The Sydney Morning Herald from Sydney, New South Wales, Australia • Page 8

I Tin Sydney Morning Herald. Monday. Junt 1968 How it happened. from the makers documents newspapers will be rewriting tho human story of the thalidomide victims. It is a terrible story, of children born to lifelong pain and humiliation, and of brave people struggling under every kind of disadvantage to make the best of their own, their children's or their patients' broken lives.

That tragic story has often been told, and each learns what he can from it. But are there other, more practical lessons to be learnt? How could educated men, doctors and scientists, make such a mistake and, having made it, refuse to admit it? Was it blind, unavoidable tragedy, or was it that avoidable kind of tragedy which men call crime? These and many other matters are questions for the Court. Here at least, in three articles by a special correspondent beginning today, is the full story, as the prosecution will put it, of what happened. of them lied to doctors who questioned them; then when the reports became too insistent to be ignored did all they could to suppress them and, with money, to induce other doctors to write favourable reports. AND THAT this same drug, which the sales department called "the apple of our eye" because it was so profitable, caused an epidemic of monstrously deformed babies.

All this the nine defendants deny. As far as the nerve damage to adults is concerned, they maintain that they acted promptly and responsibly when the danger was first brought to their attention. As for the deformities, they say there is still no proof that thalidomide was the cause. Ever since the news of the disaster became known to the public in November, 1961, there has been intense interest in the story of thalidomide. Hundreds of journalists have converged on the trial, and hundreds of ities.

Some died. Some were killed at birth. Some, tragically handicapped, are still alive. The drug was sold across the world under many names. It became notorious as thalidomide.

This is what the prosecution case amounts to: THAT in 1958 the nine men in the dock put on sale a drug which, even when taken according to instructions, caused an unacceptable degree of bodily harm. THAT they failed to test it properly. THAT they went out of their way to advertise it as safe when they could give no guarantee that it was. THAT in fact it was so very arvf rom safe that it caused those who took it to itch, shake, sweat, vomit, and even to lose the power to stand upright. THAT when these reactions were reported to them they first systematically brushed them aside; that some Today the eyes of the world are on a converted canteen in the little town of Alsdorf, West Germany, where seven men are on trial charged with causing bodily harm and negligent killing.

The trial is expected to last two years. There are 14 Judges. The prosecution alone will produce 352 witnesses. The evidence that has been taken runs to 70,000 pages. Two defendants who are too ill to face the Court will stand trial later.

Germany has experienced no trial remotely comparable, in scale or emotional intensity, since Nuremburg. The defendants are the owner, six present employees and two former employees of a firm called Chemie Gruenenthal. Few of the victims will appear in court. There are thousands of them: in Germany alone at least 1,000 adulte suffering from severe nerve damage and perhaps 5,000 babies born with appalling deform THAL DOMIDE FILE as the following sent to doctort in CsnaHa- ft niDii iiuM.iuiutt, iiiiiiiiji iihii i ijhu i ii mil ni n.iiiiin p. i ji ii nmZ4mi)mmt-iffm tuff 'V- -i I 1 -'rfl 1 X-f-P f( vT 'V THE FIRM OF Chemie Gruenenthal has its headquarters in the little town of Stolberg, near the Belgian border, in a sturdy thrcc-storcy building which started life as a copper foundry in the eighteenth century.

The onion-domed roofs and walls of rough masonry overlook a courtyard lined with laurels and Mercedes. Gruenenthal was set up after World War I. It was an olT-ihoot of an old family firm called Dalli-Werke, Maurcr and Wirtz, which makes soaps, detergents and cosmetics in Aachen. The head of the new firm was Hermann Wirtz, a member of the family. Their first pharmaceutical products were antibiotics; first foreign ones made under licence, and later two new drugs discovered in their own laboratories, called xanthocillin and tyro-thricin.

In July, 1946, the company took on, as head of its research lab. a 32-year-old called Dr Heinrich Mueckter. Mucckter had qualified both as a chemist and as a doctor before the war. During the war he was a senior doctor (chefarzt) at the Institute for Typhus and Virus Research at Cracow, in Poland, which came under the German Army High Command. Human guinea pigs died According to evidence presented at the Nuremburg Nazi doctors' trial, this institute provided Weigl serum out of the intestines of lice which was used to inoculate 31 human guinea pigs taken from among the prisoners at the infamous Buchen-wald concentration camp.

