Welcome to part two of the Conversation’s thalidomide series. In this longer read, medical historian Sarah Ferber explains how thalidomide shaped worldwide drug regulations.
Thalidomide caused thousands of spontaneous abortions and deaths of newborns in the late 1950s and early 1960s, and left more than 10,000 children severely disabled. What guarantee is there that the same thing can’t occur again today?
To answer that question, it’s important first to acknowledge that the effects of the drug on survivors never ended. For them it’s not about recurrence; the thalidomide scandal is still happening. Survivors now experience the early onset of age-related conditions such as osteoarthritis, joint mobility issues and coronary heart disease.
As one thalidomider in Germany, Fernandez Garcia, said:
We’re living the second (thalidomide) tragedy; our survival … We are alive, but what is ‘life’ for us?
Lifelong physical and emotional impact has been compounded by the need for ongoing legal claims for compensation. Lyn Rowe, a thalidomide survivor in Melbourne, only won her legal case for compensation in 2012. This was the same year in which the Chemie-Grünenthal apologised for the first time for the effects of thalidomide.
Ever since the drug’s capacities to heal serious medical conditions began to emerge, the thalidomide story was never going to be one of shocking revelation followed by a straightforward solution of market withdrawal.
Originally a treatment for non-life-threatening conditions such as sleeplessness, tension and morning sickness, thalidomide’s possible uses have now expanded to include several conditions including cancer of the bone marrow (multiple myeloma), lupus, and ulcers caused by AIDS.
Today, doctors prescribe the drug with full knowledge of its potential harms, working with manufacturers and governments to ensure women of childbearing age either do not take the drug at all or do so having been informed of the need to avoid pregnancy.
Even so, in Brazil, where leprosy is endemic, between 1970 and 1996, there were 33 new cases of thalidomide-affected births. New cases have been identified a recently as 2007, leading some experts to believe the true figure is masked by the paucity of health-care services in affected areas.
Drug regulation after thalidomide
In the United States, Dr Frances Kelsey of the Food and Drug Administration (FDA) ensured thalidomide never entered the local market because she was concerned about its side effects for users. Kelsey’s wariness was vindicated by revelations of the drug’s devastating effects in pregnancy.
Thalidomide precipitated the rapid passage of the 1962 Kefauver-Harris Amendment to the US Food, Drug and Cosmetic Act. The act had provided for drug safety since 1938, following an earlier drug disaster involving the ingestion of sulfanilamide solvents.
For most of the middle years of the 20th century, drug safety for the developing fetus was rarely considered. The Kefauver-Harris Amendment insisted on drug efficacy, as well as safety, which had to be grounded on extensive pre-clinical trials.
New regulations gave the FDA authority to mandate rigorous trial design and monitoring through institutional review boards (or ethics committees). The FDA was also to be notified of serious adverse events, and it could require market withdrawals. Crucially, the amendment also provided for informed consent of trial subjects.
The United Kingdom responded to the thalidomide disaster by establishing a Committee on the Safety of Drugs in 1963 and a Yellow Card Scheme (1964) for reporting suspected drugs reactions. And in 1968 the British Parliament legislated to ensure oversight of “safety, efficacy [and] quality of medicinal products” through the Medicines Act.
Meanwhile, the 1965 European Economic Community Directive 65/65 to “safeguard public health” made trade in pharmaceuticals between member nations subject to the approval of a “competent authority” within exporting countries. This took into account the drug’s characteristics, uses and safety, based on evidence from trials.
Most countries now have more stringent processes in place to identify, as far as possible, the side effects of new drugs on users or their offspring.
On the specific question of the risks of causing birth defects, multi-generational animal studies and greater knowledge of which species to study increases the likelihood of identifying drugs which will harm the developing human fetus.
The need for multi-generational animal studies was underscored by another disaster involving diethylstilboestrol (DES), a drug marketed in the mid-20th century to prevent miscarriage.
