Advisory Committee on Human Radiation Experiments, Interview with William Silverman, by Gail Javitt, February 14, 1995

Page 1

ADVISORY COMMITTEZ ON H W RADIATION EXPHRIMENTS Edited for clarity and accuracy by after the interview. Comments in brackets were added by Dr.Silver x an

Page 2

MS. JAVITT: I'm here this morning with Dr. William Silverman. This is Gail Javitt. We're here in Greenbrae, California. It's a beautiful sunny Why don't we start, Dr. Silverman, with a brief sketch of your background and training. What was it that made you decide co become I grew up in California in the Depression, and knew rsther early in my life that I wanted to 30 into medicine. As a matter 0 2 facc, had an interest in pediatrics. I had several childhood friends who died and that sort of pushed me in this direction. I went to UCLA and I came to San Francisco to so to medical school. I graduated iz 1942. I had my first years of pediatric traininq here in San Francisco. For the third year of my training, I went to Columbia University in New York. I t was a very, very exciting piace in

Page 3

includiq the transfcsion, foscers the belief system. MS. J’XVITT: IC the context of therapy, that rationale, is plausible, I mean, the desire to keeg a sick person hamy. But i n the context of experirnertation with healcty scbjeczs, how did tne DR. SILVERMAN: By sweeping his doubts under the rug. Exactly. I know, this thought does cone up, buc you sweep it under the rug. You were sayir.g %his is Like warfare. I medn I think Rotban’s thesis is right on target. You know, tkis patient is a soldier and he is drafted into this war against disease. MS. JAVITT: I mean when they are not MS. JAVITT: What about when they are not DR. SILVERMAN: It would be even more difficult to justify, but never underestimate a . rationalist. Everyone must be enrolled in the Dr Will im Silvmnan 25

Page 4

to be a draftee, because everyone musc be coxicerned2 with medicine's war to corquer disease and extegd3 5 It was avery skallm : be. Whsn ;rou say that you're surprised, I am not only surprised, but6 amazed that I ever allowed myself to think that way.7 8 But I swept my doubts under the rug. I kept them as And there was very little discussioc10 il between doctors about these issues. For example, there was, let me just give you acother anecbote. Is12 1 4 MS. JAVITT: This is wonderful. DR. SILVERMAN: There was a time when I became very interested in a disorder called retro - lental' fibroplasia. The very first infant who developed this eye condition was my patiecc. The baby was the first surviving child of t h e Professor of Biochenistry and his wife. She had a past history or' one miscarzia5e after another. This

Page 5

infant was tke fFrsz who survived. 6 1,200 grams in those days was considered to be very marginal. I kept this child alive in a brand new unit7 at Babies Hospital. We had just instituted a policy of examining the eyes routinely, which we had never done before. A d in this baby's eyes we saw, f o r the10 11 first time, these early changes of the disorder develop right before o u r eyes.12 13 MS. JAVITT: So that you knew or you had an inkling that it was something in the treatment that14 was causing the blindness. DR. SILVERMAN: This was the first inkling that this eye disease developed after birth, and was not present at the time of birth. Previously, it was thought to develop in utero, long before birth. In this first infant we examined the eyes and saw they were perfectly nomal. Suddenly, four

Page 6

weeks afzer delivery, the blood vessels or' t h e rexixa began to develog abnonally. A Fellow in Opnthalnoloq-y examined the eyes of all prenature infants every week. This i s the first abnorxality he found. Acd this was my pa2iect. Voi: CEE imagins the ezotional tazmoil. We were absolutely convinced this child was going to become blind. Until now this disorder 0 had only been described i n Boston, and no one knew 10 homoce, adrenocorticotropic hormone, wnich had been used as an ami-inflammatory agent, mighc inhibit the11 12 prolifsrztion of t?.e retixl blood vessels. MS. JAVITT: Right. They were hot stuff.13 DR. SILVERMAN: Hot stuff. Exactly. But14 I this steroidal drug had never been used'on a human infants, although it had been given to adult pstients 17 and adult animals. 19 since this was the Professor of Biochemistry and his 20 wife.. The whole Medical Center was involved. The

