THE UNFOLDING TRAGEDY OF DRUG-DEFORMED BABIES

JUNE CALLWOOD May 19 1962

THE UNFOLDING TRAGEDY OF DRUG-DEFORMED BABIES

JUNE CALLWOOD May 19 1962

THE UNFOLDING TRAGEDY OF DRUG-DEFORMED BABIES

JUNE CALLWOOD

Many pregnant women in Canada took a drug called thalidomide (sold under trade names TALIMOL and KEVADON ) during the past year. At least eight have since given birth to infants with defective arms or legs. More such births are expected. This tragic side-effect of thalidomide was first detected in West Germany. The drug was withdrawn from sale there on November 27. and in Britain 5 days later. Here is the timetable of official action in Canada: DECEMBER 1 — Drug manufacturers reported to Ottawa that thalidomide was suspect and removed from sale in Germany and the U. K.

DECEMBER 7 — With Ottawa's approval the manufacturers warned Canadian doctors not to prescribe thalidomide for pregnant women.

FEBRUARY 23 — Press accounts of deformed births in Europe said thalidomide was still sold in Canada. Press inquiries in Ottawa brought assurances that adequate measures had been taken. MARCH 2 — Ottawa decided “sufficient evidence” warranted asking manufacturers to withdraw the drug entirely.

MARCH 5 — Manufacturers wrote doctors, druggists and hospitals not to issue thalidomide and to return all supplies.

MARCH 20 — Birth of deformed baby, whose mother had taken

thalidomide, reported in Toronto. Health Minister .1. W. Monteith asked and got a report on the drug from his department. MARCH 30 — Similar deformed birth in Winnipeg prompted a question in parliament. Minister said “efforts are being made to make sure any drug still on the market is picked up.”

APRIL 6 — Manufacturers reported 10% to 15% of druggists refused to give up their supplies. Federal authorities wrote manufacturers that refusal violated the law, and “may result in seizure of the product and/or prosecution.”

APRIL 10 — Maclean's discovered, by a random check of drug stores across Canada, that thalidomide was still on sale in at least four cities, including Ottawa. Reported this to the government. APRIL 10 — For the first time, federal food and drug inspectors were ordered to check drug stores and recover any thalidomide still on sale. For the first time, federal authorities wrote to doctors directly (previous communications from Ottawa had gone only to the manufacturers).

APRIL 15 — It is probable that by this date thalidomide was no longer sold in Canada. It is therefore probable no unborn children have been exposed to it since then, and that congenital deformity from this cause will not occur after mid-November.

A SMALL TABLET that sold for about ten cents has> precipitated the medical tragedy of this age. Across Canada, expectant mothers who used the pill containing a new drug, thalidomide, to relieve morning sickness in early pregnancy are waiting now to discover whether or not their babies will be massively deformed.

Their ordeal is shared by obstetricians, who prescribed the drug in innocent faith in its advertised ability to prevent morning sickness harmlessly. It is shared by two pharmaceutical companies who manufactured the tablets under the names Kevadon and Talimol. in the belief they were bringing Canadians the safest sedative ever devised. It is also shared by government officials who were warned of the risk of the drug three months before they took any action, and four months before their decision was enforced.

The effect of this drug is that babies may be born without arms and legs. At the time of writing, eight Canadian women have given birth to living and otherwise healthy infants suffering from varying degrees of phocomelia, a deformity so rare before thalidomide that few doctors had ever seen it. and some medical dictionaries don't even list it. In phocomelia, the baby has crude hands joined to the shoulders, and foot-like appendages at the hip. “Seal-limbs,” they have been called.

Some of the deformed Canadian babies were born in this totally helpless state, others were more mildly afflicted. One in Toronto had normal legs and feet but the forearms were missing, so that the hands were where the elbow's should have been.

Within a few weeks in late wanter and early spring, three such babies w'ere born in Toronto, one in Montreal, one in Ottawa, one in Winnipeg,

one in Edmonton and one in Vancouver. In all cases the mothers had taken thalidomide early in their pregnancies. Two were the wives of doctors, using samples of thalidomide donated to their husbands.