A large clinical trial in 1953 showed that the drug did not prevent miscarriage but it continued to be used even into the early 1970s and possibly as late as 1987.
In 1971, a new study revealed exposure to the drug in utero dramatically increased the likelihood of a rare cancer in DES daughters, clear cell cancer of the vagina/cervix, and other serious risks for DES mothers and sons.
Drug trials or ‘pharmacovigilance’
The late 1940s and 1950s saw the development of the randomised, double-blinded, placebo-controlled experiment, which later became the benchmark for drug tests. Trials in humans are now standardised according to a phased model:
Phase I clinical trials test a new biomedical intervention for the first time in a small group of people (around 20 to 80) to evaluate safety (to determine a safe dosage range and identify side effects).
Phase II clinical trials study an intervention in a larger group of people (several hundred) to determine efficacy (whether it works as intended) and to further evaluate its safety.
Phase III studies study the efficacy of an intervention in large groups of trial participants (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions (or not intervening, if that’s the standard). Researchers also monitor side effects and collect information that will allow the intervention to be used safely.
Phase IV studies are done after an intervention has been marketed. These are designed to monitor the effectiveness of the approved intervention in the general population and to collect information about any harmful effects associated with widespread use over longer periods. They may also be used to investigate the potential use of the intervention in a different condition, or in combination with other therapies.
The process is subject to regular modifications and exceptions – such as in relation to placebos, or if an unproven treatment is better than none – but the basic characteristics remain in place internationally.
Access to abortion
Societal changes have also had an impact on the introduction of new drugs.
In many jurisdictions today, termination of pregnancy is an accepted part of reproductive medicine, particularly with the advent of extensive prenatal testing methods. Indeed, the risk of exposure to thalidomide was one of the reasons activists in the 1960s argued for the right to terminate pregnancy.
Education about the risks of taking drugs that can cause birth defects is the most valuable first response.
In the case of the acne treatment isotretinoin (marketed in the United States as Accutane), Roche pharmaceuticals identified it as a treatment for severe acne in 1972, but because of the history of thalidomide, decided against marketing it until the early 1980s.
However, when the drug came to the market, attempts to ensure women did not become pregnant proved inadequate. The FDA estimated that between 1982 and 1986, up to 1,000 affected babies were born and that there had been a similar figure for spontaneous abortions.
The FDA also speculated that around 5,000 women had elected to terminate their pregnancies rather than give birth to an affected child.
Return of thalidomide to the United States
In the 1980s, the HIV/AIDS epidemic opened the door for more liberal trials based on the provision of “investigational” drugs to individuals. Equity arguments also led to the 1994 removal of restrictions on women of childbearing age participating in drug trials, reversing a 1977 FDA decision.
In 1997, the pharmaceutical company Celgene, with the supported of HIV/AIDS activists, sought FDA permission to market thalidomide, ostensibly for the treatment of leprosy, but in reality, as an experimental “off-label” treatment. By this time, scientific research into the possible uses of the drug was proceeding rapidly and the FDA actively initiated the move to relaunch thalidomide.
One motivation was to ensure a black market in the drug did not place women at greater risk than a regulated market would do.
Following consultation between stakeholders which included (belatedly) thalidomiders themselves, the FDA approved Celgene’s plan to market thalidomide, as Thalomid.
Celgene designed a program to minimise the risk of exposure to pregnant women, through registration of patients, doctors and pharmacists, with particularly close attention to the prevention of pregnancy. To date, there appear to have been no affected births in the US under these programs.
But worldwide, the question surrounding thalidomide remains one of not whether, but when. Pill sharing and inadequate advice about the risks impede the prevention of more thalidomide-affected births.
There is valid moral case for thalidomide to be available for serious illnesses, even to women of childbearing years. But if education efforts fail or prescribing is not closely monitored – and this can be anywhere – risk-minimisation measures can only go so far.
Ultimately, the risk and responsibility are great for the woman, and absolute for any affected child who was not able to consent to its use.
Stay tuned for other instalments in the thalidomide series this week.