Page 7

perxission, because of who he w a s ? who he w a s . First we discussed the dile-nna. We said, look, we've got to do sometlIi-?g. The child is going to go blind. We gave the treatment and it worked. We were extremely excited about this because no one had demonstrated that the condition appeared after birth. No one even thought about what oce migk': ' d o to n a l t the eye changes and save tke DR. SILVERMAN: The first changes of retrolental fibroplasia are vasoproliferative. The retinal vessels of premature infants are susceptible because the retina is not completely vascularized at the time of prenature birth. As these vessels grow out to vascularize the retina, they become wildly proliferative and invade the vitreous. You see a very disordered

Page 8

paccerr; of vascirlar ~ zowc2raz ker char, t ken or zal We gave ACTH to this infant and cSe eye changes improved. We reduced the dose and the chanses worseced. We increased tke dose, and a@i? tSe eye changes improved. We slowly reduced and then stopped the drug. Finally, the infant left the hospital with began to grow in an orderlyof proliferating wildly, way and co vascularize the retina. MS. JAVITT: Now was this a child in an increased oxygen environment or not? DR. SIL VE WM : In those days, oxygen was given routinely to all [premature] births. And, of course, this child had been raised in oxyqen. They were raised in oxygen to reduce the periodic breathing. This gets us back to the problem I told you about earlier. When you elevate the concentration

Page 9

of oxy5e2, very small pre rat ure infants be s into If you try to use lower concentrations of oxygen o r room air,periodic breathing returns. [Dr. Silverman subsequently added: This was taken as a sign that the brain needed more oxycjer~; the provision of high oxygen should reduce hypo xi c brain damage. ] So cause and effect.. Raise the oxygen, and the susceptible babies breathe rec pla rly. [ Dr.Silverman added: The connection betwean oxygen and eye aamege had not been established. ] So all infants received this treatment.Brea tn iq was rhythmic. The baby developed this eye disorder. We cured it with ACTH, o r so we thought. The child ' s response to this extremely powerful steroid was horrific. The infant cried constantly. She could not gec errough toeat,despite eating prodigious amounts of form la. Growth stopped. These disturbing effects of ACT3 were obvious. Wedid know the mechanism for these effects,even in those primitive days. But on tSe

Page 10

2we thought this justified the treatner.:. The child 3 went home with normal eyes. 4Following this success, we went on to 5 treac 30 other infa,r),ts, because now that w ewers 6ex mining the eyes,we found that the disorder was 7 much more common than we had realized. Moreover, w e , 8 now had a successful treatment.Itwas working. 9 We never asked cAe p zz enc s ' per xl is sion to 1 0 give this horrific,v ~ r ypcwerful hormor,e. The babies 1 2 wer,': on to develop severe disease and blindness. 1 3 MS. JAVITT: Even inthe ACTX environment? 1 4 DR. S1LVE.W : Even with the ACTH. Two 15 did not respond,we thought, but the majority did. 1 6 MS. JAVITT: Was this considered a n 17eq eri mental treatment or the only tre ac ment ? Did you 1 9 DR. SILVEaMILu: There was no other 20 possible treatment, but it was obviously exper*ental, 2 1 and w e were using a veTy crude and poorly desigrred

Page 11

ex peri a ez t to deternice cause azc effect. At the end of about a year, word of OUT experience had leaked out.People all around this country and in other parts of t be world heard wka t we were doing - and they began to treat with ACTH. MS. JAVITT: What year was the firs : child DR. SILVERMAN: Itwas 1950, and all of the others were treated in 1950an a early1951. We were urged s tro q ly tc publish ocr experience. Why publish it? One, w e had cure to prevent b li ad ness, bur two, and much more in port ant, to secure priority so that we would be credited with medical community, by the Nobel Prize Committee. But interestingly enough, atthe end of this time when w e were urged to publish -- when Isay we,Richard Day and I were involved with this - -

Page 12

Exactly. I was a young, eager investigacor and he was At this time, we were very worried because the metabalic eff3cts of A C Z i were so horzzfidous,, particularly the arrest of growth. givins ACTH growzh began asdin, but did noc r 5 c x z . to nomcl. Was there a Fernanent effect? We simply ACT3 has a massive effect on the body politic; other organs were affected. Fie said to ourselves, we really have a responsibility to find out if ACTH works as well as we thought and what are the limits of this powerful treatment. We were beginnizg to be inflgenced by the new fornat for clinical research, the ari tish randomized control trial, which appeared in 1948. We said, before we recommecd ACTX to others, we must get 21 much better evidence. We reed to evaluate treatinent