The history of thalidomide will be cited by doctors, researchers, drug manufacturers and governments for years to come. It most certainly w'ill alter attitudes, methods of testing, and regulating all over the world. Canada, unhappily, has the poorest record of all. The drug had only been on the Canadian market for eight months when the medical directors of both companies manufacturing it visited Ottawa to warn officials that doctors in Europe suspected thalidomide of damaging human embryos. More than three months later, on March 2. the Department of Health decided the drug should be withdrawn. But six weeks Ja ter. on April I I. it was still being sold over drug store counters.

There is no w'ay of determining how' many infants arc casualties of the delay until next November, when the last child who could possibly have been exposed will be born. All those actually born up to now would have been deformed anyway, even if action had been taken the moment the danger was known. Thalidomide attacks the fetus in the second and third month of pregnancy, or six to seven months before birth: it's still only six months since this fact became known. What the delay has done, in Canada, is prolong the threat through the months of summer and autumn.

No one can guess how many babies in all are likely to be affected by the drug. Canadians purchased about four million thalidomide tablets during the year they were available. This figure doesn't include the number of samples, already significant, which were distributed generously. It is impossible to discover how many of the pills were used by pregnant women, but it is known that CONTINUED ON PAGE 65

continued from page 13

The new drug be~er creileiitials than most. It was welcomed warmly by the medical p-ofession

many obstetricians had good reason to be delighted with thalidomide and were prescribing it regularly. "I'm getting the best sleep I’ve ever had in my life,” a twentyone-year-old Toronto woman assured her obstetrician happily. Her baby girl is the one most grievously deformed. The obstetrician who delivered Winnipeg’s first case of phocomelia prophesied sadly, "This is going tc happen again."

British medical journals provide the only estimates available on the probability that a woman who has been taking thalidomide in her early pregnancy will give birth to a deformed baby. Two doctors. reporting independently in The Lancet. bcheved that twenty percent are harmed. one baby in every five. The odds are sufficiently steep to move I he Lancet in a recent editorial to raise the issue of therapeutic abortions in such cases. Canadian doctors won’t have to decide: the thalidomide pregnancies here arc now beyond the three-month period, and abortions arc no longer feasible.

In any case, some doctors say, thalidomide is not yet proven conclusively to be the fetus-harming agent. Thousands of women have taken thalidomide in their early pregnancies and delivered normal babies. It could turn out that these women with the damaged babies were all using some other product not yet suspected.” a Toronto doctor commented. "Thalidomide may be the victim of a coincidence.” In Edmonton, the University of Alberta’s professor of obstetrics. Dr. J. R. Vant. cautioned that the thalidomide hasn't yet heen ‘‘pinpointed as the sole cause."

1 he circumstantial evidence, however, is strong. Suspicion began late last summer in West Germany, where an epidemic number of severely malformed babies was appearing. The deformity was of such a rare type, phocomelia, that the genetic factors which cause most abnormalities could be ruled out. So could the other known agents that can damage babies, such as X-ray. cortisone, insulin, folic acid deficiency, maternal infection with rubella (German measles), polio, or the sometimes suspected Asian influenza and mumps. Each of these leaves a distinctive stamp. German measles, for example, under some conditions can cause cataracts; cortisone, cleft palate. No element causing a disturbance of limb growth had ever been detected before.

The time of damage was narrowed to the sixth to eighth week of pregnancy when the embryo, thirty millimetres long and weighing only a few grams, puts out arm and leg buds. The German doctors were discovering a common factor in their studies—the mothers during this period had been taking one of West Germany’s most popular new sedatives, called Contergan. It had been considered such a safe sedative that it was sold without prescription. It contained a new substance, thalidomide. synthesized in 1954 by a West German pharmaceutical giant. Chemie Gruenenthal. and successfully tested on animals for three years before it was licensed for sale. In September, a fouruniversity research team launched an investigation of the phenomenon. On November 18 Dr. Widukind Lenz, a University of Hamburg pediatrician with a special interest in human genetics, told a conference of worried doctors that he suspected thalidomide.

His findings, published in The Lancet of January 6, were shocking. He personally had seen fifty-two dreadfully malformed infants whose mothers had taken thalidomide in early pregnancy. “1 have re-

ceived letters from the German Federal Republic. Belgium. England and Sweden reporting one hundred and fifteen additional cases in which this drug is thought to be the cause." he added.

