t i me at a phar macol ogy meet i ng.
He was Dr . Ral ph Smi t h, al so a Canadi an,
and al so a phar macol ogi st .
He sai d t he agency was expandi ng, and
how woul d I l i ke t o wor k t her e as a medi cal of f i cer .
I t di d not
seem l i ke a bad i dea and so I mul l ed i t over , and when my husband got t he j ob of f er i n Washi ngt on t oo, I accept ed.
J ust t o show
how t he j ob mar ket had changed, I al so got an of f er f r om t he Nat i onal I nst i t ut es of Heal t h f or anot her j ob at t he same t i me, so t hi ngs wer e l ooki ng up. I went t o t he Food and Dr ug Admi ni st r at i on i n 1960. I st ar t ed on August 1, and t he f i r st mont h I was t her e, t he FDA was i n a t empor ar y bui l di ng- - Wake Hal l , I bel i eve i t was cal l ed- whi ch was out i n t he ar ea wher e t he Rober t F. Kennedy St adi um now i s.
Then, af t er a mont h, we moved i nt o ot her t empor ar y bui l di ngs
on t he Mal l , on 7t h St r eet , cl ose t o t he HEW ( Depar t ment of Heal t h, Educat i on, and Wel f ar e) bui l di ng.
These wer e Wor l d War
I I t empor ar y bui l di ngs, pr e- f abs, and we wer e l ucky because some
44
gover nment agenci es wer e st i l l i n Wor l d War I pr e- f abs. My f i r st mont h was spent goi ng ar ound and f i ndi ng out what t he par t s of t he agency di d and t hen I came back t o our l i t t l e pr e- f ab.
Onl y t he Bur eau of Medi ci ne was i n i t ;
t he agency had bi gger bui l di ngs.
ot her par t s of
Af t er my shor t i ndoct r i nat i on
per i od, I was gi ven my f i r st ass i gnment s as a r evi ewer of new dr ug appl i cat i ons.
I had been hi r ed as a medi cal of f i cer and
t hi s meant t hat I woul d r evi ew t he medi cal par t r at her t han t he phar macol ogy of new dr ug appl i cat i ons.
Dr . Smi t h, who br ought me
i n, was l ooki ng f or medi cal of f i cer s, not phar macol ogi st s.
I had
t he medi cal t r ai ni ng as wel l as my phar macol ogi cal t r ai ni ng, and t her e wer e cer t ai n advant ages t o bei ng a medi cal of f i cer at t hat t i me.
I n t hose days phar macol ogi st s wer e not act ual l y i n t he
Bur eau of Medi ci ne, but i n, I bel i eve i t was cal l ed, t he Bur eau of Sci ence. peopl e.
But t hey used t o wor k wi t h t he Bur eau of Medi ci ne
We woul d send our appl i cat i ons over t her e f or t hem t o
r evi ew t he ani mal wor k.
So my r evi ew wor k was t o be on t he human
s t udi es f r om t he s t ar t . Bef or e t ur ni ng t o t hal i domi de, I have t o descr i be a New Dr ug Appl i cat i on i n t he set t i ng of when I f i r st came t o t he FDA. Thi ngs wer e somewhat di f f er ent f r om what t hey ar e now, but i n essence, at t hat t i me, when a dr ug f i r m f el t i t had a dr ug t hat was r eady t o be mar ket ed, t hey woul d come t o t he Food and Dr ug Admi ni st r at i on wi t h what was known- - and st i l l i s, of cour se- - as a " New Dr ug Appl i cat i on" ( NDA) .
Thi s was a compi l at i on of mat er i al
45
t o show t hat t he dr ug was saf e f or i t s pr oposed use or uses. woul d consi st of t hr ee par t s.
It
Ther e woul d be a chemi st r y par t
whi ch descr i bed t he dr ug, how i t was made, what di f f er ent i ngr edi ent s went i nt o i t , how t he manuf act ur er woul d i nsur e pur i t y at al l st eps al ong t he way, how t hey woul d i nsur e t hat t he dr ug woul d al ways be t he same each t i me t hey made i t , how st abl e i t was- - t hese and var i ous ot her sundr y aspect s woul d come under t he chemi st r y par t .
The chemi st s i n our gr oup r evi ewed t hat
par t . Then t her e woul d be phar macol ogy- - t he ani mal st udi es t hat had been done t o show t he dr ug was saf e.
These st udi es woul d
usual l y be t o t est f or acut e t oxi ci t y, i n whi ch a si ngl e dose of var yi ng amount s was gi ven t o ani mal s- - usual l y r at s, mi ce, or dogs- - i n essence, t o see how l i t t l e ki l l ed t hem r at her t han how much t hey coul d t ol er at e.
What i s usual l y done i s t o have a
l ar ge gr oup of ani mal s and t hen det er mi ne t he dose whi ch wi l l ki l l hal f of t hem.
Thi s i s t he LD 50.
I f t he dose t hat woul d
ki l l al l of t hem had t o be f ound, t her e woul d al ways be a f ew ver y r esi st ant ones.
At t he ot her end, i f i t was t he dose t hat
woul d ki l l t he l east number , t her e woul d al ways be a f ew sensi t i ve ones.
I nst ead, a f ai r l y l ar ge gr oup of ani mal s was
sel ect ed and t hen t he r esear cher woul d see at what cut - of f poi nt 50 per cent of t hem sur vi ved, or t o say i t t he ot her way, at what poi nt 50 per cent di ed.
That woul d be t he LD 50.
Thi s gi ves a
measur e of whet her i t i s an ext r emel y t oxi c dr ug or a r el at i vel y
46
non- t oxi c dr ug.
Then t her e ar e al so st udi es i n whi ch t he dr ug i s
gi ven f or a l ong per i od of t i me at var i ous dosage l evel s, al ways choosi ng one whi ch wi l l gi ve some adver se ef f ect s. some i dea of t he t oxi ci t y.
Thi s gi ves
Wi t h a ver y hi gh dose t her e mi ght be
l i ver pr obl ems, f or exampl e.
Thi s woul d not necess ar i l y mean
t hat t he dr ug coul d not be used i n man because i t mi ght be ef f ect i ve at a much l ower dose, but at l east i t woul d al er t peopl e t o l ook out f or t hat .
That woul d be t he phar macol ogy
par t , and i t usual l y was r evi ewed by t he phar macol ogi st s. Somet i mes, i n t hose days, t he medi cal of f i cer s woul d f eel t hey coul d do t hat as wel l .
Nowadays i t i s al ways done by t he
phar macol ogi st s. Fi nal l y t her e woul d be t he cl i ni cal st udi es.
These woul d be
t he cl i ni cal t r i al s i n whi ch t he dr ug had been gi ven t o physi ci ans who wer e supposed t o be adequat el y t r ai ned, and t he physi ci ans wer e supposed t o make car ef ul obser vat i ons and honest l y r ecor d t hei r f i ndi ngs of t he t r i al s.
The case r epor t s
woul d be submi t t ed i n t he appl i cat i on. We knew t hat many cl i ni cal t r i al s wer e poor l y per f or med, par t i cul ar l y at t hat t i me.
As a newcomer I must say I was qui t e
shocked somet i mes at t he cal i ber of t he wor k t hat had gone i nt o t he appl i cat i ons i n suppor t of saf et y. i mpr oved over t he year s.
That has def i ni t el y
Our r equi r ement s ar e now much mor e
st r i ngent , and t he whol e sci ence of cl i ni cal phar macol ogy and t he t est i ng of dr ugs has devel oped gr eat l y i n t he l ast f i f t een or
47
t went y year s.
We now have bet t er met hods of t r yi ng out dr ugs.
We have bet t er - t r ai ned peopl e, who, i f t hey ar e not doi ng t hese st udi es, ar e at l east desi gni ng t hem and seei ng t hat t hey ar e done pr oper l y. t hat .
The Kef auver l egi sl at i on had somet hi ng t o do wi t h
I t st r engt hened t he r equi r ement s f or one t hi ng.
And, as a
consequence of t he t i ght ened i nvest i gat i onal dr ug r egul at i ons, by whi ch t he dr ug compani es now have t o send i n t he st udi es r i ght f r om t he st ar t , t he l egi sl at i on has done a gr eat deal t o i nsur e bet t er st udi es. At t he t i me I ar r i ved at t he FDA I t hi nk t her e wer e about t wel ve or t hi r t een medi cal of f i cer s i n t he gr oup r evi ewi ng new dr ug appl i cat i ons- - and a number of t hose peopl e wer e hal f - t i me. I t was ver y di f f i cul t i n t hose days t o get peopl e t o wor k as medi cal of f i cer s i n t he gover nment .
The pay was ver y l ow
compar ed t o what a physi ci an coul d ear n el sewher e, and many physi ci ans di d not l i ke t hat t ype of desk wor k.
The FDA depended
a l ot , f or exampl e, on peopl e who had j ust compl et ed t hei r r esi denci es and wer e st ar t i ng out i n pr act i ce i n t own and woul d gi ve hal f a day t o r evi ewi ng appl i cat i ons.
Ther e woul d be a
pr et t y bi g t ur nover of physi ci ans goi ng t o, say, dr ug f i r ms, whi ch of cour se happens now.
Thi s i s t o be expect ed because t he
same t ype of ski l l s ar e ut i l i zed at t he FDA as at t he dr ug f i r ms. Ther e i s no quest i on t hat we have l ost a number of peopl e t o i ndust r y. Ther e wer e a f ew ot her medi cal of f i cer s.
For exampl e, at
48
t hat t i me t her e wer e t hr ee or f our medi cal of f i cer s st at i oned t hr oughout t he count r y. Wei l er st ei n.
One was i n San Fr anci sco, Dr . Ral ph
One was i n Chi cago. I cannot r emember t he man' s
name, but he was qui t e act i ve. Yor k ar ea.
I t hi nk t her e was one i n t he New
For a whi l e t hese posi t i ons al l di ed out , and t hen
t hey st ar t ed r evi vi ng t hem agai n.
As I r ecal l , t he Di vi si on of
Ant i bi ot i cs was r eal l y a di f f er ent sect i on under i t s own r ul es at t hat t i me, because t hey had pet i t i ons, not new dr ug appl i cat i ons. So t hey wer e not i ncl uded i n t he number of medi cal of f i cer s I gave. My i mmedi at e super vi sor was Dr . Ral ph Smi t h, but t her e was al so Dr . I r wi n Si egel , who was deput y t o Dr . Smi t h and had a l ot t o do wi t h i ndoct r i nat i ng new peopl e.
I woul d of t en go t o hi m
wi t h pr obl ems, and t hen t o Dr . Smi t h. I was not swamped wi t h t oo much wor k at f i r st .
I cannot
r emember t he appl i cat i on l oad at t hat t i me, but i t was not hi ng l i ke i t i s now wi t h t he i nvest i gat i onal dr ug exempt i ons and t he much l ar ger new dr ug appl i cat i ons t hat t he medi cal of f i cer s have t o eval uat e.
The vol ume of t he NDAs has i ncr eased.
For exampl e,
I t hi nk t he t hal i domi de NDA was f our vol umes; now t he NDAs come i n 150 t o 200 vol umes or mor e. met r opol i t an phone book i n si ze. t hi ckness.
I woul d descr i be a vol ume as a That gi ves an i dea of
The i ncrease i n si ze of NDAs i s cer t ai nl y, i n par t ,
due t o t he mor e det ai l r equi r ed t o est abl i sh bot h saf et y and now, of cour se, ef f i cacy as wel l .
49 Thalidomide
I came on t he f i r st of August 1960 and I t hi nk I got t he t hal i domi de appl i cat i on i n ear l y Sept ember 1960. was t he second one t hat was gi ven t o me.
I bel i eve i t
I was t he newest per son
t her e and pr et t y gr een, so my super vi sor s deci ded, " Wel l , t hi s i s a ver y easy one.
Ther e wi l l be no pr obl ems wi t h sl eepi ng pi l l s. "
So t hat i s how I happened t o get t he appl i cat i on. anot her one qui t e l i ke t hat one.
I never got
I know t he ot her dr ug gi ven t o
me at t he same t i me was a r ect al enema, whi ch I t hi nk had t he name of Lavema.
I t di d get mar ket ed, so I must have appr oved i t .
I came t o r evi ew t hal i domi de, t hen, as a new dr ug appl i cat i on.
At t hat t i me, we had si xt y days af t er r ecei pt of
t he NDA i n whi ch ei t her t o r ej ect i t , or i f we had no obj ect i on or i f we f or got t hat t he 60 days had el apsed, t he dr ug aut omat i cal l y became appr oved and t he company coul d put i t on t he mar ket .
I t was possi bl e t o say t hat t he appl i cat i on was
i ncompl et e and t hen det ai l t he def i ci enci es.
Ther e woul d, of
cour se, be a pr od on t he f i f t y- ni nt h day af t er t he ar r i val of ever y appl i cat i on t o make sur e t hat at l east some l et t er had been i ssued t o t he f i r m i f t her e was a mat t er f or concer n.
Ther e was
al ways t he f ear , t hat t hr ough somebody bei ng asl eep at t he swi t ch t he si xt y days mi ght go by and t hen t he appr oval woul d be aut omat i c.
I under st and i t had happened once.
We had t o be pr et t y speci f i c i n sayi ng t hat an appl i cat i on was i ncompl et e.
Revi ewer s had t o be f ai r about t hi s, and al l
50
t hr ee di sci pl i nes woul d mar shal t hei r obj ect i ons.
I t r eal l y was
not spor t i ng t o hol d one appl i cat i on asi de and t hen when t he si xt y days had el apsed j ust t o sneak t hat i ncompl et e i n.
We wer e
supposed t o t r y and pass on or descr i be why when t he appl i cat i on was bei ng t ur ned down.
I n gener al , we wer e supposed t o do an
honest and t hor ough r evi ew.
Thi s coul d be done on a smal l
appl i cat i on. The t hal i domi de appl i cat i on was r evi ewed by t hr ee peopl e: a chemi st , a phar macol ogi st f or t he ani mal wor k, and a medi cal of f i cer , whi ch, of cour se, was mysel f .
The chemi st was Lee
Gei smar , who i s s t i l l wi t h t he Food and Dr ug Admi ni st r at i on, and t he phar macol ogi st was J i r o Oyama, who I bel i eve i s not wi t h t he agency any mor e.