Ten of the prisoners died as a result of being given the virus. Mueckter's precise role at the institute is not clear. The Polish authorities merely say: 'Mueckter was loyal to his German superiors but committed no criminal acts against the Polish population." Apart from Wirtz and Mueckter, the most important of the other executives at Gruenenthal were self-made men: Jacob Chauvistre, who had 6tarted with Dalli-Werke straight from school and worked his way up to joint managing director; Hermann Leufgcns, the other joint managing director, who had also worked his way up from a commercial apprenticeship, and Klaus Winandi, the sales manager, who had worked for Dalli-Werke before the war, and had been a prisoner of war. AH five are defendants in the present trial. Chemie Gruenenthal, in fact, was a small firm typical of the many such firms which brought about the postwar economic miracle in Germany.

It was run by ambitious, competent men, who thought in terms of "mv company, right or wrong." Certainly none of them could see far beyond the pany's interests. Thalidomide was discovered by accident. In the spring of 1954 Mueckter was looking for an effective diuretic: working with a substance called carbonic anhy-drase. (A diuretic is a drug that reduces body fluids and therefore obesity. Since obesity and associated heart disease was becoming a big medical problem in the West it was expected to be a good seller.) To arrive at the final chemical, Mueckter and his two assistants, Dr Herbert Keller and Dr Wil-helm Kurtz, had to go through a number of different stages, each of which yielded a byproduct.

As a matter of routine they tested the by-products for pharmacological action. One of them looked promising. It was a pipcridinc compound of gluta-minc. It was white and tasteless and it crystallised into fine needles. They labelled it KI7.

It became known internationally as thalidomide. Mueckter was a good enough chemist to suspect from its molecular structure that K17 could have a sedative action, because of its similarity to glute-thimide, already in use as a sedative. He was also a shrewd businessman; shrewd enough to have a contract which gave him 1 per cent of Gruenenthal's turnover as a bonus over and above his and shrewd enough to see that in KI7 Gruenenthal could be on to a good thing. The sleeping pill boom that has been a phenomenon of modern Western civilisation was already well under way in Britain alone it was estimated that one million people took some sort of pill every night. There was a huge market for a new sedative, especially one free from barbiturates with their unpleasant side-effects and danger of suicide.

Mueckter's work changed gear. KI7 became the focus of his research program. In the first weeks of 1955 his team began pharmacological and toxicologi-cal tests on animals, mainly on rodents. The results of the tests on animals were summarised in a paper by Kunz, Keller and Mueckter, published in 1956. The extraordinary thing about their findings was not that KI7 had a sedative action they had suspected this but that it apparently had no dos toxalis 50, the fatal dose that kills half the laboratory animals in an experiment.

In other words it appeared that thalidomide was incredibly Japan, for which Gruenenthal were not responsible. Once they had decided to launch the drug they determined to do it properly. They spent money copiously. They bought 50 advertisements in the major medical journals and sent out 200,000 letters to doctors. The theme was set out in a circular dated September 26.

1957, issued by Mueckter's scientific research department, and addressed to all associates. The idea was to emphasise "sure to work, and completely non-poisonous." The circular continued: 'The atoxicity proved in animal experiments makes Contergan completely safe and this gives the preparation its special opportunity." This was no ordinary claim. No previous sedative was known to have these properties. Yet it was a claim that was to appear again and again in the instructions on publicity in notes to doctors and chemists, and in the packets sold to the public. And the claim worked.

Drive for use in pregnancy The next stage in Gruenenthal's sales campaign proved to be the decisive step in the tragedy. They began promoting it for use by pregnant and nursing women. On May 2, 1958, Dr Augustin Peter Blasiu, who was retained by the company, published an article in "Medizinische "Experiences Gained with Contergan in Gynaecological Practice," based on tests in his own private nursing home in Munich. The article said that he had used Contergan on 370 patients, of whom 160 were nursing mothers since 1956. "Side effects were not observed, either with mothers or babies," he reported.

