Questions and answers on thalidomide

This presentation answers frequently asked questions about the hypnotic (sleep-inducing) agent Contergan and its active drug substance thalidomide:

1. When was thalidomide first launched on the market as a sleeping pill?
2. What tests did Grünenthal do on the Contergan active drug substance thalidomide before launching the product?
3. What legal requirements for testing medicines were in force when thalidomide was launched?
4. When did Grünenthal become aware of the side effects of thalidomide and how did the company react?
5. How does thalidomide cause deformities?
6. Why did it take years to demonstrate the connection between thalidomide and deformities?
7. Who were the defendants in the criminal proceedings, and why?
8. How did the criminal case proceed?
9. How did the State help the thalidomide victims?
10. What did Grünenthal do to help thalidomide victims?
11. What benefits have thalidomide victims received to date?
12. What did Grünenthal do with thalidomide after the thalidomide tragedy?
13. What are the effects of thalidomide in the treatment of leprosy and cancer?
14. What were the consequences of the thalidomide tragedy for drug safety?
15. How has Grünenthal managed to recover economically from the thalidomide tragedy?
16. What is Grünenthal's response to the thalidomide issue today?
17. How does Grünenthal support the Contergan victims today?

1. When was thalidomide first launched on the market as a sleeping pill?
Grünenthal launched Contergan as a sleeping pill on the German market on 1 October 1957. The active drug substance thalidomide was sold in a total of 46 countries, under other brand names in some cases.

2. What tests did Grünenthal do on the Contergan active drug substance thalidomide before launching the product?
Grünenthal tested the active drug substance thalidomide in the animal models customarily used by pharmaceutical manufacturers at that time: mouse, rat and rabbit.

3. What legal requirements for testing medicines were in force when thalidomide was launched?
There was no uniform legislation for pharmaceutical products in the Federal Republic of Germany when thalidomide was launched in 1957. The principle of self-monitoring applied. There were no laws providing for effective investigation of the side effects of medicines. Active drug substances did not have to be tested for their propensity to cause damage to unborn life (teratogenicity).

4. When did Grünenthal become aware of the side effects of thalidomide and how did the company react?
Two different side effects were reported for thalidomide. The first was irritation of the nerves in the hands and feet, usually of elderly people (polyneuritis). Grünenthal received the first reports in October 1959. In response, Grünenthal modified the package insert in 1961 and applied for prescription-only status for thalidomide in May 1961.
Then, half a year later on 16 November 1961, the Hamburg pediatrician Dr. Widukind Lenz voiced his suspicions of a connection between deformities in unborn children and thalidomide. The same suspicion was expressed shortly afterwards by the Australian gynaecologist Dr. William G. McBride. Grünenthal reacted with all possible speed and removed the product from the market within 12 days, i.e. on 27 November 1961. The courts later confirmed that Grünenthal's response had been rapid. The courts also confirmed that it would have been impossible for Grünenthal at that time to make a connection between the polyneuritis and the deformities.

5. How does thalidomide cause deformities?
Damage caused by thalidomide occurs only if the sleeping pill is taken during the "sensitive phase" of organ development. This "sensitive phase" is from the 27^th to the 40^th day after conception, or the 34^th to 50^th day after the last menstrual period.

6. Why did it take years to demonstrate the connection between thalidomide and deformities?
The laboratory animals used at the time did not develop deformities after exposure to thalidomide. It was not until 1964, three years after the market recall, that teratogenicity was demonstrated in white New Zealand rabbits.

7. Who were the defendants in the criminal proceedings, and why?
The defendants were nine senior and scientific Grünenthal employees. The court attempted to establish whether they had been guilty of neglect in connection with the thalidomide tragedy.

8. How did the criminal case proceed?
It opened on 27 May 1968 and closed on 18 December 1970. The proceedings were the longest and most complex in German legal history up to that point in time.
The court on the one hand recognised wrongdoing on the part of the defendants in their handling of the neuritis issue, but on the other hand affirmed that Grünenthal could not have predicted the effects of thalidomide on pregnant women and had therefore not been remiss. In terms of the contemporary state of scientific knowledge, the court found that the teratogenicity was improbable, "if not in fact outside the realms of the possible based on experience to date." The court took a favourable view of the fact that the company recalled the product from the market within just 12 days.

9. How did the State help the thalidomide victims?
A law setting up a "Hilfswerk für behinderte Kinder" (Disabled Children's Relief Foundation) entered into force on 31 October 1972. This law was intended to provide assistance to all children with disabilities, not just those damaged by thalidomide. The purpose of this foundation was, firstly, to provide benefits to thalidomide victims, and secondly, to promote people with disabilities through institutional facilities and research projects. Money from the foundation was used to pay thalidomide victims a one-off capital sum in compensation and a life-long pension.

