Sulfanilamide and Diethylene Glycol - ACS Publications - American

6 Sulfanilamide and Diethylene Glycol

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on March 19, 2018 | https://pubs.acs.org Publication Date: August 23, 1984 | doi: 10.1021/bk-1984-0228.ch006

JAMES HARVEY YOUNG Emory University, Department of History, Atlanta, GA 30322

In 1937 the S. E. Massengill Company in Tennessee marketed a liquid dosage form of sulfanilamide, un aware that the solvent used, diethylene glycol, was poisonous. Before the Food and Drug Administration could track down this "Elixir Sulfanilamide", 107 persons had died. The manufacturer was assessed the largest fine ever levied under the Food and Drugs Act of 1906. The crisis prompted research in the FDA's division of pharmacology which developed a statis tically based method for determining the comparative toxicity of compounds. The episode was also re sponsible for a provision in the Food, Drug, and Cosmetic Act of 1938 requiring that the safety of new drugs must be established prior to marketing, a precedent later applied to pesticides, food and color additives, and medical devices. In a promotional brochure sent t o p h y s i c i a n s i n October 1937, t h e S. E. M a s s e n g i l l Company o f B r i s t o l , Tennessee, announced "A New S u l f a n i l a m i d e " U_). "Our r e s e a r c h d e p a r t m e n t has j u s t r e l e a s e d a n E l i x i r S u l f a n i l a m i d e , " t h e r e p o r t r e a d , "40 g r s t o t h e f l u i d o u n c e . I t i s i d e a l f o r y o u r p a t i e n t s who c a n t a k e l i q u i d s — b u t l i t t l e e l s e . A l s o , i t i s not unpleasant t o t a k e , so i s s u i t a b l e f o r c h i l d r e n . The c o l o r i s b r i l l i a n t r e d . . . . " Thus began t h e m a r k e t i n g o f a t h e r a p e u t i c s o l u t i o n t h a t m i x e d two c h e m i c a l compounds, one t h e f i r s t d r u g t o combat e f f e c t i v e l y b a c t e r i a l i n f e c t i o n s , the other a powerful poison. The p r e s c r i b i n g o f E l i x i r S u l f a n i l a m i d e c a u s e d o v e r a h u n d r e d d e a t h s , many o f them o f c h i l d r e n ; p r o v o k e d n a t i o n a l p a n i c ; and spurred a d e s p e r a t e e f f o r t , l e d b y t h e Food and Drug A d m i n i s t r a t i o n , t o t r a c k down t h e l e t h a l " e l i x i r " and t o remove i t from d r u g s t o r e s and homes. In the longer r u n , the E l i x i r S u l f a n i l a m i d e d i s a s t e r l e f t i t s mark o n r e g u l a t o r y l a w , and hence on p h a r m a c e u t i c a l m a n u f a c t u r i n g , and prompted s i g n i f i c a n t i n novation i n toxicology.

0097-6156/83/00228-0105 $06.25/0 © 1983 American Chemical Society

Parascandola and Whorton; Chemistry and Modern Society ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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Sulfanilamide By t h e m i d - 1 9 3 0 s most r e s e a r c h e r s and c l i n i c i a n s c o n c e r n e d w i t h i n f e c t i o u s d i s e a s e s had abandoned hope t h a t c h e m i c a l a g e n t s would e v e r be d i s c o v e r e d t o p r o v i d e e f f e c t i v e t r e a t m e n t for b a c t e r i a l i n f e c t i o n s (£, _3). The o p t i m i s m o f t h e t e e n s , s p u r r e d by P a u l E h r l i c h ' s p i o n e e r i n g c h e m o t h e r a p y f o r s y p h i l i s , had l e d to many e f f o r t s i n E u r o p e and A m e r i c a t o d e v e l o p chemical s y n t h e t i c d r u g s t h a t w o u l d combat germs i n the body, but t h i s o p t i m i s m had waned, b a t t e r e d b y a s e r i e s o f f a i l u r e s , d r u g s glowingly announced—especially i n Germany—that with experience had n o t p r o v e d o u t . E m i l von B e h r i n g * s o l d d i c t u m had r e g a i n e d currency: " i n n e r d i s i n f e c t i o n i s a v a i n dream" (2^). T h e r e f o r e , G e r h a r d t Domagk's announcement o f P r o n t o s i l i n 1935 ( 4 , _5) s p a r k e d scant initial i n t e r e s t and t h e u s u a l skepticism. The B r i t i s h b a c t e r i o l o g i s t R o n a l d Hare assumed P r o n t o s i l t o be " [ a ] n o t h e r o f t h o s e damned compounds f r o m Germany w i t h a t r a d e name and o f unknown c o m p o s i t i o n t h a t a r e no use anyway" ( 6 ) . Domagk's d a t a were t o o s k e t c h y , h i s p e r f e c t r e s u l t s i n animal e x p e r i m e n t s too p a t , the accompanying c l i n i c a l r e p o r t s t o o r e s o n a n t w i t h a t e s t i m o n i a l t o n e (2^). French s c i e n t i s t s a t t h e Pasteur Institute, however, p r o m p t l y d i s p e l l e d some o f P r o n t o s i l ' s m y s t e r y , s p l i t t i n g t h e m o l e c u l e i n t o a r e d dye component and an o l d c h e m i c a l , s u l f a n i l a m i d e , i t s 1909 p a t e n t l o n g s i n c e l a p s e d G O . The s u s p i c i o n a r o s e t h a t Domagk, a n I . G. F a r b e n i n d u s t r i e r e s e a r c h e r , had r e d i s c o v e r e d s u l f a n i l a m i d e , and t h a t t h e m a n u f a c t u r e r had h e l d i t o f f t h e m a r k e t u n t i l i t c o u l d be p r e s e n t e d i n a new, complex, d i s g u i s e d , and p a t e n t a b l e f o r m (2^ 2> · Whether o r n o t t h e s u s p i c i o n was t r u e , t h e F r e n c h s c i e n t i s t s , b y s h o w i n g t h a t s u l f a n i l a m i d e was t h e t h e r a p e u t i c a l l y a c t i v e f r a c t i o n o f P r o n t o s i l , s h a t t e r e d the g i g a n t i c Germany company's p r o f i t a b l e p l a n s . Persuasive proof o f sulfanilamide's true antibacterial prowess came f r o m L e o n a r d C o l e b r o o k and h i s team o f r e s e a r c h e r s i n t h e m a t e r n i t y ward o f Queen C h a r l o t t e ' s H o s p i t a l i n London (_7, 8, 9 ) . M a n a g i n g t o o b t a i n s a m p l e s o f P r o n t o s i l l a t e i n 1935, Colebrook q u i c k l y demonstrated the drug's remarkable e f f e c t i v e n e s s i n c u r b i n g p u e r p e r a l f e v e r . The u t i l i t y was soon expanded t o other severe s t r e p t o c o c c a l i n f e c t i o n s . C o l e b r o o k announced h i s p r o m i s i n g r e s u l t s d u r i n g the summer o f 1936 a t a n i n t e r n a t i o n a l c o n g r e s s o f m i c r o b i o l o g y i n London (_3, 6 ) . P e r r i n H. Long o f t h e J o h n s H o p k i n s U n i v e r s i t y , a t t e n d i n g t h e c o n f e r e n c e , l e a r n e d o f C o l e b r o o k ' s p r e s e n t a t i o n and c a b l e d the news t o h i s c o l l e a g u e s . On September 1 he and E l e a n o r A. B l i s s began e x p e r i m e n t s w i t h m i c e , w i t h s u c h p r o m i s i n g r e s u l t s t h a t a week l a t e r Long t r e a t e d a c h i l d d e s p e r a t e l y i l l w i t h e r y s i p e l a s , a woman w i t h i n f e c t i o n f o l l o w i n g a n a b o r t i o n , and t h e n many more s e v e r e c a s e s o f s t r e p t o c o c c a l i n f e c t i o n ( 3 , 1 0 , 11 ). Long and B l i s s had n o t y e t p u b l i s h e d t h e i r e n c o u r a g i n g