Now, i n t hose days, as I ment i oned, t he
phar macol ogi st was i n anot her bui l di ng and anot her bur eau ent i r el y.
The chemi st s wer e i n a separ at e di vi si on or br anch- - I
cannot r emember what t hey wer e desi gnat ed as i n t hose days- - and t he medi cal of f i cer s wer e i n st i l l a t hi r d.
Nowadays, t he
ar r angement has t he chemi st , t he phar macol ogi st , and t he medi cal of f i cer wor ki ng vi r t ual l y si de- by- si de wi t hi n t he same di vi si on i n t he same bui l di ng and on t he same f l oor .
Thi s means t hat t hey
can f r equent l y get t oget her and exchange pr obl ems. Unf or t unat el y, i n t hose days, we wer e separ at ed.
We wer e
not much of a t eam, al t hough Lee Gei smar and I wer e i n t he same bui l di ng, and I am sur e we woul d go t o meet i ngs t oget her .
In
t hose days t he medi cal of f i cer s act ual l y got gr eat suppor t f r om
51
t he chemi st s, who wer e t he ones, i n a way, who i nst r uct ed us mor e t han anyone el se di d i n t he ar t of dr awi ng up t hese l et t er s t o dr ug compani es- - usi ng t he r i ght sect i ons of t he l aw.
Lee woul d
have had a gr eat deal of wor k and r esponsi bi l i t y i n t hi s ar ea. Ther e was no r eason why a dr ug shoul d have t o f ai l i n al l t hr ee ar eas t o be r ej ect ed, but i f i t f ai l ed i n even one aspect i t woul d st i l l be hel d f or t hat si xt y days.
I f t he chemi st r y,
f or exampl e, was i ncompl et e, t he chemi st al one coul d hol d i t .
In
t hose days t he l et t er s went out under t he medi cal of f i cer ' s si gnat ur e; now t hey go out f r om t he di vi si on di r ect or . Al l t hr ee of us f ound pr obl ems r evi ewi ng t hal i domi de t he f i r st t i me ar ound.
The chemi st ' s r evi ew showed t hat t her e wer e
some mat t er s t hat had t o be cl ear ed up.
I t hought t he chemi st r y
pr obl em was i nt er est i ng because Lee Gei smar had been t r ai ned i n Ger many, and coul d r ead Ger man.
Si nce t he dr ug was or i gi nal l y
made by a Ger man f i r m, a l ot of t he submi ssi ons wer e i n Ger man. Of cour se, t he company was supposed t o t r ansl at e t he mat er i al , and Lee f ound t hat t hey had made mi st akes i n t r ansl at i on. r at her i nt er est i ng t hat we coul d pi ck t hat up.
I t was
I do not know i f
t he mi st akes wer e of any gr eat si gni f i cance, but i t was ver y handy havi ng someone who coul d r ead f or ei gn l anguages, because many of t hese ear l y chemi cal st udi es wer e done i n Ger many.
Dr .
J oseph Mur r ay of Mer r el l cal l ed on Lee Gei smar , t he chemi st who r evi ewed t he appl i cat i on.
She had some i nf or mat i on on t he
chemi st r y, but even at t hat dat e- - 6 J anuar y 1961- - t he chemi st r y
52
was not set t l ed compl et el y; t her e wer e some pr obl ems. Fr om t he phar macol ogi cal st andpoi nt , t hal i domi de l ooked good, but t he phar macol ogi st di d poi nt out t hat t her e was a quest i on about absor pt i on.
I n hi s r evi ew, I t hi nk he i ndi cat ed
t hat how saf e i t was mi ght be a mat t er of t he absor pt i on of t he dr ug.
Thal i domi de i s rel at i vel y non- t oxi c i n ani mal s but i t i s
ver y poor l y absor bed.
I n ani mal s i t coul d be t aken i n l ar ge
dos es or al l y wi t hout i l l ef f ect s . As r egar ds t he cl i ni cal ar ea- - whi ch was my own ar ea- - i t was expect ed t hat an i deal sl eepi ng pi l l woul d meet cer t ai n cr i t er i a, such as t he f act t hat i t woul d not pr oduce a hangover t he next day and so on.
The cl ai ms made i n t he NDA f or t hal i domi de wer e
t oo gl owi ng f or t he suppor t i n t he way of cl i ni cal back- up.
That
was t he i ni t i al t hi ng t hat per haps l ed us t o r equi r e mor e subst ant i at i on.
The cl ai ms wer e j ust not suppor t ed by t he t ype
of cl i ni cal st udi es t hat had been submi t t ed i n t he appl i cat i on. I cannot r emember what t he exact number of doct or s' r epor t s i n t he i ni t i al submi ssi on was, I t hi nk about t hi r t y, and many of t hem wer e mor e t est i moni al s t han sci ent i f i c st udi es.
That was
t he good bul k of t hem. The appl i cat i on may have sat i sf i ed t he phar macol ogi st ' s cri t er i a or t he FDA' s cri t er i a f or phar macol ogi cal wor k, but i f t he cl i ni cal par t was st i l l poor t hen t hi s woul d be a nonappr oval .
But i t woul d al so be a concer n i f t he phar macol ogy
wer e i ncompl et e.
I f t he medi cal r evi ewer was uneasy about t he
53
cl i ni cal wor k, t hen he or she woul d cer t ai nl y want mor e phar macol ogy st udi es.
As I not ed, we al l t hr ee f ound
def i ci enci es i n t he t hal i domi de appl i cat i on, and t ol d Mer r el l so. Then t hey br ought t oget her mor e i nf or mat i on, but we st i l l f ound def i ci enci es so t hey r esubmi t t ed. I n t hose days, when a dr ug was under r evi ew t her e woul d be a gr eat cur i osi t y on t he par t of t he dr ug compani es.
I t was
under st andabl e t hat t he f i r ms woul d want t o know how t he r evi ew was pr ogr ess i ng and, of cour se, t hat t hey woul d have consi der abl e di sappoi nt ment when t hose si xt y- day l et t er s came. i f t hat i s st i l l t he case.
I do not know
I am out of t ouch wi t h t hat aspect of
i t now, as I am not on t he r evi ewi ng end.
Ther e ar e mor e f or mal
meet i ngs set up now, and t he f i r ms ar e di sc our aged f r om maki ng cont i nual cont act s wi t h FDA r evi ewer s. I have been asked whet her t he dr ug compani es had t oo gr eat an access t o me.
That i s a r at her har d quest i on t o answer
because one has t o be f ai r and see t hei r i nt er est s.
Many of t he
dr ug compani es genui nel y f eel t hat t hey have a r eal l y good dr ug ( and occasi onal l y t hey do) , and t hey have spent a l ot of t i me get t i ng t hese appl i cat i ons r eady- - l i ni ng up t he peopl e t o do t he wor k, get t i ng t he ani mal st udi es, et c. - - so t hei r hopes ar e r i di ng hi gh.
Wi t h t hal i domi de, because i t had been successf ul l y
mar ket ed i n Eur ope, I t hi nk one of t he poss i bl e r easons why Mer r el l ' s appl i cat i on was so poor was t hat i t seemed l i ke a sor t of pushover , t hat i t woul d have no pr obl em at al l bei ng appr oved.
54
Per haps t hey had not gi ven t he appl i cat i on t he at t ent i on i t deser ved, such as get t i ng t he best peopl e as i nvest i gat or s, whi ch i s a st andar d appr oach i n t he case of an unknown dr ug.
It is
necess ar y i n t he case of t hal i domi de t o t ake t he Eur opean exper i ence wi t h t he dr ug i nt o consi der at i on. Dr . J oseph Mur r ay was t he cont act man f r om Mer r el l .
Hi s
backgr ound was i n bact er i ol ogy; he was a bact er i ol ogi st , not an M. D.
I t hi nk he was qui t e f r ust r at ed, t o put i t mi l dl y, by t he
pr obl ems r ai sed i n t he r evi ew.
I suppose he had been gi ven t he
r esponsi bi l i t y of get t i ng t he NDA appr oved as qui ckl y as possi bl e, and t o have t hese r oadbl ocks t hr own up must have been qui t e annoyi ng. My f i r st di ssat i sf act i on wi t h t he t hal i domi de appl i cat i on, as I ment i oned, cent er ed on t he qual i t y of t he cl i ni cal r epor t s, because t hey wer e mor e i n t he nat ur e of t est i moni al s r at her t han wel l - desi gned, wel l - execut ed st udi es.
I r equest ed Mer r el l , I
bel i eve, t o get bet t er cl i ni cal st udi es and t o pr ovi de us wi t h a l i t t l e bet t er evi dence of t hese var i ous and sundr y cl ai ms t hat t hey had made. Thal i domi de had been mar ket ed and ver y wi del y di st r i but ed i n Eur ope si nce about 1957.
The next st ep i n t he st or y was pr obabl y
i n l at e J anuar y or ear l y Febr uar y of 1961 when my at t ent i on was dr awn t o a l et t er t o t he edi t or by Dr . Lesl i e Fl or ence i n t he Br i t i sh Medi cal J our nal of 31 December 1960 i n whi ch he r epor t ed per i pher al neur i t i s, a ver y pai nf ul t i ngl i ng of t he ar ms and
55
f eet , i n pat i ent s r ecei vi ng t he dr ug t hal i domi de f or a f ai r per i od of t i me.
Thi s ef f ect was ver y sever e i n some cases, and
possi bl y not r ever si bl e.
I was br owsi ng t he j our nal when I r ead
t hi s i n l at e J anuar y or ear l y Febr uar y 1961. t he j our nal s we br owsed t hr ough. t hat .
The BMJ was one of
I t s f or mat i s ver y amenabl e t o
Al t hough t hi s i ss ue had been publ i shed on 31 December
1960, t her e was a pr obl em wi t h del i ver y of our j our nal s- - I t hi nk i t was a mai l st r i ke- - and t he j our nal di d not r each us unt i l l at e J anuar y or ear l y Febr uar y.
But t he per i pher al neur i t i s di d not
seem t he sor t of si de ef f ect t hat shoul d come f r om a si mpl e sl eepi ng pi l l .
We i mmedi at el y dr af t ed a l et t er t o t he company
aski ng f or mor e i nf or mat i on and mor e pr oof of saf et y.
I t was
appar ent t hat t hi s ef f ect mi ght be associ at ed wi t h t he use of t he dr ug. We l at er l ear ned t hat t hi s ef f ect had been r ecogni zed not onl y at t hi s t i me, but ear l i er i n Eur ope, and i t was t he mai n r eason why t he dr ug had been r emoved f r om over - t he- count er st at us i n Ger many and made a pr escr i pt i on i t em.
( I do not t hi nk i t was
ever sol d over - t he- count er i n Engl and. )
The l abel i ng of t he dr ug
by t he Eur opean compani es had car r i ed a war ni ng of t he possi bl e si de ef f ect of per i pher al neur i t i s, and I bel i eve i t was on t he l abel s at t he t i me t hat t he appl i cat i on was submi t t ed t o us because t hese si de ef f ect s ar e of t en r eal i zed bef or e t hey ar e r epor t ed i n pr i nt i n j our nal s.
Despi t e t hi s si de ef f ect bei ng
known i n Eur ope at t he t i me we r ecei ved t he appl i cat i on,
56
communi cat i ons wer e poor i n t hose days, and we wer e si mpl y not awar e of t hi s t i l l we had had t he dr ug f or about si x t o ei ght mont hs.
So t her e was an awar eness of t hi s adver se ef f ect bef or e
t hi s publ i cat i on appear ed, but not by us. We have no way of knowi ng whet her Mer r el l i n gener al was awar e of t hi s pr obl em.
They di d have r epr esent at i ves over seas,
but somet i mes t he f or ei gn oper at i ons of a domest i c dr ug f i r m ar e compl et el y separ at e f r om t hose i n t he Uni t ed St at es.
Dr . Mur r ay
cl ai med t hat he had not ed t he l et t er i n t he BMJ at about t he same t i me we di d.
I t seemed t o be a sur pr i se t o hi m.
But he di d not
br i ng i t up wi t h us, al t hough we had sever al phone cal l s i n t hi s per i od. cal l .
I asked hi m about i t , I t hi nk, on about t he t hi r d phone He had evi dent l y been awar e of t he r epor t , but had not
vol unt eer ed t he i nf or mat i on t hat t hal i domi de coul d cause per i pher al neur i t i s . As a f ol l ow- up t o t hi s l et t er i n t he BMJ , t her e was a meet i ng i nvol vi ng Dr . Mur r ay, Dr . Smi t h, and me.
Dr . Mur r ay
cl ai med t hat at t hi s meet i ng he was abl e t o convi nce me t hat Mer r el l had f i r st l ear ned of t he t oxi c si de ef f ect s of t hal i domi de f r om t he December i ssue of t he Br i t i sh Medi cal J our nal .
I f t hat was t he cas e I t hi nk t hei r i nt el l i gence was
ver y poor because t he pr obl em was wel l r ecogni zed.
They shoul d
have known i t i f t hey had done t hei r homewor k, or i f cont act s had been good bet ween t he t wo cont i nent s.
I do not t hi nk we had any
way of knowi ng whet her Eur opean busi ness ass oci at es had not i f i ed
57
t he Ci nci nnat i company t hat t hi s was an appar ent l y est abl i shed si de ef f ect .
The Food and Dr ug Admi ni st r at i on expl or ed ver y
t hor oughl y whet her Mer r el l had been negl i gent i n t hi s mat t er .
As
I r ecal l t hey coul d not est abl i sh anyt hi ng. I cannot r ecal l i f I was t aken aback by al l t hi s, but when I came t o t he Food and Dr ug Admi ni st r at i on I was unawar e of cer t ai n t hi ngs t hat I l ear ned af t er I ar r i ved her e!
For i nst ance, t he
f act t hat many of t hese cl i ni cal st udi es wer e poor l y conduct ed and poor l y r epor t ed, and t hat t her e was s ome l axness i n at t ent i on t o det ai l s such as t hi s. I t appear ed t hen as t hough Dr . Mur r ay had not pr ompt l y dr awn t hi s si de ef f ect t o our at t ent i on.
He di d go r at her pr ompt l y
over seas t o Eur ope t o l ook i nt o t he mat t er and cer t ai nl y gave t he i mpr essi on on hi s r et ur n when he r epor t ed t o us t hat t hi s s i de ef f ect was not par t i cul ar l y ser i ous and possi bl y was t i ed i n wi t h an i nadequat e di et - - per haps some vi t ami n def i ci enci es- - because he st at ed t her e wer e r egi onal di f f er ences i n wher e i t was not ed.