Page 13

British developed the randomized trial. 4 DR. S1LVERX.W: In 1948, the first mode n on the effect of streptomycin on pulmonary tuberculosis. When streptomycin arrived on the scene, Britain did n o t have enough money to buy an adequate 9 supply of this new drug. But they did have enough noney to buy a small. azounr,. Bradford EiLl, a statistician, arped that to get the best possible use . or' this small supply we nusc have a trial wich This became the first randomized trial which had been carried out in 1946 and published in 16 1948. The plan had been worked out in agriculture by 17 FLsner in the 1920's. There were a couple of human control trials before this, but the streptomycin trial 19 was the first randomized trail and conscientious 20 effort to use rigorous scientific methodology. 21 Richard Day and I had become interested in

Page 14

the f o m a = , parziczlarly becexse of all zke u:?resol-;ek questions about retrolental fi bro pl asia. That was what motivated us to go to OUT chief, RCstia McIntosh, and ask for perxission to evaluate ACTX treetnecf with We sat there a n a told him we had a drug which seemed to be very effective, but there were disturbing side effects. We felt that our post hoc infants who did not respond. Dr. Blodi, the ophthalmology fellow who was looking at the eyes of our babies, also examined the eyes of infants at Liilcoln Hos?itai, and he observed an infant who developed eye changes that spontaneously improved without ACTH. obligation to do a proger control clinical trial. " DR. SILVERMJW: To humanity. To the infants under our care, exactly. And we had a scientific obligation to gez the right answer.

Page 15

really tell you whether we felt we had a moral obligation as well, it was never discussed in those - What did happen will be of great interest to you. We did carry out a cor.trolled clinical trial. Infants who developed the early changes of retrolental fibroplasia were randomized to receive either ACTH or no treatment. There w a s no alternative treatment that could be used. MS. JAVITT: No treatment still meant increased oxygen though. Is chat correct? DR. SILVERMAN: Increased oxygen was used f o r all infants long before the eye changes turned up. The changes appeared when the infants were six, seven' weeks of age. This eye disease began l o n g after the tine of exposure to oxygen. Many infants were still i n oxygen, but at lower concentrations, and some infants had come off oxygen at the tine the eye changes were seen. Oxygen exposure and the early changes of eye disease were

Page 16

separaced by several vee s s .1 2 MS. JAVITT: Ididn ' t realize that, because when I was reading this, and in retro spec, ny3 6realize there was a separation between the exposure and the effect .7 DR. SILVERMAN: Yes there was a separationa 9 betweea cause zide ii e cz. As the trial proceeded, one baby inth e10 Frernaccre nursery was a privace patient or' one of the enroll this infant, not the parents. You understand? responsible guardian in those days.15 W e told him w e ' r e doicg this trial because we need to find out whetfier the treatinent was safe acd er'zective. E e refused t o allow this child t o18 be enrolled in the trial, and he insisted that th e19 baby be given ACTH. 21 MS. JAVITT: He felt that was the tSerapy.

Page 17

demonstrated it w o r k s in 2 8 patients. This is my patient, I do not want this child to be enrolled, 'because I want to use ACTH." He gave the child ACT3 and the eye changes improved 5 u = the child died. At the conclusion of the trial, in about one year, we found that the eyes of babies in the two groups, the treated and untreated, were exactly the same. There was no difference whatsoever. Buz there was or-e difference: There were nore deaths in those who were treated. DR. SILVERMAN: With ACTH. MS. JAVITT: Could you link the deaths to DR. SILVERMAN: Yes. One of the complications of ACTti, we found, is an increased susceptibility to infections. DR. SILVERMAN: The mortality was related to fatal infections.

Page 18

The doctor who refzsec to er,roll h i s pacient in the trial treated w i t h ACTH ar,d that, child died of infection. So it was a very dranacic demonstration of how far o f f we could be wit5 weak evidence and the importance of always keegi,-,sirr a i d the possibility of unexpected complications. This experience changed my life. From this point on, I realized for the first time what my it was to carry out trials. I had a moral responsibility to protect my patients a s well as a scisztific res?ocsibility to gez the right amwer. You can i.na9ir.e the …