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r e s u l t s when Long r e c e i v e d a t e l e p h o n e c a l l from E l e a n o r Roosevelt (3). F r a n k l i n D. R o o s e v e l t , J r . , h i s m o t h e r s a i d , l a y d e s p e r a t e l y i l l i n Massachusetts General H o s p i t a l . The d o c t o r s t h o u g h t h e m i g h t be d y i n g . An i n f e c t i o n i n h i s t h r o a t had spread t o h i s s i n u s e s and was now, c a r r i e d t h r o u g h h i s b l o o d , e n g u l f i n g h i s body. A week l a t e r , o n December 1 6 , 1 9 3 6 , y o u n g Roosevelt s p h y s i c i a n , George L o r i n g Tobey, J r . , t o l d r e p o r t e r s t h a t h i s p a t i e n t had responded " b e a u t i f u l l y " t o treatment w i t h a trade f o r m o f s u l f a n i l a m i d e and was now o u t o f d a n g e r (12). H i s mother and f i a n c e e E t h e l d u P o n t h a d l e f t h i s b e d s i d e f o r t h e f i r s t t i m e i n n e a r l y t h r e e weeks. Headlines the n a t i o n over c a r r i e d the news. "Young R o o s e v e l t Saved b y New D r u g , " r e p o r t e d t h e New Y o r k T i m e s , and t h e n e x t d a y , i n an e d i t o r i a l , h e r a l d e d "DOMAGK's d i s c o v e r y as t h e o u t s t a n d i n g t h e r a p e u t i c a c h i e v e m e n t o f t h e l a s t decade" ( 1 3 ) . Under s i m i l a r c i r c u m s t a n c e s a decade e a r l i e r C a l v i n Coolidge, J r . , had d i e d o f s t r e p t o c o c c a l i n f e c t i o n Ο ) . F r a n k l i n D. R o o s e v e l t , J r . , s u r v i v e d , r e c o v e r e d , g r a d u a t e d f r o m H a r v a r d t h e n e x t J u n e , and a week l a t e r m a r r i e d M i s s d u P o n t ( 1 4 , 15). The R o o s e v e l t c a s e h e l p e d t r i g g e r t h e " e x p l o s i v e s u d d e n n e s s " ( 1 6 ) w i t h w h i c h A m e r i c a n p h y s i c i a n s and t h e A m e r i c a n p u b l i c g e n e r a l l y developed a widespread i n t e r e s t i n s u l f a n i l a m i d e . C h e m i c a l m a n u f a c t u r e r s b e g a n t o p r o d u c e t h e raw d r u g and s e l l i t to pharmaceutical f i r m s w h i c h p r o c e s s e d i t i n t o p i l l s and c a p s u l e s f o r d i s t r i b u t i o n t o p h y s i c i a n s and p h a r m a c i s t s (17). At l e a s t a hundred f i r m s were making p r o p r i e t a r y brands o f s u l f a n i l a m i d e t a b l e t s i n 1 9 3 7 , among them t h e M a s s e n g i l l Company. Use o f t h e d r u g q u i c k l y assumed t r e m e n d o u s p r o p o r t i o n s . , Public i n t e r e s t quickened f u r t h e r w i t h the report that s u l f a n i l a m i d e c o u l d c u r e g o n o r r h e a , news t h a t s u r f a c e d a m i d s t a m a j o r P u b l i c H e a l t h S e r v i c e c a m p a i g n a g a i n s t v e n e r e a l d i s e a s e ( 1J$). T h i s l e d , d e s p i t e PHS w a r n i n g s , t o w i d e s p r e a d s e l f - d o s a g e w i t h s u l f a n i l a mide s e c u r e d f r o m d r u g g i s t s ' w i t h o u t a p h y s i c i a n ' s p r e s c r i p t i o n . The h a z a r d s o f s u c h s e l f - d o s a g e became i n c r e a s i n g l y a p p a r e n t a s adverse r e a c t i o n s which c o u l d r e s u l t from s u l f a n i l a m i d e ' s use b e g a n t o be r e c o g n i z e d and r e p o r t e d i n t h e m e d i c a l literature (19). The m a j o r i t y o f s t r e p t o c o c c a l i n f e c t i o n s o c c u r r e d i n c h i l d r e n u n d e r t e n , s o t h e new d r u g p r o v e d a p a r t i c u l a r b l e s s i n g t o the v e r y young ( 2 0 ) . The b i g t a b l e t s o f s u l f a n i l a m i d e c o u l d be administered s u c c e s s f u l l y i nh o s p i t a l s t o a l l but the smallest b a b i e s . Most s i c k c h i l d r e n , h o w e v e r , r e c e i v e d t r e a t m e n t a t home, and m o t h e r s f o u n d i t d i f f i c u l t t o g e t them t o s w a l l o w l a r g e p i l l s . This circumstance seemed t o c a l l f o r a l i q u i d d o s a g e f o r m . A number o f a t t e m p t s t o f i n d a s u i t a b l e v e h i c l e , h o w e v e r , p r o v e d unavailing.


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Diethylene

Glycol

S u c c e s s a t f i n d i n g a s o l v e n t f o r s u l f a n i l a m i d e , w h i c h had e l u d e d o t h e r s , q u i c k l y crowned t h e e f f o r t s o f H a r o l d Cole W a t k i n s , c h i e f c h e m i s t , c h i e f p h a r m a c i s t , t r o u b l e - s h o o t e r , and d e v e l o p e r o f new f o r m u l a s a t t h e M a s s e n g i l l Company (2_1, 2 2 ) . L e a r n i n g f r o m a company s a l e s m a n t h a t a good m a r k e t a w a i t e d a l i q u i d d o s a g e f o r m , W a t k i n s s e t t o w o r k i n J u l y 1937 and i n a few days developed a formula. He knew f r o m h i s r e a d i n g t h a t g l y c o l s p o s s e s s e d r e m a r k a b l e s o l v e n t p r o p e r t i e s , a n d t h e company had f o u n d t h i s c l a s s o f c h e m i c a l s s a t i s f a c t o r y , «used i n v e r y s m a l l amounts, i n s e v e r a l o t h e r d r u g s . So W a t k i n s s o u g h t t o d i s s o l v e s u l f a n i l a m i d e i n d i e t h y l e n e g l y c o l and found t h a t he c o u l d d i s s o l v e a s much a s 75 g r a i n s i n a s i n g l e f l u i d o u n c e . When c h i l l e d , however, the drug tended to s e p a r a t e out. So W a t k i n s d e c i d e d o n a r a t i o o f 40 g r a i n s p e r o u n c e . M i x i n g 80 g a l l o n s o f w a t e r and 60 g a l l o n s o f d i e t h y l e n e g l y c o l , W a t k i n s added 58 1/2 pounds o f s u l f a n i l a m i d e powder, p l u s s m a l l q u a n t i t i e s o f e l i x i r f l a v o r , s a c c h a r i n , c a r a m e l , amaranth s o l u t i o n , and r a s p b e r r y e x t r a c t . He t h e n s e n t h i s " E l i x i r S u l f a n i l a m i d e " — a k i n i n c o l o r t o t h e o r i g i n a l P r o n t o s i l — t o t h e company's " c o n t r o l l a b o r a t o r y , " where t h e new p r o d u c t was c h e c k e d f o r a p p e a r a n c e , f l a v o r , a n d f r a g r a n c e , and approved. C o m m e r c i a l d i s t r i b u t i o n began f r o m B r i s t o l on September 4, and s h o r t l y a f t e r w a r d s f r o m t h e company's b r a n c h p l a n t i n K a n s a s C i t y , t o w h i c h t h e f o r m u l a had b e e n s e n t (23). W a t k i n s had made no t e s t s w h a t s o e v e r t o a s s e s s t h e t o x i c i t y of e i t h e r the separate i n g r e d i e n t s o r the combination o f i n g r e d i e n t s i n t h e f i n a l f o r m u l a ( 2 1 , 22^). He l a t e r s t a t e d t h a t t h e r e was no p o i n t i n m a k i n g t e s t s , s i n c e t h e a c t i o n o f t h e i n g r e d i e n t s was w e l l u n d e r s t o o d ( 2 2 ) . The g l y c o l s , r e l a t e d t o g l y c e r i n e , had been w i d e l y u s e d b y d r u g c o m p a n i e s , and, W a t k i n s a v e r r e d , w e r e w e l l known n o t t o be t o x i c . T h e o d o r e Klumpp, t h e Food and D r u g A d m i n i s t r a t i o n ' s c h i e f m e d i c a l o f f i c e r , who i n t e r v i e w e d W a t k i n s s o o n a f t e r d i s a s t e r s t r u c k , e x p r e s s e d amazement a t t h e c h e m i s t ' s " r e v e l a t i o n o f ignorance" (22^). F o r anyone a l e r t t o t h e l i t e r a t u r e , w a r n i n g s i g n s abounded. E t h y l e n e g l y c o l was f i r s t p r e p a r e d i n F r a n c e i n 1859, and d i e t h y l e n e g l y c o l s o o n t h e r e a f t e r , b u t p r i o r t o 1925, when a p l a n t was e r e c t e d i n West V i r g i n i a t o p r o d u c e g l y c o l s , t h e s e chemicals possessed l i t t l e commercial importance (24). Their m a i n u s e s were t o l o w e r t h e f r e e z i n g p o i n t o f d y n a m i t e , t o c o o l a i r p l a n e e n g i n e s , and t o p r o t e c t automobile r a d i a t o r s from freezing. D i e t h y l e n e g l y c o l , however, d i d not work w e l l a s an a n t i f r e e z e : i t s s u c c e s s as a s o l v e n t , w h i c h W a t k i n s p r i z e d , made i t u n s u i t a b l e , f o r i f s p i l l e d i t would d i s s o l v e a car's p a i n t . The h y g r o s c o p i c p r o p e r t i e s o f d i e t h y l e n e g l y c o l gave i t a r o l e a s h u m e c t a n t f o r t o b a c c o , p r i n t i n g i n k , g l u e , c e l l o p h a n e , and, i n m i n u t e q u a n t i t i e s , f o r t o o t h p a s t e and d r u g a m p u l e s .


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1

F o r some y e a r s p r i o r t o W a t k i n s employment o f d i e t h y l e n e g l y c o l , t h e Food and D r u g A d m i n i s t r a t i o n had a d v i s e d a g a i n s t t h e use o f g l y c o l s o l v e n t s i n f o o d s , declaring that definite, c o m p r e h e n s i v e c o n c l u s i o n s as t o t h e p h y s i o l o g i c a l a c t i o n o f t h e s e c h e m i c a l s c o u l d n o t be r e a c h e d on t h e b a s i s o f e x i s t i n g s c a n t y r e s e a r c h (25). The p r i m a r y m a n u f a c t u r e r , C a r b o n and C a r b i d e C h e m i c a l s C o r p o r a t i o n , had c o n s i s t e n t l y d i s c o u r a g e d use o f d i e t h y l e n e g l y c o l i n e i t h e r f o o d o r d r u g s ( 2 6 ) . B e g i n n i n g i n 1931 more e x p l i c i t r e p o r t s o f t h e p o i s o n o u s n a t u r e o f t h e chemical a p p e a r e d i n m e d i c a l j o u r n a l s (27.» 2 8 ) . The p o i n t a b o u t W a t k i n s , h o w e v e r , was not j u s t t h a t he d i d n o t know t h e relevant l i t e r a t u r e ; he d i d n o t t a k e e l e m e n t a r y p r e c a u t i o n s and t e s t f o r toxicity. Dawn o f