10. What did Grünenthal do to help thalidomide victims?
Grünenthal paid a voluntary sum of 114 million deutschmarks into the "Disabled Children's Relief Foundation". The federal government of the day added another 100 million deutschmarks.

11. What benefits have thalidomide victims received to date?
Thalidomide victims received a one-off capital sum in compensation depending on the severity of their disability and receive a life-long monthly pension. An independent medical commission under the auspices of the foundation determines the degree of disability and adjusts the level of payment accordingly.
Some of the benefits of the foundation in figures: Approximately 2800 people are entitled to benefits. A total sum of approximately 440 million euros was paid up to the end of 2007.

12. What did Grünenthal do with thalidomide after the thalidomide tragedy?
By an executive management resolution, thalidomide was no longer marketed commercially in the wake of the thalidomide tragedy, and Grünenthal derived no profit from its production. Grünenthal continued to make thalidomide available for humanitarian purposes until June 2003. Background: AS early as the 1960s, thalidomide was found to be of benefit in the treatment of leprosy, and later in the treatment of cancer.
Starting in the 1970s, Grünenthal dispensed thalidomide tablets to supply the drug to leprosy hospitals for use in combating a complication of leprosy called ENL. The tablets were dispensed in accordance with an agreement with the World Health Organisation (WHO). Distribution was strictly monitored by national health authorities. In some instances, doctors had to requisition the tablets by a special procedure and provide medical reasons for their use.
Starting in the 1990s, thalidomide was also put to use in the treatment of patients with refractory immune disorders and cancers.
In all cases, Grünenthal explicitly pointed out the risks of thalidomide and provided explicit warnings. Written confirmation of receipt of these instructions was required.
Grünenthal stopped dispensing thalidomide tablets with effect from 15 June 2003 when the supply of adequate quantities of the active drug substance came to be assured by other companies.

13. What are the effects of thalidomide in the treatment of leprosy and cancer?
In 1964, the Israeli physician Jacob Sheskin discovered that thalidomide is effective in the treatment of a painful inflammation of the skin in leprosy patients. Thalidomide also inhibits the production of new blood vessels. Since the 1990s, thalidomide has therefore also been used to treat severe diseases such as cancer.

14. What were the consequences of the thalidomide tragedy for drug safety?
The thalidomide tragedy had far-reaching implications for medicines legislation in Germany. Requirements for the testing of medicines were first defined in a Communication issued in 1964. In parallel, the German Pharmacology Society drafted scientific guidelines in its capacity as a professional medical association.
The extensive reform of the Drug Law in 1978 was described as "the outstanding social consequence of the thalidomide catastrophe". This sounds terrible for the victims, but in view of the millions of protected consumers this was a great step forward in developing safe medicines. Therefore for the first time in Germany there was a stringent procedure for approving and monitoring new medicines. Since then companies have to submit extensive dossiers documenting the efficacy, safety and quality of medicines to the authorities before any medicine is released for sale. The authorities then decide whether the benefit of a drug has been established and whether or not the risks of its side-effects constitute an acceptable level of risk for the patients concerned (benefit/risk ratio). Where the objective is to cure life-threatening diseases, severe side-effects are deemed to be tolerated (e.g. severe vomiting and loss of hair associated with chemotherapy). Manufacturers of medicines are assessed on a regular basis by independent experts and compliance with laws and regulations is verified by the authorities in on-site audits.

15. How has Grünenthal managed to recover economically from the thalidomide tragedy?
The Wirtz family decided that other companies in the group should support Grünenthal financially. This rescued the company and saved jobs, which was a high priority for the Wirtz family. Grünenthal achieved its first successes in pain management in 1977, especially with the painkiller Tramal^®.

16. What is Grünenthal's response to the thalidomide issue today?
Grünenthal advocates a factually objective and historically sound engagement with this issue. The company provides employees with information on the intranet and at events. The public has access to information on the Grünenthal website and in published material. The company also responds to numerous queries from the national and international media.

17. How does Grünenthal support the Contergan victims today?
Grünenthal supported the government parties' bill in the German parliament to double thalidomide pensions. As adults the victims need more aid and medical care. Grünenthal is also making its own voluntary contribution to provide additional aid to the victims. The company will pay 50 million Euros into the Thalidomide Foundation. This money will double the capital stock of the Foundation to provide the victims with an additional personal sum annually.

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