I
never di d see t hi s cl ai m wr i t t en up anywher e i n t he l i t er at ur e. I t was not unt i l somet i me l at er t hat we l ear ned t hat t hi s was appar ent l y a sever e si de ef f ect , and qui t e wi del y di st r i but ed; qui t e a number of peopl e suf f er ed f r om i t . not i mpr essed by Dr . Mur r ay' s r epor t .
We wer e
We r equest ed document at i on
and we asked hi m t o cont act al l t he i nvest i gat or s i n t he Uni t ed St at es who had used t he dr ug i n pat i ent s f or a pr ol onged per i od of t i me t o f i nd out i f t hey had any cases of per i pher al neur i t i s
58
i n t hei r pat i ent popul at i on. t hi s means.
I bel i eve sever al wer e l ocat ed by
Al so, of cour se, we wer e not awar e of t he wi despr ead
di st r i but i on t hat t hal i domi de had had i n t he Uni t ed St at es. I had asked Mer r el l ear l i er f or a l i st of i nvest i gat or s who had been gi ven t hal i domi de, and t he l i st had some t hi r t y or f or t y i nvest i gat or s on i t .
We asked t hat each of t hese be speci f i cal l y
quest i oned as r egar ds t he per i pher al neur i t i s.
Now, t he wor di ng
i n t he l et t er t o Mer r el l was such t hat i t gave an excuse f or t hem t o pr ovi de t he FDA onl y wi t h a l i st of t hose i nvest i gat or s who had had t hal i domi de l ong enough t o have had pat i ent s on i t f or a per i od of t i me; I t hi nk we asked f or t he names of t hose pat i ent s who had been usi ng i t f or f our mont hs or so.
We di d not get t he
l i st of t he per sons t hat had r ecei ved t hal i domi de i n t he dr i ve t o publ i ci ze t he dr ug, t hat i s, t he ot her t housand or so pat i ent s. We di d not become awar e of t hi s wi despr ead di st r i but i on of t hal i domi de unt i l af t er t he dr ug had been wi t hdr awn.
Ther e wer e
t he genui ne i nvest i gat or s who had wor ked wi t h i t f or a l ong per i od and whose f i ndi ngs had been submi t t ed t o us, and t hen t her e wer e t hose physi ci ans who wer e t ol d t hat t he dr ug was about t o come t o mar ket and t hat t hey need not bot her much about keepi ng r ecor ds. The next devel opment was t hat i n Apr i l 1961 t he company t r i ed a new appr oach t o move i t s appl i cat i on f or war d by t r yi ng t o pr ove t he val ue of t he dr ug t hr ough maki ng compar i sons of i t s saf et y t o t he l ack of saf et y of bar bi t ur at es.
I t was cont i nual l y
59
bei ng sai d t hat you coul d not commi t sui ci de wi t h t hal i domi de. di d not t hi nk t hat was a suf f i ci ent r eason unt o i t sel f .
I
Mar i l yn
Monr oe' s deat h coi nci ded wi t h t he t i me t he publ i ci t y on t hal i domi de appear ed, and t hi s was, and st i l l i s, a f avor i t e quot e:
" I f Mar i l yn Monr oe had t aken t hal i domi de she woul d st i l l
be al i ve. "
I shoul d poi nt out t hat I t hi nk t her e i s a gr ai n of
t r ut h i n t he ar gument t hat many peopl e make a sui ci de gest ur e and wi l l t ake pi l l s hopi ng and assumi ng t hat somebody wi l l f i nd t hem i n t i me and pump t hem out .
One coul d admi t t edl y t ake many
t hal i domi de t abl et s i n most cases and sur vi ve.
But t hi s di d not
out wei gh t he pot ent i al danger , and i t di d not out wei gh what was unknown about t hal i domi de at t hat t i me. On 25 May 1961, I wr ot e a l et t er t o Dr . Mur r ay expr essi ng concer n t hat evi dence of neur ol ogi cal t oxi ci t y appar ent l y was known t o Mer r el l wi t hout bei ng f or t hr i ght l y di scl osed i n t he appl i cat i on.
I t hi nk Dr . Mur r ay was r at her upset at r ecei vi ng
t hi s l et t er .
He t hought i t was sl i ght l y l i bel ous. Obvi ousl y, i n
t hat t el ephone conver sat i on I had at t he t i me I wr ot e t o hi m, he was awar e of t he pr obl em of per i pher al neur i t i s.
So I t hi nk I
was on per f ect l y saf e gr ound i n sayi ng t hat he had not f or t hr i ght l y di s cl os ed i t .
I t was ver y di f f er ent i f a pr obl em
was di sc l osed t he day af t er an appl i cat i on had been appr oved because wi t hdr awi ng an appl i cat i on was qui t e a t edi ous pr ocedur e. I t was as wel l t o make sur e ever y pr obl em t hat was seen had been i r oned out bef or e an appl i cat i on was appr oved.
60
I suspect t hat Mer r el l knew about t hese pr obl ems even bef or e Dr . Mur r ay had seen t he l et t er .
I t hi nk t hi s because when he
phoned me i t was t he day t he l et t er went out f r om her e, so he had not r ecei ved my l et t er .
I t l ooks as t hough t he l et t er was dat ed
t he same day he phoned, so t hat I mi ght not phone hi m and say, "We have l ear ned t hi s. "
I mi ght j ust put i n t he l et t er ,
" pr ovi ded t hat i t was i n t he si xt y- day f r amewor k. " I t was t he si de ef f ect of per i pher al neur i t i s t hat l ed us t o ask about t he use of t hal i domi de i n pr egnancy because, at j ust about t hat t i me, t her e was an i nt er est i n t he ef f ect s of dr ugs i n t he f et us.
The agency was al er t ed t o a pr obl em about embr yos and
newbor ns bei ng unabl e t o handl e dr ugs i n t he same way t hat an adul t can.
They do not have t he mat ur e enzyme syst ems, t he
mat ur e ki dney syst ems, and so on.
An ar t i cl e had appear ed i n
1960 t hat assembl ed t he i nf or mat i on known up t o t hat t i me. wer e ot her occur r ences wi t h cer t ai n dr ugs.
Ther e
One of t he vi t ami n K
pr epar at i ons was shown t o have a sever e ef f ect on t he new bor n. The dr ug chl or ampheni col ( Chl or omycet i n) , was shown t o be par t i cul ar l y t oxi c f or ver y smal l babi es because t hei r l i ver s wer e not abl e t o met abol i ze t he dr ug as an adul t ' s l i ver coul d. The pedi at r i ci ans i n t he FDA wer e wor ki ng ver y cl osel y t o devel op gui del i nes about t he saf et y of dr ugs i n i nf ant s.
These woul d
i ncl ude, of cour se, t he saf et y of dr ugs f or f et uses t hat mi ght be used i n pr egnancy.
Al so j ust about t hat t i me st er oi d hor mones
wer e used i n t hr eat ened mi scar r i ages, and i t t ur ned out t hat a
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number of t he f emal e babi es bor n t o mot her s who had t hi s t r eat ment had some degr ee of mascul i ni zat i on because of t hese pr ogest i n t ype dr ugs.
Al l of t hese t hi ngs wer e maki ng us t hi nk,
" When you gi ve a dr ug t o a pr egnant woman you ar e exposi ng, i n f act , t wo peopl e t o t he dr ug, t he mot her and t he chi l d. " Ot her peopl e besi des us i n t he Food and Dr ug Admi ni st r at i on wer e i nt er est ed i n t hese quest i ons.
Ther e was, f or exampl e, Dr .
I r vi n Ker l an who was i n t he adver se r eact i on ar ea; he was ver y i nt er est ed and ver y concer ned about t he ef f ect s of dr ugs.
Ker l an
was al so a pedi at r i ci an and he wor ked cl osel y wi t h pedi at r i ci ans. He had wor ked wi t h t he pedi at r i c gr oup i n dr awi ng up t he war ni ng about , " bear i n mi nd t he chi l d i s not a smal l adul t . "
Anot her
was Dr . J ohn Nest or , who was a medi cal of f i cer and a pedi at r i ci an; he t oo was par t i cul ar l y i nt er est ed i n t hi s ar ea. Dr . I r wi n Si egel was i nt er est ed i n t hi s t oo, because he was a cl i ni cal phar macol ogi st who was ver y knowl edgeabl e about dr ugs and had a good cl i ni cal backgr ound.
Thus, t he Food and Dr ug
Admi ni st r at i on was becomi ng i ncr easi ngl y awar e of t hi s ar ea.
I
was i nt er est ed i n i t because of my own pr act i cal exper i ence wi t h t he qui ni ne and embr yo st udy ear l i er .
So when t he t hal i domi de-
per i pher al neur i t i s quest i on came up, t hen we want ed t o know what had been t he exper i ence wi t h t hal i domi de i n pr egnancy. Her e was a dr ug t hat gi ven f or t hr ee or f our mont hs coul d cause sever e neur opat hy.
Wi t h t hal i domi de, a gr owi ng i nf ant
mi ght , per haps, be exposed t o i t f or f i ve or si x or up t o ni ne
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mont hs.
Thi s was t he sor t of dr ug t hat was t aken as a mi l d
sedat i ve/ hypnot i c, and t he mot her mi ght t ake i t a l ot dur i ng pr egnancy.
I do not know exact l y what t he genesi s of t hi s
concer n was.
But I t hi nk i t was t he f act t hat t hi s was somet hi ng
we wer e t hi nki ng about i n t er ms of al l dr ugs, due t o ot her r ecent exampl es.
I t was i n t he set t i ng; i t was real l y a new t hi ng- - t hi s
concer n about saf et y of dr ugs and chi l dhood. Mer r el l , t he dr ug company, di d not know of any pr obl ems wi t h t hal i domi de i n pr egnancy, but t hey had not conduct ed a st udy, except f or one usi ng i t i n l at e pr egnancy i n or der t hat t he mot her mi ght be mor e comf or t abl e, whi ch we di d not f eel was suf f i ci ent .
We poi nt ed out t hat t hi s was a r el at i vel y shor t
per i od of use compar ed t o what mi ght be t he ef f ect s of ni ne mont hs of use.
Of cour se we wer e not t hi nki ng i n t er ms of absent
ar ms or l egs necessar i l y.
We j ust t hought t hat i f i t di d
somet hi ng t o t he adul t i n t hi s per i od of t i me, i t mi ght wel l have an adver se ef f ect on t he chi l d.
The dr ug company was unwi l l i ng
t o under t ake a st udy, but t hey di d agr ee t o put a bi g war ni ng on t he l abel i ng, t hat t hi s dr ug shoul d not be t aken dur i ng pr egnancy si nce i t was not known what i t s ef f ect s woul d be.
We wer e r eal l y
mor e concer ned about t he per i pher al neur i t i s, whi ch t hey wer e al so wi l l i ng t o put on t he l abel i ng, but , f or one r eason or anot her , t hey never qui t e sat i sf i ed our demands.
Then, qui t e
suddenl y, t he news came f r om Eur ope about t he def or mi t i es. I n t he meant i me, Dr . Mur r ay was gr owi ng mor e f r ust r at ed.
He
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was par t i cul ar l y di sappoi nt ed because Chr i st mas i s appar ent l y t he season f or sedat i ves and hypnot i cs , and t he company had hoped t hat wi t h t he submi ss i on i n Sept ember 1960 t he dr ug woul d be out i n t i me f or t hat Chr i st mas season.
Then i t l ooked l i ke a second
Chr i st mas season was comi ng ar ound wi t h no dr ug.
He i ndi cat ed i n
a memo t hat t hey wi shed t o get i t out because i t was a seasonal dr ug. Mer r el l cont i nued t o t r y and convi nce me and t he FDA.
In
ear l y Sept ember 1961, Mer r el l hel d a conf er ence i n whi ch t hey cal l ed i n t hei r c l i ni cal i nves t i gat or s .
Thi s s or t of event i s
di f f i cul t , because t he dr ug company br i ngs i n peopl e f r om t he out si de, somet i mes peopl e associ at ed wi t h uni ver si t i es and so on, who have wor ked f or t he f i r m and ar e i nt er est ed i n phar macol ogy and dr ugs.
They t hi nk t he Food and Dr ug Admi ni st r at i on i s
obst r uct i oni st and so on.
Of cour se, t he dr ug company has
sel ect ed t he peopl e whom t hey know ar e goi ng t o back t hem.
So
such a conf er ence i s qui t e an or deal , t her e i s no quest i on about i t.
But when t he quest i on " I s t hal i domi de saf e i n pr egnancy?"
ar ose at Mer r el l ' s conf er ence, t hat ended t he cr i t i ci sm of t he FDA as peopl e r eal i zed t hat t he dat a wer e not t her e. r eal l y coul d not be sai d t o be saf e.
The dr ug
I t hi nk i t was at t hat t i me
t he suggest i on was advanced t hat i f t hal i domi de wer e t o be r el eased t hey woul d have t o put on a di scl ai mer t hat i t s s af e use i n pr egnancy was not known.
Thi s t ype of di scl ai mer was t he sor t
of t hi ng we had done bef or e, and I t hi nk we sai d, " I f you can
64
j ust gi ve us some cas e hi st or i es of wher e i t has been used t hr oughout pr egnancy. . . "
The i r oni c t hi ng was t hat Dr . Mur r ay
sai d, " Had t her e been any pr obl ems wi t h t hi s t hey woul d have been obser ved si nce t he dr ug has been so wi del y used. "
Thus t her e was
a r eal i zat i on of t he i ncrease i n t hi s t ype of bi r t h def ect , but i t had not been connect ed t o t he dr ug.
But we wer e not awar e
t hat t he Eur opeans had al r eady not i ced an i ncr ease i n phocomel i a. I n f act , FDA r ecor ds show t hat one of Mer r el l ' s cl i ni cal i nvest i gat or s had del i ver ed def or med babi es.
Thi s was ver y
i nt er est i ng because H. Wei cker was ver y cl ose t o i t .
He had a
hunch and he wr ot e ar ound t o var i ous cent er s i n t he Uni t ed St at es t o see i f t hey had exper i enced any i ncr ease i n t hese def or mi t i es, whi ch he knew had occur r ed i n Ger many.