Disaster

On O c t o b e r 11, A m e r i c a n M e d i c a l A s s o c i a t i o n o f f i c i a l s i n C h i c a g o r e c e i v e d two t e l e g r a m s , one f r o m t h e p r e s i d e n t o f t h e T u l s a C o u n t y M e d i c a l S o c i e t y i n Oklahoma, t h e o t h e r f r o m t h e S p r i n g e r C l i n i c o f T u l s a ( Z 3 , 29, 3 0 ) . S i x d e a t h s had o c c u r r e d f o l l o w i n g the a d m i n i s t r a t i o n of E l i x i r S u l f a n i l a m i d e - M a s s e n g i l l . What, t h e t e l e g r a m s i n q u i r e d , was t h e c o m p o s i t i o n o f t h i s d r u g ? The ΑΜΑ r e p l i e d immediately. No p r o d u c t made by the M a s s e n g i l l Company had b e e n a c c e p t e d by t h e Α Μ Α s C o u n c i l on Pharmacy and C h e m i s t r y , a body c r e a t e d i n 1905 t o t e s t t h e c l a i m s of p r o p r i e t a r y medicines s o l d or p r e s c r i b e d through p h y s i c i a n s (23, 31). Nor had the C o u n c i l r e c o g n i z e d any s o l u t i o n of sulfanilamide. S i m u l t a n e o u s l y , t h e ΑΜΑ t e l e g r a p h e d t h e M a s s e n g i l l Company i n B r i s t o l r e q u e s t i n g t h e f o r m u l a (22). The company c o m p l i e d , a s k i n g , h o w e v e r , t h a t t h e c o m p o s i t i o n be r e g a r d e d as a t r a d e s e c r e t and be k e p t c o n f i d e n t i a l . D i e t h y l e n e g l y c o l became i m m e d i a t e l y s u s p e c t , i t s p r e s e n c e v e r i f i e d by t h e ΑΜΑ i n the f i r s t sample o f t h e d e a t h - d e a l i n g d r u g r u s h e d f r o m T u l s a t o Chicago. The ΑΜΑ a l s o s e c u r e d a g a l l o n o f t h e E l i x i r f r o m M a s s e n g i l l and bought more on t h e open m a r k e t i n T u l s a , w h i c h i t used i n p r e l i m i n a r y a n i m a l experiments to demonstrate the drug's poisonous p o t e n t i a l . D e a t h s i n T u l s a mounted, and a St. Louis pathologist r e p o r t e d a s e r i e s of deaths a c r o s s the M i s s i s s i p p i R i v e r i n East St. L o u i s ( 3 2 ) . M o r r i s F i s h b e i n , e d i t o r of the J o u r n a l of the American M e d i c a l A s s o c i a t i o n , wrote a w a r n i n g to appear i n the O c t o b e r 23 i s s u e ( 2 9 ) , and on O c t o b e r 18 met w i t h r e p o r t e r s t o g i v e them an advance copy o f t h e t e x t ( 2 3 ) . The p r e s s and r a d i o q u i c k l y a l e r t e d the n a t i o n to the c a t a s t r o p h e i n p r o g r e s s . The ΑΜΑ a r r a n g e d f o r more p r o b i n g r e s e a r c h r e g a r d i n g E l i x i r S u l f a n i l a m i d e ' s t o x i c i t y , t u r n i n g t o P e r r i n Long a t Johns Hopkins and h i s c o l l e a g u e , Ε. K. M a r s h a l l , J r . , who had discovered s u l f a n i l a m i d e ' s mode o f a c t i o n i n t h e body, and t o Ε. M. K. G e i l i n g , P a u l R. Cannon, and Ε. M. Humphreys o f t h e U n i v e r s i t y o f 1



110

CHEMISTRY AND MODERN SOCIETY

Chicago (2!, 2 3 ) . The ΑΜΑ a l s o e s t a b l i s h e d l i a i s o n with the Food and Drug A d m i n i s t r a t i o n . FDA had r e c e i v e d i t s f i r s t word of the T u l s a deaths on October 14 i n a telephone i n q u i r y from a New York p h y s i c i a n a s s o c i a t e d with a pharmaceutical company (23). Immediately the agency sent inspectors to T u l s a from Kansas C i t y ( 3 3 ) . They learned that s u s p i c i o n s had surfaced on October 7 when autopsy cases began to accumulate, . a l l r e v e a l i n g kidney degeneration, with anuria having preceded death. The symptoms resembled mercuric c h l o r i d e poisoning, except f o r the absence of e n t e r i t i s and l i v e r damage. E l i x i r Sulfanilamide had been found to be the drug common to the nine deaths so f a r discovered, eight of them among c h i l d r e n being treated f o r s t r e p t h r o a t s , the n i n t h an adult male with gonorrhea. The county medical s o c i e t y had appointed a committee of i n q u i r y and had urged the T u l s a R e t a i l Druggists A s s o c i a t i o n to suspend s e l l i n g E l i x i r S u l f a n i l a m i d e . A T u l s a p a t h o l o g i s t had confirmed the drug's t o x i c i t y on guinea pigs. The i n s p e c t o r s had been i n v i t e d to attend a postmortem examination of the a d u l t man. His kidneys were " e x c e s s i v e l y enlarged," about f i f t y percent l a r g e r than normal. "Clotted, p u r p l i s h congestion" appeared "on [the] periphery of [the] kidneys." Samples of E l i x i r Sulfanilamide c o l l e c t e d by the i n s p e c t o r s were sent to C e n t r a l D i s t r i c t headquarters i n Chicago (33). The

S. E. M a s s e n g i l l Company

The f i r s t reports from T u l s a led the FDA to d i s p a t c h the agency's c h i e f medical o f f i c e r , Theodore G. Klumpp, accompanied by an i n s p e c t o r , W i l l i a m T. Ford, from C i n c i n n a t i , to the plant i n B r i s t o l at which E l i x i r Sulfanilamide had been conceived and f i r s t prepared (2J_, 2 2 ) . The S. E. M a s s e n g i l l Company, the l a r g e s t pharmaceutical company i n the South, had begun i n 1897 as a p a r t n e r s h i p between two b r o t h e r s , one of whom had died i n 1926 ( 3 4 , 3 5 ) . The s u r v i v o r , Samuel Evans M a s s e n g i l l , a man i n h i s s i x t i e s , con tinued to manage the f i r m . M a s s e n g i l l admired h i s ancestry: i n 1769 a d i r e c t forebear had become the second permanent white s e t t l e r i n what would l a t e r be Tennessee, and M a s s e n g i l l ' s f a t h e r had served i n the Confederate c a v a l r y before attending medical school and l i v i n g out h i s l i f e as a country doctor and r a i s e r of g a i t e d horses. M a s s e n g i l l h i m s e l f had been graduated from the U n i v e r s i t y of N a s h v i l l e Medical School, but had not p r a c t i c e d , launching h i s drug manufacturing f i r m instead (37^). This venture had pros pered. By 1937 the f i r m made a wide array of drugs f o r human and animal use, i n c l u d i n g many p r i v a t e formulas f o r physicians and d r u g g i s t s (32, 3 6 ) . Manufacturing was done i n the B r i s t o l and Kansas C i t y p l a n t s , and the company a l s o had d i s t r i b u t i n g o f f i c e s



6. Y O U N G


i n New Y o r k and San F r a n c i s c o ( 3 4 ) . Some f i v e h u n d r e d e m p l o y e e s w o r k e d f o r M a s s e n g i l l , i n c l u d i n g a c o r p s o f 160 d e t a i l men t o make i t s p r o d u c t s known. M a s s e n g i l l d r u g s went o v e r s e a s , e s p e c i a l l y t o L a t i n A m e r i c a and E g y p t (35^). Prompt s e r v i c e was a M a s s e n g i l l hallmark. S. E. M a s s e n g i l l e n j o y e d a n e x c e l l e n t r e p u t a t i o n i n h i s community, and B r i s t o l c i v i c l e a d e r s and p h y s i c i a n s s t a u n c h l y s u p p o r t e d h i m i n h i s t i m e o f t r o u b l e s w h i c h h a d j u s t begun ( 3 8 ) . T h r o u g h most o f t h e y e a r s t h a t t h e Food and Drugs A c t o f 1906 had b e e n i n e f f e c t , e n f o r c e r s o f t h a t law h a d p a i d l i t t l e h e e d t o t h e M a s s e n g i l l Company's e x i s t e n c e (26). No t h o r o u g h i n s p e c t i o n by i n v e s t i g a t i o n a l p r o c e d u r e s h a d p r e c e d e d t h e E l i x i r Sulfanilamide c r i s i s . The company i t s e l f deemed i t s r e c o r d u n d e r t h e l a w " s p l e n d i d , " more a d m i r a b l e t h a n t h a t o f most d r u g m a n u f a c t u r e r s (24). Only t h r e e c a s e s had been brought a g a i n s t t h e company by FDA, a l l d u r i n g t h e 1930s. Two p r o s e c u t i o n c a s e s t h e company s e t t l e d by p a y i n g s m a l l f i n e s , $250 and $150, r a t h e r t h a n u n d e r t a k i n g t h e e x p e n s e s o f a t r i a l (22., 4 0 ) . These i n v o l v e d F l u i d e x t r a c t o f C o l c h i c u m , o v e r s t r e n g t h when j u d g e d by t h e o f f i c i a l s t a n d a r d o f t h e N a t i o n a l F o r m u l a r y , and T i n c t u r e o f A c o n i t e , w h i c h t h e FDA f o u n d u n d e r s t r e n g t h . The t h i r d c a s e , c o n c e r n i n g a s e i z u r e o f E l i x i r T e r p i n H y d r a t e and C o d e i n e , went t o t r i a l as b o t h a d u l t e r a t e d and m i s b r a n d e d , t h e government f i n d i n g a d i s p a r i t y between t h e q u a n t i t y o f both i n g r e d i e n t s s t a t e d o n t h e l a b e l and a c t u a l l y p r e s e n t i n t h e m e d i c i n e ( 4 1 , 4 2 ) . The j u d g e d r u l e d f o r t h e g o v e r n m e n t . When Dr. Klumpp and I n s p e c t o r F o r d met D r . M a s s e n g i l l i n h i s B r i s t o l o f f i c e , t h e p r o p r i e t o r " l o o k e d w o r r i e d " and o f f e r e d h i s " f u l l c o o p e r a t i o n " (22). He h a d a l r e a d y done " a l l t h a t * was humanly p o s s i b l e , " M a s s e n g i l l s a i d , t o r e c a l l o u t s t a n d i n g s t o c k s of E l i x i r Sulfanilamide. Some 375 t e l e g r a m s h a d b e e n s e n t f r o m B r i s t o l , and more f r o m o t h e r company b r a n c h e s , a t o t a l o f 1100, t o t h e f i r m ' s s a l e s m e n , who h a d d i s t r i b u t e d s m a l l sample b o t t l e s , and t o c o n c e r n s , m o s t l y d r u g w h o l e s a l e r s , whose o r d e r s h a d been filled. Klumpp i n s i s t e d , s i n c e t h e s e r e c a l l t e l e g r a m s h a d g i v e n no h i n t o f h a z a r d , t h a t M a s s e n g i l l d i s p a t c h f o l l o w - u p t e l e g r a m s reading: " I m p e r a t i v e y o u t a k e up i m m e d i a t e l y a l l e l i x i r s u l f a n i l a m i d e y o u may h a v e d i s p e n s e d . P r o d u c t may be d a n g e r o u s t o life. Return a l l stocks a t o u r expense" (23). That t h e d i e t h y l e n e g l y c o l i n h i s E l i x i r S u l f a n i l a m i d e had caused the deaths b e i n g i n c r e a s i n g l y r e p o r t e d , Dr. M a s s e n g i l l , i n h i s c o n v e r s a t i o n w i t h t h e FDA o f f i c i a l s — o r t h e r e a f t e r — , d i d n o t a d m i t . No s p e c i a l t o x i c i t y t e s t s h a d been made o n t h e E l i x i r , he a c k n o w l e d g e d , i n d e e d , no a n i m a l t e s t s a t a l l (21^, 2 2 ) . Without specifying d e t a i l s , Massengill asserted that h i s c o n t r o l department saw t o i t t h a t a l l d r u g s were " a l l r i g h t " b e f o r e their r e l e a s e . The r e a l blame l a y , he s u g g e s t e d , n o t w i t h t h e s o l v e n t but w i t h t h e s u l f a n i l a m i d e . M a s s e n g i l l s t a t e d , as Klumpp r e p o r t e d t h e c o n v e r s a t i o n ( 2 2 ) , " t h a t t h e d r u g s u l f a n i l a m i d [ e ] had been so e x p l o i t e d by p h y s i c i a n s and t h e p r e s s t h a t e v e r y o n e i n t h e c o u n t r y was g o i n g w i l d


