Grünenthal

Under Head of Research and former Nazi scientist Heinrich Mückter, Grünenthal synthesised thalidomide in 1954 and acquired a 20-year patent. Soon after obtaining its patent in April 1954, the company started clinical trials, and from November 1956, marketed the drug for the treatment of respiratory infections under the trade name Grippex, a combination drug that contained thalidomide, quinine, vitamin C, phenacetin, and acetylsalicylic acid. Researchers at Chemie Grünenthal also found that the drug was particularly effective for pregnant women suffering from morning sickness, although no trials were run with pregnant women. In 1957, the company began marketing thalidomide as Contergan. [6][7]

In 1958, an unusual number of deformities in newborns were reported in Germany. However, scientists first assumed nuclear tests to be the reason for that.[8] Only in late 1961, researchers found out that Contergan must be the cause.[9] In November 1961, thalidomide was thus taken off the market.[10][11]

Thalidomide caused severe deformities in the children of women who took the drug during pregnancy. Experts estimate that the drug thalidomide led to the death of about 2,000 children and serious birth defects in more than 10,000 children, about 5,000 of them in West Germany. East German regulatory authorities did not approve thalidomide, and the U.S. Food and Drug Administration (FDA) also declined to approve the drug.[6] One reason for the initially unobserved side effects of the drug and the subsequent approval in Germany was that at that time drugs did not have to be tested for teratogenic effects. Thalidomide had only been tested on rodents, as was usual practice at the time.[12]

In the UK, the British pharmaceutical company The Distillers Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd. (which became part of Diageo plc in 1997) marketed thalidomide under the brand name Distaval as a remedy for morning sickness throughout the United Kingdom, Australia, and New Zealand. Their advertisement claimed, "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child...Outstandingly safe Distaval has been prescribed for nearly three years in this country." [6] Around the world, more and more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid 1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under 37 (some reports suggest 51) different trade names.

In the US, representatives from Chemie Grünenthal initially approached Smith-Kline and French with a request to market and distribute the drug in North America. A newly discovered memorandum, found hidden in 2010 the archives of the U.S. Food and Drug Administration shows that, as part of their in-licensing approach, Smith-Kline and French conducted animal tests and ran a clinical trial of the drug in the U.S. involving 875 people, including pregnant women, in 1956–57. In 1956, researchers at SKF involved in clinical trials, noted that even when used in very high doses, thalidomide could not induce sleep in mice. When administered at doses 50 to 650 times larger than that claimed by Chemie Grunenthal to be "sleep inducing", the researchers still could not achieve the hypnotic effect in animals that it had on man. After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. Later, Chemie Grünenthal, in 1958, reached an agreement with William S Merrell Company of Clarinbridge, Galway, to market and distribute thalidomide throughout the United States. [6]

The U.S. Food and Drug Administration refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September, 1960. The official in charge of the FDA, Frances Oldham Kelsey, did not rely on information from the company which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company requested approval six times and was refused each time. Nevertheless, a total of 17 children with thalidomide-induced malformations were born.[13]

A Long Island, New York family sued the drug maker after their twins were born with deformities in May 1961. Their son was born without arms, with hands growing from his shoulders, and their daughter suffered from a number of internal deformities. The mother was a German woman who had met her husband in 1959 while studying at the University of Florence. She came to the United States with Contergan tablets she had brought from Germany and a prescription from her physician. The lawsuit alleged that Chemie Grünenthal was negligent in the testing of thalidomide and that they failed to warn of its effects on unborn children.[14]

By 1968, the company stated that thalidomide was not recommended for use "during pregnancy as such". The qualifying term obstetrics was employed. It was used in hindsight to strengthen the argument that doctors would interpret the word to mean that thalidomide was safe during the final stage of pregnancy only. This is a fallacious form of reasoning according to the German Medical Association, which defines obstetrics as starting with conception.[15]

As a result of the thalidomide scandal, the Health Law in West Germany was strengthened and new requirements for pharmaceutical testing were created; the Federal Ministry of Health was established in 1962.