Ther e was onl y one cent er
i n t he Uni t ed St at es t hat di d show some cases and t hat was i n Ci nci nnat i .
But Wei cker was t hr own of f because he was gi ven t o
under st and t hat t he dr ug was mar ket ed i n t hi s count r y. t hought , "I t can' t be t hal i domi de. "
So he
He di scount ed, I t hi nk, t he
Ci nci nnat i r esul t s as not bei ng anyt hi ng l i ke what was happeni ng i n Ger many.
I f t hal i domi de was t he cause, t hen sur el y t he
def or mi t i es woul d be i n t he St at es as wel l as i n Ger many. di d not r eal i ze t hat t he dr ug had never been mar ket ed.
But he
We have
copi es of t he l et t er t he Ger man f i r m sent out and i t woul d gi ve one t o under st and t hat t he dr ug was bei ng mar ket ed i n t hi s count r y.
I har dl y t hi nk t he company woul d have been conf used
about t hi s, but i t cer t ai nl y gave out t he i nf or mat i on.
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Now t he ext r aor di nar y t hi ng was t hat i t was qui t e a l ong t i me bef or e a posi t i ve connect i on bet ween t hal i domi de and t he def or mi t i es was made.
The company cl ai med i t was a f al se
associ at i on and t hat i t coul d not possi bl y be t he dr ug.
I t had
been so wi del y used, and i t was not possi bl e t hat t hi s was j ust comi ng t o publ i c at t ent i on.
Even t he speci al i st s, t he
t er at ol ogi st s who speci al i zed i n bi r t h def ects, had di f f i cul t y, because t hi s was not a t ypi cal dr ug t hat caused a t ypi cal def ect . The def ect s occur r ed i n doses t hat had absol ut el y no ef f ect i n t he mot her .
Even i f one l ooked onl y at t he mot her , t he dr ug di d
not have many adver se ef f ect s ( per haps a l i t t l e dr owsi ness) , so i t was unusual i n t hi s respect .
Thi s, I t hi nk, was anot her
r eason why i t t ook so l ong f or gener al accept ance t hat t he dr ug was at f aul t . On 30 November 1961, Dr . Mur r ay of Mer r el l i nf or med t he FDA t hat t he Ger man f i r m was wi t hdr awi ng t he dr ug f r om t he mar ket . I r emember ver y wel l when he cal l ed and t ol d us about t he i nf or mat i on t hey had r ecei ved f r om Ger many possi bl y l i nki ng t he dr ug wi t h bi r t h def ect s.
I was- - I admi t i t - - ver y sur pr i sed.
Thi s was what we had been want i ng t o make sur e woul d not happen wi t h t he dr ug and i t appear ed i t had.
Our obj ect i ons, as I have
poi nt ed out , wer e r eal l y on t heor et i cal gr ounds, l ar gel y based on t he f act t hat t her e was no evi dence t hat i t was saf e. had such evi dence we had t o quest i on t he saf et y.
Unt i l we
We r ecei ved
f ur t her i nf or mat i on f r om t wo FDA of f i ci al s who wer e i n Ger many at
66
appr oxi mat el y t he t i me t he news came out . what t hey had f ound.
They wr ot e a r epor t on
Mer r el l not i f i ed us t hat t hey wer e
di scont i nui ng cl i ni cal t r i al s wi t h t he dr ug i n t he Uni t ed St at es unt i l t hey got f ur t her i nf or mat i on concer ni ng t hese pr el i mi nar y r epor t s f r om Ger many on bi r t h def ect s.
So, i n essence, we wai t ed
f or f ur t her i nf or mat i on and we di d get some i n t he f or m of l i t er at ur e r epor t s.
I bel i eve we got a l ong memo f r om t he U. S.
Sci ent i f i c At t aché.
The sci ent i f i c at t aché i n Eur ope sent a
r epor t , f or exampl e, t o t he Nat i onal I nst i t ut es of Heal t h- possi bl y ear l y i n J anuar y 1962- - expl ai ni ng or descr i bi ng t he ci r cumst ances of t he pr obl em wi t h t he dr ug i n Eur ope. Today we woul d j ust f l y over t o Eur ope and i nvest i gat e t hi s mat t er our sel ves.
Thi s i s one of t he gr eat benef i t s of t he
i mpr ovement s i n t he l aw and t he gr eat er st r ess on saf et y and so on: we have become much mor e act i ve i n pur sui ng t hese cl ues and set t l i ng mat t er s our sel ves, not necessar i l y dependi ng on secondor t hi r d- hand i nf or mat i on.
We have become much mor e cl osel y
al l i ed, as i t wer e, wi t h f ood and dr ug est abl i shment s i n ot her count r i es, wi t h exchange of i nf or mat i on.
Ther e ar e ot her
count r i es whi ch have adopt ed r egul at or y sys t ems, and we do have a f ai r exchange of i nf or mat i on wi t h t hose count r i es. So, i n November 1961 Mer r el l i ndi cat ed t o us t hat t hey woul d not do any f ur t her t est i ng on t he dr ug unt i l t hey got mor e pr eci se i nf or mat i on.
Mer r el l t hen sent out war ni ng l et t er s t o
doct or s i n t he Uni t ed St at es on 5 December 1961.
Thi s f i r st
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l et t er onl y went t o a r at her l i mi t ed number of i nvest i gat or s- t hose whose names had been submi t t ed i n t he NDA, f or exampl e.
So
t he t hi r t y or f or t y i nvest i gat or s t hat wer e named i n t he New Dr ug Appl i cat i on wer e cont act ed, and we ass umed t hat t hese wer e al l t he peopl e t hat had t he dr ug. On 8 Mar ch 1962 t he f or mal wi t hdr awal of t he appl i cat i on was submi t t ed.
Ther e i s not hi ng t hat woul d l ead me t o t hi nk we had
r equest ed t he wi t hdr awal .
I t hi nk Mer r el l wi t hdr ew i t of t hei r
own accor d when t hey wer e f i nal l y convi nced t hat t her e r eal l y was a pr obl em r el at ed t o t he dr ug. t hat i t was not so.
Unt i l t hat t i me t hey wer e hopef ul
As I r ecal l , t hey di d r equest per mi ssi on t o
cont i nue t hr ee t ypes of st udi es ( one was cancer ) wher e t her e woul d be no hazar d i nvol ved. I t may seem t hat t her e was a r at her l ong per i od bet ween November and Mar ch.
But , f or any adver se r eact i on r epor t l i ke
t hi s, t her e i s al ways a per i od of doubt wher e one i s not sur e t hat t her e i s a r eal cor r el at i on.
Except f or r at her smal l not es,
t her e wer e no publ i shed ar t i cl es on t he pr obl em of def or mi t i es, f or exampl e, unt i l about Febr uar y 1962.
We wer e awar e t hat t hi s
dr ug was i n t he i nvest i gat i onal st age, and we f el t t hat i t was wel l under cont r ol by t he sponsor s.
I n ot her wor ds, we bel i eved
t hat t hey had i nf or med t hei r i nvest i gat or s and had war ned t hem. At a cer t ai n poi nt t he FDA began t o suspect t hat al l was not r i ght .
My r ecol l ect i on i s t hat when we got t he l et t er i n Mar ch
1962 i ndi cat i ng t he company wi shed t o wi t hdr aw t he appl i cat i on,
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i t i ndi cat ed t hat i n December 1961 al l act i ve i nvest i gat or s had been not i f i ed of t he pr obl em and t ol d t o di scont i nue st udi es unt i l t he mat t er was cl ear ed up.
The company t hen st at ed t hat a
l et t er had now been i ss ued on 21 Febr uar y 1962 t o al l i nvest i gat or s- - al l who had r ecei ved t he dr ug- - t el l i ng t hem of t hi s.
Thi s l ed us t o t hi nk at t he FDA t hat t her e mi ght have been
some peopl e who had not r ecei ved t he ear l i er l et t er .
My
r ecol l ecti on i s t hat t hi s i s what l ed us t o r equest t he l i st of al l t he physi ci ans who had been suppl i ed wi t h t he dr ug. Thi s was t he l et t er t he FDA sent t o Mer r el l on 11 Apr i l 1962.
Now, i n any dr ug t r i al , one expect s a cer t ai n number of
t he physi ci ans never t o bot her t o t est t he dr ug or j ust t o i ndi cat e t hey ar e di si nt er est ed i n i t , so one knows t hat of t en f ewer per sons have used t he dr ug t han t hose who have been sent i t.
Cer t ai nl y t he l at t er i s t he bi gger number . We got r ei nf or cement of our bel i ef t hat i t was t he dr ug t hat
caused t he def or mi t i es f r om Dr . Hel en Tauss i g, a r enowned woman pedi at r i c car di ol ogi st , at t he J ohns Hopki ns Uni ver si t y.
Dr .
Taussi g was f amous f or devel opi ng t he Bl al ock- Taussi g sur ger y f or bl ue babi es. She had had many r esi dent s t r ai n under her i ncl udi ng one, Dr . J ohn Nest or , whom I have al r eady ment i oned and who wor ked f or t he Food and Dr ug Admi ni st r at i on.
She l ear ned of t hi s
pr obl em of def or mi t i es f r om a Ger man physi ci an who had t r ai ned wi t h her i n Bal t i mor e.
Her s peci al t y was pedi at r i c hear t
def ect s, and t he Ger man physi ci an wr ot e t o her t hat many of t hese
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chi l dr en had car di ac def ect s and t hat she shoul d come t o Ger many and l ook t hem over .
She came back wi t h st r i ki ng phot ogr aphs
af t er havi ng t al ked t o ever yone over t her e.
She t al ked t o dr ug
manuf act ur er s, t o par ent s of def or med chi l dr en, t o sci ent i st s, and t o epi demi ol ogi st s.
She r ecei ved suppor t f or t hi s t r i p f r om
t he Amer i can Hear t Associ at i on, t he Mar yl and Hear t Associ at i on, and t he NI H, and she spent about si x weeks i n Ger many vi si t i ng var i ous cent er s wher e t hey had had exper i ence wi t h t hese def or mi t i es.
We al ways l i nk t hal i domi de wi t h l i mb def ect s, but
act ual l y a number of t he chi l dr en had congeni t al hear t di sease, t oo.
Thi s, of cour se, was her pr i mar y i nt er est . Dr . Tauss i g cal l ed Dr . Nest or about t he end of Mar ch or
ear l y Apr i l 1962 and t ol d hi m she was j ust back f r om Eur ope wher e she had seen some ver y shocki ng ef f ect s, appar ent l y due t o a dr ug; she wi shed t o di scuss t hem wi t h r epr esent at i ves of t he Food and Dr ug Admi ni st r at i on.
On 6 Apr i l 1962 he and I dr ove over t o
her home i n Bal t i mor e and she t ol d us what she had l ear ned.
She
was t he f i r st - hand cont act who was abl e t o show us t he evi dence- t he pi ct ur es, t he case hi st or i es, and t he var i ous bi t s and pi eces of evi dence t hat l ed t o t he concl usi on t hat t hi s was def i ni t el y dr ug- r el at ed.
I r emember s he was par t i cul ar l y st r uck by t he f act
t hat some of t hese af f ect ed chi l dr en wer e chi l dr en of empl oyees of t he dr ug f i r ms i n quest i on.
She was not awar e at t he t i me
t hat t hi s dr ug was on cl i ni cal t r i al i n t hi s count r y.
So, I
t hi nk she had cal l ed Dr . Nest or mor e as a mat t er of i nt er est and
70
concer n, not knowi ng t hat t her e was some exper i ence wi t h t he dr ug i n t hi s count r y.
She was gat her i ng her i nf or mat i on j ust af t er
Mer r el l had f or mal l y wi t hdr awn i t s appl i cat i on. She was named pr esi dent of t he Amer i can Hear t Ass oci at i on, so she was much est eemed.
She t al ked about t he dr ug at t hat
soci et y' s meet i ng, and got peopl e much mor e concer ned t han t hey had been i n t he past .
She i nf or med a meet i ng of t he Amer i can
Col l ege of Physi ci ans on 11 Apr i l 1962 about t he out br eak of phocomel i a.
She even t al ked bef or e t he House Commi t t ee t hat was
consi der i ng, at t hat ver y t i me, st r engt heni ng t he Uni t ed St at es dr ug l aws.
She pr esent ed her f i ndi ngs t her e, and I was i n t he
audi ence. Our r equest f or t he compl et e l i st f r om Mer r el l f ol l owed our vi si t wi t h Dr . Taussi g and our r eal i zat i on t hat t hi s was a ver y def i ni t e associ at i on and t hat t her ef or e we woul d have t o t ake al l t he measur es we coul d t o make sur e t hat none of t he dr ug was r emai ni ng i n t hi s count r y wher e i t mi ght be used. sent on 11 Apr i l 1962.
The l et t er was
I n suppl yi ng t hi s l i st , t he company al so
gave us t he copi es of t he f or m l et t er s t hey had sent out dat ed December 1961 and Mar ch 1962.
I n t hei r wor di ng t he company
st at ed t hat al l act i ve i nvest i gat or s as wel l as ot her s who had r ecei ved t he dr ug wer e cont act ed by l et t er on 20 Mar ch 1962. Thi s was what made us r eal i ze t hat not al l t he i nvest i gat or s had r ecei ved t he l et t er of December 1961.
Ther e mi ght be per sons who
wer e unawar e of t he pr obl em and had suppl i es of t he dr ug i n t hei r
71
possessi on.
So t hi s was t he begi nni ng of t he i nspect i on of ever y
i ndi vi dual i nvest i gat or who had got t en t he dr ug and t her e wer e over 1, 000.
Fol l owi ng t he r ecei pt f r om Mer r el l of t he compl et e
l i st of mor e t han 1, 000 physi ci ans who had r ecei ved t he dr ug, we br oke down t he l i st i nt o speci al t y ar eas i n var i ous st at es.
Thi s
was t he pr el ude t o goi ng ar ound t o each one of t he doct or s i ndi vi dual l y, pi ck up t he suppl i es of t he dr ug t hey had on hand, f i nd out i f t hey had used t he dr ug, and i f i t was bei ng used i n any pr egnant women, and i f t hey had any bi r t h def ect s as a r esul t .
Out of t hat we got t wo or t hr ee r epor t s.