The general tone of his article was entirely favourable to Con-tegan except for one major flaw, it did not mention pregnant women. As Dr Blasiu said later: This drug was never prescribed for pregnant women. It is my basic rule never to give sleeping pills or tranquillisers to mothers-to-be. In mv article I say that I gave Contergan only to nursing mothers and operation cases." In view of this Gruenenthal's next action is inexplicable. They sent to 40,245 general practitioners a leaflet containing extracts from Dr Blasiu's report with a carefully-worded letter implying that thalidomide could be taken safely during pregnancy.

The letter reads: Dear Doctors, In pregnancy and during birth the feminine organism is under great strain. Sleeplessness, unrest and tension arc constant complaints. The prescription of a sedative and hypnotic that will hurt neither mother nor child is therefore often necessary. Blasiu has given many patients in his gynaecological department and in his obstetrical practice Contergan and Contergan forte. Depth and length of sleep were good and patients could be easily awakened from deep sleep.

Contergan had no effect on the nursing baby." In a statement to the German authorities in 1964, Blasiu stated that he knew nothing of this letter, and that, if he had known, he would have taken steps to have it stopped. "I would most emphatically have resisted the circulation of such a letter using my name and referring to my report. I con-Rider that this letter from the firm to the medical profession is unfair, misleading and irresponsible That thalidomide was safe, even for expectant and nursing mothers, was now one of the main themes of the company's advertising and was to remain so until it withdrew the drug from the market. Yet the claim continued to be based on dubious premises. As late as 1961, Gruenenthal were approving claims in sales leaflets such OBGYN patient No side effects in pregnancy or lactation When 100 mg.

of Kevadon was administered for insomnia to expectant mothers (16) and nursing mothers (12) all of the babies were born or nursed without any abnormalities or harmful effects from the medication Reference 16 is a report by Dr Ray Nulsen, called Treatment of Insomnia in the Third Trimester of Pregnancy," which was published in the "American Journal of Obstetrics and Gynaecology." Dr Nulsen, aa American, was examined for a deposition on April 14, 1966. (Merrell, a large American pharmaceutical concern, was associated with Gruenenthal in trying to get the authorities in the United States to accept thalidomide for sale there.) Part of the examination goes as follows: Q. Now, did you know, sir, that an article was published in the "American Journal of Obstetrics and Gynaecology" entitled Trial of Thalidomide in Insomnia Associated with the Third A. Yes. Q.

And does it bear your name? A. Yes. Q. Now, sir, did you physically write the article? A. No.

Q. Who wrote it? A. Dr or someone at the Merrell company. Q. Did you supply for this article any of the information with respect to the chemical facta contained in this article? A.

No. Q. Did you supply any of tha footnotes for the article? A. No. So Gruenenthal were quoting, as support for their claim that thalidomide was safe to use on pregnant mothers, first a doctor who had not tested the drug on pregnant women at all, and second, a doctor whose report had been written for him by an employee of a pharmaceutical company closely linked with Gruenenthal itself.

First complaint giddiness The first complaint about Contergan from an independent source reached Gruenenthal in July, 1958. Professor Gustav Schmaltz, in Frankfurt, had not been testing the drug, merely giving it to his patients as Gruenenthal prescribed. He reported that thalidomide caused giddiness and slight disturbance of balance in the elderly. Gruenenthal re-plied: "We feel obliged to say that this is the first time such side-effects have been reported to us This was simply not true. All through the early clinical trials, from 1955-1957, criticism had been raised on just these points dizziness and disturbance of balance by three of the nine doctors whose tests had been quoted at the original Thalidomide Symposium back in 1955.

The year 1959 was "Breakthrough Year" for Contergan. The publicity campaign was hav. ing its effect. Sales figures increased dramatically; they went up fourfold from May to December. But 1959 was also the year that complaints from well-known members of the German medical profession about side effects grew from a trickle to an indignant and persistent flow.

Gruenenthal's reception of these complaints shows how committed the company had become to the success of Contergan. The first major signs of trouble were nothing to do with malformed babies for which thalidomide was eventually to become so notorious. Because of the nine-month delay of pregnancy, it was some time before the medical profession began to catch on to the tragic effect on the unborn child. What they did start to notice early in 1959 was the emergence in adult of a worrying nervous disorder called penpheral neuritis. It ii with this illness that much of the story is concerned.