He described the babies, two out of three of whom are alive: completely without one to four limbs, defective development of arms or legs, seal-flipper hands

and feet, absence of the external ear. deformities of the eyes, esophagus, intestinal tract. "The risk to the fetus of taking the drug between the fourth to eighth week of pregnancy may be definitely higher than twenty percent. I venture the estimate that at least two thousand, possibly more than three thousand Contergan babies have heen born in West Germany since 1959."

Other doctors were coming to the same conclusion. A New South Wales doctor described similar abnormalities in a letter to The Lancet, wondering if any other doctors had been noticing such babies.

On November 27, Germany withdrew the drug from the market. Five days later. Great Britain withdrew its thalidomide compounds. One of them. Distaval, had

been tracked down by a Scots pediatrician. Dr. A. L. Speirs. who observed ten babies of the phocomelia type born in one small maternity unit in Stirlingshire. None of the mothers recalled taking any drugs and their doctors were vague, so Dr. Speirs searched chemists’ orders dating back a year and found that eight of the ten mothers had taken Distaval. I he ninth had taken a sedative of unknown ingredients: only in the tenth case was there no evidence of drugs that he could discover.

Drug companies all over the world had obtained the license to manufacture thali-

domide in compounds under whatever brand name they chose. Since only Canada and the United States have government control over the acceptance of new drugs, thalidomide has been introduced elsewhere without any official scrutiny. In many countries, therefore, the drug companies took the initiative and withdrew thalidomide voluntarily.

I he situation was different in North America. I he United States was holding up acceptance of thalidomide. The Foods and Drugs Administration had asked for further information on one aspect of the

drug, its tendency to cause a mild neuritis side-effect in some cases. While the additional material was being gathered, the storm in Germany and Great Britain became visible to the informed eye and the application was dropped.

Canada’s Food and Drug Directorate, however, had accepted thalidomide on April 1, 1961. to be manufactured under the name Kevadon by the William S. Merrell Company of Cincinnati, and the name Talimol by the Frank W. Horner Company of Montreal.

The submissions of the companies each

made a stack of documents a foot high, weighing five pounds. In compliance with Canada’s Food and Drugs Act with regard to new drugs, the submissions had contained a thorough description of the drug —which occupied nine pages—methods of its manufacture, and a four-hundred page report on the testing. Thalidomide had been tested more carefully than most new drugs. Over a three-year period, it had been found to be harmless to vital organs. It was later found to be so safe that even massive doses didn't harm would-be suicides. To check its effect on embryos, fifteen hundred pregnant rats were treated with the drug and none produced abnormal offspring. ("It goes to prove.’’ said Dr. A. L. Chute, chief of medicine at the Toronto Hospital for Sick Children, "that man is not a rat. a cat or a monkey/’)

The Food and Drug Directorate of the Department of National Health and Welfare accepted thalidomide with the understanding that doctors would be warned about its weakness—the occasional neuritis side-effect. Because it was a sedative, it could be sold by prescription only.

It was welcomed warmly by the medical profession, despite the abundance of new drug products every year. Being suicideproof. it was ideal for disturbed patients. It induced a quick, relaxing seven-hour sleep with no grogginess afterward. It was safe for people with cardiac or respiratory disease and safe for children. Distantly related to the tranquilizer family, it also turned out to be beneficial for the treatment of early pregnancy nausea, a condition with a high nuisance rating. Obstetricians recommended it to their colleagues.

During the weeks when the drug was being withdrawn from the market in Germany and Great Britain, Dr. .1. Murray and Dr. T R. MacDougal. medical directors of the companies supplying Canadians with thalidomide, went to Ottawa to see Dr. C. A. Morrell, director of the Food and Drug Directorate. Dr. Morrell, a mild, careful man. has been thirty-two years with the government and is recognized as one of the country's top experts in bioassay, the science of studying toxicity by the examination of living material.

In April Dr. Morrell said. “The two medical directors told us they had rumors from Germany from the patent holder, Gruencnthai, that thalidomide was suspected of causing some birth abnormalities. At that stage it was all unconfirmed reports; Lenz hadn’t published yet. It seemed pretty vague. It didn't occur to us to w ithdraw the drug.”

The reports from Germany, as relayed to him. were truly unimpressive. Gruenenthal was quoting Dr. Lenz as claiming to have had a "vision” indicating that thalidomide was the cause of the deformities. ( By telephone from Hamburg, Dr. Lenz indignantly denied this statement.)

