Thalidomide: the drug that won’t go away

It became the watchword for everything that was wrong with the pharmaceutical industry and ushered in an era of tougher regulations. But despite the terrible legacy of thalidomide – the morning sickness pill that caused anywhere from 10,000 to 100,000 horrific birth deformities and deaths – it’s still being prescribed to young women and their partners.

In the past year, three women in Europe became pregnant while they – or their partner – were taking thalidomide. Two of the pregnancies ended prematurely, and the third was allowed to go to term after ultrasound scans revealed no abnormalities. One of the women had an abortion, and the other – a young woman from Sweden – suffered a miscarriage.

Thalidomide causes a miscarriage in 90 percent of cases.

Drug regulators fear that the ‘off-label’ use of the drug is responsible for these high-risk pregnancies. Although thalidomide has been approved as a treatment for multiple myeloma, a cancer of the blood that usually affects people over the age of 75, up to a quarter of prescriptions are being written for off-label use – for conditions in which its safety and effectiveness have not been assessed.

The off-label conditions include Crohn’s disease and lupus, diseases that are more likely to afflict younger people, and women in particular. Men who take the drug are also told to use contraceptives, as the chemical compounds that cause deformities can be transmitted in sperm.

Although a test for pregnancy and advice about contraception are supposed to be given with every thalidomide prescription to women of child-bearing age and their partners, the European Medicines Agency (EMA) fears that the protocols aren’t always being followed. It claims that pharmacies and doctors in Spain, Denmark, the Netherlands and Sweden are especially guilty of failing to follow the pregnancy prevention program, as it’s known.

Relaxing the controls

Around 70 percent of off-label prescribing is happening in the US, and controls there could soon become even looser. The Food and Drug Administration (FDA) wants to lower its risk assessment as a way of reducing the cost of drugs. This could include the removal of pregnancy testing and advice for patients taking thalidomide, a process known as the REMS (risk evaluation and mitigation strategies) program. The FDA’s new commissioner, Scott Gottlieb, says that REMS has been used cynically by drug companies to stop competitors from releasing cheaper generic alternatives.

Thalidomide wasn’t widely used in the US in the 1960s, and so patients and doctors may be less aware of its dangers, says Glenn Harrison, chair of the Campaign for the Prevention of Thalidomide Births in Europe (CPTBE). “Any weakening of the pregnancy prevention program would put thousands of patients at risk of pregnancy while taking thalidomide. Americans are not generally aware of the extraordinary dangers that thalidomide poses to unborn children, and so they are less likely to take concerns over reducing the strengths of the REMS programs seriously,” he said.

The three European cases were also very concerning, he said. “We believe that more education is needed for patients taking thalidomide, as many are not aware of the scandal in the 1960s.”

Skin deep

Thalidomide was first approved for use in the US in 1998 as a treatment for erythema nodosum leprosum (ENL), a painful skin condition that is often a complication of leprosy. The drug has been prescribed for ENL since 1965 in Brazil, where 33 cases of severely deformed babies were reported in the following decades; even with the introduction of tougher birth control requirements with every prescription, a further 100 cases were reported between 2005 and 2010.

Despite the restrictions on its use in the US during the 1960s – its manufacturer applied for a license six times and was refused each time – some supplies were released for marketing and distribution tests. Even with this limited supply, there were 17 children born in the US with deformities that had been caused by the drug.

Although the drug was taken off the market in the West in 1961 at the height of the birth deformities scandal, it was reintroduced in 2008 as a treatment for multiple myeloma, usually under the brand name Immunoprin. A thalidomide derivative was also approved by the FDA in 2013 for treating multiple myeloma. Pomalidomide, marketed as Imnovid, is a chemical analog of thalidomide, which means it causes similar severe birth defects. Today, the drug is used in 48 countries.

Thalidomide’s off-label uses include Crohn’s disease, lupus, neurodermatitis, or itchy skin, and Behcet’s disease, which can cause inflammation in blood vessels and organs. The most common off-label use is for treating systemic lupus erythematosus, or lupus, a chronic inflammatory disease that’s more common in women.

The EMA, which reported on the recent thalidomide pregnancies, discovered that 2,118 thalidomide prescriptions were written in 2015, with the US responsible for around 70 percent, followed by France and the UK. Although some countries reported that just 3.7 percent of all thalidomide prescriptions were for off-label use, others were seeing 25 percent of prescriptions written for conditions other than multiple myeloma, and the rate is rising.

Thalidomide changed the landscape of drug control and licensing. Although 10,000 cases of severe deformities were identified, estimates of the real damage it caused range from 10,000 to 100,000 cases, and around half of the babies born with defects eventually died. Grumenthal, the German manufacturer of the drug, paid out 100 million Deutsche Marks to families (equivalent to about $25 million at the time or $205 million today), while in the UK, the drug’s distributor, Distillers, paid £20 million ($56 million at the time, equivalent to $450 million today) in compensation.

The scandal also triggered tougher drug regulation standards. In the US, the FDA started to demand stronger evidence of effectiveness and a more careful assessment of side-effects; in the UK, the Medicines Act of 1968 ushered in a new regulatory body.

Not only . . . but also

Think thalidomide, and we think of catastrophic birth defects. But the drug can do much more damage still.

• It can cause ‘excessive’ – and life-threatening – blood clots, and can interfere with the formation of new blood cells, raising the risk of infection. It can also increase the risk of anemia and damage nerve cells, causing peripheral neuropathy, a problem that is invariably irreversible.

• It also interferes with the heart and raises the chances of a heart attack,
high blood pressure, and changes in the heart’s rhythm.

• It can damage the liver and cause severe skin reactions. It can stop menstruation.

• More commonly, in around 10 percent of all patients, it causes sleepiness, tremor, dizziness, tingling, numbness, constipation, confusion, depression, reduced coordination, heart failure, breathing difficulties, lung disease and inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness – and a general sense of feeling unwell.

The woman who said no

Frances Oldham Kelsey, a reviewer at the Food and Drug Administration (FDA), on six occasions refused to authorize the use of thalidomide. She wouldn’t accept evidence presented by the drug’s distributor, Richardson-Merrell, and instead insisted on new tests.

Richardson-Merrell had acquired the rights to thalidomide after it had been dropped by pharmaceutical company Smith, Kline and French. SKF researchers failed to replicate the drug’s supposed major benefit – of reducing anxiety and insomnia – in tests on mice in 1956.

President John F Kennedy awarded Kelsey the President’s Award for Distinguished Civilian Service in 1962 – one year after thalidomide was taken off markets across the West – and the FDA presented her with the first eponymous Kelsey Award for excellence in drug safety in 2010.

Thalidomide’s days of damage

The severity of birth deformities depends on when in the pregnancy the mother started taking the drug.

Before day 20: miscarriage

On day 20: brain damage to the unborn child

On day 21: damage to the eyes

On day 22: damage to the ears and face

On day 24: damage to the arms

Up to day 28: damage to the legs

Thalidomide doesn’t seem to cause any damage to the fetus if taken after the first 42 days of pregnancy.

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