By t hi s
quest i oni ng and by l ooki ng at bi r t h st at i st i cs, we coul d ass oci at e t en cases of phocomel i a wi t h t he t hal i domi de t hat was r el eased f or cl i ni cal t r i al s i n t hi s count r y, and seven or mor e cases i n t hose who had got t en t he dr ug over seas. As I r ecal l , Mr . Wi nt on Ranki n t ook l eader shi p on t hi s pr obl em i n t he FDA i n many r espect s, over and above Dr . Smi t h and Dr . Si egel , who wer e i n t he Bur eau of Medi ci ne. Mer r el l ' s r epl y on 25 Apr i l 1962.
We r ecei ved
That was t he r epl y t hat gave
t he compl et e l i st of over a t housand physi ci ans and t he copi es of t hese f or m l et t er s t hat went out t o t he physi ci ans bot h i n December and Mar ch. The next si gni f i cant dat e i n t he chr onol ogy of event s i s 20 J ul y 1962, when E. R. Beckwi t h met wi t h Lar r i ck and t ol d t he FDA Commi ss i oner t hat a r ecal l had been under t aken and compl et ed. Thi s was al most t wo mont hs af t er we had r ecei ved t he l i st wi t h
72
t he l ar ger number of i nvest i gat or s on i t .
But I was not t oo much
i nvol ved i n t hi s aspect ; I was back on ot her I NDs and NDAs. Anot her gr oup was t aki ng over i n t hi s.
But I t hi nk one t hi ng t o
not e i s t hat an i nspecti on and r ecal l l i ke t hi s i s a f ai r l y ponder ous t hi ng.
I t t akes a l i t t l e t i me t o get out t he
di r ect i ons, quest i onnai r es, and ot her t hi ngs t hat t he physi ci ans have t o be asked, so an over ni ght r ecal l cannot be made. I do not know what t he Mer r el l r ecal l consi st ed of - - whet her t hey si mpl y sent l et t er s of not i f i cat i on or whet her det ai l men went f r om of f i ce t o of f i ce wi t h not i f i cat i ons.
I t was ar ound
t hat t i me, t hough, t hat we di d come i nt o possessi on of di r ect i ons t o det ai l men t hat made us r eal i ze t hat t hi s dr ug was bei ng handl ed ver y casual l y by t he f i r m when i t was bei ng di st r i but ed t o t he i nvest i gat or s.
They wer e t ol d t hat t he dr ug was vi r t ual l y
r eady t o be appr oved and, i n ess ence, i t was a det ai l i ng pr ocedur e t o get t hem f ami l i ar wi t h t hi s dr ug.
But we wer e not
awar e of t hi s ear l i er . I di d meet wi t h t he r epr esent at i ves f r om Mer r el l pr obabl y about t hat t i me, and I t hi nk t her e i s a repor t of t hat - - I have a memo of t hat i n t he f i l e.
Mer r el l of f i ci al s wer e anxi ous t o
l ear n i f I had been t r eat ed per haps a l i t t l e har shl y by t hei r r epr esent at i ve.
We di scuss ed some of t he aspect s and pr obl ems of
t hi s i n t he handl i ng of t he dr ug. I n t he memo t hat I wr ot e on t hi s meet i ng I addr essed mysel f t o of f i ci al s i n t he FDA, not i ng t he pr essur e t hat had been put on
73
me.
I t has been sai d t hat I was t ol d by t hem, " I f you can' t
st and t he heat , get out of t he ki t chen! " t hat .
I cannot say I r emember
The meani ng t hat was conveyed t o me was t hat t hi s went
wi t h t he j ob.
I do not bel i eve t hi s was addr ess ed so much at t he
pr essur e I had r ecei ved- - al t hough t hi s ent er ed i nt o i t . t her e was a f ai r amount of pr essur e, i n gener al .
Rat her ,
I t hi nk I
al ways accept ed t he f act t hat one was goi ng t o get bul l i ed and pr essur ed by i ndust r y.
As I expl ai ned ear l i er , i t was
under st andabl e t hat t he compani es wer e ver y anxi ous t o get t hei r dr ugs appr oved; t he manuf act ur er ' s goal was t o get dr ugs on t he mar ket .
They may have been a l i t t l e over - eager , and t her ef or e
br ought some pr essur e t o bear .
Ther e was, f or exampl e, t he t i me
t hey kept cal l i ng me, and t hey j ust came r i ght out and sai d, " We want t o get t hi s dr ug on t he mar ket bef or e Chr i st mas, because t hat i s when our best sal es are. " I mi ght not e t hat bef or e I came t o t he FDA, i t was ver y common f or r evi ewer s and peopl e t her e t o go out t o l unch at f ancy r est aur ant s wi t h t he dr ug f i r m r epr esent at i ves.
Ther e was an end
t o t hat by t he t i me I came, but I st i l l used t o hear t al es of eat i ng at t he Ri ve Gauche and t hi ngs l i ke t hat .
The dr ug company
men wer e i n qui t e a bi t t o t he FDA, and I do not know i f t hi s has st opped now. I t hi nk t he Agency i n gener al t ends t o be under pr ess ur e, not onl y f r om manuf act ur er s, but al so f r om t he publ i c and Congr essi onal commi t t ees and so on.
I t i s a way of l i f e i n t he
74
Food and Dr ug Admi ni st r at i on, and i t was common t o accept t hi s pr essur e and r eal i ze i t was i nevi t abl e. I wr ot e i n a memo, " I t r i ed t o put acr oss t he concept t hat i n some cases expedi ency mi ght di ct at e t hat anot her al t er nat i ve t o qui t t i ng mi ght be t o yi el d t o t he pr essur e, t her ef or e I f el t some at t ent i on shoul d be gi ven t o t he f act t hat cer t ai n compani es di d seem t o be exer t i ng t oo much pr ess ur e. " pr obabl y a good deal l ess of t hi s. ar r anged meet i ngs and so on. wr ot e t he memo.
Now t her e i s
Ther e ar e mor e or der l y
I was qui t e new t o t he j ob when I
An exper i enced bur eaucr at woul d not wr i t e t hat
ki nd of memo. Wi t h r egar d t o t he number of t hal i domi de- af f ect ed bi r t hs det er mi ned by t he FDA, as I r ecol l ect , we obt ai ned i nf or mat i on of some sevent een def or med chi l dr en bor n i n t hi s count r y; i n about hal f of t hese t he dr ug had been obt ai ned over seas- - ei t her br ought back or t he mot her had been over seas at t he t i me t hat she was pr egnant and r et ur ned home t o del i ver i n t hi s count r y.
Ther e i s
a l i st of ei ght or ni ne cases i n t hi s count r y i n t he hear i ng r epor t .
I do not bel i eve we have uncover ed addi t i onal cases
si nce t hen. wer e.
I do not cl ai m t hat t hese wer e al l t he cases t her e
The r ecor ds make i t di f f i cul t t o get i nf or mat i on.
Thi s
t ype of dr ug may be handed out r at her casual l y t o a pat i ent who may never be seen agai n.
The pat i ent s may not even have been
awar e t hat t hi s was a dr ug t hat l at er caused a pr obl em.
Ther e
ar e even var i ous r easons why par ent s do not wi sh t o publ i ci ze t he
75
f act t hat t hey have had such a pr obl em.
I n addi t i on, of cour se,
we woul d onl y f i nd t he cases of t he chi l dr en t hat had been bor n def or med.
To t hi s day I do not t hi nk we know how many
st i l l bi r t hs or abor t i ons wer e r el at ed t o t he dr ug.
I n f act, i t
may not have been r ecogni zed t hat t he mot her was pr egnant i f t he baby was s o badl y damaged ear l y i n i t s devel opment t hat t he pr egnancy t er mi nat ed, per haps even bef or e t he mot her knew she was pr egnant . Ther e wer e pr obabl y not many mor e cas es i n t he Uni t ed St at es.
We do know t hat t hi s t ype of def or mi t y has been
r ecogni zed f or cent ur i es, and we do get r epor t s t oday of si mi l ar t ypes of def or mi t i es.
But , obvi ousl y, t her e ar e ot her ext er nal
or i nt er nal f or ces t hat may l ead t o t hi s def or mi t y.
Thal i domi de
i s onl y one of t hem. Thi s r ecal l , of cour se, caught t he eye of t he per sons who wer e pr ess i ng f or dr ug r ef or m, and t her e was a ver y st r i ki ng newspaper ar t i cl e i n t he Washi ngt on Post by a r epor t er , Mor t on Mi nt z, t hat al so got a l ot of at t ent i on.
I n next t o no t i me, t he
f i ght i ng over t he new dr ug l aws t hat had been goi ng on f or f i ve or si x year s suddenl y mel t ed away, and t he 1962 amendment s wer e passed al most i mmedi at el y, and unani mousl y. The 1962 Kef auver - Har r i s Amendment s and t he 1963 i nvest i gat i onal dr ug r egul at i ons i nt r oduced a number of new pr ocedur es whi ch l ed t o t he st r engt heni ng of t he cont r ol of dr ugs ent er i ng t he mar ket i n t he Uni t ed St at es.
The gr eat est change
76
was t hat bef or e a company coul d even st ar t t est i ng a dr ug i n man i t had t o submi t t o t he FDA t he i nf or mat i on t hat l ed i t t o bel i eve i t was saf e t o do so.
Thi s woul d consi st of cer t ai n
chemi st r y backgr ound mat er i al and not necess ar i l y be as compl et e as woul d be r equi r ed f or a New Dr ug Appl i cat i on.
Then t her e
woul d be ani mal st udi es, t he ext ent of whi ch, i n i ni t i al submi ssi on, woul d depend on t he t ype of cl i ni cal t r i al s i t was pr oposed t o under t ake.
Thi r d, t he company woul d descr i be t he
pr oposed cl i ni cal t r i al s: who t hey woul d be done by; t he qual i f i cat i ons and f aci l i t i es of t he i nvest i gat or s; and t he t ype of popul at i on t hat woul d be i nvol ved- - whet her i t was vol unt eer s, women, chi l dr en, si ck pat i ent s, and so on.
Then, as addi t i onal
i nvest i gat or s wer e added t o t he t r i al s, t hei r names woul d be submi t t ed t o t he FDA so t hey wer e awar e of t he ext ent of t he i nvest i gat i on.
And at l east once a year t he company was r equi r ed
t o send i n a r epor t bri ngi ng i nf or mat i on up- t o- dat e.
I n t he
i nt er i m, i f any sever e or al ar mi ng si de ef f ect s devel oped, t he company was r equi r ed t o t el l t he Food and Dr ug Admi ni st r at i on i mmedi at el y.
When t he dr ug company sel ect ed i nvest i gat or s t o do
t hei r st udi es, t hese i nvest i gat or s i n t ur n wer e r equi r ed t o make cer t ai n commi t ment s t o t he company: t hat t hey wer e qual i f i ed; t hat t hey woul d keep good r ecor ds; t hat t hey woul d advi se t he company of any adver se ef f ect s; t hat t hey woul d get pat i ent consent ; t hat t hey woul d suppl y compl et e case hi st or i es; and so on.
77
One ver y dr amat i c l ast mi nut e addi t i on t o t he 1962 amendment s was by Senat or J acob J avi t s of New Yor k.
He had
r ai sed t he quest i on, " Do peopl e know t hey ar e get t i ng i nvest i gat i onal dr ugs?"
I t was ver y cl ear f r om our sur vey of
t hese 1, 000 doct or s i n t he t hal i domi de case t hat many of t he mot her s and pat i ent s had not been t ol d t hi s, and t he doct or s t hemsel ves di d not qui t e under st and t he st at us of t he dr ug.
So a
ver y i mpor t ant amendment t o t he l aw, not a r egul at i on, was t hat pat i ent consent must be obt ai ned bef or e a new dr ug, an unappr oved dr ug, was gi ven i n a cl i ni cal t r i al . Nowadays we know exact l y what i s bei ng t est ed and who i s t est i ng i t and we get r esul t s back as soon as possi bl e.
Then i f
we get r epor t ed adver se r eact i ons, we may st op t he st udi es and so on.
We have much bet t er exchange of i nf or mat i on wi t h ot her
count r i es.
Ot her count r i es adopt ed t hese par t i cul ar t ypes of
r egul at i ons t hat ar e t he same as our s, and I hope t hat t hi s wi l l do somet hi ng at l east t o pr event anot her t hal i domi de or el i xi r of sul f ani l ami de t r agedy.
The t r oubl e i s t hat wi t h t hese gr eat new
devel opment s t hat come al ong at i nt er val s- - we ar e now i n a ver y dr amat i c per i od wher e we ar e get t i ng al l t hese exci t i ng new dr ugs- - t he ent r y of new dr ugs can out r un, or go f ast er , t han our r egul at i ons cont r ol .
We hope t hi s wi l l not be t he case and we
keep a ver y shar p eye on i t . I bel i eve t he news about t he wi despr ead di st r i but i on of t hal i domi de
was t he ent r ee t o get t i ng t he Kef auver - Har r i s
78
Amendment s appr oved.
My endeavor s i n i nvest i gat i ng t he saf et y of
t hal i domi de al so l ed t o my r ecei vi ng t he Pr esi dent ' s Awar d f or Di st i ngui shed Feder al Ci vi l i an Ser vi ce i n August 1962.
It is
act ual l y document ed somewher e t hat i t was Kef auver ' s gr oup t hat sent my name f or war d t o t he pr esi dent , because t he l i st of sel ect ees t hat year had al r eady been announced, and I was ver y much a l ast mi nut e addi t i on, j ust t wo or t hr ee weeks bef or e t he event . I t was an i nt er est i ng cer emony i n t he Rose Gar den, and t he ast r onaut s wer e i n t he backgr ound. I am not sur e.
Maybe i t was j ust J ohn Gl enn.
I have pi ct ur es somewher e t hat t hey pr ovi ded.
My
husband and daught er s wer e pr esent . My br ot her s St uar t and J ohn and my ni ece Nancy came f r om t he West coast .
I was al l owed t o
br i ng t wel ve peopl e, amongst whom I t hi nk t hr ee wer e t o be f r om t he FDA and t he r est coul d be per sonal ones. I keep my medal i n t he bank now.
Af t er I got r obbed once or t wi ce I t hought t hat I
had bet t er put i t away. I guess t he r obber s di d not see i t i n my house or di d not t hi nk i t was wor t h anyt hi ng! So I j ust popped i t i n t he bank. The event i t sel f was i nt er est i ng.