It was agreed that a letter should be sent to all doctors warning them not to prescribe the drug for pregnant women, or for premenopause women who might become pregnant. The letters were sent on December 7th. by first class mail, and the envelopes were clearly marked DRUG WARNING.

In January and February, the British Medical Journal and The Lancet carried reports from doctors who found that mothers of distorted infants had taken thalidomide during their early pregnancies. On February 23. Time Magazine published an article entitled Sleeping Pill Nightmare, and mentioned that thalidomide was still being sold in Canada.

Newspapermen approached Dr. Morrell for statements. He was quoted in the Toronto Star as saying thalidomide would not be removed from the Canadian market because Canada "has no cases yet” and the

“Why shouldn’t I sell the stuff?” asked a Toronto druggist. “It’s safe for an adult male, isn’t it?”

evidence against the drug “is only statistical.’’ A spokesman in his department told the Globe and Mail that the letter to doctors was considered an "adequate” safeguard. He added. “You shouldn’t jump off the deep end.”

The Lancet of February 10 contained the meticulous report of the Scots pediatrician. Dr. Speirs. along with pictures of six of the infants with their faces decently covered. One little girl had only a head, an armless body and feet.

That Lancet reached our library on February 28. The date is stamped right on it.” Dr. Morrell said later.

On March 2 the department decided there was “sufficient evidence" to warrant asking the manufacturers to withdraw the drug, according to a statement made four weeks later in the House of Commons by Health Minister .1. Waldo Monteith. The minister learned of the thalidomide controversy on March 20. when the first case in Toronto was reported in newspapers. He asked for a memorandum briefing him on the situation and received it March 23. He was ready with the information when a question was asked in the house on March 30. the day after the first phocomelia baby was reported in Winnipeg.

Earlier the drug companies had agreed with the department that they would recall the thalidomide by writing doctors and pharmacists. The alarmed drug companies did a thorough job. The Canadian distributor of the William S. Merrell Company on March 5 telegraphed its salesmen to pick up the drugs, sent two telegrams to wholesalers, instituted meetings of sales executives to ensure that hospital and institutional pharmacies weren’t overlooked. Frank W'. Horner Limited put sixty salesmen to work picking up supplies, sent letters to 20.457 physicians, 5.209 drug stores and 1.985 hospitals.

In the meantime. Dr. Lenz had reported he was receiving information on from three to ten new cases every day. Another West German doctor had word of ninetyfive new cases over a period of a few weeks. Doctors were also writing about abnormal births to women who said they hadn't taken thalidomide. "The painstaking detective work reported by Speirs provides impressive evidence.” declared a Canadian Medical Association Journal editorial on March 10. "that cursory inquiry will fail to reveal a history of thalidomide ingestion in many cases."

At about this time, the drug salesmen were having an unexpected problem. From "ten to fifteen percent" of the pharmacists they approached refused to give up supplies of thalidomide because it was much in demand. One Toronto doctor complained: "It’s the best sedation we’ve ever had.” On April 6 Dr. Morrell equipped the companies with a letter from him, explaining that druggists who failed to comply would be liable to prosecution.

On April 10. six weeks after the drag officially had heen withdrawn. a Maclean’s reporter phoned a drug store, its number chosen at random, in the west end of Toronto. Thalidomide was still on the store’s shelves.

"Why not?” asked the pharmacist. “Jt’s safe for an adult male, isn’t it?”

To the suggestion that any drug in a home medicine cabinet might be taken by a woman, he retorted, “That’s not my problem. I’m not sending back the rest of my supply until people stop asking for it.”

Maclean’s telephoned seventy-seven drug stores in eleven Canadian cities from coast to coast. None still sold the drug in any of the stores that were asked in Victoria,

Vancouver. Regina, Winnipeg. Quebec City, Fredericton or Halifax. Winnipeg pharmacists, in particular, were surprised and even indignant to be asked; they are offering refunds to customers who will bring in partly used bottles. But of the twenty-four drugstores that Maclean's telephoned in Toronto, five were still selling thalidomide; three out of eight in Edmonton. three out of thirteen in Montreal, three out of eight in the Ottawa-Hull area (one in the capital city itself).

We passed this information on to the government and the drug manufacturers.

