Before medications are made available for public use, they are required to undergo a rigorous development, testing, and approval process. These strict regulations were put in place largely due to the controversial use of thalidomide that began in the late 1950s.
All medications originate from lab research, through identifying which proteins or genes are causing a specific disease. This provides an understanding of how the disease or condition manifests. Experiments are conducted to find which compounds are able to act on the disease-causing protein or gene, and inhibit its effects on the body. Before a drug is considered for human trials, it has to undergo pre-clinical testing, which involves testing the drug on stem cells or animals. This is necessary to assess the safety and efficacy of the drug.
There are then four phases of clinical trials that are conducted on humans. Phase I involves testing a drug on a small group of 20-100 healthy volunteers. During this phase, a range of doses are administered in order to calculate the maximum tolerable dose, while side effects are closely monitored. This stage largely assesses whether it can be deemed safe for widespread human use.
Phase II trials test a drug on 100-500 patients that have the disease. Patients have the medication delivered to them in a variety of ways, including tablets, solutions and injections, to find the optimal method of administration. These trials are often double blind, with neither the patient nor the researcher being aware of whether the actual drug or a placebo is being administered.
Once a drug has entered Phase III, it is tested on a much larger scale, typically on 1,000-5,000 patients with the disease. Again, the drug is compared against other treatments or a placebo in a double blind manner. This large-scale comparison allows for a risk-benefit analysis of the medication to assess whether it is a better alternative to pre-existing options.
The results of the clinical trial are then submitted to regulatory agencies, such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and European Medicines Agency (EMA). If approval is granted, the medication will then become available for patient use. Whether a drug becomes widely available on the NHS is at the discretion of the National Institute of Clinical Excellence (NICE).
Monitoring the safety of the drug does not stop post-approval. Phase IV clinical trials are longitudinal in nature, and provide further information about the side effects, long term risks, and effectiveness of the drug across the wider population.
The MHRA is responsible for the protection of public health, through approving medications for marketing and conducting ongoing risk-benefit analyses of available medications. They have also developed the Yellow Card Scheme which enables individuals to report adverse side effects, defective medicines, and other safety concerns when taking medications.
The Thalidomide Scandal
The testing and approval of medications has not always been strictly regulated. The biggest factor contributing to the management of medicine today is the well-known thalidomide scandal, a primary example of where medicine went wrong.
Thalidomide was developed by Chemie-Grünenthal, a German pharmaceutical company, and was initially marketed as a sleeping pill due to its sedative properties. However, it was soon discovered to also provide relief against the symptoms of morning sickness in pregnant women.
Use of the drug led to the birth of over 10,000 babies with severe birth defects, the most prevalent being poorly developed limbs, a condition known as phocomelia. Other birth defects attributed to the use of thalidomide included congenital heart disease, nerve paralysis, and malformation of the eyes and ears. It is unknown how many children were affected by thalidomide, as many pregnancies resulted in miscarriages or stillborn births.
Thalidomide was withdrawn from use in the UK in 1961. The catastrophic consequences of its use led to the Medicines Act 1968, with the Committee on Safety of Medicines being established just two years later.
Investigations into the incident brought a number of issues to attention. The drug was prescribed under the belief that it was safe for human use, however no tests were performed to analyse the effects in pregnant woman and foetuses. Research had only been conducted on rodents, in which no fatal dose of thalidomide was established. In fact, research performed after the thalidomide scandal revealed that high doses of the drug had little effect on the foetuses of pregnant rodents. This highlighted the importance of human testing, as a substance can cause different effects across different species.
Our current understanding of thalidomide also tells us that it exists in two optical configurations. One configuration is not harmful and reduces the symptoms of morning sickness, while the other interferes with foetal development. Within the body, the two configurations can interconvert, meaning that even if a pure dose of the harmless configuration were to be administered, both will ultimately be present in the body.
Today, thalidomide is still prescribed as a treatment for leprosy and myeloma. However, its use is tightly regulated in order to avoid history from repeating itself.