111


112


w i t h i t and u s i n g i t f o r e v e r y t h i n g and now t h e d i s a s t r o u s e f f e c t s o f i t were c o m i n g o u t . . . . [ T ] h e y d o n ' t know much a b o u t s u l f a n i l a m i d [ e ] b u t t h a t i t was w e l l r e c o g n i z e d t h a t i t was d a n g e r o u s when u s e d w i t h o t h e r d r u g s . He s t a t e d h i s o p i n i o n t h a t the f a t a l i t i e s f r o m E l i x i r S u l f a n i l a m i d e were due n o t t o t h e E l i x i r S u l f a n i l a m i d e i t s e l f , b u t t o t h e f a c t t h a t t h o s e t h a t were k i l l e d took other drugs w h i l e t a k i n g t h e E l i x i r S u l f a n i l a m i d e , t h e c o m b i n a t i o n o f w h i c h k i l l e d them." In later public state ments M a s s e n g i l l a d h e r e d t o s i n i s t e r s y n e r g i s m as h i s e x p l a n a t i o n o f t h e d i s a s t e r . W i t h i n a few days h e t o l d t h e p r e s s : " I do n o t f e e l t h a t t h e r e was any r e s p o n s i b i l i t y o n o u r p a r t " ( 2 3 ) . And h e w r o t e t h e ΑΜΑ: " I h a v e v i o l a t e d no l a w " ( 2 3 ) . Klumpp and F o r d a l s o t a l k e d w i t h W a t k i n s (2_1» 22^. Besides f i n d i n g o u t how h e h a d happened t o h i t upon t h e E l i x i r S u l f a n i l a m i d e f o r m u l a , t h e y p r o b e d h i s b a c k g r o u n d a s a c h e m i s t . He had b e e n g r a d u a t e d f r o m t h e U n i v e r s i t y o f M i c h i g a n S c h o o l o f Pharmacy i n 1901, W a t k i n s s a i d , w i t h t h e d e g r e e o f p h a r m a c e u t i c a l c h e m i s t , and a f t e r w a r d s h a d e x p e r i e n c e d a p e r i p a t e t i c c a r e e r . He had done r e s e a r c h i n a l k a l o i d s f o r s e v e r a l y e a r s , t h e n w o r k e d f o r a w h i l e i n the a n a l y t i c a l l a b o r a t o r y o f Merck, f o l l o w e d by s h o r t s t i n t s i n v a r i o u s w h o l e s a l e and p h a r m a c e u t i c a l h o u s e s , many o f them i n w e s t e r n s t a t e s . I n 1929 he had s i g n e d a s t i p u l a t i o n w i t h t h e P o s t O f f i c e D e p a r t m e n t a g r e e i n g t o abandon t h e s a l e o f a w e i g h t - r e d u c t i o n remedy w h i c h he was p r o m o t i n g w i t h e x c e s s i v e c l a i m s (22). D u r i n g t h e d e p r e s s i o n , W a t k i n s had b e e n i d l e some o f the time, b e f o r e j o i n i n g M a s s e n g i l l . What i m p r e s s e d Klumpp and F o r d most about W a t k i n s was what t h e y deemed a c e r t a i n c a l l o u s n e s s i n h i s c o n v e r s a t i o n . He s p o k e of a p r e p a r a t i o n o f c o l l o i d a l s u l f u r he had d e v i s e d . When m a r k e t e d , t h i s compound r e s u l t e d i n t h e d e a t h o f a number o f p e o p l e . "Mr. W a t k i n s t o l d a b o u t t h i s e v e n t , " Klump w r o t e , " a s i f i t were an o r d i n a r y i n c i d e n t i n t h e b u s i n e s s o f m a k i n g and marketing pharmaceuticals." W a t k i n s was g e t t i n g r e a d y t o r e l e a s e a product c o n t a i n i n g another drug, cinchophen, about which t h e FDA h a d i s s u e d s t r o n g w a r n i n g s . " I t w o u l d seem," t h e FDA's h e a d p h y s i c i a n c o n c l u d e d ( 2 1 ) , g e n e r a l i z i n g f r o m W a t k i n s ' words t o t h e b r o a d e r pharmaceutical m a r k e t p l a c e , " t h a t a g r e a t many d r u g s a r e b e i n g compounded and p l a c e d upon t h e A m e r i c a n m a r k e t w i t h o u t a d e q u a t e t e s t i n g . The e x p r e s s e d o r i m p l i e d a t t i t u d e o f c e r t a i n d r u g m a n u f a c t u r e r s seems t o be t h a t d r u g s c a n b e t e s t e d o n t h e A m e r i c a n p u b l i c . I f t h e y f a i l t o k i l l , o r i n j u r e i n s u c h a way t h a t t h e i n j u r y c a n be d e t e c t e d and t r a c e d t o i t s s o u r c e , t h e p r o d u c t s h a v e t h e n met t h e i r t r i a l s s u c c e s s f u l l y . The c o n c l u s i o n i s u n e s c a p a b l e t h a t such drug m a n u f a c t u r e r s are p e r f e c t l y w i l l i n g to w a i t f o r r e p o r t s of death o r i n j u r y f o r information concerning the t o x i c i t y o f t h e i r drugs." W a t k i n s t o l d Klumpp and F o r d t h a t , when news o f t h e d e a t h s had f i r s t r e a c h e d h i m , h e h a d h i m s e l f t a k e n a huge o r a l d o s e o f d i e t h y l e n e g l y c o l , w i t h o u t i l l e f f e c t s . Klumpp d o u b t e d W a t k i n s '



6. Y O U N G

1

s t o r y , b u t e v e n i f i t were t r u e , Klumpp o b s e r v e d , such a " f u t i l e , heroic gesture" a f t e r the fact could not counterbalance the f a i l u r e t o t e s t the drug properly p r i o r t o i t s d i s t r i b u t i o n .


The

Massive Search

The 1906 l a w d i d n o t r e q u i r e p r e m a r k e t t e s t i n g . Nor d i d i t p r o v i d e t h e Food and Drug A d m i n i s t r a t i o n w i t h a u t h o r i t y t o s e i z e d r u g s b e c a u s e t h e y were d a n g e r o u s . I n d e e d , o n l y an odd h a p p e n s t a n c e gave t h e FDA l e g a l s a n c t i o n t o t r a c k down and remove t h e l e t h a l l i q u i d f r o m d r u g s t o r e s , p h y s i c i a n s ' o f f i c e s , and t h e homes o f p a t i e n t s f o r whom i t h a d been p r e s c r i b e d (23^)· The company h a d named t h i s f o r m o f s u l f a n i l a m i d e an " e l i x i r , " i m p l y i n g an a l c o h o l i c s o l u t i o n . Since i t contained diethylene g l y c o l instead o f a l c o h o l , i t was m i s b r a n d e d . "Had t h e p r o d u c t been c a l l e d a 'solution, r a t h e r than an ' e l i x i r , ' " S e c r e t a r y o f A g r i c u l t u r e Henry A. W a l l a c e s a i d , "no c h a r g e o f v i o l a t i n g t h e law c o u l d have been b r o u g h t . " The company's t e l e g r a m s prompted t h e r e t u r n o f a l a r g e q u a n t i t y o f t h e " e l i x i r " t o t h e m a n u f a c t u r e r , where i t was t a k e n u n d e r s t a t e o r f e d e r a l c o n t r o l ( 2 3 ) . To s e c u r e t h e r e m a i n d e r o f t h e 240 g a l l o n s w h i c h h a d been p r o d u c e d , t h e FDA l a u n c h e d t h e l a r g e s t and most z e a l o u s s e a r c h t h a t h a d been u n d e r t a k e n d u r i n g t h e t h r e e d e c a d e s t h a t t h e 1906 law h a d been i n f o r c e . A l m o s t t h e e n t i r e f i e l d f o r c e o f 239 i n s p e c t o r s and c h e m i s t s p a r t i c i p a t e d . State a u t h o r i t i e s , p a r t i c u l a r l y i n states having drug i n s p e c t o r s , and o f f i c i a l s i n a number o f c i t i e s , p r o v i d e d a c e r t a i n amount o f h e l p , b u t some FDA a g e n t s t h o u g h t g r e a t e r a s s i s t a n c e m i g h t h a v e been r e n d e r e d ( 4 3 ) . The q u i c k a c t i o n a c c o u n t e d f o r most o f t h e " e l i x i r . " Toward t h e end o f November, S e c r e t a r y W a l l a c e r e p o r t e d t o t h e C o n g r e s s , o f t h e 240 g a l l o n s p r o d u c e d , 228 g a l l o n s and two p i n t s h a d been " s e i z e d . . ., d e s t r o y e d , c o l l e c t e d as l a b o r a t o r y s a m p l e s , o r w a s t e d by s p i l l a g e and b r e a k a g e " (23^). (Twelve years l a t e r a b o t t l e t h a t h a d been m i s s e d t u r n e d up i n a b a t c h o f o l d m e d i c i n e s t a k e n f r o m a d e f u n c t Texas c l i n i c . ) ( 4 4 ) E l e v e n g a l l o n s and s i x p i n t s o f E l i x i r S u l f a n i l a m i d e had been d i s p e n s e d , m o s t l y on t h e p r e s c r i p t i o n o f p h y s i c i a n s , a s m a l l amount by t h e o v e r - t h e c o u n t e r s a l e o f d r u g g i s t s ( 2 2 0 . About h a l f o f t h e " e l i x i r " r e a c h i n g p a t i e n t s h a d been consumed; t h e o t h e r h a l f was r e t r i e v e d b e f o r e i t c o u l d be t a k e n . Finding that " e l i x i r " i n the possession o f the s i c k , o r i n t h e hands o f s u r v i v o r s o f t h o s e who h a d d i e d , l e d t o many a d v e n t u r e s on t h e p a r t o f food and d r u g o f f i c i a l s , and gave them a gloomy p i c t u r e o f the s t a t e o f h e a l t h c a r e i n t h e n a t i o n . A t t h e s t a r t , g e t t i n g r e c o r d s f r o m t h e M a s s e n g i l l d e t a i l men posed some difficulties. Most were c o o p e r a t i v e i n i n d i c a t i n g where s a l e s had been made and p h y s i c i a n s ' samples l e f t ( 2 3 ^ . B u t some s a l e s m e n p r o v e d t o be e l u s i v e , and a few r e l u c t a n t t o p r o v i d e 1