I t hought t hat I was
accept i ng t he medal on behal f of a l ot of di f f er ent f eder al wor ker s.
Thi s was r eal l y a t eam ef f or t .
t o be si ngl ed out .
I guess one per son had
But , anyway, t her e i s no doubt t hat
t hal i domi de di d ensur e t hat t her e woul d be some i mpr ovement s i n t he l aw on dr ug r egul at i on.
But , i t has t o be r emember ed t hat I
79
was ver y new t o t he agency and pr et t y nai ve about how t hi ngs wer e done and br ought about when I was i nvol ved wi t h t hal i domi de. Post-Drug Amendments Reorganizations of New and Investigational Drugs in the Bureau of Medicine
Af t er t he Kef auver - Har r i s amendment s, t he Bur eau of Medi ci ne of t he FDA was r eor gani zed i n such a way t hat i t i ncl uded t wo br anches.
One br anch handl ed t he I NDs, t hat i s, t he not i ce of
cl ai m f or i nvest i gat i onal exempt i on f or a new dr ug- - t he mat er i al t hat t he company submi t t ed pr i or t o st ar t i ng human t r i al s. coi ned t he acr onym I ND f or t hi s.
We
Peopl e t hi nk i t means
I nvest i gat i onal New Dr ug, and, i n a way, per haps t hey ar e cor r ect .
We al r eady had t he desi gnat i on NDA, New Dr ug
Appl i cat i on.
We r eal i zed we had t o get a second set of i ni t i al s
t hat woul d be i n keepi ng wi t h NDA and not i n l i ne.
So we hi t
upon I ND, and what i t st ands f or i s t he not i ce of cl ai m of i nvest i gat i onal exempt i on f or a new dr ug. t he I ND Br anch. Appl i cat i ons.
That was one br anch,
The second br anch consi der ed t he New Dr ug As soon as t he manuf act ur er f el t he had obt ai ned
enough i nf or mat i on- - t he cl i ni cal t r i al s and backgr ound mat er i al t hat t he dr ug was t hen saf e and ef f ect i ve f or t he var i ous pr oposed uses- - he woul d, as bef or e, submi t a New Dr ug Appl i cat i on.
A second gr oup of medi cal r evi ewer s wer e i n t hat
br anch. I became chi ef of t he I nvest i gat i onal Dr ug Br anch. t i me, some of t he phar macol ogi st s wer e st i l l separ at e.
At t hat The
80
medi cal of f i cer s wer e st i l l i n our ol d bui l di ng- - t he t empor ar y quar t er s on 7t h St r eet - - and t he chemi st s, i ndeed, wer e st i l l separ at e.
I n essence, I had about t wel ve or t hi r t een physi ci ans
who l ooked over I ND appl i cat i ons t o see whet her i t woul d be saf e t o st ar t st udi es.
We st ar t ed wi t h a bi g gr oup of I NDs because
t he l aw went i nt o ef f ect ar ound 1 J une, and f or any dr ug t hat was under t est at t hat t i me, or somewhat bef or e, t he compani es had t o pr ovi de t hese new I NDs.
Then, as new dr ugs came t o cl i ni cal
t r i al , t hey woul d be added.
I t hi nk t her e wer e about t wo or
t hr ee hundr ed I NDs t o begi n wi t h, and by t he mi d- sevent i es t hey wer e comi ng i n at a r at e of about si x or ni ne hundr ed a year . Per haps a t hi r d of t hem wer e f or dr ugs t hat had a mar ket i ng pot ent i al .
Many of t hem wer e f or st udi es by i ndi vi dual
physi ci ans or smal l gr oups of physi ci ans who, per haps, wer e usi ng t he dr ug t o st udy i t s met abol i sm i n a per son.
Ot her I NDs wer e
f r om physi ci ans who wi shed t o use a mar ket ed dr ug f or unappr oved use; f r equent l y a company woul d be wi l l i ng t o gi ve t hem some backgr ound i nf or mat i on but woul d not want t o sponsor a t r i al , so t he physi ci an di d i t hi msel f . Then about 1965 or 1966 we had a r eor gani zat i on of t he br anches, because t her e wer e some pr obl ems, and t her e was anot her i nqui r y.
Fi r st , t he l oad of I NDs was ver y l ar ge f or t he smal l
gr oup avai l abl e t o r evi ew t hem, and, second, t her e wer e some pr obl ems of over l ap as t o who was r esponsi bl e when an NDA was i n f or a dr ug but cl i ni cal t r i al s wer e cont i nui ng.
Exampl es wer e
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br ought t o l i ght t hat agai n t her e was t hi s t endency of wi despr ead di st r i but i on of a dr ug wi t h i nadequat e cont r ol .
A wel l - known
exampl e of t hi s was DMSO ( di met hyl sul f oxi de) , whi ch happened af t er t hal i domi de.
Agai n we wer e not i f i ed af t er war ds of t he
i nvest i gat or s who had r ecei ved t he dr ug.
Ther e was a t endency
f or t hi s s udden bl ossomi ng out and a f ear t hat t he compani es mi ght not be abl e t o moni t or t hese gr eat number s of i nvest i gat or s suf f i ci ent l y wel l , ei t her f or saf et y or t o get good i nf or mat i on on whet her a dr ug mi ght be usef ul or saf e. I nst ead of havi ng a separ at i on bet ween t he I ND dr ug br anch and t he NDA dr ug br anch, t he new r ear r angement was t hat t he medi cal r evi ewi ng st af f was br oken down i nt o si x di vi si ons based on t he t ype of dr ug or condi t i on f or whi ch i t woul d be used- endocr i nes, r adi ophar maceut i cal s, and so on.
Now, bot h t he I NDs
and t he NDAs wer e r evi ewed wi t hi n t he appr opr i at e di vi si on.
I
bel i eve i t was at t hat t i me t he phar macol ogi st s became par t of t he di vi si on and t he chemi st s, i nst ead of bei ng a separ at e br anch or what ever , j oi ned t hem i n a br anch of phar macol ogy- chemi st r y. I t was a t eam concept wher e t he medi cal of f i cer , chemi st , and phar macol ogi st wor ked r i ght wi t hi n t he same di vi si on.
Thi s i s
essent i al l y st i l l t he ar r angement . Creation and Work of the Scientific Investigations Function
For about si x mont hs I was di r ect or of t he di vi si on t hat deal t wi t h ant i cancer dr ugs and r adi oi sot opes.
Then t he pr obl em
of t he sci ent i f i c val ue of some of t he cl i ni cal r epor t s came i nt o
82
quest i on agai n.
Ear l i er i n t he I ND days, when i t was a separ at e
br anch, we had act ual l y gone out and r evi ewed some of t he st udi es conduct ed by cl i ni cal i nvest i gat or s and compar ed t hem, f or exampl e, t o t hose submi t t ed t o t he company and t o us.
We f ound
some r at her ser i ous di scr epanci es, and a pr ocedur e was devel oped wher eby i nvest i gat or s f ound t o be doi ng t hi s t ype of st udy poor l y coul d be di squal i f i ed f r om r ecei vi ng i nvest i gat i onal dr ugs i n t he f ut ur e.
Some wer e keepi ng ver y poor r ecor ds, somet i mes t hey wer e
f al si f yi ng t he i nf or mat i on, and t her e wer e a var i et y of pr obl ems. Thi s r eal l y st ar t ed bef or e t he Kef auver - Har r i s Amendment s. I t hi nk some of t he f i r st wor k was done ar ound 1960- 1961, when one i nvest i gat or was f ound t o be f al si f yi ng r ecor ds and was act ual l y pr osecut ed by t he J ust i ce Depar t ment ; he pl eaded nol o cont ender e.
Ther e wer e one or t wo ot her s whi l e t he
I nvest i gat i onal Dr ug Br anch was oper at i ng because t hi s was a par t i cul ar ar ea about whi ch we had t o be concer ned.
Then when
t he r eor gani zat i on occur r ed and t he di vi si ons t ook over and handl ed bot h t he I NDs and NDAs, t hi s t ype of wor k r at her f el l by t he waysi de.
I t was r eal i zed t hat t her e was no gr oup t hat coul d
ensur e t hat t he i nvest i gat i onal dr ug r egul at i ons per t ai ni ng t o cl i ni cal i nvest i gat or s wer e bei ng enf or ced or f ol l owed.
Nobody
was r esponsi bl e f or l ooki ng out f or t he poor per f or mer s or cr ooks or what have you as we had done i n t he I nvest i gat i onal Dr ug Br anch.
Dr . J ames Goddar d, FDA Commi ss i oner , deci ded t hat t he
i ssue was suf f i ci ent l y i mpor t ant t hat t her e shoul d be a separ at e
83
uni t f or med t hat woul d concent r at e i n t hi s ar ea and r epor t di r ect l y t o t he Bur eau of Medi ci ne di r ect or . So, i n ear l y 1967 t he f or er unner of my gr oup, t he Sci ent i f i c I nvest i gat i ons St af f , was s et up i n t he Bur eau of Medi ci ne di r ect or ' s of f i ce; i t became known af t er a ser i es of r eor gani zat i ons as t he Of f i ce of Sci ent i f i c Eval uat i on. consi st ed of f i ve pr ogr ams.
It
Some of t hese wer e sur vei l l ance, t o
make sur e t hat t he i nvest i gat or was bei ng t ol d of hi s obl i gat i ons: t hat he was awar e of pat i ent consent and t he t ype of consent he got ; t hat he was awar e of t he need t o keep good r ecor ds; t hat he r epor t ed adver se r eact i ons; and so on. doi ng t hi s we act ual l y ver i f i ed some of hi s wor k.
Whi l e
One pr ogr am,
f or exampl e, i nvol ved a mor e or l ess r andom sel ect i on of New Dr ug Appl i cat i ons- - t hose j ust about t o be accept ed, say, or under r evi ew.
We vi si t ed t he sponsor t o f i nd out what moni t or i ng
f aci l i t i es he had and, j ust on a r andom basi s, vi si t ed maybe ei ght or t en i nvest i gat or s. When we f i ni shed our vi si t s we not i f i ed bot h t he company and t he i ndi vi dual i nvest i gat or of any di scr epanci es t hat we f ound. Ther e was a f eel i ng t hat t he r esponsi bi l i t y f or i nf or mi ng t he i nvest i gat or and keepi ng sur vei l l ance over hi m r est ed wi t h t he sponsor , and t hi s was a message we wer e t r yi ng t o get acr oss. I t hi nk t her e was accept ance of i t .
We had anot her pr ogr am
af t er 1967 i n whi ch we vi si t ed t he i nst i t ut i onal r evi ew commi t t ees- - t he commi t t ees t hat wer e supposed t o r evi ew, appr ove,
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and al most moni t or , as i t wer e, any ongoi ng st udy i nvol vi ng i nvest i gat i onal dr ugs i n i nst i t ut i onal i zed per sons.
These woul d
be hospi t al i zed pat i ent s, pat i ent s i n ment al i nst i t ut i ons, pr i soner s, and so on.
We had st i l l anot her pr ogr am t o see t hat
t he ani mal st udi es wer e bei ng car r i ed out pr of essi onal l y, honest l y, appr opr i at el y, and compl et ed i n a r easonabl e t i me. Ther e wer e or i gi nal l y f our i n t he di vi si on- - mysel f and Dr . Al an Li sook who i s an M. D. , and Dr . El wood Har ki ns and a secr et ar y.
Then we got t wo of what we used t o cal l Food and Dr ug
Of f i cer s i n t he ol d days. Of f i cer s.
Lat er t hey became Consumer Saf et y
Bot h wer e peopl e who had act ual l y wor ked as i nspect or s
i n t he f i el d, and t hey hel ped us her e. I t was a f ai r l y smal l di vi si on t o car r y out f i ve oper at i ons. We di d have ass i st ance.
I n t he f i el d t her e wer e a number of
of f i ces t hr oughout t he Uni t ed St at es, and cer t ai n i nspect or s i n t hese of f i ces got speci al t r ai ni ng i n conduct i ng t hi s t ype of i nspect i on.
They wer e cal l ed t he 200- C I nspect or s.
compl et ed some of t hese assi gnment s t hemsel ves.
They
As f or ot her s i n
t he di vi si on, Dr . Li sook, f or exampl e, woul d go out or pr epar e a t al k t hat I woul d pr esent on t he t ype of pr obl ems t hat we encount er ed. Our modus oper andi at t he begi nni ng was t o l ook wher e t he money was, par t i cul ar l y i n pr i son st udi es, whi ch we knew t ended t o be poor l y per f or med.
We had vi si t ed some pr i sons pr evi ousl y
and seen t hat t he ci r cumst ances, t hei r equi pment , t hei r
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per sonnel , and so on, wer e not up t o scr at ch. gr oups we l ooked at par t i cul ar l y.
A l i t t l e l at er we par t i cul ar l y
l ooked at st udi es i n nur si ng homes. t he pr i sons.
So t hose wer e
We def i ni t el y st ar t ed wi t h
Then t he exposé of pr i son st udi es came, and, i t
came i n a cur i ous way, because a coupl e of men named Aust i n R. St ough and Cr anf i l l K. Wi sdom had a f r anchi se as i t wer e t o do dr ug st udi es i n a number of pr i sons i ncl udi ng, I t hi nk, one i n Al abama and one i n Okl ahoma.
Act ual l y Al an Li sook had been down
t her e t o Al abama, and al t hough t he dr ug st udy was not t he gr eat est , we coul d not r eal l y pi n any sci ent i f i c f aul t on t hem wi t h r egar d t o accur acy. al l .
The subj ect s wer e act ual l y t her e, af t er
I nt er est i ngl y enough, t he agency had a cont r act wi t h St ough
and Wi sdom when t hey wer e i n Okl ahoma t o st udy somet hi ng about t he t oxi ci t y of hai r dyes or excr et i on of hai r dyes i n t he ur i ne, I t hi nk i t was.
I n Al abama t hey j ust di d dr ug st udi es.
t hey wer e a wel l - known gr oup. pl asma f or pr ocess i ng.
Anyway,
Then t hey got a cont r act t o suppl y
I n some way t he NI H was i nvol ved, but
Cut t er Labor at or i es act ual l y di d t he wor k of get t i ng t he var i ous f r act i ons of ant i bodi es or what ever one get s out of pl asma, gl obul i n.