“The law isn't very clear on this point.” said an official of the Horner company. “I’m shocked.” a Merrell official said, "but there is a point where our responsibility ceases." Nevertheless, both companies reacted briskly. Horner took its entire sales force off every other job and gave them one assignment: get back thalidomide.

The Department of National Health found that there was a law to cover the situation that was both clear and carried adequate penalties—up to a five thousand dollar tine and three months in prison. On April 10. for the first time, federal inspectors were ordered to go round and check on drug stores. One of them incredulously reported hack that the first pharmacist he called on not only had thalidomide in supply, hut had just received a new prescription for it.

The department, thoroughly agitated, then sent letters directly to Canada’s doctors. asking them to destroy or return their samples of thalidomide. On April 10. 108.748 tablets distributed by Horner as samples were still unaccounted for; only 14.304 had been returned. Horner sent out more letters on April 12, in envelopes marked URGENT WARNING.

Dr. Morrell also requested that doctors notify him of all abnormal births of the phocomelia type. It has never been a reportable disease, a fact which hampers medical statisticians searching for a normal incidence with which to compare the present outbreak. The Hospital for Sick Children in Toronto, for example, lumps phocomelia with one hundred and twentyfour other defects in a single category called diseases of the bone and joint. The number of congenital bone and joint diseases seen annually in the hospital is fewer than one.

The cruelty of the phocomelia abnormality has had one distinct medical advantage: it is so rare it attracted attention immediately. A more common congenital malformation would not have been noticed so quickly, nor connected with a specific cause.

A Maclean’s reporter telephoned Dr. Lenz in Hamburg on April 12. He was continuing to see new phocomelia cases, he said. "I now have seen two hundred and ninety of them, personally.” He had begun to suspect that the proportion of babies damaged when mothers took thalidomide in early pregnancy was “appreciably higher" than twenty percent. He roared a denial that he had ever notified Gruenenthal of a vision. “Thalidomide kept emerging in case after case. I wouldn’t call that a vision.”

However, even bitter critics of drug manufacturers and their promotion methods impute no blame in this case to the makers of thalidomide. Dr. Mark Nickerson, professor of pharmacology at the Manitoba Medical School and such a stout foe of the drug industry that he has testified against it before a Washington congressional committee, states: "In this case, I don’t see how they could have caught it.”

But the University of Toronto’s professor of pharmacology. Dr. E. A. Sellers, predicted: “This will put a scare into the drug houses, as far as testing for effects on future generations is concerned.”

The Canadian Medical Association had decided some months ago to submit to the May sitting of the Royal Commission on Health a request for an expansion of the Food and Drug Directorate’s facilities to include more medical representation and quicker, clearer information to doctors about new drugs. At present such information all comes from manufacturers, and is both ornate and vulnerable to bias.

There is a general feeling that the food and drug directorate is understaffed and overworked. The directorate employs three hundred and twenty-seven men and women on an annual budget of two million dollars to handle "dozens” of new drug submissions monthly. I'he United States counterpart employs nearly twenty-five hundred people, with a budget of about twenty-two million.

Thoughtful men are putting some of the responsibility for this horror on the patient. “We are too soft,” remarked Dr. Chute of Sick Children’s. “There is too much demand on the part of the public for relief of mild or even moderately severe symptoms. People won’t put up with the slightest discomfort or headache; they demand medication from their doctors. If they can't get it from one, they’ll go to another.”

Dr. Garnet P. Hamblin, a Toronto pediatrician, commented, "I find patients are eager to try a brand-new drug, can hardly wait to get at it. You’d think that they’d be reluctant, prefer that someone else go first. Maybe they’ll be less enthusiastic after thalidomide.”

“We don't really know what is happening at the cellular level,” another doctor observed. “When we take drugs it is always a calculated risk.”

But what of the thousands of babies with phocomelia? Two out of three display no medical cause why they will not have normal life spans. A doctor shook his head wearily. “You should look at the one I’m treating, you should look at that child. It’s hard to tell, she’s two months old, but her intelligence seems normal.”

The infant's mother, he said, considered putting the child in a nursing home. She returned home from an inspection of one and reported desolately, “That’s no place for my baby.”

“She’s caring for the infant herself now,” the doctor added. “I don’t know what will happen.”

By November, Canadians will know how much damage has been done. It will all be over, all but the crying. ★