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CHEMISTRY A N D M O D E R N SOCIETY

needed i n f o r m a t i o n . A d e t a i l man i n Texas had t o be j a i l e d by s t a t e a u t h o r i t i e s before he would r e v e a l h i s r e c o r d of s a l e s . S e a r c h e r s f o r t h e d a n g e r o u s " e l i x i r " o f t e n worked t o t h e borders of exhaustion. A t i r e d Alabama s t a t e i n s p e c t o r s i g n e d a c h e c k " E l i x i r S u l f a n i l a m i d e " (45^ 4 6 ) . In A t l a n t a , an e l d e r l y FDA i n s p e c t o r , who a l s o was i l l , d r o v e t h r o u g h t h e r a i n i n t o t h e n o r t h G e o r g i a m o u n t a i n s t o a d r u g s t o r e t h a t c o u l d n o t be r e a c h e d by phone ( 4 7 , 4 8 ) . A p i n t b o t t l e o f t h e " e l i x i r " had been s e n t t o t h e d r u g g i s t , and t h e i n s p e c t o r was c h a r g e d w i t h b r i n g i n g i t back. The d r u g g i s t had t h e b o t t l e , but f o u r o u n c e s o f i t s r e d c o n t e n t s were m i s s i n g , a l l p r e s c r i b e d b y a d o c t o r f o r one p a t i e n t , name unknown. When the p h y s i c i a n r e t u r n e d f r o m h i s r o u n d s , h e s a i d t h a t h e k e p t no r e c o r d s but b e l i e v e d h e had p r e s c r i b e d the m e d i c i n e f o r a woman named L u l a R a k e s . He d i d not know where she l i v e d , and h e r surname was not uncommon i n t h e r e g i o n . The i n s p e c t o r , s h o u t i n g an i n q u i r y t o the d e a f d r u g g i s t , a t t r a c t e d t h e a t t e n t i o n o f a b y s t a n d e r , who v o l u n t e e r e d the g u e s s t h a t L u l a l i v e d e i g h t m i l e s o v e r the r i d g e i n Happy H o l l o w . The i n s p e c t o r drove over the d a r k mountain r o a d , o n l y to f i n d L u l a s home abandoned. A n e i g h b o r s a i d t h a t the Rakes' f a m i l y had moved one v a l l e y f a r t h e r on. D r i v i n g onward t h e i n s p e c t o r a t l a s t found t h e h o u s e , and L u l a was t h e r e . Busy w i t h t h e m o v i n g , she had t a k e n o n l y a few d o s e s o f h e r m e d i c i n e , b u t she c o u l d not r e c a l l what she had done w i t h t h e b o t t l e . An hour of c o n v e r s a t i o n and e x p l o r i n g f i n a l l y l e d t o t h e m e d i c i n e , w i t h many o t h e r a r t i c l e s i n a p a p e r s a c k u n d e r a bed. The i n s p e c t o r began h i s weary way home. O t h e r t a l e s had l e s s happy e n d i n g s . In South C a r o l i n a an i n s p e c t o r found o n t h e g r a v e o f a b l a c k man a p a r t l y used b o t t l e o f E l i x i r S u l f a n i l a m i d e , b e a r i n g t h e name o f t h e p h y s i c i a n who had d e n i e d h a v i n g p r e s c r i b e d i t (49^). I n a c c o r d a n c e w i t h G u l l a h c u s t o m , the m e d i c i n e — a s w e l l a s d i s h e s , s p o o n , and a b o t t l e o f c a t s u p — w h i c h h e had been u s i n g when he d i e d a c c o m p a n i e d h i m t o his f i n a l r e s t i n g place. I n A r k a n s a s an i n s p e c t o r found among d r u g s t o r e p r e s c r i p t i o n s t h a t two ounces o f the " e l i x i r " had been s o l d t o " J e w e l l " Long (4i> ). B o t h t h e d r u g g i s t and t h e p h y s i c i a n s a i d t h e y knew no such p e r s o n , t h e l a t t e r a s s e r t i n g h e must h a v e t r e a t e d a n i t i n e r a n t laborer. A f t e r s e a r c h i n g o u t a number o f Long f a m i l i e s w i t h o u t s u c c e s s , the i n s p e c t o r a r r i v e d i n the neighborhood o f the next L o n g on h i s l i s t , t o l e a r n t h a t a L o n g g i r l , s e v e n y e a r s o f age, named " J e n e l l , " had d i e d t h e day b e f o r e , and h e r f u n e r a l was a t t h a t moment u n d e r way i n h e r home. The i n s p e c t o r went t o t h e h o u s e , w a i t i n g an o p p o r t u n i t y t o t a l k w i t h t h e b e r e a v e d p a r e n t s . The p h y s i c i a n who had d e n i e d k n o w i n g " J e w e l l " d r o v e up t o t h e house. O t h e r p h y s i c i a n s and d r u g g i s t s , c o n c e r n e d a b o u t t h e i r r e p u t a t i o n s and a b o u t damage s u i t s , t u r n e d up p l a y i n g c o w a r d l y o r v i l l a i n o u s r o l e s i n the somber " C h r o n o l o g i c a l f i l e o f I n s p e c t o r s ' & others' reports regarding deaths caused by t h e E l i x i r , " 1



6. Y O U N G


c o m p i l e d i n FDA h e a d q u a r t e r s (_50) . One d o c t o r went t o a d r u g s t o r e and e x t r a c t e d and d e s t r o y e d a p r e s c r i p t i o n he h a d g i v e n f o r t h e f a t a l " e l i x i r " (43, 49). A d r u g g i s t s c r a t c h e d out from t h e i r p r e s c r i p t i o n s t h e names o f t h r e e p a t i e n t s who h a d d i e d . Such i n c i d e n t s , h o w e v e r , were more t h a n c o u n t e r b a l a n c e d by examples o f e a r n e s t e n d e a v o r t o a i d i n t h e s e a r c h f o r E l i x i r S u l f a n i l a m i d e p r e s c r i b e d i n good f a i t h . One p h y s i c i a n p o s t p o n e d h i s w e d d i n g t o h e l p t r a c k down t h e " e l i x i r " p r e s c r i b e d f o r a boy o f t h r e e who h a d moved w i t h h i s f a m i l y i n t o t h e m o u n t a i n s ( 4 5 ) . T h i s quest proved s u c c e s s f u l , i n time t o save t h e l a d . Many p h y s i c i a n s s h a r e d t h e r e m o r s e o f a New O r l e a n s d o c t o r : "Nobody but A l m i g h t y God and I c a n know what I h a v e been t h r o u g h i n t h e s e p a s t few d a y s . . . . [T]o r e a l i z e t h a t s i x human b e i n g s , a l l o f them my p a t i e n t s , one o f them my b e s t f r i e n d , a r e dead b e c a u s e t h e y t o o k m e d i c i n e t h a t I p r e s c r i b e d f o r them i n n o c e n t l y , . . . as recommended by a g r e a t and r e p u t a b l e p h a r m a c e u t i c a l f i r m i n T e n n e s s e e ; w e l l , t h a t r e a l i z a t i o n h a s g i v e n me s u c h days and n i g h t s o f m e n t a l and s p i r i t u a l agony as I d i d n o t b e l i e v e a human b e i n g c o u l d u n d e r g o and s u r v i v e " ( 2 3 ) . A l l t h o s e who p e r s i s t e d i n t a k i n g t h e p r e s c r i b e d " e l i x i r " beyond t h e o n s e t o f i n i t i a l symptoms u n t i l t h e dosage l e d t o t h e i r deaths s u f f e r e d "stoppage o f u r i n e , severe abdominal pain, n a u s e a , v o m i t i n g , s t u p o r " ; some went i n t o c o n v u l s i o n s ( 2 3 ) . One h u n d r e d s e v e n d e a t h s were r e p o r t e d among p a t i e n t s , a h i g h p r o p o r t i o n o f them c h i l d r e n , who h a d t a k e n E l i x i r Sulfanilamide ( 5 1 , 5 2 ) . The d e a t h t o l l spanned t h e c o u n t r y f r o m t h e A t l a n t i c t o the P a c i f i c , a l t h o u g h most o f t h o s e who d i e d l i v e d i n t h e S o u t h ( 2_3 ). Had t h e e n t i r e 240 g a l l o n s been t a k e n as m e d i c i n e , i t was e s t i m a t e d , some f o u r t h o u s a n d v i c t i m s w o u l d have l o s t t h e i r l i v e (53). The