So t hey woul d dr aw t he bl ood f r om t he pr i soner s, spi n
down t he r ed cel l s, r ei nj ect t hem back i n t he pr i soner s, and t hen sel l t he pl asma.
But t hey wer e pr et t y car el ess i n t he appar at us,
and an epi demi c of hepat i t i s br oke out i n t he pr i sons. wer e a number of deat hs, as I r ecal l .
Ther e
Thi s l ed t o an i nqui r y by
t he st at e of Al abama, whi ch appoi nt ed a boar d headed by t he
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chai r man of medi ci ne at t he uni ver si t y. One of t he r ecommendat i ons of t hi s boar d was t hat st udi es done i n pr i sons- - maybe j ust Al abama pr i sons, but anyway pr i sons- shoul d be r evi ewed by an i mpar t i al r evi ew boar d.
The NI H had
j ust set up such a r equi r ement f or gr ant s and cont r act s, and t hei r suggest i on was t hat t hi s shoul d al so be appl i ed t o t hese pr i son st udi es, because t he peopl e t hat r evi ewed some of t he wor k t hey di d f ound f l aws, or pr obl ems, or hazar ds.
I t hi nk t hey wer e
shocked at t he equi pment and so on, much as we wer e. That l ed t he agency i n some way t o consi der t he I nst i t ut i onal Revi ew Boar d ( I RB) as a r equi r ement f or dr ug st udi es, r egar dl ess of whet her t he st udi es wer e f unded by t he NI H or not .
I t hi nk i t had been consi der ed ear l i er but di smi ssed as
i mpr act i cal , because t he number of si t es doi ng dr ug st udi es gr eat l y out number ed t hose t o whi ch gr ant s or cont r act s wer e awar ded.
Under t he syst em devel oped by t he NI H, t he i nst i t ut i on
got assur ance f r om or made an assur ance t o t he NI H t hat i t woul d have such a commi t t ee, t hat i t woul d consi st of cer t ai n peopl e, t hat t her e woul d be a r easonabl e bal ance bet ween sc i ence and nonsci ence peopl e, and so on.
But we r eal i zed t hat we di d not have
t he manpower t o set up and appr ove al l t hese assur ances.
I nst ead
we devel oped t he r egul at i ons whi ch ar e added as a l ong par agr aph t o t he cl i ni cal i nvest i gat or st at ement s, descri bi ng t he commi t t ees and sayi ng t hey shoul d f ol l ow t he di r ect i ons s et up by t he agency.
So t hat was t he t i e- i n bet ween t he pr i sons and
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r evi ew commi t t ees.
Dr . Li sook was t he man who went t o al l of t he
pr i sons and knew what t hey wer e l i ke and some of t he si ns of omi ss i on t hat wer e commi t t ed. So we publ i shed t he r egul at i ons, and t her e wer e t o be no mor e pr i son st udi es except f or t he good of t he pr i soner s or somet hi ng l i ke t hat .
They wer e goi ng t o r equi r e an i ndependent
commi t t ee at t he FDA, t o l ook over t hem, whi ch I t hought was a l ousy i dea.
Anyway, what ever t he pr oposal was, one of t he dr ug
f i r ms and a uni on of pr i soner s or a gr oup of pr i soner s chal l enged us, and we st ayed t hose r egul at i ons.
We di sagr eed wi t h t he i dea
t hat some pr oposed of out l awi ng t he use of pr i soner s al t oget her because we r eal l y f ound no maj or pr obl ems wi t h t he dr ug t est i ng. I was on t he commi t t ee at t he t i me when t hey wer e r econsi der i ng t he var i ous I RB and consent r equi r ement s. mi ne had t o do wi t h t he pr i soner r equi r ement s.
I am not so sur e
t hat I was not r oped i n as secr et ar y or s omet hi ng. t hen I see mi nut es of what we di scussed.
I t hi nk
Ever y now and
But at t hat t i me- - I do
not know wher e t he f i gur e came f r om- - 90 per cent of al l Phase I st udi es wer e done i n pr i sons i n t hi s count r y.
Now, i n Eur ope,
t hey shudder ed at t he ver y t hought of st udi es i n pr i sons, because of t he Ger man war t i me exper i ence. The FDA di d not ant i ci pat e t hat t he pr i son popul at i on t hat was t he pr i mar y popul at i on f or Phase I t est s woul d di sappear and t her e was some concer n.
I t hi nk t he compani es di d not want t o
get i nvol ved i n any way, and t her e was a gr eat out cr y at t he t i me
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when t hi s t hr eat of l oss of dr ug t r i al candi dat es came up. The concer n was:
Wher e wi l l we get t he subj ect s f or Phase I st udi es
i f we cannot go t o pr i sons?
One dr ug f i r m r epr esent at i ve even
sai d wi t h a per f ect l y st r ai ght f ace, "I t hi nk we wi l l have t o t hi nk of somet hi ng l i ke nat i onal conscr i pt i on wher e you gi ve your t i me t o be i n t he dr ug t est s. "
I suppose t hat was t he r het or i c
of t he t i me. We now see par t i cul ar gr oups t hat popul at e t he Phase I t est s, l i ke st udent s or st r eet peopl e.
We vi si t t hese si t es, i f
t hey ar e doi ng cer t ai n t ypes of st udi es, a bi oequi val ency, f or exampl e. now.
Act ual l y, we do not l ook at t oo many Phase I st udi es
Our f ocus has changed.
Unl ess we happen t o get a
compl ai nt , and occasi onal l y one wi l l come t hr ough and we wi l l l ook i nt o i t - - somebody di d not get pai d when t hey t hought t hey shoul d or somet hi ng l i ke t hat .
But t he bi oequi val ence st udi es
and t he Phase I st udi es s eem basi cal l y t o be done ei t her i n st udent s or i n st r eet peopl e whi ch can be a bi t of a pr obl em. Ther e have been, f or exampl e, adver t i sement s i n t he Washi ngt on paper s about par t i ci pat i ng i n dr ug st udi es, hel pi ng peopl e out , and get t i ng pai d.
A bus wi l l pi ck you up at Uni on St at i on or
somet hi ng, t r anspor t you t o Bal t i mor e, say.
So t hey ar e r eachi ng
out and get t i ng peopl e. I t hi nk maybe t her e ar e di f f i cul t i es i n f i ndi ng r ecrui t s f or st udi es, because t he pr obl em i s of t en i n t he dr opout s.
Peopl e
wi l l dr op out of t he st udy, and t hi s, of cour se, i s expensi ve f or
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t he f i r ms, because t hey may have t o scr ap t he st udy and so on. I f t her e was a gr eat demand t o get i nt o t hese st udi es, pr obabl y t her e woul d be l ess l i kel i hood of peopl e dr oppi ng out . know i f t hat i s t r ue or not . on t hat .
I do not
We do not have any har d i nf or mat i on
I t i s j ust my specul at i on.
But t her e i s an i ncr easi ng
demand f or t hem t hr ough t he gener i c t est i ng, and i t i s a l i t t l e bi t of a pr obl em wher e peopl e come f r om and so on. Now qui t e a bi t of dr ug t est i ng i s done over seas, because many over seas count r i es, Engl and, f or exampl e, do not r equi r e an I ND f or doi ng Phase I t ype st udi es.
We wi l l accept t he dat a
unl ess we have r eason t o t hr ow i t out . I t hi nk t he amendment s and I ND r egul at i ons hel ped t he FDA get much bet t er cl i ni cal i nvest i gat i ons, and t hi s was not t he onl y i mpr ovement .
We had a much bi gger or gani zat i on, we
at t r act ed many exper i enced physi ci ans, and we dr ew up gui del i nes t o speci f y how we t hought cer t ai n dr ugs shoul d be t est ed.
Al so,
we had bet t er l i ai son- - bet t er cont act - - I t hi nk, wi t h t he sponsor s, and i n a mor e or der l y f ashi on, because t he I ND r equi r ement s i ndi cat ed t hat t he st udy shoul d pr oceed wi t h what we cal l ed Phase I t r i al s f i r st , meani ng, t hat t hese wer e i n nor mal vol unt eer s.
Phase I I mi ght be an ext r emel y l i mi t ed cl i ni cal
st udy under exper t s, i nvol vi ng f i ve or t en cent er s.
Fi nal l y,
Phase I I I mi ght be a mor e gener al t est , not ext endi ng i n t he way t hal i domi de di d, but pr oceedi ng i n an or der l y f ashi on t hat mi ght i nvol ve, say, a hundr ed i nvest i gat or s.
Thr oughout t hese st ages
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t he company i s supposed t o keep i n t ouch wi t h t he FDA by way of r epor t s at year l y i nt er val s, medi cal of f i cer s' r evi ews, i ncomi ng r epor t s, r epor t s of t he new pr ot ocol s or new per sons added, and t he FDA may- - at any t i me- - chal l enge t he qual i f i cat i ons or what have- you of t he i nvest i gat or , f or exampl e, whet her he has t he f aci l i t i es t o do i t . I t hi nk t hi s ki nd of scrut i ny has i ncreased t he qual i t y of t he i nvest i gat i onal wor k bei ng done.
Al so, cl i ni cal phar macol ogy
devel oped t r emendousl y f r om t he si xt i es i nt o t he mi d- sevent i es. Ther e wer e mor e wel l - qual i f i ed peopl e i n t he f i el d.
Now,
admi t t edl y, t hose wer e not t he peopl e who wer e goi ng t o wor k on a r at her mundane what mi ght be cal l ed " me- t oo" t ype of dr ug. was har der t o at t r act good i nvest i gat or s f or t hose.
It
So, some of
our pr obl ems l ay wi t h t he l ess gl amor ous dr ugs. I am now i n what we cal l bi or esear ch moni t or i ng.
Ever y t i me
a r egul at i on i s made i nsi st i ng peopl e do somet hi ng some way, t her e has t o be an i nspect i onal pr ogr am, t o make sur e t hey ar e doi ng i t t hat way.
So we go out on r egul ar vi si t s t o doct or s.
We make sur e t hey ar e conduct i ng t he st udi es as t hey sai d t hey woul d; t hat t he pat i ent s have gi ven consent , t hat f or al l t he t r i al s, bef or e t hey ar e begun, t hey have got t en t he appr oval of t he l ocal commi t t ee of bot h sci ent i st s and non- sci ent i st s.
We go
out t o t he ani mal l abor at or i es and make sur e t hat t hey ar e f ol l owi ng our Good Labor at or y Pr act i ces, whet her t hei r r ecor ds ar e accur at e, wi t h no f udgi ng- - and bel i eve me we f i nd f udgi ng i n
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al l ar eas, cl i ni cal and ani mal .
We go t o t hese I nst i t ut i onal
Revi ew Boar ds t hat r evi ew t he st udi es f r om t he poi nt of vi ew of t he pat i ent consent .
We do accept f or ei gn st udi es under t he
under st andi ng t hat we may go out and i nspect t hose t oo.
So we
f r equent l y go t o Canada or Engl and, or el sewher e, and l ook at i mpor t ant st udi es t o make sur e t hat t hey ar e done pr oper l y. Ot her count r i es have adopt ed, f or exampl e, our Good Labor at or y Pr act i ces, and we wor k wi t h t hem i n t hat r espect .
The Canadi an
l aws ar e vi r t ual l y t he same as our s and we wor k ver y cl osel y, wi t h Canada par t i cul ar l y, but al so wi t h Engl and i n a t r i par t i t e commi t t ee.
We ar e abl e t o di sc uss common pr obl ems, so t hat i s a
gr eat st ep f or war d. We al so exami ne mor e cl osel y t he cl i ni cal i nvest i gat or s who ar e wor ki ng on dr ug t r i al s.
When I f i r st came t o t he FDA i t was
wor d of mout h t hat t her e was a smal l gr oup of i nvest i gat or s who wer e wor ki ng on a l ot of di f f er ent st udi es.
A bunch of us woul d
j ot down a name when we saw i t and compar e not es. same t hi ng I had done when I wor ked at t he AMA.
I t was t he Then once we got
t he I ND syst em i n, we had a dat a r et r i eval syst em.
One of t he
t hi ngs t hat went i nt o t hat - - f i r st , i t was I BM car ds- - was t he physi ci an' s name and t he dr ug he was s t udyi ng, and so we coul d t hen mat ch t hem up. f ashi on.
Of cour se we have t hat now i n a gl or i f i ed
We wer e st ar t i ng t o do t hat a bi t manual l y as I r ecal l ,
even devel opi ng i nf or mal l i st s, and t hen we wer e t hi nki ng of doi ng i t mor e f or mal l y.
I t was so much easi er once we had t he
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I ND.
Wi t h t he NDA t her e wer e onl y t he f ew peopl e t he company had
chosen who sent i n st udi es.
I n t he t hal i domi de st udy, as I have
not ed, we bel i eved we had somet hi ng l i ke f or t y i nvest i gat or s, but yet we f ound out l at er t hat over a t housand peopl e had got t en t he dr ug.
But now we can keep a good t ab on t hi s. I have r ecor ded a l i st of i nel i gi bl e i nvest i gat or s i n a
paper on t he bi or esear ch moni t or i ng pr ogr am. shot up.
I t i s cl ear how i t
I t was qui t e modest at t he begi nni ng because we di d not
have much of a sys t em.
Fr om t he f i r st one i n 1964 up t o December
of 1990, t her e ar e sevent y- one l i st ed.
Ear l i er on, t hese
i nvest i gat or s t ended t o be mor e f avor abl e t o t he dr ugs.
We had
one pr ogr am whi ch was t o l ook at peopl e who wer e par t i ci pat i ng i n over a cer t ai n number of st udi es but i t was not ver y f r ui t f ul . We have al so had some ver y good peopl e who have wor ked on a number of st udi es. Theor et i cal l y, we do not know how t hese i nvest i gat or s ar e compensat ed and ar e not pr i vy t o t hat i nf or mat i on, but obvi ousl y t hey do get some compensat i on.
I guess i n t he ear l y days i t was
t he honor of havi ng your name i n t he publ i shed paper , whi ch t he company usual l y wr ot e.
But I am sur e t hat t her e woul d be al ways
some f i nanci al r ewar d, i ncl udi ng i n some cases st ock i nt er est s and so on.
For s ome dr ugs we di d r un some f i gur es.
The
i nvest i gat or s ar e pai d, and t hey have al ways been pai d f ai r l y wel l .
The pat i ent s, except i n Phase I t est s, ar e r ar el y pai d.