In 1968, Grünenthal executives were tried for involuntary manslaughter. In 1970, the indictment was closed due to the minor guilt of the defendants and insufficient public interest in further proceedings.

In 1970, Grünenthal paid DM 100 million to the Contergan Foundation for Disabled People, and the German government paid reparations of DM 320 million. Between 1997 and 2008, Grünenthal declined further payments to thalidomide victims. At the end of 2007, the British entrepreneur Nicholas Dobrik organised a group of victims and began an international campaign for further reparations.[16] On 8 May 2008, Grünenthal announced it would voluntarily pay further €50 million to the Thalidomide Foundation to help to improve the lives of thalidomide victims.[17]

In August 2012, the company issued its first apology in a half-century, saying it regretted the consequences of the drug. Harald Stock, Grunenthal's chief executive, said the company had failed to reach out "from person to person" to the victims and their mothers over the past 50 years.[18] The company has refused to compensate the Spanish victims of the drug who have sued the company.[19]

In 1964, Israeli physician Jacob Sheskin discovered the positive effect of thalidomide in the treatment of leprosy. Since the 1970s, Grünenthal has delivered thalidomide tablets to leprosy clinics to assist the fight against leprosy. The delivery takes place under strict conditions and by virtue of an agreement with the World Health Organization.[20] Grünenthal provided thalidomide to more than 1,000 patients with leprosy in the United States until a few months before July, 1986. The drug is especially helpful to patients with leprosy in treating an extremely painful allergic reaction of the skin. The company discontinued exporting thalidomide because of liability fears. A lack of insurance coverage for those requiring the drug was also a problem.[21]

In July 2010, the British Prescription Medicines Code of Practice Authority received a complaint from a Grünenthal employee, stating that Grünenthal produced and distributed false and misleading data on its own products. After a review it was concluded that Grünenthal produced and distributed Versatis material and data that contained off-label information and flawed cost-comparison calculations (in favour of its own product), and knowingly concealed the fact that one of the authors was a Grünenthal employee. The panel concluded that the company’s activities reduced confidence in the pharmaceutical industry and thus ruled a breach of the ABPI Code of Practice for the Pharmaceutical Industry.[22]

In November 2010, the Medicines and Healthcare products Regulatory Agency advised the British authorities that it was concerned that Grünenthal was promoting its unlicensed medicine, Tapentadol, to health professionals. Furthermore, these promotional activities included misleading comparisons with competitor pharmaceutical products and the deliberate pressuring of healthcare decision makers to make sure that the new Grünenthal product would be sold after registration. In summary, Grünenthal was found guilty of misleading and unlawful behaviour, and as a result, the appeal board decided to carry out multiple audits at Grünenthal in 2009 and 2010 to review its practices.[23]

These cases were preceded by similar cases in 2007, where Grünenthal was found guilty of distributing misleading information on its pharmaceutical products to healthcare professionals.[24]

The company has focused on the treatment of pain and is doing its own research and development in this field.[25] Grünenthal developed the drug Tramadol, which is marketed under the brand name Tramal, one of the best-selling opioid painkillers. Other business units are gynecology, dermatology, and anti-infectives.[26] Current products include the birth control pill Belara and the matrix pain patch Transtec. Unlike Tramadol, which is a Schedule IV(C-IV) medication, the drug Tapentadol HCl, as licensed by Grünenthal, is Schedule II(C-II) in the U.S. (meaning it is a potent agonist, therefore subject to abuse similar to other C-II opioids, such as oxycodone and morphine).

In 2018, Grünenthal acquired the pain-related brands Nexium and Vimovo and the US-rights for Qutenza (capsaicin). The company began building a US structure to commercialise the latter asset through Averitas Pharma.[27][28][29] Later in 2018, Grünenthal obtained global rights for Qutenza.