Judgment

B e s i d e s s e i z i n g E l i x i r S u l f a n i l a m i d e w h e r e v e r i t c o u l d be t r a c e d , t h e Food and Drug A d m i n i s t r a t i o n saw t o t h e f i l i n g o f c r i m i n a l c h a r g e s a g a i n s t D r . M a s s e n g i l l and h i s f i r m , b o t h i n K n o x v i l l e and i n K a n s a s C i t y ( 5 4 ) . B e c a u s e he h a d c o n c e d e d two e a r l i e r p r o s e c u t i o n c h a r g e s , he was a s e c o n d o f f e n d e r and t h u s s u b j e c t t o more s e v e r e s a n c t i o n s u n d e r t h e 1906 l a w . M a s s e n g i l l termed t h e p e n d i n g l e g a l a c t i o n s " r i d i c u l o u s " (34). B e c a u s e o f t h e many c o u n t s and h i s s t a t u s as a s e c o n d o f f e n d e r , M a s s e n g i l l s a i d , he c o u l d be f i n e d $261,000 and s e n t t o j a i l f o r 261 y e a r s . By i t s " c o n t i n u o u s g o u g i n g , " t h e FDA seemed determined to secure h i s " f i n a n c i a l r u i n . " Considering himself "blameless" i n the episode ( 5 5 ) , M a s s e n g i l l i s s u e d a s e r i e s o f documents o f f e r i n g h i s d e f e n s e . I n "A D e s c r i p t i o n o f G l y c o l s " and "The F a c t s about S u l f a n i l a m i d e " M a s s e n g i l l d o w n p l a y e d t h e t o x i c i t y o f d i e t h y l e n e g l y c o l and blamed s u l f a n i l a m i d e ' s i n t e r a c t i o n w i t h o t h e r d r u g s f o r d e a t h s t h a t had occurred ( 5 6 , 57). F i n a l r e s u l t s w o u l d show, he


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i n s i s t e d , t h a t many more p e o p l e had been a i d e d by h i s p r o d u c t t h a n had been k i l l e d by i t . He c l a i m e d c r e d i t f o r t h e prompt and c o m p l e t e r e m o v a l o f E l i x i r S u l f a n i l a m i d e f r o m t h e m a r k e t and blamed t h e p r e s s f o r o v e r s e n s a t i o n a l r e p o r t i n g i n o r d e r " t o u n f a i r l y c r e a t e p r e j u d i c e " and t o i n j u r e the company. No " e r r o r had been made i n compounding the f o r m u l a . " I n d e e d , "few, i f any," pharmaceutical m a n u f a c t u r i n g p l a n t s i n t h e U n i t e d S t a t e s were " b e t t e r s u i t e d " than M a s s e n g i l l f o r t h e i r task. N o n e t h e l e s s , w h i l e m a k i n g such p r o t e s t a t i o n s o f r e c t i t u d e , the company f i r e d W a t k i n s , a c k n o w l e d g e d a c e r t a i n m o r a l r e s p o n s i b i l i t y , and s e t t l e d o u t o f c o u r t a number o f s u i t s b r o u g h t by t h e b e r e a v e d f a m i l i e s o f v i c t i m s (^Z> 2§.) · A t one s t a g e i n t h i s p r o c e s s , Time r e p o r t e d t h a t t h e h i g h e s t amount p a i d up t o t h a t p o i n t had been $2000 (37). L a t e r t h e FDA r e p o r t e d a rumor t h a t h a l f a m i l l i o n d o l l a r s had been expended i n s e t t l i n g damage s u i t s (55). When, f o l l o w i n g n o r m a l p r o c e d u r e s , t h e FDA o f f e r e d t h e M a s s e n g i l l Company an o p p o r t u n i t y f o r a h e a r i n g b e f o r e t h e c h i e f o f t h e C i n c i n n a t i S t a t i o n , no one a p p e a r e d i n p e r s o n ( 5 9 ) . I n s t e a d , company a t t o r n e y s s e n t a w r i t t e n r e p l y t o the c i t a t i o n , a s s e r t i n g t h a t no v i o l a t i o n o f the law had o c c u r r e d . L a t e r W a l t e r G. C a m p b e l l , c h i e f o f t h e Food and Drug A d m i n i s t r a t i o n , o f f e r e d the l a w y e r s an o p p o r t u n i t y t o make an a p p e a r a n c e b e f o r e h i m and p r o v i d e a d d i t i o n a l s t a t e m e n t s , b u t i t was n o t a c c e p t e d . C a m p b e l l and h i s s t a f f a n t i c i p a t e d t h a t the b a t t l e i n c o u r t w o u l d be h a r d f o u g h t . They knew t h a t company a g e n t s h a d been a c t i v e g a t h e r i n g a f f i d a v i t s from p a t i e n t s who had used E l i x i r S u l f a n i l a m i d e and who w o u l d t e s t i f y t h a t t h e y had not been harmed (5_5) . Some w o u l d s a y t h a t the m e d i c i n e had h e l p e d them. P e r h a p s as many as 680 such documents, t h e FDA b e l i e v e d , h a d been collected (60). I t was a l s o a n t i c i p a t e d t h a t t h e company i n t e n d e d t o a s s e r t t h a t s u l f a n i l a m i d e a f f l i c t e d t h e same p r o p o r t i o n o f p a t i e n t s who t o o k i t a l o n e as had been a f f l i c t e d w h i l e t a k i n g i t mixed w i t h d i e t h y l e n e g l y c o l , about f i f t e e n p e r c e n t i n both circumstances. FDA o f f i c i a l s , b e l i e v e d , however, t h a t t h e i r own c a s e w o u l d p r o v e t o be more p e r s u a s i v e . G r a n t e d i t s l e g a l b a s i s was somewhat n a r r o w . The government w o u l d a s s e r t t h a t the d r u g " f e l l b e l o w the p r o f e s s e d s t a n d a r d under w h i c h i t was s o l d , " i n t h a t E l i x i r S u l f a n i l a m i d e had been l a b e l e d t o p o s s e s s t h e same t h e r a p e u t i c a c t i o n as s u l f a n i l a m i d e , whereas " i t s p r i n c i p a l a c t i o n was t h a t o f an a c u t e p o i s o n " ( 6 1 - 6 5 ) . Therefore, the term " Q u a l i t y Pharmaceuticals," as w e l l as t h e word " E l i x i r , " on t h e l a b e l s c o n s t i t u t e d m i s b r a n d i n g and a d u l t e r a t i o n . The m a g n i t u d e o f t h e d i s a s t e r broadened t h e t h r u s t o f t h e government's c h a r g e . Nor was t h e r e any doubt t h a t d i e t h y l e n e g l y c o l had been t h e f a t a l component. The n a t i o n ' s leading s c i e n t i f i c experts, first b r o u g h t i n t o the a f f a i r by the ΑΜΑ, would so t e s t i f y , on the b a s i s of c o n t i n u i n g experiments. These i n c l u d e d P r o f e s s o r Long o f Johns H o p k i n s and P r o f e s s o r s G e i l i n g and C a n n o n — a s w e l l as A n t o n


6.


YOUNG

J . C a r l s o n , a f r e q u e n t and s k i l l f u l w i t n e s s i n FDA's b e h a l f — o f Chicago. FDA's own s c i e n t i s t s a l s o had been w o r k i n g o v e r t i m e p r e p a r i n g f o r the t r i a l . I n September 1938 Dr. M a s s e n g i l l s a t t o r n e y s f i l e d a dem u r r e r t o the government's c h a r g e s , c l a i m i n g t h a t he had not v i o l a t e d t h e law. The j u d g e o v e r r u l e d t h i s p l e a ( 5 4 , 65^). When M a s s e n g i l l a p p e a r e d i n c o u r t , on t h e day h i s t r i a l was s c h e d u l e d t o b e g i n , O c t o b e r 3, he changed h i s p l e a f r o m not g u i l t y t o g u i l t y on a m a j o r i t y o f t h e c o u n t s i n the c h a r g e a g a i n s t h i m , s a y i n g he w o u l d do l i k e w i s e i n the c a s e i n v o l v i n g s h i p m e n t s o f t h e " e l i x i r " made f r o m K a n s a s C i t y . M a s s e n g i l l was f i n e d $150 each on 174 c o u n t s , the $26,100 t o t a l b e i n g t h e l a r g e s t f i n e e v e r a s s e s s e d u n d e r the 1906 law. FDA o f f i c i a l s , who d i d not p r e s s for M a s s e n g i l l s i m p r i s o n m e n t , e x p r e s s e d t h e m s e l v e s as b e i n g "much g r a t i f i e d a t the outcome" ( 6 6 ) . When W i l l i a m F o r d l a s t t a l k e d w i t h H a r o l d W a t k i n s , i d l e a t home, t h e c h e m i s t a s k e d t h e FDA i n s p e c t o r t o keep h i m i n mind i f F o r d " h e a r d o f anyone w a n t i n g a man" (58). Before the t r i a l , W a t k i n s t o o k h i s own l i f e ( 6 7 ) .