An i nvest i gat or mi ght r ecei ve a t housand dol l ar s a pat i ent f or a
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one- week st udy and mi ght have t went y, t hi r t y, or f or t y pat i ent s. Cer t ai nl y when di squal i f i ed, f or many of t hese i nvest i gat or s t hi s i s a concer n- - t hei r l i vel i hood i s t aken away or somet hi ng. Or t hey cl ai m t hat i f we make t hem have an agr eement or somet hi ng, i t wi l l cut down t he number of st udi es.
Ther e ar e no
bones about i t , some peopl e obvi ousl y ar e maki ng dr ug t r i al s t hei r busi ness. I n f act , we had one who sai d, " Thi s i s a ver y compet i t i ve busi ness. "
He was r ef er r i ng t o t he busi ness of bei ng a cl i ni cal
i nvest i gat or . hear i ngs.
We have hi m on r ecor d i n one of our i nf or mal
I was a l i t t l e shook up t o t hi nk of dr ug t r i al s i n
t er ms of bei ng a busi ness, but I guess t hey ar e. The suspi ci ous i nvest i gat or s wer e pr et t y obvi ous when t her e was t oo gr eat a success r epor t ed.
Thei r r esul t s can be compar ed
wi t h a l ot of di f f er ent r esul t s f r om ot her peopl e.
These ar e al l
wr i t t en out and you can r eal l y go over t hem pr et t y wel l .
J ohn
Nest or was one of t he ear l y i nvest i gat or s i n t hi s ar ea.
He i s
sor t of a l egend ar ound her e.
For exampl e, t her e was a gener al
pr act i t i oner on t he out ski r t s of Washi ngt on who di d a l ot of st udi es, and one of t hem i nvol ved t he use of a bal l i st ocar di ogr aph, whi ch i s a ver y sophi st i cat ed i nst r ument f or measur i ng t he out put of t he hear t by seei ng how much t he pat i ent j er ks when hi s hear t beat s.
Anyway, J ohn j ust coul d not bel i eve,
because he was a pedi at r i c car di ol ogi st , t hat a gener al pr act i t i oner on t he out ski r t s of Washi ngt on woul d have access t o
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a bal l i st ocar di ogr aph.
I t i s a hospi t al i nst r ument .
He f ound
not onl y t hat t he man di d not have access , but t he man was out of t he count r y f or much of t he t i me when al l t hese case r epor t s wer e f i l l ed i n, and he di d not have t he compet ency t o conduct t he t est s.
He was t est i ng a wi de var i et y of subst ances, t oo- - di d not
st i ck t o j ust one.
I t r eal l y got J ohn' s goat t hat someone coul d
cl ai m t o be usi ng a bal l i st ocar di ogr aph, wi t hout havi ng t he ski l l s and knowl edge t hat i t woul d t ake t o r un one, or t he f i nances t o buy one.
Of cour se, al l t hese event s ar e avai l abl e
i n nar r at i ves at t he r ecor ds.
I do not t hi nk ever yt hi ng i s
dest r oyed of t hese ear l y i nvest i gat i ons.
We have t he r ecor ds,
t he r epor t s, on most of t hem at t he FDA.
Some f r audul ent
i nvest i gat or s wer e pr osecut ed. One f unny st or y was i n Vet Medi ci ne. vet .
They di squal i f i ed a
I guess t hey pr osecut ed hi m, and t hey had t o cal l t he pet s'
owner s as wi t nesses, and t he r epor t s woul d be Fi do wi t h a br oken l eg and al l t hi s sor t of t hi ng, what he di d, and how wonder f ul t hi s medi ci ne was. somet hi ng.
Wel l , Fi do j ust had a l i t t l e scr at ch or
I t was al most as t hough i t wer e a par ody on one of
our i nvest i gat i ons, but t hese wer e r eal pat i ent s. To t ur n t o i nf or med consent , t he st at ement s i n t he 1962 l aw and t he Food and Dr ug r egul at i ons about t hi s ar e exact l y t he same.
They used t he same wor ds, because f r ankl y t hi s was a new
concept f or t he Food and Dr ug Admi ni st r at i on.
We never i magi ned
we coul d have got t en away wi t h anyt hi ng, however much we t hought
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t he doct or shoul d do, because at t hat t i me t he doct or s f el t t hey wer e t he Lor d Al mi ght y.
That t he pat i ent shoul d t ake what t he
doct or gi ves t hem because doct or knows best .
And i f t he doct or
t hi nks i t i s i mpor t ant t hat t hi s dr ug be st udi ed i n a f ashi on t hat t he pat i ent does not know he i s get t i ng an unpr oven dr ug- not t o wor r y.
Bi g Daddy wi l l t ake car e of you.
We had t o dr aw up a r epor t t i t l ed " Consent f or Use of I nvest i gat i onal New Dr ugs On Humans: St at ement of Pol i cy. " 3 sent i t ar ound.
We
I t hi nk I st i l l have some of t he backgr ound
t hi ngs we sent out t o a number of peopl e ar ound t he count r y.
I
do not know what t he r eason was why i t was not put i nt o t he l aw at t hat t i me.
I guess t her e has al ways been a di f f er ence of
opi ni on as t o whet her a pol i cy st at ement has t he f or ce of l aw. At l east we wer e abl e t o use i t as a gui de and quot e i t , but I do not know i f we had had a cour t case whet her i t woul d have been chal l enged.
Thi s i s a t echni cal pr obl em.
I have hear d some of
t he l awyer s say i t was j ust as good as a r egul at i on. Obvi ousl y peopl e conduct i ng t r i al s gave t he l east possi bl e t hought t hey coul d t o consent .
We r an acr oss t hi ngs.
I have
f i l es f ul l of st at ement s such as " I her eby agr ee t o t ake t hi s dr ug.
I t i s doi ng ver y wel l i n Eur ope, and I absol ve Dr . So- and-
so, t he hospi t al , t he j ani t or , and ever yone el se f r om any har m t hat I may suf f er i n t he cour se of t aki ng t he dr ug. "
Li t er al l y
t hat t ype of consent was ext r emel y common, and some hospi t al s' 3
Cf . 32 Fed. Reg. 3994- 3995 ( 11 Mar ch 1967) .
96
l egal depar t ment s r equi r ed i t f or pr ot ect i on even t hough i t woul d not st and up i n a cour t of l aw.
We al most never s ee i t any mor e.
Some peopl e r eal l y wer e not ver y happy wi t h t he t hought of i nf or med consent .
Loui s Lasagna' s vi ew was somet hi ng al ong t he
l i nes of even wel l - i nf or med r esponsi bl e cl i ni ci ans had r ej ect ed t he i dea of get t i ng i nf or med consent f r om pat i ent s.
I n ot her
wor ds, t her e pr obabl y wer e t i mes i n whi ch i t was okay t o wi t hhol d t he pat i ent s' consent . r ebut t al .
My r epl y t o t hat was not r eal l y cast as a
I t was j ust a st at ement of pl ai n f act .
I was pl eased
wi t h t he way my ar t i cl e on i t came out , because i t l ai d t he gr ound wor k f or t he handout , I t hi nk i n a way, of t hat pol i cy st at ement t o some ext ent .
4
Ther e was an i nf or med consent pol i cy i n t he agency at t he t i me, even t hough i t was not i n wr i t i ng.
The onl y t hi ng i n
wr i t i ng was t hi s l i t t l e bi t i n t he 1572s and 73s t he i nvest i gat or si gned t hat he woul d get i nf or med consent unl ess i t was i mpossi bl e and so on.
I n t he same way t he sponsor si gned t hat he
woul d see t hat hi s i nvest i gat or s wer e awar e t hey had t o get i nf or med consent .
Ther e was absol ut el y not hi ng t o i ndi cat e what
i nf or med consent was.
I am sur e a par t of my paper on i nf or med
consent was based on what t he NI H had i n t hei r l i t t l e handbook. I t hi nk t hey gave some gui del i nes or gui dance i n t hat l i t t l e 4
F. O. Kel sey, “Pat i ent Consent Provi si ons of t he Feder al Food, Dr ug, and Cosmet i c Act , ” i n I . Ladi mer and R. W. Newman, eds. , Cl i ni cal I nvest i gat i on i n Medi ci ne: Legal , Et hi cal , and Mor al Aspect s ( Bost on: Bost on Uni ver si t y LawMedi ci ne Resear ch I nst i t ut e, 1963) , pp. 336- 344.
97
yel l ow Bi bl e t hi ng.
The NI H pr eceded us, I t hi nk.
gui dance; I cannot r emember what i t was.
They had some
Any t hought s I woul d
get or i gi nal l y woul d come f r om t he f ew i nspect i ons we had made wher e we f ound t hese t er r i bl e exampl es of ei t her l ack of consent or poor consent .
My st at ement s t her e wer e ones t hat many peopl e
at one t i me or ot her had echoed and whi ch we t hought wer e r easonabl e ones. Then, of cour se, t her e was t he l oophol e t hat i n Phase I I I i nf or med consent need not be i n wr i t i ng, because Phase I I I i n t hose days was t he l at e st ages wher e t hey wer e j ust di st r i but i ng a dr ug r at her wi del y t o get di f f er ent exper i ences f or t oxi ci t y and so f or t h, and a l ot was known about t he dr ug.
You coul d get
i nf or med consent , but i t was t o t el l t he peopl e t hat t hi s mar vel ous dr ug act ual l y was not t echni cal l y appr oved.
But you
had t o make a not at i on i n t he pat i ent ' s r ecor d t hat you had so got t en consent . Wel l , we woul d go out ; Dr . Li sook woul d go out . woul d say, " Oh, yes, I got t he i nf or med consent . " i n your pat i ent r ecor ds?"
The doct or " Wher e i s i t
Of cour se, i t woul d not be t her e.
I
guess t he doct or di d not have qui t e t he ner ve t o wr i t e i n t hat he had got i t , but he di d not mi nd t el l i ng us, ver bal l y assur i ng us. So i t was honor ed i n t he br each mor e t han t he obser vance even af t er t hose gui del i nes.
But when we had a sur vey i n whi ch we
l ooked at cl i ni cal i nvest i gat or s- - i t was f r om ni ne sponsor s and l ar ge smal l , and mi ddl e- si zed compani es, and a whol e pi l e of
98
i nvest i gat or s- - I t hi nk we t abul at ed what we saw i n t he way of consent s, and t he r esul t s wer e not t he gr eat est . I hope t hi s l at er di scussi on gi ves an i ndi cat i on of my post t hal i domi de car eer .
Essent i al l y, t o sum up my wor k at t he FDA
si nce 1962, I have been i n t hr ee r evi ew di vi si ons.
I was head of
t he new I ND br anch r esponsi bl e f or set t i ng up t he whol e I ND syst em f or t he f i r st t i me t hi s mat er i al had t o be submi t t ed.
We
had a ver y i nt er est i ng oper at i on goi ng, and t hen, of cour se, t hat was di ssol ved.
I went br i ef l y i nt o a r evi ew di vi si on- - t hat was
t he ant i - cancer and oncol ogy di vi si on- - i n t he next r ear r angement and t hen I moved i nt o t hi s new uni t i n 1967 t hat I have been i n ever si nce.
I t has kept changi ng names; i t has kept changi ng
cent er s; i t has kept changi ng t hi s, t hat , and t he ot her . t i me we wer e uni t ed wi t h Bi ol ogi cs, f or exampl e.
At one
But st i l l i t
does essent i al l y t he same t hi ng, moni t or i ng t he conduct of st udi es, at f i r st i t was t he cl i ni cal st udi es, t hen we soon got i nt o t he ani mal st udi es, and t hen t he I RBs.
Fi nal l y came t he
agency- wi de bi or esear ch moni t or i ng pr ogr am.
That i s wher e we ar e
t oday, and i t was a l ong t i me bef or e we got i nt o compl i ance.
I
must say we came i n wi t h my ki cki ng and scr eami ng, because I di d not t hi nk we r eal l y bel onged t her e. t oo bad.
But act ual l y i t has not been
I al ways f el t we shoul d be ver y cl ose wi t h t he
r evi ewer s and t he r evi ewi ng medi cal of f i cer s, and get l ot s of f eedback bet ween t hem and us.
But we have managed t o pr eser ve
our pr of essi onal out l ook and cont i nue t o have a good r appor t , I
98
i nvest i gat or s- - I t hi nk we t abul at ed what we saw i n t he way of consent s, and t he r esul t s wer e not t he gr eat est . I hope t hi s l at er di scussi on gi ves an i ndi cat i on of my post t hal i domi de car eer .
Essent i al l y, t o sum up my wor k at t he FDA
si nce 1962, I have been i n t hr ee r evi ew di vi si ons.
I was head of
t he new I ND br anch r esponsi bl e f or set t i ng up t he whol e I ND syst em f or t he f i r st t i me t hi s mat er i al had t o be submi t t ed.
We
had a ver y i nt er est i ng oper at i on goi ng, and t hen, of cour se, t hat was di ssol ved.
I went br i ef l y i nt o a r evi ew di vi si on- - t hat was
t he ant i - cancer and oncol ogy di vi si on- - i n t he next r ear r angement and t hen I moved i nt o t hi s new uni t i n 1967 t hat I have been i n ever si nce.
I t has kept changi ng names; i t has kept changi ng
cent er s; i t has kept changi ng t hi s, t hat , and t he ot her . t i me we wer e uni t ed wi t h Bi ol ogi cs, f or exampl e.
At one
But st i l l i t
does essent i al l y t he same t hi ng, moni t or i ng t he conduct of st udi es, at f i r st i t was t he cl i ni cal st udi es, t hen we soon got i nt o t he ani mal st udi es, and t hen t he I RBs.
Fi nal l y came t he
agency- wi de bi or esear ch moni t or i ng pr ogr am.
That i s wher e we ar e
t oday, and i t was a l ong t i me bef or e we got i nt o compl i ance.
I
must say we came i n wi t h my ki cki ng and scr eami ng, because I di d not t hi nk we r eal l y bel onged t her e. t oo bad.
But act ual l y i t has not been
I al ways f el t we shoul d be ver y cl ose wi t h t he
r evi ewer s and t he r evi ewi ng medi cal of f i cer s, and get l ot s of f eedback bet ween t hem and us.
But we have managed t o pr eser ve
our pr of essi onal out l ook and cont i nue t o have a good r appor t , I