A German thalidomide victim learning to use his artificial arms and hands in a clinic at Frankfurt harmless, even when taken in large doses. It could not kill. This was a vital finding. It was to be the basis of Gruenenthal's advertising for the next five or six years, and was one of the main reasons why the use of thalidomide became so widespread. But how good were the tests employed by Mueckter, and his colleagues to decide that thalidomide had "extremely low toxicity?" In 1965 scientists at the Uni- and a drop in temperature, shivering and a buzzinc in the ears.

But undeterred, Jung told the thalidomide symposium in December: "We have in KI7 a substance which at the correct dose level has no undesirable side effects. 1 believe that K17 is a satisfactory drug, and that with the necessary propaganda it will succeed in the pharmaceutical market" So further trials followed. Again K17 was sent out to specialists. Two replied favourably but any satisfaction this might have given Gruenenthal was shattered by a critical report from Dr Ferdinand Pia-cenza, the doctor in charge of the Wasach Sanatorium near Oberstdorf. Dr Piacenza said he had been forced to break off tests with thalidomide because of "absolute non-toleration." He described various side effects including, significantly, symptoms of what he considered to be allergic reaction.

Effects blamed on dosage Mueckter replied on behalf of Gruenenthal: "We have never had such a negative report as yours." He blamed too high a dose for the reactions in Pia-cenza's patients "K17 is such a strong sedative that in general small doses are sufficient" and dismissed Piacenza's suggestion that K17 was an allergy-producing substance. "The only explanation left is that (the reactions) are a disturbance in the nervous system, following loo high a dosage over a long period of time." This remark of Mueckter's is significant on two counts it shows that he was aware that KI7 could affect the nervous system and that there was a point at which dosage became too high. It is odd, therefore, that when KI7 went on the market, the company's instructions should include the vaguely worded phrase, "In case of sleeplessness Contergan can be taken in higher doses without any danger." Thalidomide's prospects at this stage were not good. In the three years since the drug had been discovered, testing had been sporadic. The numbers and controls had been inadequate, not all the possible trials on animals had been carried out, the trials on humans had left many questions unanswered and had given rise to misgivings about toleration and side effects.

Yet, on September 2. 1957. at a meeting between Mueckter. Winandi and managing director Chauvistre. it was decided to put thalidomide on the market.

Thalidomide went on sale on Tuesday, October 1, 1957. After some deliberation Gruenenthal had chosen the word CONTERGAN as a brand name. Thalidomide was exported to about II European, 7 African, 17 Asiatic and 1 1 American countries. In addition it was pro-duccd by a number of firms under licence, under a total of 51 names such as Softenon, Softenil, Distaval, Babysitter (a version specially for children), and Neu-rosedyn. There were a few imi-tations of the drug in Italy and versily of Stockholm were asked to analyse the German report They made die following points: "The number of animal experiments in the toxicity tests was far too small: that because of this, a low frequency of side effects could not be detected, -though these are important for a sedative like thalidomide and very necessary if the substance is to be declared unpoisonous.

The conventional toxicoiogica) and pharmacological tests are most unsatisfactory. Kunz Keller and Mucckter openly tried to hoodwink the reader by creating a false impression of the scope of their tests" The prosecutor puts it like this: "This sales talk ignored the fact universally recognised in pharmacology that no amount of experiments conducted on any amount of animals can entitle a manufacturer to speak of 'guaranteed non-toxicity' and 'harmlcssness' for human beings." Gruenenthal had no qualms. They went ahead with clinical trials. The preliminary results of the effect of thalidomide on human beings were given at a 'Thalidomide Symposium" held in the Gruenenthal factory on December 16, 1955. The nine doctors Gruenenthal had recruited for the tests included dermatologists, psychiatrists and neurologists.

Their verdict was hardly overwhelmingly favourable. Four were in favour of the drug, four had mixed reactions and one was decisively against it. The main report in favour was by Dr Hermann Jung, a part-time Gruenenthal employee earning about 200 DM a month (about $35) as a routine tester. Early in 1955 in a clinic in Cologne he gave K17 to 20 fiatients, mostly tubercular, for our weeks. Cm the basis of these trials he reported at the beginning of June that the drug was ready to be marketed.

He went on experimenting however and in later tests found that K17 produced dizziness, constipation i ii hi Mill- MinHi TrMimrim'Mtfir -J TODAY forbidden marriage partners the mingling of genes of close relatives is fraught with peril Everyon It talking about Its honesty, wit and maturity. Read it today in TOMORROW Complaints flow in i.