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Impact upon S c i e n t i f i c

Research

The E l i x i r S u l f a n i l a m i d e e p i s o d e had a marked i n f l u e n c e upon r e s e a r c h i n b o t h i n d u s t r y and government. I n t h e 1930s, t h e v a n g u a r d among A m e r i c a n p h a r m a c e u t i c a l m a n u f a c t u r e r s had r e a c h e d a new p l a t e a u o f s c i e n t i f i c competence. E a r l i e r , w h i l e cons i d e r a b l e r e s e a r c h t o o k p l a c e i n company l a b o r a t o r i e s , much o f i t was h e l d i n low e s t e e m by p h y s i c i a n s and a c a d e m i c s (6ÉS, 69). S c i e n t i s t s who moved f r o m u n i v e r s i t i e s t o i n d u s t r y were e x p e l l e d f r o m membership i n the A m e r i c a n S o c i e t y f o r P h a r m a c o l o g y and Experimental Therapeutics (^0). The new wave o f enhanced s c i e n t i f i c a c h i e v e m e n t i n i n d u s t r y may be e x e m p l i f i e d by t h e p l a n s i n i t i a t e d by George W. Merck. I n 1933 M e r c k e s t a b l i s h e d a R e s e a r c h L a b o r a t o r y a t Rahway, New J e r s e y , p o s s e s s i n g a campus a t m o s p h e r e and o f f e r i n g i n t e r d i s c i p l i n a r y teams o f s c i e n t i s t s " t h e g r e a t e s t p o s s i b l e l a t i t u d e and s c o p e i n p u r s u i n g their i n v e s t i g a t i o n s , the utmost f r e e d o m t o f o l l o w l e a d s promising s c i e n t i f i c r e s u l t s no m a t t e r how u n r e l a t e d t o what one w o u l d c a l l p r a c t i c a l r e t u r n s , " as w e l l as f r e e d o m t o p u b l i s h (7_1, 72.)· Other m a j o r companies f o l l o w e d s u i t , v a s t l y a u g m e n t i n g manpower and equipment d e v o t e d t o d r u g r e s e a r c h . The a r r i v a l o f s u l f a n i l a m i d e a c c e l e r a t e d t h e s e t r e n d s ( 7 3 ) . P h a r m a c e u t i c a l c h e m i s t s employed by m a n u f a c t u r e r s p l u n g e d i n t o r e s e a r c h on d e r i v a t i v e s and a s s o c i a t e d p r e p a r a t i o n s , q u i c k l y d i s c o v e r i n g more e f f e c t i v e a n a l o g u e s . The o l d dream o f u s i n g chemistry to d e v i s e s y n t h e t i c drugs capable of combatting d i s e a s e germs i n the body had been c o n v e r t e d i n t o r e a l i t y . Sulfanilamide h e l p e d p r o v i d e " p r o o f t h a t the i m p o s s i b l e had become f e a s i b l e " (_74), s t i m u l a t i n g a much b r o a d e r q u e s t f o r c h e m o t h e r a p e u t i c agents. E l i x i r S u l f a n i l a m i d e u n d e r l i n e d the need t o c o n s i d e r


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s a f e t y a s a p r i m a r y f a c t o r i n t h e s e a r c h . Soon the law w o u l d make s a f e t y a s i n e qua n o n . The E l i x i r Sulfanilamide c r i s i s placed urgent research p r e s s u r e s on Food and D r u g A d m i n i s t r a t i o n s c i e n t i s t s . Glycol s o l v e n t s p l a y e d a c o n s i d e r a b l e r o l e i n food f l a v o r i n g s , f o r e x a m p l e , so more r e s e a r c h a s w e l l as s t r e n u o u s r e c a l l e f f o r t s f o l l o w e d news o f t h e d e a t h s f r o m d i e t h y l e n e g l y c o l ( 2 j j , 75.» 7 6 ) . These e f f o r t s expanded i n t o a c l o s e r s c r u t i n y g i v e n t o a l l t y p e s o f s o l v e n t s , d i l u e n t s , and e x c i p i e n t s u s e d i n m a k i n g d r u g s . The m a j o r FDA c o n c e r n came t o be b e t t e r c o m p r e h e n s i o n o f diethylene glycol's toxicology. The imminent t r i a l i n c o u r t required this. I n a more b a s i c s e n s e , t h e c r i s i s made FDA s c i e n t i s t s aware o f i n a d e q u a c i e s i n t h e s t a t e o f t h e d i s c i p l i n e . In constant c o n t a c t w i t h t h e i r p e e r s a t t h e ΑΜΑ and a t t h e U n i v e r s i t y o f C h i c a g o and J o h n s H o p k i n s , a team o f FDA s c i e n t i s t s launched a p r o j e c t that "developed t h e f i r s t v a l i d process f o r determining t h e c o m p a r a t i v e t o x i c i t y o f compounds, a s t a t i s t i c a l l y b a s e d and l e g a l l y d e f e n s i b l e p r o c e s s t h a t opened t h e d o o r t o modern t o x i c o l o g i c a l t e s t i n g m e t h o d s " ( 7 7 ) . A D i v i s i o n o f P h a r m a c o l o g y h a d b e e n f o r m a l l y s e t up i n t h e Food and Drug A d m i n i s t r a t i o n i n 1935, composed m o s t l y — a s one o f i t s members, E d w i n P. L a u g , r e m e m b e r e d — o f " b i o c h e m i s t s who t h e n changed s a i l s and became p h a r m a c o l o g i s t s " (_78). To s t u d y t h e t o x i c i t y o f l e a d and a r s e n i c p e s t i c i d e r e s i d u e s formed t h e d i v i s i o n ' s i n i t i a l purpose, b u t the E l i x i r S u l f a n i l a m i d e c r i s i s brought an almost t o t a l s h i f t o f e f f o r t t o d i e t h y l e n e g l y c o l . The c o n c e p t o f L e t h a l Dose 50 h a d a l r e a d y been c o i n e d , d e v e l o p i n g f r o m i n n o v a t i v e r e s e a r c h i n E n g l a n d by J . W. T r e v a n (79) and i n A m e r i c a by T o r a l d S o l l m a n n ( 7 8 ) . Y e t t h a t c o n c e p t was as y e t r u d i m e n t a r y . " [ l ] n t h o s e d a y s , " a s Dr. Laug put i t w i t h o u t t o o much e x a g g e r a t i o n , " i f you had two r a t s and you k i l l e d one and d i d n ' t k i l l t h e o t h e r one, t h e n t h a t was c a l l e d a n LD 50." The E l i x i r S u l f a n i l a m i d e d i s a s t e r made t h e s e FDA s c i e n t i s t s r e a l i z e t h a t a s t a t i s t i c a l l y s i g n i f i c a n t way o f d e f i n i n g LD 50 was n e e d e d , so t h a t two p o i s o n s c o u l d be a c c u r a t e l y compared. H e r b e r t E. C a l v e r y gave g r e a t i m p e t u s t o t h i s q u e s t and b r o u g h t i n t h e s t a t i s t i c i a n C h e s t e r I . B l i s s (80) a s a p a r t - t i m e c o n s u l t a n t . B l i s s was a n e n t o m o l o g i s t who h a d s p e n t t h r e e y e a r s i n E n g l a n d w i t h t h e p i o n e e r b i o m e t r i c i a n R. A. F i s h e r (81_) , and h a d a p p l i e d t h e s t a t i s t i c a l a p p r o a c h s o a s t o compare t h e k i l l i n g power o f various insecticides. B l i s s helped t h e FDA b i o c h e m i s t s t o f o r m u l a t e p r o t o c o l s f o r b o t h a c u t e and c h r o n i c t o x i c i t y s t u d i e s o f t h e g l y c o l s i n v a r i o u s a n i m a l s ( 7 8 ) . The f i r s t p a p e r , by L a u g , C a l v e r y , Herman M o r r i s , and G e o f f r e y Woodard, a p p e a r e d i n 1939 (82). Other a r t i c l e s f o l l o w e d (24, 83, 84, 85). The r e s u l t s p r e s e n t e d i n t h e s e p a p e r s , and the m e t h o d o l o g y u n d e r l y i n g t h e r e s u l t s , came a t a c r u c i a l t i m e , t h e i n i t i a l s t a g e o f t h e c h e m o t h e r a p e u t i c r e v o l u t i o n , d u r i n g w h i c h h u n d r e d s o f new drugs would e n t e r the m e d i c a l m a r k e t p l a c e . E l i x i r S u l f a n i l a m i d e had waved t h e w a r n i n g f l a g o f t o x i c i t y , and i n r e s p o n s e FDA


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s c i e n t i s t s had d e v e l o p e d s o p h i s t i c a t e d methods f o r s t u d y i n g t h e t o x i c i t y of chemicals i n animals. A l s o , as t o s t r u c t u r e , t h e D i v i s i o n o f P h a r m a c o l o g y s e r v e d as a p r o t o t y p e r e s e a r c h g r o u p , i m i t a t e d by u n i v e r s i t i e s and by t h e most f o r w a r d - l o o k i n g e l e m e n t s of the p h a r m a c e u t i c a l i n d u s t r y , which sent s c i e n t i s t s to observe how t h e FDA team went a b o u t i t s m i s s i o n and t h e n formed o r r e f o r m e d r e s e a r c h g r o u p s o f t h e i r own ( 7 8 ) . I n f l u e n c e on Food and Drug

Law

I n a d e q u a c i e s i n t h e Food and Drugs A c t o f 1906, r e c o g n i z e d by r e g u l a t o r s f r o m t h e s t a r t , had been f r e q u e n t l y v o i c e d i n p u b l i c . The R e p u b l i c a n a s c e n d a n c y o f t h e 1920s, h o w e v e r , d i d n o t p r o v i d e a c l i m a t e c o n d u c i v e t o r e f o r m (5>3, 86 ι 87.). A t t h e v e r y s t a r t o f t h e New D e a l , u n d e r t h e a e g i s o f R e x f o r d G. T u g w e l l , a s s i s t a n t s e c r e t a r y of a g r i c u l t u r e , a complete r e v i s i o n o f the law was i n t r o d u c e d i n t o t h e C o n g r e s s . I n a h o s t o f ways t h i s measure w o u l d have toughened r e g u l a t i o n o f t h e f o o d , d r u g , and cosmetic i n d u s t r i e s . Had t h e b i l l become l a w , i t m i g h t have a v e r t e d the E l i x i r S u l f a n i l a m i d e d i s a s t e r , f o r i t would have l i c e n s e d drug manufacturers. A l l e l e m e n t s o f i n d u s t r y combined t o condemn t h e " T u g w e l l b i l l " w h i c h , i t was d e c l a r e d , w o u l d t u r n t h e FDA i n t o a s i n i s t e r m a c h i n e t o s o v i e t i z e A m e r i c a n m a n u f a c t u r i n g . The b i l l had been i n t r o d u c e d i n t o t h e S e n a t e by R o y a l S. C o p e l a n d , a c o n s e r v a t i v e h o m e o p a t h i c p h y s i c i a n f r o m New Y o r k , who began a l o n g campaign o f compromise aimed a t g e t t i n g t h e b i l l i n t o a f o r m t h a t m i g h t make i t a c c e p t a b l e t o members o f t h e C o n g r e s s . P r e s i d e n t F r a n k l i n D. R o o s e v e l t gave f o o d and d r u g law r e f o r m a v e r y low p r i o r i t y on h i s l i s t o f New D e a l o b j e c t i v e s . I n O c t o b e r 1937, when E l i x i r S u l f a n i l a m i d e h i t t h e h e a d l i n e s , t h e C o n g r e s s was i n r e c e s s (53.)· A f o o d and d r u g b i l l , much d i l u t e d f r o m i t s 1933 f o r m , had p a s s e d t h e S e n a t e b u t was b o t t l e d up i n a c o m m i t t e e o f t h e House. W a l t e r G. C a m p b e l l , FDA's c h i e f , i n h i s f i r s t p u b l i c announcement about E l i x i r Sul f a n i l a m i d e , s a y i n g t h a t t h e agency was a s s i g n i n g i t s e n t i r e f i e l d f o r c e t o t r a c k down t h e d r u g , l i n k e d t h e d i s a s t e r t o t h e l a n g u i s h i n g b i l l ( 1_8). O t h e r p o i s o n o u s d r u g s , w h i c h t h e FDA c o u l d n o t keep o f f t h e m a r k e t , had a l r e a d y k i l l e d and i n j u r e d many c i t i z e n s (86). The b i l l p e n d i n g b e f o r e t h e C o n g r e s s d i d n o t c o n t a i n any p r o v i s i o n s t h a t w o u l d have p r e v e n t e d t h e E l i x i r Sulfanilamide tragedy. P u b l i c p o l i c y r e q u i r e d , Campbell i n s i s t e d , t h e r e i n v i g o r a t i o n and t h e enactment o f t h a t b i l l . A f e d e r a l l i c e n s i n g s y s t e m f o r d r u g s m i g h t w e l l be r e q u i r e d ( 1 8 ) . The r e p o r t t h a t t h e S e c r e t a r y o f A g r i c u l t u r e made t o t h e C o n g r e s s on t h e E l i x i r S u l f a n i l a m i d e a f f a i r r e i t e r a t e d this argument (23). The r e p o r t c i t e d a l e t t e r w r i t t e n t o P r e s i d e n t R o o s e v e l t by t h e m o t h e r o f one o f t h e " e l i x i r ' s " f i r s t v i c t i m s i n T u l s a , a l i t t l e g i r l o f s i x . The m o t h e r t o l d how h e r c h i l d had d i e d i n agony, and begged t h e P r e s i d e n t t o g e t a law so t h a t o t h e r


