Large organic molecules such as drugs often have complex spatial arrangements. This leads to a phenomenon known as stereoisomerism, which refers to molecules having the same atoms but a different arrangement in space. A subset of stereoisomers is known as enantiomers, which means that the molecules are non-superimposable mirror images of each other. This blog deals with the case of the drug Thalidomide, with both enantiomers shown below:
Thalidomide was developed and marketed as a tranquilizer and to treat morning sickness by the German pharmaceutical company Chemie Grunenthal in 1957 (Moghe et al., 2008). The therapeutic effects were attributable to one of the enantiomers. However, it was common practice at the time to produce both enantiomers since producing only one enantiomer or separating the mixture is expensive and would translate into a higher market price (Sheldon, 1993).
The problem in this case was that the pharmaceutical company did not know that the enantiomer of Thalidomide was teratogenic i.e. it caused birth defects. Limb malformations in infants started to appear within the first year of sales of the drug (Lenz, 2012). However, it was not until November 1961 that it was recognised that the increasing cases of limb malformations in infants was due to Thalidomide (Smithells and Newman, 2012). The rationale of Chemie Grunenthal in this case was to reduce the production cost, to make it more affordable and increase market share. However, the company did not realise that there was a potential for side effects. The company’s rationale is represented in loop R1 in the diagram below, while the unintended consequence can be seen in loop B1.
The problem in the mental model of Chemie Grunenthal (and most of the pharmaceutical industry at the time) was the unproven assumption that enantiomers of a therapeutic drug did not cause any effects. This led to the B1 dynamic seen in the diagram above which eventually led to the withdrawal of the drug from the market in several countries and the company having to pay a 100 million German marks fine to the victims (Lenz, 2012). This case led to significant media coverage resulting in to an increase in pharmaceutical industry regulations, with the FDA creating strict requirements for the testing of both enantiomers during the drug development stage (FDA, 2012). In fact, nowadays most drugs are marketed as pure enantiomers and usually accompanied by claims of greater effectiveness and reduced side effects (Nguyen et al., 2006). Hence, this case highlights the fact that sometimes unintended consequences of a policy can be so significant that a re-evaluation of the mental model of a whole industry may be altered.
References:
FDA. Development of New Stereoisomeric Drugs. http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm (accessed January 14, 2012).
Lenz, W. The History of Thalidomide. http://www.thalidomideuk.com/proflenz.htm (accessed January 14, 2012).
Moghe, V. V.; Kulkarni, U.; Parmar, U. Thalidomide. Bombay Hospital Journal 2008, 50 (3), 472-476.
Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral Drugs: An Overview. International Journal of Biomedical Science 2006, 2 (2), 85-100.
Pasieka, A. S and R Enantiomers of Thalidomide. http://www.visualphotos.com/image/ 1x6039114/s_and_r_enantiomers_of_thalidomide_molecules (accessed January 14, 2012).
Sheldon, R. A. Chirotechnology: Industrial Synthesis of Optically Active Compounds; Marcel Dekker: New York, 1993.
Smithells, R. W.; Newman, C. G. H. Recognition of Thalidomide Defects. http://www.thalidomideuk.com/smithellsnewman.htm (accessed January 14, 2012).
Figure 1: Therapeutic Thalidomide (on the left) and its enantiomer (Pasieka, 2012)
Thalidomide was developed and marketed as a tranquilizer and to treat morning sickness by the German pharmaceutical company Chemie Grunenthal in 1957 (Moghe et al., 2008). The therapeutic effects were attributable to one of the enantiomers. However, it was common practice at the time to produce both enantiomers since producing only one enantiomer or separating the mixture is expensive and would translate into a higher market price (Sheldon, 1993).
The problem in this case was that the pharmaceutical company did not know that the enantiomer of Thalidomide was teratogenic i.e. it caused birth defects. Limb malformations in infants started to appear within the first year of sales of the drug (Lenz, 2012). However, it was not until November 1961 that it was recognised that the increasing cases of limb malformations in infants was due to Thalidomide (Smithells and Newman, 2012). The rationale of Chemie Grunenthal in this case was to reduce the production cost, to make it more affordable and increase market share. However, the company did not realise that there was a potential for side effects. The company’s rationale is represented in loop R1 in the diagram below, while the unintended consequence can be seen in loop B1.
Figure 2: Causal Loop Diagram in the case of the Thalidomide Scandal
The problem in the mental model of Chemie Grunenthal (and most of the pharmaceutical industry at the time) was the unproven assumption that enantiomers of a therapeutic drug did not cause any effects. This led to the B1 dynamic seen in the diagram above which eventually led to the withdrawal of the drug from the market in several countries and the company having to pay a 100 million German marks fine to the victims (Lenz, 2012). This case led to significant media coverage resulting in to an increase in pharmaceutical industry regulations, with the FDA creating strict requirements for the testing of both enantiomers during the drug development stage (FDA, 2012). In fact, nowadays most drugs are marketed as pure enantiomers and usually accompanied by claims of greater effectiveness and reduced side effects (Nguyen et al., 2006). Hence, this case highlights the fact that sometimes unintended consequences of a policy can be so significant that a re-evaluation of the mental model of a whole industry may be altered.
References:
FDA. Development of New Stereoisomeric Drugs. http://www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm122883.htm (accessed January 14, 2012).
Lenz, W. The History of Thalidomide. http://www.thalidomideuk.com/proflenz.htm (accessed January 14, 2012).
Moghe, V. V.; Kulkarni, U.; Parmar, U. Thalidomide. Bombay Hospital Journal 2008, 50 (3), 472-476.
Nguyen, L. A.; He, H.; Pham-Huy, C. Chiral Drugs: An Overview. International Journal of Biomedical Science 2006, 2 (2), 85-100.
Pasieka, A. S and R Enantiomers of Thalidomide. http://www.visualphotos.com/image/ 1x6039114/s_and_r_enantiomers_of_thalidomide_molecules (accessed January 14, 2012).
Sheldon, R. A. Chirotechnology: Industrial Synthesis of Optically Active Compounds; Marcel Dekker: New York, 1993.
Smithells, R. W.; Newman, C. G. H. Recognition of Thalidomide Defects. http://www.thalidomideuk.com/smithellsnewman.htm (accessed January 14, 2012).
I would have done away with the first paragraph as it is all chemistry which can be complex to readers, with the result that they will be discouraged to keep on reading. I would have placed a small explanation of for example an enantiomer, after the citing it the first time.This will make readers understand the unintended consequences more as they do not need to go up and re read the chemical definitions.
ReplyDeleteThe Thalidomide drug issue was a very big one indeed and I agree that there were several unintended consequences.
ReplyDeleteAlthough I agree with you on the point that they ignored what the enantionmer did, I feel that the greater issue in the case was the fact that the drug trials were not conducted well. Drug trials are very costly and bring about a great delay in the profits from the drug which inclined the pharmaceutical company to restrict the extent of testing. The lack of sufficient stringent policy in FDA standards allowed this to happen allowing for the birth defects. In fact you clearly state that the changes in FDA policy were in relation to the testing procedure rather than the separation of the 2 enantiomers in the final product. I therefore believe that the mental model should include the testing protocol regulation.