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f a m i l i e s w o u l d not have t o s u f f e r as h e r s had done. W i t h the l e t t e r the mother s e n t a p i c t u r e o f h e r d a u g h t e r ' s s m i l i n g f a c e (88, 89). The " s i m p l e , d i r e c t , s t r a i g h t f o r w a r d l i c e n s i n g a u t h o r i t y " w h i c h the FDA hoped t o be g i v e n as a r e s u l t o f the Elixir S u l f a n i l a m i d e p r e s s u r e p r o v e d t o be t o o extreme a remedy f o r C o n g r e s s t o g r a n t ( 9 0 , 9^, 92). Nor w o u l d C o n g r e s s c o n s i d e r c o n t i n u o u s i n s p e c t i o n o f d r u g m a n u f a c t u r i n g , a n a l o g o u s t o the p a t t e r n p r e s c r i b e d i n 1906 f o r meat p r o c e s s i n g . Industry o p p o s i t i o n was f a r t o o s t r o n g . Some i n d u s t r y c o u n t e r - s u g g e s t i o n s w o u l d have e l i m i n a t e d any type o f p r e - m a r k e t i n g controls. Senator Copeland a g a i n f a s h i o n e d a compromise, based o n b u t s t r o n g e r t h a n a s u g g e s t i o n by the P r o p r i e t a r y A s s o c i a t i o n ' s c o u n s e l (9_3), w h i c h C o n g r e s s a c c e p t e d and e v e n t u a l l y i n c l u d e d , a s s e c t i o n 505, i n the Food, D r u g , and C o s m e t i c A c t ( 5 3 ) . These r e s u l t s d i d not come as q u i c k l y as a c o n s e q u e n c e o f the E l i x i r S u l f a n i l a m i d e p r e s s u r e as m i g h t have been e x p e c t e d ( 5 3 , 94). From 1933 t o 1937, a m i d s t the d e p r e s s i o n and i n t r i g u e d by more p u b l i c i z e d New D e a l b a t t l e s , the g e n e r a l p u b l i c knew l i t t l e about the p r o t r a c t e d C o n g r e s s i o n a l s t r u g g l e t o s e c u r e a new food and d r u g law. T h i s c o n t e s t had made the f r o n t page o f the New Y o r k Times o n l y o n c e , when a f i g h t b r o k e out i n the S e n a t e g a l l e r y (94). E l i x i r S u l f a n i l a m i d e d i d b r i n g "a new e m o t i o n a l c o n t e n t " and g r e a t e r u r g e n c y t o the c o n s i d e r a t i o n o f the f o o d and d r u g b i l l (53). The p r e s s h e a d l i n e d the c r i s i s and l i n k e d the d i s a s t e r t o the u n e n a c t e d law. L e t t e r s from c o n s t i t u e n t s t o members o f the C o n g r e s s i n c r e a s e d i n volume. Committed p a r t i s a n s o f r e f o r m became more v i g o r o u s and o u t s p o k e n , e m p l o y i n g s h a r p e r l a n g u a g e . Segments o f i n d u s t r y , opposed t o the 1933 d r a f t but s a t i s f i e d by s u b s e q u e n t compromise, urged a n end o f d e l a y . " I t is a fine t h i n g , " e d i t o r i a l i z e d A d v e r t i s i n g and S e l l i n g , " t o t a k e a f i r m s t a n d a g a i n s t s i n and s u l p h a n i l a m i d e . . . but . . . t h a t i s n ' t good enough" (_95). B u s i n e s s s h o u l d a p p r o v e the w h o l e b i l l . Even the most i n t r a n s i g e n t f o e s o f l e g i s l a t i o n were somewhat s h a k e n . N o n e t h e l e s s , more t h a n e i g h t months e l a p s e d between the first r e p o r t s o f deaths from E l i x i r S u l f a n i l a m i d e and t h e e n a c t m e n t o f the law (53). Two more m a j o r o b s t a c l e s had t o be o v e r c o m e — w h o s h o u l d c o n t r o l f o o d and d r u g a d v e r t i s i n g , the FDA or the F e d e r a l T r a d e C o m m i s s i o n , and what p r o c e s s o f c o u r t a p p e a l s h o u l d g o v e r n FDA r e g u l a t i o n - m a k i n g — b e f o r e enough c o n s e n s u s came t o g e t t h e law p a s s e d . L i c e n s i n g may come sometime, C a m p b e l l w r o t e a f t e r the new law had gone i n t o e f f e c t , but t h e c l i m a t e was n o t r i g h t f o r i t i n 1938 ( 9 0 ) . " M e a n w h i l e , t h e r e seems no a l t e r n a t i v e . . . e x c e p t t o u n d e r t a k e , t h r o u g h the g r a d u a l d e v e l o p m e n t o f powers t h a t have been c o n f e r r e d upon us by . . . s e c t i o n 505 and t h e a u t h o r i t y t o make f a c t o r y i n s p e c t i o n s , a more e f f e c t i v e r e g u l a t i o n o f t h e p r o d u c t i o n and m a r k e t i n g o f p h a r m a c e u t i c a l p r o d u c t s t h a n was p o s s i b l e under the o l d s t a t u t e . . . ."



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YOUNG


121

S e c t i o n 5 0 5 — t h e "new d r u g s " p r o v i s i o n — d e f i n e d a new d r u g as one " n o t g e n e r a l l y r e c o g n i z e d among e x p e r t s q u a l i f i e d by s c i e n t i f i c t r a i n i n g and e x p e r i e n c e t o e v a l u a t e t h e s a f e t y o f d r u g s , as s a f e f o r use under t h e c o n d i t i o n s " l i s t e d i n t h e l a b e l i n g (96). The law f o r b a d e t h e m a r k e t i n g o f new d r u g s i n i n t e r s t a t e commerce u n t i l t h e i r m a n u f a c t u r e r s had p e r s u a d e d FDA o f f i c i a l s t h a t the d r u g s were s a f e . The a p p l i c a t i o n s u b m i t t e d f o r t h e agency t o c o n s i d e r had t o i n c l u d e samples o f t h e d r u g , a l i s t o f i t s components and a s t a t e m e n t o f i t s c o m p o s i t i o n , a d e s c r i p t i o n o f the methods o f m a n u f a c t u r e , and f u l l r e p o r t s o f i n v e s t i g a t i o n s made t o d e t e r m i n e w h e t h e r o r n o t t h e d r u g was s a f e f o r u s e . S h o u l d the FDA r a i s e no p r o t e s t w i t h i n a s p e c i f i e d t i m e l i m i t , t h e d r u g c o u l d be r e l e a s e d i n t h e m a r k e t p l a c e . I f the a g e n c y , f o r c a u s e , r e f u s e d t h e a p p l i c a t i o n , t h e d r u g was b a r r e d f r o m i n t e r s t a t e commerce. R i g h t s o f a p p e a l f r o m FDA's d e c i s i o n s t o t h e f e d e r a l c o u r t s were s p e c i f i e d . The law p e r m i t t e d t h e use o f d r u g s f o r i n v e s t i g a t i o n a l p u r p o s e s by q u a l i f i e d e x p e r t s i n order to t e s t f o r s a f e t y . T h i s "new d r u g " p r o v i s i o n , by h o l d i n g p h a r m a c e u t i c a l comp a n i e s t o s t r i c t e r s t a n d a r d s , a l s o s p u r r e d them toward i n novation. Competent s c i e n t i s t s added t o i n d u s t r i a l s t a f f s t o e n s u r e the s a f e t y o f some new d r u g s a l s o s p e n t t i m e e x p l o r i n g what o t h e r new d r u g s might be d i s c o v e r e d . I n t h e e a r l y 1940s a commentator c r e d i t e d t h e 1938 law w i t h h a v i n g " e n c o u r a g e d r e s e a r c h " (97). T h i s added more c h a r g e t o t h e e x p l o s i o n o f chemotherapy. A minor precedent f o r premarket t e s t i n g of c h e m i c a l s i n t h e 1938 law had been e s t a b l i s h e d , on a v o l u n t a r y b a s i s , s h o r t l y a f t e r the 1906 law had gone i n t o e f f e c t , w i t h r e s p e c t t o c o a l - t a r dyes used t o c o l o r f o o d s (9

Sulfanilamide and Diethylene Glycol - ACS Publications - American

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